Annual Meeting Proceedings Part 1 - American Society of Clinical ...

Volume 30, Issue 15S, Part I of II May 20, 2012 

JOURNAL 

CLINICAL 

OF 

ONCOLOGY 

Official Journal of the 

American Society of Clinical Oncology 

2012 ASCO Annual Meeting Proceedings 

www.jco.org 

48th Annual Meeting 

June 1-5, 2012 

McCormick Place 

Chicago, IL

48th 

Annual Meeting of the 


June 1–5, 2012 

Chicago, Illinois 

2012 Annual Meeting Proceedings Part I 

(a supplement to the Journal of Clinical Oncology) 

Copyright 2012 American Society of Clinical Oncology

Editor: Michael A. Carducci, MD 

Managing Editor: Jennifer Giblin 

Editorial Coordinator: Lauren Burke 

Production Manager: Donna Dottellis 

Executive Editor: Lisa Greaves 

Requests for permission to reprint abstracts should be directed to Intellectual Property 

Rights Manager, American Society of Clinical Oncology, 2318 Mill Road, Suite 800, 

Alexandria, VA 22314. Tel: 571-483-1300; Fax: 571-366-9530; Email: permissions@asco.org. 

Editorial correspondence and production questions should be addressed to Managing Editor, 

Annual Meeting Proceedings, American Society of Clinical Oncology, 2318 Mill Road, Suite 

800, Alexandria, VA 22314. Email: abstracts@asco.org. 

Copyright © 2012 American Society of Clinical Oncology. All rights reserved. No part of this 

publication may be reproduced or transmitted in any form or by any means, electronic or 

mechanical, including photocopy, recording, or any information storage and retrieval system, 

without written permission by the Society. 

The American Society of Clinical Oncology assumes no responsibility for errors or 

omissions in this document. The reader is advised to check the appropriate medical literature 

and the product information currently provided by the manufacturer of each drug to be 

administered to verify the dosage, the method and duration or administration, or 

contraindications. It is the responsibility of the treating physician or other health care 

professional, relying on independent experience and knowledge of the patient, to determine 

drug, disease, and the best treatment for the patient. 

Abstract management and indexing provided by The Conference Exchange, Cumberland, 

RI. Composition services and print production provided by Cenveo Publisher Services, 

Richmond, VA.

Volume 30, Issue 15S Supplement to May 20, 2012 

JOURNAL OF 

CLINICAL 

ONCOLOGY 

CONTENTS 

Official Journal of the 


2012 ASCO ANNUAL MEETING PROCEEDINGS 

Special Award Lecture Abstracts ............................................................................................................. 1s 

Plenary (Abstracts LBA1 – 4) ....................................................................................................................... 5s 

Breast Cancer—HER2/ER 

Scheduled presentations (Abstracts 500 – TPS670) ........................................................................................ 7s 

Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy 

Scheduled presentations (Abstracts LBA1000 – TPS1148) ............................................................................... 49s 

Cancer Prevention/Epidemiology 

Scheduled presentations (Abstracts 1500 – TPS1616) ....................................................................................... 86s 

Central Nervous System Tumors 

Scheduled presentations (Abstracts 2000 – TPS2107) ..................................................................................... 115s 

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy 

Scheduled presentations (Abstracts 2500^ – TPS2622) .................................................................................. 142s 

Developmental Therapeutics—Experimental Therapeutics 

Scheduled presentations (Abstracts 3000 – TPS3118) ...................................................................................... 173s 

Gastrointestinal (Colorectal) Cancer 

Scheduled presentations (Abstracts LBA3500^ – TPS3643) .......................................................................... 203s 

Gastrointestinal (Noncolorectal) Cancer 

Scheduled presentations (Abstracts LBA4000 – TPS4153) ............................................................................. 239s 

Genitourinary Cancer 


continued on following page 

Journal of Clinical Oncology (ISSN 0732-183X) is published 36 times a year, three times monthly, by the American Society of Clinical Oncology, 2318 Mill Road, Suite 800, 

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Editorial correspondence should be addressed to Stephen A. Cannistra, MD, Journal of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Phone: 

703-797-1900; Fax: 703-684-8720. E-mail: jco@asco.org. Internet: www.jco.org. 

POSTMASTER: ASCO members should send changes of address to American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 

Nonmembers should send changes of address to Journal of Clinical Oncology Customer Service, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 

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Volume 30, Issue 15S Supplement to May 20, 2012 

................................................................................................................................................... 

Gynecologic Cancer 

Scheduled presentations (Abstracts LBA5000 – TPS5116) .............................................................................. 327s 

Head and Neck Cancer 

Scheduled presentations (Abstracts 5500 – TPS5602) .................................................................................... 356s 

Health Services Research 

Scheduled presentations (Abstracts 6000 – 6137) ............................................................................................ 382s 

Leukemia, Myelodysplasia, and Transplantation 

Scheduled presentations (Abstracts 6500^ – TPS6643) .................................................................................. 416s 

Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers 

Scheduled presentations (Abstracts 7000 – TPS7113) ...................................................................................... 452s 

Lung Cancer—Non-small Cell Metastatic 

Scheduled presentations (Abstracts LBA7500 – TPS7619) .............................................................................. 480s 

Lymphoma and Plasma Cell Disorders 


Melanoma/Skin Cancers 

Scheduled presentations (Abstracts LBA8500^ – TPS8606) .......................................................................... 540s 

Patient and Survivor Care 


Pediatric Oncology 

Scheduled presentations (Abstracts 9500 – TPS9597^) .................................................................................. 606s 

Sarcoma 

Scheduled presentations (Abstracts 10000 – TPS10103) .................................................................................. 630s 

Tumor Biology 

Scheduled presentations (Abstracts 10500 – TPS10635) ................................................................................. 656s 

Author Index ...................................................................................................................................................... 692s 

www.jco.org



2012 Abstracts 

Abstract Session Descriptions for Scheduled Presentations 

Oral Abstract Sessions 

Oral Abstract Sessions include didactic presentations of the abstracts of the highest scientific merit, as determined by 

the Scientific Program Committee. Experts in the field serve as Discussants to place the findings into perspective. The 

Plenary Session includes the abstracts selected by the Scientific Program Committee as having practice-changing 

findings. 

Clinical Science Symposia 

Clinical Science Symposia provide a forum for science in oncology, combining didactic lectures on a specific topic 

with the presentation of abstracts. Experts in the field classify studies on the basis of the strength of the evidence and 

critically discuss the conclusions in terms of their applicability to clinical practice. 

Poster Discussion Sessions 

Poster Discussion Sessions highlight selected abstracts of clinical research in poster format. The posters are grouped 

by topic and are on display for a specified time, followed by a discussion session in which experts provide 

commentary on the research findings. 

General Poster Sessions 

General Poster Sessions include selected abstracts of clinical research in poster format. The posters are grouped by 

topic and are on display for a specified time. Trials in Progress (TPS) abstract presentations are presented within a 

track’s general poster session. 

Publication-Only Abstracts 

Publication-only abstracts were selected to be published online in conjunction with the Annual Meeting, but not to be 

presented at the Meeting. 

All presented and publication-only abstracts are citable to this Journal of Clinical Oncology supplement. For citation 

examples, please see the Letter from the Editor. 

This publication contains abstracts selected by the ASCO Scientific Program Committee for presentation at the 

2012 Annual Meeting. Abstracts selected for electronic publication only are available in full-text versions 

online at abstract.asco.org and JCO.org. The type of session, the day, and the session start/end times are 

located to the right of the abstract number for scheduled presentations. To determine the location of the 

abstract session, refer to the Annual Meeting Program or the ePlanner, the online version of the Annual 

Meeting Program, available at chicago2012.asco.org. 

Dates and times are subject to change. 

All modifications will be posted on ASCO.org.

Letter from the Editor 

The 2012 ASCO Annual Meeting Proceedings Part I (a 

supplement to the Journal of Clinical Oncology) is 

an enduring record of the more than 2,700 abstracts 

selected by the ASCO Scientific Program Committee for 

presentation at the 48th Annual Meeting of the American 

Society of Clinical Oncology, held June 1–5, in 

Chicago, Illinois. Accepted abstracts not presented at 

the meeting are available in full-text versions on 

ASCO.org and are included in the online supplement to 

the May 20 issue of Journal of Clinical Oncology at 

JCO.org. 

The majority of abstracts selected for presentation are 

included here in full and are categorized by scientific 

track. Abstracts are ordered numerically according to 

presentation type within a track. Presentation types 

include Oral Abstract Sessions, Clinical Science Symposia, 

Poster Discussion Sessions, and General Poster 

Sessions. Abstracts include the presenting author only. 

The full list of abstract authors and their disclosure 

information can be found online at abstract.asco.org. 

Certain abstracts are represented here by abstract title 

and presenting author only. These include Clinical 

Review Abstracts (CRA), many of which will have important, 

and in some cases, immediate implications for 

patient care; Late-Breaking Abstracts (LBA), which 

feature results of phase III trials for which data were not 

available at the time of ASCO’s regular submission 

deadline; and Plenary Abstracts, which were selected by 

the Scientific Program Committee for their potential to 

have practice-changing results. The full-text versions of 

abstracts within these three designations will be publically 

released on ASCO.org on the morning of their 

scheduled presentation at the Annual Meeting (abstracts 

scheduled for presentation on Tuesday will be 

released on Monday morning). These abstracts will also 

be included in the 2012 ASCO Annual Meeting Proceedings 

Part II, an online supplement to the June 20 issue of 

Journal of Clinical Oncology on JCO.org. Print versions 

of these abstracts will be available onsite at the Annual 

Meeting in the ASCO Daily News. 

All of the abstracts carry Journal of Clinical Oncology 

citations. The following are citation examples for print 

and electronic abstracts, respectively: 

J Clin Oncol 30:5s, 2012 (suppl; abstr LBA1) 

J Clin Oncol 30, 2012 (suppl; abstr e12000) 

Should you have any questions or comments about this 

publication, we encourage you to provide feedback by 

contacting us at abstracts@asco.org. 

Michael A. Carducci, MD 

Editor, 2012 ASCO Annual Meeting Proceedings

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www.jco.org. In addition, all ASCO Special Articles, Editorials, 

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series, and Correspondence articles are free immediately 

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Disclaimer 

The ideas and opinions expressed in JCO do not necessarily 

reflect those of the American Society of Clinical Oncology 

(ASCO). The mention of any product, service, or therapy in 

this publication or in any advertisement in this publication 

should not be construed as an endorsement of the products 

mentioned. It is the responsibility of the treating physician or 

other health care provider, relying on independent experience 

and knowledge of the patient, to determine drug dosages and 

the best treatment for the patient. Readers are advised to 

check the appropriate medical literature and the product 

information currently provided by the manufacturer of each 

drug to be administered to verify approved uses, the dosage, 

method, and duration of administration, or contraindications. 

Readers are also encouraged to contact the manufacturer 

with questions about the features or limitations of any 

products. ASCO assumes no responsibility for any injury or 

damage to persons or property arising out of or related to 

any use of the material contained in this publication or to any 

errors or omissions. 

Copyright 

Copyright © 2012 by American Society of Clinical Oncology 

unless otherwise indicated. All rights reserved. No part of this 

publication may be reproduced or transmitted in any form or 

by any means now or hereafter known, electronic or 

mechanical, including photocopy, recording, or any 

information storage and retrieval system, without permission 

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ASCO Abstracts Policy 

Public Release of Abstracts 

ASCO has implemented changes to its abstract distribution to ensure simultaneous public release of important 

scientific information. Please note the new release schedule. 

The abstracts published in the 2012 ASCO Annual Meeting Proceedings Part I, including those abstracts 

published but not presented at the Meeting, were publicly released by ASCO at 6:00 PM (EDT) on Wednesday, 

May 16, 2012. These abstracts are publicly available online at ASCO.org, the official website of the Society. 

Plenary, Late-Breaking, and Clinical Review Abstracts (Newly Released Abstracts) will be publicly released 

according to the following schedule: 

● Newly Released Abstracts presented on Saturday, June 2, will be publicly released that day on ASCO.org at 

12:01 AM (EDT). These abstracts will also be available in the Saturday issue of ASCO Daily News in Section D. 

● Newly Released Abstracts presented on Sunday, June 3, will be publicly released that day on ASCO.org at 

12:01 AM (EDT). These abstracts will also be available in the Sunday issue of ASCO Daily News in Section D. 

● Newly Released Abstracts presented on Monday, June 4, and Tuesday, June 5, will be publicly released on 

Monday, June 4, on ASCO.org at 12:01 AM (EDT). These abstracts will also be available in the Monday issue of 

ASCO Daily News in Section D. 

In the unlikely event that ASCO publicly releases an abstract in advance of the scheduled time, the release will be 

publicly announced on ASCO.org. 

Abstract Notice 

All abstracts presented at and published in conjunction with the Annual Meeting are included in online 

supplements to the Journal of Clinical Oncology. The abstracts released on May 16, 2012, are included in the May 

20 (Vol. 30, No. 15S) issue (2012 Annual Meeting Proceedings Part I), and the Plenary, Late-Breaking, and Clinical 

Review Abstracts, released on a daily basis during the Meeting, are included in the June 20 (Vol. 30, No. 18S) 

issue (2012 Annual Meeting Proceedings Part II). 

Copyright 2012 American Society of Clinical Oncology

ASCO Conflict of Interest Policy and Exceptions 

In compliance with standards established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006; 

24[3]:519–521) and the Accreditation Council for Continuing Medical Information (ACCME), ASCO strives to 

promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, 

and identification and management of potential conflicts. According to the Society’s Conflict of Interest Policy, the 

following financial and other relationships must be disclosed: employment or leadership position, advisory role, 

stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 

2006;24[3]:520). 

The ASCO Conflict of Interest Policy requirements apply to all abstract authors. Per the ASCO Conflict of Interest 

Policy Implementation Plan for CME Activities, all Oral Abstract Presenters will be subject to the same disclosure 

review and management strategies as faculty who participate in ASCO CME activities. 

For clinical trials that began accrual on or after April 29, 2004, the Conflict of Interest Policy places some 

restrictions on the financial relationships between a trial’s Principal Investigator (PI) and the trial’s company 

sponsor (J Clin Oncol. 2006;24[3]:521). If a PI holds any restricted relationships, his or her abstract may be 

ineligible for placement in the 2012 Annual Meeting unless the Ethics Committee grants an exception. Exceptions 

are generally not granted for PIs who have employment relationships with their trial’s company sponsor or stock 

in the company sponsor. Abstracts that receive exceptions will be subject to additional management strategies, 

including but not limited to additional peer review, advance slide review, and session audits. ASCO will collect 

information on accrual initiation date, financial relationships of the principal investigator, and National Institutes 

of Health (NIH) funding upon abstract submission. NIH-funded trials are exempt from the PI restrictions in the 

Conflict of Interest. Abstracts for which authors requested and have been granted an exception in accordance with 

ASCO’s Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. 

For more information on the ASCO Conflict of Interest Policy, the Conflict of Interest Policy Implementation Plan 

for CME Activities, and the restrictions on PIs, please visit www.asco.org/rwi.

2012 ASCO Annual Meeting Proceedings Special Awards 

1s 

ABSTRACTS 

The American Society of Clinical Oncology 


June 1–5, 2012 



SPECIAL AWARD LECTURE ABSTRACTS 

David A. Karnofsky Memorial Award and Lecture 

Saturday, June 2, 9:30 AM 

Progress in chronic lymphocytic leukemia (CLL): A tribute to Dr. David A. Karnofsky. 

Kanti R. Rai, MB,BS; North Shore-Long Island Jewish Medical Center, New Hyde Park, NY 

My own journey in cancer research started in 1958 when I was a 26-year-old resident in pediatrics and was called 

upon one day to see and admit a 3-year-old named Laurie. Laurie, it turned out, had acute lymphoblastic 

leukemia (ALL).The attending hematologist helped me in making the diagnosis that night. I took care of Laurie 

not only that night but throughout her disease course. As, unfortunately, was the case with all children with acute 

leukemia in 1958, after whatever treatment we were able to give, Laurie died a few months later. The 

hematologist, Dr. Arthur Sawitsky, had watched how very involved I had become in Laurie’s care and how deeply 

her death affected me, and counseled me to pursue leukemia research and become a hematologist. After I 

completed my hematology fellowship, Dr. Sawitsky helped me join the research team of a world-class 

hematologist, Dr. Eugene P. Cronkite, at the Brookhaven National Laboratory. It was while working with Dr. 

Cronkite and seeing patients with all hematologic malignancies that I was intrigued by the wide spectrum of life 

expectancies of patients carrying the same diagnosis of chronic lymphocytic leukemia (CLL). David Karnofsky 

himself had already written about CLL in the 1950s. He, as well as several other hematologists of that era, had 

mentioned that CLL, in contrast with ALL, was not a very exciting disease, not much was happening with patients 

with CLL. Both Cronkite and Sawitsky encouraged me to study this disease. We then developed a relatively simple 

staging system, which was rapidly integrated in practice by clinicians, and it became possible to classify all CLL 

patients, on a prospective basis, into three distinct prognosis groups. It became possible to initiate therapeutic 

trials and ask research questions. Within two decades after clinical staging was developed, my colleague, 

Nicholas Chiorazzi, who is the leader of our CLL basic research team, demonstrated that one of the fundamental 

differences between the good prognosis and bad prognosis groups was that the former had somatic 

hypermutations in the IgVH genes while the latter did not. CLL has become a disease that, today, fascinates 

molecular biologists, immunologists, as well as clinicians. Promising new therapies targeting the B-cell receptor 

signaling pathways have become a reality. I feel certain that this progress, indeed, is in the tradition that Dr. 

Karnofsky started. 

Science of Oncology Award and Lecture 

Sunday, June 3, 1:00 PM 

Normalizing tumor microenvironment to treat cancer: Bench to bedside to biomarkers. 

Rakesh K. Jain, PhD; Harvard Medical School and Massachusetts General Hospital, Boston, MA 

For the past three decades our laboratory has focused on one challenge: How do we improve the delivery and 

efficacy of therapeutics in cancer patients? Working on the hypothesis that the abnormal tumor microenvironment 

fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging 

technologies as well as mathematical and animal models to unravel the complex biology of the tumor 

microenvironment. Using these tools, we showed that the blood and lymphatic vessels as well as the extracellular 

matrix associated with tumors are abnormal. We further showed that these abnormalities generate a hostile tumor 

microenvironment (e.g., hypoxia, high interstitial fluid pressure). Our work also revealed how these abnormalities 

fuel malignant properties of a tumor as well as prevent treatments from reaching and attacking tumor cells. We 

next hypothesized that creative manipulation of the microenvironment should improve treatment outcomes. 

Toward this end, we discovered that “normalizing” the tumor vessels and matrix would allow cancer therapies to 

penetrate the mass and to function more effectively. Originally designed to destroy tumor vessels, we showed, 

first in mice and then in rectal and glioblastoma cancer patients, that antiangiogenic drugs could, paradoxically,

2s Special Awards 

also “normalize” them, creating a window of opportunity to attack the cancer more effectively. Moreover, tumor 

blood vessels’ normalization and improvement in tumor perfusion was associated with longer patient survival. 

These observations led to a number of clinical trials aimed at identifying biomarkers of response and resistance to 

antiangiogenic drugs. Our findings also opened doors to treating other vascular diseases, such as age-related wet 

macular degeneration, a leading cause of blindness, and neurofibromatosis-2, which can lead to deafness. More 

recently, we discovered that drugs capable of normalizing the extracellular matrix improve the delivery and 

efficacy of molecular and nanomedicine. We are currently exploring this as a potential means of enhancing the 

delivery of chemotherapeutics to desmoplastic tumors (e.g., pancreatic ductal adenocarcinomas). 

ASCO–American Cancer Society Award and Lecture 

Saturday, June 2, 3:00 PM 

Reducing breast cancer risk: Progress toward resolution. 

Rowan T. Chlebowski, MD, PhD; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 

Torrance, CA 

Randomized, full-scale clinical trials have 1) addressed lifestyle change in adjuvant breast cancer; 2) changed 

concepts regarding menopausal hormone therapy and breast cancer; and 3) identified new approaches to breast 

cancer risk reduction. The Women Intervention Nutrition Study (WINS) randomly assigned 2,437 women to 

standard therapy � a lifestyle intervention targeting fat intake. Intervention participants reduced fat intake, lost 

weight, and experienced a statistically significant increase in disease-free survival (HR 0.76, 95% CI 

0.60–0.98, p � 0.03). Long-term follow-up is underway and the European SUCCESS-C study will evaluate the 

emerging hypothesis that weight loss and increased physical activity will improve breast cancer outcome. The 

Women’s Health Initiative (WHI) placebo-controlled trials randomly assigned 16,000 women with no prior 

hysterectomy to estrogen plus progestin and 10,739 postmenopausal with prior hysterectomy to estrogen alone, 

and opposite breast cancer findings were seen. Estrogen plus progestin significantly increased breast cancer 

incidence, delayed diagnosis, and increased breast cancer mortality (mortality HR 1.96, 95% CI 1.00–4.05, 

p � .048). Estrogen alone significantly reduced breast cancer incidence and breast cancer mortality (mortality 

HR 0.37, 95% CI 0.13–0.91). The findings led to a worldwide reduction in hormone therapy use with substantial 

reduction in breast cancer incidence seen in many countries. In the MAP.3 randomized primary prevention trial, 

breast cancer incidence was significantly lower in the exemestane versus placebo group (HR 0.35, 95% CI 

0.18–0.70, p �0.002). Emerging studies evaluated additional agents for chemoprevention. In cohort analyses 

in 154,768 WHI study participants breast cancer incidence was lower in bisphosphonate users (HR 0.68, 95% 

CI 0.52–0.88, p � 0.01). In cohort analyses in 68,019 WHI clinical trial participants, women with diabetes 

using metformin had lower breast cancer incidence (HR 0.75, 95% CI 0.57–0.99, p � 0.04). These findings 

support consideration of combination regimens for breast cancer risk reduction with toxicity profiles favorable for 

board implementation. 

B. J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology 

Sunday, June 3, 9:45 AM 

Geriatric oncology: Realities and hopes around a patient’s history. 

Matti S. Aapro, MD; Clinique de Genolier, Genolier, Switzerland 

One of the significant milestones in the development of geriatric oncology was in 1988 when B. J. Kennedy 

commented in his Presidential Address at the ASCO Annual Meeting about the gaps in our knowledge in this 

important field. Recognition of the situation by a major society like ASCO boosted the efforts of the research 

community. The French GELA group demonstrated the feasibility of standard high-grade lymphoma chemotherapy 

in elderly patients, and CALGB showed its importance in adjuvant treatment of breast cancer (Aapro M. 

Launching the Journal of Geriatric Oncology: A historical milestone. J Geriatric Oncol. 2010;1:2–3). This 

presentation will address the many prejudices and sad realities of geriatric cancer patients, by following a slightly 

modified true patient history. We should recognize that there is a lot to do to overcome the obstacles that continue 

to mean that older individuals do not receive the best possible care. But evidence for treatments tailored to the 

real status of the patient and the true nature of the cancer is accumulating. The International Society for Geriatric 

Oncology has identified three key areas of priority in this field: education, clinical practice, and research 

(Extermann M, Aapro M, Audisio R, et al. Main priorities for the development of geriatric oncology: A worldwide 

expert perspective. J Geriatric Oncol. 2011;1:270–273). Education should be targeted at both the professional 

and the population levels. In clinical practice, pilot models of multidisciplinary collaboration should be expanded 

first to key reference centers, and a two-step approach to screening and evaluation should be used to optimize 

resource use. In research, several strategies can render trials more relevant for older patients. These priorities are 

fully detailed in a monograph that can be viewed online at www.siog.org or ordered from siog@genolier.net.

Special Awards 

Pediatric Oncology Award and Lecture 

Friday, June 1, 2:45 PM 

Toward the total cure of childhood acute lymphoblastic leukemia with personalized therapy. 

Ching-Hon Pui, MD; St. Jude Children’s Research Hospital and the University of Tennessee Health Science 

Center, Memphis, TN 

The cure rate of approximately 90% achieved in childhood acute lymphoblastic leukemia (ALL) attests to the 

effectiveness of risk-directed therapy developed through well-designed clinical trials and the successful 

translation of laboratory discoveries. With optimal systemic and intrathecal therapy, central nervous system 

relapse can now be totally prevented without the need of prophylactic cranial irradiation. The results of allogeneic 

transplantation have also been improved by more precise HLA matching, killer immunoglobulin-like receptor 

genotyping, and better supportive care. Further improvements in treatment outcome and quality of life for these 

patients will almost certainly require continued dissection of ALL pathophysiology and the mechanisms of drug 

resistance as they relate to the genetic and epigenetic changes for individual patients. The high-risk leukemic cell 

genetic abnormalities alone can no longer be considered justification for stem cell transplantation, given the 

improved chemotherapy and the substantial heterogeneity among these patients in cooperating mutations, 

development stages of the transformed cells, and host pharmacogenetics. Recent advances in global genomic 

analyses have identified new recurrent somatic lesions in the leukemic cells that offer not only additional 

prognostic information but also the opportunity to apply novel targeted therapy. Notably, the recently identified 

mutational spectrum in early T-cell precursor ALL—a subset of ALL with an extremely dire prognosis— 

recapitulates that of acute myeloid leukemia, while its global transcriptional profile is similar to that of normal 

and myeloid leukemia hematopoietic stem cells, suggesting that additional myeloid-directed therapy might 

benefit patients with this leukemia variant. Finally, it may be possible to improve the outcome of “BCR-ABL1like” 

ALL, a new subtype of high-risk B-cell precursor ALL with an IZKF1 alteration, by targeting recently 

identified activation mutations with tyrosine kinase inhibitors. As the repertoire of targeted therapeutics 

including cell- and antibody-based treatment increases, we can look forward to a total cure of ALL with 

acceptable toxicity. 

3s

2012 ASCO Annual Meeting Proceedings Plenary Session 

5s 

LBA1 Plenary Session, Sun, 1:00 PM-4:00 PM 

Primary results from EMILIA, a phase III study of trastuzumab emtansine 

(T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally 

advanced or metastatic breast cancer (MBC) previously treated with 

trastuzumab (T) and a taxane. Presenting Author: Kimberly L. Blackwell, 

Duke University Medical Center, Durham, NC 

The full, final text of this abstract will be available at 

abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 

2012, and in the Annual Meeting Proceedings online 

supplement to the June 20, 2012, issue of Journal of 

Clinical Oncology. Onsite at the Meeting, this abstract will 

be printed in the Sunday edition of ASCO Daily News. 

ABSTRACTS 

The American Society of Clinical Oncology 


June 1-5, 2012 



2 Plenary Session, Sun, 1:00 PM-4:00 PM 

Long-term follow-up results of EORTC 26951: A randomized phase III 

study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors 

(AOD). Presenting Author: Martin J. Van Den Bent, Erasmus University 

Medical Center, Daniel den Hoed Cancer Center, Rotterdam, Netherlands 







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6s Plenary Session 

3 Oral Abstract Session, Sat, 3:00 PM-6:00 PM 

Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) 

as first-line treatment in patients with indolent and mantle cell lymphomas 

(MCL): Updated results from the StiL NHL1 study. Presenting Author: 

Mathias J. Rummel, Universitaetsklinik, Giessen, Germany 







4 Plenary Session, Sun, 1:00 PM-4:00 PM 

Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone 

sensitive metastatic prostate cancer (HSM1PC) patients (pts): 

Results of S9346 (INT-0162), an international phase III trial. Presenting 

Author: Maha Hussain, University of Michigan Comprehensive Cancer 

Center, Ann Arbor, MI 








500 Oral Abstract Session, Sun, 8:00 AM-11:00 AM 

Impact of concurrent (CON) and sequential (SEQ) radiotherapy (RT) with 

adjuvant aromatase inhibitors (AI) in early-stage breast cancer (EBC): NCIC 

CTG MA.27. Presenting Author: Abdullah Khalaf Altwairgi, NCIC Clinical 

Trials Group, Queen’s University, Kingston, ON, Canada 

Background: Optimal timing of administration of adjuvant (adj) RT and AI in 

EBC is unknown. Methods: MA.27 was a phase III RCT of exemestane to 

anastrozole in postmenopausal women with hormone receptor positive EBC 

(Goss et al. Cancer Res. 70(24, Suppl):75s, 2010). The final trial database 

was used for this retrospective analysis. Median follow-up was 4.1 years. 

MA.27 patients received CON-AI [any overlap with AI; 4233 (57%) 

patients], SEQ-AI [RT preceded AI, no overlap with AI; 1010 (14%) 

patients] and No RT [AI only; 2128 (29%) patients]. Outcome measures for 

this analysis were: event free survival (EFS; time to locoregional or distant 

disease recurrence, new primary BC, or death from any cause), locoregional 

recurrence (LRFS), distant recurrence (DDFS) and overall survival (OS). RT 

groups were compared univariately (uni) with stratified log-rank tests, and 

multivariately (multi) with step-wise stratified Cox regression adjusted by 

stratification factors: nodal status, adj chemotherapy (chemo), celecoxib, 

aspirin, and trastuzumab. Results: 7371 eligible women received AI; were 

included in the analysis; and 71% (5243) received adj RT. CON-AI and 

SEQ-AI groups were comparable by median age (63 v 63), proportion T1 

tumours (75% v 75 %), and mastectomy rate (10% v 11%). The frequency 

of axillary dissection for CON-AI and SEQ-AI was 48% v 44%, proportion 

N0 was 73% v 69%, and proportion receiving adj chemo 29% v 41%. 

CON-AI had similar uni results to SEQ-AI: EFS, HR�0.86, p�0.20; LRFS, 

HR�0.82, p�0.51; DDFS, HR�0.92, p�0.59; and OS, HR�1.04, 

p�0.80. In multi analyses, CON-AI had better EFS than SEQ-AI patients 

[stratified HR of CON-AI to SEQ-AI 0.78 (0.66 – 0.91), p�0.001]; as well, 

age�70 (p�0.0001), ECOG PS�1 (p�0.0001), L-sided tumours 

(p�0.02), T2-T4 (p�0.0001), N2/N3 (p�0.0001), and no adj chemo 

(p�0.01) had significantly shorter EFS. There was no multi difference 

between CON-AI and SEQ-AI for LRFS (p�0.50), DDFS (p�0.72), or OS 

(p�0.85). Conclusions: Patients receiving CON-AI had significantly better 

EFS than SEQ-AI suggesting timing of administration of AI and RT may 

affect patient outcomes. Further research is necessary to confirm these 

findings. 


Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): The influence 

of menopausal status and age on treatment effects. Presenting Author: 

Helen Marshall, CTRU, Leeds, United Kingdom 

Background: The AZURE trial evaluated the use of zoledronic acid (ZOL) in 

addition to standard adjuvant therapy in patients with stage II/III breast 

cancer. Although analysis of the primary endpoint in the total study 

population showed no significant effects on disease outcomes, prespecified 

subgroup analyses identified significant benefit in both invasive 

disease-free survival (IDFS) and overall survival (OS) in women �5years 

postmenopause (Coleman et al. NESM. 2011;365:1396–1405). Here we 

evaluate the treatment modifying effects of both menopausal status and 

age. Methods: 3360 patients were randomized to receive standard (neo) 

adjuvant systemic therapy �/- ZOL 4mg iv every 3-4 weeks for 6 doses, 

then at reduced frequency to complete 5 years treatment. Results: ZOL had 

no overall effect on IDFS or OS at a median follow-up of 59 months. 

Pre-specified subgroup analyses showed significant heterogeneity of treatment 

effect (chi2 1 �7.91; p�.0049) on IDFS between those who were �5 

years post-menopause (n�1041; adjusted HR� 0.75; 95% CI 0.59-0.96, 

p�0.02) and all other (pre, peri and unknown status) menopausal groups 

(n�2318; adjusted HR� 1.15; 95% CI 0.97-1.36, p�0.11). The treatment 

interaction between the two menopausal groups was related to 

differences in first extra-skeletal IDFS events (chi2 1 � 14.00, p�0.0002), 

rather than first recurrence in bone (chi2 1 � 0.14, p�0.70). In women 

aged �40, a significant worsening in extra-skeletal IDFS events was seen 

(HR � 1.68; 95% CI � 1.14-2.47, p�.008). Although the ZOL effect on 

IDFS improved by age from a negative effect in younger patients (�40) to a 

beneficial effect for those aged 54 and over (chi2 1(trend) � 5.96, 

p�0.015, using Cox model analysis to test for an interaction effect 

between age, menopausal status and treatment for IDFS (using age 55 as a 

cut-off) showed that the age effect is reversed by menopausal status, with 

this model providing a significantly better fit (chi2 2 � 22.8, p�.00001) 

than the aforementioned linear model. Conclusions: These results suggest 

menopausal status is more informative than age in the selection of patients 

for treatment with ZOL. In women aged �40, ZOL may increase extraskeletal 

recurrence. 



Effect of osteoporosis in postmenopausal breast cancer patients randomized 

to adjuvant exemestane or anastrozole: NCIC CTG MA.27. Presenting 

Author: Lois E. Shepherd, NCIC Clinical Trials Group, Queen’s University, 

Kingston, ON, Canada 

Background: NCIC CTG MA.27 compared adjuvant steroidal [exemestane 

(E)] and non-steroidal [anastrozole (A)] aromatase inhibitors (AIs) and 

showed neither to be superior in breast cancer outcomes. AIs are known to 

increase the risk of osteoporosis. We examined the effects of baseline or 

subsequent self reported osteoporosis on disease outcomes. Methods: 

MA.27 enrolled 7,576 women. Event free survival (EFS) was the primary 

endpoint. Distant disease-free-survival (DDFS) was a secondary outcome. 

MA.27 permitted bisphosphonates to prevent or treat osteopenia or 

osteoporosis unless prohibited by enrollment to one of two cohorts in a bone 

substudy. Osteoporosis was considered present for this analysis if reported 

at baseline or prior to relapse or breast cancer death. Multivariate stratified 

Cox regression was used to examine the effects of trial therapy, osteoporosis, 

baseline patient and tumour characteristics on EFS; DDFS; bone only 

relapse; bone concurrent with other relapse; and non-bone recurrence. 

Bone marrow recurrence (N�8) was excluded. Results: Osteoporosis was 

reported at baseline by 654 of 7576 (8.6%) women, and prior to relapse by 

an additional 661 women. EFS events occurred in 693/7576 (9.15%). 

Osteoporosis was significantly associated with better EFS [HR 0.81 (95% 

CI 0.66-0.99), p�0.04] with no difference in multivariate HR of E vs A: 

1.02, 95% CI 0.88-1.19, p�0.77. Women experienced 313 (4.1%) DDFS 

events. Osteoporosis was associated with better DDFS [HR 0.71 (95% CI 

0.51-0.98), p�0.04], adjusted HR of E to A: 0.94 (95% CI of 0.75-1.17), 

p�0.56. Both EFS and DDFS interactions of osteoporosis with trial therapy 

were not significant (p�0.05). Osteoporosis was not significantly associated 

with the site of relapse. Conclusions: Osteoporosis had a significant 

prognostic association with improved EFS and DDFS in women treated with 

AIs. We plan to investigate the use of bisphosphonates, raloxifene treatment 

prior to randomization, and markers of bone resorption with outcome. 


Whole genome sequencing to characterize luminal-type breast cancer. 

Presenting Author: Matthew James Ellis, Department of Internal Medicine, 

Division of Oncology, and Siteman Cancer Center, Washington University 

Medical Center, St. Louis, MO 

Background: To correlate clinical features of estrogen receptor positive 

breast cancer with somatic mutations, massively parallel sequencing 

(MPS) was applied to tumor and normal DNAs accrued from patients 

treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was 

applied to 77 baseline tumor biopsy samples from the preoperative 

letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 

2342) followed by targeted sequencing in another 240 trial samples. 

Standard statistical approaches were used to compare mutation status and 

clinical parameters and pathway-based correlation was used to assess 

interactions between signaling perturbations induced by gene mutations 

and response to neoadjuvant AI. Results: Eighteen genes were significantly 

mutated above background. Aside from PIK3CA mutations, the list is 

dominated by loss-of-function mutations in tumor suppressor genes. Five 

(RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to 

benign and malignant hematopoietic disorders. Clinical correlation revealed 

that TP53 mutation was associated with PAM50 LumB status, 

high-grade histology and high proliferation rates whereas loss-of-function 

mutations in MAP3K1 associate with PAM50 lumA status, low proliferation 

rates, and low grade histology. Mutations in GATA3 were associated with 

greater suppression of proliferation upon AI treatment suggesting mut- 

GATA3 may predict endocrine response. Notably, mutations in MAP3K1 

were more common in PIK3CA mutant cases, suggesting cooperation. 

Pathway analysis demonstrated that rare MAP2K4 mutations produce 

similar pathway perturbations as MAP3K1 mutation, a logical finding since 

MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by 

lncRNA MALAT1 mutations were associated with multiple poor clinical 

outcome features. Rare mutations in druggable kinases included two in the 

kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type 

breast cancer is driven by specific patterns of somatic mutations, however 

most druggable or potentially prognostic mutations are infrequent. Prospective 

clinical trials based on these findings will require comprehensive 

genome sequencing approaches and large scale investigations. 

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7s

8s Breast Cancer—HER2/ER 


Intrinsic subtype and its clinical significance in early node-negative breast 

cancer: Results from two randomized trials of adjuvant chemoendocrine 

therapy. Presenting Author: Ewan K. A. Millar, The Kinghorn Cancer 

Centre, Sydney, Australia 

Background: Gene expression profiling has identified four main intrinsic 

subtypes of breast cancer which have distinct clinical behaviours and 

responses to therapy. A simplified immunohistochemical (IHC) panel can 

provide meaningful discrimination and help guide patient management. 

Methods: Using tissue microarrays (TMA) created from two randomized 

trials of adjuvant chemoendocrine therapy in node negative early breast 

cancer (IBCSG VIII and IX,n� 1220) we assessed intrinsic subtype as 

follows: “luminal A” (LA): ER and/or PR present, Ki-67 low (�median: 

19%), HER2-; “Luminal B” (LB): ER and/or PR present, Ki-67 

high(��19% median) and/or HER2� (IHC 3� or FISH amplified); HER2 

enriched: ER and PR negative, HER2 positive (IHC 3� or FISH amplified), 

Triple Negative (TNP): ER, PR and HER2 negative. p53� and high cyclin 

D1 expression were then assessed to determine if they provided any further 

additive discriminatory value. Results: The standard definitions of intrinsic 

subtype demonstrated a significant difference in disease-free survival 

between the subtypes in both trials VIII and IX (p� 0.02), but this was not 

significant in multivariate analysis. The discrimination between luminal A 

and B tumors could not be improved upon by the addition of p53 or cyclin 

D1 expression. The standard definitions demonstrated that TNP and 

HER2-enriched tumors benefited from the addition of chemotherapy to 

endocrine therapy, but LA and LB did not. p53� was associated with a 

poorer prognosis in ER� luminal tumors but improved prognosis in ERnon-luminal 

tumors (Interaction p � 0.002). Conclusions: Intrinsic subtyping 

using a panel of ER, PR, HER2 and Ki67 provides meaningful 

prognostic information to help guide patient management in early breast 

cancer. Whilst it predicts benefit from the addition of chemotherapy in TNP 

and HER2-enriched tumors it did not in this series do so for LB. Although 

p53 status did not improve the definition of luminal tumors, p53� 

appeared to have a divergent effect on outcome dependent on ER status. 

LBA506 Oral Abstract Session, Sun, 8:00 AM-11:00 AM 

Evaluation of lapatinib as a component of neoadjuvant therapy for HER2� 

operable breast cancer: NSABP protocol B-41. Presenting Author: Andre 

Robidoux, National Surgical Adjuvant Breast and Bowel Project and Centre 

Hospitalier de l’Universite de Montreal, Montreal, QC, Canada 








13-gene signature to predict rapid development of brain metastases in 

patients with HER2-positive advanced breast cancer. Presenting Author: 

Renata Duchnowska, Military Institute of Medicine, Warsaw, Poland 

Background: Brain metastases (BM) of breast cancer constitute an important 

part of therapeutic failures and are associated with severe morbidity 

and mortality. The risk of BM is particularly high in HER2� advanced 

breast cancer pts. We earlier developed in this group a 13-gene signature 

strongly predicting for rapid development of BM (J Clin Oncol 2008; 26: 

45s). Now, we validated these results in an independent group of pts and 

on culture model system. Methods: Discovery group included 87 samples 

analyzed using cDNA synthesis, annealing, selection, extension, ligation 

and array hybridization (DASL). Independent validation group included 75 

samples analyzed using quantitative reverse-transcriptase PCR. 3D culture 

validation model system used immortal, non-tumorigenic human MCF10A 

breast epithelial cells with and without ectopic expression of HER-2 and 

RAD51, a DNA double strand break repair gene (one of the three genes of 

this group overexpressed in 13-gene signature). The number and morphology 

of breast acini were scored using indirect immunoflourescence and 

confocal microscopy. Results: Median brain metastasis-free survival (BMFS) 

in the discovery group for ‘high’ vs. ‘low’ expression signature tumors was 

36 months and 66 months, respectively (P�0.0068), and in the validation 

group 54 and 86 months, respectively (P�0.032). Short BMFS was also 

associated with ER-negativity; BMFS in the cohort of ‘high’ 13-gene 

signature and ER- tumors vs. other 3 groups was 31 months and 66 months 

in discovery group, and 41 and 77 months in validation group (P�0.0001 

and P�0.02, respectively). Overexpression of RAD51 in MCF-10A breast 

cells altered their three-dimensional acinar morphology and increased the 

percentage of invasive structures by 6.5 fold, both in the presence and 

absence of HER2 overexpression. Conclusions: 13-gene signature and 

ER-negativity predict rapid development of BM in HER� advanced breast 

cancer pts. RAD51 may promote aggressiveness in breast epithelial cells. 

These data may be useful in the design of BM preventive trials and may 

prompt new treatment strategies. 

507 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM 

Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free 

survival (RFS) in early breast cancer (BC): Results from the FinHER trial. 

Presenting Author: Sherene Loi, Jules Bordet Institute, Brussels, Belgium 

Background: Tumor PIK3CA mutations (mts) and lymphocyte infiltration 

(LI) are prognostic in BC, but their importance is unknown in HER2positive 

(HER2�) BC treated with adjuvant trastuzumab (T). Methods: The 

FinHER trial randomized 1010 patients (pts) with pN� or high-risk pN- BC 

to 3 cycles of docetaxel (D) or vinorelbine, followed by 3 cycles of FEC. Pts 

with HER2� BC were further randomized to 9 weeks of T or no T (n�232). 

Pts treated with D and T had superior outcome in prior analyses. BC 

samples were subjected to somatic hotspot mt profiling (Sequenom) and 

quantification of percentage tumor LI using full-face H&E sections. RFS 

and interactions with T were explored with Kaplan-Meier and Cox regression 

analyses. Results: The median FU time was 62 months. 935 (92.6%) and 

687 (68.1%) tumors underwent LI and mt analysis, respectively. Correlation 

of LI assessment between 2 pathologists was 0.78 (p�0.001). 54 mts 

detected in 13 genes were evaluated. PIK3CA mts (exons 1,2,9,13,18,20) 

was present in 25.3% (n�174) and ERBB2 mt in 4.5% (n�31) BCs. Only 

1 AKT mt was found and none in KRAS, BRAF, NRAS or PTEN. In 

ER�/HER2-, HER2� and ER-/HER2- subtypes the prevalence of PIK3CA 

mts was 30.2%, 19.5% and 9.2%; ERBB2 mt 6.3%, 1.9% and 2.6%, 

respectively (both p�0.05). Neither PIK3CA nor ERBB2 mts were associated 

with RFS overall or within BC subgroups. No interaction was found for 

the benefit with T and presence of PIK3CA mt in HER2� BC (interaction 

p�0.17 T vs no T). Increasing LI was associated with favorable RFS in 

ER-/HER2- BC (continuous score adjusted p�0.032); 3-y RFS was 90% 

with extensive LI (�30% infiltrated) vs 66% with non-extensive LI 

(p�0.007). In HER2� BC, whilst there was no association with prognosis 

overall, there was a significant interaction with the benefit from T vs. no T 

and increasing LI (continuous score interaction p�0.042) with 3-yr RFS 

96% vs 78% for extensive and non-extensive LI treated with T respectively 

(p�0.014). Conclusions: We report 3 clinically relevant findings from this 

large clinical trial dataset: 1) PIK3CA mts were not prognostic; 2) LI is a 

strong prognostic factor in ER-/HER2- BC and 3) for the first time that 

extensive LI predicts benefit from adjuvant T. 



A phase I/IB dose-escalation study of BEZ235 in combination with 

trastuzumab in patients with PI3-kinase or PTEN altered HER2� metastatic 

breast cancer. Presenting Author: Ian E. Krop, Dana-Farber Cancer 

Institute, Boston, MA 

Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated 

in resistance to trastuzumab (T) in HER2� breast cancer. BEZ235, a 

potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth 

inhibition and apoptosis in HER2� breast cancer models, including those 

harboring PI3K pathway alterations, and with T resistance. In a Phase I 

study, BEZ235 was well tolerated as a single agent in pts with advanced 

solid tumors. The aim of this study was to determine the MTD of BEZ235 in 

combination with T in pts with T-resistant HER2� metastatic breast cancer 

(mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant 

HER2� mBC (i.e. disease progression during adjuvant therapy or metastatic 

disease on therapy with T) received oral BEZ235 daily, with weekly T 

(2 mg/kg). Pts were eligible for enrollment if a tumor sample was 

demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. 

Dose escalation was guided by a Bayesian logistic regression model with 

overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts 

were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 

dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 

mg/day (10 pts), administered either in capsule form (400 mg) or in sachet 

form (600 mg and 800 mg). The MTD of BEZ235 in combination with T 

was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 

mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 

800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) 

suspected to be related to study treatment were diarrhea (4 pts) and nausea 

(2 pts). No deaths related to study treatment occurred. 1 pt with lung and 

brain metastases had a partial response. 4 pts had disease stabilization for 

�4 cycles (16 weeks), including 1 pt with liver metastases, in whom 

BEZ235/T treatment resulted in disease stabilization for more than 21 

cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated 

an acceptable safety profile in pts with HER2� mBC and PI3K 

pathway alterations. Following the Bayesian model recommendation, the 

MTD for BEZ235 in combination with T was estimated to be 600 mg/day. 

The safety expansion arm is ongoing at the MTD. 


SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER�/ 

HER2- metastatic breast cancer (MBC). Presenting Author: Ingrid A. Mayer, 

Vanderbilt-Ingram Cancer Center, Nashville, TN 

Background: Mutations in PIK3CA, the gene encoding the p110a subunit of 

PI3K, have been associated with antiestrogen resistance in ER� BC. In general, 

antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This 

suggests that treatment of ER�/PI3K mutant BC should include PI3K inhibitors 

plus antiestrogens. Methods: We conducted a phase Ib trial of letrozole (2.5 

mg/d) with the pan-PI3K inhibitor BKM120 in post-menopausal patients (pts) 

with ER�/HER2 MBC. BKM120 (100 mg/d) was given continuously (Arm A) or 

intermittently (5 on/2 off days; Arm B). Upon toxicity, BKM120 was reduced to 

80 and 60 mg/d. Treatment continued until unacceptable toxicity or disease 

progression. Disease was assessed every 2 months. FDG-PET was done at 

baseline and at 2 weeks in all pts in Arm A. Results: Fifty-one pts were accrued; 

49 had progressed on an AI previously. Median age was 56 years (range 34-77); 

95% had bone and 70% visceral metastases. Toxicities and outcomes are 

summarized in the table. The only DLT* in Arm A and B were transaminitis and 

depression, respectively; both at 100 mg. Over 50% of Arm A pts had �25% 

reduction in their peak SUV at the 2-week FDG-PET. Pts who did not exhibit a 

metabolic response by FDG-PET progressed rapidly on therapy. Three pts in Arm 

A had a PI3K mutation; one of them has had stable disease on treatment for �12 

months. Conclusions: The combination of letrozole/ BKM120 is safe in pts with 

AI-refractory ER�/HER2 MBC. Arm B is ongoing and will be updated at the 

meeting. All tumor biopsies will be analyzed for PI3K pathway alterations. 

FDG-PET at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K 

pathway inhibition in most patients. Its value in predicting treatment response 

remains to be determined. 

ArmA(N�20) Arm B (N�31) 

Grade (%) 

Grade (%) 

Toxicity 

1 2 3 Total 1 2 3 Total 

Hyperglycemia 50 10 10 70 16 3 0 19 

Nausea 55 10 0 65 12 0 0 12 

Fatigue 25 40 5 70 9 3 0 12 

Transaminitis 35 25 15* 75 16 6 6 16 

Diarrhea 40 10 0 50 19 0 0 19 

Anxiety 25 15 5 45 3 3 0 6 

Depression 15 35 5 55 3 6 3* 12 

Rash 30 0 5 35 3 0 0 3 

Outcomes Arm A (N�20) Arm B (N�31) 

CR 1 0 

PR 1 0 

SD >4 months 9 4 

PD 7 8 

Non-evaluable 2 5 

Still on treatment 1 17 

Median TTP (months) 4 (2-11) N/A 

Discontinued due to toxicity 6 3 

Treatment > 8 weeks without interruption 17 N/A 



PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/ 

dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) 

patients (pts). Presenting Author: Mafalda Oliveira, Breast Cancer Group, 

Vall d’Hebron University Hospital, Barcelona, Spain 

Background: The role of PI3Kp dysregulation as a predictor of sensitivity to 

PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two 

cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts 

treated in �3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No 

dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: 

PIK3CA mutation (PIK3CAmut) or PTEN low (HScore�50). Cohort A: pts 

treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in 

combination with hormonal therapy (HT), chemotherapy (CT) and/or 

trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp 

alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A 

(n�17): HR�/HER2- 88%, HER2� 6%, triple negative 6%; median age 

43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 

exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 

pts. Cohort B (n�15): HR�/HER2- 40%, HER2� 60%; median age 49, 

median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all 

exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. 

Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis 

(OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA 

status and PI3Kp dysregulation, are shown. No differences were found 

according to PTEN status. Conclusions: These results suggest that the best 

outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in 

combination with HT/CT/T. Activity of non selective PI3Kpi used as single 

agents seems to be limited, making results from prospective trials with 

selective PI3K� inhibitors and PI3Kpi in combinations eagerly awaited. 

Months 

Median 

(95%CI) 

Cohort A 

n�17 

TTP 

OSMBC 

OSPI3Ki 

Cohort B 

n�15 

TTP 

OSMBC 

OSPI3Ki 

PIK3CA PI3Kp dysregulation 

WT Mut p No Yes p 

n�7 n�10 n�5 n�12 

7.4 

(3.5-11.2) 

95 

(0-206.9) 

NR 

1.4 

(0-3.6) 

47.1 

(12.4-81.9) 

8.5 

(2.8-14.2) 

0.026 

0.217 

0.048 

4.9 

(1.5-8.2) 

95 

(-) 

NR 

1.4 

(0-3.3) 

47.1 

(13.6-80.7) 

5.7 

(1.8-9.5) 

n�10 n�3 n�7 n�8 

3.6 (1.2-6.1) 

NR 

NR 

8.4 (-) 

NR 

NR 

0.053 

0.212 

0.223 

3.6 (0.7-6.6) 

55.7 (53.5-57.8) 

5.9 (2.6-9.2) 

3.7 (2.2-5.2) 

NR 

NR 

0.092 

0.097 

0.039 

0.451 

0.216 

0.306 

511 Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and 

4:45 PM-5:45 PM 

Randomized trial of marker-directed versus standard schedule zoledronic 

acid for bone metastases from breast cancer. Presenting Author: Robert 

Edward Coleman, CR-UK/YCR Sheffield Cancer Research Centre, Sheffield, 

United Kingdom 

Background: Zoledronic acid (ZOL) reduces skeletal morbidity associated 

with metastatic bone disease by 30-50%. Current recommendations are for 

indefinite administration of intravenous 3-4 weekly (w) ZOL 4mg. Over 

recent years it has become clear that the risk of skeletal morbidity is related 

to the rate of bone resorption. We have compared a marker directed 

schedule of ZOL (M-ZOL), using measurements of urinary n-telopeptide of 

type I collagen (NTX), to a standard treatment schedule (S-ZOL) in patients 

with bone metastases from breast cancer. Methods: The primary endpoint 

was skeletal related events (SRE). A non-inferiority study was designed with 

80% power and (one-sided) 5% alpha to demonstrate that M-ZOL retained 

67% of the efficacy of S-ZOL. This required 1500 patients, assuming a 

SRE rate of 0.7/year. Following minimisation for known prognostic factors, 

patients were randomised to receive S-ZOL 3-4 w or M-ZOL (15-16w; 8-9 w 

or 3-4w if NTX levels were �50, 50-100, �100 nmol/mmol creatinine 

respectively), with the schedule adjusted according to NTX measured every 

16 weeks. The study duration was 24 months. Results: Due to lower than 

expected recruitment, the study closed in 2009 following recruitment of 

289 patients. 90% of patients had received �4 cycles of ZOL or 

pamidronate prior to randomisation. The median number of ZOL infusions 

administered to S-ZOL patients was �2x that received on M-ZOL. 46 

(32%) S-ZOL and 55 (38%) M-ZOL patients experienced an SRE. The 

numbers of SRE were 94 and 138 in the S-ZOL and M-ZOL arms, with the 

excess in SRE being largely due to more patients on M-ZOL experiencing 

�2 SRE. Multivariate analysis adjusting for key minimisation factors and 

baseline NTX for all SRE showed a hazard ratio for M-ZOL vs. S-ZOL of 1.41 

(90%CI 0.98-2.02, p�.12). NTX levels were significantly higher at all time 

points in the M-ZOL treated patients. Osteonecrosis of the jaw was 

uncommon with 3 cases with S-ZOL and 1 with M-ZOL. Conclusions: The 

study is underpowered to demonstrate non-inferiority in SRE outcome 

between the treatment strategies. However, the results suggest that the 

adjustment of ZOL schedule based on NTX values alone may represent 

sub-optimal management. 


9s



4:45 PM-5:45 PM 

Effects of everolimus (EVE) on disease progression in bone and bone 

markers (BM) in patients (pts) with bone metastases (mets). Presenting 

Author: Michael Gnant, Comprehensive Cancer Center, Medical University 

of Vienna, Department of Surgery, Vienna, Austria 

Background: BOLERO-2, a multinational, double-blind, placebo-controlled, 

phase III study in postmenopausal women with estrogen-receptor–positive 

breast cancer (BC) refractory to non-steroidal aromatase inhibitors (NSAIs), 

showed significant clinical benefits with the addition of EVE to exemestane 

(EXE) (Baselga J, et al. NEJM. 2011 Epub). As bone resorption is an 

important factor in BC mets, it is interesting to study bone-related effects of 

EVE. In preclinical studies, mTOR inhibition was associated with decreased 

osteoclast survival and activity. Exploratory analyses in BOLERO-2 

evaluated the effect of EVE vs placebo (PBO) on BM levels and BC 

progression in bone in pts with bone mets at baseline. Methods: Eligible pts 

were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 

mg once daily) or PBO. Bone turnover markers were exploratory endpoints 

analyzed at 6 and 12 wks after treatment initiation, and included 

bone-specific alkaline phosphatase, amino-terminal propeptide of type I 

collagen, and C-terminal cross-linking telopeptide of type I collagen. 

Progressive disease in bone (PDB) was defined as worsening of a preexisting 

bone lesion or a new bone lesion. Results: Baseline disease 

characteristics, including bone mets at baseline (n � 370, 76% EVE vs n � 

184, 77% PBO), were well balanced between arms (N � 724), and 

baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo 

median follow-up, progression-free survival (primary endpoint), overall 

response rate, and clinical benefit rate (P � .0001, all) were significantly 

higher with EVE (n � 485) vs PBO (n � 239). BM levels at 6 and 12 wks 

increased vs baseline with PBO, but decreased with EVE. The cumulative 

incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 

6.16%, respectively) and this trend was sustained beyond 6 months. 

Updated results will be presented. All bone-related adverse events reported 

were grade1/2 and occurred with similar frequency in EVE- (2.9%) and 

PBO- (3.8%) treated patients. Conclusions: Exploratory analyses from 

BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover 

and BC progression in bone in pts receiving EXE therapy for NSAI-refractory 

BC. 


4:45 PM-5:45 PM 

Impact of body mass index (BMI) on the efficacy of zoledronic acid in 

premenopausal patients with hormone receptor positive breast cancer: An 

analysis of the ABCSG-12 trial. Presenting Author: Georg Pfeiler, Department 

of Obstetrics and Gynecology, Medical University of Vienna, Vienna, 

Austria 

Background: Zoledronic acid (ZOL) improves disease outcome in premenopausal 

patients with breast cancer (BC), especially in those with low 

estrogen environment. Obesity is associated with increased estrogen serum 

levels, which might influence the efficacy of ZOL. We investigated the 

impact of BMI on the efficacy of ZOL in premenopausal patients with BC. 

Methods: ABCSG-12 examined the efficacy of ovarian suppression using 

goserelin (3.6 mg q28d SC) in combination with anastrozole (ANA) or 

tamoxifen (TAM) � ZOL 4 mg IV q6mo) in premenopausal women with 

endocrine-responsive BC. BMI was calculated using the prospectively 

collected data on patients’ height and weight at study entry. BMI definitions 

of the WHO were used: normal 18.5-24.9 kg/m2 , overweight: BMI 

25-29.9 kg/m2 , obese BMI � 30 kg/m2 ). Disease-free survival (DFS) and 

overall survival (OS) were calculated by Kaplan-Meier method and results 

were compared by using the log-rank test and Cox proportional hazard 

modeling. Results: Two thirds of the patients were normal weight (1,111) 

and one third was overweight (391) or obese (182). Normal weight patients 

treated with ZOL experienced the same benefit as overweight/obese 

patients treated with ZOL compared to patients without ZOL regarding 

disease free survival (HR 0.75, 95%CI 0.53 1.05 p � 0.09 and HR 0.71, 

95%CI 0.46 1.1, p�0.12, respectively) as well as overall survival (HR 

0.67, 95% CI 0.37 1.22, p�0.19 and HR 0.64, 95%CI 0.32 1.28, 

p�0.19, respectively). No difference regarding DFS and OS could be 

detected between normal weight and overweight/ obese patients treated 

with ZOL (HR 1.05, 95%CI 0.69 1.59, p�0.83 and HR 1.27, 95%CI 0.62 

2.61, p� 0.51). Comparing normal weight patients with ZOL to obese 

patients with ZOL, again no difference could be observed. Conclusions: The 

significant outcome benefit of adjuvant zoledronic acid in ABCSG-12 can 

be demonstrated both in normal weight and overweight/obese premenopausal 

patients with early breast cancer, indicating that the bone marrow 

microenvironment changing impact of adjuvant bisphopshonate treatment 

does not correlate with patients’ BMI. 


4:45 PM-5:45 PM 

Adjuvant zoledronic acid (ZOL) in postmenopausal women with breast 

cancer and those rendered postmenopausal: Results of a meta-analysis. 

Presenting Author: Walter Gregory, Clinical Trials Research Unit, University 

of Leeds, Leeds, United Kingdom 

Background: A number of groups have now reported results of randomised 

trials of adjuvant zoledronic acid (ZOL) for women with early stage breast 

cancer. Following an interaction effect observed in the AZURE trial, where 

postmenopausal women appeared to benefit from ZOL, we performed a 

meta-analysis, from both publications and presented data, of the most 

recent results from these trials. We also looked at recently reported large 

studies of clodronate and ibandronate in older or postmenopausal women 

to further examine this hypothesis. Methods: DFS data from 8735 women in 

7 trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, 

GAIN) that included a randomization to ZOL vs. control or clodronate/ 

ibandronate vs. control were examined. Median follow-up was 5 years. 14% 

of women experienced a DFS event. The ABCSG-12 study was included 

since, although it included only premenopausal women, they were all 

treated with goserelin, effectively rendering them postmenopausal, prior to 

and during treatment with ZOL. We analysed the subgroup of women aged 

�50 in the NSABP-B34 study in the absence of information on menopausal 

status, and included only postmenopausal women from the AZURE 

and GAIN trials. Sensitivity analyses confirmed that exclusion of some 

older, small, clodronate studies that lacked DFS data, or failed to report by 

age or menopausal status would be unlikely to alter these findings. Results: 

For the 5 ZOL studies alone, there was a very substantial and highly 

significant DFS benefit for ZOL, 2P�.0006, with a hazard ratio of 0.76, 

and therefore a DFS risk reduction of 24% (95% CI 11%-35%). The results 

were, in the main, extremely consistent, with the exception of the very small 

E-ZO-FAST study, which had only 30 events. The risk reduction lessened to 

18% (95% CI 8%-26%) when adding in the clodronate and ibandronate 

studies, but the result remained highly significant (2P�.00075). 

Conclusions: These meta-analysis results, including more than 8000 

women in a range of studies, now provide strong evidence that ZOL is an 

effective adjuvant treatment for postmenopausal women with early stage 

breast cancer, and that the treatment benefits are substantial. 


4:45 PM-5:45 PM 

Progression of genomic signatures in local and metastatic estrogen receptorpositive 

(ER�) breast cancer: Relevance to palliative treatment. Presenting 

Author: William Fraser Symmans, University of Texas M. D. Anderson 

Cancer Center, Houston, TX 

Background: Biological progression of ER� breast cancer accelerates 

clinical progression and resistance to treatments. Methods: One laboratory 

used Affymetrix U133A gene expression microarrays to profile 588 biopsy 

samples from patients with ER� breast cancer: 74 AJCC Stage I, 155 

Stage IIA, 105 Stage IIB, 127 Stage III, 127 Stage IV (27 at presentation, 

100 relapsed). We evaluated stage dependence of ER [ESR1, PGR, 

sensitivity to endocrine therapy (SET) index], proliferation [MKI67, AU- 

RKA, genomic grade index (GGI)], invasion [PLAU (uPA)], PI3-kinase 

(PIK3CA-GS), VEGF, genomic subtype [PAM50, 3-gene classifier (ESR1, 

ERBB2, AURKA)], and housekeeper control genes. Significance was 

evaluated through ordinal median regression (P � 0.002, for multiple 

testing) after adjusting for staging method (clinical or pathologic). Exploratory 

Cox regression analyses of progression-free survival (PFS) and overall 

survival (OS) were performed when treatment was hormonal therapy (HT, 

N�58) or chemotherapy (CT, N�27) after biopsy of metastatic ER� breast 

cancer (MBC). Results: Stage progression was associated with reduced SET 

index and increased proliferation (GGI, MKI67, AURKA) and metabolism 

(GAPDH). These changes occurred between Stages IIB and III, and Stages 

III and IV. Luminal B and proliferation subtypes were more prevalent in 

Stage IV and less in Stage I. Interestingly, invasion (PLAU) genes were 

lower in MBC. Only SET index demonstrated a significant interaction with 

treatment (HT or CT) for MBC (PFS: p�0.018). SET was predictive of PFS 

and OS following HT, as a continuous score (PFS: HR�0.69, 95%CI 0.49 

to 0.97, p�0.035; OS: HR�0.61, 95%CI 0.40 to 0.94, p�0.025) or 

dichotomized at median value (PFS: HR�0.43, 95%CI 0.24 to 0.76, 

p�0.003; OS: HR�0.37, 95%CI 0.18 to 0.77, p�0.006). Genomic 

subtype was prognostic for PFS irrespective of treatment type. High 

PIK3CA-GS expression predicted OS in the HT subset. Conclusions: Stage 

progression was associated with decreased ER-related transcription (SET) 

and increased proliferation, grade, higher risk subtype, and metabolism. In 

MBC samples, only SET index was predictive of PFS and OS with palliative 

hormonal therapy. 



4:45 PM-5:45 PM 

Mammostrat as an immunohistochemical multigene assay for prediction of 

early relapse risk in the TEAM pathology study. Presenting Author: John 

M. S. Bartlett, Ontario Institute for Cancer Research, Toronto, ON, Canada 

Background: Some postmenopausal patients with hormone sensitive early 

breast cancer remain at high risk of relapse despite endocrine therapy, and 

might benefit additionally from adjuvant chemotherapy. The challenge is to 

prospectively identify such patients. The Mammostrat test uses five 

immunohistochemical markers to stratify patients regarding recurrence 

risk, and may inform treatment decisions. We tested the efficacy of this 

panel in the TEAM trial. Methods: Pathology blocks from 4598 TEAM 

patients were collected and TMAs constructed. The cohort was 47% node 

positive and 36% were also treated with adjuvant chemotherapy. Triplicate 

0.6mm2 TMA cores were stained and positivity for p53, HTF9C, CEACAM5, 

NDRG1, SLC7A5 assessed. Cases were assigned a Mammostrat risk score, 

and distant relapse free (DRFS) and disease free survival (DFS) analysed. 

Results: In multivariate regression analyses, corrected for conventional 

clinicopathological markers, Mammostrat provided significant additional 

information on DRFS after endocrine therapy in ER positive node negative 

patients (N�1226) not receiving chemotherapy (p�0.004). Further analyses 

in all patients not exposed to chemotherapy, irrespective of nodal status 

(N�2559) and in the entire cohort (N�3837) showed Mammostrat scores 

provide additional information on DRFS in these groups (p�0.001 and 

p�0.0001 respectively; multivariate analyses). No differences were seen 

between the two endocrine treatment regimens. Conclusions: The Mammostrat 

score predicts DRFS for both exemestane and tamoxifenexemestane 

treated patients irrespective of nodal status and chemotherapy. 

The ability of this test to provide additional outcome data following 

treatment provides further evidence for its’ utility in risk stratification of ER 

positive postmenopausal breast cancer patients. 


4:45 PM-5:45 PM 

Gene methylation in random FNA samples as biomarkers for breast cancer. 

Presenting Author: Vered Stearns, Sidney Kimmel Comprehensive Cancer 

Center at Johns Hopkins University, Baltimore, MD 

Background: Current methods to determine breast cancer risk are insufficiently 

sensitive to select women most likely to benefit from preventive 

strategies. We hypothesized that candidate gene promoter hypermethylation 

may provide an individualized risk profile. We performed a prospective 

study to determine whether DNA cumulative methylation index (CMI) 

varies by menstrual phase or menopausal status, and to correlate CMI with 

established risk factors. Methods: We obtained random fine needle aspiration 

(rFNA) samples from healthy women age 35-60 and determined their 

menopausal and menstrual status, lifetime Gail risk, mammographic breast 

density, and cytologic atypia assessed as the Masood score. We evaluated 

CMI of 11 candidate genes in rFNA cells using the Quantitative Multiplex 

Methylation-Specific PCR (QM-MSP) technique. We used Wilcoxon test 

and ANOVA model to compare CMI across menopausal and menstrual 

(follicular, mid-cycle, luteal) categories, respectively. We used linear 

regression model to adjust for age and BMI. Methylation scores were 

log-transformed in the analysis. Results: We enrolled 390 women at the 

Avon Breast Centers at Johns Hopkins and Northwestern, the majority 

through the Love/Avon Army of Women, and 380 completed study 

procedures. Median age 50 (36-60), mean BMI 28 (18.7-50.8), 52% were 

postmenopausal. Mean life-time Gail risk 14.6 (5.6-54.1), mean percent 

mammographic density 19.6 (2.5-72.8), and mean Masood score (N�354) 

13.6 (7-18). QM-MSP analysis was completed on 229 samples. We did not 

observe differences in CMI among menopausal (P�0.4895) or menstrual 

categories (P�0.2333). There was no association between CMI and 

life-time Gail risk (P�0.706) or breast density (P�0.4116). We observed a 

significant correlation between CMI and Masood score (P�0.0167). 

Conclusions: CMI correlates with degree of cytologic atypia and is potentially 

a robust indicator of breast cancer risk since it does not vary with 

menstrual or menopausal status. Next, we will select genes that best reflect 

changes in the clinical parameters to create a gene methylation signature 

that will be validated in other studies and correlated with breast cancer risk. 


11s 


4:45 PM-5:45 PM 

Validation of IHC4 algorithms for prediction of risk of recurrence in early 

breast cancer using both conventional and quantitative IHC approaches. 

Presenting Author: Jason Christiansen, HistoRx, Inc, Branford, CT 

Background: Hormone receptors, HER2 and Ki67 are residual risk markers 

in early breast cancer. Combining these markers into a unified algorithm 

(IHC4) provides information on residual recurrence risk of patients treated 

with hormone therapies. This study aimed to independently investigate the 

validity of the IHC4 algorithm for residual risk prediction using both 

conventional (DAB)-IHC and quantitative immunofluorescence (QIF- 

AQUA). Methods: The TEAM pathology study recruited �4500 samples 

from patients treated in the TEAM trial. TMAs were stained for ER, PgR, 

HER2 and Ki67 using QIF-AQUA technology or DAB-based immunohistochemistry 

(DAB-IHC). Central HER2 FISH was performed. Quantitative 

image analysis was used to generate expression scores that were normalized 

to produce “IHC4 algorithm” as well as novel algorithm scores. 

Algorithm scores were compared with disease recurrence in univariate and 

multivariate Cox Proportional Hazards models. Results: Both DAB-IHC and 

QIF-AQUA IHC4 continuous models were significant (P�0.0001) for 

prediction of disease recurrence with a continuous Hazard Ratio (HR) of 

1.011 (1.010 – 1.013) for QIF-AQUA IHC4 versus 1.008 (1.007 – 1.010) 

for the DAB-IHC IHC4 model using the published IHC4 algorithm (Cuzick 

et al 2011). Binning continuous model scores (4 bins) by Kaplan-Meier 

survival analysis was used to graphically illustrate these effects. De novo 

models for both DAB-IHC and QIF-AQUA were also significantly (P�0.0001) 

predictive of residual risk in early breast cancer. Additionally, all 4 models 

were independent predictors of recurrence (P�0.0001) with other recognized 

clinical prognostic factors in multivariate analysis. Although results 

from DAB and QIF-AQUA were modestly correlated, the QIF-AQUA model 

showed enhanced prediction of recurrence in both Cox Proportional 

Hazards Modeling and C-index calculations. Conclusions: Either conventional 

DAB or QIF-AQUA methods of IHC provided evidence supporting the 

clinical utility of IHC4 algorithms in the context of the TEAM study. With 

careful standardization, either of these IHC4 assays should be considered 

for prediction of residual risk in early breast cancer. 


4:45 PM-5:45 PM 

Dual effects of metformin on breast cancer proliferation in a randomized trial. 

Presenting Author: Andrea De Censi, E. O. Ospedali Galliera, Genoa, Italy 

Background: Metformin lowers breast cancer risk in observational studies in 

diabetics, but evidence for its clinical activity is scanty. We studied the 

metformin antiproliferative effect in a pre-surgical study. Since the antidiabetic 

effect of metformin is heterogeneous according to obesity and insulin resistance 

(IR), we also determined whether its antiproliferative effect was modified by risk 

biomarkers. Methods: After tumor biopsy, we randomly allocated 200 nondiabetic 

women with breast cancer to either metformin, 850 mg/bid (n�100) or 

placebo (n�100) for 4 wks. The primary endpoint was the post-pretreatment 

change in Ki-67 between arms. We explored effect modifications by STEPP and 

tested biomarker thresholds that showed an interaction with treatment on Ki-67. 

Results: Overall, median (IQR) Ki-67 was 19 (14-31) at baseline and 21 (14-32) 

after 4 wks and 18 (12-29) at baseline and 20 (13-31) after 4 wks in the 

metformin and placebo arm, respectively with mean increase of 4.0% (95%CI, 

-5.6 to 14.4) on metformin versus placebo. Multivariate analyses showed an 

increase of Ki-67 after 4 wks placebo in the following subgroups: HOMA� IR 

threshold, IGFBP3� highest quartile, IGFBP1� lowest quintile, IGFratio (IGF1/ 

IGFBP3)� median, CRP� inflection point at STEPP analysis, HER2�ve tumors 

(versus –ve). Metformin blunted the increase of Ki-67 noted on placebo in these 

subgroups. Conclusions: Overall, metformin did not affect Ki-67 in most subjects 

with breast cancer. However, in exploratory analysis we identified subgroups of 

patients where metformin showed antiproliferative effect. Further studies to a 

personalized approach are warranted with selection of study populations. 

Post-pretreatment median change in Ki-67 by treatment arm and biomarker 

thresholds. 

Risk biomarker threshold Placebo Metformin p interaction 

HOMA>2.8 0(n�29) 0 (n�24) 0.03 

HOMA4614ng/ml 0(n�27) 0 (n�23) 0.04 

IGFBP-32mg/L 2(n�25) 0 (n�37) 0.08 

CRP



4:45 PM-5:45 PM 

Reduction in Ki-67 in benign breast tissue of high-risk premenopausal 

women with the SERM acolbifene. Presenting Author: Carol J. Fabian, 

University of Kansas Medical Center, Kansas City, KS 

Background: Selective Estrogen Receptor Modulators (SERMs) are approved 

for reduction of risk for breast cancer; however, uptake and use is 

limited. We conducted a pilot study of a 4th generation SERM to determine 

tolerability and effect on tissue biomarkers in healthy women at high risk 

for development of breast cancer. Methods: Premenopausal women at 

elevated risk for breast cancer were screened by random periareolar fine 

needle aspiration (RPFNA) performed during the follicular phase of the 

menstrual cycle. Women were eligible if breast epithelial cells exhibited 

evidence of cytologic hyperplasia with or without atypia, as well as Ki-67 

�2% by immunocytochemistry. Following 6-8 months of open-label 

acolbifene (20 mg/d), the RPFNA was repeated. The primary endpoint was 

modulation of the proportion of cells that expressed Ki-67. Body composition 

(DEXA), pelvic sonography, mammographic breast density, and serum 

levels of IGF-1/IGFBP3 and several bioavailable hormones were assessed 

pre and post intervention. Results: 76 women were screened by RPFNA, 

with 25 eligible and enrolled in the intervention over a 9 month period. All 

25 (7 on oral contraceptives) subjects completed the study, had a second 

RPFNA, and were evaluable. Median Ki-67 at baseline was 4.6% (range 

2.4 – 21.9%) and off study 1.4% (range 0 – 6.6%); median change was a 

reduction of 3.0% (range -20.2% to �2.8%; decreased in 23, increased in 

2) or a relative reduction of 77%. The end-of-study Ki-67 was significantly 

less than baseline (p�0.001, 2-tailed Wilcoxon test). There were no 

statistically significant changes in cytomorphology over this short intervention 

period. There was a marginal effect on breast density (16 decreased; 8 

increased; p�0.067). Adverse events were minimal with greatest grade of 

3 reported by 2 subjects, grade 2 by 7 subjects, and grade 1 by 11 

subjects. No serious adverse event was reported and no subject discontinued 

the study due to an AE. Conclusions: Based on preliminary evaluation 

showing favorable modulation of proliferation and minimal adverse events, 

further investigation of acolbifene, a fourth generation SERM, as a breast 

cancer chemoprevention agent for premenopausal women appears warranted. 

Supported by NO1-CN-35135. 


4:45 PM-5:45 PM 

Mucin-1 protein and mRNA expression in breast cancer: Predictive value 

for therapy response and survival after neoadjuvant chemotherapy. Presenting 

Author: Bruno Valentin Sinn, Charité Universitätsmedizin Berlin, 

Berlin, Germany 

Background: Mucin-1 (MUC1) is expressed in normal epithelial cells and in 

breast cancer. Immunotherapeutic agents targeting MUC1 are currently 

tested in clinical trials. Methods: We evaluated the frequency of MUC1 

expression by immunohistochemistry (IHC; n � 691) and quantitative 

RT-PCR (qRT-PCR; n � 286) in formalin-fixed paraffin-embedded (FFPE) 

pre-treatment biopsies from patients of the GeparTrio trial (NCT 00544765). 

mRNA levels were analyzed as a continuous variable, a distribution-based 

cut-off was chosen for IHC data. The predictive value for therapy response 

and survival after neoadjuvant anthracycline/taxane-based chemotherapy 

(CTX) was evaluated. Results: MUC1 was detectable by IHC in 95%. 

qRT-PCR covered a dynamic range of 3 orders of magnitude. IHC and 

mRNA data were correlated (p � 0.001). MUC1 was detected in higher 

quantities in HR� tumors (p � 0.001), the lowest levels were found in 

HR-/HER2- tumors (p � 0.001). High MUC1 protein and mRNA expression 

were associated with lower probability of pathologic complete response 

(pCR) in the overall population (p � 0.001) and in HR� (p � 0.004 and � 

0.001), HER2- (p � 0.001) and HR�/HER2- tumors (p � 0.001). In 

multivariable logistic regression, MUC1 was independently predictive (high 

MUC1 protein: odds ratio (OR) 0.464, 95% CI 0.300 – 0.719, p � 0.001; 

MUC1 mRNA (per 20-dCT unit): OR 0.673, CI 0.546 – 0.829, p � 0.001). 

MUC1 protein and mRNA expression were associated with longer patient 

survival in the overall population (p � 0.03 and � 0.001) and in HER2tumors 

(p � 0.005 and � 0.001). MUC1 mRNA was also prognostic in 

HR� (p � 0.001) and HR�/HER2- tumors (p � 0.001). In multivariable 

analysis, protein and mRNA expression were independently prognostic 

(high MUC1 protein: hazard ratio (HR) 0.388, CI 0.166 – 0.907, p � 

0.029; MUC1 mRNA per 20-dCT unit: HR 0.763, CI 0.595 – 0.909, p � 

0.005). Conclusions: MUC1 is frequently expressed in breast cancer and 

detectable by IHC and qRT-PCR from FFPE tissue. Despite its association 

with HR� status, it provides independent predictive information for 

therapy response and survival after neoadjuvant CTX. In clinical immunotherapy 

trials, MUC1 expression may serve as a predictive marker. 


4:45 PM-5:45 PM 

Aspirin use and mortality in women with stage I-III breast cancer: A 

population-based study. Presenting Author: Thomas Ian Barron, Trinity 

College Dublin, Dublin, Ireland 

Background: Recent observational studies have associated aspirin (ASP) 

use with large reductions in breast cancer (BC) mortality. However, these 

studies have provided limited information on dose or duration of ASP use, 

key issues relevant to translation of the results into clinical practice. 

Methods: Linked National Cancer Registry Ireland and prescription refill 

data (General Medical Services Ireland, GMS) were used to identify women 

aged 50-80 with incident stage I-III BC (2001-2006). ASP use was defined 

as high or low by the median number of ASP days’ supply (85 days) in the 

90 days pre-diagnosis. Full capture of ASP use is expected as the GMS 

provides all medications, including ASP, without charge. Hazard ratios 

(HR) with 95% confidence intervals (CI) for ASP use and (i) all-cause and 

(ii) BC-specific mortality were estimated using Cox proportional hazards 

models adjusted for age, stage, grade, ER, PR, HER-2 status, comorbidity 

and other drug exposures. Analyses were stratified by tumor stage and nodal 

status. Results: 2714 women with stage I-III BC were identified (median 

follow-up � 3.3 years), of whom 642 (23.7%) used ASP in the 90 days pre 

diagnosis. High and low ASP exposure groups were strongly predictive of 

post-diagnosis ASP exposure levels (High: mean post diagnosis exposure 

duration – 83% of follow-up; dose – 75mg/day in 91% of women. Low: 

mean post-diagnosis exposure duration – 58% of follow-up; dose – 

75mg/day in 80% of women). Women with any ASP use had a nonsignificant 

reduction in all-cause (HR 0.85 95%CI 0.68, 1.06) and 

BC-specific (HR 0.86 95%CI 0.65, 1.15) mortality, compared to ASP 

unexposed women. However, in the dose response analysis high ASP 

exposure was associated with a significant reduction in all-cause (HR 0.70 

95% CI 0.51, 0.95) and BC-specific (HR 0.63 95% CI 0.42, 0.96) 

mortality. No reduction was observed for low ASP exposure. The benefits of 

ASP exposure were greater in early stage, node negative disease. Conclusions: 

Only high ASP exposure was associated with a significant reduction in all 

cause and BC-specific mortality. These findings may explain inconsistent 

results from previous studies. Our findings can inform future clinical trials. 


4:45 PM-5:45 PM 

Impact of expression levels of mRNA HER2 and ESR1 on the pathologic 

complete remission (pCR) rate after neoadjuvant treatment with anthracycline-taxane 

containing chemotherapy in combination with trastuzumab in 

the GeparQuattro trial. Presenting Author: Jens Bodo Huober, University of 

Tuebingen and Kantonsspital St. Gallen, St. Gallen, Switzerland 

Background: Recent data suggest that benefit from (neo)adjuvant trastuzumab 

might be related to expression of HER2 and estrogen receptor 

(ESR1). We investigated mRNA levels of HER2 and ESR1 in core biopsies 

in HER2 positive tumors of the GeparQuattro trial and compared it to 

response to neoadjuvant treatment. Methods: In the GeparQuattro trial 445 

HER2� pts were included based on local testing and received neoadjuvant 

trastuzumab and chemotherapy (either4xEC¡4 x docetaxel (D) or4xEC 

¡ 4 x D/capecitabine (C) or 4xEC¡4x D ¡4 X C). In 217 available 

pretherapeutic core biopsies HER2 levels were analysed by IHC, SISH and 

quantitative RT-PCR using predefined cutoffs; pCR was defined as ypT0is; 

ypN0. Results: Only 73% of the tumors (158 of 217) were centrally HER2 

positive (cHER2�) by IHC/SISH, while 59 tumors (27%) were centrally 

HER2 negative (cHER2-). As all pts had received neoadjuvant trastuzumab, 

this gave us the possibility to evaluate response of HER2- tumors to 

trastuzumab. The pCR rate of cHER2� tumors was significantly increased 

(46.8%, p�0.0005) compared to cHER2-, who had a pCR rate of only 

20.3%. Similar results were obtained if HER2 positivity was determined by 

RT-PCR (pCR rate 50% vs. 17.4%, p�0.0005). Assessment of HER2 

status by RT-PCR showed a concordance of 86.2% with the IHC/SISH 

status. In uni- and multivariate logistic regression analysis of cHER2� 

cases including continuous HER2 and ESR1 mRNA levels the HER2 

mRNA expression was significantly associated with prediction for a pCR in 

(univ.: OR 1.43, 95% CI 1.11-1.83, p�0.005; multiv.: OR 1.42, 95% CI 

1.11-1.83, p�0.006). In the cHER2� tumors, the pCR rate was similar 

for ESR1 mRNA positive (47.4%) and ESR1 negative tumors (46.3%). 

Conclusions: Only pts with cHER2� tumors independently of the method 

used have an additional benefit in terms of a pCR from adding trastuzumab 

to chemotherapy. In cHER2-negative patients the pCR rate is comparable 

to the pCR rate in the non trastuzumab treated population. Increasing 

HER2 mRNA levels were associated with a better response to trastuzumab 

based treatment in cHER2 � tumors. 



4:45 PM-5:45 PM 

Vasomotor (VM) and musculoskeletal (MSK) symptoms and association 

with outcomes on extended adjuvant letrozole therapy: Analyses from NCIC 

CTG MA.17. Presenting Author: Pedro Emanuel Rubini Liedke, Massachusetts 

General Hospital, Avon International Breast Cancer Center, Boston, 

MA 

Background: Surrogate markers of clinical outcomes can potentially guide 

cancer therapy. New onset MSK symptoms and VM symptoms on aromatase 

inhibitors (AI) for hormone receptor positive (HR�) early breast cancer 

(EBC) have been investigated as markers of clinical outcomes, but results 

have been conflicting. MA.17 showed improved disease free survival (DFS) 

with letrozole (L) as extended adjuvant therapy after 5 years of tamoxifen 

(T). We performed this exploratory analysis of new onset symptoms and 

their association with clinical outcomes in the MA.17 trial. Methods: 

Patients (pts) with HR� EBC were randomized to receive L or placebo (P) 

for 5 years after 5 years of T. Symptoms were collected according to CTC v. 

2.0 at baseline, 1 month (mo), 6 mos, and every 12 mos thereafter. 

Analyses included pts with new symptoms of any grade who received 

therapy and excluded pts with baseline symptoms, EBC not HR�, and 

deaths/ relapses prior to each time point. Symptoms were categorized as 

VM - hot flashes/flushes, flushing, or sweating; and MSK - arthritis, 

arthralgia, myalgia, bone pain, or MSK other. Multivariate Cox Models 

adjusting for age, nodal status, duration of T and prior chemotherapy were 

used for analysis of DFS, distant DFS (DDFS), and overall survival (OS) 

assessed before unblinding. Hazard Ratios [HR] and 95% confidence 

intervals (CI) for patients with either VM or MSK symptoms are presented 

below for L using pts with no symptoms as controls. Results: Emergent VM 

symptoms were associated with improved DFS and DDFS on L (Table). No 

association was found for MSK symptoms at any time point. No association 

between either MSK or VM and OS was found at any time point. 

Conclusions: New VM symptoms initiating with extended letrozole were 

associated with improved outcomes. Similar findings have been seen with 

up-front AI therapy. Our results should be confirmed as they are of potential 

significance in guiding therapy. 

Month of assessment 

VM 

1 

HR (95% CI) 

6 12 

DFS 0.22 (0.05-0.92) 0.25 (0.07-0.85) 0.42 (0.15-1.18) 

DDFS 

MSK 

0.17 (0.02-1.26) 0.13 (0.02-0.99) 0.54 (0.16-1.81) 

DFS 2.33 (0.54-10.04) 0.70 (0.24-2.07) 0.68 (0.24-1.91) 

DDFS 1.91 (0.25-14.74) 0.57 (0.13-2.58) 0.45 (0.10-2.15) 


4:45 PM-5:45 PM 

Common polymorphisms in the estrogen receptor-1 may determine risk of 

hot flashes in early breast cancer patients using tamoxifen. Presenting 

Author: Vincent O. Dezentje, Department of Clinical Oncology, Leiden 

University Medical Center, Leiden, Netherlands 

Background: In breast cancer patients the occurrence of hot flashes as 

common side effect of tamoxifen therapy may be associated with effective 

estrogen receptor antagonism dependent on genetic variations of metabolic 

enzymes and the estrogen receptor. Methods: 742 early breast cancer 

patients who were randomized to receive tamoxifen, followed by exemestane 

after 2.5 to 3 years within the Tamoxifen Exemestane Adjuvant 

Multinational (TEAM) Trial were genotyped for 30 germ line genetic 

variants of 11 enzymes that are involved in the tamoxifen metabolism and 

the estrogen receptor 1 (ESR1). These genetic variants were related to the 

occurrence of hot flashes during the first year of tamoxifen use (primary 

aim) and during the complete tamoxifen treatment period (secondary aim). 

A multivariable logistic regression was used to adjust for age and adjuvant 

chemotherapy. Results: No genetic variant was associated with the occurrence 

of hot flashes during the first year. Higher age was related to a lower 

incidence of hot flashes in the first year (adjusted odds ratio 0.94, 95% CI 

0.92-0.96; p�0.001). The ESR1 PvuII XbaI CG haplotype (CG/CG vs 

CG/other � other/other: adjusted odds ratio 0.44, 95% CI 0.21-0.92; 

p�0.03), ESR1 PvuII XbaI TA haplotype (TA/TA � TA/other vs other/other: 

adjusted odds ratio 1.86, 95% CI 1.09-3.14; p�0.02) and age (adjusted 

odds ratio 0.94, 95% CI 0.92-0.97; p�0.001) were associated with the 

occurrence of hot flashes during the total tamoxifen treatment period. No 

association was found between the CYP2D6 predicted phenotype and hot 

flashes. Conclusions: Common polymorphisms in the estrogen receptor-1 

might help to predict the occurrence of hot flashes in breast cancer patients 

treated with adjuvant tamoxifen. If replicated, this may provide clinicians 

with a tool to offer more personalized hormonal therapy. 


13s 


4:45 PM-5:45 PM 

Genetic variants associated with toxicity-related discontinuation of adjuvant 

aromatase inhibitor (AI) therapy. Presenting Author: Norah Lynn 

Henry, University of Michigan Medical Center, Ann Arbor, MI 

Background: Discontinuation of adjuvant AI therapy due to intolerable 

symptoms occurs in up to 30% of patients. Predictors of which patients will 

be unable to tolerate these medications have not been defined. We 

hypothesized that inherited variants in candidate genes are associated with 

treatment discontinuation because of AI-associated toxicity. Methods: We 

prospectively evaluated reasons for treatment discontinuation in women 

with hormone receptor positive breast cancer initiating adjuvant AI through 

a multicenter, prospective, randomized clinical trial of exemestane (exe) 

versus letrozole (let). Using multiple genetic models, we evaluated potential 

associations between 136 single nucleotide polymorphisms (SNP) in 

24 candidate genes, selected a priori, primarily with roles in estrogen 

metabolism and signaling, and discontinuation of AI therapy because of 

toxicity. To account for multiple comparisons, statistical significance was 

defined as p�0.0003. Results: Of the 467 enrolled patients who had 

available germ line DNA, 152 (33%) discontinued AI therapy because of 

toxicity. After adjusting for multiple covariates, multivariable analyses 

revealed that two inherited genetic variants in ESR1, which encodes 

estrogen receptor (ER) alpha, and one in CYP19A1 were associated with 

increased risk of discontinuation of AI therapy because of toxicity (Table). A 

variant in NCOR1 (ER co-repressor) was associated with decreased risk of 

discontinuation of letrozole because of toxicity. Conclusions: Variants in 

genes involved in estrogen metabolism and signaling may be associated 

with toxicity of AI therapy. 

Statistical model Gene SNP AI HR (95% CI) p value 

Recessive CYP19A1 rs28566535 Either 8.2 (2.7-24.9) �0.0002 

Exe 8.1 (1.6-41) 0.012 

Let 7.5 (1.5-38.1) 0.016 

ESR1 rs9322335 Either 4.2 (2-8.6) �0.0001 

Exe 10.5 (2.9-38.7) �0.0004 

Let 3.3 (1.2-9.1) 0.018 

ESR1 rs9322336 Either 3.7 (1.8-7.4) �0.0004 

Exe 7.2 (2.7-19.5) 0.0001 

Let 3 (1-8.8) 0.050 

Additive NCOR1 rs1065822 Either 0.7 (0.5-0.9) 0.015 

Exe 1.1 (0.7-1.6) 0.77 

Let 0.3 (0.2-0.6) �0.0002 


4:45 PM-5:45 PM 

Impact of adjuvant trastuzumab on outcomes of HER2-positive breast 

cancer patients treated with HER2-targeted therapy in the metastatic 

setting. Presenting Author: Rashmi Krishna Murthy, University of Texas 

M. D. Anderson Cancer Center, Houston, TX 

Background: Trastuzumab (T) was approved for the adjuvant treatment of 

women with early-stage, HER-2 overexpressing (HER2�) breast cancer in 

2006. There are limited data outlining the outcomes of patients with 

HER2� breast cancer who receive adjuvant T-based therapy and then 

receive T and/or lapatinib in the metastatic setting. Methods: We identified 

540 patients with HER2� breast cancer treated with T or lapatinib as part 

of their first-line treatment for metastatic disease from 01/1997 to 

11/2011. HER-2 positivity was assessed by immunohistochemistry (score, 

3�) or fluorescence in situ hybridization (HER2/CEP17 ratio � 2). We 

excluded 17 patients from this analysis because they were either lost to 

follow-up or received less than 2 cycles of therapy at the institution. 

Statistical analyses were performed using the chi-square test to compare 

proportions between groups and the Cox proportional hazards regression 

analysis to compare survival times and estimate the corresponding hazard 

ratio with 95% confidence interval. Results: Of the 523 patients eligible for 

analysis, 76 patients had received T in the adjuvant setting and 447 had 

not. In the group who did not receive adjuvant T, 48% (213/447) of 

patients achieved a complete or partial response (CR/PR), whereas only 

13% (14/76) achieved a CR/PR in the adjuvant T group (P�.0001). After 

adjustment for age, disease-free interval, post-menopausal status, stage at 

presentation, ER/PR status, and nuclear grade, the odds ratio was 0.27 (CI 

0.13 - 0.56, p � 0.0004). Overall survival from first evidence of metastasis 

was significantly longer in the group who did not receive adjuvant T (39 

months vs. 24 months, HR � 1.8, 95% CI 1.3-2.4). For OS, the adjusted 

hazard ratio was 1.5 (CI 1.04 - 2.1, p � 0.029). Age, DFI and stage were 

also significant predictors of OS. Conclusions: Patients with HER2� 

metastatic breast cancer who were T naive, had a higher response rate 

(CR/PR) to front line HER2 targeted therapy and a longer OS compared to 

patients with metastatic HER2� breast cancer who received T in the 

adjuvant setting. These findings highlight the importance of recognizing a 

pre-treated population and calls for further research in this area. 




4:45 PM-5:45 PM 

Results from a phase Ib study of trastuzumab emtansine (T-DM1), 

paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic 

breast cancer (MBC) previously treated with trastuzumab. Presenting 

Author: Shanu Modi, Memorial Sloan-Kettering Cancer Center, New York, 

NY 

Background: The antibody–drug conjugate T-DM1 has shown single-agent 

activity in phase II studies in patients (pts) with HER2–positive MBC. 

Preclinical data suggest synergy for T-DM1 combined with taxanes and with 

P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study 

evaluating the safety and tolerability of T-DM1 (qw and q3w) � T (qw) � P 

(q3w) in pts with HER2-positive MBC previously treated with trastuzumab. 

A3�3 dose-escalation scheme is used for T-DM1 � T to determine the 

maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive 

dose-limiting toxicity (DLT) criteria were modified to establish a more 

clinically relevant MTD. Results: We report interim results with T-DM1 (qw 

and q3w) � T(�P) using modified DLT criteria. 24 pts have been enrolled 

in these cohorts; median age was 53 yrs (range, 23–69)*; median number 

of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below. 

Conclusions: Data support combining T-DM1 � T � P at the MTD for future 

clinical trials. The MTD for weekly T-DM1 � T is 2.4 mg/kg � 80 mg/m2 qw; MTD for weekly T-DM1 � T � P is 2.4 mg/kg � 80 mg/m2 qw � 840 

mg LD, 420 mg q3w. Updated results will be presented, including the MTD 

for T-DM1 q3w � Tqw� P q3w, outcomes from pts with prolonged 

follow-up, and duration of response from an extension trial. 

Dosing † DLTs MTD Gr 3/4 AEs* SAEs* Best response* 

T-DM1 (1.6–2.4 mg/kg qw) � 

T (65–80 mg/m 2 qw) 

4 cohorts 

n�12 

T-DM1 (2.4 mg/kg qw) � 

T (80 mg/m 2 qw) � 

P (840 mg LD, 

420 mg q3w) 

1 cohort 

n�3 

T-DM1 (2.4-3.6 mg/kg q3w) � 

T (65-80 mg/m 2 qw) 

3 cohorts 

n�9 

None 2.4 mg/kg qw � 

T80mg/m 2 qw 

None 2.4 mg/kg qw � 

T80mg/m 2 qw � 

P (840 mg LD, 

mg q3w) 

G3 peripheral neuropathy, 

G3 neuropathy (n�2), 

G3 fatigue (n�2), 

G3 neutropenia (n�3), 

G3 thrombocytopenia, 

G3 sepsis, G3 ulcer 

TBD TBD G3 hypokalemia, 

G4 febrile neutropenia, 

G3 abdominal pain 

G3 sepsis, G3 ulcer 

SD�6 

PR�3 

PR 

unconfirmed�1 

NA�2 

NR NR NA�2 

G4 febrile neutropenia SD�3 

PR 

unconfirmed�1 

NA�4 

*Based on data available from 22 pts as of data cutoff: Jan 24, 2012; NR�none reported; NA�not available. † Pts receiving P 

added to T-DM1 q3w � T qw to be enrolled. 


4:45 PM-5:45 PM 

Phase IB/II study of the HSP90 inhibitor AUY922, in combination with 

trastuzumab, in patients with HER2� advanced breast cancer. Presenting 

Author: Anthony Kong, Churchill Hospital, Oxford University Hospitals 

NHS Trust and University of Oxford, Oxford, United Kingdom 

Background: AUY922 is a novel HSP90 inhibitor that causes degradation of 

oncogenic proteins. A Phase I study in advanced solid tumors gave a 

recommended Phase II dose (RP2D) of 70 mg/m2 . In the Phase II part of 

the study, single-agent AUY922 showed preliminary activity in HER2� 

metastatic breast cancer (mBC) (Schröder et al ASCO 2011). This Phase 

Ib/II study assessed safety and efficacy of AUY922 � trastuzumab (T) in 

pts with T-refractory HER2� advanced/mBC. Methods: Pts with HER2� BC 

(ECOG PS �1) who progressed on 1–2 prior anti-HER2 regimens with at 

least 1 T-containing regimen, received weekly AUY922 (55 or 70 mg/m2 , 

IV) � T (2 mg/kg) in a 28-day cycle. The Phase Ib primary objective was to 

define a MTD/RP2D of AUY922 combined with T using an adaptive 

Bayesian logistic regression model. The Phase II primary objective is to 

evaluate preliminary antitumor activity at this dose (ORR). Secondary 

objectives included evaluation of PK, safety and preliminary efficacy (PFS, 

OS). Results: In the Phase Ib part (11 pts) there was 1 DLT (Grade [Gr] 3 

diarrhea), and the full standard single dose of AUY922 was recommended 

for use in combination with T. As of 11th January 2012, 31 HER2� BC pts 

(median age 51 years [range 29–71]; 84% invasive ductal carcinoma; 

52% estrogen receptor-positive; 81% had received �2 prior antineoplastic 

regimens) received AUY922 at 55 mg/m2 (n�5) or 70 mg/m2 (n�26) � T. 

The most common study drug-related AEs (all Gr) were diarrhea (25 [81%] 

pts), visual AEs (e.g. vision blurred, visual impairment, photopsia) (25 

[81%] pts), and nausea (11 [35%] pts). Gr 3/4 AEs were rare; most 

frequently diarrhea and visual impairment (both 6%). Treatment was 

ongoing for 13 (37%) pts at the cutoff date. Preliminary Phase II best 

overall response data (RECIST, investigator assessed) was available for 22 

pts at AUY922 70 mg/m2 . Any partial responses were reported in 5/22 

(23%) pts. Conclusions: The data suggests AUY922 � T is well tolerated. 

Common AEs were considered manageable, and eye disorders were 

reversible with treatment interruption, dose reduction or discontinuation. 

The combination of AUY922 � T is active in pts with HER2� mBC who 

progressed on T-based therapy, and the regimen warrants further investigation. 


4:45 PM-5:45 PM 

Phase Ib study of open-label AMG 386 plus paclitaxel (P) and trastuzumab 

(T) or capecitabine (C) and lapatinib (L) in patients (pts) with HER2� 

locally recurrent or metastatic breast cancer (MBC). Presenting Author: 

Hans Wildiers, Universitair Ziekenhuis Gasthuisberg, Department of General 

Medical Oncology, Leuven, Belgium 

Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis 

by blocking interaction of angiopoietins 1 and 2 with the Tie2 

receptor. This interim analysis evaluates the tolerability and efficacy of 

AMG 386 � P/T or C/L in HER2� MBC. Methods: In part 1, pts in cohorts 

A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P 

80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in 

cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or 

C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14 

Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg; 

A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were 

expanded to n � 20 if � 1of6or�2 of 9 pts had dose-limiting toxicities 

(DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary 

endpoints included efficacy and pharmacokinetics (PK). Interim results 

from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at 

interim analysis; all received � 1 dose of study treatment (A1, A3, B1; n � 

20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and 

31.3 wks. Across cohorts, there was 1 DLT in A1. AEs � 50% were 

peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined, 

and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), 

and peripheral edema in B1. AEs grade �3 occurring in � 2 pts were 

peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n � 5, 4, 

3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia 

(n � 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1, 

50% in A3, and 50% in B1. Median (95% CI) progression-free survival was 

14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration 

of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not 

evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes 

were apparent in any PK parameters in these combinations relative to 

within study or historical monotherapy PK data. Conclusions: In this 

ongoing phase 1b study of pts with HER2� MBC, interim results suggest 

that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity. 

Updated data will be presented. 


4:45 PM-5:45 PM 

A randomized phase II study (VEG108838) of lapatanib plus pazopanib 

(L�P) versus lapatanib (L) in patients with ErbB2� inflammatory breast 

cancer (IBC). Presenting Author: Massimo Cristofanilli, Fox Chase Cancer 

Center, Philadelphia, PA 

Background: ErbB2 amplification is frequently reported in IBC and there is 

evidence of positive association between ErbB2 and VEGF expression. We 

evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2� IBC. 

Methods: We conducted a multicenter, randomized clinical trial for patients 

(pts) with relapsed ErbB2� IBC. Cohort 1: Pts stratified (prior trastuzumab; 

cutaneous disease only vs systemic) and randomized 1:1 to receive 

L 1500 mg � placebo or L 1500 mg � P 800 mg, QD. Due to high 

incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg� P 800 mg 

in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 

(87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to 

receive L 1500 mg � placebo or L 1000 mg � P 400 mg (double-blind) or 

P 800 mg (open-label), respectively, QD. Treatment continued until PD, 

unacceptable toxicity or death. Primary endpoint was ORR. Secondary 

endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were 

randomized and treated: L, n�38; L�P, n�38. ORR was 29% for the L 

arm, and 45% for the L�P arm. Median PFS was 16.1 and 14.3 wks, 

respectively, for the L and L�P arms. The most frequent Grade �3 AEs 

were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 

8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose 

reductions due to AE were 3% and 21% and dose interruptions due to AE 

were 11% and 55% in the L and L�P arms, respectively. Cohort 2: 88 pts 

were randomized (87 treated): L, n�36; P, n�14; L�P, n�38. The ORR 

was 47%, 31%, and 58% for the L, P, and L�P arms, respectively. Median 

PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L�P arms, 

respectively. The most frequent Grade �3 AEs were ALT increased (0%, 

0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and 

fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 

13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 

39% of pts in the L, P, and L�P arms, respectively. Conclusions: This 

prospective, randomized study confirmed the clinical activity of lapatinib 

single agent in metastatic ErbB2� IBC. Furthermore, we demonstrated 

increased toxicity associated with the combination without a clinically 

meaningful improvement in efficacy. 



4:45 PM-5:45 PM 

Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1) 

following anthracycline-based chemotherapy as adjuvant or neoadjuvant 

therapy for early-stage HER2-positive breast cancer. Presenting Author: 

Chau T. Dang, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: T-DM1 has demonstrated clinical activity as a single agent in 

patients (pts) with previously untreated MBC. In a previous phase II 

randomized trial of T-DM1 vs trastuzumab � docetaxel, T-DM1 had no 

clinically significant cardiac events, no cases of post-baseline left ventricular 

ejection fraction (LVEF) �40%, and fewer grade �3 adverse events 

(AEs; Hurvitz, ESMO 2011). This phase II study assessed the clinical 

safety and feasibility of T-DM1 following anthracycline-based chemotherapy 

in the adjuvant or neoadjuvant setting for early-stage HER2positive 

breast cancer. Methods: TDM4874g (NCT01196052) is a phase II 

single-arm, open-label study of T-DM1 (3.6 mg/kg q3w IV; up to 17 cycles) 

following completion of doxorubicin/cyclophosphamide (AC; q2w or q3w 

for 4 cycles), or 5-fluorouracil/epirubicin (100 mg/m2 )/cyclophosphamide 

(FEC; q3w for 3-4 cycles) chemotherapy in pts with early-stage HER2positive 

breast cancer. Pre-chemotherapy LVEF by MUGA/ECHO �55% 

was required for enrollment. Co-primary endpoints are safety and rate of 

pre-specified cardiac events following initiation of T-DM1 treatment. An 

interim analysis was planned for the first 60 pts evaluable for cardiac safety 

(received �1 T-DM1 dose). Results: For pts in the interim analysis (20 

received AC, 40 FEC), the most common all-grade T-DM1-related AEs were 

nausea (n�20), asthenia (n�17), and headache (n�17); 8 pts had grade 

3/4 T-DM1-related AEs (including 3 with grade 3 increased aspartate 

aminotransferase [AST] and/or alanine aminotransferase [ALT]). No deaths 

occurred. Two pts had AEs leading to T-DM1 discontinuation (grade 3 AST 

and grade 2 ALT increase; grade 3 thrombocytopenia). No pre-specified 

cardiac events occurred; no pts delayed or discontinued T-DM1 due to 

cardiac AEs; there were no reports of grade �2 left ventricular systolic 

dysfunction, heart failure, or LVEF �50%. Results will be updated with 

data from all 153 enrolled pts. Conclusions: T-DM1 following anthracyclinebased 

chemotherapy was not associated with cardiac toxicity in pts with 

early-stage HER2-positive breast cancer; this study continues without 

modification. 


4:45 PM-5:45 PM 

A phase I trial of the IGF-1R antibody IMC-A12 in combination with 

temsirolimus in patients with metastatic breast cancer. Presenting Author: 

Gini F. Fleming, The University of Chicago Medical Center, Chicago, IL 

Background: mTOR plays a critical role in promoting tumor cell growth. In 

preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated 

by feedback up-regulation of AKT mediated by IGF-1R. We designed a 

phase I trial to determine the maximum-tolerated dose (MTD), doselimiting 

toxicities (DLT) and pharmacodynamic effects of the IGF-1R 

antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) 

with metastatic breast cancer (MBC) where mTOR is frequently activated. 

Methods: A3�3 phase I design was chosen. Tem and IMC-A12 were 

administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC 

refractory to standard therapies. Tumor response was evaluated by RECIST. 

Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and 

C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion 

were compared to baseline (BL) using paired t-test. Results: Of 26 pts 

enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid 

condition (1). MTD was determined from remaining 22 pts aged 34-72 

(median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER� 

cancer. Median number of regimens for MBC was 4. Two DLTs at the 

starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), 

then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose 

escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in 

DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, 

neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting � 

4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were 

significantly elevated on d2 (p �0.002) and d8 compared to BL (p 

�0.001), but C-peptide levels were not found to differ from BL. Conclusions: 

The MTD for the combination of IMC-A12 and tem in pts with MBC is lower 

than that observed for single agents alone. A phase II study is ongoing in 

MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, 

N01-CM62205 and N01-CM-2011-00071. 

DL Tem (mg) IMC-A12 (mg/kg) No. DLT 

1 25 3 3 2: gr 2 mucositis with trt delay 

-1 20 3 1 1: gr 3 neutropenia and leukopenia 

-2 15 3 6 1: gr 3 mucositis 

-2A 15 4 6 0 

-2B 15 5 3 1: gr 2 thrombocytopenia with trt delay 

1: gr 3 neutropenia with trt delay 


15s 

533^ Poster Discussion Session (Board #23), Sat, 1:15 PM-5:15 PM and 

4:45 PM-5:45 PM 

Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in 

patients with HER2-positive metastatic breast cancer in the CLEOPATRA 

study. Presenting Author: Michael Ewer, University of Texas M. D. 

Anderson Cancer Center, Houston, TX 

Background: Addition of trastuzumab (T) to chemotherapy has transformed 

outcomes in pts with HER2-positive breast cancer. In pts who had received 

anthracyclines (A), T has been associated with cardiac dysfunction. 

Monitoring cardiac tolerability of anticancer drugs is important, including 

that of a new regimen combining T with a second anti-HER2 antibody that 

inhibits HER2 dimerization, pertuzumab (P). In CLEOPATRA, efficacy and 

safety of P�T�docetaxel (D) were studied in HER2-positive 1st-line MBC 

(Baselga 2012). Methods: CLEOPATRA, a randomized, double-blind, 

placebo-controlled, ph III trial, enrolled 808 pts; 804 were included in the 

safety population. A baseline (BL) LVEF �50%, no history of congestive 

heart failure, and no LVEF decline to �50% during/after prior T were 

required. Treatment was administered q3w until disease progression or 

unmanageable toxicity (P/placebo [Pla]: 840 mg, followed by 420 mg; T: 8 

mg/kg, followed by 6 mg/kg; D [�6 cycles recommended]: 75 mg/m2 , 

escalating to 100 mg/m2 if tolerated). LVEF was assessed by ECHO or 

MUGA at BL, every 9 wks during treatment, at discontinuation, and up to 3 

yrs thereafter. Adverse events (AE) were monitored continuously and 

graded according to NCI-CTCAE v3.0. Results: The incidence of any cardiac 

disorder (grade �1) as assessed by the investigators was similar with 

Pla�T�D (16.4%) and P�T�D (14.5%). LVSD (grade �1) was the most 

frequent cardiac AE and more common with Pla�T�D. At the time of data 

cutoff for this analysis, 8/11 symptomatic LVSD events had resolved; none 

fatal. All pts who developed symptomatic LVSD had �1 potential cardiac 

risk factor (prior A, prior T, radiation, smoking, diabetes, hypertension, 

other). Compared to the overall pt population, only prior A and radiation 

were higher in pts who developed symptomatic LVSD. Conclusions: CLEO- 

PATRA provides evidence that P�T�D does not increase overall cardiac 

disorders, specifically symptomatic LVSD, compared to Pla�T�D. 

n (%) Pla�T�D(n�397) P�T�D(n�407) 

LVSD (grade >1)* 33 (8.3) 18 (4.4) 

Symptomatic LVSD (grade >3)* 7 (1.8) 4 (1.0) 

LVEF decline to 10% points from BL † 

25/379 (6.6) 15/393 (3.8) 

* NCI-CTCAE v3.0. † Pts with post-BL LVEF assessment. 


4:45 PM-5:45 PM 

Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): 

Results from a phase II randomized discontinuation trial (RDT). Presenting 

Author: Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA 

Background: Dysregulation of MET and VEGF signaling has been implicated 

in breast cancer development and progression, including tumor invasion 

and dissemination. Cabozantinib (cabo) is an oral, potent inhibitor of MET 

and VEGFR2. A RDT evaluated activity and safety in 9 tumor types, 

including MBC. Methods: Eligible patients (pts) were required to have 

progressive measurable disease per RECIST. Pts received cabo at 100 mg 

qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed 

q6 wks. Treatment � wk 12 was based on response: pts with PR continued 

open-label cabo, pts with SD were randomized to cabo vs placebo, and pts 

with PD discontinued. Primary endpoint in the randomized discontinuation 

phase was progression-free survival (PFS). Results: Enrollment to this 

cohort is complete (n � 45); all pts are unblinded. Baseline characteristics: 

median age 56; invasive ductal 86%, invasive lobular 7%; ER� 93%, 

HER2� 18%, triple- 5%; visceral disease 91%; bone metastases 73%; 

median prior lines of therapy 3 (range 1-8), including 71% with prior 

anthracyclines. Median follow-up was 2.9 mos (range 0.1 -16). 21 pts 

(47%) completed Lead-in stage with only 9 randomized to continue cabo (n 

� 5) or placebo (n � 4). Median PFS from Study Day 1 was 4.1 mos. At wk 

12, objective response rate was 14% and disease control rate 48%. Tumor 

regression was observed in 25/39 pts (64%) with �1 post-baseline tumor 

assessment. 4/10 pts evaluable by bone scan had partial resolution of bone 

lesions. Of 12 pts receiving narcotics for bone pain, 5 pts reported 

improved pain and 2 pts had decreased narcotics use, per investigator. 

4/14 evaluable pts (29%) with bone metastases experienced �50% 

decline in serum NTx. Most common Grade 3/4 AEs were palmar-plantar 

erythrodyesthesia (13%) and fatigue (11%). One related Grade 5 AE of 

respiratory compromise was reported during the Lead-in stage. Conclusions: 

Cabo demonstrated a 14% rate of objective tumor regression in heavily 

pretreated MBC pts. Observed effects on bone scan and pain are consistent 

with those seen in other malignancies. The safety profile of cabo was 

comparable to that seen with other VEGFR TKIs. 



536 General Poster Session (Board #1A), Sat, 8:00 AM-12:00 PM 

Statin use and the development of bone metastasis in breast cancer 

patients. Presenting Author: Gentry T. King, Albert Einstein Medical 


Background: The Mevalonic Acid Pathway has been implicated in the 

promotion of a microenvironment suitable for establishment of bony 

metastasis from breast cancer. The statins, which act on this pathway, have 

been shown to have in-vitro anti-neoplastic activity against breast cancer. 

This study was designed to evaluate the association of statin use and 

development of bony metastasis in breast cancer patients. Methods: 

Medical records of patients treated for stage II-III breast cancer from 1999 

to 2010 were retrospectively reviewed. Statin use was defined as medication 

use for at least 3 months in patients with no evidence of disease after 

initial diagnosis and treatment. The primary outcome was development of 

metastasis to bone. Secondary outcomes were overall survival, disease free 

survival and other sites of distant metastasis. Results: A total of 841 

patients were included in the study of which 223 used statins. Both 

unadjusted and multivariate analysis adjusted for age, race, grade, stage , 

BRCA status, showed that patients on statins had a significantly lower 

incidence of metastasis to bone (OR 0.49, 95% CI 0.25-0.96, p�0.04). 

Adjusted analysis for other sites showed a trend towards decreased 

incidence of metastasis for statin users, but was not statistically significant 

(95% CI 0.39-1.08, p�0.10). Overall survival was increased in statin 

users with mean survival of 66.45 �/- 2.48 months versus non-users 

58.78 �/ - 1.41 months (p�0.05). Statin users had significantly longer 

disease free survival with a mean of 63.65 �/- 2.49 months versus 53.96 

�/- 1.42 months in non statin users (p�0.00). Conclusions: The use of 

statin drugs in patients with breast cancer was significantly associated with 

decreased incidence of metastasis to bone, but not to other distant sites. 

The role of statins in chemoprevention of bone metastasis should be further 

explored. 

538 General Poster Session (Board #1C), Sat, 8:00 AM-12:00 PM 

Randomized trials of adjuvant tamoxifen versus tamoxifen and octreotide 

LAR in early-stage breast cancer: NCIC CTG MA.14 and NSABP B-29. 

Presenting Author: Judy-Anne W. Chapman, NCIC Clinical Trials Group, 

Queen’s University, Kingston, ON, Canada 

Background: MA.14 and B-29 examined whether the addition of Octreotide 

(SMS 201-995 pa LAR; OCT) to 5 years adjuvant tamoxifen (TAM) 

prolonged disease-free survival (DFS). Excessive gallbladder (GB) toxicity 

in B-29 led to DMC recommended stopping of OCT and MA.14 shortening 

of OCT to 2 years. Data for the 2 trials were pooled. Methods: Median 

follow-up of the 667 MA.14 patients was 9.8 years, and of the 893 B-29 

patients, 6.8 years for ITT analysis. The primary endpoint was DFS, defined 

as time from randomization to time of (local, regional or distant) breast 

cancer recurrence; any second primary cancer other than squamous or 

basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular 

carcinoma in situ of the breast; or death. The primary test statistic was a 

pooled stratified log-rank test, with stratification within each trial by 

applicant stratification factors. Multivariate assessment was with Cox 

regression. Results: MA.14 patients were all postmenopausal with 97% 

�50 years of age while 62% of B-29 women were �50. 53% of MA.14 

patients were lymph node negative (LN-), while all of B-29 patients were 

LN-. 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, 

while 53% of B-29 received concurrent chemotherapy. 90% of 

MA.14 patients were hormone receptor positive while 100% of B-29 were 

positive. MA.14 patients experienced a 5 year DFS rate of 80% on TAM and 

76% on TAM�OCT, while B-29 patients had a 5 year rate of 88% for both 

arms. The pooled 5 year rates were 85% and 83%. Pooled univariate 

stratified Cox HR of TAM�OCT to TAM was 0.99 (95% CI 0.81-1.20; 

p-value� 0.69). The HR for MA.14 was 0.93 (0.72-1.19; p� 0.50) and for 

B-29 was 1.09 (0.80-1.50; p�0.59). Multivariate pooled HR of TAM�OCT 

to TAM was 0.98 (0.81-1.20; p�0.84). Patients who were older 

(p�0.0006), and had higher T stage (p�0.0001) with LN� (p�0.0008) 

had shorter DFS. Conclusions: OCT did not significantly improve DFS for 

women who were a broad spectrum of patients: pre- or post-menopausal, 

LN- or LN�, and received sequential, concurrent or no adjuvant chemotherapy. 

Neither study had the intended duration of OCT due to GB toxicity; 

thus, the results do not negate targeting the insulin - IGF-I receptor family. 

537 General Poster Session (Board #1B), Sat, 8:00 AM-12:00 PM 

ACE inhibitors and angiotensin receptor blockers use and breast cancer 

outcomes in patients treated with neoadjuvant systemic chemotherapy. 

Presenting Author: Young Kwang Chae, University of Texas M. D. Anderson 


Background: There is a growing body of evidence to suggest that ACE 

inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) might have 

anti-tumor properties. We investigated whether the use of ACEI/ARBs 

during chemotherapy affects the clinical outcomes of breast cancer 

patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. 

Methods: We included in this analysis 1449 patients with 

diagnosis of invasive primary breast cancer diagnosed at the MD Anderson 

Cancer Center between 1995 and 2007 who underwent neoadjuvant 

chemotherapy. Of them, 160 (11%) patients were identified by review of 

their medical record, as ACEI/ARBs users. We compared pathologic 

complete response (pCR) rates, relapse-free survival (RFS), diseasespecific 

survival (DSS) and overall survival (OS) between ACEI/ARB users 

and non-users. pCR was defined as no evidence of invasive carcinoma in 

the breast and axillary lymph nodes at the time of surgery. Descriptive 

statistics and Cox proportional hazards model were used in the analyses. 

Results: There was no difference in the pCR rates between ACEI/ARB users 

(16%) versus non-users (18.1%) (p�0.50). After adjustment for important 

demographic and clinical characteristics, no significant differences between 

ACEI/ARB users and nonusers were observed in RFS (HR�0.81; 

95% CI�0.54-1.21; P�0.30), DSS (HR�0.83; 95% CI�0.52-1.31; 

P�0.42), or OS (HR�0.91; 95% CI �0.61-1.37; P�0.66). In a subgroup 

analysis among ARB users, the 5-year RFS was 82% vs 71% in ACEI/ARB 

non-users (P�0.03). In the multivariable analysis, ARB use was also 

associated with a decreased risk of recurrence (HR�0.35; 95% CI�0.14- 

0.86; P�0.02). However, no statistically significant differences in DSS or 

OS were seen. Conclusions: No differences in pCR and survival outcomes 

were seen between ACEI/ARB users and non-users among breast cancer 

patients receiving neoadjuvant chemotherapy. ARB use may be associated 

with improved RFS. Further research is needed to validate this finding. 

539 General Poster Session (Board #1D), Sat, 8:00 AM-12:00 PM 

BOLERO-2: Health-related quality-of-life in metastatic breast cancer 

patients treated with everolimus and exemestane versus exemestane. 

Presenting Author: J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, 

AR 

Background: BOLERO-2, a phase III study, randomized 724 patients with 

hormone-receptor–positive metastatic breast cancer, who had recurrence 

or progression on/after prior nonsteroidal aromatase inhibitor therapy, to 

everolimus (EVE) plus exemestane (EXE) or EXE and placebo. A preplanned 

12-month median time interim analysis demonstrated that EVE�EXE 

significantly improved progression-free survival (PFS) vs EXE�placebo but 

that EVE�EXE resulted in a higher rate of grade 3/4 toxicity. Per-protocol 

patient reported health-related quality-of-life (HRQoL) data are limited; 

here we report on additional post-hoc analyses of these outcomes. Methods: 

Using the EORTC–QLQ-C30 questionnaire, HRQoL was assessed at baseline 

and every 6 weeks thereafter until progression. The QLQ-C30 consists 

of 30 items combined into 15 subscales, including a Global Health Status 

(GHS) where higher scores (range 0 to 100) indicate better HRQoL. This 

analysis included a protocol-specified time to definitive deterioration (TTD) 

analysis at a 5% decrease in QoL relative to baseline, with no subsequent 

increase above this threshold. We report additional sensitivity analyses 

using 10-point minimally important difference (MID) decreases in QLQ- 

C30 score relative to baseline. Treatment arms were compared using a 

stratified logrank test and a Cox proportional hazards model adjusted for 

trial stratum (visceral metastases and previous hormone sensitivity), age, 

sex, race, baseline score and ECOG performance status, prognostic factors, 

and treatment history. Results: Baseline QLQ-C30 GHS scores were not 

statistically significantly different across treatment groups (64.7 vs 65.3; 

difference -0.7 [95% CI; -4.3, 3.0]). The median TTD in HRQoL was 7.0 

months (95% CI; 5.6, 8.3) for EVE�EXE vs 5.6 (95% CI; 4.2, 7.0) for EXE 

(P � .0792). Adjusted HR (0.80) approached significance (95% CI; 0.63, 

1.02). At the 10-point MID, median TTD for EVE�EXE was 9.7 months 

(95% CI; 8.3, 11.2) vs 8.4 months (95% CI; 6.3, 12.5) for EXE. Adjusted 

HR was 0.90 (95% CI; 0.69, 1.18). Conclusions: These additional analyses 

demonstrate that in addition to significantly improving PFS, EVE�EXE 

does not compromise HRQoL. 


540 General Poster Session (Board #1E), Sat, 8:00 AM-12:00 PM 

BOLERO-2: Everolimus with exemestane versus exemestane alone in Asian 

patients with HER2-negative, hormone receptor-positive breast cancer. 

Presenting Author: Shinzaburo Noguchi, Osaka University, Department of 

Breast and Endocrine Surgery, Osaka, Japan 

Background: Estrogen-receptor–positive (ER�) breast tumors can become 

refractory to aromatase inhibitor (AI) therapy. The mTOR pathway plays a 

critical role in hormone-resistant advanced breast cancer (ABC). Accordingly, 

the addition of everolimus (EVE) to exemestane (EXE) was evaluated 

in an international, phase III study (BOLERO-2) in patients with ER� aBC 

refractory to letrozole or anastrozole. This report presents updated analyses 

from the population of Asian patients enrolled in this study. Methods: 

Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 

mg/day) or with matching placebo. The primary endpoint was progressionfree 

survival (PFS). Secondary endpoints included overall survival, response 

rate, quality of life, and safety. Results: EVE � EXE significantly 

improved PFS versus EXE alone (HR � 0.44; 95% CI, 0.36-0.53; P � 

.0001) in the overall study population at median follow-up of 12.5 months. 

Of 143 patients of Asian origin (n � 106; 74% Japanese) enrolled in this 

study, 98 received EVE � EXE and 45 received EXE � placebo. At the time 

of database lock, 55 Asian patients (56%) in the combination arm had 

experienced disease progression compared with 34 patients (76%) in the 

EVE � placebo arm. Combination therapy reduced the risk of disease 

progression versus EXE alone by 44% among Asian patients (HR � 0.56; 

95% CI, 0.37-0.87; P � .05). Commonly reported adverse events in the 

combination arm were consistent with previous clinical studies of mTOR 

inhibitors and included stomatitis (80%), rash (49%), dysgeusia (31%). 

Adverse events that occurred more frequently in the Asian subset versus 

Caucasians included stomatitis (80% vs 54%) and rash (49% vs 37%), 

whereas dyspnea (8% vs 24%) and asthenia (1% vs 17%) occurred less 

frequently in the Asian subset versus Caucasians. Conclusions: The addition 

of EVE to EXE significantly prolonged PFS in Asian patients versus EXE 

alone. Adverse events were higher in the combination arm but generally 

manageable. Combining EVE with an AI is a safe and effective treatment 

option for Asian women with non-steroidal AI resistant/refractory ER� ABC. 

542 General Poster Session (Board #1G), Sat, 8:00 AM-12:00 PM 

Impact of the EndoPredict-clin score on risk stratification in ER-positive, 

HER2-negative breast cancer after considering clinical guidelines. Presenting 

Author: Martin Filipits, Institute of Cancer Research, Comprehensive 

Cancer Center, Medical University of Vienna, Vienna, Austria 

Background: Many ER-positive, HER2-negative breast cancer patients are 

treated by adjuvant chemotherapy according to current clinical guidelines. 

We retrospectively assessed whether the combined gene expression/ 

clinicopathological EndoPredict-clin (EPclin) score improved the accuracy 

of risk classification in addition to considering clinical guidelines. Methods: 

Three clinical breast cancer guidelines (National Comprehensive Cancer 

Center Network (NCCN), German S3 and St. Gallen 2011), and the EPclin 

score - assessed by quantitative RT-PCR in formalin-fixed paraffinembedded 

tissue - were used to assign risk groups in 1,702 ER-positive, 

HER2-negative breast cancer patients from two randomized phase III trials 

(Austrian Breast and Colorectal Cancer Study Group 6 and 8) treated with 

endocrine therapy only. Results: Although all analyzed clinical guidelines 

identified a low-risk group with improved metastasis-free survival, the 

overwhelming majority of all patients (81-94%) were classified as intermediate 

/ high risk. In contrast to that, the EPclin classified only 37% of all 

patients as high risk and that stratification resulted in the best separation 

between low and high risk groups (p � 0.001, HR � 5.11 (3.48-7.51). 

Consequently, the majority of all patients deemed intermediate / high risk 

by the clinical guidelines was re-classified as low risk by the EPclin score. 

Kaplan Meier analyses demonstrated that the re-classified subgroups (47 

to 57% of all patients) had an excellent 10-year metastasis-free survival of 

95% comparable to the clinical assigned low-risk groups although encompassing 

a higher proportion of the trial patients. Conclusions: The EPclin 

score predicted distant recurrence more accurately than all three clinical 

guidelines and is especially useful to reclassify patients considered as 

intermediate / high risk by the guidelines. The data suggests that the EPclin 

score provides clinically useful prognostic information beyond common 

clinical guidelines and can be used to accurately identify the clinically 

relevant group of patients who are adequately and sufficiently treated with 

adjuvant endocrine therapy alone. 


17s 

541 General Poster Session (Board #1F), Sat, 8:00 AM-12:00 PM 

Response pattern in 844 patients with infiltrating lobular carcinoma (ILC) 

of the breast after neoadjuvant chemotherapy. Presenting Author: Cristina 

Pirvulescu, Helios Klinikum Berlin-Buch, Berlin, Germany 

Background: Patients (pts) with infiltrating lobular carcinoma (ILC) have a 

different response to neoadjuvant chemotherapy compared to patients with 

non-lobular carcinoma (NLC). The aim of our analysis was to characterize 

correlates of the outcome impact of neoadjuvant chemotherapy in ILC and 

to compare those with NLC. Methods: Between 1998 and 2006; 6377 

breast cancer patients were enrolled to 7 randomized neoadjuvant chemotherapy 

trials in Germany. For 6205 (98.3%) pts the histological type was 

available. 844 (13.6%) were classified as ILC, 5361 (86.4%) were 

classified as NLC. Endpoints of the analyses were: pathological complete 

response (pCR) defined as no invasive and no in-situ residuals in the breast 

and the lymph nodes, type of surgery, disease-free (DFS), local recurrence 

(LRFS) and overall survival (OS). Results: ILC was associated with older age, 

larger tumor size, negative nodes, lower grading, and hormone receptor 

(HR) positivity (all p�0.0001). The majority of pts with ILC were HR 

positive (717 pts, 86.9%) and had G1-G2 tumors (603 pts, 78.6%). 

Patients with ILC had a significant lower pCR rate than pts with NLC (pCR 

6.04% vs. 16.4%, p�0.001). In the ILC group, pts with HR positive, 

triple-negative and HER2-positive tumors had a pCR rate of 5%, 18.3% 

and 9.2%, respectively. One of 35 pts with G1 and HR positive ILC had a 

pCR. Breast conservation therapy (BCT) in pts with pCR was 72.5% in the 

ILC group and 85.5% in the NLC group (p�0.0001). Predictors for pCR in 

the multivariate analysis were for ILC: patient age, grading and HR status. 

ILC pts had a significantly longer LRFS compared to NLC pts (with or 

without pCR after neoadjuvant chemotherapy, mean 112 months 95%CI 

[109.7-115.7] vs. 106 months 95%CI [104.4-107.4], p�0.002). 

Conclusions: In patients with ILC age, grading and HR status were 

predictive for pCR. Pts with ILC have a more favourable outcome after 

neoadjuvant chemotherapy despite a significantly lower pCR rate compared 

to pts with NLC. 


Interpathologists discrepancies in Ki67 assessment in the PACS01 trial: 

An independent prognosis factor. Presenting Author: Frederique Madeleine 

Penault-Llorca, Centre Jean Perrin, Clermont-Ferrand, France 

Background: Several reports suggest an inter-observer variability in Ki67 

assessment. Nevertheless, there is no large study that evaluates the rate of 

discrepancies, together with their impact. Methods: Ki67 expression was 

assessed on 663 samples from patients with ER-positive breast cancers 

included in the PACS01 trial (Roche, J Clin Oncol, 2006). Ki67 staining 

was done using MiB1 antibody (Dako, Copenhagen, Denmark, Dilution 

1:250). Prognostic and predictive values have been reported previously 

(Penault-Llorca, J Clin Oncol, 2009). A second central review was done by 

a senior breast pathologist from a French Cancer center. A discrepancy was 

defined as either a false positive or false negative result. Cut-off for 

positivity was defined at 15% according to data from Cheang et al (JNCI, 

2009). Results: The rate of discrepancy was correlated with the percentage 

of stained tumor cells. A 10% discrepancy rate between the 2 pathologists 

was observed when the first pathologist reported �10% tumor cells 

stained. Same low rate of discrepancy (10%) was observed if more than 

30% cancer cells were stained according to the first assessment. At the 

opposite, discrepancy rates were 47%, 45%, 22%, 34% when the first 

pathologist reported 10-15%, 15-20%, 20-25% and 25-30% tumor cells 

stained. Overall, 36% of the patients presented a grade II tumor together 

with Ki67 �10% or �30%. We then evaluated the impact of discrepancy 

in terms of prognosis. Patients presenting a concordant result between the 

two pathologists showed a better outcome as compared to patients 

presenting a discrepancy, independently to the percentage of tumor 

stained (p�0.05, patients with concordant Ki67 ranged between 10-30% 

versus those with one reader �10% and the other one �10%-�30%). 

Conclusions: Discrepancy rates between pathologists are acceptable when 

Ki67 is either �10% or �30%. A Ki67 ranged between 10 and 30% could 

define a grey zone in which Ki67 should be reported with caution or be 

double checked by another pathologist. Survival analysis suggested that 

inter-observer discrepancies could act a prognostic factor. Such finding 

could reflect underlying intra-tumor heterogeneity. 




A dendritic metagene that predicts prognosis and endocrine resistance in 

breast cancer. Presenting Author: Bianchini Giampaolo, Fondazione San 

Raffaele del Monte Tabor, Milan, Italy 

Background: High expression of dendritic-associated genes in estrogen 

receptor-positive (ER�), highly proliferative breast cancer is associated 

with good prognosis in untreated patients (pts) and poor response to 

neoadjuvant endocrine therapy (Dunbier SABCS 2010). We examined the 

prognostic and predictive value of a dendritic metagene (DM) signature in 

subgroups defined by proliferation and estrogen-related genes (Bianchini 

SABCS 2011). Methods: We evaluated Affymetrix HGU133A-based gene 

expression profiles from ER� untreated (n�511) and adjuvant tamoxifen 

(TAM)-treated pts (n�606). Three previously defined scores were assessed: 

MKS for proliferation (Bianchini, Cancer Res 2010); estrogenrelated 

score (ERS) adopted from Oncotype DX; and DM (Bianchini JCO 

2010). Median cut-off points were used. Outcome was assessed according 

to distant relapse. Results: DM was significantly predictive for early (within 

5 years) relapse. In TAM-treated pts with low-MKS tumors, DM was not 

significantly prognostic. The table shows hazard ratios (HRs) for low vs. 

high-DM by ERS in untreated and TAM-treated pts with high-MKS. In 

low-DM, the 5-yrs distant-event free survival was 92.3% and 60.6% (HR 

6.58 (2.55-17.0); p�0.001) and in high-DM it was 80.7% and 79.8% 

(HR 1.06 (0.48-2.32); p�0.88), respectively in high and low-ERS 

respectively. The interaction between DM and ERS was significant only in 

TAM-treated tumors (p�0.003). In high-MKS/low-ERS tumors, DM retained 

significance over the 10-year period in multivariate analysis adjusting 

for clinical variables (HR� 2.27 (1.13-4.58); p�0.02). Conclusions: 

For high-MKS, untreated and TAM-treated tumors with low-ESR, high-DM 

is associated with a low risk of relapse, and for untreated tumors with 

high-ERS. These data suggest that high infiltration of tumor by dendritic 

cells may be a novel mechanism of endocrine resistance. DM could refine 

risk in poor prognosis ER� tumors and rationalize immuno-modulating 

strategies. 

Untreated/high MKS TAM-treated/high MKS 

>High-ERS No.of pts/events HR (CI 95%) p No.of pts/events HR (CI 95%) p 

Low 

(vs high-DM) 

116/21 2.9 (1.1-7.9) 0.039 127/15 0.4 (0.1-1.1) 0.067 

Low-ERS Low 

(vs high-DM) 

169/64 3.0 (1.8-5.0) �0.0001 175/46 2.3 (1.3-4.2) 0.007 


Adjuvant capecitabine for invasive lobular/mixed early breast cancer (EBC): 

USON 01062 exploratory analyses. Presenting Author: Joyce 

O’Shaughnessy, Baylor Sammons Cancer Center, Texas Oncology, US 

Oncology, Dallas, TX 

Background: Randomized phase III USON 01062 trial determining if 

patients with EBC would benefit from addition of capecitabine to docetaxel 

after AC (AC-T vs AC-XT). AC-T: docetaxel 100mg/M2 IV; AC-XT: docetaxel 

75mg/M2 IV with capecitabine 825mg/M2 PO BID 14/7 days every 21days 

for 4 cycles. The primary endpoint, improvement in disease-free survival 

(DFS) at 5 years, was not met (HR�0.84, p�0.12) likely due to 

lower-than-expected event rate. The secondary endpoint, overall survival 

(OS), was improved with capecitabine (HR 0.68, p�0.01) (O’Shaughnessy, 

J. ASCO, 2011). Methods: Molecular analyses demonstrate that pleomorphic 

lobular (mixed lobular/ductal) carcinomas evolve from the same 

precursor and/or through the same genetic pathway as classical lobular 

cancers (Reis-Filho, J., J Path, 2005). We conducted exploratory analyses 

to evaluate the addition of adjuvant capecitabine in ductal vs lobular or 

lobular/ductal (mixed) EBC within USON 01062. Histology was classified 

according to local pathology assessment on patients’ primary cancers. 

Results: In ductal patients (n�2195), there was no difference in DFS 

(HR�0.92, p�0.48) and OS (HR�0.75, p�0.07) with AC-T vs AC-XT. In 

lobular/mixed patients (n�355), adding capecitabine improved DFS 

(HR�0.55, p�0.055) and OS (HR�0.38, p�0.04). There was no difference 

in DFS (HR�1.004, p�0.98) in the ER� ductal patients (n�1258) 

with the addition of capecitabine. Conclusions: Ductal and lobular cancers 

have distinct histologic and molecular characteristics; lobular cancers are 

generally less sensitive to chemotherapy (Cristofanilli, M. JCO, 2005). This 

exploratory analysis suggests that patients with lobular/mixed EBC may 

benefit from adjuvant capecitabine. This hypothesis requires evaluation in 

other adjuvant capecitabine trials. 

Hazard ratio by disease histology in patients with different treatment. 

End point Treatment 

Events in ductal 

n�2,195 (%) 

Events in lobular/mixed 

n�355 (%) HR P value 

DFS All patients 254 (11.6) 43 (12.1) 1.003 0.98 

AC-T 132 (12.0) 27 (15.3) 1.25 0.30 

AC-XT 122 (11.1) 16 (8.9) 0.75 0.28 

OS All patients 156 (7.1) 21 (5.9) 0.80 0.33 

AC-T 89 (8.1) 15 (8.5) 1.02 0.95 

AC-XT 67 (6.1) 6 (3.4) 0.52 0.13 


A meta-analysis of receptor status discordance between primary breast 

cancer and metastases. Presenting Author: Gaetano Aurilio, European 

Institute of Oncology, Medical Oncology, Milan, Italy 

Background: There is an increasing awareness that biology of breast cancer 

may evolve over time. The discordance in estrogen (ER), progesterone 

(PgR) and HER2 receptor status between primary breast cancer and 

metastases is being intensively investigated and a large amount of data has 

been produced. However, results from different studies seem to be 

conflicting and heterogeneous. To highlight this issue, a meta-analysis of 

published data was performed. Methods: A literature search was performed 

with Medline. All studies published from 1983 to 2011 comparing 

changes inER, PgR and/or HER2 status in patients with matched breast 

primary and recurrent tumors were included. We used random-effects 

models to estimate pooled discordance proportions. Results: We selected 

42 articles, mostly reporting retrospective studies. Twenty-eight, 20 and 

27 articles were focused on ER, PgR and HER2 changes, respectively. A 

total of 2806 tumors were evaluated for ER discordance, 1809 for PgR 

discordance and 2801 for HER2 discordance. The heterogeneity between 

study-specific discordance proportions was high (I2 �75%, p�0.0001) for 

ER, PgR and HER2. Pooled discordance proportions were 20% (95% CI: 

16-25%) for ER, 33% (95% CI: 28-38%) for PgR and 9% (95% CI: 

6-12%) for HER2. Pooled proportions of tumors shifting from positive to 

negative and from negative to positive were 24% and 12% for ER 

(p�0.0115), respectively. The same figures were 44% and 15% for PgR 

(p�0.0001), and 14% and 6% for HER2 (p�0.04). Conclusions: To our 

knowledge, this is the first meta-analysis addressing this topic. The findings 

strengthen the concept that changes in receptor expression may occur 

during the natural history of breast cancer and therefore clinical implications 

with possible impact on treatment choice cannot be excluded. 

However, the high heterogeneity observed in our analysis may explain the 

disagreement among oncologists on performing a reassessment of the 

biological features. In our opinion, only high-powered prospective and 

randomized trials could clarify the controversies in this field. 


Bisphosphonates in the adjuvant setting of breast cancer therapy: Effect on 

survival—A systematic review and meta-analysis. Presenting Author: Liath 

Vidal, Davidoff Center, Rabin Medical Center, Petach Tikva, Israel 

Background: The role of bisphosphonates (BP) in the adjuvant setting in 

breast cancer has been evaluated in several studies, yielding inconsistent 

evidence. We performed a systematic review and meta-analysis of all 

randomized controlled trials (RCTs) that evaluate the effects of BP 

treatment on survival in patients with early breast cancer in the adjuvant 

setting. Methods: RCTs that compared BP therapy in addition to the 

standard adjuvant therapy (cytotoxic or hormonal) with standard adjuvant 

therapy only were identified by searching the Cochrane Library, LILACS, 

MEDLINE databases and conference proceedings (12.2011). Hazard 

ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative 

risks of adverse events were estimated and pooled. All statistical tests were 

two-sided. Results: Thirteen trials met the inclusion criteria., among which 

are the two recently published abstracts of large scale RCTs (NSABP-B34, 

GAIN) evaluating a total of 15,762 patients. Ten trials reported the OS 

outcome. Meta-analysis revealed no statistically significant benefit for BP 

(HR 0.89, 95% CI � 0.79 to 1.01). Nine trials reported the DFS outcome. 

Meta-analysis revealed no statistically significant better DFS for the 

intervention (HR 0.95 (0.80-1.11)). Six trials reported DFS stratified upon 

menopausal status. Postmenopausal patients who were treated with BP 

therapy had statistically significant better DFS than the control group (HR 

0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated 

with HR of OS (coefficient, -0.23; standard error, 0.144). BP 

therapy resulted in less fractures in the intervention arm, but higher 

incidence of osteonecrosis of the jaw and pyrexia. Conclusions: Our 

meta-analysis indicates a positive effect for adjuvant BP on survival 

outcomes only in postmenopausal patients with breast cancer. Metaregression 

appraised the effect of confounders such as chemotherapy, 

showed a negative association between chemotherapy use and the effect of 

bisphosphonates on survival. Further large scale RCTs are warranted to 

unravel the specific subgroups and adjuvant treatments that would benefit 

from the addition of BP in the adjuvant setting. 


549^ General Poster Session (Board #2G), Sat, 8:00 AM-12:00 PM 

A prospective clinical utility study of the impact of the 21-gene recurrence 

score assay (Oncotype DX) in estrogen receptor positive (ER�) node 

negative (pN0) breast cancer in academic Canadian centers. Presenting 

Author: James Ashley Davidson, British Columbia Cancer Agency (Fraser 

Valley Centre), Surrey, BC, Canada 

Background: The Oncotype DX 21-gene Recurrence Score assay (RS) can 

potentially predict the magnitude of chemotherapy benefit in patients with 

stage I-II, node-negative, ER� disease who will be treated with tamoxifen 

for 5 years. While use in the United States has grown significantly since its 

introduction, it is not yet routinely ordered by oncologists in most parts of 

Canada. The primary purpose of this study was to measure the impact of the 

Oncotype DX test on the physician’s treatment recommendation in ER� 

pN0 breast cancer in British Columbia. Methods: After providing informed 

consent, patients and medical oncologists completed respective pre-RS 

questionnaires indicating their treatment preferences and level of confidence 

and a decisional conflict scale (patients only). At a subsequent visit, 

after the RS result was known and discussed, the patient and oncologist 

completed a second set of questionnaires. The proportion of physician 

treatment recommendations that changed from baseline to follow-up (post 

RS) were calculated with 95% confidence interval (CI). A prospective 

health economic (HE) analysis was also performed. Results: From May 

2010 to July 2011, two participating BCCA centres enrolled 156 patients. 

Of the 150 for whom successful RS assay results were obtained, physicians 

changed their chemotherapy recommendation in 45 cases (30%; 95% CI 

22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% 

CI 13.9-27.3%) adjuvant chemotherapy. As a secondary end-point, in 84 

cases (56%; 95% CI 47.7-64.1%) there was a change in either the 

planned chemo and/or endocrine therapy recommendation. There was an 

overall significant improvement in physician confidence post RS (p � 

0.001). Patient decisional conflict also significantly decreased following 

the RS assay (p � 0.001). The HE analysis is ongoing and will be presented 

separately. Conclusions: Within the context of a publicly funded health care 

system, the RS assay significantly affects adjuvant treatment recommendations 

in ER� node negative breast cancer, in addition to reducing patient 

decisional conflict. 


Safety of everolimus for women over 65 years of age with advanced breast 

cancer (BC): 12.5-mo follow-up of BOLERO-2. Presenting Author: Kathleen 

I. Pritchard, Sunnybrook Odette Cancer Centre, University of Toronto, 

Toronto, ON, Canada 

Background: Postmenopausal women with estrogen-receptor–positive (ER� ) 

BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are 

usually treated with the steroidal AI exemestane (EXE); but there is no 

currently approved treatment for this indication. The BOLERO-2 trial 

showed that adding everolimus (EVE), an oral inhibitor of mammalian 

target of rapamycin (mTOR), to EXE significantly improved clinical benefit 

beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). 

As many women with advanced BC are elderly, the tolerability profile of EVE 

� EXE in this population is of interest. Methods: BOLERO-2 is a phase III, 

randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO), 

both plus EXE (25 mg once daily) in postmenopausal women with advanced 

ER� BC progressing or recurring after NSAIs. Safety data with a focus on 

elderly patients are reported at 12.5 mo median follow-up. Results: 

Baseline disease characteristics, age, and prior cancer therapy were well 

balanced between treatment arms (N � 724). At 12.5 months’ median 

follow-up, the addition of EVE to EXE significantly improved progressionfree 

survival in patients �65 (HR � 0.37; P � .05) or �65 years of age (HR 

� 0.56; P � .05). Adverse events (AEs) of special interest (all grades) 

occurring more frequently with EVE vs PBO (overall study population) 

included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash 

(44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia 

(15.4% vs 2.5%). Elderly EVE-treated patients (�65 years) had similar or 

marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis 

(14.6%), and hyperglycemia (12.5%) compared with the overall 

population. Grade 3/4 AEs in patients �70 years of age (n � 161) reported 

only among patients receiving EVE (n � 118) included fatigue (10.2%), 

anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea 

(6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). 

Conclusions: Adding EVE to EXE was well tolerated in the overall population 

and in elderly patients with advanced BC; grade 3/4 AEs were uncommon 

and manageable. Overall, AEs were consistent with the known safety profile 

of EVE. 


19s 


CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in 

breast cancer patients taking tamoxifen. Presenting Author: Bavanthi 

Balakrishnar, Westmead Hospital, University of Sydney, Sydney, Australia 

Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen 

is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The 

CYP2D6 gene is highly polymorphic with a number of relatively common 

reduced function alleles. The aim of this study was to determine whether 

plasma endoxifen levels were reflected by CYP2D6 genotype or adverse 

effects in individuals taking tamoxifen. Methods: Plasma endoxifen was 

measured by High Performance Liquid Chromatography / Mass Spectroscopy 

in 90 breast cancer patients taking 20mg tamoxifen per day. Ten 

CYP2D6 single nucleotide polymorphisms were assessed to designate four 

putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), 

intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and 

adverse effects were documented. The study was part of an ongoing 

Australian trial of tamoxifen dose escalation. Results: There was marked 

variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 

14.3). Endoxifen levels were significantly associated with metabolizer 

categories (p�0.001, r� -0.44), but were not distinctive between categories. 

For example, in the EM category (n�46) endoxifen levels ranged from 

3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 

nM) substantially overlapping the PM category (n�11); 6.1-24.7 nM. 

Consistent with an impact of non-CYP2D6 genotype related factors on 

endoxifen levels, endoxifen was significantly lower in 18 patients taking 

CYP2D6 inhibitor medications (p�0.005). There was no association 

between endoxifen levels and vasomotor symptoms or other adverse effects 

of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients 

taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or 

adverse effects. Therapeutic monitoring of endoxifen levels may be a useful 

approach to assess tamoxifen activity. 


Prospective comparison of recurrence score and independent central 

pathology assessment of prognostic tools in early breast cancer (BC): Focus 

on HER2, ER, PR, Ki-67 results from the phase III WSG-Plan B trial. 

Presenting Author: Oleg Gluz, West German Study Group, Moenchengladbach, 

Germany 

Background: Use of multi-gene real-time PCR (RT-PCR) based assays e.g. 

Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR, 

HER2, KI-67) is currently controversially discussed in early BC. Here, we 

present the final WSG-planB trial correlation analysis of risk assessment 

tools and first prospective comparison of independent central pathology 

IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial 

(n�2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS 

has been used as selection criterion for cht omission in HR� BC (if RS�11 

in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2 

(IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in 

all tumors. Results: From 04/09 to 11/11, 3196 patients have been 

recruited and 2448 randomized. RS distribution in 2551 HR� tumors: 

0-11 (18%), 12-25 (60%), �25 (22%). In 354 pN0-1 patients, cht was 

omitted based on low risk RS (88% compliance). Central grade for n�3038 

and IHC/FISH results are currently available in n�1476. Moderately 

significant correlations were only found between RS and both central grade 

(rs�0.313; p�0.001) as well as Ki-67 (rs�0.374; p�0.001) and a weak 

one for uPA/PAI-1, particularly due to poor correlations within the RS group 

�26. In 1476 locally HER2- cases, n�9 were found as 3� and/or FISH� 

by central analysis. In 6 HR�/HER2� cases, RS revealed 2 positive, 2 

equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR 

central pathology revealed 4 negative results. 24 locally HR� cases are 

assessed as HR- in central pathology (2%). Among these, 6 were ER 

positive by RT-PCR. Final correlation analyses will be presented at the 

meeting. Conclusions: These first prospective data demonstrate that highrisk 

status according to RS is predictive of high risk by other factors, but the 

converse is not true. Regarding controversial HER2 and HR status by 

RT-PCR and IHC/FISH, we found few cases with false-negative or positive 

RT-PCR results in HER2- BC by local pathology. However, these discrepancies 

could potentially have a substantial impact on clinical patient 

management. 




Cost-effectiveness of zoledronic acid (ZOL) in postmenopausal women with 

early breast cancer receiving adjuvant letrozole. Presenting Author: Mei 

Xue, Pharmerit North America, LLC, Bethesda, MD 

Background: In the ZO-FAST trial, postmenopausal women with early breast 

cancer and a bone mineral density (BMD) T-score � –2 and receiving 

adjuvant letrozole (2.5 mg/day) were randomized to either immediate ZOL 

(4 mg/6 months) treatment (upfront ZOL) or to the same therapy but only 

when BMD T-score decreased to � –2 or fracture occurrence (delayed 

ZOL). After 60 months, upfront ZOL increased both BMD and disease-free 

survival (P � .05) relative to delayed ZOL. The present analysis assessed, 

from a US payer perspective, the cost effectiveness of upfront ZOL vs 

delayed ZOL in this population. Methods: A Markov state-transition model 

was developed to estimate the lifetime costs and quality-adjusted life-years 

(QALYs) for a hypothetical cohort of postmenopausal women with early 

breast cancer receiving letrozole with upfront or delayed ZOL. Consistent 

with ZO-FAST, patients were 57 years of age and breast cancer recurrencefree 

at baseline. Patients could progress over time to Local Recurrence, 

Contra-lateral Tumor, Distant Recurrence, or Death. Transition probabilities 

were derived from ZO-FAST, supplemented with literature. Costs and 

utilities were literature based. All outcomes were discounted 3% per year. 

Results: Compared to delayed ZOL, upfront ZOL resulted in better overall 

survival, disease-free survival, and QALYs, but at a higher cost (Table). In 

the base case, the incremental cost/QALY gained with upfront vs delayed 

ZOL was $7,967. In � 95% of 1,000 probabilistic sensitivity analysis 

runs, upfront ZOL costs less than $38,376/QALY gained. Conclusions: 

Upfront ZOL may increase survival and QALY and, at a cost per QALY well 

under the $50,000/QALY threshold, is very cost-effective in this population. 

Life-years 

(95% CI) 

Upfront ZOL 20.90 

(20.15-21.68) 

Delayed ZOL 19.29 

(18.32-20.29) 

Difference 1.61 

(0.22-3.03) 

Disease-free 

life-years 

(95% CI) 

20.17 

(19.34-21.06) 

18.12 

(17.02-19.26) 

2.06 

(0.48-3.63) 

QALY 

(95% CI) 

14.36 

(13.58-15.02) 

13.43 

(12.58-14.20) 

0.93 

(1.12-1.75) 

Lifetime cost 

(95% CI) 

$86,594 

($62,904-$111,010) 

$79,159 

($53,964-$103,680) 

$7,436 

(–$2,050-$16,738) 

Incremental 

cost per QALY 

$7,967 

(95% upper CI 

limit � $38,376) 


Obesity at diagnosis and breast cancer (BC) recurrence risk based on the 

21-gene assay recurrence score (RS). Presenting Author: Kimberly Ridolfi, 

Medical College of Wisconsin, Milwaukee, WI 

Background: Obesity at diagnosis has been associated with poorer overall survival 

in BC patients. The Oncotype Dx 21-gene assay RS has been shown to predict 

the risk of distant recurrence in estrogen receptor (ER) positive BC. This study 

aimed to evaluate if an association exists between body mass index (BMI) and 

RS. Methods: Retrospective chart review of patients (pts) with BC diagnosed 

2005-2010 and a 21-gene assay was performed. Risk factors including BMI, 

hormone use, and menopausal status were collected as well as tumor characteristics 

such as ER/PR/HER2 status, stage, and grade. Univariate analysis of the 

association between BMI level (�30 vs �30), and RS (�18 vs �18), stage (I vs 

II), and grade (1 vs 2 vs 3) was conducted using Chi square test. Correlation of 

BMI with RS (0-100) was also assessed via Spearman’s correlation. All tests 

were at a two sided significance level of 0.05. Results: Of 495 pts with a RS 

value, 482 had a BMI within 6 months of diagnosis. Median BMI was 27.7 

kg/m2 (range 17-63). BMI for pts presenting with stage 2 disease is significantly 

higher (30�6.9) than those with stage 1 (29�7.8), p�0.04 (Wilcoxon rank sum 

test). No association was found between BMI level and stage, grade or RS. See 

Table. Mean RS was 18.8 vs 18.2 (BMI �30 vs �30), p�0.79 (Wilcoxon rank 

sum test). Conclusions: This is the largest study of the association between BMI 

and the RS. Obesity (BMI�30) has been associated with increased recurrence 

and death from BC. However, we found no association between BMI and RS. This 

suggests that poorer outcomes among obese ER� breast cancer patients may not 

be due to intrinsic tumor biology (as reflected in the RS), but to other non-tumor 

factors, whether higher circulating estrogen levels, reduced efficacy of aromatase 

inhibitors, other comorbidities, difficulty with chemotherapy or other 

unidentified factors. Further study is warranted. 

BC in pts with BMI 30. 

BMI 30 (N�184) 

N % N % p value* 

Grade Grade 1 99 33.2 56 30.4 0.44 

Grade 2 162 54.4 96 52.2 

Grade 3 34 11.4 28 15.2 

Unknown 3 1.0 4 2.2 

Stage I 213 71.5 123 66.9 0.14 

II 71 23.8 57 31.0 

Unknown 14 4.7 4 2.2 

Risk group RS�18 166 55.7 98 53.3 0.67 

RS�18 132 44.3 86 46.7 

*Chi-Square test, excluding unknown. 


Chemotherapy-induced amenorrhea in premenopausal breast cancer patients 

treated with adjuvant anthracycline and taxane based chemotherapy 

within the SUCCESS study. Presenting Author: Julia Katharina Neugebauer, 

Department of Gynecology and Obstetrics, Ludwig-Maximilians- 

University, Munich, Germany 

Background: Chemotherapy induced amenorrhea (CIA) is often used as a 

surrogate marker for cytotoxic gonadal damage. The aim of this analysis was 

to identify predicitve factors for CIA in premenopausal breast cancer 

patients treated with adjuvant chemotherapy. Methods: The German multicenter, 

phase III SUCCESS trial compared 3 cycles of FEC q3w followed by 

3x docetaxel q3w vs. FEC followed by Doc�gemcitabine as adjuvant 

treatment in patients with node positive or high risk node negative primary 

breast cancer. Premenopausal patients with hormone receptor positive 

tumors underwent endocrine treatment with tamoxifen (Tam) for 5 years. 

Additional goserelin (GnRH) for 2 years was given in the following cases: 

Age �40 years at study entry, premenopausal hormone status or regular 

menses within 6 months after chemotherapy. We retrospectively investigated 

CIA rates of 1.189 initially premenopausal patients during diseasefree 

follow-up. Results: Median age at diagnosis was 44 years (range 

21-50). The median follow up time was 44 months (range 1-62). 791 

patients (66.5%) received endocrine treatment. Tam intake was reported 

in 370 patients, GnRH in 29 patients, Tam�GnRH in 392 patients. In 963 

patients (81.0%) CIA occurred for �3 months after chemotherapy. In 

22.7% of initially amenorrheic patients CIA was temporary. 192 patients 

(16.2%) had continuous menstrual bleeding. In multivariate analysis the 

risk of CIA was significantly higher in older patients, increasing by factor 

1.32 per life year (p�0.0001). Tam intake was also associated with 

increased CIA rates (p�0.0032). Patients with combined Tam�GnRH 

were more likely to resume menses compared to patients without endocrine 

therapy (p�0.0056). Factors like the cytotoxic regimen, tumor stage, 

grading, the patient�s BMI or the use of GnRH analogues as ovarian 

protectants during chemotherapy did not correlate with CIA rates. 

Conclusions: Age was the strongest predictor for CIA. Tam administered 

alone increased CIA rates. Opposite effects were observed for patients who 

received Tam�GnRH. The addition of gemcitabine to sequential anthracyline-taxane 

based chemotherapy did not influence CIA. 


Everolimus (RAD) as treatment in breast cancer patients with bone 

metastases only: Results of the phase II RADAR study. Presenting Author: 

Nicolai Maass, University of Aachen, Aachen, Germany 

Background: RAD001 is an orally bioavailable rapamycin ester analogue, 

which acts by selectively inhibiting mTOR (mammalian target of rapamycin), 

a key player in downstream signaling of different pathways. In vitro, 

RAD stops formation and activity of osteoclasts. Treating progressive bone 

metastases in breast cancer (bc) with RAD seems reasonable. Methods: We 

evaluated RAD in a placebo-controlled, phase II, randomized discontinuation 

study in bc patients (pts) with bone metastases only. Pts were eligible 

if they had HER2-negative, hormone-receptor (HR)-positive or –negative 

bc, with a maximum of 2 previous lines of endocrine therapy (ET) and 1 

previous line of chemotherapy (CT). All pts received zoledronate and pts 

with HR-positive bc could receive ET. All pts started with RAD during a 

run-in phase of 8 weeks. Pts with stable disease were randomized to RAD or 

placebo; pts with response continued with RAD and pts with progression 

went off study. Primary outcome was time to progression (TTP) in pts being 

stable on 8 weeks of RAD. It was assumed that placebo would obtain a 

median TTP of 8 weeks which would be increased to 16 weeks, thus 

requiring 76 randomized pts. It was expected that 70% of all pts would 

have stable disease after the run-in phase. Overall, 110 pts were needed. 

Due to slow recruitment and dysbalance between randomized and discontinued 

pts, recruitment stopped in 12/ 2010. Results: From 11/06 until 

12/10, 89 pts were enrolled. Median age was 59.5 years. 93% had 

HR-positive disease. 15% had prior chemotherapy; 58% had prior ET for 

metastases. 1/3 received concomitant ET. Three pts did not start therapy, 

41 discontinued during run-in phase, 32 due to progression. Six continued 

as responder. 39 pts with SD after run in phase were randomized to RAD or 

placebo. Twenty-seven stopped due to progression; 9 discontinued due to 

AE, 4 are still on treatment. 15 pts had 20 serious adverse events; 1 

hyperglycemia and one alveolitis. The TTP in patients with RAD was 8.5 

months vs. 2.9 months with placebo (HR: 0.559; 95% CI [0.284-1.10] 

p�0.092. Conclusions: Pts with bone metastases only had a longer TTP on 

RAD compared to pts on placebo. Overall 7/89 showed a sustained 

response on RAD � zoledronate � ET. 


557 General Poster Session (Board #3H), Sat, 8:00 AM-12:00 PM 

Predicting the Oncotype DX score: An inexpensive guesstimation. Presenting 

Author: Catherine Pesce, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: Oncotype DX Recurrence Score [RS] is used to predict the 

benefits of chemotherapy added to adjuvant hormone therapy in ER 

positive early stage breast cancer. It is also prognostic. However, its 

expense may be a concern in some health care systems and communities. 

In addition, it is labor intensive, requiring shipment of tissue samples to a 

single laboratory with an average 10-14 day turnaround time (in the US). A 

reliable and inexpensive estimator of the Oncotype DX risk score using 

readily available pathologic variables from tumor specimens could be 

useful. Methods: We reviewed our prospective database of patients with 

Oncotype DX results obtained over 2.5 years (1155 specimens with 

Oncotype DX scores, September 2008 – March 2011) and identified 766 

invasive ductal carcinomas with known ER status, PR status, histologic 

grade, and nuclear grade. Through linear regression analysis, we predicted 

recurrence score for each tumor using these four parameters. After 

categorizing according to the same risk classification as in Oncotype DX 

(low risk: RS�18, intermediate risk: RS 18-30, or high risk: RS�30) we 

compared our predicted recurrence score to actual Oncotype DX recurrence 

score. Results: Overall 69.7% of specimens were assigned the same risk 

category as with the Oncotype DX level. In the predicted low risk group, 

1.7% of patients were actually high risk. None of the predicted high risk 

patients had a low score. Conclusions: We found a strong correlation 

between scores estimated using our model and actual reported Recurrence 

Scores. If validated, our model could provide a clinically useful estimation 

of risk at lower cost. 

Predicted risk level Actual risk level 

Low risk Intermediate risk High risk Total 

Low risk 358 

97 

8 463 

(77.3%) (21.0%) (1.7%) (59.7%) 

Intermediate risk 95 

168 

34 297 

(32.0%) (56.6%) (11.5%) (38.3%) 

High risk 0 

1 

15 16 

(0%) (6.2%) (93.8%) (2.1%) 

Total 453 

266 

57 776 

(58.4%) (34.3%) (7.4%) 


Everolimus for postmenopausal women with advanced breast cancer: 

Updated results of the BOLERO-2 phase III trial. Presenting Author: 

Martine Piccart, Institut Jules Bordet, Université Libre de Bruxelles, 

Brussels, Belgium 

Background: Current treatment options for postmenopausal patients with 

estrogen-receptor–positive (ER� ) breast cancer (BC) who relapse or progress 

on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BO- 

LERO-2 trial supports the activity of everolimus (EVE; an oral mammalian 

target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase 

inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in 

this patient population. Long-term PFS and survival data are awaited. 

Methods: BOLERO-2 is a phase III double-blind, randomized, international 

trial comparing EVE (10 mg once daily) plus EXE (25 mg once daily) versus 

placebo (PBO) plus EXE in postmenopausal women with advanced ER� BC 

progressing or recurring after NSAIs (letrozole or anastrozole). Patients 

were randomized (2:1) to EVE � EXE or PBO � EXE. The primary endpoint 

was PFS by local investigator assessment. Main secondary endpoints 

included centrally assessed PFS, overall survival (OS), safety, bone 

turnover, and overall response rate (ORR). Results: Baseline disease 

characteristics including tumor burden and prior cancer therapy were well 

balanced between treatment arms (N � 724). Median PFS was doubled 

and response rates were consistently improved with EVE � EXE (n � 485) 

vs PBO � EXE (n � 239) in interim analyses. Median PFS by local 

assessment was ~3 mo with PBO � EXE vs 6.9 mo (hazard ratio [HR] � 

0.43; P � .0001) and 7.4 mo (HR � 0.44; P � .0001) with EVE � EXE at 

7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported 

with EVE � EXE (17.2%) vs PBO � EXE (22.7%) at 12.5 mo follow-up. 

Safety profiles were consistent with previous reports for mTOR inhibitors. 

PFS data including 528 events (protocol-specified final analysis), and 

updated OS and safety data will be presented. Conclusions: Adding EVE to 

EXE markedly prolonged PFS in patients with NSAI-refractory advanced 

ER� BC. There were fewer deaths among patients receiving EVE, and 

further follow-up will evaluate the effect of EVE on OS. 


21s 


Aromatase inhibitors and cardiac outcomes in women undergoing cardiac 

angiography after early breast cancer. Presenting Author: Bostjan Seruga, 

Institute of Oncology Ljubljana, Ljubljana, Slovenia 

Background: Data show that in post-menopausal women with early breast 

cancer, longer use of aromatase inhibitor (AI) is associated with increased 

odds of ischemic heart disease. Here we explore the association between 

adjuvant AI use and cardiac disease in women undergoing cardiac 

angiography after a diagnosis of early breast cancer. Methods: We linked a 

database of 7,681 women who underwent cardiac angiography at the 

University Clinical Center of Ljubljana between December 2004 and 

November 2010 with the Cancer Registry for Slovenia. Women with early 

breast cancer that subsequently underwent cardiac angiography were 

identified. Information on cardiovascular risk factors was retrieved from the 

patients’ charts and from discharge letters after cardiac angiography. The 

endpoint of interest was a diagnosis of ischemic heart disease or left 

ventricular dysfunction (IHD-LVD) without evidence of valvular heart 

disease at the time of angiography. Conditional, logistic regression was 

used to test for associations between variables. Results: Among 117 eligible 

women 75% (n�88) were postmenopausal and 62% (n�73) had hormonal 

receptor positive (HR�) disease. Of these 42% (n�31) were treated with 

AI. Overall, 48% (n�56) of women were found to have IHD-LVD. In 

patients with HR� breast cancer, use of AIs was significantly associated 

with IHD-LVD as compared to tamoxifen alone (HR 2.50, 95% CI 

1.01-6.29, p�0.046). For each year of AI therapy, there was a trend for 

higher odds of IHD-LVD (OR: 1.25, 95% CI 0.95-1.67, p�0.116). This 

effect appeared independent of age, body mass index, baseline hypertension, 

hypercholesterolemia, diabetes and heart disease or prior anthracyclines 

exposure. Among all patients, use of anthracyclines and left-sided 

irradiation was associated with non-significant increases in IHD-LVD (HR 

2.37, 95% CI 0.89-6.09, p�0.45 and HR 1.28, 95% CI 0.69-2.40, 

p�0.44 respectively). Conclusions: Compared to tamoxifen, AIs are associated 

with a time dependent increase in IHD-LVD. This risk appears 

independent of other risk factors for heart disease. Anthracycline exposure 

and left breast or chest wall radiation showed non-significant associations 

with IHD-LVD in this small cohort. 


The impact of the Oncotype Dx breast cancer assay in clinical practice: 

Systematic review and meta-analysis. Presenting Author: Josh John Carlson, 

University of Washington, Seattle, WA 

Background: Many studies have evaluated the Oncotype Dx Breast Cancer 

Assay (ODX) and its impact on adjuvant chemotherapy (ACT) treatment 

decisions. However, it can be difficult for clinicians and other stakeholders 

to interpret the collective findings of these studies, as they were conducted 

in diverse settings and have limited sample sizes. To address this issue, we 

conducted a systematic review and meta-analysis to synthesize ODX results 

and provide insights about the utility of ODX in actual clinical practice. 

Methods: We performed a systematic review of ODX studies using PubMed, 

Embase, ASCO, and SABCS. Studies were included if patients had ER �, 

node -, early stage breast cancer, reported use of ODX to inform actual ACT 

decisions, and reported outcomes of interest, including: 1) distribution of 

ODX recurrence scores (RS); 2) impact of ODX on ACT recommendations; 

3) impact of ODX on ACT use; and 4) proportion of patients following the 

treatment suggested by the ODX RS. Results: A total of 28 studies met 

inclusion criteria. The distribution of RS categories was 48.8% low, 39.0% 

intermediate, and 12.2% high (21 studies, 4,156 patients). ODX changed 

the clinical-pathological ACT recommendation in 33.4% of patients (8 

studies, 1,437 patients). In patients receiving ODX, receipt of ACT was: 

28.2% overall, 5.8% low, 37.4% intermediate, and 83.4% high. High RS 

patients were significantly more likely to follow the treatment suggested by 

ODX vs. low RS patients RR: 1.07 (1.01–1.14). Conclusions: The pooled 

results for the impact of ODX on ACT recommendations are consistent with 

most individual studies to date. However, the proportion of intermediate RS 

results is nearly 2-fold higher than reported in the ODX development 

studies by Paik et al., which may have implications for the clinical utility 

and cost impacts of testing. Also, high RS vs. low RS patients were more 

likely to follow the ODX results, suggesting a tendency toward aggressive 

treatment despite a low ODX RS. Finally, there was a lack of studies on the 

impact of ODX on ACT use vs. standard approaches, suggesting additional 

studies are warranted. 

Count Mean % classified (95% CI) 

High RS 509 12.2% (10.5-14.0) 

Int RS 1,487 39.0% (36.3-41.7) 

Low RS 2,026 48.8% (45.2-52.3) 




Assessment of the prognostic and predictive utility of the breast cancer 

index (BCI): An NCIC CTG MA.14 study. Presenting Author: Dennis Sgroi, 

Massachusetts General Hospital, The Avon Foundation, Boston, MA 

Background: Breast Cancer Index (BCI), a continuous risk index, combines 

the ratio of HOXB13 to IL17BR (H/I) and the molecular grade index (MGI) 

(Jerevall et al., British J Cancer, 2011). Here, the prognostic and predictive 

performance of BCI for BC relapse in MA.14 trial was examined. Methods: 

MA.14 randomly assigned 667 hormone receptor positive (HR�) women to 

5 years of tamoxifen (TAM) �/- 2 years of octreotide LAR (TAM-OCT). A 

representative subgroup of 299 patients was profiled by RT-PCR for BCI. 

The primary objective was to determine the prognostic performance of BCI 

based on relapse-free survival (RFS) with median 9.8 years follow-up. 

Association of BCI was assessed with step-wise forward stratified Cox 

regression. Pre-defined categories of low (L), intermediate (I) and high (H) 

BCI risk groups were used to provide adjusted 5- and 10-year RFS. Results: 

292 of 299 patient samples passed internal analytical quality control. The 

292 patients contained 49% LN� patients and had 19.9% BC relapses. 

Both continuous and pre-specified BCI risk groups were significant multivariate 

factors (p�0.0001; p�0.007) with higher BCI associated with shorter 

RFS. Adjusted univariate hazard ratios and 95% CI were 2.53 (1.36 – 

4.71) for BCI-H vs -L and 1.28 (0.65 – 2.52) for BCI-I vs -L. With both LNand 

LN� included, BCI-L had 5- and 10-year RFS of 94.0% and 87.5%; 

-I, 91.8% and 83.9%; and -H, 81.5% and 74.7%. No significant 

difference in BCI’s ability to stratify patients into 3 risk groups was 

observed between LN-/no chemotherapy subgroup vs balance of MA.14 

patients (p�0.26). Higher pathologic T-stage was multivariately associated 

with shorter RFS (p�0.01). Interactions between trial therapy and BCI 

was not significant (p�0.40). Conclusions: This study confirmed the strong 

prognostic effect of BCI on breast cancer recurrence. BCI was prognostic in 

both LN- and LN� patients. The lower 10-year RFS in the BCI-L group than 

in our previous studies reflected the mixed LN-/LN� population examined. 

Like the parent MA.14 trial, BCI did not predict benefit of adding OCT to 

TAM therapy (Pritchard et al., J Clin Oncol, 2011). This retrospective study 

is an independent validation of the prognostic performance of BCI within a 

prospective trial. 


Impact of exogenous female hormone use (EHU) on breast cancer (BC) 

recurrence as assessed by the 21-gene assay (Oncotype DX). Presenting Author: 

Wendy M. Ledesma, University of Wisconsin Carbone Cancer Center, Madison, 

WI 

Background: Observational studies suggest that EHU, such as oral contraceptive 

(OCPs) or postmenopausal hormone replacement therapy (HRT), increases the 

risk of developing BC. However, the prognosis of women taking EHU compared to 

nonusers remains controversial. The Oncotype Dx 21-gene assay RS predicts the 

distant recurrence risk for early stage, HR� BC. We assessed RS in patients (pts) 

on EHU at diagnosis (users) vs nonusers. Methods: Retrospective chart review 

was conducted on BC pts with a RS, diagnosed 2005–2010. Stage, grade, 

estrogen (ER), progesterone (PR) and HER2 receptor status were abstracted. 

Manual review of medications, as well as electronic data pull within �5yrs of 

diagnosis, defined users as pts on EHU within 1 yr of diagnosis for �1 yr. 

Nonusers had been on EHU � 5 yrs before diagnosis or never. Comparisons 

between EHU users and nonusers were made using two-sample tests; chi-square 

or Fisher’s exact test for discrete data such as stage and ER status and t-test or 

Wilcoxon rank sum test for continuous data such as RS. All tests were at a 

two-sided significance level of 0.05. Results: 495 pts had RS. EHU was 

documentable for 475, 77 were using exogenous hormone at diagnosis. Type of 

hormone use included systemic HRT (48%), OCPs (36%), other (4%), and 

unknown (12%). For users vs nonusers, mean RS was 17 vs 19, (p�0.007, 

t-test). See table for other predictors. Conclusions: Prior study shows21-gene 

assay predict distant recurrence risk for HR�BC. In our study, an association 

existed between EHU and lower RS, suggesting that BC developing on EHU may 

have less risk of recurrence. Prospective evaluation is warranted. 

Users at diagnosis versus nonusers. 

Nonusers N�398 Users N�77 P-value 

RS # 

19 (9.2) 17 (6.3) 0.007* 

Age # 

57 (10.3) 54 (9.4) 0.04* 

Stage I 280 (70%) 54 (70%) 0.8 ^ 

II 105 (26%) 18 (23%) 

Grade 

Unknown 

1 

13 (3%) 

117 (29%) 

5 (6%) 

32 (42%) 0.013 ^ 

2 217 (54%) 40 (52%) 

3 57 (14%) 3 (4%) 

ER 

Unknown 

� 

7 (2%) 

386 (97%) 

2 (3%) 

74 (96%) 1 $ 

- 4 (1%) 0 

PR 

Unknown 

� 

8 (2%) 

340 (85%) 

3 (4%) 

70 (91%) 0.11 ^ 

- 49 (12%) 4 (5%) 

HER2 

Unknown 

� 

9 (2%) 

4 (1%) 

3 (4%) 

1 (1%) 0.6 $ 

- 368 (92%) 69 (90%) 

Unknown 26 (7%) 7 (9%) 

# Mean(SD);*t-test; ^ Chi-square test (excluding unknown); $ Fisher’s exact test (excludes 

unknown). 


Association of the phosphorylation of the estrogen receptor at serine 118 

and 167 with prognosis in postmenopausal breast cancer patients. Presenting 

Author: Karin J. Beelen, Netherlands Cancer Institute, Amsterdam, 

Netherlands 

Background: The sensitivity of the estrogen receptor (ER�) to anti-estrogen 

therapy can be affected by phosphorylation events. In premenopausal 

breast cancer patients, phosphorylation of the ER� at serine 118 

(ER�S118-p) is predictive for benefit from adjuvant tamoxifen. Since 

ER�S118-p represents the common hallmark of different signaling cascades 

that differ in E2 dependency, the resulting effect on estrogen 

sensitivity may differ between pre- and postmenopausal patients. Phosphorylation 

of serine 167 (ER�S167-p) has been associated with favorable 

disease outcome, but whether ER�S167-p can predict tamoxifen sensitivity 

is currently unknown. We tested the predictive value of both ER�S118-p 

and ER�S167-p for benefit from adjuvant tamoxifen in postmenopausal 

breast cancer patients. Methods: We collected primary tumor blocks from 

563 ER� positive (stage I-III) postmenopausal patients who had been 

randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA 

trial). The median follow-up of patients without a recurrence event was 9.4 

years. Immunohistochemistry was performed on a TMA using monoclonal 

antibodies for ER�S118-p and ER�S167-p. The percentage of positive 

nuclei was scored and a score of � 10 % was considered as positive. 

Multivariate Cox models were used to assess hazard ratios (HRs) for 

recurrence free interval and the interaction between these phosphorylations 

and tamoxifen treatment. Results: We did not find a significant 

interaction between either ER�S118-p (p�0.99) or ER�S167-p (p�0.44) 

and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen 

in postmenopausal patients is not dependent on the presence of one of 

these phosphorylations. Both tamoxifen treated patients as well as control 

patients had a better prognosis when their tumor was positive for ER�S118-p 

(adjusted HR 0.60 p�0.02) or ER�S167-p (adjusted HR 0.62, p�0.02) 

compared to patients whose tumor did not express these ER� phosphorylations. 

Conclusions: In postmenopausal patients ER�S118-p and ER�S167-p 

are both associated with better prognosis, but do not predict differential 

benefit from tamoxifen. 


Effect of MDV3100, an androgen receptor signaling inhibitor, on tumor 

growth of estrogen and androgen receptor-positive (ER�/AR�) breast 

cancer xenografts. Presenting Author: Anthony D. Elias, University of 

Colorado Anschutz Medical Campus, Aurora, CO 

Background: The androgen receptor (AR) is detected by immunohistochemistry 

in approximately 75% of all invasive breast cancer; with ~88% of ER� 

tumors expressing AR. Potent inhibition of AR activity could be a therapeutic 

strategy in ER�/AR� breast cancer. MDV3100 is an androgen receptor 

signaling inhibitor (ARSI), which inhibits AR activity via three mechanisms: 

inhibition of androgen binding to AR, inhibition of AR nuclear translocation, 

and inhibition of nuclear AR-DNA binding. MDV3100 has demonstrated 

an overall survival benefit in men with post-docetaxel prostate 

cancer. Methods: Two ER�/AR� breast cancer cell lines, MCF7 and BCK4 

(recently derived from a pleurocentesis), were used to assess the proliferative 

effect of dihydrotestosterone (DHT) and estradiol (E2). The efficacy of 

MDV3100 at blocking DHT-mediated proliferation was compared to bicalutamide 

in ER�/AR� breast cancer cells. MCF7 xenograft studies were 

performed to determine if MDV3100 can affect DHT or E2 mediated 

proliferation in vivo. Results: Both bicalutamide and MDV3100 inhibited 

DHT-mediated proliferation of ER�/AR� cell lines. Although MDV3100 

binds AR very effectively and does not bind ER, it also uniquely inhibited 

E2-mediated proliferation, while bicalutamide slightly enhanced E2 mediated 

proliferation. Results presented here demonstrate that MDV3100 

inhibited E2-stimulated tumor growth of MCF7 mammary xenografts as 

effectively as tamoxifen. Conclusions: MDV3100 blocked both DHT- and 

E2-mediated growth of breast cancer cells, whereas bicalutamide enhanced 

E2-mediated proliferation. MDV3100 may have unique therapeutic 

utility in patients with AR� breast cancer, regardless of ER status. 

Funding: DOD Breast Cancer Program Idea Award BC074403, Avon 

Foundation for Women, and University of Colorado Cancer Center pilot 

project funds to JKR. 



Prognostic factor Ki67 for breast cancer patients in each subgroup. 

Presenting Author: Naoki Niikura, Tokai University School of Medicine, 

Isehara Kanagawa, Japan 

Background: Immunohistochemical (IHC) Ki67 has described it as a 

prognostic and predictive marker for breast cancer. The St. Gallen 

Consensus Meeting determined that Ki67 labeling index is chiefly important 

for distinguishing between “Luminal A” and “Luminal B (HER2 

negative)” subtypes and is a predictive marker for chemotherapeutic 

efficacy. However, the high and low cutoff points remain controversial. Our 

objective is to compare survival in patients with low, intermediate, and high 

Ki67 levels in each subgroup. Methods: We retrospectively identified all the 

patients in the Tokai University breast cancer database for whom IHC Ki67 

data were available between January 1, 2000, and December 31, 2010. 

Ki67 was defined as low if �10% Ki67 was detected, as Intermediate if 

10–20% Ki67 was detected, and as high if �20% Ki67 was detected. To 

assess Ki67 levels and survival outcomes, survival curves were calculated 

using the Kaplan–Meier method and compared using the log-rank test. 

Results: We identified 1331 primary breast cancer patients without 

metastasis, of whom 686 received neoadjuvant or adjuvant chemotherapy. 

Patients with high Ki67 had poorer relapse-free survival (RFS) than 

patients with intermediate (p � 0.009) and low Ki67 (p � 0.001). Patients 

with intermediate Ki67 had poorer RFS than patients with low Ki67 (p � 

0.001). In ER-positive cases (n � 1059), patients with high and intermediate 

Ki67 had poorer RFS than patients with low Ki67 (p � 0.001 and p � 

0.002, respectively). In HER2-positive and ER-negative cases (n � 103), 

patients with high Ki67 had poorer RFS than patients with low Ki67 (p � 

0.002). In triple-negative cases (n � 164), patients with high Ki67 tended 

to have poorer RFS than patients with low Ki67 (p � 0.064). Conclusions: 

Our data demonstrated that low, intermediate, and high Ki67 levels may be 

used to differentiate prognosis in ER-positive cancer patients as well as 

HER2-positive and triple-negative cancer patients. 


Characterization of the overall survival benefit in ENCORE 301, a randomized 

placebo-controlled phase II study of exemestane with and without 

entinostat in ER� postmenopausal women with metastatic breast cancer. 

Presenting Author: Pamela Klein, PMK Consulting, San Mateo, CA 

Background: Histone deacetylase inhibitors (HDACi) prevent the emergence 

of drug tolerant clones and sensitize cells to a variety of anti-cancer 

therapies. We previously reported ENCORE 301, a randomized placebo 

controlled phase 2 study comparing exemestane with (EE) and without (EP) 

the HDACi entinostat met its primary endpoint of prolonging progression 

free survival (PFS) (4.3 months vs 2.3 months) and extending overall 

survival (OS) benefit (26.9 vs 19.8 months). In order to characterize and 

better understand the OS benefit, exploratory analyses were conducted. 

Methods: Hazard ratios (HR) for treatment were estimated from the Cox 

proportional hazards model, with EP serving as the reference treatment in 

the calculations. Inferential comparisons between treatment groups were 

made using the log-rank test. Results: Analysis of OS across multiple 

subsets of interest demonstrated a consistent benefit in EE group versus 

EP. Sensitivity analysis of baseline characteristics potentially impacting 

OS did not identify any factors that influenced the effect of EE on OS. 

Examination of treatments received during follow-up after discontinuation 

of EE and EP demonstrated balance between treatment group for patients 

receiving chemotherapy (48% EE: 44% EP), hormone therapy (37% EE: 

35% EP), bisphosphonates (2% EE; 0% EP), radiation (6% EE; 5%EP), 

and surgery (0% EE: 2% EP). Compared to EP, OS was longer in EE group 

for patients whose first subsequent treatment was a hormone therapy (EE 

median not reached vs EP median 20.5 months; HR 0.65 [95% CI 0.26, 

1.58]) or chemotherapy (EE median 26.9 months vs EP median 17.6 

months; HR 0.51 [95% CI 0.25, 1.04]). Updated PFS and OS data will 

also be presented along with correlation analysis of PFS and OS. Conclusions: 

Analyses of baseline characteristics, subsequent treatment and subsets of 

prognostic factors in ENCORE 301 did not identify any contributing factors 

that account for the extended OS benefit in the EE treatment group. Long 

lasting effects of entinostat on progenitor cells, emergence of drug tolerant 

cells and or priming to subsequent therapies cannot be ruled out. 


23s 


Prognostic significance of PI3K pathway (PI3Kp) dysregulation in metastatic 

breast cancer (MBC) patients (pts). Presenting Author: Alejandro Navarro, 

Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, 

Spain 

Background: PI3Kp dysregulation represents a potential target for therapies that 

are currently being tested in clinical trials. This observational retrospective study 

aims to evaluate the prognostic implications of PI3Kp dysregulation in MBC. 

Methods: MBC pts with PI3Kp status assessment from Sep09 to Sep11 were 

reviewed. PIK3CA mutation status analyzed in paraffin-embedded tissue by DxS 

PI3K Mutation Test Kit or Sequenom MassARRAY. PTEN status determined by 

IHC. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) 

PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore�50). 

Results: 232 MBC pts screened, median age 49.8 (22.9-83.1) and median MBC 

lines 4 (1-15). Distribution: HR�/HER2- 99 (43%), HER2� 52 (22%), triple 

negative 35 (15%), unclassified 46 (20%). Sites of metastasis: visceral 173 

(75%), only skin 10 (4%), only bone 49 (21%). PIK3CA status assessed in 174 

pts, 53 (22.8%) bearing a mutation (21 exon9, 32 exon20). PTEN status 

assessed in 229 pts, PTEN low 61 (26.6%). PI3Kp dysregulation in 103/185 

pts (55.6%). Time to progression to first line MBC treatment (TTP) and overall 

survival after MBC diagnosis (OS) are shown. Disease free survival (DFS) and 

distant-disease free survival (DDFS) in pts initially diagnosed with early breast 

cancer (n�193) has also been calculated. Conclusions: These results suggest 

that PI3Kp dysregulation, either by PIK3CA mutation or PTEN low, does not 

seem to have impact on disease recurrence, response to first line MBC treatment 

or overall MBC survival. 

PIK3CA PTEN PI3Kp dysregulation 

Median (95%CI) WT Mut Normal Low No Yes 

n�174 n�229 n�185 

n�121 n�53 n�168 n�61 n�82 n�103 

TTP (m) 12.0 

11.8 

13.0 

11.5 

12.3 

11.8 

(10.3-13.8) (9.6-14.0) (11.4-14.6) (7.4-15.6) (10.0-14.5) (9.1-14.5) 

p�0.780 p�0.891 p�0.516 

OS (y) 5.5 

5.0 

5.6 

5.1 

5.5 

5.0 

(4.1-6.9) (3.3-6.7) (4.9-6.3) (3.0-7.3) (3.9-7.1) (3.5-6.5) 

p�0.882 p� 0.460 p�0.443 

n�158 n�189 n�167 

n�107 n�51 n�132 n�57 n�69 n�98 

DFS (m) 45.0 

36.6 

38.6 

49.6 

36.0 

46.0 

(35.6-54.4) (28.6-44.6) (32.2-45.1) (42.6-56.5) (24.3-47.7) (38.5-53.4) 

p� 0.476 p�0.071 p�0.163 

DDFS (m) 51.0 

44.6 

46.3 

57.1 

40.0 

49.6 

(43.1-58.8) (32.5-56.7) (35.8-56.8) (44.3-69.9) (22.5-57.5) (39.7-59.4) 

p� 0.505 p� 0.289 p� 0.254 

568^ General Poster Session (Board #5C), Sat, 8:00 AM-12:00 PM 

Prospective study of the impact of using the 21-gene recurrence score 

assay on clinical decision making in women with estrogen receptorpositive, 

HER2-negative, early-stage breast cancer in France. Presenting 

Author: Joseph Gligorov, APHP Tenon APREC, CancerEst, University Paris 

VI, Paris, France 

Background: The 21-gene Oncotype DX Recurrence Score (RS) is a 

validated assay to help inform the appropriate treatment of estrogen 

receptor-positive (ER�), early stage breast cancer in the adjuvant setting. 

Treatment traditions regarding choice of adjuvant treatment vary significantly 

in different countries. This prospective multicenter study is the first 

to assess the impact of using the Oncotype DX assay in the French clinical 

setting. Methods: A total of 100 consecutive patients with ER�, HER2negative, 

node negative or pN1 (mi) breast cancer were enrolled. Overall 

treatment recommendation change, change from chemoendocrine to 

endocrine alone and change from endocrine alone to chemoendocrine 

treatment were recorded. Medical oncologists completed questionnaires 

regarding their confidence in their recommendation before and after 

knowing the patient’s RS. A preliminary analysis was conducted on the first 

92 evaluable patients with data available at the time of abstract submission. 

Final data will be presented at the meeting. Results: Prior to Oncotype 

DX 49% of patients were recommended chemoendocrine treatment and 

51% endocrine treatment alone. After having the RS, 26% were recommended 

chemoendocrine treatment and 74% endocrine treatment alone. 

The overall reduction in chemotherapy recommendation from 49% to 26% 

was significant (p�0.001). Of patients originally recommended chemoendocrine 

treatment, 58% were changed to endocrine treatment alone after 

having the RS. Of patients originally recommended endocrine treatment, 

11% were changed to chemoendocrine treatment after receiving the RS. 

There was a significant improvement in physician confidence in treatment 

recommendations (p�0.002) when using Oncotype DX. Conclusions: These 

are the first prospective data regarding the impact of using Oncotype DX in 

France. Using Oncotype DX was associated with a significant change in 

treatment decisions and an overall reduction in chemotherapy use. The 

data are consistent with those presented from Germany, Spain, the UK and 

the US. 




Evaluation of Oncotype DX testing and subsequent patterns of care in 

patients (pts) with early-stage breast cancer (ESBC). Presenting Author: 

Meghan Fitzgerald, Cardinal Health, Specialty Solutions, Dublin, OH 

Background: Cardinal Health Specialty Solutions (CHSS) partners with 

payers to manage clinical care pathways in oncology and rheumatology. 

Observations from one such pathway with CareFirst BlueCross BlueShield 

revealed that pts with estrogen receptor-positive ESBC who underwent 

Oncotype DX testing and were found to have high-risk Recurrence Scores 

(RS) received less chemotherapy than expected. To better understand 

physician behavior as it relates to Oncotype DX testing, CHSS examined 

patterns of Oncotype DX use in a large private practice oncology group with 

a robust electronic medical record (EMR), Georgia Cancer Specialists 

(GCS). We aimed to determine the RS risk distribution among pts who 

received Oncotype DX testing and assess the patterns of care that followed. 

Methods: Using GCS EMR data from 2009 to 2011, the number of pts who 

were eligible to undergo Oncotype DX testing was compared to the number 

of pts who underwent testing. Pts were considered eligible for testing if they 

had node-negative, estrogen receptor-positive, HER2-negative ESBC. We 

determined the number of pts with a RS value in the low- (RS �18), 

intermediate- (RS 18-30), and high-risk (RS �31) groups along with the 

number of pts who subsequently received chemotherapy in each category. 

Results: Of the 1908 patients identified with ESBC, 788 were eligible for 

Oncotype DX testing and 288 (37%) underwent testing. Fifty percent of pts 

were in the low-, 34% in intermediate-, and 16% in the high-risk groups. 

Six percent of low-, 41% of intermediate-, and 83% of high-risk pts 

received chemotherapy. Seventeen percent of pts in the high-risk group did 

not receive chemotherapy. Conclusions: The use of chemotherapy in the 

low- and intermediate-risk groups was as expected based on adjuvant 

chemotherapy guidelines; however, an under utilization of chemotherapy 

was found in high-risk pts. There also appears to be a noteworthy underuse 

of Oncotype DX testing in eligible pts. Further data analysis is needed to 

understand the low use of Oncotype DX testing in eligible pts and to explain 

the lower than expected use of chemotherapy in high-risk pts. 


Evaluation of variables that may impact chemotherapy (CT) administration 

after determination of Oncotype DX (ODX) recurrence score (RS). Presenting 

Author: Kristina E. Bowen, Georgia Cancer Specialists PC, Atlanta, GA 

Background: Cardinal Health Specialty Solutions (CHSS) partners with 

payers to manage clinical care pathways in oncology and rheumatology. 

Observations from one such pathway with CareFirst BlueCross Blue Shield 

revealed lower than expected use of CT in patients (pts) with estrogen 

receptor-positive early-stage breast cancer (ESBC) at high-risk for recurrence 

by ODX RS. To better understand physician behavior, CHSS examined 

patterns of care in a large private practice oncology group with a robust 

EMR, Georgia Cancer Specialists (GCS). Pt characteristics and physicianprescribing 

patterns were analyzed to determine variables that most 

impacted the physician’s decision to treat high-risk pts with CT. Methods: 

Using the GCS EMR from 2009 to 2011, we retrospectively identified pts 

with ESBC (stage I-II, node-negative, estrogen receptor-positive, HER2negative) 

who underwent ODX testing. We determined the number of pts 

with a RS value in the low- (RS �18), intermediate- (RS 18-30), and 

high-risk (RS �31) groups along with the number of pts who subsequently 

received CT in each category. The use of CT in high-risk pts was analyzed by 

pt age, tumor size, tumor grade, and physician prescribing patterns. 

Results: Of the 1908 pts identified with ESBC, 788 were eligible for ODX 

testing and 288 (37%) underwent testing. Fifty percent of pts were in the 

low-, 34% in intermediate-, and 16% in the high-risk groups. Six percent of 

low-, 41% of intermediate-, and 83% of high-risk pts received CT. In 

high-risk pts analyzed by age, CT was used in 100% of pts � 45 years (y), 

86% in pts 46-55 y, 86% in pts 56-65 y, and 25% in pts �66 y. CT use in 

high-risk pts was 82% and 86% in pts with tumor sizes �2 cm and 2-5 cm, 

respectively; and, 100%, 60%, and 91% in pts with grade 1, 2, or 3 

tumors, respectively. Of the 41 physicians who were evaluated, 10 (24%) 

used ODX �15% of the time, 13 (32%) used ODX 15-40%, 10 used (24%) 

used ODX 41-60%, and 8 (20%) used ODX � 60% of the time. There were 

no significant differences in patterns of CT use. Conclusions: The less than 

expected use of CT in high-risk patients appears to be related to physician 

preference and pt age. Tumor size and grade did not appear to influence 

choice of therapy. 


Treatment pattern by hormone receptors and HER2 status in patients with 

metastatic breast cancer in the United Kingdom, Germany, France, Spain, 

and Italy (EU-5): Results from a physician survey. Presenting Author: Mitch 

DeKoven, IMS Health, Alexandria, VA 

Background: The differences in country-specific treatment patterns across 

Europe for Stage IV metastatic breast cancer (mBC) patients have not been 

extensively studied. This study compared treatment choices, by biomarker 

status, between various lines of therapy (LOT) in clinical practice in the 

EU-5 countries among newly diagnosed stage IV mBC patients. Methods: 

The IMS LifeLink Oncology Analyzer (OA) database, based upon practicing 

oncologist surveys, was used to identify mBC patients aged �21 and 

surveyed between July 2008 – June 2010. The database encompasses over 

100,000 unique patients per year, treated by nearly 3,000 physicians, 

including nearly 60,000 patients and 800 physicians in the EU5. Results: 

A total of 152,311 mBC patients were included in the study. In Italy, 

30.8% of HER2�/HR� patients received chemotherapy following mBC 

diagnosis, as compared to only 8.6% in France. The majority of these 

patients in France received chemotherapy plus a HER2 targeted therapy 

(58.2%) as their first treatment. For HER2�/ HR- patients, chemotherapy 

plus a HER2 targeted therapy was provided to the majority of the patients in 

France (70.8%), with the UK providing this regimen to the fewest patients 

with this biomarker status (44.9%). Monotherapy hormonal regimens were 

given as a first LOT for HER2-/HR� patients (UK 64.7%, Spain 52.8%). 

Triple negative patients received chemotherapy (UK 84.1% as compared to 

France 57.3%) or chemotherapy plus bevacizumab (France 36.6% as 

compared to UK 0.9%) as a first treatment. Conclusions: Thisstudy 

confirmed that chemotherapy combined with HER2-targeted therapy was 

the most frequent initial treatment option for HER2� patients, while the 

vast majority of ER/PR� patients were initially treated by hormonal 

therapy, suggesting that a personalized medicine approach has been 

accepted in the EU-5. However, the use of HER2-targeted therapy and 

bevacizumab greatly varied; while they were most frequently used in 

France, they were least frequently opted for in the UK. Also, fewer 

treatment options existed for triple negative patients and patients with 

HER2� disease following trastuzumab treatment. 


Synchronous bilateral breast cancer (SBBC): Concordance of receptor 

status between right and left breast. Presenting Author: Palak Desai, Rush 

University Medical Center, Chicago, IL 

Background: This analysis was prompted by a patient who presented with 

SBBC who had and ER�, HER2- cancer in one breast and an ER-, HER2� 

cancer in the other. Since both breasts have the same genetic background 

and environmental exposures, concordance should be virtually identical 

unless other factors are at play. Methods: SBBC was defined as bilateral 

cancer diagnosed concurrently or within 6 months of each other. Cases 

were identified retrospectively from patients seen at Rush University 

Medical Center. This analysis was limited to invasive SBCC (ISBBC). 

Estrogen receptor (ER) and Her2/neu (HER2) status were assessed according 

current ASCO/CAP guidelines. Correlation between ER and HER2 

status was determined using � statistic. Results: From January 1998 to 

December 2012, 33 cases of ISBBC were diagnosed. In 65% of cases 

synchronous disease was diagnosed concurrently. The average age at 

diagnosis was 56. The majority were multiparous and 79% post menopausal. 

About half of the patients (55%) had at least one first degree 

relative with a history of breast or ovarian cancer and 9% of the cohort had a 

deleterious mutation in BRCA1 or BRCA2. Infiltrating ductal was most 

common (74%) followed by infiltrating lobular (21%). 53% of breasts 

specimens also contained ductal carcinoma in situ. 68% of tumors were ER 

positive and 8% were HER2 positive. Concordance in ER status was seen in 

73% of cases (kappa coefficient 0.14) and in HER2 status was 64% 

(Kappa coefficient 0.35). Conclusions: Despite identical hereditary and 

environmental exposure, some patients develop ISBBC cancers with 

discordant receptor status. While this is the exception, it suggests that 

other factors influence important tumor characteristics. 

R breast � (n) R breast – (n) Total 

ER status 

L breast � 22 4 26 

L breast - 5 2 7 

Total 27 6 33 

HER2 status 

L breast � 1 2 3 

L breast - 1 28 29 

Total 2 30 32 



In situ quantitative measurement of mRNA to predict response to trastuzumab 

in a cohort of metastatic breast cancer patients. Presenting Author: 

Maria Vassilakopoulou, Yale University, New Haven, CT 

Background: Trastuzumab therapy is currently selected based on assessment 

of HER2 by either immunohistochemistry (IHC) for protein overexpression 

or fluorescence in situ hybridization (FISH) to detect gene 

amplification. We sought to determine the predictive value of in situ 

quantitative measurement of mRNA on a cohort of trastuzumab-treated 

metastatic breast cancer patients. Methods: A tissue microarray composed 

of ninety metastatic breast cancers treated with various chemotherapy 

regimens combined with trastuzumab was constructed. HER2 intracellular 

domain (ICD), HER2 extracellular domain (ECD) and HER2 mRNA were 

assessed using the AQUA method for quantitative immunofluorescence. 

For HER2 protein evaluation CB11was used to measure ICD and SP3 to 

measure ECD of the HER2 receptor. In addition, HER2 mRNA status was 

assessed using the RNAscope assay ERRB2 probe according to manufacturer’s 

protocol modified for detection with Cy-5 Tyramide. Cytokeratin was 

used in order to create the tumor mask and signal was quantified within the 

mask. Primary endpoints included time to progression (TTP) from trastuzumab 

initiation and overall survival (OS) times. Statistical analysis was 

performed using Kaplan-Meier analysis and the Cox proportional hazard 

model. Results: HER mRNA was tightly correlated with ICD HER2, as 

measured by CB11 (r2�0.35), but not with ECD HER2 as measured by 

SP3 (r2�0.14). Both ICD HER2 and HER2 mRNA were predictive of 

response to trastuzumab, but ECD was not. Multivariate analysis including 

age, histological grade and hormone receptor status shows the ICD to be 

predictive of TTP (p�0.0377). HER2 mRNA levels were significant for 

prediction of TTP (p�0.0344) in multivariate analysis including age and 

histological grade. Conclusions: The expression of ICD, as detected by 

CB11 and HER2 mRNA levels were significantly associated with TTP in this 

trastuzumab-treated metastatic cohort. The ECD, as detected by SP3 is 

neither predictive of response, nor tightly correlated with HER2 mRNA. In 

situ assessment of HER2 mRNA has the potential to identify breast cancer 

patients who derive benefit from trastuzumab treatment. 


Fertility preservation options and the young breast cancer patient: A survey. 

Presenting Author: Manuela Jacobsen Junqueira, Memorial Sloan- 

Kettering Cancer Center, New York, NY 

Background: Approximately 15% of breast cancers (BC) are diagnosed in 

reproductive aged women. Management of the disease in this age group 

frequently includes chemotherapy and hormonal therapy, which can both 

affect fertility. Considering that age at first delivery has been steadily 

increasing, young women may face BC before completion of childbearing. 

Methods: In this prospective study, women referred to our institution for 

surgical treatment of BC were asked, before their first visit, to fill out a 

questionnaire regarding their reproductive history and fertility preservation 

knowledge. Eligible patients included women between the ages of 18 and 

45, with a newly diagnosed BC, who had not yet started treatment. Results: 

Sixty women were eligible with a median age of 40 (range 20-45). 98% of 

responders (59 out of 60) had been diagnosed within the previous 2 

months. 78% (47/60) had a college or post-graduate degree. 80% (48/60) 

had been pregnant before, while 86.5% (45/52) reported having had 

children. 81% (47/58) were premenopausal, and only 3 patients reported 

not having had periods for more than 1 year. 50% of responders (30/60) 

declared no interest in future childbearing, 25% were definitely interested, 

and 25% were undecided. However, only 9% (5/57) reported having 

received information on fertility preservation options before the survey. 

Women who have been pregnant were significantly less likely to consider 

fertility preservation options prior to treatment (egg/embryo/ovarian tissue 

cryopreservation [6% vs. 50%, p�0.001]), or after treatment (egg/embryo 

donation, surrogacy or adoption [6% vs. 58%, p�0.0001]). Conclusions: 

This pilot study was designed to gather information on reproductive health 

of newly diagnosed young BC patients and to assess their willingness to 

consider various fertility preservation options before or after treatment. Our 

study population consisted of mostly women who had been pregnant and 

had children. We found that 50% of the women were unsure or wanted 

future children. Yet, only 9% had received information on fertility options 

at diagnosis. This pilot study highlights the need for education and/or 

intervention in fertility preservation options for young women with breast 

cancer. 


25s 


ER� mRNA expression in ER�-negative and triple-negative breast cancers. 

Presenting Author: Young Choi, Yale University School of Medicine, 

Bridgeport, CT 

Background: ER� is the main prognostic and therapeutic marker in breast 

cancer (BC). About 30% of BC cases are negative for ER (ER�-) and do not 

benefit from antiestrogen therapy (TAM). We aim to study ER-beta (ER�) 

expression in ER�- and triple negative (TN) cancers to explore alternate 

pathway of treatment in this cohort. Methods: We studied 67 ER�- BC cases 

including 44 TN together with 74 ER� �BC cases obtained from patients 

aged 29 to 97 years old between 2003 and 2010. The histology included 

110 intraductal, 12 medullary and 19 other types. 78 cases were grade 3, 

52 were grade 2, and 11 were grade 1. RNA was extracted from FFPE and 

mRNA levels of ER� isoform and ER� were determined by real-time 

quantitative reverse transcription PCR. IHC stains were done on TMA the 

sections for ER�, PR, Her-2, Ki-67, CK5/6 and Cyclin D1. Results: ER� 

isoforms were highly expressed in ER�-, TN, basal-like and HER2 type BC 

cases. ER�2 was the major ER� variant expressed. Ki-67 proliferating cells 

(�20% nuclear staining) were mostly in ER�- rather than ER�� cases 

(69.0% vs. 31.0%) as were cyclin D1- cells (82.2% vs. 17.8%). On the 

other hand, in ER�� BC, ER� mRNA expression was consistently high and 

upregulated, and ER�, low and down regulated, and the ratio of ER�� to 

ER�� ranged from 3 to 100. ER�1, 2 and 5 were co-expressed with ER� in 

56%, 63%, and 30% of cases, respectively. Overall, ER� mRNA levels did 

not show any significant correlation with age, tumor size, lymph node status 

and histological grades. Conclusions: ER�-dependent proliferating tumor 

cells may render them more sensitive to TAM, and increase the effectiveness 

of TAM and its metabolites in ER�- and TN cases. Increased overall 

survival after adjuvant TAM ER�-BC may be directly related to ER� 

over-expression. ER� isoform is potential selective therapeutic target in a 

sub-cohort of ER�- BC. Additionally, when ER� and ER� are co-expressed, 

ER� appears to play a distinct role from its action in ER�- BC. 

Types (# of cases) ER�1* ER�2* ER�5* 

ER�- (67) 39 42 15 

TN (44) 41 46 25 

HER2� (38) 66 82 37 

HER2 type (19) 74 85 47 

Basal-like type (11) 51 64 36 

Ki-67� /ER�- (27) 55 70 37 

Grade 3 (78) 41 46 31 

Grade 2 (52) 39 54 29 

* % mRNA expression. 


Estrogen receptor (ER) signaling in normal, BRCA (B) 1 and B2 mutation 

associated, and ER-positive breast cancer (BC) mammary cells. Presenting 

Author: Elgene Lim, Dana-Farber Cancer Institute, Boston, MA 

Background: ER is expressed in �70% of sporadic BC and activates genes 

driving cell proliferation and tumorigenesis. B1 and B2 mutation associated 

BC have predominant triple negative and ER� phenotypes respectively, 

yet hormonal manipulation with oophorectomy reduces BC risk in 

both B1 and B2 carriers. We have previously performed genome-wide 

analysis of ER binding sites in MCF-7 BC cells, and identified distinct 

mechanisms of ER signaling. Here, we seek to elucidate differences in ER 

signaling between non-malignant (normal, B1 and B2) and ER� BC 

mammary cells. Methods: Breast tissue were obtained from patients 

undergoing reduction mammoplasties (normal), prophylactic mastectomies 

(B1 and B2 carriers) and surgical excision of ER� BC. After 

dissociation into a single-cell suspension, ER� EpCAM�CD49f- mature 

luminal (ML) and EpCAM�CD49f� luminal progenitor (LP) subpopulations 

were obtained by flow cytometry. Following estrogen stimulation, RNA 

was extracted for gene microarray analysis. ER chromatin immunoprecipitation 

and DNA sequencing (ChIP-seq) was performed and DNA libraries 

prepared and sequenced. Results: Triplicates ofnormal, prophylactic B1 

and B2, and ER� BC tissues were analyzed.Gene ontology analysis 

indicates different gene expression signatures between non-malignant 

tissue and MCF-7 BC cells following estrogen stimulation. Genes that 

promotes cell cycling and proliferation were downregulated in nonmalignant 

tissue, but were upregulated in BC cells (P � 10-5 ). Hierarchical 

clustering of the gene microarray by mutation status revealed distinct LP 

gene signatures in normal, B1 and B2 breast tissue, whilst the ML 

signatures were largely indistinguishable between the three tissue types. 

Conclusions: There are contrasting differences in ER signaling between 

normal mammary and BC cells, with estrogen having anti-proliferative 

effects in normal luminal cells compared to pro-proliferative effects in BC. 

Our data suggest that alterations in ER signaling play a major role in breast 

tumorigenesis. Differences in the LP population between B1 and B2 breast 

tissue may account for their distinct BC phenotypes. 




Molecular subtyping using MammaPrint and BluePrint as an outcome 

predictor in 180 U.S. breast cancer (BC) patients. Presenting Author: 

Lisette Stork-Sloots, Agendia, Amsterdam, Netherlands 

Background: Combined use of MammaPrint and a molecular subtyping 

profile (BluePrint) identifies disease subgroups with marked differences in 

long-term outcome and response to neo-adjuvant therapy (Glück 

SABCS2011). The aim of this study was to evaluate the prognostic value of 

Molecular Subtyping using MammaPrint and BluePrint in women with early 

stage BC treated at US Institutions following National Comprehensive 

Cancer Network (NCCN) standard guidelines. Methods: Frozen tumor 

samples from 180 BC patients (TI-III, N0-Ib) median age 57 years at 

diagnosis (range 28-89) were suitable for hybridization on full genome 

array. MammaPrint and BluePrint Molecular Subtypes were determined 

and survival for Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint 

High Risk), HER2-type and Basal-type patients was assessed. 

Patients were treated either with breast conserving therapy or mastectomy 

with axillary lymph node dissection between 1992 and 2005. The median 

follow-up is 12.7 years. 71% was ER positive and 20% Her2 positive by 

IHC/FISH. 58% received adjuvant endocrine therapy (ET) (excluding 13 

patients unknown treatment), 64% received adjuvant chemotherapy (CT) 

(excluding 12 patients unknown treatment) and 33% received both. 

Results: 61 (34%) Patients with MammaPrint Low Risk/Luminal-type 

(Luminal A) showed 5-year DFS of 97% (34% received CT and 69% ET) 

and 50 (28%) patients with MammaPrint High Risk/Luminal-type (Luminal 

B) had a 5-year DFS of 98% (60% received CT and 68% ET). Patients with 

BluePrint Basal-type tumors (46 (26%)) had a 5-year DFS of 80% (78% 

received CT); HER2-type (23 (13%)) had a 5-year DFS of 78% (87% 

received CT without HER-2 targeted therapy). Conclusions: In this retrospective 

study evaluating 180 US patients with early BC treated according to 

standard guidelines we showed how combining BluePrint with MammaPrint 

can detect molecularly defined subgroups of patients who are at 

high risk of recurrence (HER2 and Basal-type). Furthermore, we confirmed 

that molecularly defined Luminal type disease is associated with excellent 

disease-free survival. MammaPrint and BluePrint molecular and prognostic 

stratification should be prospectively evaluated for therapeutic selection. 


Breast cancer in Sub-Saharan Africa: 1,000 patients with primary breast 

cancer in Addis Ababa followed for up to 5 years. Presenting Author: Eva 

Johanna Kantelhardt, Department of Gynecology, Martin Luther University, 

Halle/Wittenberg, Germany 

Background: There is little information on breast cancer (BC) patients (pts) 

receiving standardized treatment in Sub-Saharan Africa. This study evaluates 

pts presenting 2005-10 at the University Radiotherapy Center in 

Addis Ababa, the only institution in the country offering standardized 

radiotherapy, systemic therapy and free endocrine treatment (ET) during 

that time. Methods: All pts with histologically verified BC were included. 

Ethical approval was obtained. Axios/AstraZenaca provided free ET. Therefore, 

the majority of pts underwent regular follow-up (FUP). We analyzed 

survival at 18 months by means of Kaplan-Meier survival analysis. We 

assumed right-censoring to be unrelated to the risk of metastasis. In a worst 

case sensitivity analysis, we considered all censored pts developing 

metastasis. Results: Pts with primary diagnosis between July 1st, 2005 and 

December 31st, 2010 were included (n�1303). The majority of pts were 

female (95.2%), most (52.3%) postmenopausal. Mean age was 44.1yrs 

(20-88yrs). Stages 1-4 presented in 3/19/53/25% respectively (36% 

unknown). Grade 2 tumors were seen in 434 out of 574 pts (58%). 

Estrogen receptor was pos. in 251 out of 381 pts (66%). Most M0-pts 

(n�942) underwent surgery (84%), received chemotherapy (59%), and 

received ET (63%). Median FUP was 18.4 months, 186 events (metastases) 

occurred. Metastasis-free survival (MFS) was 86%. Worst case 

analysis on censored observations revealed that MFS declined down to 

52%. Pts with early stage 1/2 showed a better MFS than pts with stage 3 

disease (93 to 77%). Surgery (no surgery 78% vs surgery 87%) and ET 

(79% vs 89%) improved MFS. The 5-year MFS for stage 1/2 was 78% and 

stage 3 was 38%. Conclusions: To our knowledge this is the first presentation 

of clinical features in 1300 pts with BC in Sub-Saharan Africa. Most 

pts in Addis Ababa (AA) are �45yrs and present at stage 3/4. Differences to 

5-year MFS from Europe stage 1/2 around 90% (AA 78%) and stage 3 

around 70% (AA 38%) are smaller in pts treated with surgery and ET. This 

data is consistent with overall survival in a treated pt cohort from Uganda 

stage 1/2: 74% and stage 3/4: 39% (n�285) (Gakwaya Brit J Cancer 

2008). Policies should focus on earlier presentation and access to care. 


Complementary role of Ki67 index and 70-gene signature (MammaPrint) 

high-risk patients in the St Gallen risk group with uncertain chemotherapy 

suggestion. Presenting Author: Paolo Pronzato, Department of Medical 

Oncology, National Institute for Cancer Research, Genova, Italy 

Background: St Gallen (SG) Consensus Panel on adjuvant treatment 

recommends the use of proliferation markers and multigene assays when 

choosing the appropriate treatment in addition to traditional parameters. 

Ki67 predictive/prognostic value is widely accepted; we tested its role in 

increasing the accuracy of risk prediction among Mammaprint (MP) 

/High(HR) or /Low Risk (LR) breast cancer patients with a SG risk uncertain 

for chemotherapy selection. Methods: MP was determined (courtesy of 

Agendia, Amsterdam) in 3 Italian Hospitals on 305 consecutive samples of 

breast cancer patients. We focused on SG “Intermediate Risk” Group 

(HER2 neg, no VI and: ER�10�50%, or G2 or Ki67 �15�30% or N1a or 

T�2�5cm), where the indication for adjuvant CHT still remains uncertain. 

In MP/HR cases, a “low” Ki67 value (�15%) was used to eliminate CHT 

suggestion and viceversa an “intermediate” Ki67 value (�15�30%) in 

MP/LR cases. Results: Overall, 72/305 pts (26.6%) were in SG intermediate 

risk group with a median age of 64 years (26-98). Ki67 was non 

available in 4.1% of cases, MP rejected in 16.6%, HR was detected in 39 

(54.2%), whereas LR in 21 (29.2%). Ki67 resulted low in 23 MP/HR cases 

(59%), intermediate in 6 MP/LR cases (28.5%) and in 3 out 12 

MP/Rejected cases (25%). The overall concordance between MP and Ki67 

was 28/57 (49.1%), MP rejected excluded. Overall MP suggested 39/60 

CHT (65%), Ki67 29/69 (42%). Conclusions: The risk of relapse is a 

continous variable and MP evaluates it in a dichotomy (low vs high) wich 

could decrease the accuracy of the test. In the selected SG Group, the 

average risk of 5 yr relapse is around 20% (EBCTCG, Lancet 2011) and MP 

HR cases in our experience account for 55%. A low Ki67 value could help 

avoid more than 20% of cytotoxic treatments suggested by MP. In the same 

way, according to an ER value �50% (2 cases), an intermediate Ki67 value 

could suggest a more aggressive treatment in a further 13% of cases MP LR 

(6/21) or Rejected (3/12). MP probably overestimates the risk in 20% of 

cases and underestimates it in further 20%. Ki67 could be usefull for a 

more personalized treatment in patients where the indication for adjuvant 

chemotherapy added to endocrine treatment is uncertain. 


Assessment of method of breast cancer detection and Oncotype DX 

recurrence score. Presenting Author: Ciara Marie Kelly, Mater Misericordiae 

University Hospital, Dublin, Ireland 

Background: Data indicate that screen-detected (SD) cancers show more 

favourable pathological characteristics and have a better prognosis compared 

to symptomatic or interval cancers (SY). These findings can be partly 

explained by length time and lead time biases. OncotypeDX recurrence 

score (RS) provides prognostic information independent of traditional 

clinicopathological variables and provides a robust measure of tumour 

proliferation. The objective of this study was to determine whether the RS 

would vary depending on the method of detection (MOD) in patients with 

lymph node-negative, ER-positive, HER-2 negative breast cancer (BC). 

Methods: We included patients with ER-positive, lymph node-negative and 

HER2-negative BC who underwent OncotypeDX testing as part of routine 

care or a clinical trial. We retrospectively reviewed patient charts and 

extracted information on MOD (SD versus SY), clinicopathological variables 

and RS. Chi-squared test was used to test for differences between 

categorical variables and MOD. Analysis of variance (ANOVA) was used to 

investigate the relationship between RS and MOD and clinicopathological 

variables. Results: We identified 596 patients from 4 academic hospitals 

(Mater University Hospital n� 98 (16%), St Vincent’s Hospital n� 161 

(27%), Waterford Regional Hospital n� 27 (4%) and University of Texas, 

MD Anderson Cancer Center n� 310 (52%)). There were 359 (60 %) SDdetected 

and 237 (40%) SY-detected breast cancers. Clinicopathological 

variables were similar for age at diagnosis (56 versus 52 years), tumour size 

(16mm versus 18mm), grade (63% versus 61% grade 2; 15% versus 15% 

grade I; 21% versus 24% grade 3) and LVI (18% versus 18%) for SY 

compared to SD, respectively. The number of patients in each group with 

low (51% versus 50%), intermediate (41% each) or high (8% versus 9%) 

RS was similar in the SD compared to SY groups, respectively. There was a 

statistically significant association between RS and tumour grade 

(P��0.001) and lymphovascular invasion (P��0.001). We did not 

observe a statistically significant association between RS and MOD 

(P�0.086). Conclusions: In patients with clinically intermediate breast 

cancer sent for OncotypeDX testing we found no association between RS 

and MOD. 



Relationship between body mass index (BMI) at diagnosis of ER� node negative 

breast cancer (BC) and Oncotype DX recurrence score. Presenting Author: 

Caroline A. Lohrisch, British Columbia Cancer Agency, Vancouver, BC, Canada 

Background: Inferior stage-adjusted survival for BC among obese (O) women has 

been reported. This may reflect differences in treatment planned for O women, in 

treatment received (due to toxicity), or in tumor biology arising in different 

cellular environments, such as high serum insulin levels, which are associated 

with a higher risk of recurrence. Methods: We examined whether overweight (BMI 

25-30) or obese (BMI �30) women had a higher Oncotype Dx Recurrence Score 

(RS) after ER�, node negative (NN) or N0i� BC than normal weight women. 

Included were all participants at the BC Cancer Agency in a RS clinical utility 

study in consecutive ER� NN, N0i� BC (n�156) at the BC Cancer Agency and 

in the TAILORx trial (n�56). Sixteen were excluded (n�5 withdrew consent; 1 

triple negative; 3 test failed; 2 her2�; 1 neoadjuvant treatment, n�4 height and 

weight missing). Results: A similar proportion of O patients had low, intermediate, 

and high RS tumors. Cancers with a high RS were more likely to be grade 3 

(55% of grade 3 tumours had high RS, 33% intermediate RS, 12% low RS) and 

fewer were strongly ER positive (69% of high RS versus 97% of intermediate and 

low RS). Conclusions: While this data does not support differences in tumor risk 

arising in O versus non obese environments in ER�, NN BC, examination of a 

larger data set may be more informative. 

All 

RS low 

(35, n (%) 

8 (4) 

2 (2) 

4 (6) 

2 (6) 


Immunocytochemistry staining for ER and PR in circulating tumor cells as 

compared to primary tumor or metastatic biopsy. Presenting Author: 

Farideh Z. Bischoff, Biocept Inc., San Diego, CA 

Background: Hormone receptor (estrogen receptor [ER] and progesterone 

receptor [PR]) status in all breast cancer patients is recommended for 

selection of treatment options. However, the analytical sensitivity of 

immunohistochemistry (IHC) in detecting low levels of ER/PR is often poor 

and is likely due to methodological variation. Because biopsy is not often 

feasible in all patients with recurrent and/or metastatic breast disease, 

circulating tumor cells (CTCs) offer an attractive alternative source of tumor 

tissue for determining ER/PR status and can be monitored more readily to 

enable a more effective course of treatment. Methods: Twenty mL of 

peripheral blood was collected prospectively from 15 patients diagnosed 

with late stage metastatic/recurrent breast cancer. CTCs were isolated 

using the microfluidic OncoCEE platform. A cocktail of antibodies was 

utilized for CTC capture and detection with an expanded anti-cytokeratin 

(CK) cocktail mixture and anti-CD45. ER/PR protein expression was 

assessed by immunocytochemistry (ICC) on the cells captured within the 

microchannels and compared to IHC performed on the primary tumor or 

metastatic biopsy. Results: CK�/CD45-/DAPI� cells were located and 

assessed for ER/PR ICC. Among the 15 cases, a high concordance (13/15; 

87%) in ER/PR status between IHC and ICC results was observed. Two 

cases were found to be discordant where one was positive by IHC and 

negative on the CTCs, and the other was negative by IHC and positive on the 

CTCs. However, both cases that were discordant had low numbers of 

detected CTCs. Conclusions: There is significant heterogeneity between 

ER/PR protein expression in CTCs and primary tumor/metastatic biopsy, 

and this status may change over time due to therapy. ER/PR ICC on CTCs 

from peripheral blood using the OncoCEE platform is shown to be feasible 

with high concordance (87%) in ER/PR status between primary tumor/ 

metastatic biopsy (by IHC) and CTCs (by ICC). The significance of 

heterogeneity at the ER/PR protein level in CTCs ascertaining to the 

prognosis and predictive response to anti-estrogen therapy needs further 

evaluation in larger prospective clinical trials. 


27s 


The role of Ki-67 in molecular breast cancer classification. Presenting 

Author: George Stathopoulos, Errikos Dunant Hospital and Oncology Clinic, 

Athens, Greece 

Background: The Ki-67 antigen was identified the involvement in early steps 

of polymerase I-dependent ribosomal RNA synthesis. Although it seems 

that the protein has an important function in cell division, its exact role is 

still obscure and there is little published work on its overall function. The 

aim of the present study is to evaluate the contribution of Ki-67 level in 

respect of tumor recurrence in molecular classified groups of breast cancer 

patients. Methods: Breast cancer tumor samples were examined for 

histological confirmation and for estrogen and progesterone receptors, 

c-erb-B2 expression, proliferation with Grade and Ki-67. Ki-67 was divided 

in percentage levels, up to 20 and higher than 20%. Immunohistochemistry 

and Fluorescence in situ hybridization is described for the results of ER, 

PR, c-erb-B2, Ki-67 biomarkers. Formaldehyde – fixed breast samples were 

paraffin wax embedded and processed for paraffin sections. The primary 

antibodies used were: The monoclinal antibody ID5 (M7047, Dakocytomation, 

Carpinteria, CA) for the detection of ER, the monoclonal anti-PR 

antibody 636 was used. For the detection of Ki-67 we used monoclonal 

mouse anti-human Ki-67 MIB-1. The patients molecular classification was 

Luminal A, Luminal B, Her-2 subtype and basal cell (triple negative). 

Results: 847 breast cancer patients were recruited. 291 were group as 

Luminal A, 228 as Luminal B, 221 Her-2 subtype and 107 triple negative. 

Follow-up was from 3 years to 15 years since diagnosis. It was found that in 

Luminal A patients, none had Ki-67 higher than 20% and the recurrence 

was in 10.65%. In Luminal B, the Ki-67 was higher than 20% in 61% of 

the patients and recurrence 23.68%. In Her-2 subtype �20% Ki-67 was 

78.94%, recurrence 17.19%. In triple negative � 20% Ki-67 was in 

68.75% and recurrence in 29.90% of the patients. Conclusions: The data 

presented here indicate that Ki-67 level may be considered as one of 

valuable biomarkers in breast cancer patients process and recurrence. 


Correlation, comparison, and combined analysis of Ki-67 and histological 

grade for early luminal breast cancer. Presenting Author: Yoichi Naito, 

National Cancer Center Hospital East, Chiba, Japan 

Background: Both Ki-67 and histological grade are established prognostic 

factors in patients with early breast cancer. Recent international expert 

consensus employs Ki-67 to classify luminal breast cancer, and histological 

grade is described as an alternative. We investigated the prognostic 

value of Ki-67, histological grade, and their combination. Methods: Patients 

with early breast cancer treated with surgery between January 2000 and 

December 2008 were retrospectively reviewed. Inclusion criteria were as 

follows: estrogen receptor positive, HER2 negative, available for Ki-67 and 

histological grade. Clinicopathological data were retrieved from medical 

records. Ki-67 labeling index was investigated using MIB-1 antibody and 

subdivided into three categories: low 0-9%; intermediate 10-19%; high 

�20%. Histological grade was scored between 1 and 3. Disease-free 

survival (DFS) was defined as time from surgery to the first documented 

disease recurrence or death. Ki-67 categories and histological grade were 

analyzed respectively and then concomitantly for prognostic impact on 

DFS. Results: A total of 606 patients were included. Median age was 58 and 

28.1% were over 65 years. 65.4% were postmenopausal women. Progesterone 

receptor was positive in 84.0% of patients. 29.6% received neoadjuvant 

or adjuvant chemotherapy. Number of lymph node metastasis was 0 in 

70.0%, 1-3 in 21.3%, and �4 in 8.7% of patients. Ki-67 categories and 

histological grade showed weak but significantly correlation (Spearman’s 

rho � 0.385, p�0.001). High Ki-67 and histological grade 3 were 

correlated with worse prognosis to the same extent (HR 2.518, p � 0.002 

and HR 2.541, p � 0.048, respectively). For combined analysis, patients 

represented concomitant with high Ki-67 and histological grade 3 showed 

worse prognosis compared with those with Ki-67 low and histological grade 

1 (HR 3.137, p � 0.021). Conclusions: Ki-67 and histological grade were 

significantly but weakly correlated. Combined use of these two factors 

could better predict recurrence of early luminal breast cancer. 




Relapse rate after adjuvant trastuzumab in the northeast of Italy: Preliminary 

data from a multicenter observational study in a clinical setting. 

Presenting Author: Giorgio Mustacchi, UOC Centro Oncologico, ASS1 Friuli 

Venezia Giulia/Università, Trieste, Italy 

Background: Relapse Rate (RR) after adjuvant trastuzumab (AT) reported in 

clinical trials is between 15 and 21%. Information on RR and clinical 

behaviour of HER2-POS metastatic disease after AT outside clinical trials 

is limited. At ASCO Meeting 2010 RR was reported 8% (Abs 1080) to 10% 

(Abs 684), with a Survival Post Progression (SPP) of 8.8 and 5.7 months, 

respectively. It is useful to increase informations about metastatic HER2- 

POS disease after AT, outside clinical trials. Methods: HER2-POS consecutive 

cases treated with AT in 6 Hospitals of North East Italy were 

anonymously collected and merged. The following data were analyzed: 

Stage, ER/PgR Status, Chemotherapy regimens (CHT) , follow up, RR, 

Disease Free Survival (DFS), Overall Survival (OS) and SPP. Results: The 

number of patients was 413, median age 55 (24-84). Anatomic Stage was I 

in 39.7%, II in 40,3%, III in 24.4%. ER/PgR neg cases were 164 (41.6%). 

Given CHT were Anthra-based 33.4% and Anthra-Taxane 54.5%. At a 

mean follow up of 35 months (7-115) RR was 10.8% (45 cases), with a 

mean DFS of 23.8 months (3.2-74). Among relapsed patients, 37/45 

(82.2%) had ER/PgR neg tumors. One patient died NED for CHF and 22 for 

metastatic disease, with a mean OS of 37.1 months (10.2-87.9). Mean 

SPP was 17.8 months. According to DFS �12 mos , �12�24 and �24, 

mean OS was 31.3, 31.7 and 56.12(p�0.03) months; SPP was 24.2, 

14.4 and 17.8 months, respectively. Conclusions: In our experience RR 

after AT is lower than in published Phase III clinical trials. ER/PgR neg 

status seems a negative prognostic factor (82.2% in the relapsed population 

vs 41.6% overall). OS is similar for patients relapsed within 24 months 

but SPP is 10 months longer in very early relapses. Relapse after 2 years is 

correlated with a long OS (nearly 5 years), with SPP shorter vs early relapse 

(17.8 vs 24.2 months). Our preliminary results suggest different disease 

behaviors in relapsed HER2-POS Breast Cancer after AT, with different 

DFS and SPP, suggesting a different effect of further therapies. Considering 

the small RR, the study target accrual is proceeding to collect up to 

more than 1000 AT treated patients, including post-progression treatments, 

not available at the moment. 


A multicenter phase II trial of the LH-RH analogue and an aromatase 

inhibitor combination in premenopausal patients with advanced or recurrent 

breast cancer refractory to an LH-RH analogue with tamoxifen: JMTO 

BC08-01. Presenting Author: Reiki Nishimura, Kumamoto City Hospital, 

Kumamoto, Japan 

Background: The aim was to provide an endocrine therapy option against 

advanced (ABC) or recurrent breast cancer (RBC) in premenopausal 

women. We conducted an exploratory phase II trial in combination with an 

LH-RH analogue (LH-RHa) and an aromatase inhibitor (AI) to assess the 

efficacy and tolerability after failure of standard LH-RHa plus tamoxifen 

(TAM). Methods: Premenopausal patients (pts) with ER� and/or PgR� ABC 

or RBC refractory to LH-RHa � TAM were treated with LH-RHa (goserelin: 

GOS) and AI (anastrozole: ANA). The primary endpoint was an objective 

response rate (ORR). Secondary endpoints included progression-free survival 

(PFS), overall survival (OS), clinical benefit rate (CBR) based on 

RECIST, and safety assessed using CTCAE ver. 3.0. Pts with only bone 

legions were assessed using the criteria by Japanese Breast Cancer Society 

(14th Ed.). Local assessment (CR, PR or long SD of 24 weeks or longer) was 

confirmed independently by two radiologists. Results: Between September 

2008 and November 2010, 37 pts were enrolled at 10 clinical institutions 

in Japan. Eleven had recurrence either during, or within one year after the 

end of adjuvant GOS � TAM (including GOS � TAM followed by only TAM). 

The disease progressed in 26 women during GOS � TAM. Mean age and 

BMI were 43.5 years and 22.2 kg/m2, respectively. Thirty-five pts (94.6%) 

were ER�, and 36 pts (97.3%) were HER2- (one with unknown HER2 

status). Non-endocrine treatment included chemotherapy (20 pts; 54%) 

and radiation therapy (13 pts; 35%). The viscera, soft tissue, and bones 

were treated in 17, 15 and 14 pts, respectively. Pts with both measurable 

lesions and bone metastasis, measurable lesions only, and only bone 

metastasis were 21 (57%), 15 (41%) and 1 (2%), respectively. ORR was 

18.9% (95%CI: 8.0-35.2%, 1 CR and 6 PR cases), CBR 62.2% (23 pts, 

95%CI: 44.8-77.5%), and median PFS was 7.2 months. Eight pts 

(21.6%) had adverse events, but none resulted in treatment discontinuation. 

GOS � ANA was well tolerated. Conclusions: LH-RHa (GOS) � ANA 

can be a subsequent endocrine treatment for premenopausal pts with ABC 

or RBC after failure of GOS � TAM. 


Endocrine therapy in early breast cancer: Encouraging observations in a 

nontrial setting. Presenting Author: Susan Faye Dent, The Ottawa Hospital 

Cancer Centre, Ottawa, ON, Canada 

Background: Poor adherence to adjuvant endocrine therapy (ET) in women 

with hormone receptor positive (HR �) early breast cancer (EBC) is well 

documented. Given the availability of multiple ET strategies [aromatase 

inhibitor (AI) upfront, tamoxifen (TAM) to AI, AI after 5 years TAM], we 

evaluated the delivery of ET in a non-trial setting. Methods: Postmenopausal 

women with HR � EBC treated with ET (that included an AI) at 

The Ottawa Hospital Cancer Center between 01/99 and 12/06 were 

included. Data was retrospectively collected and included: demographics, 

choice/duration of ET, adherence and toxicities. Results: In 626 patients 

(pts), median age 59 years (r: 30-92) with stage I (195 pts; 31 %), stage II 

(339 pts; 54 %) and stage III (88 pts; 14 %) EBC. Treatment strategies 

included: AI (s) only (251 pts; 40 %); TAM followed by AI (s) (323 pts; 

51.6 %); AI (s) followed by TAM (16 pts; 2.6 %); TAM-AI (s)-TAM (24 pts; 

3.8 %) and unknown (12 pts; 1.9 %). Prescribed AI therapy (upfront or 

sequential) was discontinued in 39 % of cases mainly due to toxicity (62.5 

%) after median of 6, 9, or 12 months (ms) on exemestane, anastrazole and 

letrozole respectively. Common toxicities included: arthralgias (40.6 %), 

hot flushes (34 %), fatigue (25 %), myalgias (24.7 %) and osteoporosis 

(22.5%). In cases (177) where AI therapy was discontinued due to toxicity: 

98 received no further ET, 29 TAM and 50 another AI. The majority of pts 

received at least 5 years of ET (79 %; median duration 64 ms; r 1-156 ms) 

and 376 pts (60 %) completed at least 5 years of AI therapy (median 

duration 59 ms; r: 1-124 ms). 9.9 % of pts are still receiving ET. 

Conclusions: This is one of the first non-clinical trial studies to demonstrate, 

that despite poor adherence to initial ET, the majority of women are able to 

complete five years of treatment (79 %). These results are encouraging and 

reflect the practical use of mutilple endorcrine strategies that have been 

shown to be efficacious in this pt population. 


Multiple chemotherapy (CT) lines in metastatic breast cancer (MBC): 

Which survival benefit for women with hormone receptor (HR)-positive 

disease? Presenting Author: Raffaella Palumbo, Fondazione Maugeri- 

IRCCS, Pavia, Italy 

Background: Although the development of modern systemic therapies has 

clearly improved outcome of patients with MBC, the true impact of further 

CT on overall survival (OS) and QoL of these women is still debated. The aim 

of this study was to determine which benefit could be brought by successive 

CT lines in patients with HR-positive disease, aiming to identify factors 

affecting outcome and survival. Methods: This retrospective analysis 

included 980 women treated with CT for MBC at our Institution over a eight 

year period (July 2000-July 2008). With OS data updated in March 2010, 

the median follow-up was 146 months (range 48-198), OS and time to 

treatment failure (TTF) were calculated according to the Kaplan-Meyer 

method for each CT line. Cox proportional hazards model was used to 

identify factors that could influence TTF and OS. Results: Median OS 

evaluated from day 1 of each CT line decreased with the line number from 

34.8 months for first line to 8.2 months for 7 or more lines). Median TTF 

ranged from 9.2 months to 7.8 and 6.4 months for the first, second and 

third line, respectively, with no significant decrease observed beyond the 

third line (median 5.2 months, range 4.8-6.2). No statistically significant 

difference was found between HR-positive and HR-negative patients in 

terms of OS and TTF by each CT line. In univariate analysis factors 

positively linked to a longer duration of TTF for each CT line were positive 

hormonal receptor status, more than 3 hormonotherapy lines, absence of 

liver metastasis, adjuvant CT exposure, response to CT for the metastatic 

disease; in the multivariate analysis the duration of TTF for each CT line 

was the only one factor with significant impact on survival benefit for 

subsequent treatments, in both HR-positive and negative populations 

(p�0.001). Conclusions: Our results support the benefit of multiple lines of 

CT in a significant subset of women treated for MBC, since each CT line 

may contribute to a longer OS. Of interest, such a benefit was also observed 

for patients with HR-positive disease, although the number of hormonotherpy 

lines received did not significantly influence the outcome. 



Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in ER� 

HER2- breast cancer. Presenting Author: Hiroshi Yagata, St. Luke’s 

International Hospital, Tokyo, Japan 

Background: Recently, docetaxel plus cyclophosphamide (TC) has been 

established as a standard regimen for adjuvant chemotherapy in operable 

breast cancer. However, the efficacy of TC as neoadjuvant chemotherapy 

remains unclear, especially in hormone-responsive breast cancer. We 

prospectively evaluated the response to TC neoadjuvant chemotherapy in 

patients with ER� HER2- operable breast cancer. Methods: Eligible 

patients had ER� and HER2- invasive breast cancer that measured more 

than 2 cm in diameter or was node-positive clinically between March 2009 

and February 2011. Four cycles of TC (75 and 600 mg/m2 ) were 

administered intravenously every 3 weeks as neoadjuvant chemotherapy, 

followed by breast and axillary surgery. We investigated the clinical 

response on MRI and the pathological complete response (pCR) of primary 

invasive breast tumors. Results: We enrolled 43 patients in 45 lesions. 

Allred score of ER was 7 to 8 in 40 lesions, 6 in 3 lesions and 4 in 2 lesions. 

PgR was 7 to 8 in 31 lesions, 5 to 6 in 6 lesions, 3 to 4 in 5 lesions, and 0 in 

3 lesions. Nuclear grade was 1 in 31 lesions, 2 in 7 lesions, and 3 in 7 

lesions. MIB-1 index was median 22% (range, 6 to 71%) in 40 measurable 

lesions. Clinical response (CR and PR) was observed in 33 lesions (73%) 

and SD in 12 lesions without any lesions of clinical PD. pCR was achieved 

in only 1 lesions (ER 8, PgR 3, Nuclear grade 3, MIB-1 index 32.6%). 

Conclusions: Neoadjuvant TC produced a good clinical response in ER� 

HER2- operable breast cancer, while the pCR rate was very low, regardless 

of the characteristics of cancer cells. Therefore, pCR is not an appropriate 

prognostic factor in women with ER� HER2- operable breast cancer who 

receive neoadjuvant TC. Whether clinical response is related to survival 

should be addressed in future studies. The efficacy of neoadjuvant TC in 

ER� HER2- operable breast cancer is very limited, and more effective 

regimens are needed to achieve higher pCR rates. 


ESR1 gene amplification and protein expression in 946 patients with 

resected breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) 

translational research study. Presenting Author: George Pentheroudakis, 

Hellenic Cooperative Oncology Group, Athens, Greece 

Background: Discrepant data have been reported on the incidence of ESR1 

gene amplification in breast cancer, its correlation to clinicopathologic 

characteristics and its impact on prognosis. Methods: Formalin-fixed 

paraffin-embedded (FFPE) tumor tissue samples from 946 patients participating 

in two adjuvant chemotherapy phase III trials (HE10/97 and 

HE10/00) were centrally assessed in tissue microarrays by immunohistochemistry 

(IHC) for estrogen receptor (ER), progesterone receptor (PgR) 

and human epidermal growth factor receptor 2 (HER2). FISH was also 

performed for HER2, TOP2A and ESR1 using commercially available dual 

(for ESR1) and triple (for HER2 and TOP2A) hybridization probes. Results: 

The majority of patients had �T2 (69%), node-positive, ER-positive (�1% 

stained cells, 73%) tumors managed with resection, chemotherapy and 

hormonotherapy (76%). Only 38 tumors (4.0%) had ESR1 gene amplification 

(ESR1/CEN6 ratio �2) and 514 (54.3%) ESR1 gene gain (1�ratio�2). 

The number of ESR1 gene copies was 3-4 in 251 (26.5%) and 

5-10 in 42 (4.4%) of cases. HER2 and TOP2A gene amplification was seen 

in 234 (25.3%) and 101 (10.9%) of tumors, respectively. We studied the 

immunohistochemical expression of ER protein by evaluating the percentage 

of stained cells, the Allred score (0-2, 26.8%; 3-6, 62.5%; 7-8, 

10.7% of tumors) and the semiquantitative H-Score (50-100, 13.8%; 

101-200, 36.8%; 201-300, 15% of tumors). ESR1 gene amplification 

was significantly associated with taxane therapy, age �50, postmenopausal 

status, grade III-IV, absence of HER2 amplification and ER protein 

expression (p�0.05). At a median follow-up of 92 months, univariate Cox 

regression analysis showed that ER protein expression, but not ESR1 gene 

status, was a predictor of favorable outcome. In multivariate analysis, 

tumor size �5 cm, �4 involved nodes and negative/low ER protein 

expression by Allred score were independent adverse prognostic factors. 

Conclusions: Our data showed a rather low incidence of ESR1 gene 

amplification and failed to confirm its prognostic/predictive utility. ESR1 

mRNA expression data will be presented at the meeting. 


29s 


A short-term neoadjuvant pilot study comparing exemestane and letrozole 

in postmenopausal women with estrogen receptor-positive HER2-negative 

breast cancer. Presenting Author: Daishu Miura, Toranomon Hospital, 

Tokyo, Japan 

Background: Current approaches of neoadjuvant endocrine therapy (NAET) 

are focusing on biomarker analysis of the diagnostic specimens. One of the 

important things in neoadjuvant treatment is to determine the in-vivo 

responsiveness to the agent. Little is known regarding biomarker changes in 

specific agents and the association with biomarker changes and treatment 

duration. A pilot study was conducted to investigate the differences of 

biomarker changes in short-term NAET (letrozole vs. exemestane) and also 

the difference in treatment durations of each AI. Methods: Totally 120 

samples from 60 postmenopausal women with ER positive HER2 negative 

stage 1-3 breast cancers in NAET comparing letrozole (LET) and exemestane 

(EXE) were analyzed with pre- and post-treatment mRNA expression of 

ER�,ER�, PR, HER2, Ki67, PIK3CA, and MAPK using QuantiGene Assay. 

Thirty-one patients took letrozole 2.5mg daily and 29 did exemestane 

25mg daily until the surgery (median duration 22 days). Statistical tests 

were two-sided. Results: Clinical characteristics were well balanced between 

the two treatment arms. Median % changes of Ki67 were -58%, ER� 

-44%, ER� �93%, and PR -69% in LET and Ki67 -59%, ER� -30%, ER� 

�135%, PR -72% in EXE. There were no significant differences of these 

marker changes between two agents. Dividing into 4 groups in treatment 

duration, 10-14 days (q1), 15-21 days (q2), 22-28 days (q3), and over 29 

days (q4), LET had 2 peaks in Ki67 decreases (-69% (q1), -28% (q2), 

-78% (q3), -59% (q4)), whereas EXE had a peak in q2 (-62%, -77%, 

-49%, -26%). Ki67 increasing cases including primary resistance and 

tachyphylaxis were 5 (16%) in LET (3 in q2 and 2 in q4) and 3 (10%) in 

EXE (one of each in q2-4). All 8 cases had increases of ER�, PIK3CA, and 

MAPK. Conclusions: Although both LET and EXE for short duration had 

significantly decreased Ki67 mRNA level irrespective of treatment duration, 

no significant differences was found between two agents. Tumor 

resistance with AIs may be associated with the other pathways. 


Real-world aromatase inhibitor use and failure in women with metastatic 

ER�/HER2- breast cancer. Presenting Author: Pamela Landsman- 

Blumberg, Thomson Reuters, Washington, DC 

Background: Aromatase Inhibitors (AIs) have replaced tamoxifen as firstline 

therapy for postmenopausal women with metastatic, ER� breast 

cancer (BC). However, little information is available on the real-world use of 

AIs. The objectives of this retrospective claims study were to compare 

demographic, clinical and treatment characteristics of postmenopausal 

women with metastatic ER�/HER2- BC treated with AIs and experiencing 

0, 1, 2 or � 3 AI failures (AIF). Methods: Women � 55 years old, newly 

diagnosed with metastatic BC (index) were identified in the 2006-2010 

Thomson Reuters MarketScan databases and followed until chemotherapy 

or 03/31/2011. ER�/HER2- disease was defined as any endocrine therapy 

(ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) 

use and no trastuzumab or lapatinib use in the 6-month pre-or variable 

post-index periods. Those with any post-index AI use were retained for 

study. AIF post-index was defined as a switch to an alternative AI, ET or 

chemotherapy, or AI discontinuation with no further BC treatment. Patients 

were stratified by number of post-index AIF: 0, 1, 2 or � 3. Results: Among 

4,274 patients identified, 61% had � 1 AIF (1: 80%, 2: 15%, �3: 5%). 

There was no difference in pre-index AI use across AIF cohorts: 0, 1, 2, and 

�3 (54%, 52%, 48%, 56%; p�0.073). AIFs increased with Medicareeligibility 

(51%, 56%, 60%, 61%) and bone metastases at index (48%, 

53%, 62%, 63%). Among those with �1 AIF, median follow-up (FU) 

increased with each failure but there was no notable pattern to reason for 

FU end. Median FU of the 0 AIF cohort (408 days) fell between those of the 

1 and 2 AIF cohorts, 335 and 517 days. Anastrozole was the most common 

first line treatment for all cohorts except � 3 AIFs where letrozole was most 

common. Pre-index and first line fulvestrant use both increased with the 

number of post-index AIFs: 0.3%, 1.9%, 2.0%, 5.0% and 0.7%, 2.5%, 

4.0%, 14.9% respectively. There was no association between number of 

AIFs and chemotherapy use (36%, 29%, 38%). Conclusions: Over 60% of 

women with ER�/HER2- metastatic BC treated with AIs failed at least 1 

and 20% of those failed � 2. Surprisingly, increased rates of prior 

fulvestrant treatment appear associated with increasing numbers of AIF. 




Limited efficacy and significant toxicities of lapatinib (Lap) plus chemotherapy 

as neoadjuvant therapy (NAC) for HER2-positive inflammatory 

breast cancer (IBC) patients (Pts). Presenting Author: Ricardo H. Alvarez, 

The Morgan Welch Inflammatory Breast Cancer Program and Clinic, 

University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: IBC is a rare disease but the most aggressive form of locally 

advanced breast cancer with a higher frequency of HER2 neu amplification 

(HER2�) compared to non-IBC. The EGFR pathways are also important 

therapeutic targets in IBC. (Zhang D, 2009). Lap is an oral reversible dual 

kinase inhibitor of epidermal growth factor receptor of EGFR and HER2. 

Our objective was to determine the efficacy of Lap in combination with 

paclitaxel as NAC in pts with previously untreated HER2� IBC. The primary 

end-point was to determine the rate of pathological complete response 

(pCR) defined as no residual invasive disease in the breast and the axillary 

lymph nodes or Residual Cancer Burden (RCB) of 0. (Symmans FW, 2008). 

The second endpoint was to assess general safety and cardiac toxicity of 

this combination therapy. Methods: From October 2008 to May 2011, 15 

chemo-naïve pts were treated with Lap 1,250 mg/day as a single agent for 2 

weeks, followed by 12 weeks of paclitaxel (80 mg/m2 weekly) plus Lap 

(1,000 mg/day), and finally with 4 cycles of FEC-75 mg/m2 regimen plus 

Lap (1,000 mg/day) before surgery. Among 12 first pts enrolled, 6 pts had 

grade 3 diarrhea (CTCAC v3.0) and the protocol was amended to reduce the 

Lap dose to 750 mg/day. After modified radical mastectomy (MRM), 

patients received radiation therapy and one year of adjuvant trastuzumab. 

Results: Median age was 53.8 (range, 39 -70), performance status was 0 

(13 pts), 1 (2 pts), 4 pts had metastatic disease at diagnosis. 10 of 15 pts 

had MRM. One pt achieved pCR. Five pts did not complete the NAC due to 

grade 2 cardiomyopathy (1), liver dysfunction (2), diarrhea (1), and 

insurance denial after pt started treatment (1). The trial was stopped early 

due to severe toxicity (�15%) and lack of efficacy. Conclusions: Lap in 

combination with chemotherapy as NAC has a limited anti-tumor activity in 

pts with HER2� IBC with a pCR rate of 6.6%. Lap and paclitaxel was 

associated with severe diarrhea toxicity and required multiple dose reductions 

of Lap. With the recent promising results in HER2� NAC studies, the 

role of Lap should continue to be explored in combination with other 

anti-HER2 agents in IBC patients. 


Adjuvant lapatinib in women with early-stage HER2-positive breast cancer 

(HER2� BC): Analysis of the hormone receptor-negative subgroup of the 

intent-to-treat (ITT) population of the TEACH trial. Presenting Author: Ian 

Edward Smith, The Royal Marsden Hospital, London, United Kingdom 

Background: TEACH is a randomized, double-blind, placebo (P)-controlled 

trial evaluating lapatinib (L) in reducing relapse risk in trastuzumab -naive 

patients (pts) previously treated with chemotherapy for HER2� BC. The 

primary results (presented at SABCS 2011) showed a hazard ratio (HR) for 

disease-free survival (DFS) in L arm compared with P of 0.83 (95% 

confidence interval [CI] 0.70-1.00; stratified log-rank 2-sided P�.053). 

The predefined hormone receptor negative subgroup was analyzed, which 

in contrast to the hormone receptor positive subgroup of the ITT population 

(N�3147) had a significantly improved DFS. Methods: 3161 HER2� BC 

pts (Stage I-IIIc) were randomized 1:1 to L daily or P for 1 year (yr). Primary 

endpoint was DFS in the ITT population. Central nervous system (CNS) 

recurrence rate was a secondary endpoint. A subgroup analysis by Cox 

Proportional Hazards Regression Models was performed for the hormone 

receptor negative pts from the ITT population. Results: 1288 pts (41%) 

comprised the hormone receptor negative subgroup of the ITT (L:639, and 

P:649). Median time from diagnosis to randomization was 2.4 (0.3-15) 

yrs, median follow-up was 4 yrs. Median age for this subgroup was 53 

(24-87) yrs. With 85 events in L arm and 128 in P arm, the HR for DFS for 

hormone receptor negative pts was 0.68 (95%CI 0.52-0.89) favoring L. 

Most hormone receptor negative subgroups showed benefit for L: pts up to 

1 yr from diagnosis (HR 0.64; 95%CI 0.41-0.99), node negative (HR 0.57; 

95%CI 0.35-0.92), premenopausal (HR 0.59, 95%CI 0.37-0.94), and 

those who received prior anthracycline chemotherapy without taxanes (HR 

0.63; 95%CI 0.43-0.92). Node positive patients had a trend to benefit 

from L (HR 0.74; 95%CI 0.53-1.03). CNS as one site of initial recurrence 

occurred in 1% in L (n�7) and P (n�8) arms. Conclusions: Lapatinib 

improved DFS in patients early or late in follow-up from diagnosis of 

HER2�, hormone receptor negative BC. Similar subset analyses are 

important in other large adjuvant anti-HER2 therapy trials. Results might 

provide a better understanding of the subtypes of HER2� disease and help 

to further individualized therapy. 


Neoadjuvant chemotherapy versus neoadjuvant hormonal therapy in postmenopausal 

women with ER-positive, HER2/neu negative locally advanced 

breast cancer. Presenting Author: Tadeu Frantz Ambros, Jackson Memorial 

Hospital, University of Miami, Miami, FL 

Background: Postmenopausal women with large ER�/HER-2 negative 

tumors frequently receive neoadjuvant chemotherapy (NC), but pathological 

complete response (pCR) rates are low. Neoadjuvant hormonal therapy 

(NH) may offer benefit in this setting. Methods: Retrospective review of 

medical records from University of Miami/Jackson Memorial Hospital from 

1998-2011. Primary outcomes: pCR (absence of invasive tumor in breast 

and lymph nodes at surgery), recurrence free survival (RFS) and tumor size 

reduction evaluated through comparison of palpable breast mass size at 

presentation with pathological tumor size in surgical specimen, and 

categorized as good response (GR) � 30% reduction or no response (NR) � 

30%. The Kaplan-Meier method and the log-rank test were used in the 

analysis of RFS. Results: Data from 151 post-menopausal women with 

ER�/HER-2 negative BC who received NC (57%) or NH (43%) was 

analyzed. Median follow-up among alive patients with no evidence of 

disease was 5.4 years in NC and 2.9 years in NH. Mean age was higher in 

the NH group (63.3 vs 56.1, p�0.0001). There were no racial or ethnic 

differences between the groups. Clinical stage was comparable in NC and 

NH (IIA 5.8% vs 9.2%, IIB 25.6% vs 20%, IIIA 37.2% vs 29.2%, IIIB/IIIC 

31.4% vs 41.5%, p�0.775). Tumor histology was predominantly ductal in 

both groups (NC 85.7% and NH 78.5%, p�0.247). pCR was similar in NC 

and NH (4.7% vs 0%, p�0.078) along with RFS (median 8.5 yrs vs 6.0 

yrs, p�0.946). In the NC group, GR was significantly more frequent 

(77.9% vs 60%, p�0.017). Among patients in the NH group, having GR 

was predictive of longer RFS (5-year rate 83.7% vs 50.5%, p�0.014). 

Breast only pCR occurred at equivalent rates between NC and NH (9.3% vs 

3.1%, p�0.189) as did the absence of lymph node metastasis (29.1% vs 

26.2%, p�0.606). In the NH cohort 38.5% received no adjuvant chemotherapy. 

Conclusions: NH provides an effective alternative to NC and, if 

there is a GR, may preclude the need for chemotherapy in over one third of 

postmenopausal women with large ER positive/HER-2 negative breast 

cancer. 

597^ General Poster Session (Board #8H), Sat, 8:00 AM-12:00 PM 

Adverse events with pertuzumab and trastuzumab: Evolution during treatment 

with and without docetaxel in CLEOPATRA. Presenting Author: José 

Baselga, Massachusetts General Hospital Cancer Center and Harvard 

Medical School, Boston, MA 

Background: In CLEOPATRA, the HER2-dimerization inhibitor pertuzumab 

(P) was combined with trastuzumab (T) and docetaxel (D) in HER2-positive 

1st-line MBC. P�T�D significantly improved efficacy compared with 

placebo (Pla)�T�D while having little effect on safety. Pts were recommended 

to receive �6 cycles of D but could discontinue D prior to Cycle 6 

due to poor tolerability or progressive disease (PD) or continue D beyond 

Cycle 6 at investigators’ discretion. Once D was discontinued, pts received 

Pla�TorP�T until PD. To understand the full safety profile of the regimen, 

adverse events (AEs) occurring before and after D discontinuation were 

analyzed. Methods: Treatment was given q3w (Pla/P: 840 mg loading, then 

420 mg; T: 8 mg/kg loading, then 6 mg/kg; D: 75 mg/m2 , escalating to 100 

mg/m2 if tolerated; de-escalation by 25% allowed). AEs were graded 

according to NCI-CTCAE v3.0, monitored continuously during the treatment 

period, and their relationship to study drugs was assessed by 

investigators. Results: From 808 pts enrolled, 804 were analyzed in the 

safety population (pts who received �1 dose of study treatment). AEs that 

led to discontinuation of all study treatment were experienced by 5.3% 

(Pla�T�D) and 6.1% (P�T�D) of pts, whereas discontinuation of D alone 

due to AEs occurred in 23.2% (Pla�T�D) and 23.6% (P�T�D) of pts. 

Conclusions: Treatment in both arms was well tolerated. After discontinuation 

of D, there was a clear reduction in grade �3 AEs; however, the 

incidence of grade �3 diarrhea remained slightly elevated with P�T�D. 

The AE profile of P�T is consistent with that seen in previous Phase II 

studies (Gianni Lancet Oncol 2012; Baselga JCO 2010). These data 

suggest that the combination of P�T may also be well tolerated in other 

breast cancer settings, such as in adjuvant therapy, which is currently 

under phase III study (APHINITY; NCT01358877). 

Grade >3 AEs, incidence >5%. 

Incidence during 

all study treatment 

Incidence after 

D discontinuation 

AE,n(%) 

Pla�T�D(n�397) P�T�D(n�407) Pla�T(n�255) P�T(n�298) 

Neutropenia 182 (45.8) 199 (48.9) 4 (1.6) 0 (0.0) 

Febrile neutropenia 30 (7.6) 56 (13.8) 0 (0.0) 0 (0.0) 

Leukopenia 58 (14.6) 50 (12.3) 1 (0.4) 0 (0.0) 

Diarrhea 20 (5.0) 32 (7.9) 0 (0.0) 3 (1.0) 


598^ General Poster Session (Board #9A), Sat, 8:00 AM-12:00 PM 

Quality of life assessment in CLEOPATRA, a phase III study combining 

pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. 

Presenting Author: Javier Cortes, Department of Oncology, Vall d’Hebron 

University Hospital, Barcelona, Spain 

Background: CLEOPATRA compared the efficacy and safety of the HER2 

dimerization inhibitor pertuzumab (P) plus trastuzumab (T) and docetaxel 

(D) with placebo (Pla)�T�D in HER2-positive 1st-line MBC. Pts in both 

arms received a median of 8 cycles of D; Pla/P�T was continued until 

progressive disease (PD). The safety profile in both arms was similar with a 

substantial decrease in adverse events (AEs) once chemotherapy finished. 

The independently assessed progression-free survival was significantly 

improved with P�T�D compared with Pla�T�D; objective response and 

duration of response were also improved with P�T�D (Baselga NEJM 

2012). Here we report health-related quality of life (HRQoL) data from 

CLEOPATRA. Methods: Time to deterioration of HRQoL was evaluated using 

the FACT-B questionnaire and defined as decrease from baseline (BL) of 

�5 points in the TOI-PFB subscale score. Female pts completed questionnaires 

every 3rd cycle of therapy within 3 days before each tumor 

assessment until independently determined PD. An exploratory analysis 

investigated time to deterioration in breast cancer symptoms and functions. 

Results: 56.7% (Pla�T�D) and 59.5% (P�T�D) of pts experienced 

deterioration of HRQoL during the study based on TOI-PFB. The median 

time to deterioration was 18.3 vs 18.4 wks (~6 cycles) (HR 0.97; P � 

.7161). At Cycle 6, the mean reduction in TOI-PFB score from BL was –3.5 

(Pla�T�D) vs –3.0 (P�T�D). At subsequent cycles, when most pts had 

discontinued D, mean reductions were smaller, suggesting that after an 

early decline patients’ scores improved slightly. Overall, mean changes 

were small in both arms. Compliance with completion of the FACT-B 

questionnaire was �75% beyond the 1st year in both arms. An exploratory 

analysis suggested that time to deterioration in BCS score, which measures 

symptoms and issues relevant in breast cancer, was delayed with P�T�D 

(18.3 vs 26.7 wks; HR 0.77; P � .0061). Conclusions: Combining P with 

T�D appears to have no detrimental effect on HRQoL. Results suggest that 

P�T�D is associated with a substantial delay in the time to deterioration in 

BCS score as would be expected given the improved efficacy and the low 

incidence of AEs once D is discontinued. 


Trastuzumab-related cardiotoxicity among older breast cancer patients. 

Presenting Author: Mariana Chavez-Mac Gregor, University of Texas M. D. 


Background: The use of trastuzumab in the adjuvant setting is associated 

with reduction in mortality and recurrence. Although trastuzumab is 

extremely well tolerated, its use is associated with congestive heart failure 

(CHF). The incidence of this complication in the general population 

remains largely unknown, especially in older patients. In this study we 

evaluated the rates and risk factors associated with trastuzumab-related 

CHF in a large cohort of older breast cancer patients. Methods: Breast 

cancer patients � 66 years with full Medicare coverage, diagnosed with 

stage I-III breast cancer between 2005-2007, and treated with chemotherapy 

were identified in the Surveillance, Epidemiology and End Results- 

Medicare (SEER-Medicare) database. Chemotherapy and trastuzumab use, 

comorbidities and CHF were identified using ICD-9 and HCPCS codes. 

Analyses included descriptive statistics, Cox proportional hazard model 

using trastuzumab as a time-dependent variable and logistic regression. 

Results: A total of 3,983 patients were included, 847 (21.7%) of them 

received trastuzumab, median age of the entire cohort was 71 years old. 

Among trastuzumab users the rate of CHF was 28.6% compared to 18.1% 

in non-trastuzumab users (p�.0001). After adjusting for demographic and 

clinical characteristics, comorbidities, and type of chemotherapy used, 

trastuzumab users were more likely to develop CHF than non-trastuzumab 

users (HR 1.74; 95% CI 1.47-2.06). Among trastuzumab users, older age 

did not further increase the risk, however history of coronary artery disease 

(OR 2.23; 95%CI 1.56-3.19), heart valve disease (OR 1.41; 95%CI 

1.41-2.88) and emphysema -as a proxy for smoking- (OR 2.03; 95% CI 

1.13-3.63) significantly increased the risk of CHF. There was a trend for 

increased risk of CHF associated with anthracycline use (OR 1.36; 95% CI 

0.93-2.00). Conclusions: In this large cohort of older breast cancer 

patients, the risk of CHF among trastuzumab users was 1.74 times higher 

than non-trastuzumab users, which is higher than what has been reported 

in younger clinical trial participants. Among older breast cancer patients 

treated with trastuzumab, cardiac comorbidities and emphysema may 

identify high risk patients. 


31s 


Impact of hormone receptor (HR) status on clinicopathological features, 

patterns of recurrence, and clinical outcomes among patients (pts) with 

human epidermal growth factor receptor-2 positive (HER2) breast cancer 

(BC) in the National Comprehensive Cancer Network (NCCN). Presenting 

Author: Ines Maria Vaz Duarte Luis, Dana-Farber Cancer Institute, Boston, 

MA 

Background: According to gene expression profiling, HER2� BC is heterogeneous 

and appears to diverge by HR status. Methods: We evaluated 3394 

pts who presented to NCCN centers with stage I-III HER2� BC between 

2000-07. Pts were classified as HR� (ER� and/or PR�) and HR- (ER- and 

PR-). Chi-square, univariate logistic regression, log-rank test, and Cox 

hazard proportional regression were used for analysis. Results: Median 

follow-up was 51 months. 59% of patients had HR� and 41% HR- disease 

respectively. Pts with HR- BC were more likely to be postmenopausal and to 

present with higher stage and high grade disease (p�0.001). Most pts 

received adjuvant or neoadjuvant therapy; 44% received adjuvant trastuzumab. 

Recurrences were recorded for 458 pts. HR- patients were more 

likely to recur first in the central nervous system (CNS) (OR: 1.8, 95% CI: 

1.1, 2.9; p� 0.03) and less likely to recur in bone (OR: 0.5, 95% CI: 0.3, 

0.8; p�0.01). No differences in risk of lung or liver recurrence were 

observed. Combining first and subsequent sites of recurrence, the difference 

in CNS involvement was lost (p�0.107) but HR- were more likely to 

experience lung involvement (OR: 1.5, 95% CI: 1.0, 2.2; p� 0.05). After 

adjusting for age, year of diagnosis (y), race, stage, and grade, HR- had 

worse survival after initial BC diagnosis than HR� pts (Hazard Ratio of 

death [HRd] 1.4, 95% CI: 1.14, 1.7; p�0.01). However, the risk of death 

was not proportional over time with HR- having significantly increased 

hazard in the first five years: HRd 0-2 y 1.9 [1.3, 2.9]; p� 0.01; HRd 2-5y 

1.5, [1.2, 2.0]; p�0.01; HRd 5� y, 0.8, [ 0.6, 1.2], p�0.29. Conclusions: 

Clinicopathological features, sites of recurrence, and risk of death over time 

for HER2� BC differed by HR status. This suggests that HR status in 

HER2� BC is clinically relevant. These differences should be further 

explored from a mechanistic and therapeutic standpoint. 


Impact of adjuvant trastuzumab-based chemotherapy in T1ab nodenegative 

HER2 overexpressing breast carcinomas. Presenting Author: 

Jean-Sebastien Frenel, Institut de Cancerologie de l’Ouest/Site Rene 

Gauducheau, Saint-Herblain, France 

Background: HER2 overexpression has been recognized as a pejorative 

prognostic factor in node negative T1ab (T1abN0) breast tumors. Randomized 

clinical trials have shown benefit of adjuvant trastuzumab-based 

chemotherapy (ATBC) for node-positive and/or greater than 1 cm (T1c or 

more) HER2� breast carcinomas. There are no prospective efficacy data of 

ATBC in T1abN0 HER2� tumors. Methods: We retrospectively evaluated 

276 cases of T1ab node-negative HER2� breast tumors in 8 French 

Comprehensive Cancer Centers. We assessed clinical, therapeutic features 

and outcome. We estimated the probability of disease-free survival (DFS), 

analyzed associations of ATBC, patient and tumor characteristics with DFS 

and prognosis factors using the log-rank test, multivariate analysis with 

logistic regression and Cox’s proportional hazards model. Results: Out of the 

276 T1abN0 cases, 129 (47%) received ATBC (ATBC�) and 123 (45%) 

were not treated by either trastuzumab or chemotherapy (ATBC-). Of these 

252 ATBC� or ATBC- patients, decision of ATBC was associated with date 

of diagnosis (before or after ASCO 2005 Annual Meeting when interim 

results from three trastuzumab adjuvant trials were reported) and with poor 

prognosis features: negative hormone receptors (HR-) status, Elston-Ellis 

high grade, tumor size � 5 mm and age. With a median follow-up of 44 

months 16 recurrences were observed (13 in the ATBC- group, 2 in the 

ATBC� and 1 with adjuvant chemotherapy alone). Nine recurrences were 

distant metastases. A survival benefit in ATBC� was observed with a 99% 

40-months DFS versus 93% for ATBC- (logrank p-test � 0.018). In an 

exploratory analysis, two factors were significantly associated with worst 

prognosis for ATBC- that were not observed for ATBC� : HR- status (98% 

40-months DFS for ATBC� patients versus 84% for ATBC- patients; 

logrank p-test � 0.0003) and presence of lymphovascular invasion (100% 

40-months DFS for ATBC� versus 73% in ATBC- cases; logrank p-test � 

0.003). Conclusions: In our seriesATBC is associated with a significant 

reduction of risk of recurrence of T1abN0 HER2� tumors. A clear DFS 

benefit of ATBC was observed in HR- tumors and/or in presence of 

lymphovascular invasion. 




Neoadjuvant bevacizumab (B) and trastuzumab (T) in combination with 

weekly paclitaxel (P) as neoadjuvant treatment in HER2-positive breast 

cancer: Results from a phase II trial (AVANTHER). Presenting Author: 

Maria Fernandez Abad, Centro Integral Oncológico Clara Campal, Madrid, 

Spain 

Background: B in combination with T has showed meaningful activity in 

patients (pts) with metastatic HER2-positive breast cancer. AVANTHER is 

a Phase II trial of preoperative systemic therapy combining B with T and P 

in a weekly regimen in HER2 positive breast cancer to assess safety and 

efficacy of the combination. Methods: Pts with centrally-confirmed HER2positive 

(IHC 3� or FISH positive) breast cancer (stage II or III including 

locally advanced) received neoadjuvant chemotherapy (NC) with weekly P 

(80mg/m2 /week) for 12 weeks in combination with weekly T (4mg/kg 

loading dose and 2 mg/kg maintenance) and B (15mg/kg every 3 weeks) for 

4 cycles. After surgery all pts received T (1 year) and liposomal doxorubicin 

plus cyclophosphamide every 3 weeks (4 cycles); primary endpoint was rate 

of pathological complete response (pCR) in breast and axilla. For all 

patients, a tissue sample at baseline as well as at surgery was collected for 

biomarker analyses. Results: A total of 44 pts have been enrolled. Median 

tumor size: 3.9 cm. Seven (19.4%) pts had stage IIA; 17 (47.2%) stage 

IIB; 8 (22.2%) stage IIIA and 4 (11.1%) stage IIIB. Twenty-one (58.3%) 

pts had both positive-hormonal receptors and 10 (27.8%) were hormone 

receptor negative. Eight (22.2%) pts had sentinel biopsy before NC, being 

negative in 6 (16.7%) cases. Data from surgery (only from 36 pts): pCR was 

achieved in 16 (44.4%) pts. Safety and tolerability were good, with rare 

adverse events of grade �3 [1 (2.8%) episode of severe hypertension]. 

Conclusions: These data show that the combination of P with T and B 

without an anthracycline for 12 weeks is very effective as NC in HER2 

positive breast cancer pts with a high rate of pCR and minimal side effects. 


Lapatinib in HER2� early breast cancer: Quality of life analysis. Presenting 

Author: Frances Boyle, Mater Hospital, North Sydney, Australia 

Background: TEACH, a randomized, double-blind, multi-center, phase III 

study evaluated the efficacy and safety of 12 months lapatinib (N�1571) 

versus placebo (N�1576) in women with HER2� EBC. Patients receiving 

lapatinib more often reported treatment-related AEs (87% vs 47%) in the 

Intent-to-treat (ITT) population. The comparison of recurrence-free survival 

was not significant (p�.053). This analysis focuses on QOL in the ITT. 

Methods: Participants on TEACH completed the Short Form-36 version 2 

(SF-36v2) at baseline and every 6 mo. for 24 mo. SF-36v2 captures 

physical, social, mental, emotional domains of patient perceptions; summary 

scores of physical and mental components are derived from domain 

scores using norm based scoring method. Changes in the domain and 

summary scores were compared between two groups using ANCOVAs. 

Missing post-baseline data were imputed using the last observation carried 

forward method. A clinically relevant change in scores was defined as a 3-5 

point change. Results: For randomised patients who completed the SF-36, 

QOL scores decreased relative to baseline for all domains and summary 

scores across all assessments and treatment arms, however the decreases 

were small and not clinically meaningful. There were no statistically 

significant (p� 0.05) or clinically meaningful differences between arms for 

the summary scores relative to baseline (Table). Conclusions: In HER2 

positive EBC one year treatment with lapatinib is associated with a 

significant increase in AEs but it does not have a significant detrimental 

impact on QOL when compared to placebo. 

N Changes in physical summary score Changes in mental summary score 

Lapatinib – 

Lapatinib – 

Post-baseline visit Lapatinib Placebo Lapatinib Placebo placebo (95% CI) Lapatinib Placebo placebo (95% CI) 

Mo. 6 1092 1283 -0.78 -0.44 -0.33 -2.34 -1.74 -0.61 

(-0.81, 0.14) 

(-1.28, 0.07) 

Mo. 12 1007 1204 -0.84 -0.54 -0.30 -2.74 -2.29 -0.45 

(-0.84, 0.23) 

(-1.16, 0.26) 

Mo.6FU 983 1074 -0.53 -0.87 0.34 -2.22 -1.87 -0.35 

(-0.25, 0.92) 

(-1.10, 0.40) 

Mo. 12 FU 940 988 -0.88 -0.82 -0.06 -3.08 -2.76 -0.31 

(-0.65, 0.53) 

(-1.11, 0.49) 

Mo. 18 FU 834 889 -0.61 -0.89 0.27 -2.38 -2.08 -0.29 

(-0.36, 0.91) 

(-1.17, 0.58) 

Mo. 24 FU 807 824 -0.99 -0.66 -0.33 -2.78 -3.05 0.28 

(-1.00, 0.34) 

(-0.61, 1.16) 

Abbreviation: FU, follow-up. 


Quantitative HER2 levels and steroid receptor expression in primary breast 

cancers and in matched brain metastases. Presenting Author: Wojciech 

Biernat, Medical University of Gdansk, Gdansk, Poland 

Background: Breast cancer patients with HER2-positive tumors are at high 

risk for brain metastases. In the current study we examined expression of 

ER, PR and HER2 in primary breast tumors and in matched brain 

metastases, as changes of their levels might reflect modes of escape from 

therapy. Methods: Fifty-three pairs of matched formalin-fixed paraffinembedded 

samples from primary breast cancers and brain metastases were 

assayed for ER and PR status by immuno-histochemistry, whereas HER2 

expression was quantified using the novel HERmark assay. Nuclear staining 

of ER and PR �10%, and relative fluorescence of HER2 �17.8/mm2 were 

considered as positive results. Results: HER2 levels in brain metastases 

were generally higher than in the primary tumors (p � 3e-6), with a median 

increase of 1.9-fold (range 0.08 to 199-fold). There were also substantial 

differences in ER and PR status between primary tumors and brain 

metastases. Loss of steroid receptor positivity in brain metastases was more 

frequent than its gain (ER: 46% vs. 26%; p � 0.16; PR: 57% vs. 23%; p � 

0.044). These changes resulted in a net increase in the number of 

HER2-positive/ER-negative brain metastases, which more than doubled 

the proportion of primary breast tumors with this phenotype (26% vs. 11%, 

respectively; p � 0.08). Additionally, HER2 levels in the primary tumors 

significantly correlated with overall survival when stratified by ER status (p 

� 0.011). Conclusions: Brain metastases of breast cancer show significant 

changes in steroid receptor status and in quantitative HER2 levels 

compared to matched primary tumors. These data provide a rationale for 

future studies and may help in designing treatment strategies that target 

the most likely escape pathways of breast cancer. 


A randomized phase III double-blinded placebo-controlled trial of first-line 

chemotherapy and trastuzumab with or without bevacizumab for patients with 

HER2/neu-overexpressing metastatic breast cancer (HER2� MBC): A trial of the 

Eastern Cooperative Oncology Group (E1105). Presenting Author: Carlos L. 

Arteaga, Vanderbilt University, Nashville, TN 

Background: Pre-clinical and nonrandomized clinical data support synergy of the 

combination of bevacizumab and trastuzumab. We conducted a randomized 

double-blinded phase III trial of chemotherapy/trastuzumab � bevacizumab to 

evaluate efficacy (PFS after treatment initiation) of the addition of bevacizumab 

in first-line treatment of HER2� MBC. Methods: Days 1, 8 and 15 paclitaxel � 

carboplatin were administered with trastuzumab and either placebo or bevacizumab 

10 mg/kg every 2 weeks for a total of 6 months. Antibody therapy was 

then continued without chemo every 3 weeks, until disease progression or 

unacceptable toxicity. Disease assessments were performed every 3 months. 

Results: Ninety-six of the planned 489 analyzable patients (pts) were accrued 

between 2007 and 2009, at which time the study terminated due to poor 

accrual. Seventy % of pts were post-menopausal, 60% had ER�/HER2� BC. 

Median age was 55 years (28-80). Outcomes and toxicities are summarized on 

the tables below. Median follow-up was 30 months. Conclusions: The combination 

of chemotherapy, trastuzumab, and bevacizumab did not significantly 

increased toxicity, and was overall safe and well tolerated. No significant 

differences in clinical benefit were observed between both treatment arms. Data 

on CTCs and Quality of Life will be presented at the meeting. This study was 

conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, 

Chair) and supported in part by Public Health Service Grants CA23318, 

CA66636, CA21115, CA32291, CA31946, CA49957, CA27525, CA14548, 

CA17145, CA32102, CA25224, CA49. 

Outcomes Placebo (%) N�48 Bev (%) N�48 

On treatment 

Reason for discontinuation 

Best response 

PFS (# events) 

Median PFS (months) 

OS (# deaths) 

Disease progression 

Toxicity 

Death 

Withdrawal 

Other 

CR 

PR 

SD 

PD 

Not evaluable/unknown 

7 

60 

15 

0 

4 

12 

10 

42 

27 

13 

8 

34 

11.1 

12 

9 

38 

21 

4 

4 

10 

10 

42 

19 

10 

18 

30 

12.2 

14 

NS 

HR (0.95 CI) 0.65 

(0.39-1.08) p�0.10 

HR (0.95 CI) 1.23 

(0.57-2.67) p�0.60 

Placebo N�47 Bev N�45 

Toxicity 

1,2 3 4 

Grade (%) 

5 1,2 3 4 5 

Cardiac troponin T 

Hypertension 

LV diastolic dysfunction 

LV systolic dysfunction 

Cardiomyopathy 

Wound 

Hemorrhage 

Proteinuria 

Renal failure 

Thrombosis 

Neutrophils 

Infection 

2 

2 

11 

2 

2 

4 

4 

2 

2 

6 

4 

7 

9 

2 

11 

7 

2 

3 

4 

2 

2 

2 

2 

7 

2 



A neoadjuvant, randomized, open-label phase II trial of afatinib (A) versus 

trastuzumab (T) versus lapatinib (L) in patients (pts) with locally advanced 

HER2-positive breast cancer (BC). Presenting Author: Mothaffar F. Rimawi, 

Baylor College of Medicine, Houston, TX 

Background: A is an oral, irreversible, ErbB Family Blocker. This Phase II 

study investigated A, L and T monotherapy in pts with locally advanced 

HER2 (ErbB2)-positive BC in a 6-wk preoperative treatment window. 

Methods: This international, multi-institutional, open-label, randomized, 

Phase II study included pts with HER2-positive locally advanced disease 

Stage IIIa–c and inflammatory BC with no evidence of distant metastatic 

disease, at least one tumor lesion �5 cm in diameter, and an ECOG score 

0–1. Pts agreed to fresh tumor biopsies for biomarker analyses at trial 

entry, and at 3 and 6 wks of treatment. Pts received 50 mg A once daily, 

1500 mg L once daily, or T 2 mg/kg weekly after a loading dose of 4 mg/kg 

for 6 wks. Results: 73 pts were screened and 29 pts randomized and 

treated* (10 pts A, 8 pts L, 11 pts T). All pts were female, median age 49 

(range 25–88) yrs, 28/29 pts had Stage III disease, 3/29 pts had 

inflammatory BC, median tumour size was 6.4 cm, and median time to 

treatment was 1.4 months (range 0–3.4). After 6 wks of treatment, OR was 

assessed using RECIST 1.0 (Table). Best objective response during 

treatment was 80%, 75%, and 36.4% in the pts treated with A, L, and T, 

respectively. Drug-related AEs assessed by CTCAE v.3.0 occurred in all pts 

treated with A, 75% of pts treated with L, and 45.5% of patients treated 

with T (largely GI and skin-related AEs for A and L, and GI and 

musculoskeletal AEs for T). Three pts treated with A and one pt with L had 

drug-related AEs of CTCAE Grade 3. Conclusions: Afatinib showed a high 

OR rate in this Phase II trial of a 6-wk preoperative treatment window and 

compared favorably to two approved agents in HER2-positive BC, albeit at a 

slightly higher rate of AEs. Further trials will be needed to identify the 

potential role of A as a single agent or in combination with other agents in 

HER2-positive BC. 

A L T 

Partial response 7 (70.0)* 6 (75.0) 4 (36.4) 

Stable disease 2 (20.0) 1 (12.5) 6 (54.5) 

Progressive disease 0 (0.0) 1 (12.5) 1 (9.1) 

*One pt not included in this table withdrew from the study on Day 11; 

end-of-study tumor assessment showed partial response. Study closed early due 

to slow accrual. 


Correlation of quantitative p95HER2 and HER2 protein expression with 

pathologic complete response (pCR) in HER2-positive breast cancer 

patients (pts) treated with neoadjuvant (NEO) trastuzumab-containing 

therapy. Presenting Author: Jose Caetano Villasboas, University of Miami 

Sylvester Comprehensive Cancer Center, Miami, FL 

Background: Elevated p95 [HER2-M611-CTF (carboxy-terminal-fragment) 

also known as p110 or p95HER2] expression has been correlated with poor 

outcomes in HER2� pts with metastatic breast cancer treated with 

trastuzumab (T); however, limited data have been presented on the 

correlation between p95 and pCR to T in the NEO setting, where p95 was 

measured by immunohistochemistry. In the current study, we sought to 

determine whether quantitative p95 and HER2 expression correlated with 

pCR in pts treated with T � chemotherapy in the NEO setting. Methods: 

HER2 expression (H2T) was quantified by HERmark in 47 breast tumors 

using formalin-fixed, paraffin-embedded sections. Tissue remained in 40 

cases to measure p95 by VeraTag and compare to a previously published 

cutoff (Clin Cancer Res 16:4226, 2010). pCR data were available for 45 

cases. pCR was defined as the absence of invasive disease in the breast. 

Results: The overall pCR rate was 46.7% (ER�: 14.3% vs. ER-: 75%; 

Wilcoxon rank p�0.0001) and was significantly associated with higher 

H2T levels (p�0.02). In ER- subjects (N�24), no difference in H2T levels 

was observed between pCR vs non-pCR groups [median H2T�111.5 (IQR 

63.4-162.2) vs 150.5 (IQR 43 – 226.2), respectively; p�0.721]. However, 

within the ER� group (N�21), H2T levels were significantly higher in 

the pCR group vs non-pCR group [median H2T�254 (IQR 181.5-584.5) vs 

37.3 (IQR 16.4-89); p�0.024]. Using multivariate logistic regression, 

increasing log(H2T) (p � 0.011), ER-negativity (p � 0.027) and low p95 

(p � 0.074) were found to correlate or trend with pCR. Conclusions: pCR 

was significantly associated with high H2T expression in ER� HER2� 

breast cancer pts who received NEO therapy with T � chemotherapy. A 

trend towards pCR was seen in tumors that had low p95. These data 

suggest that quantitative H2T and p95 may provide additional information 

on response to T-based regimens in breast cancer, particularly ER� breast 

cancer. Additional investigation into the possible relationship between 

quantitative levels of HER2 and p95 expression and T response in the NEO 

setting in larger cohorts is warranted. 


33s 


Elevated pretreatment serum activin A and progression-free and overall 

survival in trastuzumab-treated metastatic breast cancer. Presenting Author: 

Allan Lipton, Penn State Hershey Medical Center, Hershey, PA 

Background: About half of HER2-positive metastatic breast cancer patients 

will respond tofirst-line trastuzumab-containing therapy, but most will 

progress within a year. Trastuzumab resistance remains a vexing clinical 

problem, and better predictive and prognostic biomarkers are needed. 

Activin A is a TGF-B superfamily member and regulates cell proliferation, 

apoptosis, differentiation, and immune response. Methods: Serum activin A 

was measured using ELISA (R&D Systems, Minneapolis, MN) in 60 

metastatic breast cancer patients before starting first-line trastuzumabcontaining 

therapy. Progression-free survival (PFS) and overall survival 

(OS) were analyzed using the Kaplan-Meier method and Cox modeling with 

both continuous and dichotomous (median) serum activin A analyses. 

Results: Pretreatment serum activin A levels averaged 2376 pg/ml, and had 

a median of 629 pg/ml and 25th and 75th quartile values of 406 and 1791 

pg/ml, respectively. Patients who were hormone receptor negative had 

significantly higher activin A levels (median 1287 vs 450 pg/ml, p�0.002). 

Higher serum activin A was significant on a continuous basis for predicting 

reduced PFS to first-line trastuzumab-containing therapy (p�0.003), and 

for predicting shorter OS (p�0.0001). When analyzed using a dichotomous 

(median) cutpoint, the elevated serum activin A cohort had a significantly 

reduced PFS (HR 2.79, p �0. 002) (median 6.6 mo vs. 31.1 mo) and OS 

(HR 5.24, p �0.0001) (median 19.6 mo vs. median not reached). In 

multivariate analysis for PFS with other covariates (age, line of therapy, CA 

15-3, and hormone receptor status), activin A was the only significant 

covariate (p�0.021). In multivariate analysis for OS, activin A (p�0.002) 

and CA 15-3 (p�0.03) remained significant as prognostic factors. 

Conclusions: Elevated pretreatment serum activin A predicts reduced PFS 

and overall survival in metastatic breast cancer patients treated with 

first-line trastuzumab-containing therapy. Activin A deserves further study 

as an adverse biomarker, and to select patients most likely to respond to 

activin A-targeted therapy. 


Incidence and risk of central nervous system (CNS) metastases as a site of 

first recurrence in patients (pts) with HER2-positive (HER2�) breast 

cancer treated with adjuvant trastuzumab (T). Presenting Author: Erin 

Macrae Olson, The Ohio State University Comprehensive Cancer Center, 

Stefanie Spielman Comprehensive Breast Center, Columbus, OH 

Background: T is the mainstay of adjuvant therapy in pts with HER2� 

breast cancer. CNS disease as the site of first relapse after exposure to 

adjuvant T has been reported, although the overall incidence and relative 

risk (RR) of this remains unclear. We performed an up-to-date metaanalysis 

to determine the risk of CNS metastases as the first site of 

recurrence in pts with HER2� breast cancer who received adjuvant T. 

Methods: Pubmed databases were searched for articles from 1966 to 2011. 

Abstracts presented at the American Society of Clinical Oncology and the 

San Antonio Breast Cancer Symposium were also searched for relevant 

clinical trials. Eligible studies include randomized trials with adjuvant T 

administered for 1 year in pts with HER2� breast cancer who reported CNS 

metastases as first site of disease recurrence. Statistical analyses were 

conducted to calculate the summary incidence, RR, and 95% CIs using 

fixed effects inverse variance models. Results: A total of 9,020 pts were 

included. The incidence of CNS metastases as first site of disease 

recurrence in HER2� pts receiving adjuvant T was 2.56% (95% CI 2.07% 

to 3.01%) compared to 1.94% (95% CI: 1.54% to 2.38%) in HER2� pts 

who did not receive adjuvant T. The RR of CNS as first site of relapse in 

T-treated pts was 1.35 (95% CI 1.02 to 1.78, p�0.038) compared with 

control arms without T therapy. In subgroup analyses, there was no 

significant difference in CNS incidence or risk between pts treated with 

concurrent versus sequential T (p�0.29), weekly versus every 3 week T 

(p�0.56), and no difference in the T groups between studies due to 

median follow up time in years (p�0.68). No evidence of publication bias 

was observed (Q�1.78; P�0.62; I2 � 0.0%). Conclusions: This is the 

largest report to date demonstrating that adjuvant T is associated with an 

increased risk of CNS metastases as a site of first recurrence in HER2� 

breast cancer pts. 




Phase I trial of pegylated liposomal doxorubicin and lapatinib in the 

treatment of metastatic breast cancer (MBC): Final results. Presenting 

Author: Mary E. Cianfrocca, Banner M. D. Anderson Cancer Center, Gilbert, 

AZ 

Background: Liposomal formulations including pegylated liposomal doxorubicin 

(PLD) were developed to improve the therapeutic index of anthracyclines 

(A). Lapatinib (L) is a selective, highly competitive inhibitor of ErbB1 

and ErbB2 tyrosine kinases. Conventional doxorubicin plus trastuzumab 

was effective but with unacceptable cardiac toxicity. PLD plus L may be 

effective with less cardiac risk. Methods: This is a phase I, dose-escalation 

trial of PLD 20, 30, 45 and 60 mg/m2 IV every 4 weeks (maximum of 8 

doses) and L, 1500 mg po daily until progression in patients (pts) with 

MBC. ErbB2 positivity was not required. Prior chemotherapy, endocrine 

therapy and trastuzumab were allowed. A subsequent amendment allowed 

prior L. Prior A use was limited to 240 mg/m2 of doxorubicin or 600 mg/m2 of epirubicin. Concomitant CYP3A4 inducers/ inhibitors were not allowed. 

A left ventricular ejection fraction (LVEF) of � 50% was required. The 

primary objective was to evaluate the safety (particularly cardiac), tolerability 

and feasibility of PLD and L. Results: 23 pts (PLD: 20 mg/m2 - 4 pts; 30 

mg/m2 - 3 pts; 45 mg/m2 – 13 pts; 60 mg/m2- 3 pts) have been treated; 

total of 73 treatment cycles. Dose-limiting toxicity (DLT) was not reached. 

One pt had an LVEF drop to � 50% after 4 cycles accompanied by a 

pericardial effusion due to progressive disease. Treatment-related grade 

III/IV adverse events included: 4 pts with hand-foot-syndrome (HFS), 2 pts 

each with leukopenia, infection, and skin changes, 1 pt each with pain, 

fatigue, diarrhea, mucositis, hypoalbuminemia, anemia, cough, pleural 

effusion, and edema. Grade 3 HFS occurred in 2 of 3 pts in the 60 mg/m2 cohort. Response data in 21 evaluable pts: 4 PR, 5 SD, and 12 PD. 

Preliminary pharmacokinetic (PK) analyses (7 pts) indicate L has no effect 

on PLD (45 mg/m2 ) concentrations, but L concentrations were approximately 

2-fold higher the day of PLD dosing. Conclusions: In 23 pts treated, 

PLD plus L was well tolerated with manageable toxicities and no treatmentrelated 

cardiac toxicity. DLT was not reached however grade 3 HFS 

occurred in 2 of 3 pts in the 60 mg/m2 cohort. Preliminary PK analyses 

demonstrate no effect of L on PLD, but an effect of PLD on L the day of PLD 

dosing. 


Survival outcomes in HER2-positive invasive lobular breast carcinoma. 

Presenting Author: Carlos Hernando Barcenas, University of Texas M. D. 


Background: HER2-positive (HER2�) invasive lobular breast carcinoma 

(ILC) is a rare entity and survival outcomes are not well characterized. 

Methods: We retrospectively searched for breast cancer patients treated at 

MD Anderson Cancer Center between 1992 and 2010 with a diagnosis of 

early stage (I-III) HER2�ILC or with HER2� invasive mixed ductal/lobular 

carcinoma (MIX). With the purpose of comparing survival outcomes, we 

looked for patients with a diagnosis of HER2-negative [HER2(-)] ILC, 

HER2(-)MIX, and HER2� invasive ductal carcinomas (IDC). We obtained 

data on demographics, estrogen (ER) and progesterone (PR) receptor 

status, tumor grade, chemotherapy received and survival status. A multivariate 

analysis using a Cox proportional hazards regression was performed to 

compare disease-free survival (DFS) and overall survival (OS) between the 

following groups: 1) HER2�ILC vs. HER2(-)ILC; 2) HER2�MIX vs. 

HER2(-)MIX; 3) HER2�ILC vs. HER2�MIX; 4) HER2�ILC vs. HER2�IDC; 

5) HER2�MIX vs. HER2�IDC. Results: The number of patients identified 

for each group was: HER2�ILC (N� 67), HER2(-)ILC (N� 1260), 

HER2�MIX (N� 92), HER2(-)MIX (N� 932), HER2�IDC (N� 3080). 

Specifically for both the HER2�ILC and HER2�MIX groups, 24% patients 

were stage I, 43% stage II and 33% stage III. The median age at diagnosis 

was 53 years (y) in HER2�ILC, and 49 y in HER2�MIX. The ER/PR were 

both negative in 16% of HER2�ILC patients, and in 25% of HER2�MIX. 

While 80% of patients in these two groups received chemotherapy, 36% of 

HER2�ILC patients received trastuzumab compared to 50% of HER2�MIX. 

The median follow up was 60 months in the HER2�ILC group and 53 

months in the HER2�MIX group. DFS and OS were not statistically 

different between all groups compared. However, the subgroup of ER/PR 

negative HER2�MIX patients had a better OS compared to ER/PR/HER2 

negative (triple negative) MIX patients (Hazard ratio � 0.4, 0.2 – 0.9, p� 

0.026). Conclusions: HER2�ILC and HER2�MIX are rare clinical entities 

and their survival outcomes may not differ from the more common 

HER2(-)ILC, HER2(-)MIX and HER2�IDC. ER/PR negative HER2�MIX 

may have an OS advantage over triple negative MIX tumors. 


A phase I dose-escalation study evaluating weekly paclitaxel with neratinib and 

trastuzumab in women with metastatic HER2-positive breast cancer, NSABP 

FB-8. Presenting Author: Rachel Catherine Jankowitz, National Surgical Adjuvant 

Breast and Bowel Project and the University of Pittsburgh Medical Center, 

Magee-Womens Hospital, Pittsburgh, PA 

Background: Dual blockade of ErbB receptors combined with chemotherapy 

compared with single-agent blockade improves efficacy in HER2-positive disease. 

FB-8 is single arm, Phase I dose-escalation study to determine safety and 

tolerability of weekly paclitaxel (P), the irreversible tyrosine kinase inhibitor, 

neratinib (N) and trastuzumab (T) in women with metastatic, HER2-positive 

breast cancer (MBC). Methods: Women with measurable or non-measurable MBC 

(ECOG PS 0-2)received P (80 mg/m2 IV days 1, 8, 15 of 28-day cycle), T (4 

mg/kg IV, then 2 mg/kg IV weekly), and N (oral, daily). N was dose-escalated 

using 3�3 design at 120 mg, 160 mg, and 240 mg, dose-limiting toxicity (DLT) 

determined in cycle 1. All patients (pts) received prophylactic anti-diarrheals. 

Results: All pts were taxane and trastuzumab pre-treated, with mean of 4 prior 

regimens. At N�120 mg, there was 1 DLT, grade (gr) 3 diarrhea with 

dehydration. Three more pts were enrolled; none experienced DLT. At N�160 

mg, there were no DLTs. At N�240 mg, 2 of 3 pts had DLTs: one gr 3 diarrhea 

and dehydration, one gr 3 diarrhea, dehydration, and gr 3 mucositis. After 

de-escalation to N�160 mg, 3 more pts were added. If N�160 mg is well 

tolerated, a 200 mg cohort is planned. 12 pts completed cycle 1. Efficacy data 

are available on 10: CR 1, PR 3, SD 1 (8�months). One pt* had resolution of 

non-target disease (skin and breast mass). 4 pts were off-study before the first 

scan (DLT 3 and progressive disease 1) and are considered non-responders (NR). 

The most frequent grade 3-4 adverse event was diarrhea, 3 pts. Conclusions: 

Dual anti-HER blockade with N, T combined with P is tolerable and highly active 

in pts pre-treated with anti-HER2 agents and chemotherapy. This combination 

will be studied in a phase II neoadjuvant breast cancer trial (NSABP FB-7). We 

thank Pfizer, Inc and Puma Biotechnology, Inc for their support. 

Dose 

level (mg) Prior anthracycline Prior lapatinib Prior TDM1 Cycle 

no. Best response 

120 Yes Yes No 8� SD 

120 Yes Yes Yes 4 NR 

120 No No No 1 NR 

120 No No Yes 5� CR 

120 No No No 5� PR 

120 No Yes No 5� PR 

160 Yes Yes No 2 NR 

160 No Yes Yes 3� Non-measurable* 

160 No No No 3� PR 

240 No Yes No 1 NR 

240 No Yes Yes 2� Pending 

240 Yes Yes No 1 NR 


Estrogen receptor (ER), Ki-67, p27Kip1 , and histologic grade as predictors 

of pathologic complete response (pCR) in patients with HER2-positive 

breast cancer treated with neoadjuvant chemotherapy (NAC) using fluorouracil, 

epirubicin, and cyclophosphamide (FEC), taxanes, and trastuzumab. 

Presenting Author: Sasagu Kurozumi, Saitama Cancer Center, Saitama, 

Japan 

Background: NAC with taxanes and FEC concurrently with trastuzumab is a 

potent regimen in patients with HER2-positive breast cancer (BC). Several 

studies revealed high pCR rates in BC patients treated with this regimen; 

however, predictive factors and a prognostic effect of pCR have been still 

unclear. In this study, we analyzed several factors including p27Kip1 (cyclin-dependent kinase inhibitor acting as tumor suppressor) for correlation 

with pCR. We also evaluated differences in recurrence-free survival 

(RFS) or overall survival (OS) between patients with pCR and non-pCR, and 

with positive and negative nodes after NAC. Methods: Our study included 

129 Japanese women with invasive, HER2-positive BC who received 12 

cycles of paclitaxel or 4 cycles of docetaxel followed by 4 cycles of FEC-75 

with concomitant trastuzumab for 24 weeks. We analyzed the correlation of 

pCR (no invasive lesions in the breast) and nodal status after NAC with RFS 

and OS, and analyzed the baseline expressions of ER, Ki-67, and p27Kip1 , 

and histological grade for correlation with pCR. Positive or high expression 

was defined by nuclear labeling index: ER �10%, p27Kip1 �75%, Ki-67 

�30%. Results: In 129 patients, pCR was found in 85 (66%). Patients with 

pCR after NAC had significantly better RFS than those without pCR 

(median follow-up: 41 months). Furthermore, patients with pathologically 

negative nodes after NAC had significantly better OS than those with 

pathologically positive nodes. Negative ER (79% vs. 40%), high Ki-67 

(72% vs. 47%), low p27Kip1 (71% vs. 50%), and histological grade 3 (70% 

vs. 39%) were significant predictors of pCR. Conclusions: In patients with 

HER2-positive BC, this regimen was effective achieving the high pCR rate. 

pCR and pathologically negative nodes after NAC were predictive of RFS 

and OS, respectively. The expressions of ER, Ki-67, and p27Kip1 , and 

histological grade at baseline were predictive of pCR. p27Kip1 , a new 

predictor of pCR after NAC needs to be further analyzed. 



Quantitative HER2 measurement and PI3K mutation profile in matched 

primary and metastatic breast cancer tissues. Presenting Author: Weidong 

Huang, Monogram Biosciences, South San Francisco, CA 

Background: HER2 status of primary breast cancer (PBC) is routinely used 

to determine systemic treatment for metastatic breast cancer (MBC) 

patients. Discordance rates of HER2 status between PBC and MBC range 

from 5.5% to 29% based on published meta-analyses. The clinical benefit 

of re-assessing HER2 in MBC tissues remains controversial. In this study, 

we measured quantitative HER2 expression in matched PBC and MBC 

tissues and correlated changes of HER2 with mutations in the catalytic 

domain of PI3 kinase(PIK3CA). Methods: Total HER2 protein expression 

(H2T) was quantified by the HERmark assay in 41 matched PBC and MBC 

formalin-fixed, paraffin-embedded specimens. PIK3CA mutation status in 

exons 9 (E545K and E542K) and 20 (H1047R) was determined using a 

validated pyrosequencing assay. Results: MBC samples included 5 lymph 

node, 13 viscera, 6 brain, and 17 soft tissue lesions (N�41). 27 (66%) 

cases showed higher H2T in MBC than in matched PBC; and 14 (34%) 

cases had higher H2T in PBC than in matched MBC, indicating an overall 

increase of H2T in matched MBC lesions (fold change 0.25-17.57; 

p�0.005, paired Wilcoxon rank sum test). HER2 positive conversion 

(HERmark negative/equivocal in PBC, but positive in matched MBC) was 

found in 6 (15%) cases, while HER2 negative conversion (HERmark 

positive in PBC, but negative/equivocal in matched MBC) was seen in 2 

(5%) cases. HER2 status was unchanged in 33 (80%) cases. PIK3CA 

mutations were detected in 13 (32%) of PBC and 19 (46%) of MBC 

samples. Among the HER2 positive conversion cases, PIK3CA mutation 

was identified in 50% (3/6) PBC and 67% (4/6) MBC, compared to 0% 

(0/2, PBC or MBC) in the HER2 negative conversion cases. Among cases 

with unchanged HER2 status, PIK3CA mutation was observed in 30% 

(10/33) PBC and 42% (14/33) MBC. Conclusions: Quantitative HER2 

assessment revealed a 20% discordance in HER2 status between matched 

PBC and MBC tissues, with more frequent conversion from low HER2 in 

PBC to high HER2 in MBC. PIK3CA mutation was observed more frequently 

in patients who converted from HER2 negative PBC to HER2 positive MBC. 

These results suggest that re-assessment of biomarkers in MBC tissues may 

better inform the selection of therapeutic options for patients with MBC. 


Can MRI accurately identify which patients with operable breast cancer will 

have a pathologic complete response after neoadjuvant therapy? Presenting 

Author: Carolyn Nessim, Sunnybrook Odette Cancer Centre, University of 

Toronto, Toronto, ON, Canada 

Background: With the introduction of targeted therapy based on tumor 

subtypes, an increasing number of patients that receive neoadjuvant 

chemotherapy achieve a pathologic complete response (pCR). Previous 

studies have shown that the accuracy of MRI is poor at predicting the 

response to neoadjuvant chemotherapy in locally advanced and often 

non-resectable breast cancers, where the rate of pCR is low. The purpose of 

this study is to evaluate MRI’s ability to predict a pCR in operable breast 

cancers after neoadjuvant therapy. Methods: All patients enrolled in the 

NSABP B-40, B-41, FB-5 and FB-6 protocols in a single tertiary care 

centre, that had an MRI done before and after neoadjuvant therapy were 

reviewed. A radiologist, blinded to the pathology results, interpreted the 

pre- and post- treatment MRI’s and made a prediction as to whether or not 

patients would have a pCR. In this study, a true negative was defined as a 

reading of a complete response on MRI that was confirmed as a pCR on final 

pathology. pCR was defined as having no residual invasive or in situ disease 

in the breast. Results: 129 women with a median age of 51 years were 

identified. 90% had invasive ductal carcinoma; 8% had invasive lobular. 

58% were ER�, 21% were triple negative and 21% were Her2�. 16% of 

patients had a pCR. 25% of patients had no residual invasive cancer in the 

breast. pCR rates for ER� tumors was 5%, triple negative 37%, and Her2� 

26%. 19% of patients that had a pCR had a total mastectomy. The 

sensitivity and specificity of MRI for predicting residual disease were 88% 

and 52% respectively. The positive predictive value was 90% and the 

negative predictive value was 46% with an accuracy of 82%. Conclusions: 

MRI has limited value for determining which patients had a pCR after 

neoadjuvant chemotherapy, even in operable breast cancers. When residual 

disease is suspected on MRI, it is unlikely that a pCR has been 

achieved. Surgical excision following neoadjuvant therapy remains the gold 

standard to identify which patients have achieved a pCR. Other modalities 

will need to be used in order to accurately determine which patients would 

be eligible for studies evaluating non operative management following 

neoadjuvant therapy. 


35s 


Long-term follow-up (FU) of patients with durable complete response 

(DCR) after chemotherapy (CT) and trastuzumab (T) for HER2-altered 

(HER2�) metastatic breast cancer (MBC). Presenting Author: Giuseppe 

Gullo, St Vincent’s University Hospital, Dublin, Ireland 

Background: Durable CT-induced complete response (DCR) of MBC is 

reported only anecdotally. The addition of monoclonal antibody T to 

conventional CT results in significant increase in response rates and 

prolonged survival for patients (pts) with HER2� MBC. Though CRs are 

reported in most phase II and III clinical trials of CT�T, there is lack of data 

about clinical features and long-term outcome of these pts. Methods: We 

retrospectively reviewed all pts with HER2� MBC treated at our Institutions 

with any CT�T and identified cases who achieved DCR. HER2 

positivity was defined as 3�score at immunohistochemistry and/or amplification 

at FISH test. DCR was defined as a CR according to RECIST 1.0 

criteria lasting �36 months. Results: We identified 13 pts with HER2� 

MBC who met criteria for DCR following CT�T. Their characteristics are: 

median age: 56yrs (range 30-65), stage at diagnosis: M0 54%/M1 46%, 

histology: ductal 84%/mixed ductal-lobular 8%/unknown 8%, tumour 

grade: G3 54%/G2 23%/unknown 23%, oestrogen receptors (ER): neg 

62%/pos 38%, sites of metastatic disease: liver only 54%/other visceral 

15%/bone and soft tissues only 31%, chemotherapy regimen: 

taxane�carboplatin 54%/single-agent taxane 23%/docetaxel�lapatinib 

15%, capecitabine 8%. Metastatic disease was biopsy-proven in 54% of 

pts. All pts received maintenance T. Median follow-up (FU) is 6.5 yrs (range 

3.0-11.6). Median duration of T was 59 months (17-121). At database 

cut-off date 12 pts (92%) are alive. Five pts (38%) had disease relapse (3 

on maintenance T, 2 after T discontinuation), 2 of whom had radical 

surgery. In 8 pts (62%) disease has not relapsed (characteristics: all 

1st-line therapy, ER negative 75%, liver only distant disease 75%). 

Conclusions: This is the largest series to our knowledge analyzing long-term 

FU of HER2� MBC pts with DCR following CT�T. DCR pts appear to have 

prolonged survival and a substantial subgroup of them have no further 

disease relapse. These pts are usually treated in the 1st-line setting, have 

more frequently ER-negative disease and liver-only metastases. We are 

currently investigating the molecular profile of this subset of pts. 


Neuromedin U: A potential predictive biomarker for HER2-targeted drugs. 

Presenting Author: Sweta Rani, School of Pharmacy and Pharmaceutical 

Sciences and Molecular Therapeutics for Cancer Ireland, Trinity College 

Dublin, Dublin, Ireland 

Background: Not all HER2-positive breast cancer patients respond to 

HER2-targeted drugs and some, who initially respond, subsequently 

relapse. There is a need to identify biomarkers for improved patient 

selection. Here we aimed to identify gene expression changes associated 

with response to HER2-targeted drugs. Methods: To identify mRNA changes 

associated with resistance, whole genome microarrays were used to profile 

conditioned medium (CM) from HER2-positive cell lines (SKBR3, 

HCC1954) and their lapatinib (L)-resistant variants (SKBR3-LR , HCC1954- 

LR ). Neuromedin U (NmU) over-expression, identified in this way, was 

confirmed in the L-resistant cells and corresponding CM by qPCR and 

ELISA. Pooled data from 21 published expression datasets (n�3489 

patients) was mined to relate NmU mRNA to tumour subtype and patients’ 

outcome. NmU cDNA and siRNAs were used to over-express and knockdown 

expression of NmU, respectively, prior to assessing it’s association 

with response to L, Trastuzumab (T) and Neratinib (N). Results: Analysis of 

the tumour data showed NmU expression to be particularly associated with 

poor outcome for patients with HER2-positive tumours (p�0.000005). In 

cell lines, we identified NmU mRNA and protein to be at significantly 

higher levels in L-resistant cells and corresponding CM, compared to that of 

L-sensitive SKBR3 and HCC1954. This trend was observed for T-resistant 

and N-resistant SKBR3 cells (SKBR3T , SKBR3N ) and their CM, compared 

to sensitive parent SKBR3 cells and CM. NmU cDNA over-expression in 

SKBR3 and HCC1954 increased resistance to L, T and N. Knock-down of 

NmU endogenous levels in SKBR3-LR and innately L-resistant MDA-MB- 

361 and T47D sensitised these cells to L, T and N. Further analysis of our 

NmU over-expressing and knock-down cells indicated NmU to also be 

associated with increased motility, invasion and anoikis resistance. 

Conclusions: NmU expression is prognostic of poor outcome in HER2positive 

breast tumours. In cell line models, NmU over-expression is 

associated with resistance to L, T and N. Taken together, we propose NmU 

as a possible prognostic and predictive biomarker for HER2-positive 

cancers, with potential also as a co-target to help circumvent resistance to 

these drugs. [SFI: 08/SRC/B1410] 




Use of the PRO Onc Assay (Prometheus) to measure HER2 overexpression/ 

activation in circulating tumor cells (CTCs) in women with HER2-negative 

metastatic breast cancer (MBC): A Sarah Cannon Research Institute (SCRI) 

trial. Presenting Author: John D. Hainsworth, SCRI/Tennessee Oncology, 

PLLC, Nashville, TN 

Background: HER2- targeted therapy has markedly improved the treatment 

of women with HER2- positive breast cancer. FISH testing for HER2 

overexpression is the most reliable assay method; treatment decisions are 

usually based on HER2 expression of the breast primary tumor. Accurate 

determination of HER2 status by testing CTCs may improve patient 

management by allowing ongoing assessment of HER2 status during 

treatment and/or identifying additional patients (pts) for HER2- targeted 

therapy. Methods: The PRO Onc assay uses a multiplexed immunoassay 

format to provide expression and activation profiling of HER2 and other 

signal transduction molecules. The assay can detect overexpression and 

activation (phosphorylation) of HER2, with sensitivity at a single CTC level. 

We obtained blood specimens from 57 women with metastatic HER2negative 

breast cancer who were receiving standard chemotherapy. In these 

women, HER2 status had previously been determined by FISH (32) or 0 – 

1� IHC testing (25). All specimens were tested for the presence of CTCs; 

the PRO Onc assay was performed when CTCs were identified. The HER2 

overexpression cutoff (�3.0 CU) was based on the reference value (average 

� 4SD) determined by analyzing normal blood obtained from 42 healthy 

donors. Results: 31 of 57 pts (54%) had CTCs identified. 6 of 31 pts (19%) 

had HER2 overexpressed, and 4 pts (13%) had HER2 activation without 

overexpression. 7 of 10 pts with HER2 overexpression/activation by PRO 

Onc Assay were FISH- negative; 3 were IHC- negative. Since initial HER2 

determination, these 10 pts had received a median of 3 chemotherapy 

regimens (range1-5).Conclusions: When CTCs were present, the PRO Onc 

assay identified HER2 overexpression or activation in 31% of women with 

HER2- negative MBC. The therapeutic significance of this finding is 

unknown. Since the predetermined threshold of �10% HER2- positive 

assay results was exceeded, this trial will proceed to a planned second 

portion, in which women with HER2- negative MBC (by FISH testing) and 

HER2 overexpression or activation in CTCs will receive a trial of HER2targeted 

therapy. 


Use of HER2 score correction for putative chromosome 17 (Chr-17) 

aneusomy to increase eligibility for anti-HER2 therapy. Presenting Author: 

Eugen C. Minca, Cleveland Clinic Foundation, Cleveland, OH 

Background: HER2 amplification or overexpression status directs therapy 

choice in breast carcinoma. HER2/Chr-17 ratio is commonly assessed by 

fluorescence in-situ hybridization (FISH) using a CEP17 centromeric 

reference probe and ASCO/CAP scoring criteria. However, �-centromeric 

reference probes may underestimate true HER2 status in cases with 

para-centromeric amplification. Here we present comprehensive algorithmic 

testing of an alternative Chr-17 reference locus for resolution of 

putative CEP17-aneusomic cases in a consecutive series, within a single 

health system. Methods: 150 of 1256 consecutive breast carcinoma cases 

accessioned in 2011 within the Cleveland Clinic Health System displayed a 

mean CEP17 copy number greater than 3.0 by FISH (aneusomy). The 

patients were reflex-HER2 tested by FISH with a reference probe for the 

D17S122 locus (17p12) and a corrected HER2/Chr-17 ratio was calculated. 

Cases with equivocal HER2/D17S122 ratio (1.8-2.2) were further 

reflex tested for HER2 overexpression by immunohistochemistry (IHC). 

Results: Of 117 initially non-amplified cases by HER2/CEP17, 20 (17%) 

were revised to amplified and 18 (15.3%) to equivocal by HER2/D17S122. 

Of 3 initially equivocal cases, 1 was revised to amplified and 1 remained 

equivocal. Of the 19 equivocal cases by HER2/D17S122, 3 were revised to 

positive by IHC. Overall, for CEP17 aneusomic cases tested using this 

algorithmic approach, 24 of 120 (20%) patients with initial non-amplified 

or equivocal HER2 status became eligible for anti-HER2-based therapy, 

which was also considered in 10 equivocal cases with a HER2/D17S122 

ratio of 2.0 - 2.2. A significantly lower proportion of initially amplified cases 

was revised as non-amplified by HER2/D17S122 (1 of 30, 3.3%, p�0.05). 

Conclusions: Our data, collected within a single health system for a 

consecutive case series, underscores the clinical limitations of commonly 

used FISH probes for HER2 testing and demonstrates that algorithmic use 

of a non-centromeric Chr-17 reference probe alters HER2 status and 

increases eligibility for anti-HER2 based therapy in a significant proportion 

of patients. 


Presentation and treatment of HER2-positive metastatic breast cancer patients 

already treated with adjuvant trastuzumab. Presenting Author: Davis Yuri 

Torrejon, Medical Oncology Department, Vall d’Hebron University Hospital, 

Barcelona, Spain 

Background: The introduction of trastuzumab in the clinical armamentarium has 

profoundly changed the natural history of HER2 positive breast cancer (BC). 

However, about 15% of patients with HER2 early BC treated with adjuvant 

trastuzumab continue to relapse. We aimed to analyze these patients with 

respect to clinical presentation and response to treatment. Methods: Data were 

retrieved from the institutional BC database of Vall d’Hebron. All the cases 

relapsing after exposure to adjuvant trastuzumab were analyzed. Change in 

expression of hormone-receptor (HR) and HER-2 status between primary tumour 

and corresponding local recurrence or distant metastasis was also evaluated 

Results: A total of 270 patients were identified. Twenty-six patients (9.6%) 

relapsed (Table). Overall median time from diagnosis to relapse was 27.1 

months (24.1-30.1) being 29.1 months (14.3-44.1) in HR positive and 23.1 

(9.9-36.2) in HR negative cases (p�0.037). Median time from last dose of 

trastuzumab to relapse was 7.6 (2.7-12.7) months, being 10.6 (0-27.9) and 3 

months (0-7.6) in HR positive and negative cases, respectively (p�0.026). 

Sixteen patients have already progressed to first-line therapy with a median time 

to progression (TTP) of 7.4 months with no statistical difference among HR 

positive and HR negative (4.4 and 9.8 months, p�0.3). No difference was found 

in TTP to first line therapy among early (before 12 months) and delayed (after 12 

months) progression on adjuvant trastuzumab. Among the 17 cases with primary 

tumor and matched metastatic biopsy, HER-2 negativization was detected in 2 

cases; whereas a change in estrogen and progesterone receptors was seen in 

17.6% and 29.4% of cases, respectively. Conclusions: Patients with HER2�/HR 

negative treated with adjuvant trastuzumab seems to have a significantly shorter 

time to relapse compared with the HER2�/HR� tumors. In these patients 

biopsy of metastatic lesions might help to define the best treatment options. 

HER2�/HR� (n�160) HER2 �/HR- (n�110) Total (n�270) 

No % No % No % 

Recurrence 14 8.7 12 10.9 26 9.6 

Sites 

Locoregional 5 35.7 3 25 8 30.8 

Bone 3 21.4 7 58.3 10 38.5 

Liver 6 42.8 2 16.7 8 30.8 

Lung 3 21.4 2 16.7 5 19.2 

CNS 2 14.3 3 25 5 19.2 

Death 3 21.4 8 66.6 11 42.3 


Susceptibility of HER2� breast cancer cells to poly (ADP-ribose) polymerase 

(PARP) inhibition independent of an inherent DNA repair defect. 

Presenting Author: Eddy Shih-Hsin Yang, University of Alabama at Birmingham, 

Birmingham, AL 

Background: HER2 overexpression in breast cancer confers increased tumor 

aggressiveness. Targeted therapy against HER2 has improved outcomes, 

but resistance and disease progression ultimately occurs, thus necessitating 

novel therapeutic strategies. PARP inhibitors target homologous recombination 

(HR) deficient tumors, such as the BRCA-associated breast and 

ovarian cancers. In this study, we report unexpected susceptibility of 

HER2� breast cancer cells to PARP inhibition alone independent of an 

inherent HR deficiency. Methods: Cell viability was measured using colony 

formation and ATPLite assays. Tumor growth delay was assessed in vivo in 

mice bearing breast cancer xenografts. Proteins were detected by immunoblotting. 

HR was assayed using radiation (IR)-induced Rad51 foci or a 

GFP-based HR assay. NF�B activity was measured using a NF�B-driven 

luciferase assay. Results: Surprisingly, PARP inhibition with ABT-888 

alone reduced the colony forming ability and cell viability of the HER2� 

breast cancer cell lines BT474, SKBR3, MDA-MB361, and HCC1954 

(~70 – 99% reduction at 10�M). This susceptibility did not correlate with 

an inherent HR deficit. Interestingly, HER2 overexpression itself may be 

one mechanism of susceptibility to ABT-888 as evidenced by increased 

cellular cytotoxicity and in vivo tumor growth delay of MCF7 cells stably 

expressing HER2. Further dissection of the mechanism revealed that NF�B 

transcriptional activity was significantly inhibited by ABT-888 (�95%) 

which corresponded with reduced levels of phosphorylated p65 and total 

IKK�, and a concomitant increase in IkB�. Furthermore, overexpression of 

p65 abrogated cellular sensitivity to ABT-888. Conclusions: HER2� breast 

cancer cells are highly susceptible to PARP inhibition despite being HR 

proficient. This may be, in part, due to inhibition of NF�B. Further 

investigation of whether the addition of PARP inhibition to HER2 targeted 

therapy will delay the onset of resistance to therapy is warranted to 

potentially improve outcomes in HER2� breast cancer patients. 



ADAM17 as a novel therapeutic target for HER2-positive breast cancer. 

Presenting Author: Sumainizah Sukor, St Vincent’s University Hospital, 

Dublin, Ireland 

Background: Although the HER2 gene is amplifiend/overexpressed in 

15-20% of breast cancers, only a proportion of these patients benefit from 

anti-HER2 therapy. Clearly additional biomarkers and/or therapeutic targets 

are necessary to enhance efficacy and improve outcome in these 

patients. Here, we tested the hypothesis that inhibition of ADAM17mediated 

release of HER ligands may enhance response to trastuzumab 

and lapatinib. Methods: The ADAM17-selective inhibitor, PF-5480090 

(Pfizer) both alone and in combination with lapatinib, trastuzumab or 5FU 

was tested for potential growth inhibitory effects on a panel of 4 HER2positive 

breast cancer cell lines (BT474, MDA-MB-453, SKBR3 and 

JIMT-1). Results: Using the MTT viability assay, treatment with 1 �M TMI-2 

resulted in a significant reduction in cell proliferation compared to vehicle 

control in BT474 (p�0.01), MDA-MB-453 (p � 0.005), JIMT-1 (p�0.002) 

and SKBR3 cells (p � 0.005). Addition of PF-5480090 to lapatinib 

resulted in a significant reduction in cell growth compared to lapatinib 

alone (JIMT-1: p � 0.005; SKBR3: p � 0.005; MDA-MB-453: p � 

0.005), while addition of PF-5480090 to trastuzumab resulted in significant 

reduction in cell growth compared to trastuzumab alone (JIMT-1: p � 

0.005; SKBR3: p � 0.005; MDA-MB-453: p�0.001). Addition of 

PF-5480090 to 5FU resulted in significant reduction in growth compared 

to 5FU alone (JIMT-1: p � 0.005; SKBR3: p � 0.005; MDA-MB-453: 

p�0.001). Consistent with its ability to block proliferation, addition of 

PF-5480090 significantly reduced release of TGFalpha (BT474: p�0.003; 

JIMT1: p�0.023; SKBR3: p�0.036 and MDA-MB-453: p�0.014). 

Conclusions: Inhibitionof ADAM17 resulted in growth inhibitory responses 

in HER2-positive breast cancer cell lines. Furthermore, addition of PF- 

5480090 to lapatinib, trastuzumab or 5FU resulted in significant growth 

inhibition compared to these agents alone. We propose that inhibition of 

ADAM17 may be used in combination with existing treatments for 

HER2-positive breast cancer. Acknowledgement. The authors thank SFI 

(SRC award, 08/SRC/B1410 to MTCI) for funding this work. 


Phase I/II trial of primary chemotherapy with nonpegylated liposomal 

doxorubicin, paclitaxel, and lapatinib in patients with HER2-positive, 

early-stage breast cancer. Presenting Author: Sherko Kuemmel, Kliniken 

Essen Mitte, Evang. Huyssens Stiftung/Knappschaft , Essen, Germany 

Background: Combinations of trastuzumab and anthracyclines in HER2positive 

breast cancer are highly active but associated with a high 

incidence of cardiotoxicity. The risk of cardiac damage can be significantly 

reduced through liposomal encapsulation of anthracyclines. This phase I/II 

study was initiated to evaluate the combination of non-pegylated liposomal 

doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for 

patients with early stage, HER2-positive primary breast cancer. Methods: 

Patients with newly diagnosed HER2-positive (IHC 3� or FISH�) early 

stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD 

(60mg/m2 ; day 1), paclitaxel (175mg/m2 , day 1) and lapatinib (750-1500 

mg orally daily) in 3-week intervals for up to 6 cycles. The primary 

endpoints were dose-limiting toxicities (DLT) and pathological complete 

response (pCR). Secondary endpoints include safety, incidence of cardiac 

events, and clinical response. Exploratory endpoints include molecular 

markers for sensitivity or resistance to chemotherapy and/or lapatinib 

evaluated. Results: A total of 84 patients have been included to date.No 

DLTs were observed and the maximum tolerated doses were NPLD 

60mg/m2 , paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended 

phase 2 doses (P2D) were NPLD 60mg/m2 , paclitaxel 175mg/m2 and 

lapatinib 1250mg. The treatment was generally well tolerated and associated 

with toxicities that were consistent with the known side-effects of the 

individual agents. No cardiac event has been observed to date. Preliminary 

efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast 

and lymph nodes of 37.5%, in 24 evaluable patients treated at �P2D. 

Conclusions: The combination of NPLD, paclitaxel and lapatinib is well 

tolerated and has high antitumour activity in patients with HER2-positive 

primary breast cancer. The phase II part of the study is ongoing and 

updated results will be presented. 


37s 


HER2 assessment and Ki-67 labeling index in a cohort of male breast 

cases: The Ich Network on Cancer Research (INCaRe) experience. Presenting 

Author: Giovanna Masci, Humanitas Cancer Center, IRCCS, Rozzano, 

Italy 

Background: The overall incidence of male breast cancers (MBC) is around 

1% of all breast cancers and is on the rise.Most of our current knowledge 

regarding its biology and treatment strategies has been extrapolated from 

its female counterpart. However, from literature data, it is more and more 

evident that MBC has biological differences compared with female breast 

cancer (FBC). While hormone receptors are more frequently positive in 

MBC than in FBC, HER-2 seems to be less expressed in MBC than in FBC, 

with data ranging from 0 to 18%; no data on Ki-67 have been so far 

reported. Methods: We retrospectively analyzed the immunohistochemical 

expression of hormone receptors status, HER-2 protein expression, and 

Ki-67 in 76 consecutive MBCs, treated within the Humanitas Institutes 

Network on Cancer Research (INCaRe). HER-2 determinations were carried 

out according to ASCO/ACP and NEQAS guidelines: cases with score 2� at 

IHC were further examined by fluorescent in situ hybridation (FISH). 

Results: From 2000 to 2011, we treated 76 male breast cases (age 25-87, 

median 64): 72 patients (94%) had ductal carcinoma and 4 had rare 

histotypes (2 papillary, 1 mucinous and 1 cribryform). Thirthy-two of 76 

patients (42%) had positive axillary lymph-nodes, while 6 (8%) were 

metastatic at diagnosis. Of these, estrogen receptor and progesterone 

receptor were positive in 96% and 93% patients respectively; HER-2, 

evaluable in 67 patients, was positive in 11 (16%). Ki-67 was evaluable in 

75 patients and was � 20% in 24 cases (32%), with 20/24 (26%) with 

Ki-67 � 30%. Grading was evaluable in 65 patients: G1 in 2 (3%), G2 in 

41(63%) and G3 in 22 (34%), respectively. Conclusions: In these series, 

MBC show different patterns from FBC, with some favorable aspects such 

as higher hormone receptor status and much lower HER-2 expression and 

some unfavorable features, such as higher Ki-67 values. Although further 

studies are needed to confirm these data, different treatment strategies 

would be suggested in MBC than its female counterpart. 


An assessment of disease features and immune response in breast cancer 

patients that did not recur after receiving HER2 peptide, AE37 vaccine in a 

randomized phase II trial. Presenting Author: Diane F Hale, Brooke Army 

Medical Center, San Antonio, TX 

Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived 

peptide AE36 (776-790), administered with immunoadjuvant GMCSF 

demonstrated the vaccine to be safe and capable of stimulating CD4�helper T cells with HER2 specific anti-tumor activity. Here we present analysis of 

immune markers and patient feature that may impact recurrence from an 

ongoing prospective, randomized, single-blinded Phase IIb trial of 

AE37�GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC) 

patients. Methods: After completion of standard therapy; disease-free, node 

positive or high risk node negative BC patients (pts) were randomized to 

receive either AE37�GMCSF or GMCSF in 6 monthly intradermal inoculations. 

Immunologic responses were measured using [ 3H]-thymidine incorporation 

assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in 

vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts 

(VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated 

109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR 

were younger (44 v 50 yo p�0.11), had higher grade (67% v 44% 

p�0.32), more ER/PR- (44% v 38% p�0.75), larger tumors (89% v 50% 

p�0.06), and node positive (89% v 70% p�0.37). No difference for HER2 

status (IHC 3�, 44% v 49% p�0.64). Both VR and VNR responded to 

vaccine though the mean DTH and proliferative stimulation index was 

approximately 10% less in VR pts (18 v 20 p�0.73; 1.96 v 2.2 p�0.77 

respectively). The most predictive measure was change in Tregs with VR pts 

less likely to decrease their Tregs levels (50% v 76% p�0.17) after 

vacination and more likely experience increased Tregs (17% v 8% 

p�0.48). A decrease in Tregs had an inverse trend towards recurrence 

(p�0.17). Conclusions: Preliminarily, it appears most pts immunologically 

respond to vaccine though slightly less for VR in most assays. The changes 

of Tregs appear to correlate best with disease recurrence. Whether this 

reflects an association with disease status or a failure of the vaccine is yet to 

be seen. These levels may become important in predicting risk for clinical 

recurrence in future vaccine trials. 




Efficacy of INK128, an mTORC1/mTORC2 kinase inhibitor, in breast 

cancer models driven by HER2-PI3K-AKT-mTOR pathway. Presenting 

Author: Pradip De, Department of Medicine, Emory University, Atlanta, GA 

Background: Downstream of the PI3K-AKT pathway, the mTOR has been 

shown to be essential effector in promoting cell proliferation, survival, 

mRNA translation and tumor susceptibility. Aberrant activation of the 

PI3K-AKT-mTOR pathway occurs frequently in breast tumor (BT) and 

contributes to resistance to trastuzumab (T). Using a HER2 amplified BT 

model; we investigated the antitumor efficacy of the dual mTORC1/ 

mTORC2 kinase inhibitor INK128 alone and in combination with T. 

Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, 

pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of INK128 alone and in 

combination with T were evaluated in HER2 amplified T-sensitive (BT474), 

T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, 

UACC893) BT cell lines by MTT assay and Western blots. Athymic mice 

bearing BT474 and BT474HR xenograft tumors were treated with INK128 

and T (alone and in combination). Results: (1)INK128 exhibited excellent 

in vitro cell killing activity in MTT assay with IC50’s below 50nM. INK128 

was more potent when combined with T, (2) INK128 blocked mTORC1, 

mTORC2 and thus did not cause the mTORC2 activation of AKT observed 

with rapalogues, (3) inhibition of phosphorylation of AKT(S473), P70S6K, 

S6RP, and 4EBP1(T37/46, T70) was observed following INK128 treatment, 

and the combination of INK128 and T more effectively blocked the 

PI3K-AKT-mTOR pathway, (4) INK128 dose-dependently blocked 3D-ON- 

TOP clonogenic growth of HER2� cells. This effect was potentiated in the 

presence of T and (5) xenograft data show that the combination of INK128 

and T has strongly enhanced anti-tumor effect in both sensitive and 

resistant models, something that cannot be achieved by either monotherapy. 

Conclusions: Our data suggest that 1) therapeutic targeting of the 

PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T 

therapy in HER2� BT, 2) INK128 mitigates the feedback activation of AKT 

caused by selective inhibition of mTORC1 and 3) targeting both the HER2 

and the mTORC1/2 signaling pathways is an attractive strategy to enhance 

the clinical activity of T therapy, as well as to prevent or delay the 

development of resistance. 


Impact of PIK3CA mutations and p95HER2 expression on the outcome of 

HER2-positive metastatic breast cancer patients treated with a trastuzumabbased 

therapy. Presenting Author: Andrea Fontana, Division of Medical 

Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano 

Tumori, Pisa, Italy 

Background: Currently, no biomarkers of trastuzumab (T) clinical resistance 

have been validated. The aim of this pilot study was to evaluate the impact 

of PIK3CA mutations and p95HER2 (pHER2 truncated form) expression 

on the efficacy of a T based-therapy in a HER2-positive metastatic breast 

cancer (MBC) patients (pts). Methods: 107 HER2-positive MBC pts, treated 

in the last 10 years, were evaluated. Median age was 54 years (25-79); 

ECOG performance status was 0 in 56% of pts; all pts received several lines 

of treatment including T; biomarkers molecular analysis was performed in 

70 tumor specimens. The IHC expression of p95HER2 was evaluated by a 

monoclonal antibody that specifically recognizes only the HER2 external 

domain; the HER2 integrity was defined by the presence of a homogeneous 

membrane staining (moderate or intense) in at least 30% of the cells, 

otherwise the HER2 was defined as p95HER2 positive. PIK3CA mutations 

in exons 9 and 20 were detected by automated sequencing. The molecular 

data were correlated to Time to progression (TTP) of the first line treatment 

including T and the Overall Survival (OS) by using the Kaplan-Meir method 

and the log-rank-test. Results: p95HER2 positive pts and PIK3CA mutations 

in exon 9 or 20 were detected in 42% and 22% of tumor specimens, 

respectively. p95HER2 positive tumors showed a shorter TTP and OS that 

did not reach statistical significance; PIK3CA mutations correlated with a 

worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs 41,0 

months, p� 0,046). Conclusions: These preliminary results suggest a 

possible role of PIK3CA mutational status in predicting the outcome of 

MBC pts treated with T. 


Detection of trastuzumab (T) level in human serum using quartz crystal 

microbalance (QCM) piezo-immunosensors by immobilization of a HER2 

mimotope-derived synthetic peptide and its potential application in breast 

cancer. Presenting Author: Mohammad Muhsin Chisti, Oakland University 

William Beaumont School of Medicine, Royal Oak, MI 

Background: Varied clinico-pathological response to monoclonal antibodies 

like T has been reported either due to presence of antibodies, rapid 

clearance or low density of target receptor/antigens. This demands need for 

an assay to monitor serum T therapeutic levels to ensure appropriate 

dosage. Enzyme-linked immunosorbent assay (ELISA) is still the most 

widely used technique to detect T level in human serum which is expensive 

and time consuming. For the first time, we established a platform to detect 

T level by using a small (�2.2 kDa), inexpensive, highly stable HER2 

mimotope-derived synthetic peptide immobilized on the surface of a gold 

quartz electrode. Methods: HER2 mimotope was used as a substitute for the 

HER2 receptor protein in QCM assays to detect T level. The validation 

samples were prepared from the standard T solution in 10% human serum 

at three concentrations (10, 20 and 40 ug/ml). The changes in frequencies 

(�F) of sera from 3 female patients , 61, 32 and 44 years old , with ER/PR 

positive, HER2/neu positive metastatic breast cancer were obtained by 

calculating the differences between frequency shifts in pre and post T 

infusion.T level was calculated by equation, (�F �1.0022) ÷ 0.9997 �g / 

ml. Results: We showed that assay sensitivity was dependent upon the 

amino acids used to tether and link the peptide to the sensor surface and 

the buffers used. QCM assay was capable of detecting T serum level as low 

as 0.038 nM (linear operating range of 0.038–0.859 nM). T levels of 3 

patients were 43.34, 121.96 and 193.18 �g /ml corresponding to pre and 

post infusion �F of 3.33, 11.19 and 18.31 respectively. The time frame of 

assay was 20-30 minutes. These results were in concordance with 

previously published results using ELISA. Conclusions: For the first time, we 

have established a low cost, highly sensitive, fast, synthetic peptide based 

QCM assay which could be used as a basis for developing a new generation 

of affinity-based Immunosensor assays to monitor serum levels of T and 

other monoclonal antibodies, helping physicians to determine the clinical 

efficacy of these drugs and ensuring appropriate dosages. 


Impact of single/dual HER2 inhibition and chemotherapy (CT) backbone 

upon pathologic complete response (pCR) in patients receiving neoadjuvant 

CT for operable/locally advanced breast cancer (O/LABC): A treatmentinteraction 

analysis of randomized trials. Presenting Author: Jenny 

Furlanetto, Medical Oncology, University of Verona, Verona, Italy 

Background: Although the addition of trastuzumab to neoadjuvant CT for 

O/LABC have dramatically increased pCR, clinical research is moving 

forward to further improve the overall outcome. In this regard, the DUAL 

inhibition of the HER-2 pathway and the choice of the best CT backbone 

may represent an issue to be addressed. Methods: Phase II randomized/ 

Phase III trials were considered. pCR events/rates were extracted from 

papers/presentation and cumulated (R[pCR]) according to a random-effect 

model; 95% confidence intervals (CI) were derived. A sensitivity analysis 

according to SINGLE/DUAL HER-2 inhibition and to administered CT 

(anthracyclines-taxanes: anthra-TAX; TAX alone) was accomplished, in 

order to test for interaction. Results: 7 trials (2155 pts) were gathered; 

1855 pts were enrolled in arms where anti-HER-2 targeted therapy was 

administered. HER-2 inhibition was obtained with trastuzumab, lapatinib 

and pertuzumab (alone or combined). Results according to HER-2 inhibition 

follow in the table below. With regard to CT, a significant interaction 

(p�0.0001) in favour of the addition of Anthra to TAX was found in the 

context of SINGLE HER-2 inhibition subgroup (R[pCR] 46.5%, 95% CI 

37-51, vs 26.9%, 95% CI 23-31), while no significant interaction was 

determined in the context of the DUAL subgroup (R[pCR] 49.0%, 95% CI 

26-72, vs 49.0%, 95% CI 43-55). A significant interaction (p�0.0001) in 

favour of the addition of Anthra to TAX was found for pts receiving 

trastuzumab (R[pCR] 45.5%, 95% CI 37-53, vs 26.5%, 95% CI 21-32) as 

well. Conclusions: Although biases in the pCR definition, the DUAL 

inhibition of HER-2 pathway may significantly increase pCR, regardless of 

the CT backbone; if confirmed, this strategy allows to reduce toxicities by 

sparing Anthra. For pts receiving SINGLE HER-2 inhibition, Anthra-TAXbased 

CT should be still considered the best treatment option. 

Anthra-TAX TAX 

Single Dual Single Dual 

pCR (n°)/pts 259/591 139/390 136/506 127/259 

R[pCR] (95% CI) 46.5% (37-51) 49.0% (26-72) 26.9% (23-31) 49.0% (43-55) 

Interaction test p�0.67 p�0.0001 



Prognostic role of HER2 loss after neoadjuvant therapy in patients with 

HER2-positive operable breast cancer. Presenting Author: Valentina Guarneri, 

Department of Oncology, Hematology and Respiratory Diseases, 

Modena University Hospital, Modena, Italy 

Background: Emerging literature data are consistently showing that a 

change in HER2 status adversely affect the prognosis of breast cancer 

patients. Aim of the present analysis is to evaluate the prognostic impact of 

HER2 loss in breast cancer patients with HER2 positive disease treated 

with neoadjuvant therapy with or without anti-HER2 agents. Methods: A 

total of 94 HER2 positive patients were identified from a prospectively 

maintained database. The first cohort (A) includes 40 patients treated with 

chemotherapy alone (enrolled before 2005). The second cohort (B) 

includes 54 patients treated with neoadjuvant chemotherapy in combination 

with anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression 

was evaluated by IHC or FISH on pre-treatment core biopsy and on 

surgical specimen after neoadjuvant therapy. Patients were considered as 

having HER2 positive disease in case of IHC 3� or FISH amplification. 

Results: No imbalance in terms of age, stage at diagnosis, tumor grade and 

expression of hormone receptor was observed in the two cohorts. In detail, 

67% and 61% of the patients have a co-expression of HER2 and hormone 

receptor in cohort A and B, respectively. The rate of breast conservation was 

significantly higher in cohort B (chemotherapy�anti-HER2 agents) as 

compared to cohort A (chemotherapy alone) (59% vs 38%, p�0.048). 

Similarly, the rate of pathologic complete response (pCR) was significantly 

higher in cohort B (42.6% vs 7.5% in cohort A, p�0.001). A change in 

HER2 expression from biopsy to post-therapy samples was observed in 

35% of the patients in cohort A vs 9% of the patients in cohort B (p�0.04). 

No patients achieving a pCR have recurred so far vs 25% of the patients 

with less than pCR (p�0.005). The rate of recurrence was significantly 

higher for patients experiencing a change in HER2 expression (47% vs 

15% in patients with no change, p�0.007). At 5 years, 53% of the 

patients with Her2 change and 75% of the patients without Her2 change 

were alive and free of recurrence (log rank test: p�0.03). Conclusions: The 

rate of HER2 loss was significantly higher in patients not receiving 

anti-HER2 agents as a part of the neoadjuvant therapy. In this series, the 

change in HER2 status has a negative prognostic impact. 


Effect of acquired resistance to lapatinib in HER2-positive breast cancer 

cells on the Bcl-2 family members MCL-1 and BAX. Presenting Author: 

Alex J. Eustace, National Institute for Cellular Biotechnology, Dublin City 

University, Dublin, Ireland 

Background: Lapatinib (L) is approved for the treatment of trastuzumab (T) 

resistant HER2 positive metastatic breast cancer. Not all HER2 positive 

tumors respond to L and patients who initially respond frequently relapse, 

due to the development of resistance to L. Understanding the molecular 

changes associated with L resistance may lead to the identification of 

targets to overcome resistance. Methods: SKBR3 cells were treated with 

either 250 nM L, or 125nM L and 5 �g/ml T twice weekly for 6 months to 

establish the resistant cell lines SKBR3-L and -TL. We measured by TUNEL 

assay the effect of L on apoptotic induction in SKBR3, -L and -TL cells. 

Gene array analysis of the SKBR3, -L and -TL cells identified differences in 

the expression of apoptosis-related genes, which were validated by immunoblotting. 

Finally using combinations of obatoclax (O) and L were tested in L 

resistant cells. Results: In SKBR3 cells, L (500 nM) induces apoptosis 

(15.8 � 2.0%) compared to untreated controls (4.6�2.7%), whilst in 

SKBR3-L and -TL cells L did not induce significant apoptosis compared to 

controls. Gene array analysis showed that BAX mRNA is down regulated 3.2 

fold in SKBR3-L cells compared to the parental cells. In SKBR3-TL cells, 

MCL-1 mRNA expression is increased 2.1 fold, whilst BAX mRNA is down 

regulated 2.1 fold compared to the parental cells. Immunoblotting confirmed 

that BAX protein expression was reduced in the SKBR3-L (1.5 fold, 

p�0.058) and significantly reduced in SKBR3-TL cells (2.0 fold, p�0.039) 

compared to SKBR3. MCL-1 protein expression was significantly increased 

in the SKBR3-L (1.6 fold, p�0.035) and -TL cells (2.3 fold, p�0.031) 

compared to SKBR3. Combining O (200 nM) and L (500 nM) in both 

SKBR3 and SKBR3-L cells produced greater growth inhibition than either 

drug on its own (SKBR3: 86.9�1.0% vs 73.5�3.1% for L (p�0.01) and 

44.7�7.7% for O, (p�0.01); SKBR3-L: 54.2� 8.6% vs 26.9�2.4% for L 

(p�0.027) and 33.8�10.7% for O (p�0.04)). Conclusions: Extended 

exposure to L in SKBR3-L and –TL cells alters the apoptotic response to L. 

O alone and in combination with L results in growth inhibition in L resistant 

cells. 


39s 


Effect of neratinib (N) alone and in combination with trastuzumab (T) in 

HER2-positive breast cancer (BC) cell lines. Presenting Author: Alexandra 

Canonici, Molecular Therapeutics for Cancer Ireland, Dublin, Ireland 

Background: HER-2, a member of the transmembrane receptor tyrosine 

kinase ErbB family, is over-expressed in approximately 25% of BC. HER-2 

targeted therapies, in particular, T, a monoclonal antibody targeting 

HER-2, and lapatinib (L), a reversible HER-2 tyrosine kinase inhibitor, have 

been shown to significantly improve the prognosis for HER-2 positive BC 

patients. However, resistance to T and/or L is a significant clinical problem. 

The aim of this study is to assess the activity of N (HKI-272), an irreversible 

HER-2 tyrosine kinase inhibitor, in HER-2 overexpressing BC cell lines, 

including T and/or L resistant cells. Methods: Using proliferation assays, the 

effect of N was assessed alone and in combination with T in HER-2 positive 

BC cell lines, including T and/or L resistant cell lines. The effect of N on 

HER-2 and downstream signalling molecules, Erk and Akt, was determined 

by immunoblotting. Results: HER-2 positive BC cell lines, including T 

and/or L resistant cells, are sensitive to N alone with IC50 values 

(concentration which inhibits 50% of growth) ranging from 1 to 280 nM. 

The combination of N and T has additive effects in SkBR3 and BT474 

which are sensitive to T and also in SKBR3-Lwhich are resistant to L. In the 

cell lines HCC1954, HCC1954-L, MDA-MB-453, JIMT1 and SKBR3-HL 

which are resistant to T, combined treatment with T and N showed no 

enhancement compared to N alone. Finally, N decreased phosphorylation 

of HER-2, Erk and Akt in all cell lines tested. Conclusions: Our results 

suggest that N should be studied in patients with HER-2 positive BC, 

including patients with T and/or L resistant BC. We also demonstrate that N 

in combination with T may be more effective than either agent alone in T 

sensitive cells. 


Evaluation of Ile655Val HER2 polymorphism associated with cardiac 

toxicity following the administration of trastuzumab in women with breast 

cancer. Presenting Author: Caroline Diorio, URESP, Centre de Recherche 

FRSQ du CHA Universitaire de Québec, Quebec City, QC, Canada 

Background: Trastuzumab is well tolerated without major side effects 

except for cardiac toxicity. Although a number of clinical parameters have 

been associated with trastuzumab-associated cardiac toxicity (TACT), there 

is some indication that genetic variation of the HER2 gene may play a toxic 

role in a population of metastatic breast cancer patients. However, this 

finding needs confirmation and we looked at a population of non-metastatic 

breast cancer. This study aimed to evaluate the association between 

cardiac toxicity and HER2 [Ile655Val] polymorphism in non-metastatic 

breast cancer patients treated with trastuzumab. Methods: The Ile655Val 

HER2 polymorphism was assessed in 73 women using TaqMan technology. 

For this study, the genotyping was performed using DNA extracted from 

normal breast tissue located at more than 1 cm of any other lesions. Charts 

review was used to collect information on TACT which was defined as any 

decline in LVEF � 10 % from the baseline to � 55 % or a decline in LVEF 

� 5%to�50 % (lower limit of normal). The Fisher exact test was used to 

evaluate the association between cardiac toxicity and HER2 polymorphism. 

Results: No deviation from the Hardy-Weinberg equilibrium has been 

observed for the allele and genotype frequencies. The distribution of HER2 

polymorphism was 3 Val/Val (4%), 18 Ile/Val (25%) and 52 Ile/Ile (71%). 

In this population, 19% (14/73) developed a cardiac toxicity. We found 

that 29% (6/21) of Ile/Val or Val/Val carriers compared to 15% (8/52) of 

Ile/Ile carriers showed TACT, but this association did not reach statistical 

significance (P � 0.21). Conclusions: HER2 Ile655Val polymorphism may 

be an efficient marker of TACT considering this tendency with this small 

cohort of patients. Larger sample is needed to strengthen this conclusion, 

since this result may influence on prescribing decision for adjuvant 

chemotherapy and anti-HER2 therapy in HER2 positive patients. 




Effect of heterogeneity of HER2 expression on brain metastases of breast 

cancer. Presenting Author: Mari Hosonaga, Division of Gene Regulation, 

Institute for Advanced Medical Research, Keio University, Tokyo, Japan 

Background: HER2-overexpressing or triple-negative [ER(-)/PR(-)/HER2(-)] 

breast cancers are associated with increased risk of brain metastases. The 

mechanisms leading to metastasis in each subtype are not well known. 

Methods: We introduced the wild-type HER2 gene into MDA-MB-231-luc- 

D3H2LN (231-Luc) cells, which are triple-negative breast cancer cells, 

and established HER2-expressing (63.2%) cells as 231-Luc-HER2 cells. 

We investigated the tumor formation following orthotopic inoculation and 

brain metastasis following intracardiac injection into nude mice. Metastasis 

was detected by bioluminescence imaging and confirmed in H&E 

staining and immunohistochemistry of vimentin and HER2 expressions. 

Flow cytometry analysis was used to detect the proportion of CD44�/CD24cells, 

a maker for stem-like breast cancer cells. Results: 231-Luc-HER2 

cells formed larger tumors in orthotopic xenograft models compared to 

231-Luc cells, however, no significant difference was observed in proliferation 

in vitro. Neither 231-Luc-HER2 nor 231-Luc metastasized in the brain 

from the breast after orthotopic inoculation. After intracardiac injections of 

the 231-Luc-HER2 cells, brain metastasis developed (7/13 mice, 53.8%). 

Immunohistochemical analysis revealed that most metastasized cells 

expressed HER2, although we had injected a mixture of HER2-positive and 

HER2-negative cancer cells. Interestingly, administering Lapatinib, a dual 

EGFR and HER2 tyrosine kinase inhibitor, effectively prevented HER2positive 

cells to colonize the brain. However, the HER2-negative 231-Luc- 

HER2 cells developed into brain metastases. In fact, the 231-Luc cells, 

which are HER2-negative, also metastasized in the brain (10/16 mice, 

62.5%). Flow cytometry analysis of the 231-Luc-HER2 cells showed that 

HER2-positive cells decreased the population of CD44�/CD24- (HER2�/ 

CD44�/CD24-: 86.8% and HER2-/CD44�/CD24-: 96.3%). Conclusions: 

The mechanism of brain metastases of HER2-positive breast cancer cells is 

different from that of HER2-negative breast cancer cells. It is therefore 

important to consider an additional therapeutic approach when dealing 

with HER2-negative cells in tumors having the heterogeneity of HER2 

expression. 


The effects of lapatinib and neratinib on HER2 protein levels in breast 

cancer cell lines. Presenting Author: Denis Collins, National Institute for 

Cellular Biotechnology, Dublin City University, Dublin, Ireland 

Background: HER2, a member of the c-erbB receptor tyrosine kinase family, 

is over-expressed (HER2 gene amplification/IHC 3�, �30% cells) in 

approx. 25% of breast cancers. Pre-clinical studies have shown that the 

HER2-targeted small molecule tyrosine kinase inhibitor (TKI) lapatinib 

(LAP) can increase HER2 levels in cell line models and can potentiate 

trastuzumab-mediated antibody dependent cell-mediated cytotoxicity. To 

assess the potential effects of the next generation TKI neratinib (NER) on 

expression of HER2 in breast cancer, this study compares the effects of 

LAP and NER on HER2 protein levels in the HER2-amplified SKBR3 and 

HER2-non-amplified T47D cell lines in vitro. Methods: SKBR3 and T47D 

were treated with LAP or NER (0.2, 1 and 2 �M) for 12, 24 and 48 

hours.HER2 protein levels were determined by ELISA, immunoblotting and 

high content analysis (HCA). HER2 protein was examined using two 

antibodies targeting the extracellular domain (ECD) and the intracellular 

domain (ICD) of HER2. pHER2, EGFR/pEGFR, MAPK/pMAPK and AKT/ 

pAKT levels were determined by immunoblotting. Proliferation studies 

utilized an acid phosphatase-based assay. Results: ELISA analysis confirmedsignificantly 

lower HER2 expression in T47D (44 �/- 17 pg/�g) 

compared to SKBR3 (748 �/- 296 pg/�g), p � 0.015. NER proved a more 

potent inhibitor of pHER2 and pEGFR as analyzed by immunoblotting and 

in proliferation studies (NER IC50 - SKBR3 0.03 �/- 0.01 nM, T47D 199 

�/- 70 nM, LAP IC50 - SKBR3 20 �/- 1 nM, T47D 1.2 �/- 0.2 �M). LAP 

induced an increase in both ECD and ICD-containing HER2 protein levels 

in SKBR3 and T47D cells. No increase in HER-2 levels was observed with 

NER treatment, as determined by HCA and immunoblotting. EGFR protein 

levels increased in response to lapatinib in both cell lines. Conclusions: Our 

results suggest that LAP and NER have differing effects on HER2 protein 

levels in the models examined. NER provides greater inhibition of HER2 

signaling activity but does not increase HER2 protein levels as was 

observed with LAP. Further pre-clinical assessment of combinations of LAP 

and NER with HER2 and EGFR monoclonal antibody therapies is warranted 

in HER2-amplified, HER2-non-amplified and EGFR-expressing breast 

cancer models. 


Adjuvant treatment of early-stage HER2� elderly breast cancer patients: A 

retrospective, multicenter French study. Presenting Author: Philippe Barthelemy, 

Hôpitaux Universitaires de Strasbourg, Strasbourg, France 

Background: Trastuzumab (T) is the standard of care for the adjuvant 

treatment of early stage, HER2� breast cancer (BC). However, few data are 

available for elderly HER2� breast cancer patients in this setting. In this 

current study, the patterns of care for elderly HER2� early stage BC in 7 

French cancer centres was evaluated. Methods: Medical records of all 

consecutive early stage HER2� BC patients over 70 years old treated 

between 2006 and 2011 among participating centres were retrospectively 

reviewed. Specific factors such as age, comorbidities, tumor stage, grade, 

ER/PR and HER2 status, treatment characteristics, follow-up and cardiotoxicity 

data were analysed. Results: One hundred and two patients were 

identified, median age 75.4 (range 70-95). Elderly patients presented 

mostly (57%) large tumors (pT �2), and positive lymph node involvement 

(n�61). Trastuzumab-based adjuvant treatment was administered in 62% 

of patients (n�63). 54% of patients (n�55) received adjuvant chemotherapy 

whereas five patients received neoadjuvant chemotherapy. Chemotherapy 

without T was administered in 2 additional patients. Anthracyclines 

(A)-Taxanes (Ta) combination-based chemotherapy was given in 27% of 

patients (n�16), whereas 38% received a Ta-based chemotherapy (n�23), 

35% (n�19) an A-based chemotherapy. Five patients received singleagent 

T. Treatment delays for T were required in 37% of patients (n�23) 

among whom 15 and 8 permanently or temporarily stopped T, respectively. 

The most frequent reason for interrupting or delaying therapy was cardiotoxicity 

(n�12) as well as patients refusal (n�7). A � 10% decrease in LVEF 

was observed in 18/63 (29%) of patients, among whom T was stopped in 

12. After a median 33 months follow-up, the median progression-free 

survival was not reached in patients receiving T-based therapy. The 2 and 

3-year PFS rate were 94 and 89.5%, respectively. Conclusions: In routine 

practice only 62% of elderly early stage HER2� BC patients are treated 

with a neoadjuvant or adjuvant T-based regimen. However, less than 50% 

of all patients completed their therapy. A-based chemotherapy was 

administered in around 60% of treated patients, and could explain 

cardiotoxicity in this setting. 


Lapatinib or trastuzumab? Which anti-HER2 treatment is more effective in 

the treatment of patients with HER2-positive breast cancer with brain 

metastases? An Anatolian Society of Medical Oncology Study. Presenting 

Author: Muhammet Ali Kaplan, Dicle Univercity Scholl of Medicine, 

Diyarbakir, Turkey 

Background: In the present study, we investigate that which treatment 

choice is more effective in the human epidermal growth factor receptor 2 

(HER2) positive breast cancer patients with brain metastases. Methods: Of 

405 metastatic breast cancer patients with brain metastases at referral 

centers in Turkey, 111 patients treated with lapatinib or trastuzumab after 

brain metastases eligible for the analyses were identified. Patients received 

both drugs consecutively or sequentially were excluded from the study. 

Results: Median age was 44 years (27-76) and 46 of the 111 patients 

(41.5%) had received lapatinib. Median time to development of brain 

metastases was 12.2 months (0-71). Sixteen patients (14.4%) had 

undergone surgery, 33 (29.7%) radiosurgery, and 108 (97.2%) whole 

brain radiation therapy (WBRT). Median overall survival (OS) after brain 

metastases was 15 months(95% confidence interval (CI): 12.3-17.6). 

Lapatinib usage was prolonged OS over trastuzumab alone (19.1 months vs 

12 months, p�0.039).Other parameters affecting the survival were Karnofsky 

performance score (KPS, �70), number of brain metastases (�3), 

extracranial metastases (�2), performed neurosurgery, and received radiosurgery. 

After correction for potential confounders, lapatinib therapy 

remained an independent positive predictor for survival [Odds ratio (OR), 

0.57; p�0.02). Conclusions: Although this retrospective multi-center study 

had several limitations, study results suggest that the usage of lapatinib 

after brain metastases prolonged survival compared to the usage of 

trastuzumab. This result should be support with prospective studies. 



Functional imaging of HER2-positive metastatic breast cancer using 64Cu DOTA-trastuzumab positron emission tomography (PET). Presenting Author: 

Joanne E. Mortimer, City of Hope Cancer Center/Beckman Research 

Institute, Duarte, CA 

Background: We are developing 64Cu-labeled trastuzumab (tras) as a PET 

imaging agent for women with HER2� beast cancer. To maximize image 

quality and minimize HER2 uptake in normal tissues, we pre-administered 

2 different doses of cold tras prior to injection of the imaging agent. 

Methods: Pts with advanced breast cancer were eligible if they had bx 

confirmed HER2 � disease, had not received anti-HER therapy for 6 mos. 

and had � 1 non-hepatic site of metastasis � 2 cm outside the biopsy site. 

All un-derwent staging FDG/PET and bone scan. Prior to injection of 

64Cu-tras, pts. received 5 or 50 mg (2 and 4 pts) of cold tras. PET-CT was 

obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 

18F-FDG scans. Uptake in organs and lesions were measured in terms of 

body wt-normalized SUV. Lesions with intensity � adjacent tissue were 

considered positive on PET. The number of metastatic sites identified on 

64Cu-tras/PET was compared to the number on FDG/PET. Image quality 

was assessed according to differences between the 2 pretreatment doses. 

Results: Six pts have been imaged. Tras dose had a marked effect on liver 

uptake of64Cu [SUV � 23�3 (mean�sd) and 6.3�0.6 for 5 and 50 mg 

tras, respectively; P � 0.05]. 72 CT� lesions (32 bone, 28 nodal, 9 liver, 2 

breast, 1 lung) were included in D1 and/or D2 scans. Of these, 66 of 72 

(92%), 48 of 63 (76%) and 36 of 44 (82%) were detected on FDG, D1 and 

D2 scans, respectively. Lesion SUVmax was 9�5(n�37, range 3-23) on D1 

and 11�6 (n�27, range 1-29) on Day 2. 64Cu-tras-to-FDG SUVmax ratios 

were 1.0�0.8 (range 0.2-4.3) and 1.3�1.1 (range 0.2-3.5) for D 1 and 2. 

Lesion 64Cuuptake trendedliver � bone � nodes. Conclusions: 64Cu-tras/ PET visualizes HER2� lesions in bone, liver and, to a lesser degree, lymph 

nodes. Pre-administration of cold tras improves the quality of tras/PET, 

especially of intrahepatic lesions. In the next phase of study we will perform 

64Cu-tras/PET in pts with HER2 1� and 2� disease. 


Outcome of HER2-positive breast cancer patients following metastatic 

relapse after adjuvant trastuzumab treatment since EMA regulatory approval. 

Presenting Author: Jean-Philippe Spano, Groupe Hospitalier Pitié 

Salpêtrière, AP-HP, Université Pierre et Marie Curie, Paris, France 

Background: Trastuzumab, a humanized monoclonal antibody against 

human epidermal growth factor receptor 2 (HER2) is approved in France 

since 2005 for HER2-positive breast cancer patients in the adjuvant 

setting. Efficacy of this treatment is clearly established but little is known 

related to patient outcome if they develop metastatic relapse after adjuvant 

trastuzumab. The aim of this study is to analyse these relapses with a 

special focus on efficacy of anti-HER2 treatment in this setting. Methods: 

We analysed 456 patients with HER2-positive early breast cancer treated 

with trastuzumab containing adjuvant therapy between 2006 and 2011 in 

two Departments of Medical Oncology from Université Pierre et Marie 

Curie, Paris, France. Data from patients with metastatic relapse were 

identified. Disease free survival (DFS) between end of trastuzumab and 

relapse, quality of response, and time to progression after anti-HER2 new 

treatment are reported. Results: Relapse rate was 3.3 % after adjuvant 

trastuzumab (15 pts, median age 53 years, ER� 40 %). DFS between end 

of trastuzumab and relapse was 244 days (95% CI: 91 - 397 days). One pt 

actually had a confirmed HER2-negative metastatic disease. The other 14 

pts were treated with anti-HER2 agents at relapse. On 12 evaluable pts, an 

objective response was observed in 8 pts, stabilisation in 2 pts and 

progression in 2 pts. Median time to progression after first line metastatic 

treatment was 222 days (95% CI: 114 - 330 days). Additional data about 

site of relapse and subsequent therapies are available. Conclusions: 

Relapse after adjuvant trastuzumab remains a rare event in this real life 

cohort of breast cancer pts. For these pts, we will present data of the 

patterns of relapse and response. These data may help us to determine if 

adjuvant trastuzumab has an impact on outcome of HER2 metastatic 

disease compared to data in trastuzumab naive metastatic HER2-positive 

breast cancer pts. We also plan to seek international collaboration to 

expand our analyses, as well as overall survival. 


41s 


Trastuzumab treatment in patients with advanced breast cancer (ABC) confined 

to locoregional and skeletal sites: Results from a large noninterventional study. 

Presenting Author: Christian Jackisch, Klinikum Offenbach, Offenbach, Germany 

Background: In a prospective observation study routine trastuzumab (T) treatment 

in HER2� ABC was evaluated in a total of 1,687 patients (pts) since 

2001. This large number allows the subgroup analysis of patients with the 

involvement of specific sites. Methods: Information on extent of advanced 

disease was available in 1,674 pts (99%) with HER2 overexpressing ABC. Pts 

were either pre-treated (39%) or naïve to palliative chemotherapy (CT). The 

following subgroups and their characteristics were analysed: I: locally ABC only; 

II: bone metastases allowing for concomitant local tumour; III: other. Results: 

Locally advanced lesions were found to be the sole BC manifestation in 145 pts 

(8.7%), while bone metastases � locally ABC were found in 209 pts (12.5%). 

This leaves a comparative population of 1320 pts with metastases to other sites, 

predominantly visceral metastases. The table shows the baseline and treatment 

characteristics, as well as the long term outcome based on progression/death 

observed in 79%/56% of pts. Concurrent CT (74% of total group) predominantly 

consisted of a taxane (46%) or vinorelbin (24%), with no major differences 

between the groups. Conclusions: In this HER2� cohort, palliative pts with local 

lesions only show a comparatively high-risk profile with respect to grading, 

hormone receptor status and adjuvant CT. Nevertheless, locally ABC only is a 

significant favourable prognostic factor in HER2� BC treated with T combinations, 

with a median survival of 4 to 5 years. 

ABC subgroups 

Parameter I II III 

Age [median, years] 57 59 59 

Age > 65 years [%] 27 26 28 

Grading G3 [%] 53 46 54 

Relapse-free interval [median, years] 2 2 2 

Hormone receptor positive [%] 51 71 60 

Local disease present [%] 100 28 30 

Adjuvant CT [%] 77 57 60 

Previous palliative CT [%] 26 28 42 

Previous palliative hormone therapy [%] 17 38 32 

> 1 year of T treatment [%] 54 58 47 

Concomitant hormone therapy [%] 32 44 31 

Complete remission [%] 43 12 13 

Progression-free survival [median, months] 23.5 18.7 10.3 

Progression-free survival rate at 2 years [%] 49 42 25 

Overall survival [median, months] 57.7 45.3 30.9 


Estrogen receptor in HER2-positive early breast cancer: Two different diseases? 

Presenting Author: Eva Maria Ciruelos Gil, Medical Oncology Department, 

University Hospital 12 de Octubre, Madrid, Spain 

Background: HER2� breast cancer (BC) is a well characterized subtype of BC, 

due to the predictive value of HER2 overexpression for anti-HER2 targeted 

therapies. Nevertheless, around 50% of HER2� BC are ER� and clasiffied as 

luminal B/HER2�, but their biological and clinical behaviour may be different 

from HER2�/ER- tumors. Methods: We retrospectively reviewed 347 HER2� 

(Herceptest �� or FISH�) early BC patients (see Table) diagnosed at our 

institution in 1997-2007, and were divided into two study groups: HER2�/ER� 

(group A) and HER2�/ER- (group B). ER� was defined if expressed in � 10% 

tumor cells. Results: See table below. Mean age: 54.7 y (44.6 – 65). Mean Ki 67 

was higher in B (37,2 vs 22,4%, p�0.0001). At the current FU, n¼ of events 

were insufficient to reach median DFS/OS. Mean DFS was 6.9 y (3.5 – 10.2); 

recurrent disease was higher (p 0.003) for B (54 pts, 43%) vs A (62 pts, 28%). 

5-year DFS estimates: 78.4 % (95% CI 72.3 – 83.3) and 62.3 % (95% CI 53 – 

70.27) for A and B, and 10-year DFS was 73.4% (95% CI 66.6 – 79) and 52.5% 

(95% CI 42.4 – 61.6) for A and B, respectively (p 0.0006). Most common 

recurrent sites were local (18) and bone (9) for HER2�/ER� and liver (8) and 

lung (8) for HER2�/ER-. Mean OS was 8.03y (5.4 – 10.8); 28 (12,6%) pts died 

in A, vs 26 (21%) in B (p 0.043). 5-year OS estimates: 93.9 % (95% CI 89.7 – 

96.4) and 87.6 % (95% CI 80.3 – 92.3) for A and B, and 10-year DFS was 

84.2% (95% CI 77.5 – 89.0) and 74.1% (95% CI 63.4 – 82.2) for A and B, 

respectively (p 0.01). Conclusions: ER expression in HER2� early BC defines 

two clinically distinct diseases with different long-term prognosis. These data 

may help to better individualize adjuvant therapies and future clinical trial 

designs. 

AN(%) BN(%) 

N 222 125 

T1 

104 (47) 

44 (35,2) 

T2 

94 (92,5) 

63 (50,4) 

T3 

9 (4) 

13 (10,4) 

T4 

14 (6) 

5 (4) 

Missing 

1 

N0 

120 (58,5) 

60 (51,2) 

N1 

46 (22,4) 

26 (22,2) 

N2 

28 (13,6) 

22 (18,8) 

N3 

11 (5,3) 

9 (7,7) 

Missing 

17 

8 

Neoadjuvant CT 50 (22,5) 30 (24) 

Adjuvant CT 126 (57) 88 (70,4) 

Type of CT 

44 (25) 

30 (25,4) 

No A, no T 

74 (42) 

57 (48,3) 

A, no T 

34 (19,3) 

27 (23) 

A and T 

Other 

24 (13,6) 

4 (3,3) 

Adjuvant RT 172 (77,4) 96 (77) 

Adjuvant trastuzumab 33 (14,8) 28 (22,4) 

Adjuvant HT 

213 (96) 

16 (13) 

Tam �/- LHRHa 

77 (36) 

8 (50) 

Aromatase inh. 

136 (64) 

8 (50) 




Correlation of TOP2A expression in HER2-positive breast cancer with 

pathologic response and clinical outcomes in patients undergoing neoadjuvant 

treatment based on anthracycline. Presenting Author: Elizabeth S. 

Santos, Hospital A.C. Camargo, São Paulo, Brazil 

Background: Factors predictive of response to anthracyclines can help 

selecting patients who really benefit from its use. TOP2A (a target of 

anthracyclines) and HER2 genes are both amplified in 40% of breast 

cancers. Data from literature are conflicting regarding the potential of 

TOP2A as a predictor of response to anthracyclines. Methods: We retrospectively 

analyzed data on the outcome of patients undergoing neoadjuvant 

anthracycline-based chemotherapy and evaluated nuclear TOP2A protein 

expression in breast cancer biopsies by immunohistochemistry (IHC) and 

reviewed the pathological responses after completion of neoadjuvant 

treatment. Results: From 2002 to 2011, data from 82 patients was 

reviewed. Forty nine patients had the paraffin blocks corresponding to the 

pre-treatment biopsy. All biopsies had some degree of TOP2A IHC 

expression. Patients were considered positive for TOP2A if the level of 

expression in IHC was higher than 10%. This was found in 77.6% of cases. 

Forty percent of the patients achieved pathologic complete response in 

pos-treatment surgical specimens. Correlation was observed between 

TOP2A IHC expression and tumor pathological response (p0.02). It was 

observed a difference in pathological complete response in favour of the 

group positive for TOP2A (47.4% vs. 22.7%), although not significant 

(p�0.09). No difference in PFS and OS was observed between patients 

with complete response after median follow-up of 34 months. Conclusions: 

The expression of TOP2A seems to be a promising marker to predict 

pathological response to antracycline-based neoadjuvant chemotherapy in 

HER2 breast cancer; however these findings would be better evaluated in 

prospective trials. 


Relationship between changes in left ventricular ejection and use of 

angiotensin-converting enzyme inhibitors and/or betablockers during adjuvant 

trastuzumab chemotherapy in early breast cancer: Data from the real 

world. Presenting Author: Francesco Giotta, Medical Oncology Department, 

National Cancer Institute of Bari, Bari, Italy 

Background: Adjuvant trastuzumab chemotherapy (aTrastC) improves DFS 

of pts with breast cancer and overexpression of HER-2. However, cardiovascular 

complication (CV) such as heart failure (HF) or significant left 

ventricular ejection fraction (LVEF) reduction may appear especially in 

those pts at increased CV risk. Methods: 253 women treated with aTrastC 

for EBC in 7 italian oncologic centers during the period 2008-2009 

entered in a multicenter registry and were retrospectively studied in 4 

subgroups according to the treatment with ACEi and/or BB. Occurrence of 

symptoms of HF and/or decrease in 10 points % of LVEF were recorded 

during the follow up. LVEF was measured at baseline and 3-6-9-12 

months. Results: Symptoms of HF occurred in 2% of pts who did not take 

either ACEi/ARB or BB. HF event-rate was similarly increased in pts 

receiving one or both medications, partially justified by the increased CV 

risk in these subgroups. Prevalence of decrease in LVEF � 10 points% was 

similar in all study subgroups. Trends in LVEF were characteristics for each 

study subgroup: at 3-month evaluation a significant decrease in LVEF was 

detected in ACEi/ARB and ACEi/ARB � BB group. Multiple logistic 

regression analysis showed that combined ACEi/ARB � BB therapy 

depended on history of hypertension (OR 36.7, CI 4.3-315.5) and 

reduction of LVEF from baseline to 3-month evaluation (OR 0.88, CI 

0.78-0.97) (best prediction – 3.5 points %, AUC 0.78, IC 0.65-0.91). 

Conversely, no association was found between changes in LVEF and 

ACEi/ARB or BB therapy alone. LVEF recovery from 3 to 12-month 

evaluation was inversely related to the changes in LVEF from baseline to 

3-month evaluation and did not depend on any pharmacological treatment. 

Conclusions: In clinical practice, a history of hypertension and changes in 

LVEF during the first 3 months of aTrastC for early breast cancer influence 

the use of ACEi/ARB and BB. This behaviour may explain the characteristic 

trend in LVEF showed in the subgroups of patient receiving or receiving not 

ACEi/ARB or BB. Subsequent recovery of LVEF does not seem to be related 

to any medical treatment. 


Time to brain metastasis (TTBM) from initial diagnosis of distant metastasis 

in breast cancer: Prediction of TTBM according to breast cancer 

subtypes and treatment effect. Presenting Author: Yeon Hee Park, Division 

of Hematology-Oncology, Department of Medicine, Samsung Medical 

Center, Sungkyunkwan University School of Medicine, Seoul, South Korea 

Background: Brain metastasis (BM) from breast cancer (BC) is a growing 

problem. About 10-15% patients with metastatic breast cancer (MBC) 

developed BM, with a 1 year survival of 20%. Currently, one-third of MBC 

patients with either HER2�ve tumors or triple negative BC (TNBC) tumors 

develop brain metastases. We hypothesized that MBC patients may 

predispose to BM differently during the disease courses according to BC 

subtype and treatment. We analyzed TTBM from initial diagnosis of distant 

metastasis how BC subtypes and treatment affect on TTBM. Methods: We 

retrospectively investigated 189 consecutive patients who were diagnosed 

with BM from BC between 2000 and 2009 at Samsung Medical Center. We 

analyzed TTBM according to BC subtypes and treatment effect. Results: 

The median age of 189 BM patients from BC was 48 (range 26-87) years. 

The numbers of patients with hormone receptor (HR)�ve and HER2-ve, 

HER2�ve irrespective of HR status, and TNBC were 43 (22.8%), 88 

(46.6%), and 58 (30.7%), respectively. Median TTBM of all 189 patients 

was 10.4 (95% CI, 7.7-13.1) months. We analyzed TTBC into four groups 

considering BC subtypes and treatment; HR�ve/HER2-ve (n�43), 

HER2�ve with trastuzumab (T) (n�59), HER2�ve without T (n�29), and 

TNBC patients (n�58). The median TTBMs for each group were 17.7 

months, 13.8 months, 4.3 months, and 2.9 months, respectively 

(p�0.002). BM as an initial site of distant metastasis was much more 

common in HER2�ve without T and TNBC patients than in the other 

patients’ groups (40.2% vs 20.6%, p� 0.003). Conclusions: TTBMs were 

much shorter in patients with HER2�ve without T and TNBCs than in other 

BC patients. Different approaches for evaluation and therapeutic strategy 

for BM at the time of distant metastasis may be considered for these 

populations. 

TPS646 General Poster Session (Board #15A), Sat, 8:00 AM-12:00 PM 

An open-label randomized, multicenter, phase II study on neoadjuvant 

treatment with trastuzumab plus docetaxel versus trastuzumab plus 

docetaxel plus bevacizumab according to positron emission tomography 

(PET) value modification in patients with early stage HER2-positive breast 

cancer (AVATAXHER): Design description. Presenting Author: Alexandre 

Cochet, Department of Nuclear Medicine, Centre Georges-Francois Leclerc, 

Dijon, France 

Background: For patients with early HER2� breast cancer at diagnosis, 

addition of trastuzumab (T) to 6 cycles of preoperative docetaxel (D) can 

reach a pathological complete response (pCR) in ~50% of cases, and a high 

rate of conservative surgery. pCR can be predicted by changes of Fluorodeoxyglucose 

(FDG) tumor uptake evaluated by Positon Emission Tomography 

(PET) after one cycle of therapy. In order to increase this pCR rate, adding 

an antiangiogenic compound could be considered. Pre-clinical and phase 

I-II data support that the combination of bevacizumab (B) and T is 

synergistic and safe when patients are chemotherapy naïve. The neoadjuvant 

AVATAXHER trial (EUDRACT 2009-013410-26) investigates the 

potential increase of pCR rate by combining B with T and D for patients with 

HER2� breast cancer who are not predicted for pCR by FDG PET. Methods: 

In this multicenter, open-label, phase II trial, 2 phases are planned after a 

selection period: phase I: all patients receive two cycles of therapy 

combining T (8 mg/kg at the first cycle, then 6 mg/kg) and D (100 mg/m2 ). 

FDG PET is also performed within 7 days before cycle 1 (baseline) and less 

than 3 days before cycle 2 in order to calculate changes of the tumor FDG 

uptake between baseline and after cycle 1 (�SUV). Phase 2: if �SUV�70%, 

patients will continue to receive T and D for (cycles 3 to 6: D 100 mg/m2 � 

T 6 mg/kg); if �SUV�70%, patients are randomized 2:1 to arm A (cycles 3 

to 6 D 100 mg/m2 � T 6 mg/kg � B 15 mg/kg) or arm B ( cycles 3 to 6: D 

100 mg/m2 � T 6 mg/kg). The primary endpoint is pCR rate evaluated 

post-surgery 4 to 6 weeks after the last treatment of cycle 6. Enrolment 

began in May 2010 and 125 patients were to be recruited in 26 sites. 

According to the hypothesis that 60% of patients will have a �SUV�70%, 

it is presumed that 72 patients will be randomized. There are currently 107 

patients included (as of 06 January 2012 ), 95 of them reached the phase 

1; 52 of them (55%) showed a �SUV�70% and after randomization 34 

were included in arm A and 18 in arm B. 


TPS647 General Poster Session (Board #15B), Sat, 8:00 AM-12:00 PM 

LUX-breast 3: Randomized phase II study of afatinib alone or with 

vinorelbine versus investigator’s choice of treatment in patients (pts) with 

HER2-positive breast cancer (BC) with progressive brain metastases (BM) 

after trastuzumab or lapatinib-based therapy. Presenting Author: Heikki 

Joensuu, Department of Oncology, Helsinki University Central Hospital, 

Helsinki, Finland 

Background: Approximately 1/3 of pts with HER2-positive, advanced BC 

will develop BM with a poor prognosis. Efficacy of systemic therapies is 

limited since few drugs can readily cross the blood-brain barrier. BC BM 

represents a high unmet medical need for which novel targeted therapies 

are needed. Afatinib is a small molecule, irreversible ErbB Family Blocker 

that has shown preclinical activity in trastuzumab-resistant cell lines and 

HER2-positive tumor xenografts. Its clinical efficacy has been demonstrated 

in pts with heavily pre-treated, HER2-positive metastatic BC, who 

progressed after trastuzumab therapy, with partial responses in 10% and 

clinical benefit in 46% of pts. In a Phase I afatinib trial a sustained PR was 

observed in a NSCLC pt with BM, and in a phase II trial in NSCLC, pts with 

or without BM achieved comparable outcome on afatinib. The purpose of 

this study (NCT01441596) is to investigate whether afatinib alone or in 

combination with vinorelbine has any effect on HER2-positive BC with BM 

after failure of prior trastuzumab or lapatinib. Methods: Key eligibility 

criteria: histologically confirmed HER2-positive BC; recurrent/progressive 

BM during/after prior trastuzumab or lapatinib therapy; �1 measurable BM 

(�10 mm on T1-weighted, gadolinium-enhanced MRI); extra-CNS lesions 

allowed; prior surgery, whole brain radiotherapy or stereotactic radiosurgery 

allowed; ECOG 0–2. Eligible pts are stratified by: ECOG score 0–1 vs 2; No 

of BM � 3vs�3; prior lapatinib therapy. Pts are randomized to (n � 

40/arm): Arm A: afatinib (40 mg/d oral); Arm B: afatinib (40 mg/d oral) � 

vinorelbine (25 mg/m2 / week); Arm C: investigator’s choice of medical 

treatment approved for metastatic BC. Primary endpoint: pt benefit at 12 

weeks (i.e. absence of CNS/extra CNS disease progression as per RECIST 

1.1) and no tumour-related worsening of neurological signs/symptoms or 

increase in steroid dosage. Secondary endpoints: PFS, OS, safety and 

afatinib concentration in plasma/cerebrospinal fluid in �12 pts. The study 

began in October 2011 and enrollment is ongoing. 

TPS649 General Poster Session (Board #15D), Sat, 8:00 AM-12:00 PM 

LUX-breast 1: Randomized, phase III trial of afatinib and vinorelbine versus 

trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic 

breast cancer (MBC) failing one prior trastuzumab treatment. 

Presenting Author: Nadia Harbeck, University of Cologne, Cologne, Germany 

Background: Afatinib is an ErbB Family Blocker that irreversibly blocks 

signaling from all relevant ErbB Family dimers. Afatinib is being developed 

in EGFR (ErbB1)-driven (NSCLC/HNSCC) and HER2 (ErbB2)-driven (breast) 

malignancies. In trastuzumab-resistant, HER2-positive (SUM190) xenografts, 

afatinib showed antitumor activity which was superior to lapatinib 

and increased by addition of IV vinorelbine. Afatinib monotherapy also 

demonstrated clinical activity (progression-free survival [PFS] � 15.1 wk; 

objective response [OR] � 10%) in an open-label, single-arm, Phase II trial 

in patients with HER2-positive MBC after progression on trastuzumab. 

Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, 

multicenter trial evaluating the efficacy and safety of afatinib � vinorelbine 

vs. trastuzumab � vinorelbine in patients with HER2-overexpressing MBC 

who progressed on, or after one prior trastuzumab-based treatment regimen. 

Patients are randomized 2:1 to afatinib (40 mg/d oral) � vinorelbine 

(IV 25 mg/m2 /wk) or trastuzumab (IV 2 mg/kg/wk after 4 mg/kg loading 

dose) � vinorelbine (IV 25 mg/m2 /wk). Patients receive continuous 

treatment in the absence of disease progression or adverse events. Key 

eligibility criteria include histologically-confirmed HER2-positive BC, stage 

IV disease; no prior treatment with vinorelbine or HER2-targeted treatment 

other than trastuzumab; progression on one prior trastuzumab based 

regimen in either the adjuvant (or �12 months after trastuzumab completion) 

or first-line (or �6 months after trastuzumab completion) setting; 

prior anthracycline and/or taxane chemotherapy; ECOG score 0 or 1. The 

primary endpoint is PFS and secondary endpoints include OR, overall 

survival and safety. Serum and tissue biomarkers will be assessed on 

archival tissue. HER-receptor and HER-ligand reprogramming, putative 

resistance markers and EGFR response signature will be explored in fresh 

tissue biopsies. Enrollment began in June 2010 and is ongoing, targeting 

�240 sites with a recruitment target of 780 patients. 


43s 

TPS648 General Poster Session (Board #15C), Sat, 8:00 AM-12:00 PM 

BOLERO-1: A randomized, phase III, double-blind, placebo-controlled 

multicenter trial of everolimus in combination with trastuzumab and 

paclitaxel as first-line therapy in women with HER2-positive (HER2� ), 

locally advanced or metastatic breast cancer (BC). Presenting Author: Sara 

A. Hurvitz, UCLA Hematology, Oncology and Translational Research in 

Oncology (TRIO), Los Angeles, CA 

Background: Up to 25% of BCs overexpress human epidermal growth factor 

receptor 2 (HER2). Patients with HER2 � disease have a higher rate of 

relapse and shorter overall survival (OS). Trastuzumab, a monoclonal 

antibody targeting HER2, is the standard of care and improves OS for 

HER2 � BC, but acquired resistance is common. The combination of 

trastuzumab and paclitaxel has shown good tolerability and excellent 

objective response rates (ORR) in up to 84% of patients with HER2 � 

metastatic BC (MBC) (Gasparini G, et al. BCRT. 2007;101:355-65). 

Everolimus is an orally bioavailable inhibitor of mammalian target of 

rapamycin (mTOR), a protein kinase central to multiple protein synthesis 

pathways and implicated in trastuzumab resistance. Everolimus-containing 

regimens have shown promising results in patients with ER � , HER2 – 

advanced BC in phase II/III trials; everolimus plus trastuzumab/paclitaxel 

or vinorelbine has shown encouraging ORR with an acceptable safety profile 

in phase I/II trials in patients with HER2 � MBC. The present phase III study 

was undertaken to assess the effectiveness of adding everolimus to 

first-line standard therapy in HER2 � advanced BC. Methods: Women with 

HER2 � , locally advanced or metastatic BC who have received no prior 

systemic therapy (except endocrine) are eligible. Local disease must not be 

amenable to resection with curative intent. Women with a history of central 

nervous system metastasis are excluded. Patients are randomized 2:1 

(everolimus vs control) to receive standard therapy (paclitaxel and trastuzumab) 

plus everolimus (10 mg daily) or placebo. The primary endpoint is 

progression-free survival. Secondary endpoints include OS, ORR, and 

clinical benefit rate. Additional endpoints are safety, performance status, 

and biomarkers. This trial is sponsored by Novartis Pharmaceuticals and is 

registered (ClinicalTrials.gov: NCT00876395). Enrollment began September 

2009, with a planned accrual of 717. The current accrual is 719, and 

the estimated primary completion date is October 2012. 

TPS650 General Poster Session (Board #15E), Sat, 8:00 AM-12:00 PM 

Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the 

treatment of HER2-overexpressing inflammatory breast cancer (IBC). 

Presenting Author: Charles Swanton, Translational Cancer Therapeutics 

Lab, CR-UK, London, United Kingdom 

Background: IBC is an aggressive and rare form of BC (1–6% cases). 

Despite recent treatment advances, prognosis remains poor, with 3-yr 

survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more 

frequently harbour HER2 gene amplification (~40%), and EGFR overexpression 

(~30%) associated with poor prognosis. Recent data reported clinical 

efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) 

naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family 

Blocker with preclinical activity in T-resistant cell lines, HER2-positive 

tumor xenografts and HER2-negative SUM 149 xenograft model derived 

from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, 

HER2-positive metastatic BC pts who progressed after T, with PR in 10% 

and clinical benefit in 46% of pts. The purpose of this biomarker-driven 

study is to investigate efficacy and safety of afatinib alone and in 

combination with V upon progression on afatinib monotherapy and the 

genomic changes that occur through treatment in pts with T pretreated or 

naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 

20 pts each: T-naïve and T failure. Key eligibility criteria: histologicallyconfirmed 

HER2-positive BC; investigator-confirmed IBC characterized by 

diffuse erythema and oedema (peau d’orange) while dermal lymphatic 

emboli or palpable mass are not necessary for diagnosis; no prior anti- 

HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts 

start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon 

disease progression, pts may receive afatinib (40 mg/d) � V (IV 25 

mg/m2 /week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or 

SD) for �6 months. Secondary endpoints: objective response rate, PFS, OS 

and safety. Endpoints are assessed separately for Part A and Part B. Fresh 

biopsy and blood samples are taken prior to treatment and upon progression 

in Part A, to explore predictive markers of response/resistance to 

afatinib, to describe the IBC population which may benefit most, and for 

next generation sequencing and proteomic analysis. Enrollment ongoing 

since Aug 2011. 



TPS651 General Poster Session (Board #15F), Sat, 8:00 AM-12:00 PM 

LUX-breast 2: Phase II, open-label study of oral afatinib in HER2overexpressing 

metastatic breast cancer (MBC) patients (pts) who progressed 

on prior trastuzumab (T) and/or lapatanib (L). Presenting Author: 

Tamas Hickish, Royal Bournemouth Hospital, Bournemouth, United Kingdom 

Background: Management of HER2-overexpressing MBC has improved over 

the past decade. However, pts still develop resistance to currently available 

HER2-targeted therapies and novel effective treatments are increasingly 

required as dual targeted combinations are given in early treatment lines 

already. Current therapies focus on targeting HER2 and do not inhibit all 

relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family 

Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 

(ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical 

studies have demonstrated efficacy in T-sensitive and T-resistant 

human BC xenograft models dependent on ErbB signaling. Efficacy of 

afatinib in a T-resistant SUM 190 xenograft model has been shown to be 

increased by addition of IV vinorelbine (V). Afatinib monotherapy has 

shown promising clinical benefit in 46% of HER2-overexpressing MBC pts 

who progressed on prior T, with 10% of pts achieving PR. Methods: This 

open-label Phase II trial (NCT01271725) investigates efficacy and safety 

of afatinib alone (40 mg/d) followed by afatinib ‘beyond progression’ plus 

chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed 

on prior neoadjuvant and/or adjuvant T and/or L. Pts who progress on 

afatinib monotherapy receive afatinib plus either weekly paclitaxel (P) 80 

mg/m2 or V 25 mg/m2 . Eligible pts have confirmed HER2-overexpressing 

BC, stage IV disease measurable by RECIST 1.1, progressed on T and/or L 

therapy in either neoadjuvant and/or adjuvant setting, are eligible for 

retreatment with P or V and should not have been pretreated with P (�12 

months) or V, respectively. Exclusion criteria: inadequate cardiac, renal, 

hepatic and hematological function, pre-existing gastrointestinal dysfunction, 

rapidly progressing visceral disease, ILD and active brain metastases. 

The primary endpoint is objective response (OR) and secondary endpoints 

include best overall response, duration of OR and PFS; safety will be 

assessed separately for afatinib mono- and combination therapy. Patient 

enrollment began in May 2011 in ~35 sites and 5 countries. 

TPS653 General Poster Session (Board #15H), Sat, 8:00 AM-12:00 PM 

A combination of pertuzumab, trastuzumab, and vinorelbine for first-line 

treatment of patients with HER2-positive metastatic breast cancer: An 

open-label, two-cohort, phase II study (VELVET). Presenting Author: Edith 

A. Perez, Mayo Clinic, Jacksonville, FL 

Background: Pertuzumab (P) is a humanized monoclonal antibody directed 

against the dimerization domain of HER2: it prevents HER2 heterodimerization 

and thus activation of downstream signaling. Since P targets a 

different epitope than trastuzumab (H), a more comprehensive HER2 

blockade is achieved by combining the two agents. Data from CLEOPATRA 

showed improved efficacy for P and H plus docetaxel. The combination of P 

and H has not yet been assessed with other chemotherapy partners in the 

metastatic setting. H plus vinorelbine (V) has shown comparable efficacy to 

H plus docetaxel but with a superior safety profile. VELVET will assess the 

overall response rate (ORR) of P with H�V in first-line patients (pts) with 

HER2-positive MBC. Co-administration of P and H within the same 

infusion bag will also be investigated as this could increase pt convenience 

by reducing administration and observation time. Methods: VELVET is a 

multicenter, open-label, two-cohort, Phase II trial. Pts with HER2-positive 

LABC or MBC not previously treated in the metastatic setting with 

non-hormonal anticancer therapy are eligible. Pts must have an LVEF 

�55% at baseline and an ECOG PS of 0 or 1. Study enrollment started in 

January 2012. A total of 210 pts will be included. Based on statistical 

assumptions, 95 pts must be evaluable per cohort, which assumes a 

withdrawal rate around 10%. Pts in Cohort 1 (the first 105 pts enrolled) will 

receive P and H sequentially and pts in Cohort 2 (the next 105 pts) will 

receive P and H in the same infusion bag at Cycle 2 onwards if drug 

administration in Cycle 1 was well tolerated. V will be given in both cohorts. 

Treatment duration is until disease progression or unacceptable toxicity. 

Study dose: P: 840 mg loading dose, 420 mg q3w (iv); H: 8 mg/kg loading 

dose, 6 mg/kg q3w (iv), and V: 25 mg/m2 Day 1 and 8 (first cycle) then 

30�35 mg/m2 Day 1 and 8 q3w (iv) (dose escalation at investigator’s 

discretion). The primary endpoint is ORR by independent assessment. 

Secondary endpoints include investigator assessment of ORR, time to 

response, duration of response, PFS, time to progression, overall survival, 

safety and tolerability, and QoL. 

TPS652 General Poster Session (Board #15G), Sat, 8:00 AM-12:00 PM 

A phase II trial of trabectedin (T) in patients with hormone receptorpositive, 

HER2-negative advanced breast cancer, according to xeroderma 

pigmentosum gene (XPG) expression. Presenting Author: Ahmad Awada, 

Institut Jules Bordet, Brussels, Belgium 

Background: Hormone receptor-positive, HER2-negative breast cancer (BC) 

is currently associated with 3-4 years overall survival in the metastatic 

setting and, after �2 relapses, therapeutic approaches are reduced. XPG 

expression is frequently modified in BC. T is a cytotoxic agent that forms a 

complex with the XPG, inducing cell apoptosis. As a single agent, T has 

shown anti-tumor activity in patients with poor prognosis BC, and a better 

response to T in BC patients with XPG RNA overexpression has been 

observed. Methods: This is an open-label, phase II study of T (1.3 mg/m2 in 

3-hour intravenous infusion every 3 weeks) in patients with hormone 

receptor-positive, HER2-negative advanced BC, according to their primary 

tumor’s XPG expression. Primary endpoint: to evaluate the efficacy of T in 

terms of progression free survival rate at 4 months (PFS4) according to the 

patient’s XPG expression. Secondary endpoints: Comparison of PFS, 

overall response rate, duration of response, overall survival and safety 

profile in XPG-high and XPG-low patients. Assignment: BC patients who 

have previously received anthracyclins and/or taxanes and who progressed 

after 2-5 chemotherapy lines will be assigned according to their XPG 

expression from paraffin embedded tumor samples to stratum A (XPG-high 

[�3]) or to stratum B (XPG-low [�3]) (threshold was selected from median 

XPG expression values observed in a previous trial). Statistical methods: A 

two-stage design was chosen: at a first stage 20 patients will be enrolled in 

each stratum. A futility analysis (O’Brien Fleming boundary) based on the 

primary endpoint (PFS4) will be conducted once 40 evaluable patients 

have been recruited. If � 7 out of 20 patients achieve PFS4, recruitment 

will continue to a maximum sample size of 50 evaluable patients per 

stratum. If � 22 out of 50 patients achieve PFS4, T will be considered 

active in this group (alpha error: 0.025, power: 80%). To date, 35 patients 

(16 XPG-high and 15 XPG-low) have been enrolled from three countries 

and five centers. Recruitment is ongoing. 

TPS654^ General Poster Session (Board #16A), Sat, 8:00 AM-12:00 PM 

Pertuzumab in combination with trastuzumab plus an aromatase inhibitor 

in patients with hormone receptor-positive, HER2-positive metastatic 

breast cancer: A randomized phase II study (PERTAIN). Presenting Author: 

Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX 

Background: Resistance to endocrine therapy in patients (pts) with breast 

cancer remains a major clinical concern. Preclinical studies suggest that 

complete blockade of the hormone receptor (HR) combined with the 

inhibition of HER family members may be necessary to overcome resistance 

and improve clinical outcome in HR-positive and HER2-positive 

breast cancer (BC). The combination of pertuzumab (P) and trastuzumab 

(H) with docetaxel significantly improves patient outcome by blocking, 

more efficiently and completely, the HER signalling pathway. This benefit, 

however, may be smaller in HR-positive patients. PERTAIN is the first 

clinical trial to study whether a more potent blockade of the HER pathway 

with P and H in combination with endocrine therapy may restore or enhance 

endocrine sensitivity of HER2-positive BC and provide an effective treatment 

option in pts with HER2-positive and HR-positive MBC. Methods: 

PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal 

women with HER2- and HR-positive BC, studying the efficacy of the 

combination of P plus H with an aromatase inhibitor (AI) as first-line 

therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading 

dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI 

[anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H � AI at same dose 

as Arm 1). Pts in either arm may also receive induction chemotherapy 

(docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion. 

Study medication will be administered until disease progression or unacceptable 

toxicity. Pts must not have previously been treated with anti- 

HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and 

must have no CNS involvement or clinically significant cardiovascular 

disease. The primary endpoint is PFS, and secondary endpoints include 

overall survival, overall response rate, clinical benefit rate, duration of 

response, time to response, safety and tolerability, and quality of life. The 

study opened in January 2012 and will recruit 250 pts. Analysis of the 

primary endpoint will be performed after 165 PFS events using the 

Kaplan-Meier approach. 



Docetaxel, carboplatin, trastuzumab, and bevacizumab (TCH�B) for earlystage 

HER2/neu(�) breast cancer and bone marrow micrometastases. 

Presenting Author: Joseph Baar, Seidman Cancer Center, Cleveland, OH 

Background: Bone marrow (BM) micrometastases confer a poor prognosis to 

early-stage breast cancer (BC) and HER-2/neu(�) BC is a high-risk 

phenotype. We have shown that BM-associated stromal cells support the 

survival of metastatic BC in microenvironmental niches and this activity is 

dependent on VEGF and CXCL-12. Therefore, the growth of nascent tumor 

cell clusters in BM might be impeded by disrupting stromal cells or their 

activating ligands, such as VEGF. There is also a positive association 

between HER-2/neu and VEGF expression in BC, thereby implicating VEGF 

in the aggressive phenotype of HER-2/neu overexpression. These observations 

support the use of combination therapies directed against both 

HER-2/neu and VEGF for the treatment of HER-2/neu(�) BC. We therefore 

hypothesize that an anti-VEGF agent (bevacizumab) given with docetaxel, 

carboplatin and trastuzumab (TCH) will eradicate the BM of HER-2/neu(�) 

BC micrometastases by disrupting stromal cell support within the micrometastatic 

BM niche. Methods: Subjects with AJCC Stage I-III HER2/ 

neu(�) BC will undergo a single iliac-crest BM aspirate and biopsy. If the 

BM is positive for CK� micrometastases, up to 17 patients will receive 

TCH�B therapy (docetaxel at 75 mg/m2 IV and carboplatin at AUC 6 IV 

given every 3 weeks for 6 cycles; trastuzumab at 4 mg/kg IV loading dose, 

then 2mg/kg IV every week; bevacizumab at 15 mg/kg IV every 3 weeks). 

Four weeks after the 6th cycle of therapy, a repeat BM aspiration and biopsy 

will be performed to score for response of BC micrometastases to therapy. 

Patients with a complete clinical response in BM will continue with 

trastuzumab every 3 weeks at 6 mg/kg to a total of 1 year. Patients with 

persistent micrometastases will receive both trastuzumab and bevacizumab 

every 3 weeks to a total of 1 year of therapy. These patients will then 

have a repeat BM aspirate and biopsy at the end of the 1 year to score for 

final response. The primary objective of this clinical trial is to determine 

clinical response against BC micrometastases in BM. The second objective 

is to investigate the specific contribution of VEGF and CXCL-12 signaling to 

BM support of micrometastatic BC cells. 


A phase III clinical trial to compare trastuzumab (T) given concurrently with 

radiation therapy (RT) to RT alone for women with HER2� DCIS resected 

by lumpectomy (Lx): NSABP B-43. Presenting Author: Melody A. Cobleigh, 

National Surgical Adjuvant Breast and Bowel Project, Rush University 

Medical Center, Chicago, IL 

Background: Asignificant amount of DCIS is ER negative and/or overexpresses 

HER2. This provides an opportunity to test molecular therapy in 

DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In 

T-treated HER2� patients, apoptosis occurs within 1 wk of single agent T 

use, with T found in ductal aspirates. Ample safety evidence for T exists. T 

given during whole breast irradiation (WBI) may improve results for 

Lx-resected HER2� DCIS. A trial to examine this question will enhance the 

understanding of breast tumor biology and the prevention of such tumors 

and could possibly extend breast-conserving surgery benefits for women 

with DCIS. Methods: After Lx for pure DCIS, each patient’s DCIS lesion is 

centrally tested for HER2 by IHC analysis. HER2 2� tumors undergo FISH 

analysis. HER2 3� or FISH� patients can be randomly assigned to 2 doses 

of T, 3 weeks apart during WBI or to WBI alone. Women �18 yrs. with a 

margin-clear Lx for pure DCIS, with ECOG status 0/1 who are and clinically 

or pathologically node negative are eligible. Centrally tested DCIS must be 

HER2 �. ER and/or PR status must be known before randomization. 

Primary aims are to determine if T decreases ipsilateral breast cancer 

recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary 

aims are to determine the benefit of T in preventing regional or distant 

recurrence and contralateral invasive breast cancer or DCIS. B-43 will 

determine if DFS, recurrence-free interval, and OS can be improved with 

the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive 

analysis of primary endpoints performed at163 ipsilateral breast cancer 

events (7.5 - 8 yrs. after protocol initiation) with an 80% power to detect a 

hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 

100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in 

the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 

40% hazard reduction if the compliance were perfect, with a 10% 

noncompliance rate. As of 12-31-11, 763 patients have been randomized. 

NCT00769379 Grant support: PHS NCI-U10-CA-69651, -12027, and 

NCI P30-CA-14599 from the US NCI and Genentech, Inc. 


45s 


LCCC 1025: A phase II study evaluating the mTOR inhibitor everolimus 

with trastuzumab and vinorelbine to treat progressive HER2-positive breast 

cancer brain metastases. Presenting Author: Carey K. Anders, University of 

North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, 

Chapel Hill, NC 

Background: HER2� breast cancer (BC) is an aggressive subset of BC with 

high rates of brain metastases (BM) and poor survival. A recent study 

illustrates activation of the PI3K/mTOR pathway in approximately twothirds 

of BCBM across all subtypes. Everolimus, a novel oral derivative of 

rapamycin that selectively inhibits mTOR, is clinically-active in combination 

with trastuzumab (with or without chemotherapy) in advanced HER2� 

BC. Everolimus penetrates the blood brain barrier. We are evaluating the 

efficacy and safety of everolimus plus trastuzumab and vinorelbine in 

patients (pts) with HER2� BCBM. Methods: Pts with HER2� BCBM 

progressing following cranial radiation and measuring � 0.5cm are eligible 

for enrollment. Treatment with prior vinorelbine or mTOR inhibition is 

prohibited. Steroid treatment is allowed if stable or decreasing doses �7 

days prior to study entry. Pts with leptomeningeal disease are excluded. Pts 

receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine 

25mg/m2 (both IV days 1, 8, 15) of a 21 day cycle. Intra- and extracranial 

disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and 

CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial 

response rate (RR) assessed by modified RECIST. Secondary objectives 

include extracranial RR (assessed by RECIST 1.1), intra- and 

extracranial time to progression, progression free survival, overall survival, 

quality of life, and correlative science endpoints. Statistical considerations: 

In this two stage design, a sample size of 28 evaluable pts (n�11 in 

Stage 1) has 80% power to detect a difference between the null (�5% 

intracranial RR) and alternative hypothesis (�5%) at a 0.05 significance 

level. If 1 pt has a CR, PR or SD for � 3 months in the 1st stage, 17 

additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts 

will be enrolled. Correlative studies: Archival primary and/or metastatic 

tissues are required from all pts to evaluate intrinsic BC subtype, protein 

(p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may 

be predictive of response or resistance to this novel combination 

(NCT01305941). 


HALT MBC: HER2 suppression with the addition of lapatinib to trastuzumab 

in HER2-positive metastatic breast cancer (LPT112515). Presenting 

Author: Nancy Lin, Dana-Farber Cancer Institute, Boston, MA 

Background: Dual blockade of HER2 with the combination of trastuzumab 

(T) and lapatinib (L) enhances antitumor activity in HER2-positive breast 

cancer (BC) preclinical models due to the complementary mechanisms of 

action of the 2 agents. In patients (pts) with T-treated HER2-positive 

metastatic BC (MBC), treatment with the combination was associated with 

longer progression-free (PFS) and overall survival (OS) compared with L 

alone. In pts with stage II/III BC, preoperative treatment with the combination 

plus paclitaxel (P) resulted in significantly higher pathologic complete 

response rates compared with P combined with either agent alone. This 

evidence supports the concept of dual HER2 blockade as a treatment 

strategy for HER2-positive MBC. The present study is designed to evaluate 

whether the addition of L improves PFS among women with HER2-positive 

MBC receiving T as maintenance therapy. Methods: In this open-label, 

Phase III study, 280 pts will be stratified by line of treatment (first/second) 

and hormone receptor status (positive/negative), then randomized 1:1 to 

receive maintenance treatment with either L (1000 mg qd, continuously) in 

combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w) 

alone. Pts will receive study treatment until disease progression, death, 

discontinuation due to adverse events, or other reasons. The primary 

endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and 

safety. Key eligibility criteria include pts with HER2-positive MBC who 

have completed 12 to 24 weeks of first- or second-line treatment with T 

plus chemotherapy with an objective response or stable disease at time of 

chemotherapy discontinuation. Pts with stable brain metastases are 

eligible if entering the study on second-line treatment. Efficacy endpoints 

will be analyzed in the ITT population. A total of 193 PFS events is required 

to detect a 50% increase in median PFS (hazard ratio�0.67) for L plus T 

compared with T alone (median PFS 27 vs 18 weeks, respectively). The 

hypothesis will be tested using a 1-sided test with 80% power and a type I 

error of 0.025. The trial is currently open for accrual in the United States 

and Canada. 




WJOG6110B (ELTOP): Randomized phase II trial comparing trastuzumab 

plus capecitabine (HX) and lapatinib plus capecitabine (LX) in HER2positive 

metastatic breast cancer patients previously treated with trastuzumab 

and taxanes. Presenting Author: Toshimi Takano, Toranomon 

Hospital, Tokyo, Japan 

Background: In patients with HER2-positive metastatic breast cancer 

(MBC) previously treated with trastuzumab and taxanes, there are now two 

standard strategies: trastuzumab beyond progression or switch to lapatinib. 

A randomized trial comparing trastuzumab plus capecitabine (HX) and 

capecitabine alone (X) after first-line trastuzumab-based chemotherapy 

(GBG-26) showed that HX was superior to X in terms of time to progression 

(TTP). Another randomized trial comparing lapatinib plus capecitabine 

(LX) and X in patients previously treated with anthracyclines, taxanes, and 

trastuzumab (EGF100151) showed that LX was superior to X in terms of 

TTP. To evaluate which strategy is better, we are conducting an open-label, 

randomized phase II trial comparing HX and LX. Methods: Primary endpoint 

is progression-free survival, and secondary endpoints are overall response 

rate, overall survival, proportion of patients progressing brain metastases as 

site of first progression, and safety. Major eligibility criteria include: (1) 

HER2-positive MBC, (2) previously treated with taxanes, (3) disease 

progression or distant relapse while receiving trastuzumab, (4) previously 

untreated with capecitabine, S-1, and anti-HER2 drugs other than trastuzumab, 

(5) previously treated with no more than two chemotherapy 

regimens for MBC, (6) no symptomatic brain metastases (asymptomatic 

brain metastases are allowed), and (7) baseline left ventricular ejection 

fraction �50%. Patients in the HX arm receive capecitabine 2,500 

mg/m2 /day on days 1 to 14 plus trastuzumab (8 mg/kg loading dose and 

6mg/kg thereafter) on day 1 every 3 weeks. Patients in the LX arm receive 

capecitabine 2,000 mg/m2 /day on days 1 to 14 plus lapatinib 1250 

mg/day on days 1 to 21 every 3weeks. Large-scale biomarker analyses are 

also performed to explore predictive factors of trastuzumab or lapatinib 

efficacy. We are investigating biomarkers related to HER family and other 

receptors, PI3K/Akt pathways, ligands, Fc�R, circulating tumor cells, and 

so on. This study has just begun and 7 of planned 170 patients have been 

enrolled. 


ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and 

endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV) 

and endocrine therapy. Presenting Author: William Gradishar, Northwestern 

University, Chicago, IL 

Background: Approximately 50% of human epidermal growth factor receptor 

2 positive (HER2�) breast cancers are also hormone receptor-positive 

(HR�). For patients with HER2�/HR� disease, combining the aromatase 

inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L) 

has been shown to improve outcomes vs letrozole alone. Similar results 

were found for the combination of trastuzumab (T; a humanized monoclonal 

antibody targeting HER2) and anastrozole vs anastrozole alone. Finally, 

the combination of L and T has been shown to improve outcomes vs L alone. 

Methods: This phase III, randomized, open-label, multicenter trial (ALTER- 

NATIVE) will enroll postmenopausal female patients with HER2�/HR� 

metastatic breast cancer (MBC) who have not received prior treatment for 

MBC, have received neo/adjuvant T and endocrine therapy, and are not 

candidates for chemotherapy. Patients will be randomized 1:1:1 to 1 of 3 

treatment arms: L plus T plus an AI; T plus an AI; or L plus an AI. The AI can 

be letrozole, anastrozole, or exemestane, to be selected by the investigator. 

The primary objective of ALTERNATIVE is to examine the efficacy of L/T/AI 

compared with T/AI alone. The primary efficacy endpoint is overall survival 

(OS; time from randomization until death due to any cause) for L/T/AI vs 

T/AI. Secondary efficacy objectives include: comparisons of OS between 

T/AI and L/AI as well as between T/L/AI and L/AI, comparisons of 

progression-free survival, overall response rate, time to response, duration 

of response, safety, and tolerability for all 3 treatment groups. The study is 

powered to detect a 42% reduction in risk of death (hazard ratio�0.70) in 

patients who receive L/T/AI (median 28.5 months) vs T/AI (median 20 

months) using a 1-sided test for superiority with ��0.025. The required 

number of total events to achieve a power of 80% is 249. Secondary 

comparisons are not powered and will be based on the ITT population. This 

study is currently recruiting, with a target of 525 patients. If its objectives 

are reached, it will provide a valuable, chemotherapy-free treatment option 

for HER2�/HR� MBC patients. Clinical trial registry number: 

NCT01160211. 


The PERSEPHONE trial: Duration of trastuzumab with chemotherapy in 

women with HER2-positive early breast cancer. Presenting Author: Helena 

Margaret Earl, Department of Oncology, University of Cambridge, and 

NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom 

Background: Persephone is a phase III randomised controlled trial comparing 

six months of trastuzumab to the standard 12 month duration in 

patients with HER2 positive early breast cancer in respect of disease free 

survival, safety and cost-effectiveness. A Persephone sister study, the 

PHARE trial run by the National Institute for Cancer, successfully closed to 

recruitment in 2010. A prospective meta-analysis is planned once each 

trial has reported individually. Methods: A total of 4000 patients will be 

randomised into each of the two treatment groups. The power calculations 

assume that the disease-free survival (DFS) of the standard treatment of 12 

months trastuzumab will be 80% at 4 years. On this basis, with 5% 1-sided 

significance and 85% power, a trial randomising 2000 in each arm will 

have the ability to prove non-inferiority of the experimental arm defining 

non-inferiority as ‘no worse than 3%’ below the control arm 4 year DFS. 

Primary outcome is disease-free survival non-inferiority (equivalence) of 6 

months trastuzumab compared with 12 months in women with early breast 

cancer. Secondary outcomes are overall survival non-inferiority (equivalence); 

expected incremental cost effectiveness; cardiology function and 

analysis of predictive factors for development of cardiac damage. Two 

mandatory sub-studies are: Tumour block collection to discover molecular 

predictors of survival with respect to duration of trastuzumab treatment and 

blood sample collection, used to discover single nucleotide polymorphisms 

(SNPs) as genetic/pharmaco-genetic determinants of prognosis, toxicity 

and treatment outcome. A third optional sub-study is the quality of life 

questionnaires. Results: Persephone opened to recruitment in October 

2007. To date, 1847 patients (46%) of its total have been randomised 

from 147 UK sites. Recruitment is due to complete by December 2013 and 

the first planned interim analysis of the primary outcome will be mid-2016. 

The IDSMC last reviewed the trial in June 2011 and congratulated the Trial 

Management Group on the conduct of the trial and the quality of the data. 

No safety concerns were identified, and the IDSMC proposed that the trial 

continue to planned recruitment. 


HIT: A multicenter phase I-II study of trastuzumab administered by 

intrathecal injection for leptomeningeal meningitis of HER2� metastatic 

breast cancer. Presenting Author: Maya Gutierrez, Hôpital René Huguenin/ 

Institut Curie, Saint-Cloud, France 

Background: Leptomeningeal metastases (LM) are commonly associated 

with breast cancer (BC), announcing short term prognosis that intrathecal 

(IT) chemotherapy poorly modifies. Incidence is particularly marked in 

HER2� tumours. With the better control of extra-cerebral disease and 

prolonged survival yielded by intra-venous (IV) trastuzumab (T), the main 

hypothesis is that intra-cerebral recurrences are not reached by this high 

molecular weight (148 kD) monoclonal antibody. Analyses performed in 

cerebrospinal fluid (CSF) following IV T have shown low T levels, suggesting 

that LM of HER2� BC would remain potentially sensitive to anti-HER2 

agents as long as they could by-pass the meningeal blood brain barrier. 

Intraventricular (via Ommaya port) or IT administration of T would allow 

keeping control on LM progression through high T therapeutic concentrations 

in CSF. This prospective trial is the first phase I-II study sponsored by 

Institut Curie to investigate the safety and efficacy of the IT administration 

of T for HER2� LM BC. Methods: Eligible patients must be 18�, have a 

diagnosis of LM either on CSF with HER2� cytology or on clinical/MRI 

pictures of meningitis, and normal end-organ functions. The phase I cohort 

investigates the maximum tolerated dose (MTD) and recommended dose of 

T given weekly IT (or via Ommaya port) � hemisuccinate hydrocortisone 25 

mg, while aiming at yielding a T target-concentration in CSF close to the 

plasma one (30 �g/mL) obtained with standard IV schedule. The MTD is 

defined as the highest dose level (DL) tested with �2 dose-limiting toxicity 

(DLT, any grade �3 NCI CTCAE v4.0 attributed to T) observed in �6 

patients (3�3 Fibonacci dose escalation design, 4 DL 30-150 mg) with a 

maximum of 24 patients. The phase II cohort will investigate the efficacy of 

the recommended dose (DLMTD-1) defined in cohort I on neurological 

progression-free survival at 2 months, in �19 patients. Secondary endpoints 

include CSF and MRI response, quality of life, FCGR3A influence, 

and comparative CSF/plasma pharmacokinetics. Since study activation in 

May 2011, 5 patients have been included at DL1, 3 being evaluable for 

DLT. DL2 is now open for accrual. 



A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in 

patients with advanced, HER2-positive (HER2�) breast cancer. Presenting 

Author: Pamela N. Munster, University of California, San Francisco Helen 

Diller Family Comprehensive Cancer Center, San Francisco, CA 

Background: Anthracyclines have been an effective backbone of breast 

cancer therapies for decades. However, cardiotoxicity issues associated 

with free anthracyclines have limited their effective use in the clinic and 

led to the exploration of anthracycline-free regimens, particularly with 

HER2-positive cancers that require treatment with another cardiotoxic 

agent, trastuzumab. While liposomal doxorubicin formulations have succeeded 

in reducing cardiotoxicity, they have failed to demonstrate clear-cut 

efficacy advantages and can involve other toxicities. To address the safety 

and efficacy limitations of currently available anthracyclines, we have 

designed a new liposomal formulation, MM-302, that targets doxorubicin 

to HER2-overexpressing tumor cells. Antibody fragments that bind to 

HER2 without blocking HER2-mediated signaling are coupled to the outer 

surface of pegylated liposomal doxorubicin. MM-302 specifically binds and 

enters tumor cells overexpressing HER2 with minimal uptake into normal 

cells such as cardiomyocytes which express low levels of HER2. This 

first-in-human phase I study evaluates the safety of MM-302 in patients 

and provides preliminary efficacy data in HER-2� advanced breast cancer 

(ABC). Methods: Patients aged � 18 years with histologically confirmed 

HER-2� advanced breast cancer that have progressed or recurred on 

standard therapy or for which no standard therapy exists who have adequate 

performance status, bone marrow reserve, and organ function, are eligible 

for the study. Following a standard 3 � 3 dose escalation design, the 

maximum tolerated dose (MTD) or maximum feasible dose (MFD) is 

determined and up to 25 additional patients with HER-2� ABC will be 

enrolled for a planned total of 40-49 patients. The primary endpoint is 

determination of the MTD/MFD. Secondary endpoints include determination 

of dose-limiting toxicity, adverse event(s), and pharmacokinetic and 

immunogenicity profiles of MM-302, as well as overall response and 

clinical benefit rates of MM-302. MM-302 is administered intravenously 

weekly in 4-week cycles. At the time of this submission, 8 patients have 

been enrolled in the dose escalation portion. 


OPTIMA prelim: Optimal personalized treatment of early breast cancer 

using multiparameter analysis: Preliminary study. Presenting Author: Rob 

Stein, University College London Hospitals, London, United Kingdom 

Background: “Multi-parameter” prognostic tests such as Oncotype DX are 

increasingly used to identify women with ER �ve HER2 -ve breast cancer 

treated with endocrine therapy who are unlikely to benefit meaningfully 

from adjuvant chemotherapy. The supporting evidence for predictive 

testing is retrospective and is strongest for women with negative nodes. 

Randomised trials to validate testing are in progress but more evidence is 

needed, especially for node positive disease. There is early evidence that 

other multi-parameter tests which are in development have a predictive 

utility. Methods: OPTIMA will assess the value of multi-parameter tests in a 

UK population. OPTIMA prelim, the feasibility phase, will recruit 300 

patients from May 2012 (with a 200 patient bridging extension to the main 

study). Eligible patients will have ER �ve HER2 -ve tumours with involved 

nodes (pN1-2). Patients will be randomised to the standard arm of both 

chemotherapy and endocrine therapy, or to the “test-directed treatment” 

arm in which patients will be assigned either the same chemotherapy and 

endocrine therapy or endocrine therapy only according to the result of an 

Oncotype DX test. OPTIMA prelim has 3 objectives. (1) To establish 

whether randomisation to test-directed treatment is acceptable to patients 

and clinicians. This will be done through qualitative research with in-depth 

interviews with OPTIMA researchers and by recording and analysing 

consultations when the trial is discussed with potential participants. (2) 

Alternative multi-parameter tests will be evaluated on all patients’ tumours 

and their performance will be compared to Oncotype DX using statistical 

and cost-effectiveness analysis to select a candidate test(s) appropriate for 

NHS use to be evaluated in the main trial. (3) The success of the main trial 

depends on efficient tumour sample collection and analysis to avoid 

treatment delays. The obstacles to this will be analysed in detail using a 

sample tracking database. The main study is an efficacy trial of 2-3 arms 

with the same design but uses tests selected in OPTIMA prelim. It will 

compare 5-year relapse free survival of test-directed vs. conventional 

treatment with a non-inferiority hypothesis. 



A phase I study of BKM120, a novel oral selective phosphatidylinositol-3-kinase 

(PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with 

estrogen receptor positive metastatic breast cancer. Presenting Author: Gayathri 

Nagaraj, Washington University in St. Louis, St. Louis, MO 

Background: PI3K pathway activation plays a crucial role in mediating endocrine 

therapy resistance in estrogen receptor positive (ER�) breast cancer. We have 

shown previously that BKM120 in combination with fulvestrant induced synergistic 

apoptotic cell death in long-term estrogen deprived ER� breast cancer 

(LTED) cell line models, supporting the clinical investigation of this combination 

in ER� breast cancer. Methods: The study is composed of the dose escalation 

cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard 

3�3 phase I design is employed to determine the maximum tolerated dose 

(MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER� 

metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be 

enrolled at the MTD to further examine the toxicity profile and preliminary 

efficacy of this combination. Steady state concentrations of BKM120 will be 

analyzed. Postmenopausal women with ER� MBC and measurable disease per 

RECIST are eligible. Pts who are currently taking fulvestrant without disease 

progression are eligible. There is no restriction on the number of prior lines of 

systemic therapy for metastatic disease in phase IA but � 3 lines is required in 

phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on 

day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and 

d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level 

(DL) is DL1 (Table). Correlative studies include assessing PI3K pathway 

abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen, 

and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin 

D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation 

(Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor 

biopsies collected at baseline and cycle 2 day 1 in consented patients. 

Enrollment to DL1 is complete and the study is currently enrolling pts to DL2. 

Dose levels for the dose escalation cohort (phase IA). 

DL 

BKM120 (mg) 

PO daily 

Dose 

Fulvestrant (mg) 

Day 1 of each cycle 

2 100 500 

1 80 500 

-1 60 500 

47s 


Randomized phase II open-label study of abiraterone acetate (AA) plus 

low-dose prednisone (P) with or without exemestane (E) in postmenopausal 

women with ER� metastatic breast cancer (MBC) progressing after 

letrozole or anastrozole therapy. Presenting Author: Joyce O’Shaughnessy, 

Texas Oncology-Baylor Charles A. Sammons Cancer Center and US Oncology, 

Dallas, TX 

Background: AA plus P treatment in men with metastatic castrationresistant 

prostate cancer has demonstrated a survival advantage over P 

alone. Circulating adrenal steroids including DHEA and DHEA-sulfate can 

stimulate proliferation of breast cancer cell lines in a low-estrogen 

environment. Thus, it is hypothesized that depletion of adrenal androgens 

as well as estrogens by AA, a potent CYP17 inhibitor, inhibits tumor growth 

by disruption of ER-dependent growth signaling. In a previously reported 

phase I study of AA in patients (pts) with breast cancer (Basu, ASCO 2011), 

2/21 pts who were ER� were on study for � 11 months; 1 had a confirmed 

PR and continued on treatment � 14 months. Mechanism-based adverse 

event of grade 3/4 hypokalemia occurred in 4 pts and was managed with 

potassium supplementation and low dose corticosteroids. Methods: In the 

current study, 300 postmenopausal women with ER� Her2- MBC progressing 

after letrozole or anastrozole are randomized to either AA 1000 mg � P 

5 mg daily or AA � P � E 25 mg daily vs E. Disease must have been 

sensitive to a non-steroidal aromatase inhibitor (AI) prior to study entry. 

Subjects are stratified by number of prior therapies and by AI use in 

adjuvant or metastatic setting. Central review of tissue is required prior to 

randomization. Gene expression profiling (GEP) (AR, ER, PR, Her2, 

CYP17, Ki-67, CYP 19, and 3-�-HSD) will be performed on FFPE archival 

tissue. Pre- and post-treatment circulating tumor cells and fresh tumor 

biopsies will also be obtained for GEP in a subset of pts. Primary endpoint is 

PFS. Secondary endpoints are OS, ORR, patient reported outcomes, 

changes in endocrine markers, and PK characterization of AA and E. 

Subjects randomized to E may crossover to AA � P at time of disease 

progression. One interim analysis is scheduled after 50% of PFS events 

have occurred. After review of interim data, the Data Review Committee will 

make recommendations regarding study continuation. 23pts from 45 

active sites have been randomized as of January 24,2012. (ClinicalTrials. 

gov Identifier: NCT01381874) 




ASTER 70s: Benefit of adjuvant chemotherapy for estrogen receptorpositive 

HER2-negative breast cancer in women over 70 according to 

genomic grade—A French GERICO/UCBG UNICANCER multicenter phase 

III trial. Presenting Author: Etienne Brain, Hôpital René Huguenin/Institut 

Curie, Saint-Cloud, France 

Background: The benefit of adjuvant chemotherapy (CT) is highly controversial 

for elderly breast cancer (BC) women presenting with an oestrogen 

receptor-positive (ER�) HER2-negative (HER2-) phenotype. Conversely to 

hormonal treatment (HT) that remains the cornerstone of adjuvant treatment 

for such luminal tumours, CT may severely decompensate comorbidities 

and alter quality of life in elderly patients. As disappointing as it is in 

drug development, elderly have been constantly excluded from trials 

evaluating new modern prognosis classifiers. This prospective multicentre 

trial funded by a French national grant (PHRC 2011) is the first phase III 

trial to investigate the impact on overall survival (OS) of adjuvant CT in 

elderly ER� HER2- BC patients selected with a modern prognosis classifier 

and taking into account competing risks for mortality (EudraCT 2011- 

004744-22). Methods: Following surgery, 2,000 women 70� with ER� 

HER2- BC (any pT/pN), will have a genomic grade (GG, derived from frozen 

MapQuantDx, Ipsogen) centrally assessed on formalin-fixed paraffinembedded 

samples. Only those with a high GG (estimation~700) will be 

randomized between HT alone vs CT followed by HT. CT regimen is left to 

the choice of investigators amongst 3 regimen of same duration [4 q3w 

cycles, docetaxel�cyclophosphamide, doxorubicin or non pegylated liposomal 

doxorubicin (Myocet)�cyclophosphamide, all with G-CSF], as well 

as HT (aromatase inhibitor�tamoxifen). Those with low GG or not included 

for other reasons (estimation~1,300) will be followed as an observational 

parallel cohort with HT alone. Sample size is based on 4-year OS as primary 

endpoint (87.5 vs 80%), bilateral ��0.05, ��0.20 and HR� 0.60. 

Secondary endpoints include assessment of competing risks for mortality, 

cost-effectiveness and Q-TWiST analysis, geriatric items (e.g. Lee’s 4-year 

mortality score and G8 screening tool), acceptability, quality of life 

(QLQ-C30 and specific elderly scale ELD15), and translational research on 

ageing/prognostic biomarkers and pharmacogenetic. The trial has been just 

opened to inclusion in February 2012. 


Aromatase inhibitors, arthralgias, and exercise in breast cancer survivors. 

Presenting Author: Melinda Irwin, Yale University, New Haven, CT 

Background: A substantial number of breast cancer survivors who are taking 

aromatase inhibitors (AIs) complain of side effects including arthralgias. 

Given the efficacy of AIs, it is essential that we identify approaches to 

mitigate arthralgias. We are conducting an NCI-funded trial is to examine 

the impact of a year-long exercise intervention in 180 breast cancer 

survivors taking an AI and experiencing at least mild arthralgias. Outcomes 

include severity of arthralgias, endocrine-related quality of life, % body fat, 

bone mass, and serum markers of inflammation. The purpose of this 

abstract is to present preliminary recruitment and adherence results. 

Methods: Women are being recruited via the Connecticut Tumor Registry 

and Rapid Case Ascertainment Shared Resource of Yale Cancer Center into 

the Hormones and Physical Exercise (HOPE) Study. Participants are 

randomly assigned to exercise (n � 90) or usual care (n � 90). The exercise 

intervention includes supervised resistance and unsupervised aerobic 

exercise sessions over 12 months. Data are collected at baseline, 3-, 6-, 9 

and 12-months. Results: Study recruitment began in April 2010 and will 

continue through December 2012. As of January 1, 2012, we have 

received 1605 names of potentially eligible women. Of these 1605, 777 

women are waiting to be screened (e.g., letter mailed to patient or on hold 

because recently diagnosed), 244 women could not be screened (e.g., 

unable to contact by phone), and 584 women have completed a telephone 

screening. Of the 584 women screened, 24% were ineligible because of 

discontinuing AIs because of arthralgias or chose not to take AIs primarily 

because of this potential side effect; another 36% were ineligible for 

various reasons; 24% were not interested; 11% were randomized (n � 65 

women); and 5% are undergoing baseline visits (n � 29). On average, 

women are 62 yrs old and have been taking an AI for 1.8 yrs. Twenty-three 

women have completed the trial, with high exercise adherence rates 

(attendance to supervised sessions � 82% ). Conclusions: A growing 

number of women are choosing to not take AIs or are discontinuing AIs 

because of side effects. Our study may prove beneficial for the growing 

number of women diagnosed with hormone receptor-positive breast cancer 

each year. 


MDV3100-08: A phase I open-label, dose-escalation study evaluating the 

safety, tolerability, and pharmacokinetics of MDV3100 in women with 

incurable breast cancer. Presenting Author: Anthony D. Elias, University of 


Background: MDV3100 is a novel, orally administered small molecule that 

directly binds the androgen receptor (AR) to potently inhibit AR-mediated 

signaling via three mechanisms: inhibition of androgen binding to AR; 

inhibition of AR nuclear translocation; and inhibition of nuclear AR 

association with DNA. MDV3100 is not known to agonize AR signaling, can 

be taken without prednisone, and demonstrated an overall survival benefit 

in post-docetaxel prostate cancer at 160 mg/day. AR expression is observed 

in ~70% of all breast cancer (BCa) regardless of histologic subtypes 

(estrogen receptor [ER] positive, HER2�, and triple negative [TN] disease). 

MDV3100 has demonstrated preclinical activity in AR�/TN and AR�/ 

ER� BCa and could be a potential therapeutic strategy in patients with 

AR� BCa. Methods: This Phase 1 study has 2 stages: a standard 3�3 

dose-escalation stage (S1), evaluating safety, tolerability, and pharmacokinetics 

(PK) of MDV3100, starting at 80 mg MDV3100; and a doseexpansion 

stage (S2), evaluating the recommended Phase 2 dose in ~15 

women with AR� BCa. All patients must have received �2 chemotherapycontaining 

regimens for their incurable BCa, or �3 anti-HER2 containing 

regimens for their incurable HER2� BCa to be eligible; ER� patients must 

be post-menopausal. In S1, patients will receive their assigned dose of 

MDV3100 on Day 1, and PK samples will be collected through Day 8. Daily 

dosing will begin on Day 8 and will continue until predefined discontinuation 

criterion is met. Dose-limiting toxicities will be recorded through Day 

35 and used to determine the Phase 2 dose. Extensive PK sampling is 

performed on Days 1 and 50 with predose PK samples collected throughout. 

In S2, patients with AR� BCa (defined as 10% or more tumor cells 

with nuclear AR expression) will take daily MDV3100 at the recommended 

Phase 2 dose; there is no single dose PK period. Tumor tissue submission is 

mandatory in S2. Safety and tolerability will be documented by frequent 

assessments of adverse events, vital signs, and laboratory assessments. 

Tumor assessments occur at 2 months then approximately every 3 months 

thereafter. Enrollment of 27 subjects is anticipated. 


Denosumab versus placebo as adjuvant treatment for women with earlystage 

breast cancer who are at high risk of disease recurrence (D-CARE): An 

international, randomized, double-blind, placebo-controlled phase III clinical 

trial. Presenting Author: Paul Edward Goss, Massachusetts General 

Hospital Cancer Center, Boston, MA 

Background: Bone is a common site of distant recurrence in women with 

early-stage breast cancer, and represents approximately 40% of all first 

recurrences. Tumor cells in bone release growth factors and cytokines that 

stimulate osteoclast-mediated bone resorption through the RANK ligand 

(RANKL) pathway. In preclinical studies, RANKL inhibition significantly 

delays skeletal tumor formation, reduces skeletal tumor burden, and 

prolongs survival of tumor-bearing mice. Denosumab is a fully human 

monoclonal antibody that binds to RANKL with high affinity and specificity. 

It is approved for the prevention of skeletal-related events in patients with 

established bone metastases from a variety of solid tumors. The purpose of 

the D-CARE trial is to evaluate the ability of denosumab to prolong bone 

metastasis-free survival (BMFS) and disease-free survival (DFS) in the 

adjuvant breast cancer setting. Methods: Approximately 4,500 women with 

stage II or III breast cancer, at high risk for recurrence and with known 

hormone and HER-2 receptor status, are eligible. Standard-of-care adjuvant 

or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone 

or in combination must be planned. Exclusion criteria include: a prior 

history of breast cancer (except DCIS or LCIS) or distant metastasis, oral 

bisphosphonate (BP) use within 1 year of randomization or any intravenous 

BP use. Patients are randomized 1:1 to receive denosumab 120 mg or 

placebo subcutaneously monthly for 6 months, then every 3 months for a 

total of 5 years of treatment. All patients receive vitamin D (� 400 IU) and 

calcium (� 500 mg) supplements. Primary endpoint of this event-driven 

trial is BMFS. Secondary endpoints include DFS and overall survival. 

Safety, quality of life assessments, breast density, and biomarkers are 

additional endpoints. The trial, sponsored by Amgen Inc. and registered 

with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients 

in June 2010 and is expected to complete in October 2016. Paul 

Goss and Dianne Finkelstein supported in part by the Avon Foundation New 

York. 


LBA1000 Oral Abstract Session, Tue, 9:45 AM-12:45 PM 

NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing 

dose-dense (DD) AC followed by paclitaxel (P) plus gemcitabine (G) with 

DD AC followed by P and with docetaxel, doxorubicin, and cyclophosphamide 

(TAC) in women with operable, node-positive breast cancer. Presenting 

Author: Sandra M. Swain, National Surgical Adjuvant Breast and Bowel 

Project and Washington Cancer Institute, MedStar Washington Hospital 

Center, Washington, DC 


abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 




be printed in the Monday edition of ASCO Daily News. 

CRA1002 Oral Abstract Session, Tue, 9:45 AM-12:45 PM 

CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly 

paclitaxel (P) compared to weekly nanoparticle albumin bound nabpaclitaxel 

(NP) or ixabepilone (Ix) with or without bevacizumab (B) as 

first-line therapy for locally recurrent or metastatic breast cancer (MBC). 

Presenting Author: Hope S. Rugo, University of California, San Francisco 

Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 








49s 

1001 Oral Abstract Session, Tue, 9:45 AM-12:45 PM 

Randomized phase III study of adjuvant chemotherapy for high-risk, 

node-negative breast cancer (BC) comparing FAC with FAC followed by 

weekly paclitaxel: First efficacy analysis of the GEICAM/2003-02 trial. 

Presenting Author: Miguel Martin, Hospital General Universitario Gregorio 

Marañón, Madrid, Spain 

Background: Adjuvant weekly paclitaxel (wP) sequential to anthracyclines 

improves the outcome of operable node-positive BC patients (pts) [Sparano 

NEJM 2008, Martin BCRT 2009]; however, most BC pts are currently 

node-negative at diagnosis. The role of wP in these pts is not well 

established yet. Methods: Pts aged 18-70, with T1-T3/N0 operable BC and 

at least one high-risk St Gallen 1998 criteria (size �2 cm, hormonereceptor 

[HR] negative, grade 2/3, age �35 years,) were eligible. HER2� 

pts were allowed, after 792 entered the trial, the study was amended to 

exclude them. Pts were stratified by site, menopausal status, nodal status 

diagnostic method (sentinel-node biopsy versus lymphadenectomy) and 

HR status and randomized to receive FAC x6 (500/50/500 mg/m2 every 

3w) or FAC x4¡wP x8 (paclitaxel 100 mg/m2 weekly). The primary 

endpoint was DFS. The trial was designed to detect an absolute 5-y DFS 

increase of 5% (80% FAC, 85% FAC¡wP); a sample size of 1812 

evaluable patients (906 per arm) was required to detect this difference 

(��0.05, �� 80%). Assuming a drop-out rate of 6%, 1929 pts were 

required. The first analysis of DFS was planned when a median follow-up of 

5 years was reached. Results: Between September 2003 and October 

2008, 1925 pts (FAC 974, FAC¡wP 951) were randomized. Patient 

characteristics were well balanced between arms, median age was 50, 73% 

of pts were HR positive and 9% HER2 positive. 97% of pts with FAC and 

85% of pts with FAC¡wP completed all treatment as planned. The median 

dose intensity was 98% with FACx6, 99% with FACx4 and 98% with wP. 

The most frequent grade 3-4 toxicities (�3% in either arm) with FAC vs 

FAC¡wP were neutropenia (25% vs 22%) with 4% vs 3% of febrile 

neutropenia, fatigue (3% vs 8%), sensory neuropathy (0 vs 5%), and 

vomiting (4% in each arm). After a median follow-up of 5.3 years, the 

proportion of patients disease free is 93% and 90% with FAC¡wP and FAC 

(HR for relapse 0.732, 95% CI: 0.542 to 0.990; log-rank p-value�0.0423). 

Conclusions: For pts with high-risk node-negative BC, adjuvant FAC¡wP 

was associated with a small but significant improvement in DFS compared 

with FAC, with manageable toxicity. 


A phase III, multicenter, randomized trial of maintenance versus observation 

after achieving clinical response in patients with metastatic breast 

cancer who received six cycles of gemcitabine plus paclitaxel as first-line 

chemotherapy (KCSG-BR 0702, NCT00561119). Presenting Author: 

Young-Hyuck Im, Samsung Medical Center, Seoul, South Korea 

Background: Chemotherapy provides a survival benefit in patients with 

metastatic breast cancer (MBC), but the optimal duration of chemotherapy 

remains controversial. Primary purpose of the study was to evaluate 

whether the maintenance chemotherapy with gemcitabine/paclitaxel (GP), 

which is one of the two regimens which showed a survival gain from a 

randomized trial, is superior to observation in terms of progression free 

survival (PFS) in responding patients with MBC after 6 cycles of GP as 

first-line treatment. Methods: This study is a prospective, randomized, 

multi-center, phase III study. Patients who achieved response (CR�PR�SD) 

following 6 cycles of GP chemotherapy (gemcitabine 1250 mg/m2 on day 1 

and 8 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks) randomized to 

maintenance till progression or observation arm. The trial was conducted by 

the Korean Cancer Study Group (KCSG). Results: Among total 324 patients 

enrolled between 2007 and 2010 from 10 centers, 231 responding 

patients to were randomly assigned to maintenance chemotherapy (n�116) 

or observation (n�115). Median age was 49 (range 28-76). The numbers 

of hormone receptor (HR)�ve and HR-ve patients were 172 (74.5%) and 

59 (25.5%), respectively. The median No. of chemotherapy cycles in 

maintenance group was 12 (range 6-32). During median 33 months of 

follow-up, median PFS was superior in maintenance than in observation 

(12.0 vs. 8.3 months, p�0.030). Patients � age 50 years (hazard ratio 

0.50, p�0.001) and HR-ve patients (hazard ratio 0.52, p�0.019) 

received more benefit from maintenance chemotherapy in terms of PFS. 

Median OS was superior in maintenance than in observation (36.8 vs 28.0 

months, p�0.047). Neurotoxicity (� grade 2) was more common in 

maintenance than in observation without statistical significance (41.7% vs 

33.3%, p�0.210). Serial assessment of Quality of Life (QoL) did not show 

any significant difference between two groups. Conclusions: Maintenance 

GP chemotherapy for responding patients with MBC showed clinical benefit 

in terms of PFS and OS without impairment of QoL. 


50s Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy 


RTOG 9804: A prospective randomized trial for “good risk” ductal 

carcinoma in situ (DCIS), comparing radiation (RT) to observation (OBS) 

Presenting Author: Beryl McCormick, Memorial Sloan-Kettering Cancer 

Center, New York, NY 

Background: Whole breast RT following conservation surgery (BCS) for low 

risk DCIS has remained controversial despite several large trials comparing 

RT to OBS, all showing significant benefit in local control with RT. RTOG 

9804 compares RT to OBS for mammographically detected disease, of low 

or intermediate nuclear grade, �2.5 cm size, and surgical margins � 3 

mm. Tamoxifen (TAM) use for 5 years was allowed but not required. 

Methods: The primary endpoint was ipsilateral breast local failure (LF). LF 

and contralateral breast failures (CBF) were estimated by the cumulative 

incidence method and treatment arms compared by log-rank test. Diseasefree 

(DFS) and overall survival (OS) were estimated by the Kaplan-Meier 

method and treatment arms compared by log-rank test. Patients were 

stratified by age, margin width, grade, TAM use, and primary size. With 

1790 patients, 80% power and using a 2-sided log rank test at 0.05, the 

study was designed to detect a reduction in 5-year local recurrence from 

6% to 3.5% with RT. Results: Accrual goals for the planned 1790 patients 

were not met; the study was closed early. From December 1999 to July 

2006, 636 women were randomized to receive 50 Gy in 5 weeks vs. OBS. 

43 women were ineligible on review and 8 withdrew consent. Median 

follow-up (F/U) time was 6.46 years. Mean age was 59; TAM was used in 

62% of women. There were 2 LF in the RT arm vs. 15 in the OBS arm: at 5 

years 0.4% RT vs. 3.2% OBS (p�0.0023, HR [95%CI] � 0.14 [0.03, 

0.61]). With limited events, LF is not correlated with size, grade, margin 

status, or age. The rate of CBF at 5 years was 3.0% for the RT arm vs. 1.9% 

for the OBS arm (p�0.42, HR [95%CI] � 1.46 [0.59, 3.62]) and does not 

appear to be influenced by TAM use (3.6 versus 2.7% TAM). The DFS and 

OS results were excellent. Rate of grade 1-2 toxicity was 76% in the RT arm 

vs. 30% in the OBS arm, and the rate of � 3 grade toxicities was 4% on 

both arms. Conclusions: In this “good risk” subset of DCIS, the LF rate was 

decreased significantly with the addition of RT. Longer follow-up is 

planned. 


Targeting the androgen receptor (AR) in women with AR� ER-/PR- metastatic 

breast cancer (MBC). Presenting Author: Ayca Gucalp, Memorial Sloan-Kettering 

Cancer Center, New York, NY 

Background: Patients (pts) with ER-/PR- MBC do not benefit from endocrine 

treatment (tx). Doane et al (Oncogene 2006;25:3994) described a subset of 

ER-/PR- BC with a gene expression profile similar to ER� BC but characterized 

by AR expression and AR-dependent growth in vitro. Hence, we conducted a 

multicenter phase II trial (NCT00468715) of the AR antagonist, bicalutamide 

(B) for pts with AR� ER-/PR- MBC. Methods: Pts with ER-/PR- (IHC �10%) MBC 

were consented to AR testing, confirmed centrally at MSKCC. If AR� (DAKO IHC 

�10%), pts were eligible for tx if ECOG performance status (PS) �2 and normal 

organ function. No limit on prior tx except prior trastuzumab required if HER2�. 

Eligible AR� pts who consented to tx received B 150mg orally daily in 28-day 

cycles (C). Toxicity assessed q4wks, response q12wks. Primary endpoint � 

clinical benefit rate (CBR): CR � PR � stable disease (ds) �6mo (SD). B would 

be considered worthy of further study if �4/28 pts have clinical benefit. Results: 

As of 12/21/11,436 pts consented for AR testing. 24 were ineligible, 12 await 

testing. 47/400 tested were AR� (12%). 26 received tx with B (6 ineligible for 

tx, 15 are eligible for tx with B at progression (POD) if clinically appropriate and 

study slots remains). Two AR� pts treated with B were ER� and removed from 

study. Three have received tx �12wks. Treated pt characteristics (n�24): 

median (med) age 64 (41-83), PS 0 (0-1), HER2� 1, visceral metastases 17. 

Prior chemotherapy: neo/adjuvant 16; med # regimens for MBC 1 (0-8). Med C# 

3 (2-49�). Best response: (21 evaluable pts): CBR 19% (95% CI 5-42%), 

SD�6mo 4, CR/PR 0, SD�6mo 3, POD 14. Conclusions: ~12% of ER-/PR- MBC 

pts are AR�. For these pts, AR-inhibition with B is feasible, well tolerated, and 

has activity based on pre-specified criteria. This study has closed to accrual for 

AR testing as of 1/2012. These results of the primary endpoint are not expected 

to change by accrual of the 2 remaining pts. Supported by TBCRC/Breast Cancer 

Alliance/AstraZeneca. 

Tx-related toxicity (n�26). 

Grade (n) 

Toxicity 

1 2 3 

AST/ALT/ bilirubin 5 2 3 

Nausea 2 0 1 

Bone pain 6 2 0 

Anorexia 3 1 0 

Constipation 2 1 0 

Vaginal dryness 1 1 0 

Anemia 0 1 0 

Headache 0 1 0 

Hot flashes 6 0 0 

Fatigue 5 0 0 

Edema 5 0 0 

Diarrhea 3 0 0 

Anxiety 2 0 0 

Rash 2 0 0 

Dyspnea 

No grade 4/5 events 

2 0 0 


Correlation between the DCIS score and traditional clinicopathologic 

features in the prospectively designed E5194 clinical validation study. 

Presenting Author: Sunil S. Badve, Indiana University School of Medicine, 

Indianapolis, IN 

Background: We previously reported that in the E5194 clinical trial patients 

with ductal carcinoma in situ (DCIS) treated with wide local excision (WLE) 

without radiation (RT), the DCIS Score was significantly associated with 10 

year risk of an ipsilateral breast event (IBE - recurrence of in situ or invasive 

carcinoma), whether evaluated as a continuous or categorical variable 

(P�0.02 for both). Here we evaluate correlation between DCIS Score and 

clinicopathologic (CP) features and if DCIS Score provides independent 

recurrence risk information. Methods: The study population included 327 

women with DCIS prospectively selected for treatment with WLE without 

RT, including low-intermediate grade tumors �2.5 cm or high-grade �1 

cm. CP variables included age, menopausal status, tamoxifen treatment 

(used in 29%) and expert centrally determined tumor size, grade, comedo 

necrosis, tumor type, and margin status. The association between DCIS 

Score and CP variables was examined by spearman rank correlation, and 

proportional hazards regression models were used to determine variables 

significantly associated with IBE. Results: Lesion size (p�0.009) and 

menopausal status (p�0.03) were significantly associated with IBE, while 

grade (p�0.69) and comedo necrosis (p�0.47) were not. DCIS Score was 

significantly associated with IBE after adjustment for CP features and 

tamoxifen use (p�0.02). DCIS Score was moderately correlated with grade 

(rs�0.46; 95% CI 0.37,0.54), percentage comedo necrosis (rs�0.49; CI 

0.41,0.57), and lesion size (rs�0.18; CI 0.08,0.29) but not other 

features. Exploratory analyses in all CP subgroups, including the multicomponent 

Van Nuys Prognostic Index, showed a wide range of DCIS Scores in 

each subgroup. Concordance of the grades among readers was low: local vs 

parent central, 68%; local vs central nuclear grade, 45%; parent central vs 

central nuclear grade, 37%. Conclusions: DCIS Score is moderately 

correlated with grade, comedo necrosis, and tumor size. DCIS Score 

provides recurrence risk information independent of these features and 

identifies subjects with DCIS who are at high risk for local invasive and 

in-situ local recurrence after WLE alone. 


Use of microRNA (miR) expression profiling to identify distinct subclasses 

of triple-negative breast cancers (TNBC). Presenting Author: Charles L. 

Shapiro, Division of Medical Oncology and the Breast Program, Columbus, 

OH 

Background: TNBC is divided into basal and non-basal subclasses. To 

further subclassify TNBC we performed microRNA (miR) expression profiles 

and linked them to patient overall survival. Methods: During 1996- 

2005, 365 consecutive TNBC (phenotypically estrogen, progesterone and 

HER2 negative by immunohistochemistry [IHC]) were identified from the 

NCCN Breast Cancer Data Base/Tumor Registry at OSU Medical Center. 

One hundred fifty-eight (43%) formalin-fixed paraffin embedded (FFPE) 

breast cancer and 40 normal breast tissue blocks were available and tissue 

cores were obtained for RNA. RNA was isolated using the Ambion recoverall 

total nucleic acid isolation kit and the expression of ~700 miRs was 

assessed for each sample using the nanoString nCounter method. A 

consensus-clustering algorithm (ConsensusClusterPlus, Bioconductor www- 

.bioconductor.org) was used to identify subclasses of TNBC and Kaplan- 

Meier overall survival curves were compared using the log-rank test. 

Censoring occurred at the date of death from causes other than breast 

cancer or at time of the last known follow-up, whichever occurred first. The 

median follow-up was 67 mo. (range 4-171 mo.). Results: The median age 

was 52 yrs. (range 20-84 yrs.); 81% white and 9% African-American; 

stages I, II, and III were 31%, 54% and 15%, respectively; and most 

patients received adjuvant anthracycline-based regimens with (25%) or 

without taxanes (75%). The algorithm identified 5 distinct subclasses; 1 

clustering with normal breast miR expression whereas the other 4 each had 

a unique pattern of deregulated miRs. The median overall survivals were 

significantly different across the 5 cancer subclasses (log-rank p�0.028) 

(Table). Conclusions: miR expression profiling identifies and discriminates 

5 TNBC subclasses, which do not coincide with those identified as basal 

and non-basal by IHC. Molecular analyses are ongoing to associate the 

miR-based subclasses with specific clinical features or the expression of 

specific pathways. 

Group N 

Median overall 

survival (mo.) Log-rank p 

1 12 46 0.028 

2 10 50 

3 51 66 

4 48 67 

5 37 82 



Quantitative hormone receptors, triple-negative breast cancer (TNBC), and 

molecular subtypes: A collaborative effort of the BIG-NCI NABCG. Presenting 

Author: Maggie Chon U. Cheang, British Columbia Cancer Agency, 

Vancouver, BC, Canada 

Background: Most TNBC trials focusing on biology of the basal-like subtype 

(BLBC) allow borderline (1-10% staining) estrogen receptor (ER) and 

progesterone receptor (PgR) expression by immunohistochemistry (IHC); 

however the optimal ER and PgR cut points to enrich for non-luminal 

subtypes has not been studied. In this study,we compared quantitative 

ER/PgR status with gene expression-based intrinsic subtype in order to 

determine if borderline cases should be included in TNBC trials. Methods: 

ER, PgR, and HER2 status was determined by central review of tumors 

collected from three phase III randomized trials: GEICAM 9906 (n�820), 

NCIC CTG MA.5 (n�476) and MA.12 (n�398). PAM50 intrinsic subtyping 

(BLBC, HER2-enriched, Luminal A, Luminal B and Normal-like) was 

performed using the qRT-PCR-based assay. Quantitative ER/PgR expression 

by IHC and subtype was tested using ANOVA and Fisher’s exact test. 

Results: Of 1,694 tumors, 15% were BLBC, 21% HER2-Enriched, 33% 

Luminal A, 25% Luminal B and 4% Normal-like. BLBC subtypes were 

significantly associated with low expression of ER and PgR (median � 

0.05%) compared to other subtypes (p � 0.001). The vast majority of 

BLBC (96%) did not express any ER or PgR protein by IHC. BLBC 

represented 73% of TNBC (borderline cases not included) and significantly 

more than the additional TNBC with borderline ER/PgR (p � 0.001). 

Within borderline ER/PgR and HER2-negative cases only, 17% were BLBC 

and 46% were luminal subtypes (Table). Conclusions: BLBC rarely express 

ER or PgR by IHC. The majority of borderline TNBC (1-10% ER/PgR) are 

not BLBC; half of them are categorized as luminal categories that may be 

endocrine sensitive. TNBC trials seeking to target BLBC tumor biology 

should use the ASCO/CAP guidelines of 0% as the cutoffs for ER and PgR 

negativity. 

Intrinsic subtypes by PAM50 

Basal-like HER2-enriched Luminal A Luminal B Normal-like Total 

Clinical subtypes 

ER/PgR (0%)/HER2- 207(73%) 48 (17%) 6 (2%) 15 (5%) 7 (3%) 283 

ER/PgR (1-10%)/HER2- 8 (17%) 14 (29%) 10 (21%) 12 (25%) 4 (8%) 48 

ER/PgR 11-100%/HER2- 8 (0.7%) 103 (10%) 490 (49%) 351 (35%) 47 (5%) 999 

1010 Poster Discussion Session (Board #2), Mon, 1:15 PM-5:15 PM and 

4:45 PM-5:45 PM 

ABT-888 (veliparib) in combination with carboplatin in patients with stage 

IV BRCA-associated breast cancer. A California Cancer Consortium Trial. 

Presenting Author: George Somlo, City of Hope, Duarte, CA 

Background: Platinum and PARP inhibitors have both shown activity in 

BRCA-associated breast cancer (BC) patients (pts). We have conducted a 

phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to 

define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum 

tolerated dose (MTD). Methods: BRCA 1 or 2 carriers with stage IV BC were 

eligible. Carb starting at an AUC of 6 was given IV every 21 days (length of 

planned C) and V was administered orally, BID at dose levels (L) L1 through 

L5 (highest L planned). Results: 22 pts (21 eligible/evaluable, 20 with 

measurable BC) carrying BRCA1 (10) or BRCA2 (11), or both (1) mutations 

were accrued. Median age: 45 years, (32-65); 68% of BCs were ER�, and 

10% were HER2�. In the table below are the schema, incidence of DLTs, 

and # of Cs on study. Toxicities: At L1, grade ¾ DLTs with C 1 were seen in 

2/6 evaluable pts (1 pt w/grade 3 hyponatremia, pleural effusion, and 

dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to 

deescalation of carb (AUC 5) for pts treated at Ls 2-5. At L2, 1 of 6 pts had 

grade 4 PLT. There were no DLTs at Ls 3 and L4. L5 is currently being 

expanded to 6 pts (3 currently enrolled, 1 pt with grade 4 granulocytopenia 

(Gr) and grade PLT reached DLT). Non-DLT dose delays mostly due � grade 

2 Gr or PLT were needed at 60%, 53%, 53%, and 43% of Cs in pts treated 

on Ls 1-4. Response: In 12 eligible pts treated at Ls 1 and 2, 2 complete 

and 6 partial responders (67%) and a clinical benefit (CB) of 75% were 

seen. All pts at Ls 3-5 are still being treated, and in pts treated at Ls 3 and 

4, 2 unconfirmed PRs, and 4 cases of stable disease were seen, with L5 too 

early to assess. Conclusions: The combination of Carb at an AUC of 5 and 

daily V at doses 150 to 200 mg BID is feasible and the MTD is being 

defined. In preliminary analysis, response and CB rates are better than 

expected with the individual agents alone, providing justification to 

proceed with a planned phase II randomized single agent versus combination 

trial. 

Dose levels L1 L2 L3 L4 L5 (highest planned L) 

Carb AUC 6 5 5 5 5 

Vinmg 50 BID 50 BID 100 BID 150 BID 200 BID 

#ofpts 7 (1 ineligible) 6 3 3 3 

(and 3 in screening) 

Evaluable pts 6 6 3 3 3 

DLTs 2 1 0 0 1 

# of Cs given 9 (1-15) 8.5� (1-11) 6� (6�) 3� (3� to 4�) 1� (1� to 2�) 


51s 


4:45 PM-5:45 PM 

Phase I, open-label study of olaparib plus cisplatin in patients with 

advanced solid tumors. Presenting Author: Judith Balmaña, Vall d’Hebron 


Background: Olaparib (AZD2281) is an oral PARP inhibitor active in 

advanced ovarian and breast cancers. We conducted a multicenter, 

dose-finding study assessing safety/ tolerability of olaparib capsules plus 

cisplatin in patients (pts) with advanced solid tumors (NCT00782574), for 

potential use in the neoadjuvant setting. Methods: Pts received 21-day(d) 

cycles of olaparib, continuously (Cont) or intermittently (Int), plus cisplatin 

on d1 of each cycle.Each cohort recruited �3 evaluable pts with expansion 

to �6 pts if �1 had a dose-limiting toxicity. The last cohort was expanded 

to ensure �6 pts completed 4 treatment cycles. Pts who completed 6 

combined therapy cycles or who stopped cisplatin due to cisplatin-related 

toxicity could enter the monotherapy phase (up to 400 mg BID olaparib). 

Primary objective: safety/ tolerability of �4 combined cycles; secondary 

objectives: pharmacokinetics, antitumor activity. Results: 54 pts received 

treatment; pts had breast (n�42), ovarian (n�10), pancreatic (n�1) or 

peritoneal (n�1) cancer. Median number of prior regimens � 4 (1–13). C2, 

C4 and C6 enrolled �6 pts. Most common grade (G) 3/4 AEs: neutropenia 

(n�9; 16.7%), leukopenia (n�4; 7.4%), anemia (n�3; 5.6%), vomiting 

(n�3; 5.6%). In C1–C5, 3 pts had AEs leading to discontinuation: 1 in C2 

(thrombocytopenia); 2 in C3 (fatigue; complex migraine, dyspnea). In C6, 

all pts have ended combination phase and no G3/4 hematologic AEs were 

seen. Overall, 46% of pts had a dose reduction; 32% due to hematologic 

AEs. There were no drug-related deaths. 35 pts (65%) completed �4 

combined cycles (C6, n�8). 18/54 evaluable pts (33%) had an objective 

response (complete, n�1; partial, n�17); 23 (43%) achieved stable 

disease. 7 pts (13%) had durable responses on monotherapy for �1 year. 

PK and BRCA1/2 data will be presented. Conclusions: Hematologic AEs led 

to dose reductions � schedule changes of olaparib with cisplatin 75 

mg/m2 . Tolerability improved with cisplatin 60 mg/m2 . Antitumor activity 

was seen during combination and olaparib monotherapy phases, with some 

long responders. 

1 2 3 

Cohort (C) 

4 5 6 

Cisplatin, d1/21 

Dose (mg/m2 ) 

Olaparib 

75 75 75 75 75 60 

Dose (mg BID) 50 100 200 100 50 50 

Schedule Cont Cont Cont Int 

Int 

Int 

d1–10/21 d1–5/21 d1–5/21 

n 3 13 6 14 6 12 


4:45 PM-5:45 PM 

SOLTI NeoPARP: A phase II, randomized study of two schedules of iniparib 

plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with 

triple-negative breast cancer (TNBC). Presenting Author: Antonio Llombart, 

Solti Group, Valencia, Spain 

Background: Iniparib is an anticancer agent with a mechanism of action still 

under investigation. A phase 2 randomized neoadjuvant study in patients 

(pts) with TNBC was designed to explore the activity and tolerability of two 

schedules of iniparib with weekly paclitaxel (PTX). Here we report the 

efficacy and safety results from a planned interim analysis (IA). Methods: 

The trial accrued a total of 141 pts in October 2011, of whom, 74 are 

included in this IA. All were chemo-naive, histologicallyconfirmed Stage 

II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. 

Triple negative status was centrally confirmed [ER/PR �10%, HER2 IHC 

(0�,1�) or FISH negative]. Pts were randomized (1:1:1) to receive weekly 

PTX (80 mg/m2 ,IV,d1;N�25) alone or in combination with iniparib, 

either on a once weekly (QW) (11.2 mg/kg, IV, d 1; N�25) or twice weekly 

(BIW) (5.6 mg/kg, IV, d 1, 4; N�24) schedule. The total planned treatment 

duration was 12 wks. The IA endpoint is pathological complete response in 

the breast (pCR) as assessed by independent pathologists. Results: Two/2/3 

pts in the PTX/QW/BIW arms, respectively, discontinued due to progressive 

disease per RECIST. Another 3/2/2 pts, respectively, discontinued due to 

investigator decision or an adverse event (AE). Thirteen pts presented with 

Grade 3/4 Treatment Emergent AE: 3 pts in PTX arm (1 neutropenia, 1 

presyncope, 1 ALT elevation), 3 in QW arm (1 lymphopenia, 1 hyperkalemia, 

1 pulmonary embolism), and 8 in the BIW arm (1 febrile neutropenia, 

3 neutropenia, 1 aphonia, 1 syncope, 1 radius fracture and 1 vertigo). 

Laboratory Grade 3/4 neutropenia occurred in 4% of pts in PTX, 0% in QW 

and 21% of BIW arms, with 1/2/3 pts, respectively, requiring G-CSF usage. 

There were 4/7/6 pts in the PTX/QW/BIW arms with PTX dose modifications. 

Four pts (16%) in PTX arm, 4 pts (16%) in the QW arm and 6 pts (25%) in 

the BIW arm had confirmed pCR in the breast. Conclusions: In this IA 

population, the addition of iniparib regardless of the schedule to weekly 

PTX did not seem to add clinically significant toxicity. pCR rate in the 

breast is similar across treatment arms at this IA. NCT01204125. 




4:45 PM-5:45 PM 

DNA repair metagene signature as a prognostic and predictive factor in 

molecular breast cancer subtypes. Presenting Author: Libero Santarpia, 

Istituto Toscano Tumori Hospital of Prato, Prato, Italy 

Background: We aimed to assess the prognostic and predictive role of DNA 

repair genes in breast cancer (bc) molecular subtypes. Methods: We 

evaluated Affymetrix gene expression profiling from untreated N- patients 

(N � 684), neoadjuvant treated tumors with taxanes- (N � 320), 

anthracyclines- (N � 211), and cisplatin- (N � 22) containing regimens. 

We assessed within 3 BC molecular subgroups (ER�/HER2-, HER2�, and 

ER-/HER2-) bimodality distribution, prognosis by association with distant 

relapse (N � 454, N � 105, and N � 125) and predictive value for 

likelihood of pathological complete response (pCR) (N � 208, N � 105, 

and N � 240). Moreover, we explored the function of relevant genes in BC 

cell lines. Results: Three genes (ERCC2, XRCC3, and RECQL4) showed 

bimodality in each bc subtype. Eight genes were associated with poor 

prognosis (including RECQL4) and 1 gene with good prognosis (ATM)[P� 

.0001] only in ER�/HER2- tumors. Our results suggest a subtype and 

treatment specific association with pCR although they did not satisfy 

stringent criteria for false discovery correction. In ER-/HER2- mismatch 

repair (MR) (MSH2 and MSH6) and MTMR15 genes were associated with 

response and resistance to taxane-containing regimens, respectively. 

TOP2A was the only gene associated with response to anthracycline but not 

taxanes in HER2� tumors. RECQL4 had a positive trend with higher pCR in 

both ER� and ER-/HER2- tumors. In in vitro studies we found that 

RECQL4 interacts with PARP1 and that the expression of these genes was 

correlated with sensitivity to chemotherapy and PARP inhibitors. 

Conclusions: We identified MR genes as potential predictive markers of 

response to taxanes-based regimens in ER-/HER2-. A novel gene RECQL4 

showed bimodal distribution, prognostic value, and a trend for predictive 

association with response to taxanes-based chemotherapy, which was also 

confirmed by in vitro analysis. ATM deserves further evaluation as prognostic 

marker in ER�/HER2-. 


4:45 PM-5:45 PM 

Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in 

tumors for personalized cancer therapy. Presenting Author: Srinivasan 

Madhusudan, School of Molecular Medical Sciences, Nottingham University 

Hospitals, Nottingham, United Kingdom 

Background: XRCC1 is essential for DNA base excision repair, single strand 

break repair and nucleotide excision repair. XRCC1 deficiency promotes 

genomic instability and may increase cancer risk. Methods: We evaluated 

XRCC1 immunohistochemically in early stage breast (n�2046), ovarian 

(n�157), gastric (n�140), colorectal (n�250) and pancreaticobiliary 

cancers (n�240). Pre-clinically, we evaluated a panel of XRCC1 deficient 

and proficient Chinese hamster ovary and human cancer cell lines. Double 

strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs 

(NU7441) and ATR (NU6027) were evaluated for synthetic lethality and 

cisplatin alone or in combination with DSB inhibitors for chemopotentiation. 

Results: In breast cancer,XRCC1 loss (16%) was associated with 

higher grade (p�0.0001), loss of hormone receptors (p�0.0001), presence 

of triple negative (p�0.0001) and basal like phenotypes (p�0.001). 

Loss of XRCC1 was associated with a 2-fold increase in risk of death and 

metastasis (p�0.0001) and independently with poor outcome (p�0.0001). 

In ovarian cancer, XRCC1 was positive in 44% of tumour and was 

significantly associated with higher stage (p�0.001), clear/endometroid 

type (p�0.015) and sub-optimal debulking (p�0.004). XRCC1 positive 

tumours were more resistant to platinum chemotherapy (p�0.0001). 

XRCC1 positivity conferred a 2 fold increase of risk of death (p�0.002) and 

independently associated with poor survival (p�0.002). In gastric cancers, 

XRCC1 was positive in 37% of tumours. This was significantly associated 

with high stage disease (p�0.001) and poor survival (p�0.001). Preclinically, 

KU55933, NU7441 and NU6027 were synthetically lethal in 

XRCC1 deficient compared to proficient cells as evidenced by DSB 

accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells 

were hypersensitive to cisplatin which was enhanced by DSB repair 

inhibitors compared to in proficient cells. Conclusions: This is the largest 

study to confirm the clinical significance of XRCC1 expression in solid 

tumours. XRCC1 deficiency in human tumours may be suitable for 

synthetic lethality application and exploited for cisplatin chemotherapy 

potentiation. 


4:45 PM-5:45 PM 

HAGE (DDX43) protein expression as an independent biomarker of poor 

clinical outcome of breast cancer (BC) and potential as a therapeutic target 

for ER-negative BC. Presenting Author: Stephen Chan, Nottingham University 

Hospital, Nottingham, United Kingdom 

Background: Recently, we have confirmed that HAGE is involved in 

promoting proliferation as assessed by increased thymidine incorporation 

and our preliminary results using shRNA to permanently knockdown HAGE 

expression also suggests the involvement of HAGE in tumor motility and 

metastasis. In this study we aimed to analyze the expression of HAGE in 

large well-characterized BC cohorts to determine its relationship with other 

clinico-pathological parameters and to investigate its prognostic value. 

Methods: HAGE protein expression was assessed in: a) 40 normal breast 

tissue (NBT), b) 60 invasive BCs and their matching NBT, c) BC cell lines, 

d) A series of 1650 consecutive cases of primary BC who treated with 

adjuvant CMF and/or endocrine therapies. Further validation was performed 

in 2 independent series of high risk ER- BC: a) 300 ER –BC who did 

not received any CT and b) 396 ER- BC treated with adjuvant anthracycline 

(ATC) based CT. Results: The NBT showed negative HAGE expression 

(HAGE-) throughout. HAGE overexpression (HAGE�) was observed in 10% 

of BC and was significantly associated with aggressive clinico-pathological 

features including: ER-, high grade and triple negative phenotypes. 

Moreover, HAGE� expression showed an adverse outcome with a 2-4 fold 

increase in the risk of death, recurrence and metastases (ps�0.00001) 

compared to HAGE-; ps�0.0001. Using a multivariate Cox regression 

model including ER status, grade, size and tumour stage, HAGE expression 

was confirmed as a powerful independent prognostic factor (p�0.0001). 

The poor clinical outcome of HAGE� was further confirmed in high risk 

(NPI�3.4) ER- patients who did not received any CT (p�0.0001). While, 

adjuvant CT either CMF or ATC had a positive impact on HAGE�/high risk 

ER- BC as HAGE� had a similar risk of death, recurrence and distant 

metastases to HAGE- expression. Conclusions: This is the first report which 

shows HAGE to be a potential predictor for poor prognosis in BC patients, 

and may be an attractive novel target for molecular and vaccine therapy for 

those patients. A prospective trial of adjuvant chemotherapy/vaccine to 

confirm this finding is warranted. 


4:45 PM-5:45 PM 

Cancer gene profile of metastatic breast cancer. Presenting Author: Funda 

Meric-Bernstam, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: There is great interest in using genomic information to guide 

therapy selection in cancer patients. The aim of this study was to determine 

the spectrum of genomic alterations identified in MBC patients, and 

evaluate the concordance of alterations between primary and recurrent 

tumors. Methods: We performed comprehensive profiling on formalin-fixed 

paraffin embedded samples from 42 patients with MBC using a targeted 

next generation sequencing (NGS) assay in a CLIA laboratory (Foundation 

Medicine). Genomic libraries were captured for 3,230 exons in 182 cancer 

related genes plus 37 introns from 14 genes often rearranged in cancer and 

sequenced to an average depth of 390X with 99% of bases covered 

�100X. In total 30 primary and 37 recurrent tumors were profiled, 

including 3 separate recurrences in 1 patient and matched primaryrecurrences 

in 22 patients. Point mutations, indels, copy number alterations 

and rearrangements were assessed. Alterations that are targetable 

with established or investigational therapeutics were considered “actionable”. 

Results: At least 1 genomic alteration was identified in all but 2 

breast samples (both primary tumors). Point mutations were identified in 

several cancer-related genes including PIK3CA, TP53, PTEN, CDH1, 

ARID1A, AKT1, NF1, FBXW7 and FGFR3. Amplification was observed in 

HER2; 11of12HER2 IHC positive samples were found to have HER2 

gains by NGS; in addition, a HER2 gain was identified by NGS in a HER2- 

(1� IHC) sample. Amplification of PIK3CA, IGF1R, FGFR2, AKT2, MDM2, 

and MCL1 plus a CDKN2A homozygous deletion were also identified. While 

the majority of known driver alterations (85%) were concordant in the 

matched pairs of primary and recurrent tumors, in 11 of 22 sets there was 

at least 1 discordant driver alteration, and these included both gains and 

losses of potential therapeutic targets. Overall 32 of 42 patients (76%) had 

an actionable genomic alteration. Conclusions: Genomic profiling of breast 

cancer samples reveals genomic alterations in most metastatic breast 

cancer patients. Over three quarters of patients have actionable findings, 

suggesting that genomic profiling may assist in individualized pathwaydirected 

therapy. 



4:45 PM-5:45 PM 

Tesetaxel: Activity of an oral taxane as first-line treatment in metastatic 

breast cancer. Presenting Author: Andrew David Seidman, Memorial 

Sloan-Kettering Cancer Center, New York, NY 

Background: Tesetaxel, unlike standard taxanes (docetaxel, paclitaxel), is 

not a substrate for Pgp, a major cause of taxane resistance in tumor models. 

In a DU4475 breast cancer xenograft that overexpresses Pgp, tesetaxel 

induced a 94% reduction in tumor size, markedly exceeding the activity of 

docetaxel (46%) and paclitaxel (26%). Tesetaxel is associated with 

substantially less neuropathy preclinically than equi-myelotoxic doses of 

docetaxel. In clinical studies to date, tesetaxel is not associated with 

hypersensitivity reactions (0% incidence in � 450 patients [pts]), thus 

eliminating the need for premedication and extended observation. In a prior 

study, tesetaxel (27-35 mg/m2 Q3 wks) achieved a 38% partial response 

(PR) rate as 2nd-line therapy in pts with metastatic breast cancer (MBC) 

who had progressed after multidrug anthracycline-containing regimens. To 

extend these data, we initiated a phase 2 study of tesetaxel as 1st-line therapy in women with MBC. Methods: Eligibility included MBC; HER2-; 

ECOG PS 0-1; and adequate organ function. Adjuvant chemotherapy 

(including taxanes) was allowed. Tesetaxel was administered orally without 

anti-allergic premedication at a starting dose of 27 mg/m2 once every 3 

wks. Overall response rate (ORR; RECIST) was the primary endpoint. 

Results: All 45 pts have been accrued. Median age is 58 y (range 36-80); 

median time from diagnosis, 4.0 y (range 0-21); triple negative status, 8 

pts at diagnosis, 14 at time of metastasis. Metastatic sites are lung (22 

pts), lymph nodes (22), liver (24), and bone (21). Prior treatment includes 

anti-estrogen therapy (32 pts), adjuvant chemotherapy (31), prior taxane 

(25), and radiotherapy (28). ORR in 24 pts evaluable for response is 50% 

(1 CR [4%], 11 PR [46%]); 5 responding pts had prior taxane therapy. 

Neutropenia is the most common � Grade 3 adverse event with 50% of 

casesobservedafterdoseescalationto35mg/m2 ;febrileneutropeniaandGrade 

3 peripheral neuropathy occurred in 2 pts each. There were no hypersensitivity 

reactions. Conclusions: Tesetaxel is highly active in 1st-line MBC and 

overcomes multiple limitations of standard taxanes. Updated ORR and PFS 

for all pts will be presented. Weekly dosing will be evaluated in a new cohort 

of pts. 


4:45 PM-5:45 PM 

Everolimus with paclitaxel plus bevacizumab as first-line therapy for 

HER2-negative metastatic breast cancer (MBC): A randomized, doubleblind, 

placebo-controlled phase II trial of the Sarah Cannon Research 

Institute (SCRI). Presenting Author: Denise Aysel Yardley, SCRI/Tennessee 

Oncology, PLLC, Nashville, TN 

Background: Constitutive activation of mTOR and amplified PI3K/Akt/ 

mTOR signaling are common in MBC, and increase as treatment-resistance 

is acquired. Everolimus (E), an mTOR inhibitor, has single agent activity, 

combines well with paclitaxel (P) and bevacizumab (B), and prolonged PFS 

when added to AI therapy in BOLERO-2. In this randomized phase II trial, E 

was added to P/B as first-line treatment of HER2-negative MBC. Methods: 

Women with untreated HER2-negative MBC were randomized (1:1) to P 

90mg/m2 IV (days 1, 8, and 15) and B10mg/kg IV (days 1 and 15) q28 

days with E 10mg PO (Arm 1) or placebo PO (Arm 2) daily. Response 

assessment was performed q8 weeks until progression or intolerable 

toxicity. Primary endpoint was PFS. Secondary endpoints: safety, overall 

response rate, response duration, overall survival. 110 pts allowed detection 

of improvement in median PFS from 11 to 16 months with 70% power. 

Results: Between 8/2009 and 6/2011, 112 pts were randomized (Arm 

1�55; Arm 2�57). Median age: 58 years (range: 25-79). 88% were ER� 

or PR�. Pts received a median 5 treatment cycles (range: �1- 26�); 18 

(16%) pts remain on treatment (Arm1, 9; Arm 2, 9). Median PFS were 8.8 

months (Arm 1) and 7.1 months (Arm 2) (95% CIs 7.4-9.6; 5.5-9.1 

months, p�0.79, HR 0.94). Complete responses were observed in 5% 

[Arm1, 4 (7%); Arm 2, 2 (4%)] with partial responses in 49% [Arm1, 29 

(53%); Arm 2, 26 (46%)]. Responses rates in taxane pretreated pts Arm 1 

22%, Arm 2 12%. Hematologic toxicity was similar in both arms; grade 3 

mucositis occurred in 13% of E pts. Dose reductions (47% vs 25%) and 

interruptions (42% vs 26%) were more frequent with E due to mucositis 

and rash. Treatment discontinuation rates were similar. Conclusions: The 

addition of E did not result in a significant improvement in the efficacy of 

weekly paclitaxel/bevacizumab in the first-line treatment of HER2-negative 

MBC although response rates and median PFS were better with E. Possible 

explanation for these results may include lower dose intensity in the E arm, 

treatment of less resistant pts, or intrinsic differences in E activity when 

added to antiestrogen vs chemotherapy. 



4:45 PM-5:45 PM 

Final analysis of phase II study of EZN-2208 (PEG-SN38) in metastatic 

breast cancer (MBC). Presenting Author: Cynthia R. C. Osborne, Baylor 

Sammons Cancer Center, Texas Oncology PA, US Oncology, Dallas, TX 

Background: EZN-2208 is a water-soluble PEGylated conjugate of SN38. 

EZN-2208 results in prolonged exposure of tumors to SN38 via preferential 

accumulation of EZN-2208 in the tumor and prolonged release of SN38. 

These data represent the final analysis of our study evaluating EZN-2208 in 

MBC. Methods: EZN-2208 9 mg/m2 (SN38 equivalents) was delivered as a 

60-minute IV infusion, weekly for 3 wks in 4-wk cycles. The primary 

objective was to determine the overall response rate (RR) in female patients 

with metastatic breast cancer (MBC) who had received prior adjuvant or 

metastatic therapy with either 1) anthracycline and taxane (AT) or 2) 

anthracycline, taxane, and capecitabine (ATX). Secondary objectives included 

evaluation of RR based on tumor receptor status, duration of 

response, progression-free survival (PFS), overall survival (OS), and safety. 

Results: Patients with MBC (n�164) were treated with a median (range) of 

3.3 (0.3-22) cycles of EZN-2208. The objective response rate (RR) was 

20% for AT and 9% for ATX. The clinical benefit rate (CBR�%CR � %PR 

� %SD �6 months) was 41% and 27% in patients in the AT and ATX 

cohorts, respectively. The RR and CBR among ER� patients were 11% 

(10/91 pts) and 41.8% (38/91 pts). In patients who progressed during or 

within 30 days of prior platinum-containing regimens (Platinum Progressors), 

the CBR was 20% (8/40 pts). Among triple negative breast cancer 

(TNBC) patients, the RR and CBR were 22.5% (11/49 pts) and 36.7% 

(18/49 pts). For TNBC, Platinum Progressors, the CBR was 26.1% (6/23 

pts). Overall, most common reported drug-related adverse events were 

diarrhea, nausea and neutropenia. Conclusions: EZN-2208 has notable 

activity in patients with previously treated MBC and appears to be an active 

agent for treatment of TNBC. Patients with TNBC, who had been previously 

treated with a platinum-based regimen, also derive clinical benefit from 

EZN-2208. The safety profile of EZN-2208 is acceptable with good 

tolerability in most patients. Further evaluation of EZN-2208 in MBC in 

general and TNBC in particular is warranted. 


4:45 PM-5:45 PM 

Metformin in early breast cancer (BC): A prospective, open-label, neoadjuvant 

“window of opportunity” study. Presenting Author: Saroj Niraula, 

Division of Medical Oncology and Hematology, Princess Margaret Hospital 

and University of Toronto, Toronto, ON, Canada 

Background: There is growing evidence that metformin may exert anticancer 

effects through indirect (insulin-mediated) or direct (insulinindependent) 

mechanisms. Here, we report final results of a neo-adjuvant 

“window-of-opportunity” study of metformin in women with operable BC. 

Methods: Newly diagnosed, untreated, non-diabetic BC patients received 

metformin 500 mg tid after diagnostic core-biopsy until definitive surgery(no 

other treatment). Clinical [weight, symptoms, European Organization 

for Research and Treatment of Cancer Quality of Life Questionnaire 

(EORTC-QLQ-C-30)] and biologic characteristics [insulin, glucose, homeostatic 

model assessment (HOMA), C-reactive protein (CRP), leptin] were 

compared pre- and post-metformin as were Terminal deoxynucleotidyl 

transferase-mediated dUTP nick end labeling (TUNEL, an apoptotic 

marker) and Ki67 (primary end-point) scored blinded by manual count of 

positive nuclear-staining. The planned sample-size of 40 patients gave 

90% power to detect a 5.5 percentage point change in Ki67. Results: 

Thirty-nine patients were enrolled and mean age was 51 years; metformin 

was given for 18 days (median), range 13-40 days. Twenty patients had T1 

and 19 T2/T3 tumors; 16 tumors were grade III; 24 were N0; 32 ER/PR 

positive, 5 HER-2 positive. Grade 1-2 self-limiting diarrhea, anorexia and 

abdominal distention occurred in 50%, 41% and 32%. EORTC QLQ scores 

were stable in all function domains and overall scores. Main study 

outcomes are tabulated here. Conclusions: Short-term preoperative metformin 

was well-tolerated and resulted in clinical and cellular effects in 

keeping with beneficial anti-cancer effects as demonstrated by improved 

insulin resistance (HOMA), decreased proliferation (ki67) and increased 

apoptosis (TUNEL). 

Variable (units) 

Pre-metformin 

mean (SD) 

53s 

Mean change 

(SD) p change 

Weight (kg) 70.3 (12.3) -1.2 (1.4) �0.0001 

BMI (kg/m 2 ) 26.9 (4.6) -0.5 (0.5) �0.0001 

CRP (mg/L) 2.0 (2.7) -0.2 (2.6) 0.35 

Glucose (mmol/L) 5.30 (0.56 -0.14 (0.43) 0.045 

Insulin (pmol/L) 43.4 (23.9) -4.7 (18.1) 0.069 

HOMA 1.47 (0.95) -0.21 (0.75) 0.047 

Leptin (ng/ml) 16.5 (13.0) -1.3 (7.2) 0.15 

TUNEL 0.56 (0.58) 0.49 (1.00) 0.0037 

Ki67 36.5 (24.8) -3.0 (9.8) 0.016 




4:45 PM-5:45 PM 

The impact of genetic variability on severe toxicity of (neo-) adjuvant 

chemotherapy in breast cancer patients receiving 5-fluorouracil, epirubicin, 

and cyclofosfamide (FEC). Presenting Author: Christof Vulsteke, 

Department of General Medical Oncology, University Hospitals Leuven, 

Leuven, Belgium 

Background: We assessed the impact of single nucleotide polymorphisms 

(SNP) of potential genes of interest in germline DNA on severe adverse 

events in breast cancer (bc) patients receiving (neo-) adjuvant FEC 

chemotherapy. Methods: Cases were retrospectively evaluated through 

electronic chart review for febrile neutropenia (primary endpoint), febrile 

neutropenia first cycle, prolonged grade 4 or deep (�100/�l) neutropenia, 

anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological 

grade 3-4 events. The panel of genes, genotyped using iPLEX technology on 

a MALDI-TOF based MassARRAY Compact Analyser (Sequenom Inc., CA, 

USA), included ABCBI, ABCC1, ABCC2, ABCG2, ALDH3A1, CYP2B6, 

CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, DPYD, FGFR4, GPX4, 

GSTA1, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1, UGT1A1, 

UGT1A6 and UGT2B7. These genes are involved in the metabolization of 

the studied chemotherapeutics. Because of multiple testing the false 

discovery rate (FDR) was calculated. Results: We identified 1089 patients 

treated between 2000-2010 with 3-6 cycles of FEC, for whom germline 

DNA was available.Homozygous (TT, 0.5%) and heterozygous (GT,11%) 

genotypes for rs4148350 in the Multi Drug Resistance Protein I (ABCC1/ 

MRP1), compared to wild-type (GG, 88.5%), were associated with febrile 

neutropenia, febrile neutropenia in first cycle, prolonged grade 4 or deep 

neutropenia and thrombocytopenia (80 vs 25 vs 15.7%, 40 vs 17.6 vs 

9.5%, 100 vs 41.7 vs 33.8% and 20 vs 2.8 vs 0.34% respectively; p 

0.0006, 0.01, 0.002 and 0.008 FDR 0.03, 0.65, 0.06 and 0.2). Variant 

genotypes for rs45511401 (GT/TT, 12%) in ABCC1, compared to wild-type 

(GG, 88%), were associated with febrile neutropenia, febrile neutropenia in 

first cycle and thrombocytopenia (26.5 vs 15,8%, 17.1 vs 9.7% and 3.4 vs 

0.3%, respectively; p 0.007, 0.03 and 0.005, FDR 0.2, 0.75 and 0.2). 

Conclusions: Genetic variation in the ABCC1 gene was strongly associated 

with severe hematological toxicity of FEC. Other previously described SNP 

were not validated. This is the largest bc study in which the impact of 

genetic variability on the adverse events of FEC chemotherapy was 

investigated. 


4:45 PM-5:45 PM 

Comparison of molecular (BluePrint�MammaPrint) and pathological subtypes 

for breast cancer among the first 800 patients from the EORTC 10041/BIG 3-04 

(MINDACT) trial. Presenting Author: Giuseppe Viale, European Institute of 

Oncology, Milan, Italy 

Background: Biology has become the main driver of breast cancer therapy. 

Intrinsic biological subtypes by gene expression profiling have been identified. 

Pathology can be used to define surrogates of these subtypes but these are not 

always concordant, which may lead to different treatment plans. We investigated 

the concordance between BluePrint (BP) � MammaPrint (MP) (micro array 

based) breast cancer subtypes and pathological surrogates (based on ER, PR, 

HER2, and Ki67). Contrary to the Perou gene set (evolved into PAM50), 

BluePrint was trained using pathological data. Methods: Using available data 

(centrally assessed pathology and genomic) from the MINDACT pilot phase 

(Rutgers et al 2011) 621 tumors were analyzed. Two pathology classifications 

were used: one with 4 categories and one with 5 categories (Goldhirsch et al 

2011). Based on BP 3 subtypes are formed: Luminal, HER2 and Basal. The 

Luminal subtype is further split into Luminal A (MP low risk) and Luminal B (MP 

high risk). Results: See table. Conclusions: All pathological Basal cases are BP 

Basal, apart from 1 BP HER2 case. Of the BP Basal cases, 15 are not 

pathological Basal: 1 is Luminal A, 11 are Luminal B (of which 8 are IHC ER/PR 

borderline (�1% and � 10%)) and 3 are HER2. All pathological Luminal (A & B) 

that are BP HER2 are HER2- by TargetPrint. 25 of the 26 pathological HER2� 

that are BP Luminal A are ER�. Most discordant cases are seen within the 

Luminal subtype, indicating that Ki67 discriminates Luminal A vs. B differently 

than MammaPrint does. The observed subtype discrepancies reveal potential 

important impact for treatment-decision making. MINDACT will provide important 

information. 

4 category St Gallen 5 category 

Luminal A 

Er� and/or PR� 

HER2- 

Ki67 low 

Luminal B 

ER� and/or PR� 

HER2- 

Ki67 high 

HER2 

HER2� 

Basal 

ER- 

PR- 

HER2- 

Pathology BluePrint (BP) � MammaPrint (MP) 

Luminal A 

Idem 

Luminal B (HER2-) 

Idem 

Luminal B (HER2�) 

ER� and/or PR� 

HER2� 

Erb-B2 

ER- 

PR- 

HER2� 

Basal 

Idem 

Luminal A 

BP Luminal 

MP low risk 

Luminal B 

BP Luminal 

MP high risk 

HER2 

BP HER2 

263 19 4 

(all TP* HER2-) 

111 70 4 


25 

(All ER�) 

Basal 

BP Basal 

Total 

1 287 

11 196 

3 31 1 60 

1 0 13 2 16 

0 0 1 


61 62 

Total 

*TP � TargetPrint. 

400 92 55 76 621 


4:45 PM-5:45 PM 

10-year update of E2197: Phase III doxorubicin/docetaxel (AT) versus 

doxorubicin/cyclophosphamide (AC) adjuvant treatment of LN� and highrisk 

LN- breast cancer and the comparison of the prognostic utility of the 

21-gene recurrence score (RS) with clinicopathologic features. Presenting 

Author: Joseph A. Sparano, Albert Einstein College of Medicine, Bronx, NY 

Background: At 5 years, AT did not improve disease free survival or overall 

survival and RS was a more accurate predictor of relapse than standard 

clinicopathologic characteristics for patients with hormone receptor (HR) 

positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. 

AC. Women with 1-3 N � or N - and T-size � 1cm were randomized to 4 

cycles of AT (60 mg/m2 /60 mg/ m2 ) or AC (60 mg/m2 /600 mg/m2 )q3wkx 

4. Patients(pts) with ER � and/ or PR � tumors received tam for 5 yrs. Pts 

were stratified by nodal, HR (ER� PR�, ER�PR-, ER-PR�, ER-PR-, 

ER/PR unk) and menopausal status. The primary endpoint was DFS. A 

sample of 465 pts with HR � breast cancer with 0 to 3 positive axillary 

nodes who did (N �116) or did not have a recurrence had tumor tissue 

evaluated using the 21- gene assay. Grade and HR expression were 

evaluated locally and centrally. Results: 2952 pts were randomized 

between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms 

were balanced for age, HR, menopause, nodes, surgery, grade and T-size: 

median age 51; 64% ER �; 65% LN-; grade: 10% low, 38% int., 46% 

high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the 

DFS/OS results are shown in the table below. RS was a highly significant 

predictor of recurrence including node negative and node positive disease 

(P � .0001) and predicted recurrence more accurately than clinical 

variables. Conclusions: At 11.5 yrs. median follow-up, there remains no 

difference in DFS or OS, although there continue to be fewer events in the 

AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS 

continues to be a more accurate predictor of relapse than standard clinical 

features. 

Hazard ratio (HR)*, 

5-yr DFS 

Hazard ratio (HR)*, 

10-yr DFS 

95Cl, p- value** 5 yr AT AC 95Cl, p value** 10 yr AT AC 

Overall DFS 1.02 (0.86-1.22), 0.78 85% 85% 1.02 (0.88-1.18), 0.83 77% 77% 

ER� 0.89 (0.71-1.12), 0..32 87% 88% 0.91 (0.76-1.10), 0.34 78% 79% 

ER- 1.24 (0.95-1.62), 0.12 81% 77% 1.22 (0.96-1.56), 0.11 76% 71% 

OS 1.06 (0.85-1.31), 0.62 92% 91% 1.03 (0.86-1.23), 0.73 85% 84% 

*HR�1 favors AT; **based on log-rank test. 


4:45 PM-5:45 PM 

Prognostic and predictive impact of Ki-67 before and after neoadjuvant 

chemotherapy on PCR and survival: Results of the GeparTrio trial. Presenting 

Author: Gunter Von Minckwitz, German Breast Group, Neu-Isenburg, 

Germany 

Background: We previously reported as a result of the GeparTrio phase III 

trial that response-guided neoadjuvant chemotherapy (CT) with TACx8 or 

TAC/NX, compared to TACx6, can improve survival especially in hormonereceptor 

(HR)-positive tumors. As this benefit could not be predicted by 

pathological complete response (pCR), better surrogate response markers 

are warranted. Methods: 2072 patients with operable or locally advanced 

breast cancer were treated with 2 cycles TAC before interim response 

assessment. Responders were randomized to additional TACx4 or TACx6 

and non-responders to TACx4 or NXx4. We centrally measured Ki-67 

in1165 pre-CT core biopsies and in 676 post-CT surgical samples. 

Counting patients with a pCR as having 0% Ki-67, 757 pre-/ post-CT pairs 

were available. Ki-67 percentage levels were grouped to low (0-15%), 

moderate (15.01-35%), and high (35.01-100%) according to cut-point 

finding analysis in a training and validation cohort. Results: pCR rates were 

4.2%, 12.9%, and 29.0% in tumors with low, moderate, and high pre-CT 

Ki-67 levels (p�0.0001). Pre-CT Ki-67 levels significantly predicted 

disease-free survival (DFS) (log rank p�0.0001) overall, in the HR� 

(p�0.0001), but not in the HR- (p�0.5) subgroup. Post-CT Ki-67 levels 

correlated with DFS (p�0.0001). Patients with low post-CT Ki-67 levels 

showed comparable outcome to patients with pCR. Patients with increased 

Ki-67 levels from before to after CT showed an impaired outcome compared 

to patients with stable or decreased Ki-67 levels (p�0.0001). However, 

post-CT Ki-67 levels appeared to have more prognostic relevance than 

Ki-67 changes. Low post-CT Ki-67 levels were not more frequent after 

response-guided treatments (response-guided vs conventional: p�0.153; 

TACx6 vs TACx8: p�0.335; TACx6 vs TAC/NX: p�0.420). Similar negative 

results were found for HR� and HR- subgroups. Conclusions: Pre-CT Ki-67 

levels are predictive for pCR and prognostic for DFS. Post-CT Ki-67 levels 

and changes between pre-and post-CT-Ki-67 levels are prognostic for DFS. 

As neither could predict different treatment effects on DFS, Ki67 cannot 

replace pCR as a surrogate marker for outcome after neo-adjuvant CT. 



4:45 PM-5:45 PM 

A gene expression signature of MEK pathway activation to predict survival 

in triple-negative breast cancer. Presenting Author: Justin M. Balko, 

Vanderbilt University, Nashville, TN 

Background: Tumor cell proliferation measured by Ki67 in the surgically 

removed tumor after neoadjuvant chemotherapy (NAC) has been shown to 

predict patient outcome in breast cancer. It is unclear from these studies if 

breast cancer subtype may account in part for the predictive ability of Ki67. 

Thus, we tested whether Ki67 score in the surgically-resected residual 

tumor (RT) after NAC predicted outcome in a cohort of triple negative 

breast cancer (TNBC). Gene expression profiling was performed to identify 

molecular subtype and test the association with gene modules indicative of 

signaling pathway activation. Methods: Ki67 was scored in the RT of 89 

patients with stage II-III TNBC (ER/PR/HER2 negative by IHC at diagnosis) 

that had been treated with NAC. Expression levels for 450 genes were 

quantified by Nanostring. Ki67, node and menopause status, age, therapy 

type (� taxanes), molecular subtype, and gene expression scores were 

tested for association to RFS and OS using univariate and multivariate 

CoxPH models. Results: Ki67 score in the post-NAC RT demonstrated a 

wide range (1.5-77.7%; median: 36.2%). Twenty seven % of RTs were 3� 

HER2 by IHC. Molecular subtype in the RT was as follows: 64% Basal-like; 

20% HER2-enriched; 6% LumA; 6% LumB; 4% Normal-like. In univariate 

analyses to respectively predict RFS and OS, node status (p�0.005 and 

p�0.02), number of nodes (p�0.003 and p�0.001), and the score of a 

gene expression module of MEK pathway activation (p�0.04 and p�0.01,) 

were significant. Basal-like subtype approached significance for RFS 

(p�0.1) and OS (p�0.05). In multivariate analyses, node status (p�0.002 

for RFS and p�0.001 for OS) and MEK pathway activation score (p�0.04 

and p�0.01) were significant predictors. Conclusions: Ki67 in the RT after 

NAC was not predictive of outcome in a cohort of TNBC. However, a gene 

expression signature of activated MEK was negatively associated with 

outcome. These data are consistent with the reported preclinical activity of 

MEK inhibitors against basal-like breast cancer cells and a possible role of 

this signaling pathway in chemotherapy resistance. They also support deep 

sequencing studies to identify genetic alterations in the RAS/MEK/MAPK 

pathway in TNBC. 


4:45 PM-5:45 PM 

A phase II study of preoperative (preop) bevacizumab (bev) followed by 

dose-dense (dd) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in 

combination with bev in HER2-negative operable breast cancer (BC). 

Presenting Author: Sara M. Tolaney, Dana-Farber Cancer Institute, Boston, 

MA 

Background: Two recent preop studies evaluating bev showed conflicting 

results, particularly in hormone receptor (HR)� BC. Identification of 

predictive markers and their relationship to the pharmacodynamic effects 

of bev would facilitate the identification of BCs most likely to benefit from 

bev. To accomplish these goals, we conducted a unique preop trial with a 

run-in of single agent bev followed by ddACT with bev in two cohorts, one 

with HR�HER2– BC, and a smaller triple negative (TN) cohort. Methods: 

Pts with HR�, HER2– or TN BC were eligible if their tumor (T) was �1.5 

cm and high grade, or had axillary LN involvement; or if T�2.5cm and was 

low/intermediate grade. Treatment consisted of a single dose of bev 10 

mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 

mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, 

followed by T 175 mg/m2 x1. Research core biopsies and interstitial fluid 

pressure (IFP) were assessed pre- and post- bev alone. Pathologic response 

was confirmed centrally and Miller-Payne (MP) was assessed. Results: 84 

pts with HR� and 20 pts with TN breast cancer were enrolled. Amongst 

HR� pts, 74 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. 

Amongst TN pts, 18 pts had tissue centrally reviewed and 8 (44%) had a 

pCR. Grade was found to predict MP response in both HR� and TN pts 

(p�0.001). Several biomarkers were evaluated as predictors of response to 

bev. Baseline sVEGFR1 correlated with MP response to treatment among 

TN pts (p�0.015). Single-agent bev reduced the mean vascular density by 

18.5% (p�0.049) in HR� patients and the mean IFP in the overall cohort 

and HR� patients by 20 (p�0.020) and 24.5% (p�0.001), respectively. 

The reductions in IFP correlated with higher levels of sVEGFR2 (p�0.003). 

The IFP decreased � 50% in 24/65 pts and did not change in others. Gene 

expression profiling by PAM50 is underway. Conclusions: The addition of 

bev to preop chemotherapy is well tolerated. Tumor grade appears to 

predict MP response in HR� and TN tumors, and sVEGFR1 may be a 

predictor of MP response to bev in TN tumors. Further work for biomarker 

predictors of response to bev is ongoing. 


55s 


4:45 PM-5:45 PM 

NSABP FB-6: Phase II trial of weekly paclitaxel (WP) and pazopanib 

following doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy 

for HER2-negative locally advanced breast cancer (LABC). Presenting 

Author: Antoinette R. Tan, National Surgical Adjuvant Breast and Bowel 

Project and The Cancer Institute of New Jersey, New Brunswick, NJ 

Background: Pazopanib is an oral, small molecule inhibitor of VEGFR-1, -2, 

and-3, PDGFR-�, and -�, and c-kit tyrosine kinases. The purpose of this 

trial was to determine the activity and safety profile of pazopanib when 

added to neoadjuvant WP following AC in LABC. The primary endpoint was 

pathologic complete response in the breast and nodes (pCR-BN). Methods: 

Women with HER2-negative stage IIIA-IIIC breast cancer were treated with 

AC (60 mg/m2 /600 mg/m2 ) for 4 cycles every 3 weeks followed by WP 80 

mg/m2 on days 1, 8, and 15 every 28 days for 4 cycles concurrently with 

pazopanib 800 mg orally daily prior to surgery. Postoperatively, pazopanib 

was given for 6 months. The regimen would be considered active if �14 

responses (16% pCR rate in breast and nodes) were observed in 87 

evaluable patients. Patients were considered evaluable if they received at 

least 1 dose of pazopanib. Results: Between July 2009 and March 2011, 

101 pts (median age 51 yrs, range 30-71) were enrolled; 56% had stage 

IIIA, 34% stage IIIB, and 10% stage IIIC disease. 74 pts (73%) had 

ER-and/or PR-positive tumors and 27 pts (27%) were triple negative. 8 

patients did not begin pazopanib. The pCR-BN rate in evaluable patients 

for whom surgical information was known was 18% (16/89). The pCR-BN 

rate in ER positive disease was 9% (6/65) and was 42% (10/24) in TNBC. 

Toxicities observed with WP and pazopanib included diarrhea (gr 2/3, 

10%/5%), hand-foot syndrome (gr 2/3, 11%/1%), hypertension (gr 2/3, 

12%/3%), neuropathy (gr 2/3, 14%/1%), and neutropenia (gr 3/4, 25%/ 

1%). Liver toxicity during WP and pazopanib included ALT (gr 2/3/4, 

13%/7%/1%), AST (gr 2/3, 7%/7%), and total bilirubin (gr 2, 2%). 

Conclusions: A regimen of WP and pazopanib following AC was active as 

neoadjuvant therapy in women with LABC and met the pre-specified criteria 

of interest. The activity in TNBC was notable. The toxicity profile of WP and 

pazopanib was consistent with previous experience. Support: GlaxoSmith- 

Kline. 


4:45 PM-5:45 PM 

Association of a compact 13-gene VEGF signature with OS in E2100. 

Presenting Author: Scooter Willis, Scripps Research Institute, Jupiter, FL 

Background: E2100, an open-label, randomized, phase III trial, demonstrated 

a significant improvement in progression free survival and overall 

response rate with paclitaxel plus bevacizumab compared with paclitaxel 

alone as initial chemotherapy for patients with HER2-negative metastatic 

breast cancer. Genentech completed additional clinical trials and submitted 

these data to the FDA. On 18 Nov, 2011, the FDA Commissioner 

revoked the agency’s approval of bevacizumab for the breast cancer 

indication because of the lack of evidence of an improvement in overall 

survival or a clinical benefit to patients sufficient to outweigh the risks. 

However, the Commissioner “encouraged Genentech to consider additional 

studies to identify if there are select subgroups of women who might benefit 

from this drug”. Hu et al. (BMC Medicine 2009) published a compact 13 

gene VEGF-signature associated with distant metastases and poor outcomes. 

Supervised analyses comparing patients with distant metastases 

versus primary tumors or regional metastases showed that the distant 

metastases were distinct and distinguished by the lack of expression of 

fibroblast/mesenchymal genes, and by the high expression of a 13 gene 

profile that included VEGF, ANGPTL4, ADM and the monocarboxylic acid 

transporter SLC16A3. Methods: We have investigated the VEGF signature in 

silico on Illumina DASL analysis of 122 FFPE samples remaining from 

E2100. Results: PFS benefit is seen for pacli � bev vs pacli in both 

treatment arms with the low VEGF signature (HR 0.45 95% CI .27-.77 p 

.009 n 67) and with the high VEGF signature (HR 0.57 95% CI .32-1.0 p 

.015 n 55). However, OS benefit is only seen for pacli � bev vs pacli in the 

high VEGF group (HR 0.56 95% CI .30-1.05 p .02 n 52) and not in 

patients with the low VEGF signature (HR 1.12 95% CI .66-1.90 p .81 n 

67). Conclusions: Hence, this signature, which suggests that the response 

to hypoxia includes the ability to promote new blood and lymphatic vessel 

formation, shows great potential as a predictive biomarker of those patients 

to whom bevacizumab would convey an OS advantage benefit. We note with 

great caution that this exploratory analysis of trial subset is underpowered, 

hence, this compact VEGF signature is being pursued in other bevacizumab 

trial sets. 




4:45 PM-5:45 PM 

Are mastectomy rates really increasing? Experiences from a single institution 

and a population-based database. Presenting Author: Min Yi, University 

of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Recent studies have reported increased mastectomy rates for 

the treatment of early stage breast cancer during the last decade. The aims 

of this study were to examine trends in mastectomy rates at a single 

institution and in a population-based database and to compare differences 

between the two cohorts. Methods: Patients with stage 0-II breast cancer 

diagnosed from 2000 to 2008 were identified from our cancer center 

institutional database (CC cohort, n�8,915) and the Surveillance, Epidemiology 

and End Results database (SEER cohort, n�359,572). Patients 

without primary surgery or unknown surgery type were excluded. Mastectomy 

rates by the year of diagnosis were evaluated and multivariable 

logistic regression models were built to identify clinicopathologic factors 

that predicted mastectomy as the treatment choice. Results: The proportion 

of patients treated with mastectomy decreased from 44.5% to 37.8% 

between 2000 and 2005 in the CC cohort (P�0.003) and from 42.8% to 

36.6% in the SEER cohort (P�0.0001). Subsequently, the mastectomy 

rate increased to 48.6% in the CC cohort (P�0.0001) and to 40.1% in the 

SEER cohort by 2008 (P�0.0001). Multivariable analysis found that 

patients with younger age (�50), stage 0 or II cancer vs. stage I, high grade 

tumor, low median household income, and lobular histology were more 

likely to choose mastectomy in both the SEER and CC cohorts. In the CC 

cohort, patients with preoperative breast MRI were also more likely to 

undergo mastectomy. The percentages of patients receiving preoperative 

MRI and choosing prophylactic contralateral mastectomy increased each 

year in the CC cohort. The rate of preoperative breast MRI increased from 

4.7% in 2005 to 9.6% in 2008 (P�0.0001). Patients choosing prophylactic 

contralateral mastectomy increased from 8.4% in 2005 to 11.8% in 

2008 (P�0.06). Conclusions: Our study shows that there was a decrease in 

mastectomy rates from 2000 to 2005 and a subsequent increase in 

mastectomy rates from 2005-2008 in both the CC and SEER cohorts. 

Increased use of preoperative breast MRI and the decision to undergo 

contralateral prophylactic mastectomy likely contributed to the increased 

mastectomy rates in the CC cohort. 


4:45 PM-5:45 PM 

Short-term complications and use of breast brachytherapy in the national 

Medicare population in 2008-2009. Presenting Author: Carolyn J. Presley, 

Yale New Haven Hospital, New Haven, CT 

Background: Brachytherapy as an alternative to whole-breast irradiation 

(WBI) for early-stage breast cancer has disseminated into clinical practice; 

however, current national treatment patterns and associated complications 

remain unknown. Methods: We constructed a national sample of Medicare 

beneficiares aged 66 to 94 who underwent breast conserving surgery in 

2008-2009 and who were treated with brachytherapy or WBI. We used 

hospital referral regions to assess national treatment variation and an 

instrumental variable analysis to compare complication rates between 

treatment groups, adjusting for patient and clinical characteristics such as 

age, number of comorbidities, receipt of chemotherapy or screening 

mammogram, and type of radiation facility. We compared one-year overall, 

wound and skin, and deep tissue and bone complications between 

brachytherapy and WBI using specific procedure and diagnosis codes 

identified in Medicare claims. Results: Of the 29,648 women in our sample, 

4,671 (15.8%) received brachytherapy. The median percent of patients 

receiving brachytherapy varied substantially across hospital referral regions 

(interquartile range: 7.5%-23.3%). In the bivariate analysis, 34.3% of 

women treated with brachytherapy had a complication compared to 27.3% 

of those who received WBI (P�0.001). After adjusting for patient and 

clinical characteristics, 35.3% (95% CI: 34.7, 35.8) of women treated 

with brachytherapy had a complication compared to 18.7% (95% CI: 

18.2,19.2) treated with WBI (average predicted difference: 16.5%, 95% 

CI: 15.8, 17.3, P�0.001). While brachytherapy was associated with a 

16.9% (95% CI: 10.0, 23.8, P�0.001) higher absolute percentage of 

wound and skin complications compared to WBI, there was no difference in 

deep tissue and bone complications. Conclusions: Brachytherapy is commonly 

used among Medicare beneficiaries; in some regions nearly one in 

four women who underwent adjuvant radiation received brachytherapy. 

After one year, wound and skin complications were significantly more 

common among women who received brachytherapy compared to those 

receiving WBI, but there was no difference in deep tissue and bone 

complications. 


4:45 PM-5:45 PM 

Breast cancer multifocality-multicentricity and locoregional recurrance. 

Presenting Author: Xiudong Lei, University of Texas M. D. Anderson Cancer 

Center, Houston, TX 

Background: The impact of multifocality (MF) and multicentricity (MC) on 

locoregional (LR) control for invasive breast cancer, and the optimal local 

treatment strategy for these tumors, is unknown. In particular, there is 

disagreement in the literature regarding the use of Breast Conservation 

Therapy (BCT). We evaluated a large single institution cohort of MF and MC 

breast cancers to determine if they had inferior LR control rate when 

compared to their unifocal counterparts. Methods: MF and MC were defined 

pathologically as more than one lesion in the same quadrant and more than 

one lesion in separate quadrants, respectively. Patients were categorized by 

presence or absence of MF or MC disease and by the LR treatment modality 

received – BCT (n�256), mastectomy alone (n�466), or mastectomy plus 

post-mastectomy radiation therapy (n�184). 10 patients who underwent 

BCT for MC disease against physician advice were excluded. MF and MC 

tumors were analyzed both as a group and as separate entities. Kaplan- 

Meier product limit method was used to calculate 5-year LR control rate. 

Cox proportional hazards models were fit to determine independent 

associations of MF/MC disease with LR control. Results: Median follow up 

was 52 months. Out of 3722 patients with stage I-III disease who did not 

receive neoadjuvant chemotherapy, 906 (24%) had MF (n�673) or MC 

(n�233) disease. 5-year rate of LR control rate was 99% in the MF group, 

96% in the MC group, and 98% in the unifocal group, (P � 0.44). Subset 

analysis revealed no statistical difference in LR control regardless of the 

type of LR treatment, (P � 0.67 in the BCT group, P � 0.37 in the 

mastectomy alone group, and P � 0.29 in the mastectomy plus postmastectomy 

radiation therapy group). There were 21 in-breast recurrences 

after BCT (8.2%). After controlling for other risk factors, MF and MC did not 

have an independent impact on LR control rate. Conclusions: MF and MC 

disease are not independent risk factors for LR recurrence. Patients with 

MF and MC breast cancer had similar rates of LR control to their unifocal 

counterparts, regardless of LR treatment modality. Our data suggest that 

BCT is a safe option for patients with MF tumors and that MF or MC disease 

alone is not an indication for post-mastectomy radiation therapy. 


4:45 PM-5:45 PM 

Trends in the use of breast-conserving surgery and adjuvant radiation 

therapy in patients with DCIS: A U.S. population-based analysis from 1996 

to 2007. Presenting Author: Jennifer Nishimura, Case Western Reserve 

School of Medicine, Cleveland, OH 

Background: The treatment for patients with DCIS remains controversial. 

Current guidelines based upon best available evidence suggest that breast 

conserving surgery (BCS) followed by adjuvant radiation therapy (RT) result 

in acceptable local control and breast cancer specific survival. The purpose 

of this study was to analyze trends in patterns of care as well as identify 

factors associated with surgery type and use of adjuvant radiation therapy 

in a select cohort of patients enrolled into the SEER database. Methods: The 

study included females 18 years and older with focal DCIS and known 

tumor size of 5 cm or less diagnosed between 1996 and 2007. The 

Cochran-Armitage trend test was applied to identify trends in the use of 

BCS and RT over time. Multivariate logistic regression analyses were used 

to determine factors associated with receiving BCS vs. mastectomy and 

BCS plus RT vs. BCS alone. Cox proportional hazard model was used to 

determine associations with breast cancer-specific mortality. Results: Of 

the 34,233 women with DCIS, 76.59% were treated with BCS. 66.36% of 

BCS patients received adjuvant RT over the study period. The proportion of 

women receiving BCS increased from 71.5% in 1996 to 76.9% in 2007 

(p�0.0001). Additionally, the proportion of women who underwent BCS 

and received adjuvant radiation therapy over the same time period 

increased from 55.3% to 69.7% (p�0.0001). Multivariate analysis 

demonstrated that year of diagnosis, race, marital status, geographic 

region, tumor size, tumor grade and comedo necrosis all were significantly 

associated with the use of adjuvant radiation therapy, but age was not. Cox 

proportional hazards models did not associate either surgery type or use of 

adjuvant radiation in patients undergoing BCS with breast cancer-specific 

mortality. Conclusions: Based upon reporting within the SEER database, 

the proportion of DCIS patients undergoing BCS and the BCS patients 

receiving adjuvant radiation increased over the study time period. Surgery 

type and use of adjuvant radiation therapy in patients with BCS was not 

associated with decreased risk of breast-cancer specific death in this 

cohort. 



4:45 PM-5:45 PM 

Impact of surgery and radiation of the primary among women with de novo 

stage IV breast cancer. Presenting Author: Shaheenah S. Dawood, Dubai 

Hospital, Dubai, United Arab Emirates 

Background: The aim of this retrospective study was to determine the 

impact of surgery(S) and radiation(R) therapy to the primary tumor among 

patients (pts) with stage IV denovo breast cancer. Methods: The SEER 

registry was used to identify pts with denovo stageIV breast cancer 

diagnosed between 1988 and 2008. Pts were divided into 4 groups based 

on type of treatment to primary tumor: both S�R, S alone, R alone, or no 

treatment of primary (no S/R). Breast cancer specific survival (BCS) was 

calculated from the date of diagnosis of breast cancer to the date of death 

from breast cancer or last follow up. Survival outcomes were estimated by 

the Kaplan-Meier method, and Cox models were fit to determine the 

association between treatment of primary and survival after adjusting for 

potential confounders (e.g age, grade, hormone receptor and race). Results: 

25903 pts were identified; 4640 (17.9%) S�R, 6556 (25.3%) S, 4467 

(17.2%) R, and 10240 (39.5%) no S/R. 1183 (4.6%) had surgery to sites 

other than the primary. Median age was 63 years. Median follow-up was 14 

months. Median BCS was 23 months. Median BCS among pts who 

underwent S�R, S, R and no S/R was 36 months, 31 months, 18 months 

and 15 months respectively (p�0.0001). Among pts who underwent S�R, 

median BCS among pts who did and did not have surgery to sites other than 

primary was 50 months and 41 months respectively (p�0.029). Of the pts 

treated with S�R 10-year BCS was 18%. In the multivariable model 

compared to women who were in the no S/R group those who underwent S 

(HR� 0.59, 95%CI 0.55- 0.62,p�0.0001) and S�R (HR�0.51, 95%CI 

0.47-0.55,p�0.0001) had decreased risk of death from breast cancer and 

those who underwent R (HR�1.13, 95% CI 1.04-1.21, p�0.002) had an 

increased risk of death from breast cancer. Pts who had surgery to sites 

other than the primary tumor had decreased risk of death from breast 

cancer compared to those who did not (HR�0.80, 95%CI 0.72- 

0.89,p�0.0001). Conclusions: Our results indicate that S�R of the 

primary breast tumor among pts with denovo stage IV breast cancer maybe 

associated with a decreased risk of death from breast cancer. A select 

subgroup of pts who undergo S�R may also benefit from surgery to sites 

other than the primary which may afford them maximum survival advantage. 


Impact of adjuvant chemotherapy on recurrence-free survival in patients 

with pT1a/b hormone-negative and HER2-positive breast cancer. Presenting 

Author: Yazan Migdady, Memorial Hospital of Rhode Island, Pawtucket, 

RI 

Background: T1ab triple-negative (TN) or Her-2-positive (H2�) breast 

cancers are reported to pose relatively high risk of relapse, but benefits of 

adjuvant chemotherapy are uncertain. We studied the impact of chemotherapy 

on recurrence-free survival in this group. Methods: Records of all 

consecutive cases diagnosed in Brown-affiliated centers in 2000 - 2010 

were reviewed. Factors influencing chemotherapy decision were studied 

with logistic regression, and recurrence-free interval (RFI) with a Cox 

proportional hazard model and Kaplan-Meier estimator. Results: Among 

1415 screened T1a/b N0 cases, 161 were eligible (57 TN; 104 HER2�), 

with a median age of 57 years; 66% tumors were T1b. 20% of patients 

underwent mastectomy, 76% received radiation and 30% hormonal 

therapy. Adjuvant chemotherapy was recommended in 53% of cases. 

Younger age (p�10-6 ), stage T1b (p�10-5 ), high grade (p�0.001), 

HER2�/ERPR- status (p�0.017) and diagnosis after 2006 (p�0.007) 

were significantly predictive of the medical oncology recommendation. 

There was a significant trend with decrease in anthracycline (p�0.001) 

and increase in taxane use (p�0.001). With a median follow up of 46 

months, the 5-year rate of relapse was 6.1% (95%CI 2.7-13.9%), 

somewhat higher in T1b tumors (8.1%) and without detectable difference 

in TN/HER2� subgroups. In a univariate analysis chemotherapy did not 

significantly impact the recurrence-free interval (HR�0.45; 95%CI 0.09- 

2.34; p�0.32), however there was a detectable benefit (p�0.02) for T1b 

tumors in a multivariable Cox model including age (p�0.02) and LVI 

(p�0.01). The histology, type of surgery and year of diagnosis were not 

significant. There were no relapses among ER/PR� patients who received 

hormonal therapy or HER2� patients who received trastuzumab. 

Conclusions: The risk of relapse in biologically aggressive T1ab breast 

cancers is very low with judicious use of adjuvant therapy. The benefit of 

chemotherapy is likely restricted to the highest-risk patients with T1b 

tumors, lymphovascular invasion and younger age. 


57s 


4:45 PM-5:45 PM 

Utilization of post-lumpectomy radiation therapy in women 70 years of age 

or older: A report from the National Cancer Data Base. Presenting Author: 

Katharine Yao, NorthShore University HealthSystem, Evanston, IL 

Background: The Cancer and Leukemia Group B (CALGB) 9343 trial 

published in 2004 showed no overall survival benefit from radiation in 

patients �70 years old with estrogen receptor (ER) positive, pT1 tumors 

with the use of tamoxifen. We tested the hypothesis that the use of 

radiotherapy decreased in this group of patients following publication of the 

trial, utilizing the National Cancer Data Base. Methods: 34,853 breast 

cancer patients 70 years or older with pT1N0/NX, ER positive tumors who 

underwent a lumpectomy between 2004 and 2007 were studied. Chisquare 

tests and logistic regression models were used to determine trends 

and factors related to the use of radiation. Results: The use of radiation 

decreased from 70.6% in 2004 to 66.4% in 2005, 66.6% in 2006, and 

67.2% in 2007 (p�0.001). The use of standard external beam radiation 

decreased from 58.8% in 2004 to 45.8% in 2007 while the use of 

accelerated partial breast radiation using brachytherapy (APBI) increased 

from 4.5% to 10.0%, IMRT radiation from 3.1% to 5.3%, and 3D 

conformal radiation from 3.7% to 5.7% (p�0.001). Patients between the 

ages of 86� years old were less likely to undergo radiation than patients 

70-75 years old (OR�0.12, 95% CI: 0.11-0.13). Asian Pacific Islanders 

were more likely to undergo radiation than whites (OR�1.39, 95% CI: 

1.13-1.70). In community cancer programs, 67% patients received 

radiation, compared to 69.1% in comprehensive community programs and 

65.5% in academic programs (p�0.001). The use of radiation varied by 

facility location; 73.5% of facilities located in the Midwest radiated these 

patients as opposed to 62.6% in the South. In patients who had no nodes 

examined, 37% underwent radiation as opposed to 74% who did have 

nodes examined (p�0.001). Likewise, 79.4% of patients who received 

hormone therapy underwent radiation as opposed to 54.6% of patients who 

did not receive hormonal therapy (p�0.001). Conclusions: The use of 

radiation therapy decreased only slightly and remained high in women with 

ER� stage I breast cancer over the age of 70, despite findings from the 

CALGB 9343 study. However, there was a large shift in radiation modality 

over the study period in the older patients. 


Pathologic complete response rates observed in women with locally 

advanced and inflammatory breast cancer receiving neoadjuvant carboplatin 

and paclitaxel. Presenting Author: Arvind Manohar Shinde, City of 

Hope, Duarte, CA 

Background: Pathologic complete response (pCR) following neoadjuvant 

chemotherapy (NCT) is predictive of outcome in patients with locally 

advanced breast cancer (LABC). A non-anthracycline containing NCT 

regimen (Sikov et al. JCO 10/09) may reduce the risk of associated 

secondary hematologic malignancies and cardiac toxicity while yielding 

comparable pCR rates. Methods: A retrospective review of all LABC and 

inflammatory breast cancer (IBC) cases treated from 4/09 to 12/11 with a 

NCT regimen of carboplatin (AUC of 6, administered on day 1) and 

paclitaxel 80 mg/m2 (given weekly on a 21-28 day cycle) was conducted at 

the City of Hope Cancer Center (COHCC). Pts with HER2� (HER�) tumors 

received trastuzumab during the NCT treatment. All pCRs (pCR of primary 

only – �pCR1°�; pCR of primary and lymph nodes – �pCR-All�) were 

determined by a COHCC pathologist based on final surgical specimens. 

Results: 38 pts were identified, with 39 breast primaries; 18% had IBC, 

62% of LABCs/IBCs were hormone receptor positive (HR�), 46% of tumors 

were HER2�, and 26% were triple negative. Median age was 51 [27-63]. 

All pts completed the planned number of cycles. Four pts required 

carboplatin dose reductions, 4 pts required dose reductions in paclitaxel, 3 

pts had paclitaxel changed to nab-paclitaxel, and 17 pts required G-CSF to 

complete their planned treatment. One pt receiving trastuzumab experienced 

asymptomatic LVEF decline below normal limits. Conclusions: A 

non-anthracycline-containing NCT regimen of carboplatin/paclitaxel was 

well tolerated and resulted in high pCRs when given to triple negative 

(HER2-/HR-) pts, and HER2� pts, especially with HER2�HR- subtypes. 

The findings warrant further studies of this regimen in a prospective 

randomized setting. 

HER2 status N pCR1° (%) pCR-All (%) HR status N pCR1° (%) pCR-All (%) 

HER2� BC 18 56 44 HR� 13 38 31 

HR- 5 100 80 

HER2- BC 21 38 29 HR� 11 9 0 

HR- 10 70 60 




A phase II study of foretinib in triple-negative, recurrent/metastatic breast 

cancer: NCIC CTG trial IND.197 (NCT01147484). Presenting Author: 

Daniel Rayson, QEII Health Sciences Centre, Halifax, NS, Canada 

Background: Met, a receptor tyrosine kinase, is preferentially expressed in 

basal-like compared to luminal breast cancer. In murine models, overexpression 

of the oncogenic Met receptor transgene induces tumors with human 

basal gene expression characteristics supporting Met inhibition as a 

treatment strategy for triple negative (TN) breast cancer. Foretinib is an oral 

multi-kinase inhibitor of Met, RON, AXL, TIE-2 and VEGF receptors with 

anti-tumor activity in advanced HCC and papillary renal cell cancer. 

Methods: Patients (pts) with TN breast cancer and 0-1 prior regimens for 

metastatic disease received daily foretinib 60 mg po in a 2-stage single arm 

trial. Primary endpoints were objective response and early progression rates 

per RECIST 1.1. Tumor samples were centrally reviewed to confirm 

ER/PR/HER2 status and for correlative studies including Met, PTEN and 

EGFR expression. Stage 1 accrual required 23 response-evaluable Met 

unselected patients with accrual continuing if �/� 1 response or � 17 

early progressions (PD �� 8 weeks on study) were observed. Results: 

Accrual is 29 pts to date; 24 are eligible, 22 evaluable for toxicity and 15 

for response. Median age is 56 y (43-81), ECOG PS 0-1 in 23/24. Grade 3 

laboratory adverse events were: lymphopenia (9%), elevations in ALT (5%), 

GGT (5%) and INR (5%). Treatment-related non-hematologic toxicities 

included (all/grade 3-4) fatigue (64%/5%), nausea (55%/5%), diarrhea 

(41%/5%), hypertension (32%/14%), vomiting (27%/0%), anorexia (23%/ 

5%) and rash (14%/0%). Three SAEs possibly related to foretinib included; 

asymptomatic pulmonary embolism, reversible CHF and pleural effusion 

with QTc prolongation. One PR (7%), 8 early PD (53%) and 6 SD (40%) 

have been observed to date with median SD duration of 5.4 months (range 

2.7-5.5). Preliminary correlative results (IHC): 5/8 (62.5%) evaluable Met 

positive cases had SD and 4/5 (80%) Met negative cases had PD as best 

response. Met IHC was negative in the pt with PR. Conclusions: Foretinib 

shows preliminary evidence of activity and tolerability in metastatic, TN 

breast cancer. Stage 2 of accrual will include 15 pts with pre-treatment 

biopsies of metastases and circulating tumor cell collection. 


Single institution experience with neoadjuvant chemotherapy for metaplastic 

breast cancer (MBC). Presenting Author: Anna Kaminsky, University of 

Pittsburgh Medical Center (UPMC), Pittsburgh, PA 

Background: Metaplastic breast carcinoma (MBC) is a rare subtype that 

accounts for �1% of all breast carcinomas. MBC is frequently triple 

negative and neoadjuvant chemotherapy (NAC) is often used in triple 

negative breast cancer (TNBC). The objective of this analysis is to ascertain 

response rates of MBC to NAC as compared to non-metaplastic TNBC. 

Methods: We searched the Magee Women’s Cancer Center of UPMC 

IRB-approved neo-adjuvant treatment database which contains outcome 

data on 594 patients treated from 2004-2010. 116 patients with triple 

negative breast cancer (ER /PR negative or ER /PR weakly positive (H score 

of 10 or less) and HER2 negative or indeterminate (HER2 1� or 2� 

without amplification by FISH)), were identified. Nine of these TNBCs had 

metaplastic subtype and 2 groups were analyzed: metaplastic breast 

carcinoma (MBC) (N� 9) and non-metaplastic breast carcinoma (NMBC) 

(N � 107). Tumor volume reduction (TVR), pathologic complete response 

(pCR), recurrence and mortality were compared in both groups. Results: 

Mean follow up in MBC group was 43 months and no patients were lost to 

follow up. Mean tumor size on presentation in MBC group was 4.47 cm 

while in NMBC group it was 3.33 cm. pCR was noted in 0/9 MBC and 

43/107 NMBC cases (p � 0.0253). 6/9 patients had mastectomy, 2/9 had 

breast conserving surgery (BCS) and 1/9 patients did not have a surgery yet. 

Average TVR was 28% in MBC cases compared to 74% in NMBCs when 

cases with pCR were included (p � 0.0001) and 56% when cases with pCR 

were excluded (p � 0.0202). Follow up on 9 MBC cases revealed 1 

recurrence and subsequent death (11%). Follow up on 64 NMBC patients 

who failed to achieve pCR revealed 22 recurrences (34%) and 18 of them 

subsequently died (28%).Follow up on 43 NMBC cases that achieved pCR 

revealed 3 recurrences (7%) and 1 death (2%). Conclusions: MBC was 

characterized by larger size at baseline as compared to NMBC. There were 

no pCR’s seen in MBC, but some MBC did achieve response that allowed for 

breast conservation. Although the average tumor volume reduction was 

significantly less in MBC compared to NMBC, the NMBC that failed to 

achieve pCR fared much worse than MBC who did not achieve pCR. 

Therefore, the triple negative paradox is likely not applicable to MBC. 


Comprehensive investigation of adverse event (AE)-related costs in patients 

with metastatic breast cancer (MBC) treated with first- and second-line 

chemotherapies. Presenting Author: Sara A. Hurvitz, UCLA, Los Angeles, 

CA 

Background: MBC is incurable and managed with ongoing therapy. This 

study examined the incremental costs of chemotherapy-associated AEs in 

MBC. Methods: The PharMetrics Integrated Database (2000-2010) was 

used to identify MBC pts treated either 1st or 2nd line with a taxane (T) 

(paclitaxel or docetaxel) or capecitabine (C)-based regimen for �30 days 

(defined as a treatment episode (TE)). Incremental costs attributable to 

AEs were assessed by comparing costs incurred during TEs with and 

without AEs. AEs were identified using medical claims with a diagnosis for 

�1 event of interest (e.g., infections, fatigue, anemia, neutropenia). Pt 

characteristics were balanced between comparison groups (with and w/o 

AEs) using inverse probability weighting method. Incremental monthly 

costs due to AEs were estimated during the TEs and included the following 

cost components: inpt (IP), outpt (OP), emergency room (ER), other 

medical service, pharmacy costs (chemotherapy and other drugs), and total 

healthcare costs. Statistical comparisons were conducted using Wilcoxon 

tests. Results: 3,222 women (mean age�57) received aTorCas1stor 

2nd-line therapy for MBC. Of the 2,678 1st-line pts, 69.7% received T and 

30.3% with C; average monthly total costs ranged from $9,159 to 

$10,298. AEs were commonly seen in pts treated with 1st-line T and C 

(94.6% and 83.7%). On average, the total monthly incremental cost 

associated with AEs was 38% higher ($3,547) for T and 9% higher ($854) 

for C. IP and other drug costs accounted for a majority of these costs. Of 

1,084 2nd-line pts, 66% received T and 34% C, with average monthly total 

costs ranging from $5,950 to $12,979. 94.4% of T pts and 84% of C pts in 

the 2nd-line had an AE. The average total monthly incremental cost 

associated with AEs for T was $5,320 and $4,933 for C (69.5% and 

82.9% higher vs pts w/o AEs). Pharmacy costs accounted for a majority of 

increased costs seen in pts with AEs treated with T; IP and OP accounted 

for a majority of these costs in pts treated with C. Conclusions: This is the 1st study assessing costs associated with AEs for tx of mBC. AEs are associated 

with a substantial economic burden that is mainly explained by increased 

IP, OP, and pharmacy costs. 


Association between vitamin D deficiency and breast cancer histology: A 

retrospective database review. Presenting Author: Ranjana S. Bhargava, 

University of Maryland Marlene and Stewart Greenebaum Cancer Center, 

Baltimore, MD 

Background: Vitamin D (Vit D) deficiency has been shown to be associated 

with a higher risk of developing breast cancer. Inverse association has also 

been shown between vit D level and tumor size. However, the association 

between vit D deficiency and breast cancer histology remains unclear. 

Preclinical data has suggested that vit D plays an essential role in the 

terminal differentiation of breast cells. Thus, we hypothesize that vit D 

deficiency would be associated with estrogen receptor-negative tumors, 

particularly triple-negative breast cancers (TNBC) which are associated 

with aggressive clinical course. Methods: We conducted a retrospective 

database review to obtain information including age, race, tumor histology, 

size, stage, and vit D levels in newly diagnosed breast cancer patients at 

University of Maryland Greenebaum Cancer Center. Results: 150 patients 

presented between July 2008 and August 2011 were included in this 

analysis. Average age at diagnosis was 57 (range 30-87), and 56% of 

patients were African American. Overall, 80% of the patients were vit D 

deficient at diagnosis, with levels � 30 ng/ml. African-American patients 

were more likely to be severely vit D deficient with levels � 10 ng/ml 

compared to Caucasians (33% vs. 7.5%, p� 0.0002). Patients with TNBC 

were more likely to be vit D deficient at diagnosis compared to hormone 

receptor-positive patients (93% vs. 76%, p �0.015). These patients also 

had the lowest mean (18) and median (16) of vit D levels compared to all 

other patients. This difference is also statistically significant in multivariate 

analysis when adjusted for age, race, and stage (OR 3.96; p�0.04). 

Regardless of the ER/PR status, Her 2 negative patients were more vit D 

deficient compared to Her 2 positive patients (86% vs. 61%, p�0.001). 

Unlike previous studies, no correlation was seen between tumor size and vit 

D levels. Furthermore, there is also no association between stage, nodal 

involvement, or Ki67 and vit D level. Conclusions: Vit D deficiency is 

common among patients with newly-diagnosed breast cancer, particularly 

African American patients. Patients with TNBC have a significantly higher 

likelihood of being vit D deficient than patients with other histological 

subtypes. 



Frequency of TLE3 overexpression in breast carcinoma subtypes including 

a large cohort of triple-negative patients. Presenting Author: Gargi D. Basu, 

Caris Life Sciences, Phoenix, AZ 

Background: The taxanes are an important class of agents for the treatment 

of a broad range of malignancies including breast cancer. They improve 

survival in patients with early stage and metastatic breast cancer. Transducin-like 

enhancer of split 3 (TLE3) is a transcriptional repressor which 

influences growth and microtubule stability and its expression has been 

implicated in response to taxane therapy in breast cancer. We investigated 

the tumor expression of TLE3 in breast cancer patients, including a large 

cohort of the triple negative subtype. Methods: We analyzed TLE3 (M-201), 

ER(1D5), PR(PgR636) and HER2/neu(Polyclonal) expression by immunohistochemistry 

in 978 breast cancer patients. Immunoreactivity was 

assessed by scoring the percentage of cells stained in each field and by the 

intensity of staining. Results: To sub-classify the 978 breast cancer 

patients, we utilized hormone receptors (ER and PR) and HER2 expression/ 

amplification. Overall, 36% of the total breast cancer patients were 

hormone receptor positive, 15% were HER2 positive and 49% were triple 

negative. The percentage of triple negative patients was higher in our 

cohort, given the fact that molecular profiling services are used more 

frequently for this subtype. A total of 477 patients were triple negative of 

which 61% stained positive for TLE3 expression. Of the 150 HER2 positive 

patients, 73% stained positive for TLE3 expression as compared with 82% 

TLE3 positivity in the 351 hormone receptor positive patients. By pairwise 

comparison, the hormone receptor positive vs triple-negative subtype 

showed the highest statistical significance in ratios of TLE3 positives (p 

�2.5e-10). Conclusions: Our results show that TLE3 is over-expressed in 

the majority of HER2 positive and hormone receptor positive breast cancer 

patients. Interestingly, the frequency of over-expression of TLE3 was lowest 

in the triple negative subtype thereby making it more important to identify 

those patients in this group who are most likely to respond to taxanes prior 

to therapy. To our knowledge, this is the first study providing a comprehensive 

review of TLE expression in breast cancer subtypes. 


Preclinical evaluation of PARP inhibition in breast cancer: Comparative 

effectiveness of olaparib and iniparib. Presenting Author: Maura B. Cotter, 

School of Medicine and Medical Science, University College Dublin, 

Dublin, Ireland 

Background: The main function of PARP1 is repair of single-strand DNA. 

Phase I/II clinical trials have shown that the PARP inhibitor, olaparib has 

efficacy in BRCA1/2-related breast cancer. Due to the similarities between 

BRCA1/2-associated and triple negative breast cancer (TNBC), we hypothesise 

that TNBC may also be sensitive to PARP inhibition. In order to assess 

this we addressed the effects of 2 PARP/PARP-like inhibitors, on a panel of 

breast cancer cell lines. Methods: PARP1 was measured by immunohistochemistry 

in 101 TNBC and 116 non-TN cancers. Comparative growth 

inhibitory capacity of olaparib and iniparib was evaluated using cell 

viability (MTT) and colony formation assays in 12 breast cancer cell lines 

(TN�7, non-TN�5). Results: Using immunohistochemistry, PARP1 staining 

was predominantly nuclear with some cytoplasmic staining. High 

staining intensity for PARP1 was found more frequently in ER-negative (p 

� 0.001), in high grade (p � 0.013) and in Ki67-positive ( p � 0.003) 

samples. Potentially important was the finding that high PARP1 staining 

intensity was detected more frequently in TN than non-TN samples (p � 

0.0001). IC50 concentrations across 12 cell lines ranged from 3.7-31 �M 

for olaparib and 13-70 �M for iniparib. No difference in sensitivity was 

observed between the TN and non-TN cell lines (by MTT). Olaparib also 

reduced the ability of cells to form colonies with IC50 values ranging from 

�0.01-2.5 �M. Addition of the CDKI inhibitor CDK1i (Calbiochem) to 

olaparib resulted in formation of significantly fewer colonies compared with 

either inhibitor alone, in a cell line dependent manner. Conclusions: Our 

results suggest that although PARP1 is expressed in the majority of breast 

cancer, significantly higher staining intensity was found in TN than non-TN 

samples. Furthermore, our work suggests that olaparib is a more potent 

inhibitor of the in vitro growth of breast cancer cells than iniparib. 

Combined inhibition of PARP1 with olaparib and CDK1 with CDK1i may be 

a way forward for the treatment of TNBC. Acknowledgement: The authors 

thank SFI (SRC award, 08/SRC/B1410 MTCI) for funding this work. 


59s 


Epigenetic aspects of triple-negative in patients with breast cancer. 

Presenting Author: Joaquina Martínez-Galan, Medical Oncology Department, 

Hospital Universitario Virgen de las Nieves, Granada, Spain 

Background: Identification of gene expression-based breast cancer subtypes 

is considered a critical means of prognostication. Genetic mutations 

along with epigenetic alterations contribute to gene-expression changes 

occurring in breast cancer. However, the reproducibility of differential DNA 

methylation discoveries for cancer and the relationship between DNA 

methylation and aberrant gene expression have not been systematically 

analysed. The present study was undertaken to dissect the breast cancer 

methylome and to deliver specific epigenotypes associated with particular 

breast cancer subtypes. Methods: By using Real Time QMSPCR SYBR green 

we analyzed DNA methylation in regulatory regions of 107 pts with breast 

cancer and analyzed association with prognostics factor in triple negative 

breast cancer and methylation promoter ESR1, APC, E-Cadherin, Rar B 

and 14-3-3 sigma. Results: We identified novel subtype-specific epigenotypes 

that clearly demonstrate the differences in the methylation profiles of 

basal-like and human epidermal growth factor 2 (HER2)-overexpressing 

tumors. Of the cases, 37pts (40%) were Luminal A (LA), 32pts (33%) 

Luminal B (LB), 14pts (15%) Triple-negative (TN), and 9pts (10%) 

HER2�. DNA hypermethylation was highly inversely correlated with the 

down-regulation of gene expression. Methylation of this panel of promoter 

was found more frequently in triple negative and HER2 phenotype. ESR1 

was preferably associated with TN(80%) and HER2�(60%) subtype. With 

a median follow up of 6 years, we found worse overall survival (OS) with 

more frequent ESR1 methylation gene(p�0.05), Luminal A;ESR1 Methylation 

OS at 5 years 81% vs 93% when was ESR1 Unmethylation. Luminal 

B;ESR1 Methylation 86% SG at 5 years vs 92% in Unmethylation ESR1. 

Triple negative;ESR1 Methylation SG at 5 years 75% vs 80% in unmethylation 

ESR1. HER2;ESR1 Methylation SG at 5 years was 66.7% vs 75% in 

unmethylation ESR1. Conclusions: Our results provide evidence that 

well-defined DNA methylation profiles enable breast cancer subtype 

prediction and support the utilization of this biomarker for prognostication 

and therapeutic stratification of patients with breast cancer. 


Molecular characteristics and metastasis predictor genes of triple-negative 

breast cancer. Presenting Author: Wen-Hung Kuo, Department of Surgery, 

College of Medicine, National Taiwan University, Taipei, Taiwan 

Background: Triple-negative breast cancer(TNBC) is a subtype of breast 

cancer with aggressive tumor behavior and distinct disease etiology. Due to 

the lack of an effective targeted medicine, treatment options for triplenegative 

breast cancer are few and recurrence rates are high. Although 

various multi-gene prognostic markers have been proposed for the prediction 

of breast cancer outcome, most of them were proven clinically useful 

only for estrogen receptor-positive breast cancers. Reliable identification of 

triple-negative patients with a favorable prognosis is not yet possible. 

Methods: Clinicopathological information and microarray data from 157 

invasive breast carcinomas were collected at National Taiwan University 

Hospital from 1995 to 2008. Gene expression data of 51 triple-negative 

and 106 luminal breast cancers were generated with oligonucleotide 

microarrays. A prognostic 45-gene signature for triple-negative breast 

cancer was identified using Student’s t test and receiver operating 

characteristic analysis. Results: Hierarchical clustering analysis revealed 

that the majority (94%) of triple-negative breast cancers were tightly 

clustered together carrying strong basal-like characteristics. A novel 

45-gene signature giving 98% predictive accuracy in distant metastasis 

recurrence was identified in our triple-negative patient cohort. External 

validation of the prognostic signature in an independent microarray dataset 

of 59 early-stage triple-negative patients also obtained statistical significance 

(hazard ratio 2.29, 95% CI 1.04-5.06, Cox P � 0.04), outperforming 

five other published breast cancer prognostic signatures. The prognostic 

signature was statistically predictive with the node-negative triple-negative 

patients in the validation cohort. Conclusions: The 45-gene prognostic 

signature identified in this study revealed that TGF-� signaling in immune/ 

inflammatory regulation may be critically involved in distant metastatic 

invasion of TNBC. The 45-gene signature, if further validated, may be a 

clinically useful tool in risk assessment of metastasis recurrence for 

early-stage triple-negative patients. 




Association of body mass index and outcome in advanced breast cancer. 

Presenting Author: Claudia Andreetta, Department of Oncology, University 

Hospital of Udine, Udine, Italy 

Background: Obesity represents a well-known risk factor for the development 

of breast cancer and an adverse prognostic factor in early disease. 

Overweight is associated with reduced efficacy of aromatase inhibitors in 

adjuvant setting. Few data have been reported about the potential relationship 

of overweight and outcome in advanced breast cancer (ABC). Methods: 

We retrospectively evaluated body mass index (BMI) in a consecutive series 

of 400 ABC patients treated at our institution. BMI was calculated at 

baseline of diagnosis of ABC. We evaluated association of BMI and other 

prognostic and predictive markers with Progression Free Survival (PFS) and 

Overall Survival (OS). We evaluated PFS at first and subsequent lines of 

chemotherapy (CT) and endocrine therapy (ET). Overweight patients were 

defined as having BMI � 25. Results: Overweight patients were 52%. 

Median age of the population was 58 years. Median OS was 33.7 months. 

Overall, 76% of patients presented with ER� and 17.7% with HER2� 

ABC.Overweight was associated with increased age at diagnosis, menopausal 

status and luminal B or triple negative immunophenotype. At 

multivariate analysis, BMI � 25 was associated with better PFS at first-line 

ET (HR� 0.68, 95% CI 0.46-0.99). BMI was not associated with OS. 

Conclusions: BMI at baseline does not seem to be an adverse prognostic 

factor for ABC patients. Overweight may be associated with better PFS in 

endocrine responsive ABC treated with ET, especially in first-line setting. 

The role of BMI in ABC deserves to be further investigated. 


Patterns in circulating microRNA in black (B) versus white (W) patients 

with triple-negative (TN) breast cancer (BC). Presenting Author: Iuliana 

Shapira, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY 

Background: Breast cancer is by far more common in W than in B women. 

Black women have more aggressive disease that occurs almost a decade 

earlier, it is usually triple negative and has a lower survival. Objectives to 

determine 1) if plasma miRNA expression differs between B and W women, 

and 2) if variation in miRs may explain the observed survival difference in 

TNBC in W compared to B women. Methods: We determined miRNA profiles 

in plasma collected before removal of breast tumors in three groups of W 

and B women: 1) normal controls (N), 2) TN and 2) ER/PR positive BC. 

Expression miRNA profiling of 754 miRNAs on the ABI Open Array 

detected 101miRNAs in plasma. We compared miRNA expression in 

cancer patients and race-matched controls. A moderated t-statistic through 

the R/Bioconductor ’limma’ was used to compare the mean response 

between subject factors of interest. Results with a p�0.05 were considered 

statistically significant. Characteristics: 32 patients were included in this 

analysis (mean age 50 years; range 31-68), 10 had stage III TNBC (5 B & 5 

W); 10 had stage III ER/PR�BC (5 B, 5 W); and 12 were controls (6 B, 6 W) 

Results: W TNBC patients overexpressed (15 fold higher than normal) 20 

miRs in plasma (let-7d, let7g, miR-103, -10a, 15a, -9, -99b, -181a, -18a, 

-502, -187, -365 and others), these miRs were not found in any of the B 

patients. Six microRNAs (such as miR-34a, -127 and others) were 15 fold 

higher than normal controls in B cancer patients, these miRs were not 

detected in W patients with TNBC. Four miRs in B and 8 miRs in W were not 

previously reported in association with breast cancer suggesting that they 

may be connected to the host response. Conclusions: The striking difference 

in the patterns of plasma miRNA expression between B and W 

patients may provide the key to the large difference in outcome between 

these groups when receiving similar treatments, the worse prognosis group 

may carry the miRs that promote metastasis. The seed-soil hypothesis may 

explain the better prognosis in W patients. W women may carry those 

miRNAs that support an “exaggerated” response to systemic treatment, 

while the B may have the miRs that favour metastasis. 


Neoadjuvant weekly nab-paclitaxel (wA), carboplatin (Cb) plus bevacizumab (B) 

with or without dose-dense doxorubicin-cyclophosphamide (ddAC) plus B in 

ER�/HER2-negative (HR�) and triple-negative (TN) breast cancer (BrCa): A 

BrUOG study. Presenting Author: Natalie Faye Sinclair, Department of 

Medicine, Warren Alpert Medical School of Brown University, Providence, 

RI 

Background: High risk BrCa patients (pts) often receive weekly paclitaxel 

(wP) as well as ddAC. Switching to wA(Abraxane) or adding B or Cb may 

enhance its efficacy, especially in TN pts. Methods: Pts with clinical stage 

IIA-IIIC BrCa received wA 100 mg/m2 , Cb AUC 6 � B 15 mg/kg q3wks x 12 

wks only (cohort 1/Yale) or followed by ddAC � B x 4 (cohort 2/Brown). 

Endpoints: pathologic complete response (pCR) - absence of invasive BrCa 

in breast � axillary nodes, residual cancer burden (RCB), clinical CR/ 

partial response (cCR/cPR), and toxicity. Correlative studies are being 

performed on biopsies obtained at baseline and after run-in doses of wA or 

B only. Post-op pts resume B for 34 wks; other systemic therapy, including 

ddAC in cohort 1, is at MD discretion. Results: 55 of 60 pts (median age 47, 

range 25-68; 31 HR�/29 TN) are evaluable for response (see table below). 

Median # doses wA 11,Cb 4, ddAC 4. Dose reductions: wA 25% for 

neutropenia (ANC), Cb 15% for thrombocytopenia (tcp). B 7% held for 

hypertension. Grade 3-4 toxicities (�5%): ANC 85%, tcp 35%, anemia 

25%. Serious adverse events during wA: 3 nausea/dehydration (N/D), 3 

infection w/o neutropenic fever (FN), 2 GI bleed; during ddAC: 6 (21%) FN 

despite G-CSF, 3 N/D. Conclusions: The combination of wA, q3wk Cb � B 

was well tolerated, with cCR�cPR 84%. However, overall pCR was only 

11% (27% in TN) after 12 wks of this regimen (cohort 1). Subsequent 

preop ddAC raised overall pCR to 54%, and 81% in TN, demonstrating that 

longer treatment duration or inclusion of anthracycline-based therapy 

improves responses. Results for cohort 2 compare favorably with those from 

I-SPY, GeparQuinto and NSABP B-40; the addition of Cb and/or B in TN is 

being evaluated in CALGB 40603. 

N 

cCR/cPR 

after wA 

cCR/cPR 

after ddAC pCR 

Total 55 13/33 (84%) 19 (35%) 29 (53%) 26 

HR � 28 5/17 (79%) 3 (11%) 7 (25%) 21 

TN 27 8/16 (89%) 16 (59%) 22 (82%) 5 

Cohort 1 27 4/18 (81%) 3 (11%) 10 (37%) 17 

HR� 16 2/10 (75%) 0 4 (25%) 12 

TN 11 2/8 (91%) 3 (27%) 6 (55%) 5 

Cohort 2 28 9/15 (86%) 13/11(92%)* 15 (54%) 18 (64%) 10 

HR � 12 3/7 (83%) 3/7 (91%) 2 (17%) 2 (17%) 10 

TN 16 6/8 (88%) 10/4 (93%) 13 (81%) 16 (100%) 0 

*2 pts not restaged after ddAC excluded. 


Molecular comparison of human triple-negative inflammatory breast cancer 

(TN-IBC) and human triple-negative noninflammatory breast cancer (TNnon-IBC). 

Presenting Author: Hiroko Masuda, Morgan Welch Inflammatory 

Breast Cancer Program and Clinic, University of Texas M. D. Anderson 


Background: IBC has a poor prognosis because of its high rate of recurrence. 

There is an urgent need to define the biology of IBC to develop molecularbased 

targeted therapies for this disease. TNBC has a similar poor 

prognosis. Recently, Lehmann et al. (JCI, 2011) identified 7 subtypes of 

TNBC: basal-like (BL) 1 and 2, immunomodulatory (IM), mesenchymal 

(M), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and 

“unknown.” In light of these findings, we hypothesized that the distribution 

of TNBC subtypes differs between TN-IBC and TN-non-IBC. Methods: We 

qualitatively reproduced the Lehmann et al. experiments using Affymetrix 

CEL files from the same datasets to ensure the reproducibility of their 

findings. We quantified all arrays using frozen robust multiarray analysis 

with a linear model adjustment to account for batches. Then validated the 

results in a TNBC cohort from the World IBC Consortium for which IBC 

status was known (41 cases of TN-IBC; 53 cases of TN-non-IBC). We used 

the Fisher exact test to determine associations between TNBC subtypes 

and IBC status. We used Kaplan-Meier curves and log-rank tests to 

compare clinical outcomes between TNBC subtypes. Results: We found the 

7 subtypes for both TN-IBC and TN-non-IBC. While the correspondence 

between our findings and those of Lehmann et al. was not perfect, there was 

a very significant correlation (P�2.2x10-16 ). We found no association 

between TNBC subtype and IBC status (P�.5023). As expected, we found 

that patients with IBC had significantly worse recurrence-free survival 

(RFS) than a comparison cohort of patients with advanced non-IBC that 

included not only patients with TNBC but also patients with ER-positive 

and HER2-amplified tumors (P�.0054). However, TNBC subtype did not 

predict RFS. IBC status was not a significant predictor of RFS or overall 

survival in the TNBC cohort. Conclusions: Both TN-IBC and TN-non-IBC are 

heterogeneous. TNBC subtypes are unrelated to IBC status. TN-IBC and 

TN-non-IBC have the same subtypes and clinical outcome. 

% IBC Non-IBC 

Relative M 9.7 13.2 

IM 7.3 22.6 

BL1 21.9 15.0 

BL2 7.3 3.7 

LAR 14.6 11.3 

Unk 19.5 18.8 

MSL 19.5 15.0 


RCB 

0-1 

RCB 

2-3


Racial differences in outcomes of triple-negative breast cancer. Presenting 

Author: Jose Pacheco, Washington University, St. Louis, MO 

Background: The incidence and mortality of breast cancer can differ 

significantly among racial and ethnic groups. African American (AA) women 

have a lower incidence of breast cancer, but higher mortality compared to 

other racial groups. Triple negative breast cancer (TNBC: negative for the 

expression of estrogen receptor, progesterone receptor and HER2), which is 

an aggressive type of breast cancer, occurs more frequently in AA women. 

The few studies addressing whether racial differences exist in the outcomes 

of patients with TNBC have yielded inconsistent results. Methods: The 

Washington University Medical Oncology Database captures the clinical 

information for all new patients (pts) seen at the Breast Oncology Clinic. 

Most of these pts reside in the St. Louis metropolitan area. Using this 

database, we performed a retrospective analysis to examine the association 

of race with the clinical presentation and outcome of TNBC in this 

geographically defined patient population. Results: Between May 2006 and 

March 2011, 506 pts with TNBC were entered in the database. Analysis 

was done on 499 patients for whom follow up data is available. The median 

follow up (F/U) time was 24.5 months and the median age at diagnosis was 

53 (24 to 98) years. Thirty percent of pts were AA. Only 5% presented with 

stage IV at diagnosis and the majority of tumors (86%) were high grade. 

Neoadjuvant chemotherapy was administered in 151 pts, 22% of whom 

achieved a pathologic complete response (pCR). There was no significant 

difference between races in the age of diagnosis, F/U time, tumor stage, 

grade, frequency of receiving neo/adjuvant chemotherapy and pCR rate to 

neoadjuvant chemotherapy. There was no difference in disease free survival 

(DFS) and overall survival (OS) between AA and other racial groups by 

either univariate or multivariate analysis that took into account tumor 

stage, grade, patient age and menopausal status. The HR for OS was 1.154 

(CI 0.772 – 1.725, p value 0.4860) and for DFS it was 0.947 (CI 0.650 – 

1.380, p value 0.7764) in AA compared to other races. In the 92 pts who 

recurred, there was no racial difference in time from recurrence to death. 

Conclusions: Race does not significantly affect the clinical presentation or 

outcome of TNBC in the St. Louis metropolitan area. 


Evaluation of a multiparametric system able to predict nonsentinel lymph 

node status in breast cancer patients with a micrometastatic sentinel node 

assessed by the one step nucleic acidamplification (OSNA) assay. Presenting 

Author: Simonetta Buglioni, Regina Elena National Cancer Institute, 

Rome, Italy 

Background: Axillary lymph node dissection (ALND) may not be necessary in 

women with breast cancer (BC) who have micrometastasis in a sentinel 

lymph node (SLN), owing to the low risk of non-SLN (NSLN) involvement. 

In our Institute we validated and adopted the molecular diagnostic tool 

OSNA based on the quantitative measurement of Cytokeratin 19 (CK19) 

mRNA.The aims of our work in a subgroup of women with micrometastatic 

SLN, were: 1) to correlate the copy numbers of CK19 mRNA with the risk of 

additional positive NSLNs; 2) to assess the relationships between the 

molecular subtype classification and the probability of a positive ALND; 3) 

to verify whether a combination of the new above mentioned parameters is 

able to identify a subgroup of patients with a micrometastatic SLN and a 

negligible risk of positive NSLNs in whom ALND may be avoided. Methods: 

The SLN lysates from 709 patients were analyzed by OSNA assay. We 

considered only patients with a micrometastatic SLN (copy numbers 

between 250 and 5000/�L) and the probability of having a positive ALND 

was calculated by the logistic regression model. This series of BC patients 

were divided into four main subtypes taking in account the BC classification 

as defined by a combination of estrogen, progesteron receptors and 

HER2 status. Results: OSNA positivity for micrometastasis was reported in 

91/709 cases (12,8%).The number of patients with positive ALND was 20 

(22%). The statistical analyses showed that the metastatic involvement of 

NSLNs is associated with SLNs with a high copy numbers (�2000) of 

CK19 mRNA together with HER2 subtype. Otherwise none of the luminal A 

patients with a positive SLN but presenting a copy number �1000, had a 

positive NSLNs. Conclusions: We showed that biologically-driven analyses 

may be able to build new models with higher performance in terms of breast 

cancer axillary status prediction after positive SLN biopsy for micrometastasis. 

The copy numbers of CK19 mRNA and the molecular subtypes are 

more advantageous than traditional parameters because they are not 

pathologist-dependent and therefore they are more reliable and reproducible. 



A prognostic model for predicting breast cancer (BC)-related survival in 

operable triple-negative (TN) patients (pts). Presenting Author: Elisabetta 

Munzone, European Institute of Oncology, Medical Oncology, Milan, Italy 

Background: TNBC represent a heterogeneous disease in terms of biology, 

prognosis, and treatment response. We propose a prognostic model to 

identify homogeneous subgroups of patients and tailor risk-adapted adjuvant 

therapies indications. Methods: We analyzed 1,049 pts operated in our 

institute from 1997 to 2007 for early TNBC. Pts who received neoadjuvant 

chemotherapy (CT), with T4 tumors or previous history of cancer were 

excluded. Death from BC was the primary endpoint of the study. We 

calculated an individual predicted risk using a multivariable Cox regression 

model, with age, tumor size, number of positive lymph nodes and Ki-67 

analyzed as continuous covariates, and tumor grade and perivascular 

invasion as categorical covariates. Results: Median age was 52 years, 562 

(53.4%) and 670 (65.1%) pts had a pT1 and pN0 TNBC, respectively. 

Median Ki-67 was 48%. Adjuvant CT regimens were distributed as follows: 

classical CMF 388 (37.0%), anthracycline containing regimens 455 

(43.4%), taxanes 12 (1.1%), other regimens 66 (6.3%) and no CT 128 

(12.2%). After a median follow-up of 6 years, 131 deaths from BC were 

observed (5-year cumulative incidence 11.9%). At multivariable analysis, 

age, tumor size, number of positive lymph nodes, Ki-67, tumor grade and 

perivascular invasion were associated with the risk of death and were 

included in the prognostic model. Its predictive accuracy was good (C-index 

0.73). We subsequently identified three homogeneous prognostic subgroups 

- low, medium and high-risk - according to the tertiles values of the 

predicted risk. The outcomes are shown in the table. Conclusions: We could 

identify homogeneous prognostic subgroups of TNBC pts according to 

clinical-pathological features. This prognostic model suggests that the use 

of CT in TN low-risk pts might be questionable. We are currently externally 

validating this model on a different series of pts. 

Risk subgroup Treatment No. (%) 

Deaths 

from BC 

61s 

5-year 

survival % P value 

Low-risk CT 262 (75.1) 15 95.5 0.72 

No CT 87 (24.9) 4 96.2 

Medium-risk CT 326 (93.1) 31 91.0 0.29 

No CT 24 (6.9) 4 81.6 

High-risk CT 334 (95.4) 70 78.8 0.03 

No CT 16 (4.6) 7 53.9 


Impact of biomarkers in predictivity of the efficacy and toxicity of a 

combination of panitumumab plus FEC 100 followed by docetaxel in a 

phase II neoadjuvant trial for triple-negative breast cancer (TNBC) patients. 

Presenting Author: Jean-Marc Nabholtz, Centre Jean Perrin, Clermont- 

Ferrand, France 

Background: We evaluated the combination of a standard chemotherapy 

with panitumumab as neoadjuvant therapy of operable TNBC. Complete 

pathologic response (pCR) was the primary endpoint, with toxicity and 

biologic ancillary studies as secondary endpoints. Methods: Sixty patients 

with stage II-IIIA disease were prospectively included in this multicentre 

pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 

(500/100/500 mg/m2 ) q.3 weeks followed by 4 cycles of T (100 mg/m2 ) 

q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 

weeks. All patients underwent surgery at completion of ST. Paraffinembedded 

samples and frozen samples have been systematically realised 

before and after neaodjuvant treatment in order to evalutate the biological 

profile of the tumor. Patients characteristics are : median age 50 ; median 

tumor size : 40 mm ; invasive ductal carcinoma : 96% ; Scarff-Bloom- 

Richardson Grade III : 70%, grade II : 30%, ki-67-positive : 100%, 

EGFR-positive : 78%, cytokeratine5-6-positive : 48% and p53-positive : 

59%. Pathological response showed a pCR according to Sataloff’s classification 

of 52.38% and according to Chevallier’s classification of 46.52%. 

Skin toxicity was the main side-effect : Cutaneous toxicity grade IV : 5%, 

grade III : 30%, grade II : 20%. Neutropenia grade IV : 27% ; febrile 

neutropenia : 5%. Infection : 0%. Hand-foot syndrome grade III : 3.3%. 

Ungueal toxicity grade III : 1.6%, grade II : 20%. Results: We have tested 

the predictive value of ki-67, EGFR, cytokeratine 5-6 and p53. Only ki-67 

is predictive of a pCR according to Chevallier’s classification (p�0.026), 

with a cut-off of 40% of positive cells (ROC curve): 62% of pCR if ki-67� 

40% versus 23% if not (relative risk : 2.7). Low EGFR, high p53, and high 

cytokeratine 5-6 tended to be associated with poor reponse. No correlations 

were found between cutaneous toxicities and these biomarkers. The 

cutaneous toxicities were not predictive. Conclusions: HighKi-67 is predictive 

of more pCR. High EGFR, low p53 and low cytokeratine 5-6 tended to 

be associated with better response, but the data are not significant. 




Effect of therapeutic targeting of the oncogene EMP2 in triple-negative 

breast cancer on tumor load. Presenting Author: Madhuri Wadehra, 

DGSOM at UCLA, Los Angeles, CA 

Background: Understanding tumor induced angiogenesis is a challenging 

problem with important consequences for the diagnosis and treatment of 

cancer. In this study we define a novel function for the tetraspan epithelial 

membrane protein-2 (EMP2) in the control of neoangiogenesis. EMP2 is an 

oncogene whose expression has been shown to correlate with tumor 

progression and survival in a number of human cancers including triple 

negative breast, ovarian, and endometrial tumors. In breast cancer, EMP2 

is highly expressed on the majority of invasive tumors examined, and in 

particular 70% of triple negative breast tumors showed surface expression 

of this marker. In this study, we examine the control of EMP2 on the tumor 

microenvironment and further characterize its therapeutic efficacy in 

breast cancer. Methods: A number of cancer cell lines were utilized both in 

vitro and in vivo to determine if EMP2 expression levels altered the tumor 

microenvironment. Cells were tested for their expression of pro-angiogenic 

proteins HIF-1a and VEGF-A as well as for their ability to induce endothelial 

cell migration and capillary like tube formation. Cells with modulated 

EMP2 levels were also tested in vivo for tumor formation and examined for 

histological changes in the tumor microenvironment. In addition, we 

recently constructed a fully human EMP2 IgG1 and determined its 

therapeutic efficacy in a number of triple negative breast cancer cells. 

Results: In vitro, upregulation of EMP2 promoted VEGF expression through 

a HIF-1a dependent pathway and resulted in successful capillary-like tube 

formation. In contrast, reduction of EMP2 correlated with reduced HIF-1a 

and VEGF expression with the net consequence of poorly vascularized 

tumors in vivo. Treatment of breast cancer cells with EMP2 IgG1 reduced 

tumor load with a significant improvement in survival. Conclusions: Clinically, 

EMP2 has been shown to correlate with poor survival, and these 

results suggest that this occurs in part through its control on tumor 

vasculature. In addition, we provide additional evidence on the potent 

cytotoxic effects of EMP2 treatment in vivo. 


Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. 

Presenting Author: Takafumi Sangai, University of Texas M. D. Anderson 


Background: Akt significantly contributes to cancer pathogenesis. PTEN, a 

negative regulator of PI3K/Akt signaling, is mutated or decreased, and 

PIK3CA is frequently mutated in multiple cancer lineages. We hypothesized 

that MK-2206, an allosteric Akt inhibitor, would inhibit Akt 

signaling thus blocking cancer cell growth, and PTEN and/or PIK3CA 

mutations may confer MK-2206 sensitivity in breast cancer. Methods: After 

determining sensitivity to MK-2206 in16 cell lines, the effect on Akt 

signaling was tested by reverse-phase protein array analysis and western 

blotting. The effect to cell cycle progression and cell death were analyzed 

by flow cytometry. Using RNA knockdown technique, the effect of PTEN, 

PIK3CA and Akt on MK2206 sensitivity was tested. Anti-tumor effect in 

vivo with or without paclitaxel was tested using PTEN-mutant ZR75-1 

breast cancer xenografts. Results: MK-2206 inhibited Akt signaling and 

cell cycle progression, and increased apoptosis in a dose-dependent 

manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA 

mutations were more sensitive to MK-2206 (P�0.0337), however, a 

number of lines with PTEN/PIK3CA mutations were MK-2206-resistant. 

Small interfering RNA (siRNA) knockdown of PTEN in breast cancer cells 

increased Akt phosphorylation concordant with increased MK-2206 sensitivity. 

Stable transfection of PIK3CA E545K or H1047R mutant plasmids 

into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell 

lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and 

had less growth inhibition with Akt siRNA knockdown. In ZR75-1 xenografts, 

MK-2206 treatment inhibited Akt signaling, cell proliferation, and 

tumor growth. In vitro, MK-2206 showed a synergistic interaction with 

paclitaxel in MK-2206-sensitive cell lines, and this combination had 

significantly greater antitumor efficacy than either agent alone in vivo. 

Conclusions: MK-2206 has antitumor activity alone and in combination 

with chemotherapy. This activity may be greater in tumors with PTEN loss 

or PIK3CA mutation, providing a strategy for patient enrichment in clinical 

trials. However, not all tumors with PIK3CA/PTEN aberrations are MK-2206sensitive, 

emphasizing the need for additional markers of response. 


Clinical characteristics and chemotherapy options of triple-negative breast 

cancer: Role of classical CMF regimen. Presenting Author: Min Hee Hur, 

Department of Surgery, Kwandong University College of Medicine, Cheil 

General Hospital, Seoul, South Korea 

Background: Triple-negative breast cancer is a high risk breast cancer that 

lacks the benefit of specific targeted therapy. We investigated the clinicopathologic 

characteristics between triple-negative breast cancers (TNBC) 

and non-TNBC. And we also analyzed the effect of chemotherapy options 

such as classical CMF regimen, anthracycline-based, or taxane-based 

chemotherapy. Methods: A total of 826 invasive breast cancer patients were 

evaluated from March 2003 to December 2008. We investigated them 

retrospectively, who had the median follow-up for 88 months. We examined 

the differences between TNBC compared with non-TNBC in relation to the 

clinicopathologic parameters, chemotherapy regimen, overall survival (OS). 

Results: 156 (18.9%) cases among 826 patients were triple negative breast 

cancers. There were significantly positive associations with younger age 

(below 35 years), large tumor (�2cm), high stage, poorly differentiated 

nuclear grade, poorly histologic grade in TNBC. Positive lymph node, 

lymphovascular invasion were not significantly different between TNBC and 

non- TNBC. A total of 677 patients were treated with chemotherapy. In 

TNBC patients, 142 (93.4%) patients were treated with chemotherapy 

more than in 535 (61.4%) of non- TNBC patients. The chemotherapy in 

TNBC patients was composed of classical CMF (47.9%), anthracyclinebased 

regimen (25.4%), taxane-based regimen (26.8%). 19 cases (12%) 

of TNBC experienced locoregional or systemic metastases. 48 (7.2%) 

patients of non- TNBC did local or systemic metastases. Patients with 

TNBC had worse 5-year OS than with non-TNT (95.7% vs 98.6%, 

p�0.01). Interestingly, patients treated with CMF regimen were better 

5-year OS than with anthracycline-based, or taxane-based regimen in 

TNBC (100% vs 96.9% vs 89.2%, p�0.001). There was no survival 

difference among chemotherapy regimens in non-TNBC patients. 

Conclusions: Patients with TNBC have poor prognosis compared with 

non-TNBC. Classical CMF regimen for TNBC patients may be more 

effective than anthracycline-based or taxane-based regimens. 


Preclinical evaluation of selective inhibitors of nuclear export (SINE) in 

basal-like breast cancer (BLBC). Presenting Author: Dilara McCauley, 

Karyopharm Therapeutics, Boston, MA 

Background: Basal-like breast cancers (BLBC) compose up to 15% of breast 

cancer (BC) and are usually triple negative characterized by lack of ER, PR, 

and HER-2 amplification. In addition, most BRCA1-associated BCs are 

BLBC and TNBC, expressing basal cytokeratins and EGFR. BLBC is 

characterized by an aggressive phenotype, high histological grade, and poor 

clinical outcomes: high recurrence and metastasis rates. CRM1 (XPO1) is 

the exclusive nuclear exporter of multiple Tumor Suppressor Proteins (TSP) 

including p53, p21, BRCA1&2, pRB, FOXO. CRM1 inhibition forces 

nuclear accumulation of TSPs, inducing apoptosis in cancer cells. KPT- 

SINE are novel, small molecule, irreversible inhibitors of CRM1 with potent 

anti cancer activity. Methods: The Cancer Genome Atlas (TCGA) and BC cell 

line databases were used for mRNA analyses. MTT assay was used to 

determine the cytotoxic effect of KPT-SINE (KPT-185 and KPT-330) on 44 

breast cell lines including luminal A, luminal B, HER2 positive, BLBC and 

TNBC cells. The effect of KPT-330 treatment on tumor growth was tested 

in vivo in the TNBC model MDA-MB-468 xenograft. Results: Analyses of 

nuclear pore complex (NPC)-related mRNA levels (including CRM1) 

showed clear separation of BCs into high and low NPC expression. BLBC 

subtype was enriched with high NPC transcripts while luminal BC was 

enriched in low NPC levels (p�1.53e-20). High NPC levels had higher 

mutation levels in BRCA2 (cor�0.33, p�1.83e-8) and ABL1. NPC 

expression was inversely correlated with ER mRNA expression (cor�-0.58, 

p�1.37e-7). KPT-SINE showed potent cytotoxicity on �75% of the cell 

lines (IC50 values �1 �M). Only three of 24 TNBC cell lines displayed IC50 values �1.5 �M upon KPT-SINE treatment. Genomic analyses on all BC 

lines indicated that p53, PI3K/AKT and BRCA1 or 2 status did not affect 

cytotoxicity. In MDA-MB-468 xenograft, KPT-330 displayed efficacy in a 

dose-dependent manner inhibiting nearly 100% of tumor growth compared 

with vehicle treated animals, and was well tolerated. Conclusions: These 

data show that NPC/CRM1 mRNAs are overexpressed in BLBC/TNBC and 

that CRM-1 mediated nuclear export inhibition by SINE represents a 

potentially novel and well tolerated therapy for BLBC / TNBC. 



The role and significance of FoxM1 in invasive breast cancer. Presenting 

Author: Cha Kyong Yom, Department of Surgery, Seoul National University 

Bundang Hospital, Seoul National University College of Medicine, Seongnam, 

South Korea 

Background: The Forkhead Box protein M1 (FoxM1) is known to regulate a 

variety of biologic processes in mammalian cells including cell growth and 

survival, angiogenesis, DNA damage response, chemotherapeutic drug 

resistance, and cancer cell migration and invasion. We evaluate the role 

and significance of Fox M1 in primary breast cancer in vitro and analyzed 

the relation with FoxM1 expression and clinicopathologic features. Methods: 

Immunohistochemical staining was used for evaluation of cytoplasmic 

expression of FoxM1 with TMA of invasive breast cancer. In various breast 

cancer cell lines, we evaluated FoxM1 expression and treated docetaxel/ 

cisplatin in combination with Siomycin A (FoxM1 inhibitor) for BT20 cell 

line. Results: From Nov 1995 to Jul 2007, in 84 patients with stage 1-3 

invasive breast cancer, FoxM1 expression was noted in 58.7%. Median 

follow-up duration was 85.1 months. Lymphovascular invasion was positively 

correlated with FoxM1 expression (p�0.040). In multivariate analysis, 

FoxM1 expression (p�0.005), HR negativity (p�0.002), high histologic 

grade (p�0.023), hign nuclear grade (p�0.045), lymphovascular invasiveness 

(p�0.017), and stage 3 cancer (p�0.015) matched poor disease-free 

survival. In vitro study, FoxM1 was expressed BT474, JIMT-1, BT20, 

HCC-1937, and MDA-MB-231 cell lines. The inhibition of FoxM1 had 

synergistic effect on cisplatin treatment, not docetaxel in BT20 cell. 

Conclusions: FoxM1 expression was noted in triple negative breast cancer 

cell lines and its inhibition had synergistically cytotoxic effect on BT20 cell 

line in combination with cisplatin. Although the further in vivo and clinical 

study should be needed to draw the solid conclusions, FoxM1 could be both 

a promising target of treatment for triple negative breast cancer and a 

independent prognostic factor. 


Next-generation sequencing mutational analysis of triple-negative breast 

cancer patients from matched FFPE and fresh frozen samples. Presenting 

Author: Mark Landers, AltheaDx, San Diego, CA 

Background: TNBC is an aggressive subtype of breast cancer accounting for 

10-15% of all cases. TNBC tumors (ER-/PR-/HER-) are more common in 

patients with BRCA mutations. BRCA mutations leading to homologous 

DNA repair deficient tumors enhance the efficacy of chemotherapy and 

PARP inhibitors. BRCA mutations have been identified in 20% of patients 

without family history. Identification of germline and somatic BRCA 

mutations in unselected patients could increase the number of patients 

who benefit from these therapies. Determining BRCA mutational status 

from FFPE and fresh frozen specimens may enable clinical studies in these 

patient populations.We describe the development of an NGS BRCA 

mutational assay compatible with FFPE and fresh frozen samples using 

tumor/adjacent normal matched tissues. Methods: Matched samples were 

purchased from Cureline. gDNA was isolated by lysis/column purification 

(Qiagen) and enriched for BRCA exons/flanking regions (Halogenomics 

Selector). Fragment libraries were constructed (Ion Torrent frag express) 

and prepared for sequencing by emPCR (Ion Torrent Template Xpress). 

Libraries were sequenced for 65 cycles (Ion Torrent PGM) yielding 2-4M 

reads/sample. Variants were called from tMAP aligned reads by GATK and 

VarScan. Overlapped exonic variants were filtered by p-value (�0.0001) 

from VarScan. Results: In the first patient set normalized average depth of 

BRCA exon coverage was 64X and 72X per 150K reads in FFPE and fresh 

frozen tissues respectively covering 95-100% of target. hg19 alignment 

rates varied between 97-99% across all samples. Similar numbers of 

variants were called in both FFPE (12) vs. fresh frozen (13) with a 

corresponding mean duplicate removed depth of coverage of 23.3X and 

42.4X at the called positions. 10/13 calls in fresh frozen overlapped with 

those in FFPE. A tumor specific somatic frameshift insertion in BRCA2 was 

detected in both FFPE and fresh frozen tissues. Conclusions: Results 

indicate that NGS mediated BRCA mutational analysis demonstrates 

equivalent utility in both FFPE and fresh frozen tumor samples although 

more sequencing reads are required to produce equivalent depth of 

coverage starting from FFPE samples. 


63s 


Use of gene expression and alternative splicing signatures to discriminate 

breast cancer stem cells from fibroblasts. Presenting Author: David T. 

Weaver, Verastem Inc, Cambridge, MA 

Background: Tumors frequently contain cancer stem cells (CSCs) or 

tumor-initiating subpopulations, with an ability to self-renew and regenerate 

all cell types within the tumor. Basal-like breast cancers exhibit 

features of CSCs, including expression of surface markers, even though 

these cells are rare. Given the role of CSCs in the recurrence and spread of 

cancer, there is an urgent need to develop new therapeutic agents that 

target CSCs. Development of CSC-targeted drugs will be greatly facilitated 

by biomarkers that can identify CSCs to aid in patient selection and 

determination of drug response. Defining the CSCs in tumors is complicated 

by the high mesenchymal nature of fibroblasts. Analysis of gene 

expression and alternative splicing patterns in CSCs that are not observed 

in fibroblasts may provide valuable new CSC-specific markers. Methods: 

Alternative splicing and gene expression microarray strategies were used to 

identify selected exons and differentially expressed genes between 10 

Basal human breast cancer cell lines and a combination of 12 Luminal and 

3 fibroblast cell lines. Q-PCR analysis was conducted to determine 

candidate CSC gene differential expression between Basal, Luminal, and 

Fibroblast cells lines. Results: Expression levels of 11 genes were higher 

and 24 genes were lower in the Basal cell lines versus Luminal or 

fibroblastic cell lines. Comparison of Basal cell lines to the Luminal/ 

Fibroblast cell lines identified 36 cassette exons that were included, and 

26 that were excluded in Basal cell lines. Also, 19 genes were upregulated 

in Basal cell lines compared to the other groups as detected by Q-PCR. 

Interestingly, the 19-multigene model defined the Triple Negative Breast 

Cancer patients that were Likely to Recur under standard chemotherapy 

with a p � 1.90e-03 and AUC 0.723. Conclusions: Gene and exon marker 

sets distinguish CSC versus fibroblasts and may be instructive in identifying 

patients that recur early in Triple Negative Breast Cancer. The CSCassociated 

RNA signatures identified here will be further refined to develop 

new CSC-specific diagnostic markers to stratify breast cancer patients and 

monitor response to novel CSC-targeted therapies. 


A randomized phase II trial of doxorubicin plus pemetrexed followed by 

docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel 

as neoadjuvant chemotherapy (NACT) for early breast cancer: Three-year 

follow-up data. Presenting Author: Andreas Schneeweiss, University Hospital 

Heidelberg, Heidelberg, Germany 

Background: NACT for early breast cancer allows in vivo chemosensitivity 

testing. Primary results of this randomized, non-comparative 2-arm study 

have been published (Schneeweiss et al, Ann Oncol 2011). Here we 

provide 3-year follow-up data for disease-free survival (DFS) and safety. 

Methods: 257 patients (pts) with untreated operable T2–T4a–c N0–2 M0 

breast cancer were randomly assigned to receive either four cycles of 

doxorubicin 60 mg/m² plus pemetrexed 500 mg/m² every 3 weeks (q3w) 

followed by four cycles of docetaxel 100 mg/m² q3w (AP-D; 135 pts), or 

four cycles of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² 

q3w followed by four cycles of docetaxel 100 mg/m² q3w (AC-D; 122 pts). 

Both arms were stratified according to hormone receptor (HR) status 

(estrogen and/or progesterone receptor positive vs both negative) and study 

center. Surgery was carried out within 2 months after last chemotherapy. 

Primary objective was pathological complete response (pCR) rate in the 

breast (ypT0/is). Secondary objectives included long-term efficacy and 

safety measures. DFS and adverse event data were collected from all 

patients for 3 years or until progression or death. The Kaplan-Meier (KM) 

analysis technique and Cox regression method were used as statistical 

measures. KM analyses were performed on HR-positive and -negative pts 

subgroups. Results: As reported earlier, pCR rates were 16.5% for AP-D and 

20.2% for AC-D. The 3-year DFS rate was 76% and 77% for AP-D and 

AC-D, respectively. Cox regression analysis for the overall enrolled population 

(regardless of treatment) revealed significantly longer DFS in HRpositive 

than in HR-negative pts (hazard ratio 0.35; 95% CI 0.22–0.58; p 

� 0.001). In HR-positive pts, the 3-year DFS rate was 88% (95% CI: 

81–95%) with AP-D and 83% (95% CI: 74–91%) with AC-D. In HRnegative 

pts, the 3-year DFS rate was 55% (95% CI: 40–70%) for AP-D 

and 68% (95% CI: 53–82%) for AC-D. The 3-year follow-up data did not 

reveal any changes in the safety profile compared to the previously 

published results. Conclusions: The 3-year DFS rates of both NACTs are in 

line with published studies. 




Phase II study of a novel neoadjuvant chemotherapy (NAC) for breast 

cancer (BC). Presenting Author: Miguel E. Albino, Veterans Affairs Hospital, 

San Juan, PR 

Background: The goal of this NAC study was to improve the pathologic 

response of pts with localized BC. Methods: 51 pts with localized BC �1cm 

were treated with this novel regimen consisting first of docetaxel 75 mg/m 2 , 

epirubicin 80 mg/m2 , and cyclophosphamide 500 mg/m2 (TEC) and PEG 

Filgrastim for 4 cycles. Pretreament PET scan was done and repeated after 

course 1. Following the 4th course, ER�/HER2- patients received 4 

additional TEC cycles if they achieved CR by MRI, or were switched to a non 

cross-resistant regimen (vinorelbine, bevacizumab, capecitabine) if they 

had � CR. HER2� pts were given docetaxel � trastuzumab for 4 additional 

cycles, or were switched to a different regimen if � PR. MD Anderson 

residual cancer burden (MDARCB) score was used to measure pathologic 

response and correlation with several prognostic factors was studied. 

Results: Median age � 53; 27 were postmenopausal; 42 had invasive 

ductal carcinoma, 5 invasive lobular; 12 triple negative, 11 HER2�, and 

28 ER� or PR�/HER2-. MDARCB was significantly better in HER-2� and 

triple negative tumors (table). ER� or PR�/Her2- pts had the least 

favorable MDARCB with none achieving 0 and only 21% attaining 

MDARCB�1. 59% of pts with � 5% SUV drop attained MDARCB score 0-1 

vs 13% with � 5% drop. %Ki-67 correlated well with MDARCB (table). 

Ki-67 correlated well with receptor status: 85% of Triple Neg or Her2� pts 

had Ki-67 �17 vs only 29% of ER� or PR�/Her2-. Conclusions: a) This 

novel NAC regimen leads to markedly favorable MDARCB scores in triple 

negative and Her-2� cases. b) Several factors may be useful in predicting 

response to chemotherapy, including receptor status, Ki-67, and PET scan 

response after 1st chemotherapy course. c) Ki-67 proliferative rate is 

closely correlated with receptor status. d) Early PET could be used to 

predict MDARCB. The challenge now is to improve response in ER� or 

PR�/Her2- pts. 

Factor 

MDARCB 

0 

MDARCB 

1 

MDARCB 

2 

MDARCB 

3 p N 

Triple neg or HER2� 18 (82%) 1 (5%) 2 (9%) 1 (5%) 22 

ER� or PR�/HER2- 0 6 (21%) 17 (61%) 5 (18%) 0.00001 28 

50* 

Ki-67 >17 13 (54%) 2 (8%) 8 (33%) 1 (4%) 24 

Ki-67 < 17 2 (9%) 5 (22%) 11 (48%) 5 (22%) .04 23 

% drop SUV > 5% 18 (44%) 6 (15%) 14 (34%) 3 (7%) 41 

% drop SUV < 5% 0 1 (13%) 4 (50%) 3 (38%) .04 8 

*One progressed in liver while on treatment and did not undergo surgery. 


Current patterns of chemotherapy and supportive care for early-stage breast 

cancer (ESBC). Presenting Author: Gary H. Lyman, Duke University, 

Durham, NC 

Background: ESBC is commonly treated with myelosuppressive chemotherapy, 

and high relative dose intensity (RDI) correlates with improved 

overall survival. A retrospective analysis of patients with ESBC treated from 

1997–2000 showed that 56% received an RDI � 85% (Lyman et al. JCO. 

2003;21:4524-4531). To determine current practice, we evaluated ESBC 

treatment patterns at 24 US community- and hospital-based oncology 

practices. Methods: Data were abstracted from medical records of 532 

patients with ESBC treated from January 2007–December 2009. Inclusion 

criteria included surgically resected ESBC (stage I-IIIA); � 18 years old; 

and completion of at least 1 standard chemotherapy cycle on an every 2 or 

3 week schedule. The primary endpoint was RDI over planned cycles. Other 

endpoints were incidence of dose delays � 7 days, dose reductions � 15% 

from standard, grade 3/4 neutropenia (SN), febrile neutropenia (FN), 

FN-related hospitalization, granulocyte-colony stimulating factor (G-CSF) 

use, and antimicrobial therapy. Descriptive statistics were generated for all 

endpoints. Results: In this study, mean (range) age was 55 (29–85) years. 

Relative to previously published results, chemotherapy regimens have 

shifted from mainly doxorubicin � cyclophosphamide (AC) (previously 

35%) to docetaxel � cyclophosphamide (TC; n � 221; 42%) and AC 

followed by paclitaxel (AC-T; n � 163; 31%). Mean RDI is now higher 

(93% for both TC and the most common AC-T schedule [dose dense AC-T; 

n � 84] vs 79% previously); the incidence of dose delays (16% vs 25% 

previously) and dose reductions (21% vs 37% previously) have decreased; 

and primary prophylactic use of G-CSF has increased (76% vs 3% 

previously). In this study, 40% of patients had SN, 3% had FN, 2% had an 

FN-related hospitalization, and 30% received antimicrobial therapy. These 

measures were not available in the previously published results. Conclusions: 

The observed changes between the two studies are noteworthy though 

inferential comparisons are limited by changes in treatments and other 

factors. RDI has improved over time, but 16% of patients in this study 

received an RDI � 85%. Further evaluation is needed to identify factors 

associated with lower RDI and determine outcomes for these patients. 


The first two lines of chemotherapy for anthracycline-naïve metastatic 

breast cancer: A comparative study of efficacy between anthracyclines and 

nonanthracyclines. Presenting Author: Wei-Wu Chen, National Taiwan 

University Hospital, Taipei, Taiwan 

Background: For anthracycline-naïve metastatic breast cancer (AN-MBC) 

patients, past evidence indicated that anthracyclines are beneficial in the 

first-two lines of palliative chemotherapy but with considerable toxicities. 

However, with the provision of newer chemotherapies, comparative studies 

addressing the efficacy between anthracyclines and non-anthracyclines in 

the first-two lines of palliative chemotherapy for AN-MBC were lacking. 

Methods: We collectedclinicopathological characteristics of AN-MBC patients 

who had received palliative chemotherapy in National Taiwan 

University Hospital between 2001 and 2006. Patients were classified as 

anthracycline or non-anthracycline group according to the first-two lines of 

chemotherapy. Kaplan-Meier method and log-rank test were used for the 

estimation and comparison of both overall survival (OS) and time to 

treatment failure of the first-two lines (TTF2).Cox proportional hazard 

model was used for OS and TTF2. Best composite response rate (BCRR) 

were compared with logistic regression test. Results: A total of 109 (43.1%) 

patients in the anthracycline group and 144 (56.9%) patients in nonanthracycline 

group were analyzed. Between these two groups, the distributions 

of clinicopathological variables were generally similar and their 

median OS (33.3 vs 34.2 months, p � 0.179), TTF2 (13.3 vs 12.7 

months, p � 0.104), and BCRR (59.5 vs 61.1%, p � 0.81) were not 

significantly different. Subgroup analysis showed that patients in the 

anthracycline group had a trend toward better OS in the estrogen receptor 

(ER) negative/ human epidermal growth factor receptor type II (HER2) 

positive subtype (median OS 58.0 vs 31.2 months, p � 0.081). In 

multivariate analysis, patients in the anthracycline group had a trend 

toward better OS (HR 0.72, 95% CI 0.52 - 1.00, p � 0.052). However, the 

exclusion of ER-/Her2� subtype attenuated the impact of early anthracycline 

treatment on OS (HR 0.82, 95% CI 0.56 - 1.18, p � 0.28). 

Conclusions: Our study demonstrated that anthracyclines may not be 

mandatory in the first-two lines of palliative chemotherapy for AN-MBC but 

may be more beneficial to ER-/Her2� subtype patients. 


Chemotherapy of methioninase-synchronized S/G2 phase-blocked cancer 

cells identified by cell cycle-specific fluorescent reporters. Presenting 

Author: Shuya Yano, AntiCancer Inc., San Diego, CA 

Background: Cancer cells of all types have a generally elevated requirement 

for methionine compared to normal cells. This phenomenon is termed 

methionine-dependence and may be due to excessive methylation reactions 

in cancer cells, since methionine is the global source of cellular 

methyl groups (Biochim. Biophys. Acta, Reviews on Cancer 738, 49-87, 

1984). Deprivation of methionine selectively arrests cancer cells during 

late S-phase (Proc. Natl. Acad. Sci. USA 77, 7306-7310, 1980), where 

they are highly sensitive to chemotherapy drugs which damage DNA (J. 

Natl. Cancer Inst. 76, 629-639, 1986). Methods: Cancer cells, transformed 

to express different color fluorescent reporters during specific 

phases of the cell cycle (Cell 132, 487-498, 2008), were used to monitor 

the onset of the S/G2-phase block due to methionine deprivation effected 

by recombinant methioninase (rMETase). The S/G2-phase blocked cancer 

cells fluoresced yellow or green in contrast to cancer cells in G1 which 

fluoresced red. Cancer cells, including MKN45 stromal cancer and MCF-7 

breast cancer, synchronously blocked in S/G2-phase by rMETase, were 

identified by their yellow-green fluorescence and allowed to accumulate to 

the maximum extent. At the point of maximum yellow/green cells in the 

culture, the cells were administered chemotherapy drugs which interact 

with DNA or block DNA synthesis such as doxorubicin, cisplatin or 

5-fluorouracil. We termed this procedure color-coded chemotherapy (CCC). 

Results: CCC was highly effective against the cancer cells (90% cell kill). In 

contrast, treatment of cancer cells with drugs only, and without rMETaseeffected 

S/G2-phase synchrony, led to the majority of the cancer cell 

population being blocked in G1 phase (red fluorescent) where they were 

resistant to the drugs (40% cell kill). Conclusions: CCC, which identifies, by 

fluorescent color, when cancer cells are blocked in S/G2-phase by a unique 

cell-cycle-blocking agent, rMETase, demonstrates the potential of cellsynchronization-based 

chemotherapy. 



Low-dose, short-course sunitinib may normalize tumor vasculature and 

improve tumor blood flow to enhance chemotherapy efficacy in breast 

cancers. Presenting Author: Soo-Chin Lee, National University Cancer 

Institute, Singapore, Singapore, Singapore 

Background: Small molecule VEGFR inhibitors (VEGFR-I) have failed to 

improve outcome with chemotherapy in most solid tumors. Continuous 

administration of a potent VEGFR-I may destroy vasculature and impede 

drug delivery; in contrast, low-dose, short-course VEGFR-I before chemotherapy 

may normalize tumor vasculature and enhance drug delivery. 

Methods: We conducted a phase Ib followed by phase II randomized study 

in patients with measurable primary breast tumors using low-dose sunitinib 

(Su) for 1 week prior to doxorubicin/cyclophosphamide (AC) and measured 

tumor blood flow with DCE-MRI and microvessel density and pericyte 

recoverage with CD31 and �-smooth muscle actin (SMA) staining on tumor 

biopsies, at baseline, after 1 week of Su, and 2 weeks after cycle 1 AC. 

Patients in phase Ib received 12.5-25mg Su prior to AC; in phase II, 

patients were randomized to AC�/-12.5mg Su. Results: 21 patients have 

been enrolled, including 3 patients on 25mg Su�AC, 11 on 12.5mg 

Su�AC, and 7 on AC alone. After 1 week of 25mg Su, 2/3 patients had 

reduced tumor blood flow on DCE-MRI indicating anti-angiogenic effects. 

After 1 week of 12.5mg Su, significant increase in tumor fractional plasma 

volume (Vp) occurred (�28%�28%, p�0.025) suggesting increased 

perfusion, followed by decrease 2 weeks after AC (-33%�26%,p�0.035) 

corresponding to mean tumor size change of -17�15%, while no significant 

Vp changes occurred with AC alone (p�0.823); CD31 expression 

reduced (20.7 vs 15.7, p�0.173) while SMA/CD31 double staining 

increased (2.45 vs 7.34, p�0.046) indicating lower microvessel density 

and normalization of residual vasculature, which was not seen with AC 

alone (CD31, p�0.434; CD31/SMA, p�0.605). The main toxicity of 

Su�AC and AC alone was febrile neutropenia (29% vs 43%). 14 patients 

had surgery with pathological complete response in 1/6 patients who 

received 12.5mg Su�AC. Conclusions: 25mg Su for 1 week can reduce 

tumor blood flow, suggesting that concomitant standard dose Su may 

compromise drug delivery. Low dose 12.5mg Su for 1 week is sufficient to 

normalize tumor vasculature and increase tumor fractional plasma volume, 

and may potentially improve drug delivery and treatment outcome. 


Early changes in angiogenesis and hypoxia following bevacizumab therapy 

in primary breast cancer. Presenting Author: Shaveta Mehta, University 

Department of Oncology, Oxford, United Kingdom 

Background: Bevacizumab (BV), a monoclonal antibody directed against 

vascular endothelial growth factor (VEGF), is an approved anti-angiogenic 

agent, but despite its widespread use, little is known about how tumours 

develop resistance to BV. We have conducted a window-of-opportunity 

study in which BV is administered as a short-term first-line treatment for 

primary breast cancer (PBC) patients, and assessed histological markers of 

tumour angiogenesis and hypoxia before and after therapy. Methods: 47 

patients with locally advanced breast cancer were prospectively enrolled. 

Informed consent was obtained from all patients. A single infusion of BV 

(15 mg/kg) was given 2 weeks before starting neoadjuvant chemotherapy. 

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 

core biopsies for immunohistochemistry (IHC) analysis were performed 

immediately prior to and 2 weeks after BV. 36 patients with invasive ductal 

carcinoma and good quality MRI scans and core biopsies were included in 

this analysis. Wilcoxon rank test and Spearman’s correlation test were used 

for statistical analysis. Results: IHC revealed a significant upregulation of 

carbonic anhydrase 9 (P � 0.04) and hypoxia inducible factor-1a (P � 

0.001) following BV therapy along with a significant reduction in plasmalemma 

vesicle associated protein (PLVAP) (p�0.01) and Ki67 (p� 0.006). 

DCE-MRI analysis revealed a significant reduction in vessel permeability 

and blood flow following BV, as measured by a decrease in the forward 

transfer constant Ktrans (P � 0.0001) and the reverse rate constant kep (P � 

0.0001). In addition, we found a significant negative correlation between 

CA9 levels and median Ktrans at baseline (Spearman’s rho � -0.46; P � 

0.01). Conclusions: Using combined DCE-MRI and IHC analysis, we found 

that PBC patients treated with single-agent BV showed a decrease in 

markers of tumour angiogenesis, together with a corresponding increase in 

tumour hypoxia. Our results suggest that tumour hypoxia may be a key 

mechanism governing the early onset of resistance to BV therapy, and argue 

for the use of suitable combination therapies to overcome the resistance 

and ultimately improve patient survival. 


65s 


Efficacy of low-dose capecitabine in metastatic breast cancer. Presenting 

Author: Caitlin Bertelsen, Keck School of Medicine of the University of 

Southern California, Los Angeles, CA 

Background: The FDA-approved dose of capecitabine (cape) of 1250mg/m2 twice daily (BID) is associated with treatment-limiting toxicities. Published 

reports suggest that lower starting doses of cape can be as effective as the 

approved dose in treating metastatic breast cancer (MBC). We compared 

the efficacy of lower than previously published doses of cape with results of 

registrational Phase III trials using the approved dose. Methods: We 

performed a retrospective analysis of patients treated at the University of 

Southern California hospitals who received cape as the first, second, or 

third line of chemotherapy for MBC to determine the progression-free 

survival (PFS) associated with low starting doses. The primary endpoint was 

PFS among patients with measurable disease, and secondary aims were to 

analyze the relationships between PFS and various clinical characteristics 

for all patients. Results: Patients (n�84) received a median cape dose of 

565 mg/m2 BID, often administered as a flat dose (not adjusted for body 

surface area) of 1000 mg BID. Median PFS among patients with measurable 

disease (n�62) was 4.1 months (95% confidence interval or CI � 

2.9-5.7), which was similar to the median PFS values of 4.4 months (95% 

CI � 4.14-5.42, n�480) (Sparano et al. JCO 2010;28:3256) and 4.2 

months (95% CI � 3.81-4.50, n�377) (Thomas et al. JCO 2008;25: 

5210) for single-agent cape reported in the major trials with similar 

eligibility criteria. Among all patients, PFS was shorter in measurable 

disease, triple negative and HER2� subtypes, and was similar in all lines of 

therapy. Only two patients (2.4%) discontinued cape due to toxicity. 

Conclusions: These data support the efficacy of very low doses of cape for 

MBC. Prospective randomized controlled trials testing lower starting doses 

of cape are needed to optimize the benefit/risk ratio. 

Variable Median PFS (mo) Multivariate PFS OR p value 

Entire cohort 4.4 

Non-measurable; measurable 19.7; 4.1 Ref; 1.6 0.13 

ER or PR�/HER2-; triple negative; HER2� 8.5; 3.0; 6.0 Ref; 3.2; 2.5 0.011 

DFI � 0; >0-5yr 3.0; 4.4; 8.5 Ref; 0.42; 0.36 0.031 

No trastuzumab; trastuzumab in HER2� 4.1; 9.6 Ref; 0.31 0.079 

OR � odds ratio; DFI � disease free interval; Ref � reference; yr � year. 


Accuracy of MRI, mammography (MG), and 2D and 3D ultrasound 

(2DUS/3DUS) in determining the pathologic tumor response after neoadjuvant 

chemotherapy (NACT) in breast cancer patients. Presenting Author: 

Markus Hahn, University Hospital Tuebingen, Department of Gynecology 

and Obstetrics, Tuebingen, Germany 

Background: The pathological tumor response in patients with locally 

advanced breast cancer to NACT is essential for survival and for surgical 

strategies. Therapy monitoring based on German recommendations is 

routinely performed by clinical examination, MG and 2DUS. The clinical 

value of MRI and 3DUS has not been established yet. The aim of the study 

was to determine the accuracy, sensitivity, specificity, positive predictive 

value (PPV), negative predictive value (NPV) between the different imaging 

techniques in predicting postoperative histological tumor response after 

NACT. Methods: Patients with primary breast cancer (cT1-T4, cN0-1, M0) 

undergoing neoadjuvant chemotherapy between 2005 and 2010 were 

eligible for this prospective trial. The response was measured by MRI, MG, 

2DUS and 3DUS for complete or partial remission versus stable disease 

after the last cycle of treatment and compared with the final pathological 

response. Patients with progressive disease were excluded from the study. 

Statistical analysis was done by calculating the accuracy of each imaging 

technique and the size difference between imaging and histological tumor 

size. Sensitivity, specificity, PPV and NPV were calculated for complete or 

partial pathological response. The study was approved by the local ethic 

committee (BCD001 194/2004). Results: 103 patients with the mean age 

of 47.7 (range 24.5 – 71.4) years were evaluated. The accuracy was 0.680 

(95%CI: 0.580 -0.768) for MRI, 0.563 (95%CI: 0.453-0.669) for MG, 

0.724 (95%CI: 0.618 -0.815) for 2DUS and 0.710 (95%CI: 0.588- 

0.813) for 3DUS. Sensitivity, specificity, PPV and NPV were 78%, 47%, 

75% and 52% for MRI, 61%, 45%, 69% and 36% for MG, 93%, 23%, 

74% and 60% for 2DUS, 94%, 19%, 73% and 57% for 3DUS. The mean 

(standard deviation) size difference was -1.8 mm (14.8) on MRI, 1.5 mm 

(26.0) on MG, -9.1mm (19.1) on 2DUS and for the volume difference 

-6916mm3 (15831) on 3DUS. Conclusions: The data suggest that 2DUS is 

sufficient in predicting tumor response between NACT treatment. MRI and 

MG are more accurate the 2DUS in predicting the tumor size for surgical 

planning. 




Patient-reported pain and other symptoms as prognostic factors for overall 

survival (OS) in a phase III clinical trial of patients with advanced breast 

cancer. Presenting Author: Wei Shen, Eli Lilly and Company, Indianapolis, 

IN 

Background: The safety and efficacy of gemcitabine plus paclitaxel versus 

paclitaxel in advanced breast cancer after anthracycline-based adjuvant 

therapy has been reported previously (Albain et al. 2008). This post-hoc 

analysis evaluates the prognostic effect of baseline scores of the Brief Pain 

Inventory short form (BPI-SF) and the Rotterdam Symptom Checklist 

(RSCL) on OS. Methods: Patients completed theBPI-SF and the RSCL. BPI 

“worst pain” item and BPI interference subscale scores range from 0 (no 

pain or interference with daily living) to 10. Four RSCL subscales were 

transformed to 0-100, with 100 as best score. Univariate Cox models were 

used to determine the prognostic effect of each measure on OS. Multivariate 

Cox models were used to determine the prognostic effect of each 

measure in the presence of 11 demographic/clinical variables, including 

Karnofsky performance status, age, and estrogen and progesterone receptor 

status. Kaplan-Meier curves and log-rank tests were used to compare OS 

among patient groups categorized using clinically meaningful thresholds 

and the sample median of the BPI and RSCL scores. Results: Randomized 

patients were evaluable for this analysis (n�529). In the univariate 

analysis, significant prognostic effects on OS were observed for baseline 

scores of both BPI measures (worst pain and interference) (HRs, 1.07 for 

1-point increase; all p�0.0042) and three out of four RSCL subscales 

(activity level, physical distress, quality of life) (HRs, 0.86-0.91 for 

10-point increase; all p�0.0120). In the multivariate Cox models, BPI 

worst pain remained as a significant prognostic factor (p�0.0245), as did 

RSCL activity level (p�0.0004). The median OS for patients with BPI worst 

pain score 0 (no pain) was 23.8 months (mos) versus 17.9 mos and 14.8 

mos for scores 1-4 (mild) and 5-10 (moderate/severe) (log-rank p�0.0066). 

The median OS was 23.8 mos for patients with RSCL activity scores greater 

than or equal to the sample median (�95.2) versus 14.6 mos for patients 

with scores �95.2 (log-rank p�0.0001). Conclusions: This retrospective 

analysis resulted in strong evidence that BPI-SF and RSCL provide distinct 

prognostic information for OS. 


Phase I trial of ixabepilone and vorinostat in metastatic breast cancer. 

Presenting Author: Thehang H. Luu, City of Hope, Duarte, CA 

Background: VOR, an HDAC inhibitor, induces acetylation of tubulin, and 

decreases resistance by attenuating downstream activation of AKT, c-Raf 

and HER-2. Patients (pts) with MBC treated with VOR had a TTP of 8.5 

months (range 4-14) and stable disease in 29% (Luu et al., 2008). Our 

preclinical data showed synergistic effect of IXA and VOR in MDA-MB-231 

and MCF7. Methods: The primary aims were to: 1) define the maximum 

tolerated dose (MTD) based on dose limiting toxicities (DLT), and 2) 

describe the pharmacokinetics (PK) of 2 schedules of VOR and IXA. 

Secondary aims were to describe: 1) response rate (RR) and 2) clinical 

benefit rate (CBR). The study included: 1) pts with MBC; 2) ECOG PS 0-2; 

3) adequate marrow and organ functions; 4) no prior IXA or VOR; and 5) � 

grade (gr) 1 neuropathy. Stable brain metastasis were allowed. Pts were 

randomized to schedule A: VOR (QDx14) � IXA (D2) Q21D; or B: VOR 

(D1-7 and 15-21) � IXA (D2, 9, 16) Q28D. A modified toxicity probability 

interval design (target toxicity rate� 0.2 and equivalence range �/- 0.05) 

(Ji et al, 2010) determined dose escalation guidelines. PK were assessed 

with LC-MS/MS assays. Results: Among 37 pts randomized, 36 were 

evaluable [median age (55 yrs); median prior chemotherapy regimens (3); 

ER and/or PR � (64%); HER2 � (19%)]. In cohort A, 16 pts were treated 

(1 inevaluable). The MTD was: VOR 300mg (QDx14) � IXA (32mg/m2 D2) 

Q21D (dose level 1). DLT was experienced by 27% (4/15) pts [gr 4 

neutropenia, gr 3 fatigue/AST, hyponatremia and allergic reaction to IXA]. 

In cohort B, 21 pts were treated (dose level 1, n�15; dose level 2, n�6). 

The MTD was VOR 300mg QD (D1-7 and 15-21) � IXA 16mg/m2 (D2, 9, 

16) Q28D (dose level 1), no DLTs were observed. Dose level 2 was closed 

with 50% (3/6) of pts experiencing DLTs [gr 3 neutropenia, hypertension, 

and hypokalemia]. Median cycles treated (cohort A: 6, cohort B: 4). 

Response in cohort A and B respectively was: 1 CR, 2 PR, 7 SD (RR: 20%, 

CBR: 67%) and 1 CR, 4 PR, 9 SD (RR: 33%, CBR: 93%). VOR and IXA PK 

were not influenced by the presence of the other drug, clearance values� 

220 L/h and 20 L/h/m2 , respectively. Conclusions: We established the MTD 

of VOR and IXA in pts with MBC. The combination demonstrated clinical 

activity in these heavily pretreated pts. Further studies are recommended. 


Cost-effectiveness analysis using a Markov model assessing the addition of 

bevacizumab to paclitaxel in HER2-negative metastatic breast cancer 

patients. Presenting Author: Tamer Refaat, Northwestern University, Chicago, 

IL 

Background: Metastatic breast cancer (MBC) remains an incurable disease 

despite advances in treatment modalities. In 2008, Eastern Cooperative 

Oncology Group 2100 trial (E2100) results led to FDA approval for 

bevacizumab with paclitaxel in the initial treatment of HER2-negative 

MBC. The addition of bevacizumab to paclitaxel led to a gain of around 2.5 

months of progression-free survival (PFS), no significant benefit on overall 

survival (OS), and increased toxicity. In November 2011, the FDA officially 

revoked approval of bevacizumab for HER2-negative MBC. However, both 

the European Medicines Agency (EMEA) and NCCN still endorse bevacizumab 

for this indication. One of the greatest challenges facing healthcare 

worldwide is reconciling incremental clinical benefits with exponentially 

rising costs. This study aimed to assess the cost-effectiveness of bevacizumab 

with paclitaxel for HER2-negative MBC. Methods: A Markov decision 

tree using Data 3.5 (TreeAge Software, Inc.) was created to do decision and 

cost-effectiveness analyses of using bevacizumab in combination with 

paclitaxel versus paclitaxel alone as first-line chemotherapy in HER2negative 

MBC using efficacy and toxicity data from the E2100 study. Costs 

were obtained from the Center for Medicare Services Drug Payment Table 

and Physician Fee Schedule. The model was designed from the patient and 

payer perspectives and sensitivity analyses were run. Results: The marginal 

cost between paclitaxel alone versus bevacizumab and paclitaxel was 86K 

with a marginal efficacy of 0.369 quality-adjusted life-years and marginal 

cost effectiveness of 232,720.72 USD. The expected outcome value was 

1.86 for bevacizumab and paclitaxel and 1.67 for paclitaxel alone. 

However, the combination was not cost effective and only a marginal 

survival advantage that was not significant was observed. Conclusions: This 

study demonstrates that, despite a significant PFS advantage, the addition 

of bevacizumab to paclitaxel is not cost-effective for patients with HER2negative 

MBC. Such data could be informative to policymakers who 

consider the health economics and incremental cost-effectiveness of 

medical therapies. 


Outcomes of 47 patients with human immunodeficiency virus infection 

treated for breast cancer: A 20-year experience. Presenting Author: Roberto 

Enrique Ochoa, University of Miami, Miami, FL 

Background: Patients (pts) with Human Immunodeficiency Virus (HIV) are 

living longer and non-AIDS defining malignancies have been increasingly 

reported in these patients. Methods: Retrospective review identified 47 pts 

with breast cancer (BC) and HIV who were seen at the University of Miami 

Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital between 

January 1999 and June 2011. Results: Pt characteristics: 46 

female, 1 male, mean age 46 years (range 31-65). Race: African American 

79%, Caucasian 21%. Ethnic: Hispanics 14%, non-Hispanics 86%. 

Premenopausal 68% postmenopausal 32%. Tumor characteristics: Stage: 

Tis 4%, Stage I: 6%,Stage II: 38%, Stage III: 38%, Stage IV: 9%. ER 

positive (50%) her-2 positive (15%), Triple negative (21%). HIV characteristics: 

36 pts with HIV before or concurrent with the diagnosis of BC. 6 pts 

diagnosed with HIV within 1 year of BC diagnosis. HIV dx date unavailable 

in 5 pts. 27% had AIDS. CD4 counts (in cells/�L)were: � 500 (23%); 

201-500 (37%), 51 – 200 (20%) � 50 (20%). 15 pts were diagnosed with 

BC in preHAART era. Of those dx with BC after 1996, 60% were on HAART. 

BC treatment: 43 pts had localized disease. 32 underwent modified radical 

mastectomy, 8 breast conservation and 3 pts refused surgery. 26 pts 

received curative or palliative chemotherapy. Complications of BC treatment: 

serious side effects were reported in 11 (42%) including neutropenic 

fever/sepsis (10 pts), ARDS (1 pt). Zoster infection was reported in 12% of 

the pts. 3 patients developed rapidly progressive and fatal AIDS within 6 

months of completion of chemotherapy. Survival: See Table. Conclusions: 

BC in patients with HIV infection spans the spectrum of BC presentations. 

Hormonal therapy, surgery and radiation therapy were well tolerated. 

Infectious complications were common in patients treated with chemotherapy 

and routine use of growth factors and prophylactic acyclovir should 

be considered. 

Alive (% pts) Died BC (% deaths) Died HIV (% deaths) 

Tis 3 1 (50) 1 (50) 

Stage I 3 (100) 0 0 

Stage II 8 (50) 3 (38) 4 (50) 

Stage III 3 (28) 4 (67) 2 (33) 

Stage IV 0 4 (100) 0 



Prognostic impact of weight change during chemotherapy. Presenting 

Author: Nikola S. Kasprowicz, Department of Gynecology and Obstetrics, 

Heinrich Heine University, Duesseldorf, Germany 

Background: Besides established prognostic factors such as tumor size or 

nodal status, individual host factors of the patient such as obesity, physical 

activity and diet seem to modulate the course of breast cancer (BC) as well. 

However, the specific impact of weight change during adjuvant chemotherapy 

remains unclear. The aim of this analysis was to evaluate the 

influence of weight change during chemotherapy on BC survival in a large, 

multi-center prospectively randomized trial. Methods: The ADEBAR trial 

compares two anthracycline based adjuvant chemotherapy regimen in 

patients (pts) with lymph node positive ( � 3 positive) early BC: 4 x 

epirubicin (E) 90 mg/m2 � cyclophosphamide (C) 600 mg/m2 q3w 

followed by 4 x docetaxel 100 mg/m2 q3w versus 6xE60mg/m2 � 5-FU 

500 mg/m2 d1�d8 and C 75 mg/m2 d1-14 q4w. Weight was measured 

before each cycle. The weight before the 1st and the 6th cycle was assessed. 

Significant weight change was defined as increase or decrease of � 5% of 

the initial weight. Overall survival (OS), disease free survival (DFS), and BC 

specific survival (BCSS) were assessed by Kaplan-Meier analysis. Results: 

In total, 1502 pts were included in the study. 1177 of them completed 6 

cycles of chemotherapy. Out of the 350 pts (29.7%) who changed weight 

142 pts (12.1%) lost and 208 pts (17.7 %) gained weight. There was a 

significant correlation between weight change and menopausal status 

(p�0.0001), indicating that more premenopausal pts gained and postmenopausal 

pts lost weight. All other tumor characteristics were similarly 

distributed across the groups. Pts with weight change � 5% showed a 

significantly worse outcome with respect to OS (p � 0.0028) and BCSS (p 

� 0.0258). A difference in DFS was not observed (p � 0.1917). The 

difference in OS was limited to pts who lost weight (p � 0.0008), whereas 

pts with weight gain have no significant different OS (p � 0.1246) in 

comparison to pts with constant weight. Conclusions: Our results suggest 

that weight loss during anthracycline-based treatment of early stage BC is 

associated with poorer OS. While weight normalization has shown beneficial 

effects in lifestyle intervention trials, patients should be advised not to 

lose weight during chemotherapy. 


Impact of the delivery of adjuvant anthracycline-based nontaxane chemotherapy 

schedules on the outcome of breast cancer patients: Results from a 

retrospective database analysis. Presenting Author: Isabel Chirivella, Hospital 

Clinico Universitario, Valencia, Spain 

Background: A dose-response effect has previously been observed with CMF 

and anthracycline-based schedules. The objective of this post-hoc analysis 

was to give additional information on the impact of chemotherapy delivery 

on patients’ outcome. Methods: Selection criteria were to have early breast 

cancer (stage I-IIIA) from Jan 1980 to Dec 2000, to undergo surgery as 

primary treatment and to receive an anthracycline-based non-taxane 

schedule in the adjuvant setting. G-CSF support was not given to any 

patient. Chemotherapy delivery was assessed based on � 2 vs. � 2 delayed 

cycles, � 15 vs. �15 delayed days and � 85% vs. � 85% of the relative 

dose intensity (RDI) given. Patients’ outcomes were assessed based on 5and 

10-year disease-free survival (DFS) and overall survival (OS) rates. 

Results: 793 breast cancer patients with a median age of 51 years (21-79) 

were analyzed of whom 27% had stage IIIA and 23% had stage I disease. 

As shown in the table, 5- and 10-year rates of DFS and OS significantly 

improved when adjuvant chemotherapy was optimally delivered. Conclusions: 

The dose-response effect is a key factor that should be taken into account 

when an anthracycline-based non-taxane chemotherapy is administered in 

the adjuvant setting. Delays and/or reductions of chemotherapy should be 

avoided in order to achieve the maximal benefit for the patient. This study 

was partially funded by Amgen SA. 

At 5 years, 

% (95% CI) p value 

DFS 

Overall 79 (76-82) 66 (63-70) 

> 2 delayed cycles, n�324 

73 (68-78) 

� 0.001 56 (51-62) 

< 2 delayed cycles, n�469 

84 (80-87) 

74 (69-78) 

> 15 delayed days, n�233 

72 (66-78) 

� 0.001 55 (48-61) 

< 15 delayed days, n�559 

82 (79-86) 

72 (67-76) 

< 85% of RDI, n�93 

73 (64-82) 

0.066 54 (44-64) 

> 85% of RDI, n�697 

OS 

80 (77-83) 

68 (64-72) 

Overall 90 (89-93) 78 (74-81) 

> 2 delayed cycles, n�324 

87 (83-90) 

0.003 70 (65-75) 

< 2 delayed cycles, n�469 

93 (91-95) 

84 (80-88) 

> 15 delayed days, n�233 

86 (82-91) 

0.012 70 (64-76) 

< 15 delayed days, n�560 

92 (90-94) 

81 (78-85) 

85% of RDI, n�698 

92 (89-94) 

80 (76-83) 


At 10 years, 

% (95% CI) p value 

� 0.001 

� 0.001 

0.003 

� 0.001 

� 0.001 

0.002 

67s 


Phase III trial of first-line treatment with gemcitabine plus docetaxel versus 

gemcitabine plus paclitaxel in women with metastatic breast cancer 

(MBC): A comparison of different schedules and treatment. Presenting 

Author: Lucia Del Mastro, IRCCS AOU San Martino - IST, Genoa, Italy 

Background: Weekly (W) administration of Gemcitabine�Docetaxel (G�D) 

or Gemcitabine�Paclitaxel (G�P) at low doses may be associated with 

greater efficacy and/or lower toxicity compared to the standard 3-weekly 

(3W) schedule. Methods: Patients (pts) (360) with MBC, that relapsed after 

one adjuvant/neoadjuvant regimen containing an anthracycline (unless 

contraindicated) that was completed for at least 12 months, were to be 

randomized equally to a) D 75mg/m2 on Day1 � G 1000mg/m2 on Days1/8 

q3W ; b) P 175mg/m2 on Day1 � G 1250mg/m2 on Days1/8 q3W ; c) D 

30mg/m 2 

� G 800mg/m2 on Days1/8/15 qW; or d) P 80mg/m2 � G 

800mg/m2 on Days1/8/15 qW. Primary endpoint was time to progression 

(TTP). Secondary endpoints were overall survival (OS), overall response rate 

(ORR) and overall toxicity (T). Results: Due to slow accrual rate, a futility 

analysis was performed to evaluate the chance of observing a significant 

result in favour of the alternative hypothesis. The results from this led to 

early study termination. 241 pts [median age (range) 57.0(31-77) years] 

were enrolled and randomized to: 3W G�D 60(24.9%); 3W G�P 

64(26.6%); W G�D 58(24.1%); W G�P 59(24.5%), of which 18(30.0%), 

24(37.5%), 14(24.1%) and 19(32.2%) pts respectively completed the 

study protocol (i.e. received 6 cycles, extended up to 10 for partial/ 

complete responders). Median TTP [months(95%CIs)] was 8.33 (6.19- 

10.16) in W and 7.51 (5.93-8.33) in 3W, with 86.3% of pts progressed in 

each schedule. OS did not significantly differ between treatments and 

schedules. ORR was comparable between D and P, while it was higher in W 

than in 3W (50.4% vs. 33.1%; odds ratio 0.44 [95%CI: 0.26-0.75], 

p�0.003). Grade 3/4 Ts were 69.2% and 71.9% of pts in D and P and 

showed a higher trend in 3W (75.2%) than in W (65.8%). Neutropenia was 

the most frequent grade 3/4 T (51.7% and 44.7% in D and P; 39.3% and 

56.5% in W and 3W). Conclusions: No substantial differences between 

treatments were observed in safety and efficacy. W might be associated 

with lower grade 3/4 Ts and possibly with a better tumour response 

compared to 3W. These results should be interpreted with caution due to 

early termination of the study. 


Cancer stem cell markers in locally advanced breast cancer. Presenting 

Author: Daniel G. Tiezzi, University of São Paulo, Ribeirão Preto, Brazil 

Background: the expressions of CD44/CD24, CXCR4 and ABCG2 have been 

reported as potential breast cancer stem-like cell (CSLC) markers. The 

association between the quantity of CSLCs and the response to neoadjuvant 

chemotherapy (NACT) remains unclear. Methods: we prospectively analyzed 

the expression of CD44/CD24, CXCR4 and ABCG2 in 20 patients with 

locally advanced or metastatic (LAMBC) invasive ductal carcinomas of the 

breast subjected to NACT. The mammosphere assay (Mammocult) was 

studied in 10 samples. Patients’ mean age was 55.6 � 8.2 yo. According to 

clinical stage (CS), 5 patients were IIb, 4 - IIIa, 8 - IIIb and 3 - IV. The mean 

clinical tumor diameter was 6.3 � 2.8cm. The ER, PgR and HER2 positive 

expression rates were 50%, 45% and 50%, respectively. Ten patients were 

treated with EC-T, eight were treated with EC-TH (HER2�) and two were 

treated with FEC75 combination as NACT. The median percentage CD44� / 

CD24- , CXCR4� , ABCG2� and ESA� cells within Lin- cells were determined 

by flow cytometry in fresh sampled tumors after tissue digestion. The 

relationship between flow cytometry analyses and clinical and pathological 

response to therapy was analyzed. Results: complete clinical response 

(cCR) and complete pathological response (pCR) was observed in 9 (45%) 

and 5 (25%) patients. We did not observe a significant association between 

pCR and ER, PgR or HER2 expression. We observed and association 

between the pCR with percentage of ABCG2� cells within the tumor and 

with the number of mammospheres. No correlation between pCR and 

CD44� /CD24- cell population within the tumor was observed. The median 

percentage of ESA� /Lin- /ABCG2� cells within the tumor in pCR patients 

was 0.6% and 3.5% in patients with no pCR (p� 0.02). The median 

number of sphere formation was 5/100 cells and 0.9/1000 cells in pCR 

and non-pCR patients, respectively (p� 0.02). Interestingly, there was a 

positive correlation between ABCG2 expression and the number of mammosfere 

formation (r� 0.66; p� 0.03). This correlation was not significant 

comparing to CD44�/CD24- cells or CXCR4. Conclusions: the percentage 

of ABCG2� cancer cells within the tumor and the number of mammosphere 

formation are predictive factors for pCR in LAMBC patients subjected to 

NACT. ABCG2 is a potential marker for CSLCs. 




EEG for evaluation of “chemobrain.” Presenting Author: Halle C. F. Moore, 

Cleveland Clinic, Cleveland, OH 

Background: Cognitive impairment is a poorly understood and worrisome 

potential complication of adjuvant chemotherapy (CT). We sought to 

evaluate electroencephalography (EEG) as a means to measure neurophysiologic 

function in women receiving CT for early breast cancer. Methods: 

Women planning to undergo CT for operable breast cancer and age-similar 

controls were evaluated at baseline, during CT and at 1 year with 

neurophysiologic assessments. Testing included a brief fatigue inventory 

(BFI), brief mental fatigue assessment (BMF), Processing Speed Index 

(PSI) derived from Digit Symbol Coding and Symbol Search subtests of the 

Wechsler Adult Intelligence Scale, and a sustained elbow flexion physical 

task (PT). EEG recordings were obtained at rest and after the cognitive and 

physical tasks. Data were analyzed using repeated measures of analysis of 

variance. Results: Eight patient/control pairs completed baseline and 

on-treatment evaluations; 7 pairs also completed the 1 year assessment (1 

pair withdrawn due to a second malignancy). Subjective mental fatigue 

measured by BMF is similar for patients and controls at baseline but BMF 

scores increase significantly during CT for patients relative to controls 

(p�0.033), recovering to no difference at one year. Differences in PSI are 

not observed between patients and controls or at the different time points. 

BFI scores are greater in patients at all 3 time points but endurance on the 

PT is no different from controls. During chemotherapy EEG total spectrum 

amplitudes in patients are greater than in controls at rest (p�0.05) and 

following both the cognitive (p�0.001) and physical (p�0.001) tasks. 

EEG activity prior to chemotherapy and at one year is not different between 

patients and controls. For patients but not controls EEG readings after the 

cognitive task demonstrate greater amplitude than pre-task readings during 

the time of CT treatment only (p�0.012) with a similar trend seen for the 

physical task (p�0.06). Conclusions: Patient-perceived mental and physical 

fatigue during chemotherapy correspond to significant changes in EEG 

brain activity patterns but not to cognitive testing or physical endurance 

testing. EEG may offer a sensitive means to measure alterations in brain 

function associated with CT. 


Comparing the outcome between multifocal, multicentric, and bilateral 

breast cancer and the impact of guideline-adherent adjuvant treatment: A 

retrospective multicenter cohort study of 5,308 patients. Presenting 

Author: Lukas Schwentner, Department of Gynecology and Obstetrics 

University Ulm, Ulm, Germany 

Background: Beside unifocal-unilateral (UU) breast cancer (BC) there are 

several subtypes including multifocal, multicentric and bilateral BC. This 

study tries to answer the following questions:(1) Does localization (multifocal/multicentric/bilateral) 

influence outcome concerning BC mortality? (2) 

Is there an impact of guideline-adherent adjuvant treatment in these BC 

subtypes? Methods: This German multi-center retrospective cohort study 

called BRENDA included 5277 patients obtained from 1992 until 2005. 

The definition of guideline adherence was based on the German national S3 

breast cancer guideline (2004). Results: 4085 (77.4%) were UU, 698 

(13.2%) multifocal, 282 (5.3%) multicentric and 212 (4.0%) bilateral 

BC. RFS in multifocal [p�0.003; HR�1.35 (95% CI: 1.11-1.65)], 

multicentric [p�0.001; HR�1.76 (95% CI: 1.31-2.34)] and bilateral 

[p�0.001; HR�2.28 (95% CI: 1.76-2.97)] BC was significantly lower 

compared to unilateral-unifocal BC. Concerning OAS we found only a 

borderline difference between UU and unilateral-multifocal [p�0.057; 

HR�1.22 (95% CI: 0.99-1.48)], but a significant difference between 

multicentric [p� 0.018; HR�1.42 (95% CI: 1.06-1.90)] resp. bilateral 

[p�0.001; HR�2.87 (95% CI: 2.21-3.74)] and UU-BC. There was a 

significant impact by guideline adherent adjuvant therapy [UU: p�0.001, 

HR�2.76,95%C.I.:2.25-3.38], [unilateral-multifocal: p�0.001, 

HR�2.04,95%C.I.:1.33-3.14], [unilateral-multicentric: p�0.020, 

HR�2.13,95%C.I.:1.13-4.01] and [bilateral: p�0.042, 

HR�2.10,95%C.I.:1.03-4.31]. After stratifying for 100% guideline adherent 

treatment and adjusting for age, tumor size, nodal status and grading 

there was no significant difference in RFS/OAS in patients with multifocal 

[p�0.282/p�0.610], multicentric [p�0.829/p�0.609] or bilateral BC 

[p�0.457/p�0.773] compared to patients with UU-BC. Conclusions: 

Patients with multicentric and bilateral BC have primarily a worse prognosis 

in terms of RFS and OAS. However if guideline adherent adjuvant treatment 

was applied it was no more possible to demonstrate significant differences 

in survival. 


Analysis according to prognostic factors in patients (pts) treated with first-line 

bevacizumab (BEV) combined with paclitaxel (PAC) for HER2-negative metastatic 

breast cancer (mBC) in a routine oncology practice study. Presenting 

Author: Iris Schrader, Gynäkolog.-onkolog. Gem.Praxis, Hannover, Germany 

Background: 1st-line BEV combined with weekly PAC significantly improves progression-free 

survival (PFS) and response rate (RR) vs PAC alone in HER2-negative 

mBC, as shown in E2100. We analyzed data from a German routine oncology 

practice study of 1st-line BEV–PAC according to prognostic factors. Methods: Pts 

who had received no prior chemotherapy for mBC received BEV–PAC according to 

the European label. Efficacy and safety were documented for up to 1 y (or until 

progression, death, or BEV discontinuation if earlier) with additional long-term 

follow-up. Efficacy was analyzed in clinically important subgroups. Results: Efficacy 

data were available for 818 pts. The median duration of follow-up was 11.4 mo. The 

composition of the pt population with respect to the subgroups below was generally 

similar to the population treated in E2100, except for a higher proportion of pts with 

visceral disease or metastases in �3 organs. RR was very similar across all 

subgroups analyzed. Differences in median PFS and OS were generally in line with 

the differing prognoses according to clinical characteristics. Conclusions: These data 

suggest that 1st-line BEV–PAC is typically associated with median PFS �9 moin 

the real-life setting, irrespective of baseline characteristics. 

PFS OS 

Subgroup N RR, % Median, mo p value Median, mo p value 

All 

Age, y 

818 62 9.4 – 20.8 – 

>65 262 57 9.2 0.83 20.6 0.99 

70 133 57 9.3 0.38 20.6 0.34 


Baseline comprehensive geriatric assessment to predict for toxicity of 

single-agent chemotherapy in elderly metastatic breast cancer patients: 

Results from the OMEGA study of the Dutch Breast Cancer Trialists’ Group. 

Presenting Author: Marije Hamaker, Diakonessenhuis, Utrecht, Netherlands 

Background: A comprehensive geriatric assessment (CGA) systematically 

appraises the somatic, psychosocial and functional health status of elderly 

patients. If CGA can predict toxicity of chemotherapy in elderly cancer 

patients, this assessment could be useful in deciding on optimal treatment. 

In this analysis, we evaluated the association between frailty on CGA or 

Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast 

cancer (MBC) patients treated with first-line chemotherapy. Methods: In the 

OMEGA study, MBC patients (� 65 years) were randomized between 

PEGdoxo 45mg/m2every 4 weeks or capecitabine 2000 mg/m2 on days 

1-14 every 3 weeks. Baseline geriatric assessment included functional 

status (ECOG performance status (PS), IADL), cognition (MMSE), mood 

(GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) 

and GFI. Frailty on CGA was defined as one or more of the following: 

IADL�13, MMSE �23, GDS �5, BMI �20, �5 medications or Charlson 

�2. GFI score for frailty was �4. Results: In total, 78 patients were 

randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 

65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 

patients were evaluable for toxicity and baseline CGA. Overall, 50 patients 

(70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 

toxicity related to chemotherapy was reported in 30 patients (42%) and 

50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 

20% of CGA-fit patients (p�0.02). Grade 3/4 toxicity was experienced by 

44% of GFI-frail patients, compared to 38% of GFI-fit patients (p�0.39). 

After correcting for type of chemotherapy and age, toxicity was associated 

with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 

1.77-13.59, p�0.03) while GFI-frailty was not associated with toxicity 

(OR 1.11, 95% CI 0.85-1.46, p�0.43). Conclusions: In this randomized 

study on first-line single-agent chemotherapy in elderly MBC patients, 

baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of 

chemotherapy but GFI did not. 


Participation in adjuvant clinical breast cancer trials: Is there a difference 

in survival compared to guideline adherent adjuvant treatment? A retrospective 

multicenter cohort study of 5,326 patients. Presenting Author: Achim 

Wöckel, Department of Gynecology and Obstetrics University Ulm, Ulm, 

Germany 

Background: Clinical trials (CT) usually compare a standard treatment 

regime versus innovative new substances or regimens. However participation 

in CT is available for only few patients and exclusion criteria is usually 

very strict. Therefore this study tries to answer the following questions: (1) 

Does participation in adjuvant CT improve survival in breast cancer (BC)? 

(2) Is there a difference in survival compared to guideline adherence and 

what is the role of the other treatments surrounding adjuvant breast cancer 

treatment? Methods: This German multi-center [17 participating hospitals 

all are certified as breast cancer centers] retrospective cohort study called 

BRENDA (BRENDA � quality of breast cancer care under evidence-based 

guidelines) included 5326 patients obtained from 1992 until 2005. The 

definition of guideline adherence was based on the German national S3 

guideline for diagnosis and treatment of breast cancer (2004). Results: 554 

(10,4%) patients participated adjuvant clinical trials and 4772 (89,6%) 

not. There was a trend towards a significantly impaired RFS [p�0.17; 

HR�0.87 (95% CI: 0.71-1.06)] and OAS [p�0.65; HR�0.84 (95% CI: 

0.65-1.09)] when comparing participants (PA) versus non-participants 

(NPA). When stratifying for guideline adherence (compared to PA-guideline 

conform in all adjuvant therapies) the outcome was not different in 

NPA-guideline adherent [RFS: p�0.13; HR�1.25 (95% CI: 0.94-1.67)] 

[OAS: p�0.83; HR�1.41 (95% CI: 0.96-2.06)]. However survival parameters 

were significantly impaired in non-guideline conform PA [RFS: 

p�0.005; HR�1.66 (95% CI: 1.16-2.38)] [OAS: p�0.01; HR�1.83 

(95% CI: 1.15-2.92)] and non-guideline conform NPA [RFS: p�0,001; 

HR�1.70 (95% CI: 1.27-2.26)] [OAS: p�0.002; HR�1.82 (95% CI: 

1.24-2.67)]. Conclusions: There is a strong association between guideline 

adherence in adjuvant treatment in BC and survival. PA in clinical trials 

trended to an improved survival, but only if guideline adherent treatment 

was applied. Patients who don�t have access to clinical seem to profit 

substantially of guideline adherent adjuvant treatment. 


69s 


Sequential treatment with epirubicin/cyclophosphamide, followed by docetaxel 

versus FEC120 in the adjuvant treatment of node-positive breast 

cancer patients: Final survival analysis of the German ADEBAR phase III 

study. Presenting Author: Wolfgang Janni, Universitätsklinikum Düsseldorf, 

Department of Gynecology and Obstetrics, Duesseldorf, Germany 

Background: Based on meta-analytic evidence, taxane containing adjuvant 

chemotherapy has been established as standard treatment in breast cancer 

(BC). However, in the MA-21 study, adriamycin-cyclophosphamide, followed 

by paclitaxel was significantly inferior FEC120. We prospectively 

compared a sequential epirubicin-docetaxel chemotherapy regimen to 

FEC120. Methods: The ADEBAR study was a multicenter phase III trial 

(n�1502) to evaluate whether pts with � 3 axillary lymph node metastases 

BC benefit from a sequential anthracycline-docetaxel regimen (E90C–D: 4 

cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21d followed by 4 cycles docetaxel [D] 100mg/m2 q21d) compared to 

dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 

cycles E 60 mg/m² d1�8, 5-FU 500mg/m² d1�8 and C 75 mg/m² d 1-14, 

q4w). The observation time (median – 95%CI) was 49.5 (47.4 – 51.3) m. 

Results: Treatment was stopped prematurely in 3.7% of the pts in the 

E90C–D arm and in 8.0% in the FE120C arm due to toxicity (p�0.0009). 

Antibiotic treatment was given in 10.4% (E90C–D) vs. 19.7% (FE120C), G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in 8.7% 

vs. 20.0%, respectively (p�0.0001). Haematological toxicity (leucopenia, 

neutropenic fever, thrombocytopenia, anemia) was significantly higher in 

the FEC-arm. At the time of the current analysis, 369 events of recurrence, 

were observed: 166 events in the FE120C group and 193 in the E90C–D 

group. The unadjusted hazard ratio (HR) was 0.877 (95 percent confidence 

interval, 0.722 to 1.065; p�0.3819, log-rank test). Overall survival in the 

two groups was not significantly different: (131 deaths with FEC vs. 134 

with E90C–D (HR 0.996, 0.783-1.267, p�0.9691). Subgroup analyses, 

stratifying for tumor size, lymph node involvement, hormone receptor and 

HER2-neu status showed no significant difference between the two arms. 

Conclusions: Different toxicity profiles given, hematological toxicity in the 

FE120C group was more severe than in the E90C–D. In contrast to AC-P in 

earlier studies, EC-Doc provides a feasible and effective option to FEC120. 


Randomized phase II study of two doses of pixantrone in patients with 

metastatic breast cancer (N1031, Alliance). Presenting Author: Kostandinos 

Sideras, Mayo Clinic, Rochester, MN 

Background: Pixantrone (Pix) is a novel aza-anthracenedione with structural 

similarities to mitoxantrone and promising activity against non-Hodgkin’s 

lymphoma. Due to the lack of iron binding it is theorized to exhibit less 

cardiotoxicity than the anthracyclines. Methods: N1031 is a phase II RCT of 

2 schedules of Pix, in pts with MBC. Group A pts received 180mg/m2 IV q3 

wks, and group B pts 85mg/m2 IV on days 1, 8, 15 q4 wks. Eligibility 

included prior exposure to anthracyclines and/or taxanes, and 1 to 3 

regiments in the metastatic setting (minimum of 2 if no prior adjuvant 

therapy given). Due to lack of long term cardiac safety data no more than 12 

cycles were allowed. Frequent cardiac imaging was performed per protocol. 

Primary endpoint was RR and secondary endpoints included PFS, OS, 

safety, and QOL. Planned sample size was 25 pts per group. Results: In 

total 46 pts were evaluable (23 per group), mean age 55.5 yrs (range 

38-79), 37% PS 0, 52% PS 1, and 11% PS 2. 80% of pts had prior 

exposure to doxorubicin, 72% had prior (neo)-adjuvant therapy, 76% were 

ER� and 57% received prior HT. Number of prior metastatic regiments 

was: 1 (28%), 2 (61%) and 3 (11%). Most common adverse events (%) of 

any grade were: alopecia (74), anemia (74), fatigue (85), nausea (67), ANC 

decrease (87), and skin disorder (41). Grade 3-4 adverse events (%) at 

least possibly attributed to Pix and occurring in at least 2 pts were: ANC 

decrease (57), fatigue (9), increased AST (4%). One pt from each group 

(4%) had a grade 3 decrease in EF. There were no major differences 

between the two groups except for more oral mucositis in group A (35% vs 

4%). Median number of cycles was 3 in group A (range 1-12) and 2 in 

group B (range 1-8). There was only 1 confirmed tumor response per group 

(4%,95% CI: 0.1-22%) prompting early termination of the trial. The 

median PFS was 2.7 mo (95% CI: 1.8-3.8), and the median OS was 8.9 mo 

(95% CI: 7.5-N/A). Conclusions: Pixantrone has insufficient activity in 

patients with MBC exposed to prior anthracyclines and/or taxanes. Adverse 

events were similar to prior experience with Pix. There were no major 

differences between the 2 schedules of administration. There was no 

significant cardiac toxicity seen in this trial. Correlative studies are 

underway. 




Reduction of ovarian reserve in young early breast cancer patients: First 

data of a prospective cohort trial. Presenting Author: Lea Sanders, OB/GYN, 

University of Kiel, UKSH, Kiel, Germany 

Background: Breast cancer is the most common malignancy in premenopausal 

women. Sideeffects of chemotherapy are well known nevertheless 

the precise effects on ovarian function are inadequately studied by now. 

Premenopausal women undergoing chemotherapy are at risk for symptoms 

of sexual hormone deficiency and impaired fertility. Searching for predictive 

parameters of ovarian reserve after chemotherapy this prospective 

cohort study has been set up. Methods: 36 young patients with primary 

breast cancer have been included in this trial after written consent (April 

2010 to November 2011) and after the study was approved by the local 

review board. All women were premenopausal (� 46 years). They all 

received anthracycline based “A” neo- or adjuvant chemotherapy (as FEC) 

or combinations with taxanes “T” ( as TAC or FEC/Doc). Before and 6 and 

12 months after initiation of chemotherapy age and chemotherapy related 

changes in hormone (LH, FSH, E2 and Anti-Müllerian hormone) levels, 

antral follicel count and amenorrhea as parameters of endocrine function 

and fertility were assessed.The additional impact of parity, BMI and 

nicotine use on ovarian reserve was also evaluated. Results: There is a 

correlation of antral follicle count before and 1 year after chemotherapy and 

a negative correlation of age and follicle count before and after chemotherapy 

(n.s.). This analysis shows that patients receiving “T” compared to 

those with “A” have a significant increase of LH (p�0.025) and FSH 

(mean:24 vs.59 IU/l, p�0.021) between visit 1 and 3. The type of 

chemotherapy has no influence on antral follicle count and AMH levels 

within the first 3 visits. BMI is negatively correlated with AMH at all time 

points (n.s.). BMI, nicotine abuse and age have no influence on the 

duration of amenorrhea, whereas patients with �T� showed 12 months of 

amenorrhea instead of 9 months in patients with �A� (n.s.). Conclusions: Our 

study will contribute to a better understanding and prediction of ovarian 

reserve of young early breast cancer patients undergoing chemotherapy. 

The 12 months follow up data suggest to offer fertility preserving measures 

before chemotherapy especially to patients planned for taxane containing 

chemotherapy. 


Amrubicin as second- or third-line treatment for patients with HER2negative 

metastatic breast cancer (MBC): A phase II trial of the Sarah 

Cannon Research Institute (SCRI). Presenting Author: John H. Barton, 

Tennessee Oncology, PLLC/Sarah Cannon Research Institute, Nashville, 

TN 

Background: Anthracyclines demonstrate significant activity in breast 

cancer, but the potential for cardiotoxicity is dose-limiting. Amrubicin is a 

novel anthracycline with broad-spectrum preclinical activity and low 

potential for cardiotoxicity. We present phase II results from a phase I/II 

trial of amrubicin as second/third- line therapy for HER2- negative MBC. 

Methods: Women with measurable HER2-negative MBC with 1 or 2 prior 

chemotherapy regimens for metastatic disease and normal LVEF were 

eligible. Prior anthracycline- containing adjuvant therapy was allowed. 

Amrubicin 110 mg/ m2 IV every 3 weeks was administered until disease 

progression or intolerable toxicity. Tumor assessments were performed 

every 6 weeks and LVEF assessments every 12 weeks. The primary 

endpoint was progression free survival (PFS); a median PFS � 4.5 months 

was considered a study result meriting further development of amrubicin. 

Results: 48 evaluable patients (pts) were treated from 1/2010 to 9/2011. 

Baseline characteristics included median age 57; 23% were triplenegative; 

33% had 2 prior chemotherapy regimens for MBC; 38% had 

anthracycline- containing adjuvant therapy. Median treatment duration 

was 6 weeks (2 cycles), range 1- 12� cycles. 8 pts (17%) had objective 

RECIST responses (1 CR, 7 PR); 5 of the 8 responders had received 

anthracycline-containing adjuvant therapy. 24 additional pts (50%) had 

stable disease at first reevaluation. The median PFS for all patients was 2.8 

months (95% CI 1.6- 4.0 months); median PFS was similar for pts with 1 

vs 2 previous regimens for MBC (95% CI 2.5 vs 4.0 months). 24% of pts 

were progression-free at 6 months. Neutropenia was the most common 

grade 3/4 toxicity (63%; 6% febrile neutropenia). No grade 3/4 nonhematologic 

toxicity occurred in � 5% pts. No cardiotoxicity occurred. Only 

1 pt discontinued amrubicin due to toxicity (grade 2 fatigue). Conclusions: 

Amrubicin had good tolerability, no cardiotoxicity and was active as a 

second/third-line treatment for HER2- negative MBC, including pts previously 

treated with adjuvant anthracyclines. The median PFS was comparable 

to other standard single agents in the MBC setting. 


Methallotionein expression and outcome in patients with metastatic breast 

cancer (MBC). Presenting Author: Jorge Arturo Rios-Perez, University of 

Pittsburgh Cancer Institute, Pittsburgh, PA 

Background: Platinum-based agents are important components of therapy 

of metastatic breast cancer (MBC) and triple negative breast cancer. Their 

use can be limited by development of resistance. Metallothioneins (MT) are 

low molecular weight proteins believed to bind bivalent metal ions such as 

platinum and zinc. MT expression has been associated with decreased 

survival in breast cancer patients. A proposed mechanism confers resistance 

to platinum-based agents by their inactivation or limitation of their 

activity by MT binding. Methods: MT expression in 99 women with MBC 

(selected at random from our database of 800 women with MBC) was 

determined from primary breast cancer tissue (n�80) or metastatic tissue 

n�19). MT expression was determined by immunohistochemistry, and 

graded as negative, weak, moderate or strong. Clinical data was obtained 

through our database and supplemented by chart review. Overall survival 

from breast cancer diagnosis (OS), progression free survival for first 

metastastic regimen (PFS), and time from first metastasis to death or last 

update (metastatic survival, MS), were calculated through December 2011 

using the log rank test. Results: Consistent with prior studies, moderate to 

strong MT expression was associated with decreased 5-year OS (p�.03). 

There was no correlation between MT expression and PFS or MS in this 

cohort. Surprisingly, MT expression at any degree was strongly associated 

with better MS in patients with MBC that received carboplatin-based 

regimens in the first line (n�25, p�.0005) or at any line (n�41, 

p�.0437). Conclusions: Consistent with prior studies, MT expression was 

associated with decreased survival in patients with MBC. Surprisingly, MT 

expression was associated with longer MS in patients with MBC that 

received carboplatin. These findings are inconsistent with the hypothesis 

that MT expression causes chemoresistance to platinum based agents in 

patients with metastatic breast cancer. Further studies are needed to 

elucidate the mechanisms behind these findings. 


BCL2 protein in prediction of relapse in triple-negative breast cancer 

(TNBC) treated with adjuvant anthracycline-based chemotherapy. Presenting 

Author: Katerina Bouchalova, Laboratory of Experimental Medicine, 

Institute of Molecular and Translational Medicine, Palacky University, 

Olomouc, Czech Republic 

Background: Preclinical data show an association of BCL2 expression and 

resistance to anthracyclines. The absence of BCL2 expression in prechemotherapy 

samples is associated with a higher probability of pathological 

complete response to neoadjuvant doxorubicin-based chemotherapy. The 

aim of our research is identification of markers predicting sensitivity to 

adjuvant treatment in TNBC. Here we focus on BCL2 protein as a putative 

predictor of sensitivity to adjuvant anthracycline-based chemotherapy. The 

objective was to determine whether BCL2 expression predicts relapse in 

TNBC patients treated with anthracycline-based regimens. Methods: The 

study included 187 patients with TNBC, 178 of whom were treated with 

adjuvant chemotherapy (164 had anthracyclines). BCL2 analysis was 

performed using IHC, proportion score and intensity score were counted. 

The data were analysed with software Statistica and R. Results: High BCL2 

expression predicts poor relapse free survival (RFS) in patients treated with 

adjuvant anthracycline-based regimens (logrank p�.035, hazard ratio, HR 

2.37, 95%CI 1.04-5.41). High BCL2 predicts trend to poor overall survival 

(OS) in patients treated with adjuvant anthracycline-based regimens 

(logrank p�0.075, HR 2.31, 95%CI 0.90-5.97). In univariate analysis of 

anthracycline treated patients, stage (RFS p�.0004, OS p�.0005), size 

(RFS p�.003, OS p�.00009) and nodal status (RFS p�0.018, OS 

p�.028) were associated with outcome, as well. In multivariate analysis of 

athracycline treated patients, BCL2, size and nodal status had an independent 

predictive significance for both RFS (p�.005, p�.056, p�.003) 

(logrank test, p�0.0004) and OS (p�.014, p�.006, p�.012) (logrank 

test p�0.0007). Conclusions: This study is the first to prove that high BCL2 

expression predicts poor outcome in TNBC treated with adjuvant anthracycline-based 

chemotherapy. BCL2 expression could facilitate decision 

making on adjuvant treatment in TNBC patients and its assessment should 

be included in standard diagnostics. In patients with high BCL2 expression 

other types of adjuvant treatment should be considered. Grants: IGA 

NS10286,IGA NS10357-3 and Biomedreg CZ.1.05/2.1.00/01.0030. 



Quantitative measures of FDG PET after neoadjuvant chemotherapy to 

predict breast cancer patient survival. Presenting Author: Erin-Siobhain R. 

Currin, University of Washington, Department of Medicine, Seattle, WA 

Background: In patients with locally advanced breast cancer (LABC), 

qualitative FDG positivity following neo-adjuvant chemotherapy (NC) has 

been shown to be inversely associated with survival (Emmering, Annals 

Oncol, 2008). We investigated quantitative measures of post-therapy FDG 

uptake, namely standardized uptake value (SUV) and glycolytic flux (Ki), as 

predictors of breast cancer survival. Methods: Forty-seven patients with 

LABC underwent dynamic FDG PET scans close to or at the end of NC and 

prior to surgical resection. Post-therapy FDG uptake at the primary tumor 

site was measured by mean SUV from 45-60 minutes after FDG injection, 

maximum SUV (SUVmax) from 50-55 minutes, and FDG glycolytic flux 

(Ki). Pathologic response (PR) was assessed for at the time of surgical 

resection. Cox proportional hazards models were used to estimate associations 

between log-transformed measures of post-therapy FDG uptake, PR 

and outcome. Results: Median SUVmax was 1.9 (0.9 – 9.2) and median Ki 

was 2.2 (0.02 – 47.7) mL/min/g. Median follow-up for relapse was 5.7 

years with 11 events and 6.3 years for survival with 10 deaths. PR was not 

significant for DFS (p � .39) or OS (p� .48). Post-therapy FDG uptake 

measures showed a statistically significant ability to predict survival. 

SUVmax predicted DFS (p�0.02) and OS (p�0.01). Ki was associated 

with DFS (p �0.01) and OS (p �0.01). PET measured hazard ratios were 

not attenuated in multivariate analysis controlling for known prognostic 

markers such as primary tumor PR and nodal status. However, multivariate 

survival models appeared highly influenced by one patient with the shortest 

survival time (1.3 years) and highest SUVmax and Ki. Without this patient, 

Ki remained a borderline independent predictor of DFS (p� .08) and OS 

(p� .07), but SUVmax was no longer significant for DFS (p� .32) or OS 

(p�0.26). Conclusions: Our analysis suggests that quantitative measures of 

post-therapy FDG PET provide information beyond PR for predicting which 

LABC patients are at highest risk for relapse and death. This information 

may be useful in directing post-surgery treatment. Supported by NIH grants 

CA42045, CA138293, and CA148131. 


Circulating tumor cells in metastatic breast cancer: Are they a strong and 

independent predictor of poor progression-free and overall survival? Presenting 

Author: Markus Wallwiener, Department of Obstetrics and Gynaecology, 

University of Heidelberg, Heidelberg, Germany 

Background: Circulating tumor cells (CTCs) are detected in 30–60% of 

patients with metastatic breast cancer (MBC). The aim of this prospective 

multi-center study was to evaluate the impact of CTCs on progression free 

survival (PFS) and overall survival (OS) in a large cohort of 486 patients 

with progressive metastatic disease. Methods: CTC levels were determined 

for 486 patients at nine German University Breast Cancer Centers between 

12/2007 and 06/2011. Samples of 7.5 ml blood were taken before 

initiation of a new line of therapy and CTCs were enumerated using the 

CellSearch System (Veridex LLC, Raritan, NJ, USA). CTC status (� 5 CTCs 

vs. � 5 CTCs per 7.5 ml blood) was assessed as a prognostic factor for PFS 

and OS using univariate (log-rank test) and multivariate (Cox regression 

model) statistical methods. Results: CTCs were detected in 205/486 (42%) 

patients. The median CTC count was 2 (range 0–6380) per 7.5 ml blood. 

The presence of � 5 CTCs/7.5 ml blood did not correlate with any of the 

established clinicopathological factors except estrogen receptor status (p 

� 0.038). PFS and OS were both significantly shorter in patients with � 5 

CTCs/7.5 ml than in those with � 5 CTCs/7.5 ml blood. PFS was 5.0 [95% 

CI 4.1–5.8] months vs.7.6 [95% CI 5.9–9.3] months, p � 0.001; and OS 

was 15.0 [95% CI 13.5–16.5] months vs. 18.3 [95% CI 17.4–19.2] 

months, p � 0.001. In the multivariate analysis considering all clinicopathological 

factors and the CTC status, independent predictors of reduced OS 

and PFS were site of metastasis (visceral vs. bone), number of metastatic 

sites (multiple sites vs. one site), and CTC status. Conclusions: The 

presence of � 5 CTCs/7.5 ml blood is a strong and independent predictor of 

poor PFS and OS in patients with MBC. 


71s 


Evaluation of overall survival (OS), progression-free survival (PFS), or time 

to progression (TTP) in systematic review of randomized clinical trials 

(RCT) in patients with metastatic breast cancer (MBC). Presenting Author: 

Terence Mukonje, Medical College of Wisconsin, Milwaukee, WI 

Background: Limited data exists to establish if the introduction of newer 

agents has been associated with a trend towards an improved OS over time 

in women with MBC. Methods: Trough a computer-based systematic search 

of PubMed we identified RCT that treated patients with MBC published 

between 1980 and 2011. Trials that compared systemic chemotherapy for 

MBC, and reported a median OS were included. We excluded trials that use 

concomitant hormonal treatment, investigated only immunotherapy, or if 

they enrolled only responders to an initial regimen. The data abstracted 

included: year of publication, number of patients, regimens used, number 

of patient treated as 1st line vs. refractory patients, median PFS, TTP and 

OS. Linear regression analysis was used to establish trends. Results: An 

initial searched revealed 5485 publications, 134 RCT that enrolled 

38,090 patients fulfilled our entry criteria and were included. First line 

therapy was studied in 99 trials and 35 evaluated mostly refractory 

patients. The use of adjuvant therapy has increased substantially, trials 

reported in the 1980’s had a mean of 0.07% of patients having had 

adjuvant chemotherapy compare to a mean of 48% in the last decade. 

Overall survival has significantly improved; the slope of the fitted line for 

first line clinical trials was 0.39 (p�0.001), which indicates a 0.39-month 

increase in median survival time per year. In trials of subsequent lines of 

therapy this slope was 0.19 (p�0.001). PFS or TTP was reported in 98 

trials, interestingly in contrast to OS, this has not significantly changed, the 

slope for the fitted line has remained almost flat in both first line (0.002, 

p�0.97) and refractory trials (0.01, P�0.81). Conclusions: Our study is 

the first of its kind conducted in trials of patients with MBC. It shows that 

progress has been made in the last 3 decades OS in women affected with 

MBC, however the lack of change in PFS or TTP appears to indicate that the 

increase in OS is driven by a combination of newer agents, more 

subsequent lines of therapy being offered to patients and improved 

palliative care. 


Validation of NAD(P)H quinone oxidoreductase (NQO1) expression as a 

predictive factor for adjuvant chemotherapy benefit in patients with early 

breast cancer. Presenting Author: Monica Arnedos, Institut Gustave Roussy, 

Villejuif, France 

Background: NAD(P)H:quinone oxidoreductase-1 (NQO1) has important 

antioxidant functions by stabilizing p53 from proteasomal degradation. 

NQO1 knockdown is associated with higher susceptibility to oxidative 

stress. Polymorphisms suppressing NQO1 are predictors of poor survival in 

patients with breast cancer (BC) treated with anthracyclines. BC cell lines 

with impaired NQO1 function showed resistance to epirubicin chemotherapy 

(CT) independently of p53 status suggesting NQO1 as predictive 

factor for anthracycline benefit. In this study we hypothesized that lack of 

NQO1 could predict resistance to anthracycline-containing CT in patients 

with early breast cancer (EBC). Methods: Patients were identified from two 

French multicentric trials that randomized patients with EBC to adjuvant 

anthracycline-based CT vs no CT between 1988 and 1995. NQO1 was 

determined in TMAs by automated quantitative assessment of immunofluorescence 

(On-Q-ity Inc, Waltham). Cut-off for positivity was the median 

value of NQO1 expression. Univariate and multivariate Cox regression 

models were performed. Treatment effect was assessed on long term overall 

survival (OS). Results: NQO1 expression was assessed in 600 patients. 

75% were postmenopausal, had more often grade II (62%), LN-negative 

(58%) and ER-positive (67%) BC. Higher NQO1 expression was observed 

in postmenopausal (P�0.02) patients. No relation with other clinicopathological 

factors (grade, LN or ER) was observed. Effect of adjuvant CT on 

death rates was dependant on NQO1 level. Hazard ratio (HR) for treatment 

efficacy at the four quartiles of NQO1 were 1.07 (95%CI: 0.69-1.7), 0.87 

(0.64-1.19), 0.66 (0.45-0.97), 0.46 (0.22-0.95) (interaction test: 0.1). 

Interaction test was statistically significant (0.02) when NQO1 expression 

was considered as binary variable with median value taken as cut-off. 

NQO1 remained predictive among ER� patients only. HR for OS was 0.61 

(0.36-1.02) and 1.25 (0.79-1.99) in patients with high and low NQO1 

respectively. Conclusions: This study adds to the existing data suggesting 

NQO1 expression as an independent predictor of efficacy for adjuvant 

anthracycline-containing CT. 




Analysis of pretreatment nonpharmacologic, pharmacologic factors, and 

yoga intervention on CINV outcomes in breast cancer patients undergoing 

adjuvant chemotherapy. Presenting Author: Malur R. Usharani, HCG 

Bangalore Institute of Oncology, Bangalore, India 

Background: Chemotherapy induced nausea and vomiting (CINV) is affected 

by both pretreatment patient factors, chemotherapy and antiemetic 

regimen and psychological interventions. In this study we evaluated the 

effects of mind body intervention such as yoga in modulating CINV 

outcomes controlled for the above factors. Methods: Chemotherapy naïve 

breast cancer patients with stage II and III disease participating in a 

randomized controlled trial comparing yoga (n�45) vs. supportive therapy 

(n�53) were assessed for CINV outcomes during adjuvant chemotherapy. 

Morrows Assessment of nausea and emesis was used to asses CINV 

symptoms including their frequency, severity and anticipatory nature. We 

developed a multiple regression analyses to test the role of intervention on 

CINV beyond that explained by the independent prognostic factors [age 

(�50/�50 years), stage of disease (II vs III), menopausal status (pre vs 

post), antiemetic regimen (5HT3 antagonists vs. antidopaminergics), 

administration of anxiolytics (yes/ no) and type of chemotherapy regimen 

(FAC vs. CMF)] that were included in model A. Model B includes these six 

variables plus intervention (yoga vs. supportive therapy) in predicting 

nausea and vomiting outcomes. Results: Intervention emerged as a primary 

predictor for nausea frequency (�� -0.38, p�0.002), intensity (�� -0.44, 

p�0.001 ), anticipatory nausea frequency (��-0.26 , p� 0.04) and 

intensity (��-0.38 , p�0.004 ). Age group emerged as a primary predictor 

for anticipatory vomiting frequency (��-0.39 , p�0.01 ) and secondary 

predictor for nausea frequency (��-0.41, p� 0.006). Administration of 

anxiolytics emerged as a primary predictor for vomiting intensity (��-0.40, 

p� 0.001) and secondary predictor for anticipatory nausea frequency 

(��-0.26 , p� 0.05). Conclusions: Yoga intervention influences CINV 

outcomes when controlled for pretreatment and pharmacological factors 

during chemotherapy in breast cancer patients poorly controlled for nausea 

and vomiting. 


Management of antiangiogenics’ renovascular safety in breast cancer subgroup 

and intermediate results of the MARS study. Presenting Author: Catherine 

Daniel, Curie Institut, Paris, France 

Background: Hypertension (HTN) and proteinuria (Pu) are class-side-effects of 

anti-VEGF drugs (AVD), related to the inhibition of the VEGF pathway. The MARS 

study has been conducted to assess the renovascular tolerance of AVD in the 

clinical setting. Methods: The MARS study is a multicentric prospective 

observational study of the renovascular safety of AVD in AVD-naive pts. 7 centres 

from 2009 to 2011. Data collected included: gender, age, serum creatinine 

(SCr), diabetes, HTN, hematuria (Hu) and Pu. This sub-group analysis presents 

the intermediate results for the 1st 155 pts with breast cancer (BC) receiving 

bevacizumab who completed the 1-year follow-up (f/u) (out of 337 BC pts in 

total). Results: Median age at inclusion: 62 years. Bone, visceral and cerebral 

metastasis frequencies were 74.2, 51.6 and 5.2%, respectively. Diabetes and 

HTN prevalences were 3.9% and 10.3%, respectively. Baseline renal assessment 

retrieved: Pu 14.2%, Hu 8.4%, aMDRD 98.2 ml/min/1.73m2 and 2 pts 

with aMDRD�60. The incidence of de novo Pu during f/u was 15% (Table). 

59.1% of pts with Pu at inclusion improved. Among pts with de novo Pu, 40.0% 

afterwards improved/normalized. No grade 3/4 Pu has been reported and no 

hematuria. 12.9% developed HTN. Moreover, renal function decreased by -3.2 

ml/min/1.73m2 /year and 4 pts had aMDRD�60 at the end of f/u. 32.2% 

increased their SCr: 27.1% grade 1, 4.5% grade 2, and 0.6% grade 3. All pts 

with grade 2-3 returned to normal or grade 1. No thrombotic micro-angiopathy 

(TMA) has been reported. Conclusions: These results show that 1) TMA remains 

rare, 2) Pu developed in 15% of pts, with no grade 3/4, 3) less than 13% 

developed HTN and 4) renal function was only slightly impaired with transient 

elevations in SCr. Furthermore, in case of a renovascular effect, investigators 

followed the recommendations from the French Society of Nephrology (Halimi 

JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable 

renovascular toxicity occurred. 

Renovascular effects Prevalence at inclusion (%) Incidence during f/u (%) 

Pu* 

Grade 1 

Grade 2 

Grade 3-4 

14.2 

12.3 

1.9 

0.0 

15.0 

12.8 

2.2 

0.0 

HTN 10.3 12.9 

Hu 

Traces/� 

8.4 

5.8 

0.0 

�� 

0.7 

�� 

1.9 

SCr increase* 

- 32.2 

Grade 1 

27.1 

Grade 2 

4.5 

Grade 3 

* NCI-CTC v4.03. 

0.6 


The relative value of anti-Müllerian hormone to predict premature menopause 

in patients receiving adjuvant chemotherapy for breast cancer: 

Results from the OPTION trial. Presenting Author: Robert C. F. Leonard, 

Imperial College London, London, United Kingdom 

Background: The OPTION trial in premenopausal women tested the ovarian 

protection effect of goserelin (G) given randomly before and during 

adjuvant chemotherapy for breast cancer. Methods: Using standard chemotherapy, 

women were randomised in 2 strata, under 40 yrs and over 40 yrs 

at diagnosis. 227 patients were recruited by end December 2009. 173 met 

the criteria for 1 year follow-up for this analysis; 140 patients of these had 

provided adequate data on menstrual bleeding; 87 patients were aged 

under 40 and 53 patients were aged over 40 at the time of chemotherapy. 

Cessation of menstruation during chemotherapy was defined as at least two 

consecutive cycles with no menstrual bleeding since the previous cycle and 

no return of menstrual bleeding prior to the final cycle of chemotherapy. Of 

those patients who had ceased periods during chemotherapy, those with no 

further menstrual bleeding at 12 months follow up were deemed to be 

menopausal. Patients were randomised to receive G or no G at start of 

chemotherapy. Primary endpoint was recovery of menses at 12 months 

from start of chemotherapy. AMH was measured in 117 women pretreatment, 

and at 1 year after starting chemotherapy. Results: There were 

no differences in pretreatment AMH between control and goserelin-treated 

groups, thus further analyses were performed on all women grouped 

together. AMH was lower following chemotherapy (0.40�0.65 vs 

1.38�1.82ng/ml; mean�SD; P�0.001)). Pre-treatment AMH was a 

significant predictor of post-treatment amenorrhoea (P�0.001). By multivariate 

logistic regression analysis with age and AMH, age remained 

significant (P�0.003) whereas AMH did not (P�0.07). Grouping pretreatment 

and post-chemo AMH into quartiles showed that AMH became 

undetectable in 94% of women with lowest pre-treatment AMH vs 46.2% 

of women with the highest pretreatment AMH. We have previously 

demonstrated in a small cohort that pretreatment AMH can predict 

long-term (5 year) ovarian activity in women with breast cancer. Conclusions: 

The present data confirm the value of pretreatment AMH in assessing the 

likelihood of ongoing ovarian activity after chemotherapy for early breast 

cancer. 


Neoadjuvant epirubicin, gemcitabine, and docetaxel for primary breast 

cancer: Survival and prognostic factors in two consecutive neoadjuvant 

phase I/II trials. Presenting Author: Frederik Marme, Department of 

Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, 

Germany 

Background: We previously reported primary end points of two consecutive 

phase I/II trials which evaluated two different schedules of neoadjuvant 

gemcitabine (G), epirubicin (E) and docetaxel (Doc) for primary breast 

cancer. Here we report mature survival data and evaluate prognostic factors 

for disease-free (DFS) and overall survival (OS). Methods: 151 patients were 

treated in two phase I/II trials of G, E and Doc as neoadjuvant chemotherapy 

(NAC) for T2-4 N0-2 M0 PBC between Feb. ´02 and Dec. ´04. 

Patients were treated with six cycles of GEDoc (G 800mg/m2 day (d) 1�8, 

E 60-90mg/m2 d 1, Doc 60-75mg/m2 d 1 every three weeks) or five cycles 

of G 1250mg/m2 plus E 90-100mg/m2 every two weeks followed sequentially 

by four cycles of Doc 80-100mg/m2 every two weeks (GEsDoc). 

Pathologic complete response (pCR), clinical/pathological factors were 

correlated with DFS and OS. Results: There was no significant difference in 

DFS or OS between patients in the GEDoc and GEsDoc trial (DFS: Hazard 

ratio (HR) 1.13, p�0.67; OS: HR 1.06, p�0.88) with a 5-year DFS and OS 

of 72 vs 74% and 85 vs 86%, respectively. In an univariate analysis pCR 

unexpectedly was associated with a worse OS (HR 3.11; p� 0.007). HR for 

DFS showed a similar but non-significant trend (HR 1.78; p�0.1). 

Molecular subtypes (OS: HR [lum B] 3.17; [triple negative] 5.81; [HER2] 

11.5; p�0.002), negative estrogen receptor (ER) status (OS: HR 3.14; 

p�0.002) and Ki-67 �20% (OS: HR 5.41; p�0.001) were all significantly 

associated with DFS and OS. The recently published CPS-EG score 

(Mittendorf 2011) was also significantly correlated with OS (p�0.006) and 

DFS (p�0.0006). In a multivariate analysis high Ki-67 was the only 

significant predictor of OS (HR 10.4; p�0.0026) whereas molecular 

subtype (p�0.05) and Ki-67 (p�0.04) were significantly associated with 

DFS. Conclusions: These results raise caution on the reliability of pCR as a 

single surrogate marker for survival in trials with small sample sizes. Our 

results emphazise the role of additional factors, esp. Ki-67 and subtypes. 

Integrative scores based on clinical and pathologic stage as well as tumor 

biology, might be more reliable predictors of survival. 



Prevention of chemotherapy-induced damage to ovarian reserve by sphingosine-1-phosphate 

Presenting Author: Fang Li, Laboratory of Molecular 

Reproduction and Fertility Preservation, New York Medical College, Valhalla, 

NY 

Background: Chemotherapy agents such as cyclophosphamide (Cy) and 

doxorubicin (D) are known to compromise ovarian function. We have 

previously shown that these agents alter ovarian function by causing 

apoptotic death of primordial follicles and thereby causing diminishment of 

ovarian reserve (Cancer Research 2007; Aging 2011). While assisted 

reproduction techniques exist to preserve fertility there has been no proven 

approach to pharmacologic preservation of ovarian function. Sphingosine- 

1-Phosphate (S1P) is a naturally occurring ceramide-induced death pathway 

inhibitor. Here we investigated whether S1P can prevent Cy or 

D-induced apoptotic follicle death in mouse ovaries. Methods: Eight wk old 

NOD mice (n�23) were treated with Cy (75 mg/kg), Cy�S1P (200 �M), D 

(10 mg/kg), D�S1P or vehicle only (Control). S1P was administered via 

continuous infusion using a mini-osmotic pump beginning 3 hours prior to 

single dose chemotherapy injection for 72 hours. Ovaries were removed 

72h later and serially sectioned, and stained with anti-caspase 3 (AC-3) 

antibody for the detection of apoptosis in primordial follicles. The ratio of 

apoptotic to total follicles was expressed as percentage in each group. 

Results: Both Cy and D resulted in significant increase in apoptotic follicle 

death compared to controls (48.2�11.6 vs. 28.2�8.9, p�0.016 and 

46.4�5.4 vs. 24.8�5.2, p�0.004, respectively). Percentages of apoptotic 

follicles were similar between Cy and D-treated groups (48.2�11.6 vs. 

46.4�5.4, P�NS) indicating that these agents were equally gonadotoxic. 

S1P treatment resulted in a significant decrease in the percentage of 

apoptotic follicles both in the Cy (25.6�3.5, P�0.011) and the D group 

(32.2�10.8, P� 0.013) compared to controls. In the S1P-treated groups, 

the percentages of apoptotic follicles were similar to those in untreated 

controls indicating that S1P completely blocked Cy and D-induced apoptotic 

follicle death. Conclusions: S1P can block apoptotic follicle death 

induced by highly cytotoxics agents. In addition, we showed that S1P can 

block follicle death by chemotherapy agents that act through different 

molecular mechanisms. If targeted delivery systems can be developed, S1P 

may hold significant promise in preserving fertility by pharmacological 

means. 


Phase II trial of sorafenib (S) and vinorelbine (V) in metastatic breast 

cancer (mBC) with pharmacokinetics (PK) analysis. Presenting Author: 

Cristiano Ferrario, Department of Oncology, McGill University, Montreal, 

QC, Canada 

Background: S inhibits pathways involved in cancer resistance to treatments 

(Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability 

and efficacy of full doses of S and V in mBC. Toxicity data were previously 

reported: frequent dose reductions were noted, for which we investigated a 

possible PK interaction. Indeed, the metabolism of both S and V depends 

on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RE- 

CIST), HER2 negative mBC received first-line therapy with V (30 mg/m2 days 1, 8 every 21) � S (400 mg bid). After 8 cycles patients could be 

switched to S alone. For PK analysis 6 patients started S on day 4 of cycle 

1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S) 

when V and S were administered apart from each other versus concomitantly. 

Plasma samples were collected at time 0 (oral intake of S or right 

before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7, 

24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S�M2; 

cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS 

assays. Results: 27 patients (median age 57, 35-71) received a median of 8 

cycles (1-28), with one patient still on treatment. With repeated cycles 

48% of patients required at least 1 dose reduction and 3 patients 

discontinued therapy for toxicity. 30% of patients had a partial response, 

85% had clinical benefit (including stable disease � 4 cycles). Median 

progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels 

of V were influenced by S, with a mean Cmax right after the infusion of 

1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL 

with concomitant S (cycle 2 day 1; paired t-test, p�0.004). Plasma levels 

of S and M2 showed a greater degree of interpatient variability, with no 

significant difference observed in the presence or absence of concomitant 

V. Conclusions: Combining S with V at full doses is feasible, but not devoid 

of toxicity. A PK interaction may contribute to the frequent dose reductions. 

A reasonable option in clinical practice is to start therapy at lower doses of 

both agents, with a gradual dose increase if well tolerated. Promising 

efficacy of this combination is documented, with a very high rate of disease 

control. 


73s 


A study of sperm-associated antigen 5 (SPAG5) in predicting response to 

anthracycline (ATC)/platinum chemotherapies (CT) in breast (BC) and 

ovarian cancers (OVC). Presenting Author: Tarek M. A. Abdel-Fatah, 

Nottingham University City Hospital NHS Trust, Nottingham, United 

Kingdom 

Background: Recently TOP2A alteration was found to be a predictor for 

ATC-CT and our neural network analysis of BC gene expression array (GEA) 

data has revealed SPAG5 gene as a major hubs in both TOP2A and 

proliferation pathways. In this study the molecular and clinicopathological 

functions of SPAG5 was investigated in BC and OVC. Methods: (1) A series 

of 171 BC was evaluated for SPAG5 gene copy number (using aCGH) and 

mRNA expression (using GEA) which were validated in 5 independent 

databases. (2) The expression of SPAG5 protein was evaluated preclinically 

in BC and OVC cell lines and in both 40 normal breast tissues and 

a series of 1650 primary BC and was correlated to clinicopathological and 

other biomarkers. (3) The association between SPAG5 and response to CT 

was investigated in a) 350 ER negative BC treated with adjuvant ATC-CT, b) 

250 BC treated with neoadjuvant (NEO-A)-ATC-CT, and c) 200 primary 

OVC treated with cisplatinum based adjuvant CT. Results: (1) 5% and 15% 

of the 171 BC showed amplification and gain of SPAG5 locus, respectively, 

at 17q11.2. SPAG5 mRNA expression displayed a significant correlation 

with its copy number (p� 0.0001). (2) 30% and 20% of ovarian and BC 

respectively, showed overexpression of SPAG5 protein (�). In BC, SPAG5� 

at both mRNA and protein levels showed a significant association with 

aggressive phenotypes, high mitosis, ER-, high grade, p53 mutation and 

epithelial mesenchymal transition phenotypes (ps �0.0001). SPAG5 

mRNA (�) was statistically associated with poor survivals (p�0.0001). (3) 

In ER- BC treated with adjuvant ATC-CT, SPAG5 negative (-)had 7-times 

higher risk of progression compared with SPRAG� BC (p�0.0001). 

SPAG5� BC received NEO-A-ATC based CT achieved 38% pathological 

complete response (pCR) vs. 6% of SPAG5- (p�0.0001). After controlling 

to other predictors for pCR, SPAG5 was an independent predictor (HR; 2.4; 

p�0.001). Similarly, SPAG5- OVCs were resistant to platinum (p�0.001) 

and independently associated with poor survival (p�0.001). Conclusions: 

SPAG5 is an important novel gene implicated in the survival of BC and OVC 

cells and its protein expression is an independent predictor for anthracycline/ 

cisplatinum CT. 


Receipt of locoregional therapy among young women with breast cancer. 

Presenting Author: Rachel A. Freedman, Dana-Farber Cancer Institute, 

Boston, MA 

Background: Although younger women with breast cancer have the most to 

gain from receipt of optimal care, few data are available regarding their 

receipt of locoregional breast cancer treatments. Methods: We identified 

318,083 women aged 18-64 who were diagnosed with invasive breast 

cancer at hospitals reporting to the National Cancer Data Base, a large 

national cancer registry, during 2004-2008. We used multivariable logistic 

regression to assess the association of patient age with mastectomy vs. 

breast-conserving surgery (BCS), radiation with BCS, and post-mastectomy 

radiation (PMRT) with varying indications, adjusting for patient and tumor 

characteristics, area-level socioeconomic status, and insurance. Results: 

Overall, 4% of women were aged �35 and 7% were aged 36-40. Women 

aged �35 were significantly more likely to have mastectomy than BCS 

compared with women aged 56-60 (57% vs. 35%, adjusted odds ratio [OR] 

1.97; 95% Confidence Interval [CI] 1.87-2.07) but were less likely to 

receive radiation if BCS was performed (69% vs. 80%, OR 0.77; 95% CI 

0.73-0.82). For those who underwent mastectomy, although overall rates 

of PMRT receipt were low, women aged �35 were more likely to receive 

postmastectomy radiation (PMRT) despite the presence or absence of 

clinical indications for PMRT (OR 1.11; 95% CI 1.01-1.22 for strong 

indications, OR 1.71; 95% CI 1.53-1.91 for borderline indications, and 

OR 1.49; 95% CI 1.28-1.73 for no indications [all vs. ages 56-60]). 

Conclusions: Young women with breast cancer may not be receiving optimal 

locoregional therapy. We observed lower odds of radiation after BCS but 

higher odds of PMRT for young women regardless of indications for PMRT. 

Efforts are needed to further understand and improve the receipt of 

appropriate adjuvant radiation therapy among young women to improve 

their disease-free and overall survival. 




Patterns of regional node irradiation therapy following breast-conserving 

surgery: Report from the National Cancer Data Base 2003-2007. Presenting 

Author: Ningqi Hou, University of Chicago, Chicago, IL 

Background: A recent randomized trial (MA.20) showed that regional nodal 

irradiation (RNI) in addition to breast irradiation in high risk node negative 

and 1-3 node positive patients undergoing breast-conserving therapy (BCT) 

reduced the risk of recurrence and improved disease-free survival. We 

investigated the trends of RNI use in the United States and related factors 

for the use of RNI using the National Cancer Data Base. Methods: This study 

includes 292,598 stage I-III breast cancer patients without neoadjuvant 

therapy who underwent BCT from 2003-2007. We investigated pathological, 

patient, and facility factors related to RNI use, by multivariable logistic 

regression, with odds ratio (OR) estimations. Results: The proportion of 

radiotherapy use after BCT slightly declined from 78.6% in 2003 to 75.6% 

in 2007. The use of breast irradiation plus RNI decreased from 10.8% in 

2003 to 8.3% in 2007 (p�0.0001). The number of tumor positive lymph 

nodes strongly determined the use of additional RNI: 4.4% patients with 

negative nodes, 22.8% patients with 1-3 nodes, and 39.7% patients with 

4 or more nodes received breast irradiation plus RNI after undergoing BCT 

(p�0.0001). The proportion of patients undergoing RNI significantly 

decreased over the study period from 43.3% to 37.2% in the 4� node 

positive group, and from 23.6% to 22.0% in the 1-3 node positive group. 

At comprehensive community cancer centers, 25.5% patients with 1-3 

positive nodes were treated with breast irradiation plus RNI (vs. 23.2% in 

community cancer centers and 21.1% in academic/research cancer 

centers). Among node negative patients, 11.5% of those with tumor size 

greater than 5 cm received additional RNI, compared to 4.3% in patients 

with tumors less than 5cm (p�0.0001). Other significant factors related to 

RNI use included higher tumor grade, younger age, facility location, and 

facility volume. Conclusions: The use of RNI varies by number of tumor 

positive nodes and facility factors. Only 22.8% of patients with 1-3 positive 

nodes underwent RNI. Future studies are needed to determine if the use of 

RNI will increase after publication of the MA.20 trial especially for the 1-3 

node positive group. 


SPIO-enhanced MR imaging for axillary staging to avoid sentinel node 

biopsy in patients with breast cancer. Presenting Author: Kazuyoshi 

Motomura, Department of Breast and Endocrine Surgery, Osaka Medical 

Center for Cancer and Cardiovascular Diseases, Osaka, Japan 

Background: We previously demonstrated the usefulness of SPIO-enhanced 

MR imaging for the detection of metastases in sentinel nodes localized by 

computed tomography (CT) lymphography (CT-LG) in patients with breast 

cancer (Ann Surg Oncol, 2011). These techniques have evolved and we 

report our most recent results of axillary staging using them. Methods: 

Previously unreported 87 consecutive patients with breast cancer and 

clinically negative nodes were enrolled in this study. Sentinel nodes 

identified by CT-LG were evaluated prospectively using SPIO-enhanced MR 

imaging. A node was considered non-metastatic if it showed a homogenous 

low signal intensity and metastatic if the entire node or a focal area did not 

show a low signal intensity on MR imaging. Sentinel nodes located by 

CT-LG were removed, and imaging results and histopathological findings 

were compared. Results: The mean patient age was 54.9 years (range, 

34-77). Sentinel nodes were identified by CT-LG and removed successfully 

in all patients. The mean number of sentinel nodes identified by CT-LG was 

1.16 (range, 1-2). Twenty of 22 patients with positive sentinel nodes 

definitively diagnosed by pathology demonstrated metastases on SPIOenhanced 

MR imaging. Fifty-eight of 65 patients with negative sentinel 

nodes definitively diagnosed by pathology were non-metastatic on imaging 

studies. The sensitivity, specificity and accuracy of MR imaging for the 

diagnosis of sentinel node metastases were 91%, 89%, and 90%, 

respectively. Two patients whose metastases were not detected had 

micrometastases. No adverse events were associated with either CT or MR 

imaging. Conclusions: SPIO-enhanced MR imaging provided accurate 

axillary staging, and therefore sentinel node biopsy may not be necessary 

for most patients with breast cancer. 


Primary tumor resection to improve survival and local disease control in 

stage IV inflammatory breast cancer. Presenting Author: Catherine Akay, 


Background: Inflammatory breast cancer (IBC) is a rare and aggressive form 

of breast cancer typically presenting with early metastasis. Optimal 

outcomes are achieved with multimodality treatment strategies in the 

non-metastatic setting. Data is limited, however, on the benefit of surgery 

in patients with metastatic IBC. We evaluated the effect of primary tumor 

resection on outcomes in patients with newly diagnosed stage IV IBC. 

Methods: We reviewed records of 172 patients with metastatic IBC treated 

at our institution from 1994 - 2009. All patients received systemic therapy 

with or without locoregional therapy (LRT). Patient demographics, receptor 

(ER) and HER2-neu status, grade, histology, presence of lymphovascular 

invasion, margin status, number of distant disease sites, pathologic 

response of primary tumor and clinical response to systemic therapy (CRS) 

at distant disease sites were recorded. Overall survival (OS), distant 

progression-free survival (DPFS), and chest/skin involvement at last follow-up 

were evaluated. Kaplan-Meier survival analyses, univariate (UV) and 

multivariate (MV) logistic regression models were used. Chest/skin involvement 

was compared between groups using Kruskal-Wallis test. Results: 

Seventy-nine (45%) patients underwent primary tumor resection. Average 

age was 51 (22-78). Median live-patient follow-up was 33 months. OS and 

DPFS were significantly better for patients who underwent LRT versus none 

(p�0.0001). Factors associated significantly for improved DPFS on MV 

analysis were ER and HER2-neu status (HR 0.61,0.60 p�0.02,0.05 

,respectively), LRT (HR .38, p�0.002) and CRS (HR 0.62, p�0.03). ER 

status (HR .45, p�0.001), LRT (HR .30, p�0.001) and CRS (HR 0.54, 

p�0.02) were significant predictors for higher OS on MV analysis. At last 

follow up, chest/skin involvement was moderate/severe in 11% of patients 

in LRT group versus 35% of patients in no LRT group (p�0.0001). 

Conclusions: This latest retrospective study demonstrates metastatic IBC 

patients who undergo LRT in addition to systemic therapy may have 

improved survival and local control outcomes. CRS may be used to guide 

LRT. A prospective randomized trial is needed to validate these findings. 


Breast cancer multifocality-multicentricity and survival outcomes. Presenting 

Author: Siobhan P. Lynch, University of Texas M. D. Anderson Cancer 


Background: Studies have consistently shown a correlation between multifocal 

(MF) and multicentric (MC) breast cancers and the rate and extent of 

lymph node metastases, but the literature is divided on whether there is a 

corresponding impact on survival outcomes. In the absence of compelling 

evidence to dictate otherwise, the convention according to current TNM 

staging guidelines has been to stage and treat MF and MC cancers 

according to the diameter of the largest lesions, without taking other foci of 

disease into consideration. We evaluated a large single institution cohort of 

MF and MC breast cancers to determine their frequency, clinicopathological 

characteristics and effect on survival outcomes. Methods: MF 

and MC were defined pathologically as more than one lesion in the same 

quadrant and more than one lesion in separate quadrants, respectively. 

Patients were categorized by presence or absence of MF or MC disease. 

Kaplan-Meier product limit method was used to calculate relapse-free 

survival (RFS), breast cancer-specific survival (BCSS) and overall survival 

(OS). Cox proportional hazards models were fit to determine independent 

associations of MF/MC disease with survival outcomes. Results: Out of 

3924 patients, 942 (24%) had MF (n�695) or MC (n�247) disease. MF 

and MC disease was associated with higher T-stages (T2 26% vs. 21.6%; 

T3 7.4% vs. 2.3%, P�0.001), higher nuclear grade (grade 3 44% vs. 

38.2%, P�0.001), lymphovascular invasion (26.2% vs. 19.3%, P�0.001) 

and lymph node metastases (43.1% vs. 27.3%, P�0.001). After a median 

follow up of 51 months, MC but not MF breast cancers were associated with 

significantly worse 5-year RFS (90% vs. 95%, P�0.02) and BCSS (95% 

vs. 97%, P�0.01), and a trend towards worse 5-year OS (92% vs. 93%, 

P�0.08). After controlling for other risk factors, multifocality and multicentricity 

did not have an independent impact on RFS, BCSS or OS. This was 

true for the subset of T1N0 breast cancers as well. Conclusions: MF and MC 

breast cancers occurred in 24% of the cases and were associated with poor 

prognostic factors, but they were not independent predictors of worse 

survival outcomes. Our findings support the current TNM staging system of 

using the diameter of the largest lesion to assign T-stage. 



Is there a need for sentinel lymph node biopsy in microinvasive breast 

cancer? Presenting Author: Nimmi S. Kapoor, John Wayne Cancer Institute, 

Santa Monica, CA 

Background: There is limited data on the long-term outcome of patients with 

microinvasive breast cancer. Moreover, predictors of lymph node involvement 

and the impact of multifocal microinvasion are not well understood. 

We examined the occurrence of nodal metastasis and the significance of 

multifocality on disease recurrence. Methods: Patients with T1mic breast 

cancer, defined as tumors �1mm, surgically managed at our institute 

between 1995-2010 were identified. Specimen slides were independently 

reviewed. Multivariable analysis (MVA) was used to predict lymph node 

involvement and disease recurrence. Results: Fifty-two patients with T1mic 

breast cancers were identified. Median patient age was 53 (range 30-92), 

median size of in-situ disease was 3cm (range 0.1-12cm). Ten patients 

(19.2%) had multiple foci of microinvasion (range 2-7). The majority of 

tumors were high-grade (76.9%). When the invasive tumor component was 

evaluated, 31 of 41 (73.8%) were ER positive, 40.5% were HER2�(15/ 

37), and only one was ER-/PR-/HER2-. Twenty-nine patients (55.8%) had 

breast conserving surgery and 23 had mastectomies. Lymph nodes were 

assessed in 48 patients; there was 1 macrometastasis (2.1%), 4 micrometastases 

(8.3%) and 4 (8.3%) with isolated tumor cells. Seven of 9 patients 

with lymph node involvement underwent adjuvant chemotherapy. Univariable 

analysis showed that ER(-) invasive disease and high-grade DCIS 

tumors were more likely to have involved lymph nodes. On MVA, only 

negative ER status was a significant predictor of lymph node metastasis 

(p�0.02). At median follow-up of 83 months (range 6-172 months), 3 

patients (6.3%) had disease recurrence (1 local, 1 distant, 1 local and 

distant) at 8, 17, and 130 months from presentation. All patients with 

recurrence had negative lymph nodes and only one focus of microinvasion. 

No factors predicted disease recurrence. Conclusions: Microinvasive breast 

cancer clearly has the ability to metastasize and recur, but in this series 

only 2% of patients presented with nodal macrometastasis. The evaluation 

of lymph nodes in T1mic cancer is unnecessary in the majority of patients. 

In our cohort, neither lymph node status nor multifocal microinvasion 

predicts recurrence. 


Role of axillary ultrasound after neoadjuvant chemotherapy in women with 

node-positive breast cancer (T1-4, N1-2, M0) at initial diagnosis (ACOSOG 

Z1071). Presenting Author: Huong T. Le-Petross, University of Texas M. D. 


Background: The role of axillary ultrasound (AUS) after neoadjuvant 

chemotherapy (NAC) to assess for residual nodal disease in patients 

presenting with node positive breast cancer remains unclear. ACOSOG 

Z1071 is a prospective multi-institutional trial evaluating sentinel node 

biopsy in patients with biopsy proven node positive breast cancer (T0-4, 

N1-2, M0) receiving NAC. Herein we report on the secondary objective 

evaluating the correlation of lymph node (LN) features on AUS with residual 

nodal disease. Methods: AUS images from diagnosis and after NAC were 

centrally reviewed for cortex size, LN size and LN morphology. Morphologic 

features were defined as: type I, no visible cortex, type II, � 3 mm 

hypoechoic cortex, type III, � 3mm hypoechoic cortex, type IV, generalized 

lobulated hypoechoic cortex, type V, focal hypoechoic cortical lobulation, 

and type VI, totally hypoechoic node with no hilum. Type I and II are 

considered normal. Results: Surgical and imaging data are available on 294 

patients. Median age was 50 years (range 23-93 years), mean initial tumor 

size 3cm (0 to 15cm) and clinical stage II in 64.5% and III in 35.5%. The 

maximum LN diameter decreased after NAC (mean 22mm pre-NAC to 

14mm post-NAC)(p�0.0001); however, there was no significant difference 

after NAC between the pathologically N� (13mm, range 5-46mm) 

and N0 cases (12mm, range 3-32mm)(p�0.13). LN cortical thickness 

correlated with residual nodal disease after NAC (p-value � 0.04). Using a 

cutoff point of cortical thickness of 3 mm, the sensitivity was 33% 

(48/145) and specificity 80% (66/82). AUS morphological features after 

NAC was associated with false negative rate 62%, false positive rate 28%, 

sensitivity 38%, and specificity 72%. Conclusions: AUS after NAC is useful 

to assess nodal response. Cortical thickness was the best predictor of 

residual nodal metastasis. LN size and morphological features do not 

reliably exclude residual nodal metastasis in patients after NAC. 

Morphology At diagnosis 

After NAC 

node positive 

After NAC 

node negative 

Type I 0% 15.7% 22.0% 

Type II 0.3% 46.0% 50.5% 

Type III 2.4% 13.0% 13.8% 

Type IV 26.9% 7.6% 2.8% 

Type V 13.3% 7.6% 5.5% 

Type VI 57.1% 10.3% 5.5% 


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Prognosis of early breast cancer patients treated with sentinel node biopsy: 

A prospective study from the Japanese society for sentinel node navigation 

surgery. Presenting Author: Shigeru Imoto, School of Medicine Kyorin 

University, Mitaka, Japan 

Background: Sentinel node biopsy (SNB) is a new standard of care for 

clinically node-negative breast cancer patients. Our society conducted a 

prospective study on SNB for early breast cancer patients from Jul 2004 to 

Oct 2005 (UMIN000006126). A preliminary result regarding with success 

rates of multiple mapping methods and the adverse events was presented 

at the 2007 ASCO. We observed patient’s outcome for 5 years. Methods: Of 

the 1,411 cases registered, the objects were 1,107 cases excluding cases 

with bilateral breast cancer, non-invasive breast cancer, past history of 

other malignancy or failure of SNB and cases treated with primary 

chemotherapy or endocrine therapy. Adjuvant therapy and breast irradiation 

were decided by physician’s discretion and patient’s preference. To 

evaluate the risk of isolated tumor cells or micrometastases in sentinel 

lymph nodes (SLN), clinicopathological factors were analyzed using the 

Cox regression model. Results: After a median follow-up of 62 months, 

there were 85 recurrences and 14 deaths. 5-year Kaplan-Meire estimates 

for disease-free survival and overall survival (OS) were 92.6% and 97.5% 

in 848 cases with pN0(sn), 96.2% and 100% in 26 with pN0(i�)(sn), 

89.3% and 95.3% in 68 with pN1mi(sn) and 82.8% and 92.0% in 165 

with pN1(sn) or greater nodal metastases. No axillary lymph node dissection 

(ALND) was performed in 809 cases (95.4%), 18 (69.2%), 38 

(55.9%), and 24 (14.5%), respectively. Regional node recurrence was 

found in 8 cases (0.9%), 0 (0%), 2 (2.9%) and 2 (1.2%), respectively. 

Univariate analysis showed that pN1(sn) or greater nodal metastases, 

pT2-4, nuclear grade 3, lymphovascular invasion, negative hormone 

receptor status, SNB followed by ALND, chemotherapy therapy were 

significant risk factors for OS. However, from multivariate analysis, nuclear 

grade 3, lymphovascular invasion and SNB followed by ALND were 

independent unfavorable prognostic factors (hazard ratio: 3.21, 2.61 and 

3.93). Conclusions: Although a non-randomized prospective study, isolated 

tumor cells and micrometastases in SLN did not affect patient’s survival. 

ALND should be omitted for early breast patients with those metastases. 


Post-neoadjuvant chemotherapy sentinel node biopsy and axillary sampling 

for node negative (N0) axilla. Presenting Author: Vani Parmar, Tata 

Memorial Hospital, Mumbai, India 

Background: Post neoadjuvant chemotherapy (NACT) sentinel node biopsy 

(SNB) is not a standard of care due to the wide variability in false negative 

rate (FNR), varying from 5.7% to 33%. In operable breast cancer (OBC), 

FNR of less than 10% is acceptable. We attempted to find out the reliability 

of low axillary sampling(LAS), with dissection limited below the first 

intercostobrachial nerve, to correctly identify the node negative axilla in the 

post NACT clinically node negative (N0) patients. Methods: Women with 

large operable (LOBC) and locally advanced breast cancer (LABC), post- 

NACT clinically N0, underwent concomitant blue dye-colloid guided SNB 

and LAS. The identification rate, FNR, and negative predictive value (NPV) 

of both procedures were compared. Results: Post-NACT 209 eligible women 

underwent combined LAS and SNB procedure. At presentation, the tumors 

were large (median 5.0 cm) with 70% clinically palpable nodes. All 

patients received 4 cycles of neo-adjuvant anthracycline-based chemotherapy 

and were clinically node negative after chemotherapy. SNB was 

defined as blue and/or hot node plus palpable node(s). A blue or hot node 

(median 2 nodes) was identified in 93.8%, and median of 5 sentinel nodes 

were removed. The false negative rate of SNB was 15.3% (95% CI 

8.7%-25.3%). The LAS technique comparatively had nodal yield in 98.5% 

with median 8 nodes removed; and FNR 8.5% (95% CI, 4.2%-16.6%, 

p�0.19). Comparative NPV for LAS and SNB were 94.6% and 91.8% 

respectively. Conclusions: Axillary sampling results for FNR and NPV are 

similar if not superior to SNB and could be a reliable method of axillary 

nodal evaluation in advanced breast cancers following neo-adjuvant chemotherapy. 




Accuracy of breast MRI in predicting pathologic tumor size. Presenting 

Author: Kimberly Anne Caprio, Yale University, New Haven, CT 

Background: MRI use as a preoperative planning tool is increasing in women 

with breast cancer, yet the correlation between MRI and pathologic size of 

cancers is unclear. The purpose of this study was to determine the accuracy 

of MRI in predicting pathologic tumor size, and factors that affect this 

correlation. Methods: Clinicopathologic and imaging data from 84 patients 

diagnosed with invasive or in situ breast cancer from September 2010 to 

October 2011 who had preoperative MRI were reviewed. 12 patients who 

had neoadjuvant chemotherapy were excluded. MRI detected 147 lesions 

in the remaining 72 patients. Concordance between MRI and pathology 

size was determined using Spearman rho coefficients, and factors affecting 

the accuracy of MRI in predicting tumor size within �/- 0.5 cm were 

determined. Results: There was a modest correlation between MRI and 

pathology size for all MRI detected lesions (benign or malignant) with a 

Spearman coefficient of 0.53. Of the 147 MRI detected lesions, 45 

(30.6%) had pathologic and MRI size correlating within �/- 0.5 cm; 76 

(51.7%) were overestimated (�0.5cm) by MRI, and 26 (17.7%) were 

underestimated (�0.5cm). 101 (68.7%) of the 147 lesions were found to 

be malignant (either with invasive disease or DCIS). In this subgroup, 35 

lesions (34.7%) had an MRI size within �/- 0.5 cm of the pathologic size; 

40 (39.6%) were overestimated by MRI and 26 (25.7%) were underestimated. 

Patient age, tumor histology, LVI and grade did not predict 

concordance between pathologic and MRI size. However, small MRI lesion 

size more accurately correlated with pathologic tumor size. While 51.1% of 

tumors that had concordant MRI and pathologic findings within 0.5 cm 

were �1 cm on MRI, no tumor found to be � 5 cm on MRI was within 

�/-0.5 cm on final pathology (p�0.001). Conclusions: MRI accurately 

predicts pathologic tumor size only when the size of the lesion on MRI is �1 

cm. 


Comparison of long-term results of endoscopic video-assisted breast 

surgery (VABS) between transaxillary retromammary approach (TARM) and 

periareolar approach. Presenting Author: Koji Yamashita, Nippon Medical 

School, Tokyo, Japan 

Background: The breast conserving surgery (BCS) and the sentinel node 

(SN) biopsy became to be recognized as the standard treatment for early 

breast cancers. We have reported about cosmetic effectiveness and lower 

infestation of the video-assisted breast surgery (VABS) for the breast 

diseases. We devised the trans-axillary retro-mammary (TRAM) approach of 

VABS. It needs only one skin incision in the axilla and can treat any tumor 

of the breast without making any injuries on the breast skin. We evaluated 

the aesthetic results and the curability of this surgical method. Methods: We 

have performed VABS on 300 patients since December, 2001. The newly 

devised TARM was performed on 120 patients of early breast cancer, stage 

I and II. After endoscopic SN biopsy, we elongated the axillary skin incision 

to 2.5 cm. We dissected major pectoral muscle fascia to detach retromammary 

tissue behind the tumor. We cut the mammary gland with clear 

surgical margin, and removed it through the axillary port. The breast 

reconstruction was made by filling absorbable oxydized cellulose. The 

postoperative aesthetic results were evaluated by ABNSW. Results: BCS 

was performed on 286 patients (26 after preoperative chemotherapy) and 

skin-sparing mastectomy on 14. There was no serious complication after 

surgery. Surgical margin was minimally positive in 2. The original shapes of 

the breast were preserved well. The follow-up is 126 months at maximum 

and 74 months on average. There is 3 locoregional recurrences and 14 

distant metastases. 5-year survival rate is 97.3%. With regard to TARM, 

The skin incision only in the axilla made better looks and shapes of the 

breast. It could be applied for tumors in any area of the breast without 

tumor nipple extension. The reconstruction with oxidized cellulose needs 

no excessive detachment of the skin beyond the surgical margin. The 

postoperative esthetic results were excellent and better. The sensory 

disturbance was minimal. All patients expressed great satisfaction. 

Conclusions: VABS can be considered as a good surgical procedure 

concerning locoregional control and esthetics. TARM is better on the 

patients without tumor nipple extension. 


Magnetic resonance imaging (MRI) evaluation of pathologic complete 

response (pCR) in different breast cancer subtypes after neoadjuvant 

chemotherapy (NAC). Presenting Author: Lucia Gonzalez-Cortijo, Hospital 

Universitario Quiron Madrid, Madrid, Spain 

Background: MRI is being used to address treatment response to NAC in 

breast cancer patients. However, its ability to predict pCR in histologically 

different tumors remains unclear. We tried to investigate the usefulness of 

MRI in evaluation of pCR in different breast cancer subtypes after 

treatment with NAC. Methods: Serial MRI studies were acquired before, 

during and after NAC in 75 evaluable patients. MRI interpretation included 

lesion size, morphology and dynamic enhanced evaluation imaging with 

initial and late enhancement. On the basis of the final MRI, response was 

determined to be a clinically complete response (CCR) when no residual 

tumor and no late enhancement were found. By using inmunohistochemistry 

and fluorescence in situ hybridization (FISH) for human epidermal 

growth factor receptor 2 (HER2/neu) amplification, tumors were divided 

into three subtypes: triple negative, HER2 positive, and estrogen receptor 

(ER) positive/HER2 negative. Every patient received chemotherapy with 

taxanes and anthracyclines and HER2 positive tumors were treated with 

trastuzumab. All patients received surgery. pCR was defined as no residual 

invasive tumor in the surgical specimen. Ductal carcinoma in situ residual 

disease was considered pCR. Results: 22 of 75 patients (29%) achieved a 

CCR on the final MRI. Of 22 patients with CCR all 22 (100%) were 

confirmed pathologically. 19 were pathologic complete responses and 3 

showed in situ microscopic residual disease. 12 (55%) were HER2 positive 

tumors, 4 (18%) were triple negative tumors and 6 (27%) were ER 

positive/HER2 negative tumors. The negative predictive value of MRI for 

predicting pCR after NAC was 100%. Conclusions: Absence of both residual 

tumor and late enhancement in MRI predict pCR with high accuracy in 

triple negative, HER2 positive and ER positive/HER2 negative breast 

cancer after NAC. 


The impact of primary surgery on stage IV breast cancer. Presenting Author: 

Ella Harris, Breastcheck, Dublin, Ireland 

Background: The role of primary surgery in metastatic breast cancer is 

unclear. Here in we have performed metaanalysis on available data to 

assess the role of surgery on oncological outcome in patients with stage IV 

breast cancer. Methods: A comprehensive search for published trials that 

examined outcome following removal of primary disease in stage IV breast 

cancer was performed using MEDLINE and cross referencing available 

data. Reviews of each study were conducted, and data were extracted. 

Primary outcome was overall survival related to surgical removal of primary 

disease. Results: We identified 15 relevant studies of which 10 were 

appropriate for analysis. Data was available on 28,693 patients with stage 

IV disease, of whom 52.8% underwent removal of the primary carcinoma. 

Patients undergoing primary surgery in this setting were more likely to be 

alive at 3 years 40% vs. 22% (OR 2.32 CI 2.08-2.6, p�0.01 (surgery vs. 

no surgery)). Analysis of subgroups for selection to surgery or not, favoured 

smaller tumours, fewer comorbidities, fewer metastases (p�0.01). There 

was no difference between the two groups in location of metastases, grade 

of tumour or receptor status. Conclusions: Patients undergoing removal of 

primary carcinoma in the setting of stage IV breast cancer appear to have an 

improved overall survival. However the available data suggest that these 

surgical patients probably have better prognosis stage IV disease than those 

patients not undergoing surgery. 



Prognostic impact of local therapy of the primary tumor in metastatic breast 

cancer. Presenting Author: Isabelle Katrin Himsl, Ludwig Maximilians 

University Munich, Munich, Germany 

Background: MBC is an incurable disease and the treatment aims are 

palliative. It is not known whether the difference in OS is the result of a 

selection bias or caused by dissemination of tumor stem cells in pat. 

without surgery. Methods: To identify the impact of surgical therapy of the 

primary tumor, a mono-institutional retrospective review from 1990-2006 

was done in primary MBC pts. Results: We identified 269 pts. with primary 

MBC, 63 of whom had received no surgical local treatment. Mean follow up 

is 65 m for pts., observed mortality 87%. Location of metastases were bone 

only (36%), visceral or soft tissue (one organ only, 19%), multiple organs 

(40%) and including CNS metastases (5%). 50% had G3 tumors, 25% 

negative receptor status, 7% non-resectable local disease and 57% 

symptomatic metastases. In univariate analysis, pat. without local treatment 

had a median OS of 14.4m, pts. with local therapy 28.1m (p�0.001). 

Pts. not receiving local treatment were significantly more likely to have 

multiorgan or CNS involvement (p� 0.001), symptoms at diagnosis 

(p�0.009), non-resectable tumor (p�0.001) and were more likely to die 

within the first 30d after diagnosis (p� 0.001). In multivariate analysis, 

local treatment had no significant impact on OS. The only significant 

variables were: number of involved organs, symptoms at diagnosis, receptor 

status, grading, and size of the local tumor. The effect of local treatment on 

OS was not homogenous across subgroups. Local treatment was a significant 

factor in tumors with only one involved organ or asymptomatic disease. 

In all other groups, local treatment did not result in an OS benefit. 

Conclusions: Our cohort showed significantly improved OS in univariate 

analysis if the breast primary tumor had been removed in metastatic 

disease. Yet, the decision for local treatment was biased by the extent and 

presentation of metastatic disease. Pts. with more advanced MBC seem not 

to benefit from removal of the primary tumor. However, we see significant 

influence in pts. with limited and asymptomatic MBC. The potential 

dissemination of tumor stem cells from the breast primary in metastatic but 

locally untreated disease may only influence prognosis in pts. with limited 

disease. 


Postmastectomy radiotherapy for patients with one to three positive lymph 

nodes: Utilization and benefit. Presenting Author: Dezheng Huo, The 

University of Chicago, Chicago, IL 

Background: The use of postmastectomy radiotherapy (PMRT) for patients 

with pT1-2pN1 tumors is controversial and ASCO guidelines indicate that 

there is insufficient evidence to make recommendation. We hypothesized 

that the use of PMRT in this patient group was low and has minimal impact 

on survival. Methods: The study includes 83,742 invasive breast cancer 

patients from the National Cancer Data Base who underwent mastectomy 

with pT1-2 and pN1 disease from 1998-2007. Neoadjuvant cases were 

excluded. We investigated factors related to PMRT use using cross tables 

and logistic regression. Survival analysis was conducted using Cox models 

in patients diagnosed from 1998-2002, with a median follow-up of 5.5 

years. Results: The proportion of N1 patients undergoing PMRT remained 

stable from 1998 to 2007, at approximately 20%. PMRT use increased 

with larger tumor size (15.4% in T1N1 and 24.4% in T2N1), and with 

increasing positive lymph nodes (14.6%, 23.7%, and 35.2% for patients 

with one, two, or three positive nodes, respectively). Age was significantly 

inversely correlated with PMRT use: the proportion of patients receiving 

PMRT was 31.3% for age �40 years and 8.2% for 80� years (p�0.001). 

Asians are more likely to receive PMRT (25.5%), compared to other races 

(20.3% white, 20.7% black, and 20.6% Hispanic; p�0.001). PMRT also 

varied considerably by facility location, the highest in the Northeast at 

31.3%, and the lowest in the South at 15.8% (p�0.001). There was only 

minor difference in PMRT use between different types of cancer centers. 

Insurance status, income and education level were not associated with 

PMRT use. After adjusting for prognostic factors in the Cox models, PMRT 

use was associated with a reduced mortality (hazard ratio�0.87, 95% CI: 

0.81-0.93; p�0.001). The multivariable-adjusted 5-year death rate was 

16.1% in patients receiving PMRT and 18.1% in patients not receiving 

PMRT. For pT1N1 tumors the absolute benefit was 1.3% compared to 

2.7% for pT2N1 tumors. Conclusions: PMRT use varies with facility and 

clinicopathologic factors, but not socioeconomic factors. The risks of 

radiation need to be weighed against the 2% absolute survival benefit when 

deciding on whether to use PMRT for pT1-2N1 patients. 


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Role of breast surgery in T1-T3 breast cancer patients with synchronous 

bone metastases. Presenting Author: Edoardo Botteri, European Institute 

of Oncology, Division of Epidemiology and Biostatistics, Milan, Italy 

Background: The role of breast surgery in advanced breast cancer (ABC) is 

controversial. The main potential advantage of removing the primary tumor 

is to eliminate the source of further metastatic spread. While previous 

studies addressed the question in very heterogeneous populations (e.g. 

patients with any local and distant extension), we have focused on a 

homogeneous series of ABC patients. Methods: From our institutional 

Tumor Registry we selected 191 consecutive women diagnosed between 

2000 and 2008 with locally operable (T1-T3) ABC, synchronous bone 

metastases and no other distant sites involved. The progression free 

survival (PFS) was calculated from diagnosis to the date of progression, 

defined as either a new site of metastatic disease or clinical/radiographic 

evidence of increasing tumor burden at a previously known bone metastatic 

site. Results: Median age was 51 years and 92% of the women had an 

endocrine-responsive tumor. One-hundred and thirty patients out of 191 

(68%) underwent surgery at the time of diagnosis, while 61 (32%) did not. 

Twenty-six of the operated patients (20%) had previously undergone 

neoadjuvant chemotherapy; 15 (12%) had positive or undetermined 

surgical margins. Operated and non-operated patients were similar with 

respect to age, tumor size, nodal involvement, estrogen and progesterone 

receptor status, HER2 overexpression and Ki-67, but differed in terms of 

number of bone metastatic sites: a single metastasis was detected in 34 

(26%) operated and 7 (11%) non-operated cases (P�0.02). First-line 

treatment strategies with endocrine therapy, chemotherapy and Trastuzumab 

were similarly distributed between the two groups. The 5-year PFS 

was 22.0% and 10.4% in operated and non-operated patients, respectively. 

The multi-adjusted hazard ratio was 0.62 (95% confidence interval 

0.39-0.98) in favor of surgery. The exclusion of the patients who had 

received neoadjuvant chemotherapy and patients with positive or undetermined 

surgical margins did not alter the results. Conclusions: In this large 

and homogeneous series of ABC patients with synchronous bone metastases, 

the role of breast surgery had a favorable impact on the progression of 

the disease, indicating a potential survival benefit. 


Patient factors and satisfaction in the choice of contralateral prophylactic 

mastectomy. Presenting Author: Amanda Kathleen Arrington, City of Hope, 

Duarte, CA 

Background: The percentage of women undergoing contralateral prophylactic 

mastectomy (CPM) has more than doubled in recent years. The 

underlying reasons patients choose CPM have not been fully evaluated. Our 

objective was to survey patients who have undergone a unilateral mastectomy 

with or without CPM to identify reasons surrounding their decisions. 

Methods: After obtaining IRB approval, a 30-question cross-sectional 

validated survey was mailed to 691 patients who underwent mastectomy 

from 1972 to 2011 and are receiving treatment or surveillance at City of 

Hope. The questionnaire queried the factors behind the choice of surgery 

for each patient. Demographic questions were included and patient charts 

were also reviewed. Results: The overall response rate was 53% (N�368). 

Patients were classified into those who underwent mastectomy with CPM 

(N�139, 38%) and those who underwent mastectomy without CPM 

(no-CPM) (N�229, 62%). Of returned surveys, the median age was 50; 

24% of patients reported a family history of breast cancer (42% CPM vs. 

13% no-CPM, p�0.0001) and 80% of patients had education beyond the 

high school level (87% CPM vs. 77% no-CPM, p�0.013). PM patients 

reported being “very concerned” about breast cancer more often than 

no-CPM patients (46% vs. 34%, p�0.033).The primary reasons for CPM 

were: concern of recurrence (55%), cosmetic symmetry (27%), physician 

recommendation (17%), and unclear pre-operative imaging (9%). When 

questioned about regrets, the top response was decreased sensation 

(26%). Although 81% of CPM patients were “very satisfied” with their 

decision, 32% of no-CPM patients reported the same level of satisfaction 

with their decision (p�0.0001). For no-CPM patients, the primary reasons 

for the choice of no-CPM was physician advice and “monitoring is 

sufficient”; with 18% of the responders still considering a CPM. Conclusions: 

Patients’ perceived risk of contralateral breast cancer is the primary reason 

for CPM. CPM patients tend to be more satisfied with their decision 

compared to no-CPM patients. This may be related to the active decisionmaking 

thought processes and education necessary to choose CPM. Further 

patient education is warranted to minimize the risk of regret in making this 

decision. 




Predictors of recurrence in postmastectomy patients with one to three 

positive lymph nodes. Presenting Author: Tracy-Ann Moo, New York 

Presbyterian Hospital, Weill Cornell Medical Center, New York, NY 

Background: Although the role of post mastectomy radiation therapy 

(PMRT) is well established in women with � 4 positive axillary lymph nodes 

(ALN), its indications in patients with 1-3 positive ALN is controversial. A 

recent large meta-analysis suggested a survival benefit in patients with 1-3 

positive ALN who received PMRT. However, because recurrence rates in 

this group are low, identifying a subgroup of patients at higher risk for 

locoregional recurrence (LRR) could aid decision-making about PMRT. 

Methods: From an institutional database, 1,333 breast cancer patients who 

underwent mastectomy between 1996 and 2006 and had 1-3 positive ALN 

were identified. Among these, T3/T4 tumors and those who received PMRT 

were excluded. 926 patients were analyzed. The Kaplan-Meier method and 

Cox regression was used to explore clinicopathologic features that predicted 

LRR, distant metastases (DM), and recurrence-free survival (RFR). 

Results: Median follow-up was 7yrs. LRR occurred in 49 patients and DM in 

126 patients. LRR and/or DM occurred in 146. On univariate analysis, 

factors significantly affecting LRR recurrence were increasing tumor size 

(p�0.04), age �50 (p�0.003), histologic grade (p�0.03), nuclear grade 

(p�0.008), lymphovascular invasion (LVI) (p�0.0001), and macroscopic 

ALN metastases (p�0.02). On multivariate analysis, age �50 (p�0.0012) 

and the presence of LVI (p�0.0001) predicted a higher LRR; increasing 

tumor size (p�0.0005), age �50 (p�0.04), higher histologic grade 

(p�0.01), number of positive ALN (p�0.04), LVI (p�0.02), macroscopic 

ALN metastases (p�0.02), and no chemotherapy (p�0.02) predicted a 

significantly lower RFR. Conclusions: Pts with T1-2 tumors and 1-3 positive 

ALN are at low risk of isolated LRR; however, patients �50 and with LVI 

may have additional risk that warrants consideration of PMRT. 


Feasibility of sentinel node biopsy in patients with locally advanced breast 

cancer after neoadjuvant therapy: A pilot study. Presenting Author: Ariadna 

Tibau Martorell, Hospital de la Santa Creu i Sant Pau, Medical Oncology 

Department, Barcelona, Spain 

Background: Sentinel lymph node biopsy (SLNB) is a widely used staging 

method for patients with early breast cancer. Neoadjuvant Therapy (NT) 

modifies the anatomical conditions in the breast and axilla, and thus 

reliability of SLNB after NT remains controversial. The aim of this study is 

to prospectively evaluate the feasibility and accuracy of this procedure in 

this particular group of patients. Methods: Between December 2007-2011, 

69 patients (mean age 56 years) with locally advanced breast cancer 

(LABC) were prospectively studied. Patients were T1-4, N0-1, M0. Prior to 

surgery, 61 patients received chemotherapy (CT) (adryamicin/cyclophosphamide 

followed by docetaxel) and 8 patients endocrine therapy (ET). Thirty 

nine patients were initially node-negative (cN0) and 30 patients had 

clinical/ultrasound node-positive confirmed by cytology (cN1) at presentation. 

All patients were clinical and ultrasound node-negative after NT. The 

study contained two groups of patients: group A (validation) included the 

first 29, associated with an axillary lymph node dissection (ALND) after NT, 

in order to validate the study, and group B included the last 40, only 

associated with an ALND when SLNB was positive or not found. Results: 

Whole SLNB identification rate was 89.9%, and no significant differences 

were found between patients initially cN0 (92%; 36/39) and initially cN1 

(87%; 26/30). Four of 7 patients in whom SLNB was not found had 

residual nodal metastasis after NT (3 of them were initially cN1). Sentinel 

lymph nodes were successfully identified in 87% (7/8) of patients after ET 

and in 90% (55/61) of patients after CT. There was one false negative (FN) 

case after CT in group A (9% of overall false negative rate, initially cN0) and 

there were no FN cases after ET. Positive SLNB were higher in initially cN1 

group (53%; 16/30) than in initially cN0 group (18%; 7/39). Conclusions: 

SLNB after NT (CT or ET) is safe and feasible in patients with LABC, not 

only in initially cN0 but also in initially cN1. It accurately predicts the 

status of the axilla and avoids unnecessary ALND. 


Radiofrequency ablation (RFA) of breast cancer: A multicenter retrospective 

analysis. Presenting Author: Toshikazu Ito, Rinku General Medical 

Center, Izumisano, Japan 

Background: Local ablative therapy of breast cancer represents the next 

frontier in the minimally invasive breast-conservation treatment. We 

performed a retrospective study of ultrasound-guided percutaneous radiofrequency 

ablation (RFA) of breast cancers to determine safety and 

complication related to this treatment. Methods: Four hundred and ninetyseven 

patients with core biopsy proven breast carcinoma in 10 institutions 

of non-surgical ablaton study group underwent RFA without surgical 

excision were enrolled in this study. Results: Mean patient age was 54 years 

(range 22 - 92 years). Mean tumor size was 1.6 cm. Four hundred and 

twenty-five tumors ( 86 %) were � 2 cm. The median follow-up period was 

50 months (range 3–92months). The mean required for ablation was 19 

minutes (range, 4- 72 minutes), and the average temperature of the tumor 

after ablation was 91 degrees Celsius. The local recurrence rate after RFA 

was higher in tumors of negative estrogen receptor (8 of 78, 10%) than in 

tumors of positive estrogen receptor (17 of 437, 4%; p�0.05), and was 

higher in tumors of positive HER2/neu than in tumors of negative 

HER2/neu (14.9% vs. 3.2%; p�0.01). The local recurrence rate after RFA 

was higher in tumors of positive node than in tumors of negative node 

(9.8% vs. 3.6%), and was higher in tumors without irradiation than in 

tumors with irradiation (18.2% vs. 3.2%; p�0.001). The local recurrence 

rate after RFA was higher in tumors of � 2 cm (13 of 72, 18%) than in 

tumors of � 2 cm (11 of 425, 3%; p�0.001). RFA-relating adverse events 

were observed in 17 patients of local pain, 14 patients of skin burn and 4 

patients of retraction of nipple. Conclusions: RFA is considered to be a safe 

and promising minimally invasive treatment of small breast cancer � 2cm 

in diameter. Further studies are necessary to optimize the technique and 

evaluate its future role as local therapy for breast cancer. 


Can primary tumor markers of cancer-initiating cells predict lymph node 

positivity in breast cancer patients? Presenting Author: Anees B. Chagpar, 

Yale University, New Haven, CT 

Background: Cancer initiating cells, characterized by ALDH1 positivity 

and/or colocalization of ALDH1 and CD44, have been shown to be 

associated with poor prognosis in breast cancer patients. The prognostic 

value of these tumor markers with respect to prediction of lymph node (LN) 

status remains unclear. Methods: Tissue microarrays from a cohort of 223 

breast cancer patients diagnosed between 2003 and 2007 were evaluated 

using the AQUA method for quantitative immunofluorescence for CD44 

and ALDH1. These data, along with other clinicopathologic data, were 

correlated with LN positivity. Results: The median patient age of the cohort 

was 56 (range; 26-89), with a median tumor size of 1.5 cm. 72 (32.0%) 

patients were LN positive. The median number of LNs excised was 3 (range; 

1-27). Of the LN positive patients, the median number of positive LNs was 

1.5 (range; 1-24). Levels of CD44, ALDH1, and ALDH1 colocalizing with 

CD44 did not correlate with number of positive LNs (Spearman rho 

coefficients: -0.042, 0.131, and 0.058, respectively), nor overall LN 

status. Tumor size and lymphovascular invasion (LVI) were the only factors 

found to be significantly correlated with LN status. Conclusions: While 

ALDH1 colocalized with CD44 has been found to be associated with poor 

prognosis in breast cancer patients, these markers do not predict LN status. 

Given that the only factors that reliably predict LN status are tumor size and 

LVI, further work is required to find primary tumor markers that may predict 

LN status in order to spare patients axillary surgery. 

Factor LN - LN � P value 

Median total CD44 46.6 41.6 0.499 

Median total ALDH1 390.6 442.4 0.193 

Median ALDH1 colocalizing with CD44 413.6 454.8 0.562 

Median patient age 53 52 0.083 

Median tumor size 1.25 2.40 �0.001 

LVI� 15.2% 46.7% �0.001 

ER� 78.7% 85.7% 0.332 

PR� 69.9% 73.0% 0.738 

HER2-neu� 12.8% 13.2% 1.000 

High-tumor grade 23.1% 27.0% 0.092 



Association of pathologic complete response following neoadjuvant chemotherapy 

with survival among young women with breast cancer. Presenting 

Author: Rachel Adams Greenup, Massachusetts General Hospital, Boston, 

MA 

Background: Neoadjuvant chemotherapy is increasingly being used in the 

treatment of breast cancer, yet data on efficacy and significance of 

pathologic complete response (pCR) is limited among young women. We 

sought to determine whether timing of chemotherapy impacted diseasefree 

(DFS) or overall survival (OS), and whether pCR is associated with 

improved prognosis among young women with breast cancer. Methods: We 

performed an IRB-approved review of women �40 years old who received 

treatment for stage I-III breast cancer during 1996-2008 at our institution. 

DFS and OS were determined through use of state tumor registry, death 

certificate data, and Social Security Master Death Index. Tumor biology was 

categorized as hormone receptor positive (HR�), HER-2�, or triple 

negative (TN) breast cancer. pCR was defined as lack of invasive cancer in 

the breast and axilla on final pathologic review. Cox regression analyses 

were conducted to evaluate the hazard ratios (HRs) of the association 

between chemotherapy and outcomes. Results: 370 women �40 years old 

(median age � 36.5, range: 22-40) were treated with systemic therapy for 

stage I-III breast cancer. 54.7% of tumors were HR�, 20.9% were 

HER-2�, and 24.4% were TN. After adjusting for stage, there was no 

difference in DFS or OS among women who received neoadjuvant versus 

adjuvant chemotherapy (p�0.6 and 0.5 respectively). pCR following 

neoadjuvant chemotherapy was higher among HER-2� (50%) and TN 

(28.6%) tumors when compared to HR� tumors (17.6%). Among women 

who received neoadjuvant chemotherapy, 10-year DFS and OS rates were 

significantly higher when pCR was achieved when compared to lack of pCR 

(HR�0.20, p value�0.01 and HR�0.13, p�0.05). pCR with neoadjuvant 

chemotherapy trended towards higher 10-year DFS and OS when compared 

to women who received adjuvant chemotherapy (HR�0.30, p value�0.08 

and HR�0.20, p�0.1). Conclusions: pCR after neo-adjuvant chemotherapy 

is associated with improved disease-free and overall survival in 

young women with breast cancer. Pathologic complete response may be a 

valuable surrogate marker for survival, and aid in the evaluation of 

therapeutic efficacy in young breast cancer patients. 


Clinical findings and outcomes from MRI staging of breast cancers in 

women. Presenting Author: Akshara Raghavendra, University of Southern 

California Norris Comprehensive Cancer Center, Los Angeles, CA 

Background: For patients diagnosed with breast cancer, case series have 

shown that staging MRI can detect occult breast cancers in 1-10% of 

cases. Prevalence and risk factors in underserved populations remain 

unclear. Methods: We performed a retrospective analysis of all patients, 

newly diagnosed, with breast cancer who had a preoperative staging MRI 

seen at Norris Comprehensive Cancer Center and LAC �USC, that cares for 

an underserved and minority population, from 2006 to 2011. Demographic, 

clinicopathologic and imaging data were obtained through a review 

of electronic records. Non index lesions were defined as those not known to 

be malignant, not presenting with clinical, mammographic or ultrasound 

findings, in a different quadrant and given an MRI BIRADS score of 4 or 5. 

Results: A total of 718 patients were analyzed and 148 patients (21%) had 

a total of 187 non index lesions; 63% were ipsilateral, 26% contralateral 

and 11% bilateral. As initial evaluation of non-index ipsilateral lesions, 71 

(38%) had biopsy, 24 (13%) had excision and 34 (18%) had mastectomy. 

For contralateral non-index lesions, 41 (22%) had contralateral biopsy, 6 

(3%) had excision and 11(6%) had mastectomy. Among all non index 

lesions, 111 (59%) were benign, 14 (7%) DCIS and 62 (33%) invasive 

cancer. Occult ipsilateral cancer was detected in 50 (6.9%) of patients and 

contralateral in 10 (1.4%) and bilateral in 6 (0.8%). Conclusions: The 

occult cancer detection rate with staging MRI was in this 9.2% of this 

diverse population. No clear risk factors were identified, with detailed 

factors, including BRCA status to be updated and reanalyzed. 

Variable Total series Non index lesions Occult cancers 

Total 718 148 66 

Hispanic (304/631) 48% (63/125) 50% (18/55) 33% 

African American (50/631) 8% (10/125) 8% (3/55) 5% 

Caucasian (193/631) 31% (36/125) 29% (25/55) 45% 

Asian (66/631) 10% (11/125) 9% (6/55) 11% 

Others (17/631) 3% (4/125) 3% (3/55) 5% 

Age: 50 (422/718) 59% (82/148) 55% (45/66) 68% 

Hormone receptor�/HER2– (288/513) 56% (56/94) 60% (25/39) 64% 

HER2� (105/478) 22% (24/92) 26% (10/39) 26% 

Triple negative (75/569) 13% (10/108) 9% (3/43) 7% 


79s 


Long-term rates of breast cancer in a population of women with ductal 

carcinoma in situ treated by breast-conserving surgery. Presenting Author: 

Eileen Rakovitch, Institute for Clinical Evaluative Sciences, Sunnybrook 

Health Sciences Centre, Toronto, ON, Canada 

Background: Ductal Carcinoma in Situ (DCIS) is a non-invasive form of 

breast cancer which is often treated by breast-conserving surgery. The 

addition of radiotherapy to surgery has been shown to reduce the risk of 

local recurrence (LR), but use of radiotherapy varies. It is not known to what 

extent women with DCIS are at risk for recurrent cancer due to the omission 

of radiation therapy. We studied a large provincial cohort of women with 

DCIS who were treated with breast-conserving surgery for factors which 

predict local recurrence and estimate the impact of radiotherapy on local 

recurrence and long-term rates of breast preservation. Methods: All women 

diagnosed with DCIS in Ontario from 1994 to 2003 were identified. 

Treatments and outcomes were identified through administrative databases 

and validated by chart review. Women treated with breast-conserving 

surgery, alone or with radiotherapy, were included. Survival analyses were 

used to study local recurrence (DCIS or invasive) in relation to patient 

characteristics, tumour characteristics and treatment. Results: The cohort 

included 3975 women who were treated with breast-conserving therapy; of 

these, 1949 (49%) received radiation. At 10 years median follow-up, 736 

developed LR(19%). LR developed in 259 of 1949 women who received 

radiotherapy (13%) and in 477 of 2026 women who did not (24%; 

p�0.001). The differences were significant for both invasive LR (7% vs. 

14%; p�0.001) and DCIS recurrence (6% vs.9%; p�0.001). The 10-year 

cumulative rate of mastectomy was 13% for women who received radiotherapy 

compared to 17% for those who did not (p�0.01).We estimate that 

29% (N�214) of all local recurrences diagnosed in Ontario in women 

treated for DCIS between 1994 and 2003 would be prevented if all 

patients received radiotherapy. Conclusions: The omission of radiation 

therapy after breast-conserving surgery in women with DCIS resulted in a 

substantial number of local recurrences that might have been avoided and 

lower rates of breast preservation. Improvements in guidelines that facilitate 

the selection of women in whom radiotherapy can be avoided are 

needed. 


Overuse of sentinel lymph node biopsy with breast conserving surgery for 

clinical DCIS. Presenting Author: Natalie Beckman Jones, The Ohio State 

University Medical Center, Columbus, OH 

Background: The National Comprehensive Cancer Network (NCCN) guidelines 

recommend against sentinel lymph node biopsy (SLNB) for ductal 

carcinoma in-situ (DCIS) treated with breast conservation surgery (BCS). 

SLNB is appropriate with mastectomy because it precludes subsequent 

SLNB if invasive cancer is identified. However, SLNB is commonly 

performed with BCS for DCIS. We hypothesize SLNB use in the setting of 

BCS for DCIS varies and may be over used in some cancer centers. Methods: 

We examined 6,070 cases with initial biopsy showing DCIS presenting to 

13 institutions participating in the NCCN Breast Outcomes Database from 

1998-2009. Receipt of SLNB was defined as SLNB performed at any point 

in primary treatment for those with a final diagnosis of DCIS or at the first 

surgical procedure for those upstaged to invasive cancer. Characteristics of 

patients who did and did not have SLNB were compared using Chi-square 

tests. Logistic models adjusting for clinical and pathologic variables were 

performed to assess factors associated with use of SLNB. Results: Of 3,725 

treated with BCS, 778 (20.9%) had SLNB. Among 2,345 treated with 

mastectomy, 1,484 (63.3%) had SLNB. Within BCS, patients presenting 

with clinical symptoms (vs. screening detected) were more likely to have 

SLNB (p�0.0006, OR: 1.76; 95% CI 1.31-2.36). For both groups, 

presence of comedo necrosis, year of diagnosis, and treating institution 

were predictors of SLNB (p�0.0001). 1,171 (19.3%) were upstaged from 

DCIS at initial biopsy to invasive cancer on final pathology. 212 (18.1% 

invasive cancer group) had positive nodes. Use of SLNB increased over 

time from 1998-2009 in mastectomy group. Among BCS group, SNLB use 

decreased over the first half of the study period and then remained stable at 

approximately 15% across all centers. Conclusions: Although use of SNLB 

has decreased over time, a substantial percentage of patients undergoing 

BCS for DCIS receive SNLB. Practices vary considerably across centers. 

SLNB can be performed as a second procedure for those treated with BCS 

and identified with invasive cancer, thereby avoiding unnecessary risk of 

significant morbidity. Breast programs should review their practices to 

curtail the use of unnecessary surgery for women with DCIS. 




Axillary lymph node status in breast cancer staging: What patient and tumor 

factors affect the accuracy of ultrasound-guided fine needle aspiration? 

Presenting Author: Celin Chacko, Montefiore Medical Center, Bronx, NY 

Background: The purpose of the study is to evaluate the accuracy of 

ultrasound-guided fine needle aspiration (FNA) of axillary lymph nodes(ALNs) 

in patients with breast cancer and to determine factors that 

influence accuracy of ultrasound-guided FNA. Methods: Retrospective 

review of patients with breast cancer who had FNA of ALNs as well as 

sentinel lymph node excision or complete axillary dissection. Patients 

treated with neoadjuvant chemotherapy were excluded. 55 axillary FNAs in 

54 patients were included in the final analysis. Pathology reports were 

reviewed for size of the primary tumor, FNA results, number of positive 

ALNs, and greatest tumor size in ALNs. FNA was performed if a suspicious 

lymph node was identified. Surgical sentinel lymph node biopsy or full 

axillary dissection were the reference standard. Micrometastases (� 0.2 

mm) and isolated tumor cells in the lymph node were included in the 

negative group. Atypical and nondiagnostic FNA results were considered 

negative cytologic results. Significance was analyzed using the Mann- 

Whitney test. Results: Size of the primary cancer ranged from 0.3 mm to 

8.5 cm. The sensitivity of FNA was 73%, with positive predictive value of 

97% and negative predictive value of 52%. The NPV of FNA for primary 

tumors �1 cm, 1.1-2, 2.1-5 and �5 cm is 100%, 36%, 50% and 66% 

respectively. Correlation of primary tumor size with sensitivity of FNA was 

not statistically significant. The sensitivity of FNA for lymph nodes with 

metastatic deposit � 5mm, 6-10mm, 11-15mm, 16-20mm, and 21mm� 

is 0%, 57%, 59%, 89%, and 100%, which is statistically significant (p � 

0.007). The number of positive ALNs at axillary dissection is not correlated 

to the sensitivity of FNA. The sensitivity of FNA for 1-3, 4-9 and 10� 

positive ALNs is 78%, 64% and 80%. Conclusions: Our findings indicate 

that FNA of suspicious axillary lymph nodes is valuable even in small 

tumors, which differs from the literature. The overall negative predictive 

value of FNA is 52%, so sentinel lymph node biopsy is essential after 

negative FNA. Sensitivity of FNA increases with the size of the metastatic 

deposit in the lymph node, but is not correlated to the number of positive 

ALNs found at dissection. 


Phase I/II trial of partial breast irradiation (PBI) with various concurrent 

chemotherapy regimens. Presenting Author: Lana Maria De Souza Lawrence, 

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 

Baltimore, MD 

Background: Potential benefits of concurrent chemo-radiation include: shorter 

duration of treatment, smaller interval between surgery and adjuvant therapies, 

and synergistic effects. We have previously shown that PBI with concurrent dose 

dense doxorubicin and cyclophosphamide (ddAC) is well tolerated (Zellars JCO 

2009). We performed a follow-up feasibility trial of PBI delivered concurrently 

with other various chemotherapy regimens. Methods: Women with T1-2, N0-1 

breast cancer s/p lumpectomy with �2 mm margins were eligible. Chemotherapy 

regimen was at the discretion of the medical oncologist (Table). PBI (40.5 Gy in 

15 daily 2.7 Gy fractions) was delivered within the first 2 cycles of chemotherapy. 

Primary endpoints were hematologic and non-hematologic toxicities 

graded according to Common Terminology Criteria for Adverse Events manual (v. 

3.0). Results: Thirty-four patients enrolled with median f/u of 19.2 mos. (4.0 - 

38.6). Mean tumor size was 1.8 cm (�/- 0.7 cm), 71% pN0, 68% HR �, 18% 

Her2 �. All patients completed concurrent chemo-radiation. Three patients had 

a 3-8 day delay in chemotherapy (1 grade 2 thrombocytopenia; 1 Grade 2 liver 

enzymes; 1 T desensitization). There was 1 local (DCIS) and no regional/distant 

recurrences or deaths. Toxicity: 2 grade 4 neutropenia (ddAC, TCarboH); 1 grade 

3 neutropenia (post-AC paclitaxel); 1 Grade 3 hyponatremia and DVT (TC); 1 

syncope (TAC). None had � grade 2 radiation dermatitis. Conclusions: PBI and 

concurrent chemotherapy is associated with minimal toxicity and appears to be 

well tolerated. These results deserve further investigation. Funded by The Breast 

Cancer Research Foundation. 

Regimen Patients N�34 Dose/schedule Schedule No. of cycles 

Standard AC 

then P 

Dose dense 

AC then P 

2 A 60 mg/m 2 

C 600 mg/m 2 

P80mg/m 2 

12 A 60 mg/m 2 

C 600 mg/m 2 

G-CSF 

P80mg/m 2 

TAC 1 T 75 mg/m 2 

A50mg/m 2 

C 500 mg/m 2 

TC* 16 T 75 mg/m 2 

C 600 mg/m 2 

TCarboH 3 T 75 mg/m 2 

Carbo AUC6 

C#1 H 8mg/kg, then 6mg/kg 

Q 3 wks 

Qwk 

Q 2 wks 

Qwk 

4 

12 

4 

12 

Q 3 wks 6 

Q 3 wks 4-6 

Q 3 wks 6 

Abbreviations: C, cyclophosphamide; P, paclitaxel; T, docetaxel (Taxotere); A, doxorubicin 

(Adriamycin); Carbo, carboplatin; H, trastuzumab (Herceptin); G-CSF, granulocyte colony 

stimulating factor. 

*One patient had 6 cycles of TC, all others had 4 cycles. 


Breast cancer surgery during pregnancy. Presenting Author: Rakesh Surapaneni, 

Cooper University Hospital, Camden, NJ 

Background: There is limited literature on breast surgery during pregnancy. 

We present prospective registry data on 88 breast cancer patients who 

underwent breast cancer surgery during pregnancy. Methods: The Cancer 

and Pregnancy Registry is a voluntary international registry that prospectively 

collects the clinical course, treatment, and disease outcome of 

women diagnosed with cancer during pregnancy and the perinatal and 

neonatal outcomes of their children. Results: We identified 88 patients who 

were diagnosed with breast cancer and had surgery while pregnant. 59 

patients (67%) underwent Mastectomy while29 patients (32%) underwent 

breast conserving surgery (BCS). Out of 43 patients who underwent BCS as 

their first surgery 13 patients (30.23%) required subsequent mastectomy 

during pregnancy. 15 patients (34.88%) from the BCS group and 4 

patients (8.69%) from the Mastectomy group had positive margins. There 

was no significant difference between patients who underwent mastectomy 

vs BCS based on Age (34.67 vs 34.72 P: 0.97), gestational age at surgery 

(14.05 vs 16.06 P: 0.23) or ER positivity (47.5% vs 46.4% P: 0.93). 2 

patients had neo-adjuvant chemotherapy. 17 patients (19.31%) had 

sentinel lymph node biopsy. 37 patients (42%) had a pregnancy complication. 

There was no difference in the rate of complication based on 

mastectomy vs BCS(45.8% vs 34.5% P: 0.31). There was only 1 patient 

(from mastectomy group) that delivered within 2 weeks of surgery. Of the 

17 patients (19.3%) with spontaneous preterm delivery, there was no 

difference between Mastectomy and BCS group (22% vs 13.2% P: 0.41). 

Of the 25 patients (28.4%) with birth complications, there was no 

significant difference between mastectomy vs BCS (30.5% vs 24.1% P: 

0.53). There was also no difference in mean birth weight between the 

groups (2598 grams vs 2672.3 grams P: 0.57). Conclusions: The data 

supports the safety of breast cancer surgery during pregnancy. In addition, 

there were no identified adverse effects in patients who underwent BCS as 

opposed to mastectomy. Of note, only 19% of patients underwent sentinel 

node biopsy which is considered the standard of care in early breast cancer 

patients regardless of pregnancy status. 


18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) as 

early imaging biomarker of axillary sentinel lymph node (SLN) status in 

locally advanced node-positive breast cancer (NPBC) patients (pts) receiving 

neoadjuvant chemotherapy (NACT). Presenting Author: Yanina Dockx, 

Antwerp University Hospital, Edegem, Belgium 

Background: Use of FDG-PET in the early evaluation of NACT for NPBC is 

currently under investigation. The aim of this study is to assess FDG-PET in 

NPBC pts receiving NACT in order to identify a subset of pts that can be 

spared axillary lymph node dissection (ALND) in case of response. Methods: 

All pts (period 2009-2011) had [cT2 (�3cm)-T4, pN1-3], and no prior BC 

treatment. All pts received 8 cycles (cy) of NACT �/- trastuzumab. 

FDG-PET was performed at baseline and after 2 cy. After NACT, mastectomy 

with SLN and ALND was peformed. As primary endpoint, the change 

in maximum standardized uptake value (SUVmax) in the primary tumor (PT) 

and ALNs was compared with pathological response (Jonckheere-Terpstra 

test). Logistic regression was used to determine the predictive value of a 

50% reduction in SUVmax on pathological response and SLN status. 

Results: Forty-one pts were evaluable for the primary endpoint and 31 pts 

had successful SN procedures. The median age was 49.8 years (range 

27-75). Overall, 9.8% (4/41; 95% CI 2.7 – 23.1) of pts had progressive 

disease (PD), 7.3% (3/41 ; 95% CI 1.5 – 19.9 ) stable disease (SD), 

53.7% (22/41; 95% CI 37.4 – 69.3) partial response (PR), and 21.9% 

(9/41; 95% CI 10.6 – 37.6) a complete pathological response (pCR). A 

linear trend existed between pCR and higher decreases in SUVmax of the PT 

site (p�0.008), but not with lymph node SUVmax (p�0.294). The odds of 

achieving a pCR, increased significantly when SUVmax of the PT decreased 

with �50% (OR 10.7; 95% CI 1.2 - 98.0; p�0.03), but not lymph node 

SUVmax (OR 4.75; 95% CI 0.82 - 27.5; p�0.08). Achieving a true negative 

SLN status was more likely with �50% reductions in PT SUVmax (OR 41.2; 

95% CI 4.0 - 421.9; p� 0.002). A reduction of �50% in nodal SUVmax was not predictive of negative SLN status (OR 3.33; 95% CI 0.66 - 16.8; 

p�0.1). Conclusions: Early changes in PT metabolism imaged with FDG- 

PET after only 2 cy of NACT is a promising biomarker in the management of 

the axilla in NPBC. Molecular imaging of PT biology and to a lesser extent of 

axillary lymph nodes using FDG-PET warrants further study. 



Evaluation of the stage IB designation of the 7th edition of the AJCC 

Staging System. Presenting Author: Nikolaos Andreas Dallas, University of 

Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Recent data from large cooperative group trials have questioned 

the relevance of small volume metastases identified in the sentinel 

lymph nodes (SLN) of early stage breast cancer patients. The 7th ed. of the 

AJCC staging system differentiates node negative patients (stage IA) from 

those with micrometastases (stage IB) or macrometastases (stage II or III). 

This study was undertaken to determine the utility of the stage IB 

designation. Methods: Review of a prospectively maintained database 

identified 3474 patients who underwent SLN biopsy between 1993 and 

2007. Clinicopathologic and outcomes data were recorded and patients 

staged according to the 7th ed. AJCC system. Recurrence-free (RFS), 

disease-specific (DSS) and overall survival (OS) were determined using the 

Kaplan-Meier method and compared using the log-rank test. Results: AJCC 

stage distribution included: 2246 (65%) stage IA, 207 (6%) stage IB, 685 

(20%) stage IIA, 209 (6%) stage IIB, and 127 (3%) stage III. For patients 

with stage IB disease, SLN micrometastasis was identified by H&E in 173 

(84%) and immunohistochemistry (IHC) in 34 (16%); suggesting that 16% 

would have been staged IA if enhanced evaluation had not been performed. 

Median follow-up was 6.1 yrs (range 0-17.2). The 5-yr RFS,DSS and OS 

rates for patients with stage IB disease were 98.0%, 99.5%, and 95.9% 

respectively, which did not differ significantly from patients with stage IA 

disease who had 5-year RFS,DSS and OS rates of (97.5%, p�.9), (98.8%, 

p�.7) and (96.2%, p�.8). When all stage I patients (IA and IB) were 

evaluated by ER status or grade (grade 1 vs 2 vs 3), these biologic factors 

were able to significantly discriminate patients with respect to RFS, DSS 

and OS. Conclusions: Differentiating patients with micrometastases from 

node negative patients does not stratify patients with respect to survival. 

Biologic factors (ER status and grade) are better discriminants of survival 

than the presence of small volume nodal metastases in patients with early 

stage disease. These data do not support routine use of IHC or alterations in 

adjuvant therapy decisions based on identification of SLN micrometastases. 


Breast cancer in older women. Presenting Author: David B. Pearlstone, 

Hackensack University Medical Center, Hackensack, NJ 

Background: Recent guidelines recommend minimizing breast cancer 

screening for women over the age of 75. This study examines the 

presentation and outcome of older patients with breast cancer to determine 

if increasing screening among older patients may result in better outcomes. 

Methods: A prospective database at Hackensack University Medical Center 

was queried for all patients with breast cancer diagnosed between 1/1/ 

2006 and 1/1/2011. Numerical values compared by Student’s t -test; 

categorical values by Fisher exact test. Median time to events determined 

by Kaplan-Meier; outcomes compared by log-rank test. Results: 2200 

patients were identified (� 75 years, n�335, � 75 years, n�1865). 

Among the older cohort, mean age was 81 �/- 4 years (range: 75 – 101); 

mean tumor size was 2.3 �/- 0.1 cm (range: .1 – 12). Most tumors were 

invasive and localized (in-situ: 12.7%, localized: 57.3%, node positive: 

24.0%, metastatic: 5.8%) and most commonly ductal histology (ductal: 

77.0%; lobular: 16.6%, mixed:6.2%). Only 10.0% of patients with 

invasive disease and 29.2% with positive nodes received systemic therapy; 

90.2% underwent surgical resection. Disease-free and overall 5 year 

survival was 54.9% and 62.9% (in-situ: 82.2%; localized: 67.1%; node 

positive: 57%; metastatic 22%). Older patients had larger tumors (2.30 

�/- .11 v. 1.91 �/- .04 cm; p�0.001), more locally advanced (T4) disease 

(6.7% v. 1.7%, p�.001), more invasive disease (89% v. 84%, p�.01). 

Older patients had less positive family history (21.7% v. 37.3%, p�.0001). 

There was no difference between the groups in race, presentation with 

stage IV disease, tumor grade, lymphovascular invasion, histologic subtype, 

triple negativity, or nodal positivity. Overall and disease free five year 

survival were significantly worse for older patients (OS: 90.2% v. 63.9%, 

p� .0001; DFS: 80.9% v. 54.9%, p�.0001). Conclusions: Breast cancer 

among older women leads to worse outcomes compared to younger 

patients, regardless of histology, invasiveness of disease, hormonal status, 

nodal status or tumor grade. Older women present with more invasive 

disease, larger tumors and more locally advanced disease, despite having 

less family history. This implies that continued screening beyond age 75 

may lead to less advanced presentation and better outcomes. 


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Prospective outcomes trial of immediate, implant breast reconstruction 

using acellular dermal matrix (POBRAD Trial): Pilot series results. Presenting 

Author: David Westbroek, Kings HealthPartners, London, United 

Kingdom 

Background: Acellular dermal matrices (ADM) are biological meshes of 

dermal origin (allo- or xenografts) stripped of all cellular components 

leaving a structurally intact and immunologically inert extracellular matrix. 

They are currently in use as adjunctive subdermal scaffolding during 

implant breast reconstruction to optimise aesthetic outcome. Despite 

current use in clinical practice there is no prospective data on their clinical 

efficacy, associated complication rates and cost-benefit analysis. These are 

the endpoints of our pilot cohort series, intended to provide baseline event 

rates to help power a multi-centre prospective, phase II, outcomes cohort 

study. Methods: From July 2011 to January 2012 and with our institution 

review board’s approval - 20 consecutive patients undergoing immediate, 

implant breast reconstruction were prospectively accrued to the study. 

Primary endpoints: 30-day complication rates; Secondary endpoints: 

cosmetic outcome and cost-benefit analysis. Indications for mastectomy 

included therapeutic intent and/or risk reduction. The ADM used in all 

cases was SurgiMend PRS (TEI Bioscience Inc. Boston, MA). Results: 

Preliminary 30 day complication rates are in keeping with peer reviewed 

estimates for implant based breast reconstruction. Sub-set analysis of 

cosmetic outcome and cost-benefit ratio’s are currently pending. In 

overview, ADM’s appear to deliver the aesthetic benefit of autologousimplant 

cover (eg. latissimus dorsi myocutaneous flap) without the downside 

of donorsite morbidity and prolonged in-patient admission. Conclusions: 

This is to our knowledge the only prospectively accrued dataset seeking to 

critically evaluate the clinical efficacy, cost-benefit value and enhanced 

aesthetic utillity of ADMs (SurgiMend PRS) in the immediate breast 

reconstruction setting. The early results provide new evidence in support of 

the use ADMs in breast reconstruction and validate our intention to extend 

the study to a multicentre trial. 


Scoring system for prediction of having three or more involved axillary 

nodes for breast cancer. Presenting Author: Soo Kyung Ahn, Department of 

Surgery, Seoul National University Hospital, Seoul, South Korea 

Background: Completion axillary lymph node dissection (ALND) is currently 

the standard of care in the event of a positive sentinel lymph node biopsy 

(SLNB). However, result from Z0011 indicate that women with a one or two 

involved axillary nodes and clinical T1-T2 tumors undergoing lumpectomy 

with radiation therapy followed by systemic therapy do not benefit from 

completion of ALND in terms of survival. The purpose of this study was to 

define possible predictors of having three or more involved axillary node to 

provide information for surgeons making decision about sparing intraoperative 

frozen section analysis of sentinel lymph node and completion ALND. 

Methods: We reviewed the records of 1215 patients with clinical T1-T2 

invasive breast cancer. None of these patients were in situ cancer on initial 

gun biopsy nor received neoadjuvant chemotherapy. Factors associated 

with having three or more involved axillary nodes were evaluated by 

univariate and multivariate logistic regression analysis. Results: Among 

1215 patients, 321 patients had three or more positive nodes. On a 

multivariate analysis, having three or more positive nodes was associated 

with primary tumor size by breast US, axillary LN grade according to 

cortical thickness by US, presence of axillary LN enlargement on chest CT 

and age. A scoring system to predict the probability of having three or more 

nodes based on patients’ data and preoperative image findings was 

developed from the multivariate logistic regression model. The area under 

the ROC curve was 0.827 (95% CI: 0.793-0.860), and negative predictive 

value was 90.2% for a score �2.7. Similar findings were observed for a 

validation dataset of 505 patients. Conclusions: Patients with a low 

probability of having three or more positive nodes can be identified from 

preoperative image finding. The scoring system developed will be helpful to 

surgeons making decision about sparing intraoperative frozen section 

analysis of sentinel lymph node and completion ALND. 




Phase II neoadjuvant trial with carboplatin and eribulin mesylate in 

patients with triple-negative breast cancer. Presenting Author: Sara E. 

Barnato, Northwestern University, Chicago, IL 

Background: Several neoadjuvant trials have been conducted in triple 

negative breast cancer (TNBC) with platinum agents with pathologic 

complete response (pCR) ranging from 16%-32%. Eribulin mesylate, a 

nontaxane microtubule dynamics inhibitor, has clinical activity as monotherapy 

in breast cancer and other solid tumors. A recent phase I trial found 

the combination of eribulin mesylate with carboplatin was well tolerated 

and showed activity in advanced solid tumors. The recommended dose for 

future trials was eribulin mesylate 1.1 mg/m2 and carboplatin AUC6. We 

proposed a neoadjuvant phase II trial with the combination of carboplatin 

and eribulin in patients with TNBC. Methods: This is a non-randomized, 

open-label, multi-center, phase II clinical trial of eribulin and carboplatin 

enrolling histologically-confirmed TNBC patients. Our primary endpoint is 

to determine the pCR in TNBC patients treated with the combination of 

carboplatin and eribulin. Secondary endpoints include determination of 

the clinical response rate, toxicity evaluation and measurement of stem cell 

and TLE3 as a biomarker of response to eribulin therapy. To obtain an alpha 

of 0.10 and a power of 0.90, a sample size of 30 patients is required to 

detect a pCR rate ��30%. 10 of the planned 30 patients have been 

enrolled to date. Treatment will be given every 3 weeks for a total of 4 cycles 

of therapy. There will be an initial safety run-in to evaluate the appropriate 

dose of eribulin in this population. The first 10 patients will receive eribulin 

at 1.4 mg/m2 (intravenously over 2-5 minutes) followed by carboplatin 

AUC�6 (intravenously over 30 minutes). After the 10th patient has been 

enrolled, the study will be temporarily suspended pending review; toxicity 

will be assessed for these first 10 patients (cycle 1 only) to assess whether 

this dose of eribulin will be used for the remaining patients or if a reduction 

to a dose of 1.1 mg/m2 will be required. Definitive surgery will be performed 

3-8 weeks after completion of therapy, which will conclude the duration of 

the study. Clinical Trial Registry Number NCT01372579. 


ANZ1001 SORBET: Study of estrogen receptor beta and efficacy of 

tamoxifen, a single arm, phase II study of the efficacy of tamoxifen in 

triple-negative but estrogen receptor beta-positive metastatic breast cancer. 

Presenting Author: Kelly-Anne Phillips, Peter MacCallum Cancer 

Centre, Melbourne, Australia 

Background: Targeted therapies are needed for triple negative breast cancer 

(BC). ER� is expressed in at least 20% of triple negative BCs. ER� binds 

estrogen and tamoxifen with a similar affinity to ER�. ER�has 5 isoforms 

but only ER�1 is fully functional. ER� expression has been shown to be 

significantly associated with improved distant disease free survival and 

better overall survival in tamoxifen treated ER� negative patients in 

retrospective studies. This “proof of principle” study will determine the 

efficacy of tamoxifen in patients with triple negative but ER� positive 

metastatic BC. Methods: This single arm phase II study, being conducted by 

the Australia and New Zealand Breast Cancer Trials Group, has a Simon’s 2 

stage optimal design. The primary end-point is objective response rate 

(complete and partial responses). Progression free survival and clinical 

benefit rate will also be assessed. Eligibility criteria include histologically or 

cytologically confirmed metastatic triple negative BC (ER and PR absent, 

HER2 ISH negative or IHC 0 or 1) and measureable disease as per RECIST 

1.1. Consenting patients undergo central ER� testing and confirmation of 

triple negative status on a metastatic biopsy sample. ER� positive patients 

(ER�1 nuclear staining with Allred score �4) are offered trial participation. 

To date 12 potentially eligible patients have been screened for ER�; 4 had 

Allred score �4 (although 2 of these subsequently proved to be ineligible 

for the trial), 7 had Allred scores �4 and 1 result is pending. Consenting 

patients receive tamoxifen 20mg per oral daily until disease progression, 

unacceptable toxicity or withdrawal of consent. If there are �2 responses in 

the first stage of 28 patients, an additional 38 patients will be accrued. 

Tamoxifen will be considered worthy of further research if there are �6 

responses in the total 66 patients recruited. Current accrual is 1. 

Registered on ANZCTR (12610000506099). 


A phase III, randomized trial of docetaxel plus carboplatin (TP) versus 

epirubicin plus cyclophosphamide followed by docetaxel (EC-T) as adjuvant 

treatment for triple-negative, early-stage breast cancer in Chinese 

patients. Presenting Author: Peng Yuan, Cancer Hospital, Chinese Academy 

of Medical Sciences, Beijing, China 

Background: Triple-negative [estrogen receptor (ER)-/progesterone receptor 

(PR)-/HER2-] breast cancer (TNBC) accounts for about 15% of all breast 

cancers and is associated with very poor prognosis. A combination of 

anthracycline and taxanes represents the most commonly used adjuvant 

chemotherapy for TNBC patients. BRCA1, a protein responsible for repair 

upon DNA damage, is often dysfunctional in TNBC. As a result, TNBC is 

often sensitive to DNA-damaging agents (e.g., cisplatin and carboplatin). A 

phase II study of docetaxel plus carboplatin as neoadjuvant treatment for 

TNBC achieved promising response rate (Chang, CANCER, 2010). Encouraged 

by this important finding, we are currently conducting a phase III trial 

to examine docetaxel plus carboplatin as adjuvant chemotherapy in 

patients with early-stage TNBC (registration number at www.ClinicalTrials. 

gov: NCT 01150513). Methods: All participants received radical mastectomy 

or breast-conserving surgery for pT1-3N0-2 breast cancer. All cancers 

were negative for ER, PR, HER2/Neu. All participants had adequate organ 

function and performance status. The age ranged from 18 to 70 years. 

Patients randomly received a TP regimen (docetaxel 100 mg/m2 plus 

carboplatin AUC�6 on day 1, 21 days a cycle for 6 cycles) or a EC-T 

regimen (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 on d1, 

21 days a cycle for 4 cycles; followed by docetaxel 100 mg/m2 on d1, 21 

days a cycle for 4 cycles). Adjuvant radiotherapy was permitted in both 

arms. The primary endpoint is disease-free survival (DFS). Secondary 

endpoints included adverse event and quality of life (QoL). The study 

planned to recruit 500 subjects over a period of 5 years, with 5-year 

follow-up (once every 6 months). Target hazard ratio is 0.86 (5 year DFS of 

74.0% vs. 71.0%). The estimated power is 0.80; 1-sided type 1 error was 

set at 0.05). The study was activated in June 2010 with enrollment of 110 

subjects. 


Neoadjuvant bevacizumab with weekly nab-paclitaxel plus carboplatin 

followed by doxorubicin plus cyclophosphamide (AC) for triple-negative 

breast cancer. Presenting Author: Jessica N. Snider, University of Tennessee 

Health Science Center, Memphis, TN 

Background: Triple negative breast cancer (TNBC) predominantly clusters 

with “basal like” subtype on genomic profiling. Over-expression of Secreted 

Protein Acidic and Rich in Cysteine (SPARC) has been observed in basal 

like breast cancer (Charaffe-Jaufrett et al. Oncogene 2006; 2273-84). 

Endothelial transcytosis of nab- paclitaxel occurs via albumin- gp60 

receptor-caveolin 1 interaction. SPARC entraps the albumin resulting in 

higher intratumoral accumulation, which may explain the increased efficacy 

of nab-paclitaxel (Desai et al. Translational Oncology 2009; 59-63). 

Exploiting this mechanism and the dysfunctional BRCA mediated DNA 

repair in basal tumors, we hypothesize that nab-paclitaxel � the DNA 

damaging drug carboplatin would produce high response rates in TNBC. 

Adding bevacizumab may enhance efficacy by blocking angiogenesis. In 

TNBC, pathologic complete remission (pCR) to neo-adjuvant therapy 

correlates with better disease-free survival (DFS). We hypothesize that high 

pCR rates can be achieved for patients with TNBC with this combination 

translating to an improved DFS than seen historically. Methods: Patients 

with palpable and operable TNBC � 2 cm are eligible for this single stage 

phase II trial. pCR (defined as the absence of invasive tumor cells) in the 

breast is the primary end point, while pCR in the breast � axillary nodes 

and pCR � near pCR (residual tumor � 5mm) in the breast are secondary 

end points. 57 evaluable patients are needed, assuming a pCR rate of 25% 

vs. 40% for the null and alternate hypotheses respectively. 34 patients 

have been accrued to date. Patients receive carboplatin AUC 6 day 1 and 

nab-paclitaxel 100mg/m2 days 1, 8 and 15 of a 28 day cycle for 4 cycles 

and then dose dense AC for 4 cycles. Bevacizumab is given at 10mg/kg Q 2 

weeks with chemotherapy for the first 6 cycles. Surgery and radiation are 

per institutional standards. Bevacizumab is continued postoperatively to 

complete 1 year of treatment. A core biopsy for collection of fresh tumor 

tissue is required prior to the start of study treatment. Blood is collected at 

baseline, and after 4 and 8 cycles for biomarker analysis. Gene expression 

profiling will be undertaken for correlation with response. 



ABT-888 (veliparib) in combination with weekly carboplatin and paclitaxel 

in advanced solid tumors. Presenting Author: Jorge Arturo Rios-Perez, 

University of Pittsburgh Cancer Institute, Pittsburgh, PA 

Background: The combination of paclitaxel and carboplatin is widely used 

for the treatment of patients with advanced solid tumors of diverse 

histologies. In breast cancer patients, a weekly regimen of paclitaxel has 

shown greater efficacy with comparable safety, when compared to everythree-weeks 

dosing (ECOG 1199). ABT-888 (veliparib) is an oral inhibitor 

of poly-ADP-ribose polymerase (PARP). Inhibition of PARP has been shown 

in preclinical studies to potentiate the effect of cytotoxic agents which 

induce DNA damage, such as platinum agents. The preclinical synergy of 

carboplatin with veliparib and the efficacy of the combination of paclitaxel 

with carboplatin supports exploration of this triplet regimen. Methods: This 

3�3 phase I trial will seek to determine the maximum tolerated dose (MTD) 

of the combination of carboplatin (AUC 2), paclitaxel (80 mg/m2 ), and 

veliparib in patients with advanced solid tumors. Veliparib will be escalated 

beginning at 50 mg PO BID to a maximum of 200mg PO BID. Treatment 

will be given on a weekly basis over a 21-day cycle. There will be an 

expansion cohort of 6-12 patients with triple negative breast cancer at the 

maximum tolerated dose. This group of patients will undergo mandatory 

pre- and post-cycle 1 tumor biopsies. Secondary aims of the study include 

safety and toxicity of the combination, its pharmacokinetic and pharmacodynamic 

effects, documentation of any anti-tumor response, and assessment 

of the characteristics of the tumor specimens obtained in the 

expansion cohort that may contribute to efficacy. The latter will include 

whole genome microarray analysis to evaluate expression of genes involved 

in DNA repair pathways. Currently, the recommended phase II dose has not 

been determined and enrollment is ongoing on the last planned dose level 

(veliparib 200 mg BID). 

TPS1140^ General Poster Session (Board #36A), Sat, 8:00 AM-12:00 PM 

Phase III open-label, randomized, multicenter study of NKTR-102 versus 

treatment of physician’s choice (TPC) in patients (pts) with locally 

recurrent or metastatic breast cancer (MBC) previously treated with an 

anthracycline, a taxane, and capecitabine (ATC). Presenting Author: Edith 

A. Perez, Mayo Clinic, Jacksonville, FL 

Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate 

that hydrolyzes to provide continuous exposure to SN-38. A phase 2 trial of 

single-agent NKTR-102 was conducted in pts with 3rd-line MBC; 2 

schedules (q14d; q21d) investigated a dose of 145 mg/m2. ORR was 29% 

(including 3% CR) with the prior ATC subset demonstrating an ORR of 

31%. Dosing q21d was better tolerated; in this arm, median PFS and OS 

equaled 5.3m and 13.1m, respectively. Trial Design: Pts will be randomized 

1:1 to receive single-agent NKTR-102 or TPC in an open-label, 

randomized, multicenter phase 3 study in pts with advanced breast cancer. 

Key Entry Criteria: Adult females, with ECOG 0 or 1 with adequate liver, 

kidney and marrow function. All pts must have received prior therapy with 

ATC (these drugs can be administered in the neo/adjuvant or locally 

advanced/metastatic setting). Prior A is not mandated if contraindicated. 

Prior toxicities must have resolved to � Grade 1 (except sensory neuropathy 

� Grade 2; complete resolution of prior diarrhea). Pts with brain metastases 

may be eligible, if lesions are stable for prior 3 weeks without steroids. 

Methods: Primary efficacy endpoint is OS. Secondary endpoints include: 

ORR by RECIST v1.1, clinical benefit rate (ORR�SD � 6 months), PFS 

and QoL. NKTR-102 is given IV at 145 mg/m2 over 90-min every 21 days 

without premedications. Pts randomized to TPC receive 1 of the following: 

eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or 

nab-paclitaxel (the agent must be available at the treating institution). Pts 

are stratified by region, prior eribulin and receptor status (TNBC, Her2� or 

Other). Target Accrual: ~840 pts will be required for sufficient events to 

occur in the planned follow-up time; OS will be compared using a two-sided 

log-rank test; 1 interim analysis will occur when 50% of the deaths are 

reported. PK sampling is performed in a subset of pts. CTCs (isolated by 

Apocell ApoStream technology) are serially assessed for potential predictive 

markers of response and toxicity. Enrollment is expected to remain 

open until late 2013. 


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Q-CROC-03: A prospective biopsy driven clinical trial to study the mechanisms 

of resistance to chemotherapy in triple-negative breast cancer 

patients. Presenting Author: Adriana Aguilar-Mahecha, Segal Cancer Center/ 

Jewish General Hospital, McGill University, Montreal, QC, Canada 

Background: Resistance to chemotherapy or targeted agents is the cause of 

death in most patients dying of breast cancer and one of the major 

challenges presently faced by oncologists. In triple negative breast cancers 

(TNBCs), drug resistance emerges quicker than in other breast cancer 

subtypes and contributes to the poor prognosis seen in these patients. The 

lack of targeted therapies to treat TNBC highlights the important need to 

better understand the molecular mechanisms contributing to chemotherapy 

resistance in order to develop new therapeutic strategies. However, 

the difficulty in obtaining tissue samples from drug resistant tumors has 

been one of the limiting factors in this field of study. Methods: We have 

designed a prospective phase II clinical trial where paired biopsies are 

collected from chemotherapy resistant TNBCs (NCT01276899). Four 

needle core biopsies are collected before the initiation of treatment and 2 

weeks before surgery or at the time of progression in the neoadjuvant and 

metastatic settings respectively. Metastatic sites eligible for biopsy include 

liver, lung, skin and lymph nodes. This study is presently recruiting at 5 

major health centers in Quebec and will soon open in the USA. We have 

currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic 

patients. Major challenges in patient enrolment will be discussed. We have 

standardized the methods of collection and processing of tissue and blood 

specimens to ensure their molecular integrity and compatibility with 

different genomic and proteomic molecular platforms. Analysis of tumor 

cellularity has been incorporated into our quality control and we have 

optimized the extraction of nucleic acids to obtain high yields and optimal 

quality. Paired biopsies will undergo Next Gen Sequencing, flow sorted 

aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic 

profiling using reverse phase protein arrays. Collection of clinical 

data will allow molecular profiling data to be linked to clinical response 

data so as to determine DNA, RNA and protein factors correlated with 

tumor resistance to chemotherapy. 


Randomized controlled trial comparing zoledronic acid plus chemotherapy 

with chemotherapy alone as a neoadjuvant treatment in patients with 

HER2-negative primary breast cancer. Presenting Author: Norio Kohno, 

Department of Breast Oncology, Tokyo Medical University Hospital, Tokyo, 

Japan 

Background: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate, 

and it induces osteoclast apoptosis and inhibits bone resorption by 

inhibiting the mevalonate pathway. ZOL has also been found to have 

antitumor effects that include an angiogenesis inhibiting action, an 

inhibitory effect on tumor cell adhesion to and invasion of the extracellular 

matrix, and activation of a gdT cells. In addition, it has been found to have a 

synergistic apoptosis-inducing effect when used in combination with 

antitumor drugs. In this study we will investigate the pCR rate when ZOL is 

added to anthracycline followed by taxane to treat T2 and T3 breast cancer 

patients. Methods: Women with resectable invasive StageIIA-IIIB (T � a3 

cm or T � a2 cm and lymph node positive) breast cancer who are 

HER-2-negative, between 20 and 70 years of age, and ECOG PS 0-1 are 

eligible. Patients with distant metastasis, patients who have had received 

chemotherapy, hormone therapy, or radiotherapy for breast cancer, patients 

with serious complications, such as heart disease or an infection, 

patients with a complicating dental or jaw infection or traumatic condition 

of the teeth, and patients with a history of treatment with a bisphosphonate 

within the previous 12 months are excluded. A total of 4 courses of FEC100 

are administered every 3 weeks followed by weekly paclitaxel for 12 

courses. ZOL 4mg is administered every 3-4 weeks a total of 7 times. 

Patients are randomized 1:1 to chemotherapy � ZOL group or chemotherapy 

alone group, according to the presence or absence of lymph node 

metastasis, estrogen receptor (ER) status, and their menopausal status. 

The primary endpoint is pCR. Secondary endpoints are tumor response 

rate, the breast-conserving surgery ratio, and disease-free survival (DFS). 

We calculated the sample size on the basis of a pCR rate of 18% in the 

chemotherapy alone group and 35% in the chemotherapy � ZOL group, at 

a one-sided significance rate of 5%, and test power of 80%, and as a result 

we will target a patient sample size of 180 patients. 162 of planned 180 

patients have been enrolled as of January 24, 2012. 




NSABP B-47: A phase III trial of adjuvant therapy comparing chemotherapy 

alone (six cycles of docetaxel plus cyclophosphamide or four cycles 

of doxorubicin plus cyclophosphamide followed by weekly paclitaxel) to 

chemotherapy plus trastuzumab in women with node-positive or high-risk, 

node-negative, HER2-low invasive breast cancer. Presenting Author: Louis 

Fehrenbacher, National Surgical Adjuvant Breast and Bowel Project and 

Kaiser Permanente Northern California, Vallejo, CA 

Background: Adjuvant studies utilizing trastuzumab in early HER2� breast 

cancer demonstrated a large reduction in recurrence and death. Postenrollment 

central testing showed HER2 non-amplified participants derived 

similar benefit. Methods: Selection of one of the two chemotherapy 

regimens is by physician choice: The non-anthracycline regimen is TC 

(docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) administered IV 

every 3 weeks for 6 cycles; the anthracycline regimen is AC followed by WP 

(doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered 

IV either every 3 weeks or every 2 weeks [per investigator discretion] for 4 

cycles followed by paclitaxel 80 mg/m2 IV weekly for 12 doses). Patients 

are randomly assigned to receive chemotherapy with or without trastuzumab 

therapy. For patients receiving the TC chemotherapy regimen, 

trastuzumab is given every 3 weeks during and following chemotherapy 

until 1 year after the first trastuzumab dose (8 mg/kg loading dose; 6 mg/kg 

for the remaining doses). For patients receiving the AC followed by WP 

chemotherapy regimen, trastuzumab begins with the first dose of weekly 

paclitaxel and will be given weekly for 12 doses (4 mg/kg loading dose; 2 

mg/kg for the remaining weekly doses). Following completion of WP, 

trastuzumab therapy continues with 6 mg/kg doses given every 3 weeks for 

a total of 1 year. Eligibility: Eligibility includes: node positive or high risk 

node negative female breast cancer patients; HER2 IHC 1� or 2� scores, 

but non amplified by FISH Statistical Design: The primary aim is to 

determine whether the addition of trastuzumab to chemotherapy improves 

invasive disease-free survival (IDFS). 3260 patients will be enrolled to 

provide statistical power of 0.9 to detect a 33% reduction in the hazard rate 

of IDFS using a one-sided alpha level of 0.025. Progress: Protocol was 

activated in January 2011. As of January 27, 2012, 486 of 3260 patients 

have been enrolled. Supported by NCI U10-12027, -37377, 69651, 

69974, and Genentech, Inc. 


ARTemis: Randomized trial with neoadjuvant chemotherapy for patients 

with early breast cancer. Presenting Author: Helena Margaret Earl, Department 

of Oncology, University of Cambridge, and NIHR Cambridge Biomedical 

Research Centre, Cambridge, United Kingdom 

Background: Bevacizumab is a new humanised monoclonal antibody which 

targets vascular endothelial growth factor (VEGF) and thereby the neoangiogenic 

process in cancer. Bevacizumab has shown promising anti-tumour 

effect when given concurrently with taxane-based chemotherapy in breast 

cancer. However two neoadjuvant breast cancer trials have produced 

conflicting results. The NSABP-B40 study showed significant benefit for 

bevacizumab only in the ER�ve patients (pathological complete response 

(pCR) in ER�ve population 15.2% vs 23.3%, p�0.008). Whereas the 

GEPARQUINTO trial reported significant benefit only in the triple negative 

patients (pCR 27.8% vs 36.4% p�0.021). Methods: ARTemis is a phase 

III randomised trial to determine whether the addition to neo-adjuvant 

chemotherapy of bevacizumab is more effective than standard chemotherapy 

alone in patients with HER2-negative early breast cancer. A total of 

400 patients will be randomised into each of the two treatment arms which 

will allow an absolute difference in the pCR rates in excess of 10% to be 

detected at the 5% (2-sided) level of significance with an 85% power. 

Primary outcome is pathological complete response rates after neoadjuvant 

chemotherapy, i.e. no residual invasive carcinoma in the breast, 

and no evidence of metastatic disease within the lymph nodes. Secondary 

outcomes are disease free survival, overall survival, complete pathological 

response rates in breast alone, radiological response after 3 and 6 cycles of 

chemotherapy and rate of breast conservation and toxicities. Results: 

Recruitment into ARTemis began in April 2009 and as of January 2012 

had recruited 469 (59%). ARTemis is due to complete recruitment by Dec 

2012 and the first planned interim analysis of the primary outcome will be 

Dec 2013. Conclusion: The IDSMC reviewed the trial in June 2011 and 

recommended continuation of recruitment to this important trial given 

there were no safety concerns, and results from the other neoadjuvant 

studies (NSABP-B40 and GEPARQUINTO) are conflicting. 


IBL2001: Phase (ph) I/II study of a novel dose-dense (dd) schedule of 

indibulin for the treatment of metastastic breast cancer. Presenting Author: 

Tiffany A. Traina, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Indibulin (Zybulin, ZIO-301) is a new, synthetic agent that 

inhibits tumor cell growth at the G2/M phase through destabilization of 

microtubule dynamics. It binds tubulin at a different site than taxanes and 

vinca alkaloids. Indibulin does not interact with acetylated (neuronal) 

tubulins and has not exhibited the neurotoxicity associated with other 

tubulin binders. Indibulin has potent antitumor activity in human cancer 

cell lines, including multidrug-, taxane-, and vinblastine-resistant lines. 

Norton-Simon modeling based on cell line data suggested that dd administration 

could optimize efficacy while limiting toxicity. Methods: Eligible are 

patients (pts) with metastatic or unresectable locally advanced breast 

cancer, measurable or non-measurable disease, and any number of prior 

therapies. The objective of the Ph I portion is to determine the maximum 

tolerated dose (MTD) of indibulin when given in a dd fashion (5 days 

treatment, 9 days rest (14 total) using standard 3�3 dose escalation 

schema. Ph II will seek to estimate the proportion of pts progression free at 

4 months when treated with indibulin at the dose determined in the Ph I. 

Secondary endpoints are overall response rate, proportion of subjects with 

stable disease �6 months and toxicity profile of indibulin. Optimal Simon 

two-stage design with an unpromising rate of pts who have not progressed 

at four months as 20% and a promising rate of 40% with a type I error of 

5% and power of 80% will be used. 13 pts will initially enter the 1st stage of 

the ph II portion. If there are 3 or fewer pts who do not experience disease 

progression at 4 months in the first stage of ph II, the study will be 

terminated and declared to have a negative result. If 4 or more pts do not 

progress at 4 months, enrollment in the ph II of the study will be extended 

to 43 pts. A total of 45 pts will be enrolled to allow for a 5% drop out rate to 

account for pts who may not be evaluable for the primary endpoint due to 

toxicity or study withdrawal rather than progression of disease or death prior 

to 4 months. If �13 out of 43 pts are progression-free at 4 months, the 

study will be considered to have a positive result and indibulin would be 

considered worthy of further testing in this disease. 


A phase II, single-arm, feasibility study of dose-dense doxorubicin and 

cyclophosphamide (AC) followed by eribulin mesylate for the adjuvant 

treatment of early-stage breast cancer (EBC). Presenting Author: Tiffany A. 

Traina, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Randomized trials have confirmed the benefit of the combination 

of an anthracycline (A) and cyclophosphamide (C) for the adjuvant 

treatment of EBC. The addition of taxane therapy to AC therapy has further 

improved survival. Despite the improvement in adjuvant therapies for BC, 

new approaches for improving outcomes are of significant importance and 

may involve developing improved combination regimens. Eribulin mesylate 

has demonstrated antitumor activity and significant improvement in overall 

survival (OS) in patients with heavily pretreated locally advanced or 

metastatic breast cancer (MBC) and may improve outcomes in EBC as well. 

Methods: This study will determine the feasibility of eribulin as adjuvant 

therapy following dose-dense AC for HER2 normal EBC. A completion rate 

of �80% was set as a threshold for feasibility as established adjuvant 

regimens have shown feasibility rates ranging from ~65% for trastuzumab 

to �80%. This is a phase 2, single-center, feasibility study of dose-dense 

adjuvant chemotherapy in patients with EBC. Dose-dense AC (Doxorubicin 

60 mg/m2 IV plus C 600 mg/m2 IV) on day 1 of every 14-day cycle is given 

for 4 cycles, followed by 4 cycles of eribulin mesylate at 1.4 mg/m2 over 

2-5 minutes IV on days 1 and 8 every 21 days. Growth factors are given on 

day 2 of AC cycles and only for neutropenia events with eribulin treatment. 

Feasibility is determined by the ability to complete the eribulin portion of 

the regimen without a dose delay or reduction. Exploratory objectives 

include efficacy endpoints of 3-year disease-free survival (DFS) and OS. 

Patients have histologically confirmed HER2 normal stage I-III invasive 

disease and adequate bone marrow, liver, and renal function. Thirty two of 

approximately 80 planned patients are currently enrolled. Feasibility rates 

will be calculated with growth factor support (ie, the successful use of 

growth factor support following a neutropenia event is not considered a 

dose delay)and without growth factor support (ie, where need for growth 

factors is considered a delay). Secondary endpoints include DFS and OS 

and will be estimated by Kaplan-Meier method. 



DETECT III: A multicenter, randomized, phase III study to compare 

standard therapy alone versus standard therapy plus lapatinib in patients 

(pts) with initially HER2-negative metastatic breast cancer but with 

HER2-positive circulating tumor cells (CTC). Presenting Author: Carsten 

Hagenbeck, Department of Gynecology and Obstetrics, Heinrich Heine 

University, Duesseldorf, Germany 

Background: HER2 status may change over the course of disease in breast 

cancer pts. Approx. 20-30% of pts with initially HER2-negative breast 

cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 

2009). Determining HER2 status on CTC is one option to re-evaluate HER2 

status at the time metastasis is diagnosed. Currently it is unclear if 

HER2-targeted therapy based on the assessment of HER2 status of CTC 

reveals a clinical benefit. Methods: This is a randomized, open-label, two 

arm phase III study to investigate the clinical efficacy of lapatinib, as a 

HER2-targeted therapy in initially HER2-negative metastatic breast cancer 

pts with HER2-positive CTC at the time of distant disease. As only half of 

the pts with HER2-negative metastatic breast cancer show CTC-positivity 

and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 

2010), screening of about 1420 pts is required to enroll 228 pts. Main 

inclusion criteria: metastatic breast cancer with HER2-negative primary 

tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, 

evidence of �1 HER2-positive CTC and �1 measurable metastatic 

lesion according to RECIST. Eligible pts will be randomized 1:1 to receive 

standard treatment vs. standard treatment plus lapatinib. Standard chemoor 

endocrine therapy must be approved in combination with lapatinib or 

been investigated in prior clinical trials. Primary endpoint is progression 

free survival. Secondary endpoints include overall response rate, clinical 

benefit rate, overall survival and dynamic of CTC. The DETECT III trial is 

one of the first trials where treatment is based on phenotypic characteristics 

of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with 

initially HER2-negative metastatic breast cancer but HER2-positive CTC, 

this will establish a new strategy in the treatment of metastatic breast 

cancer. 


Phase II study of the multikinase inhibitor dovitinib (TKI258) or placebo in 

combination with fulvestrant in postmenopausal, endocrine resistant 

HER2-/HR� breast cancer. Presenting Author: Fabrice Andre, Institut 

Gustave Roussy, Villejuif, France 

Background: Overcoming endocrine resistance is a critical goal in the 

treatment of hormone receptor�positive (HR�) breast cancer. Molecular 

mechanisms associated with endocrine resistance include adaptive “crosstalk” 

between the estrogen receptor and the fibroblast growth factor 

receptor (FGFR). Up to 8% of HR�/HER2- breast cancer patients (pts) 

have amplification of the FGFR1 gene, which is associated with resistance 

to endocrine therapy but can be overcome via FGFR1 inhibition in 

preclinical models. Dovitinib is a potent FGF, VEGF, and PDGF receptor 

tyrosine kinase inhibitor that demonstrated antitumor activity in heavily 

pretreated breast cancer pts with FGF pathway amplification (FGFR1, 

FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse 

resistance to endocrine therapy related to FGF-pathway amplification and 

is studied here to determine if it can improve outcomes when combined 

with fulvestrant. Methods: Postmenopausal HER2-/HR� locally advanced 

or metastatic breast cancer pts (N»150) progressing within 12 months of 

completion of adjuvant endocrine therapy or after � 1 prior endocrine 

therapy in the advanced setting will be enrolled in this multicenter, 

randomized, double blind, placebo controlled, phase II trial. Pts will 

prospectively undergo molecular screening to enrich for FGF-amplification 

(FGFR1, FGFR2, orFGF3 amplification by qPCR; 45 amplified and 30 

non-amplified pts per arm). Pts will be randomized 1:1 to receive 

fulvestrant (500 mg q4w [with an additional dose 2 wks after the initial 

dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or 

placebo until disease progression, unacceptable toxicity, or death. The 

primary endpoint is progression-free survival, with tumor assessments 

performed q8w. Secondary endpoints include overall response rate per 

RECIST v1.1, duration of response, overall survival, ECOG performance 

status and patient reported outcome scores over time, and safety. The 

pharmacodynamic effect of dovitinib on FGFR-associated angiogenic 

pathways in tumor specimens and potential predictive biomarkers of 

response to dovitinib will be explored. 


85s 


A multicenter prospective study of image-guided radiofrequency ablation 

for small breast carcinomas. Presenting Author: Takayuki Kinoshita, 

National Cancer Center Hospital, Tokyo, Japan 

Background: As the management of breast carcinoma evolves toward less 

invasive treatments, the next step is the possibility of removing the primary 

tumor without surgery. The most promising noninvasive ablation technique 

is radiofrequency ablation (RFA), which can effectively kill tumor cells with 

a low complication rate. Our preliminary studies of RFA followed by 

standard surgical resection have indicated that this technique is effective 

for surgical ablation of small (� 2cm) breast tumors without extensive 

intraductal components (EIC). Methods: To determine if RFA is oncologically 

and cosmetically appropriate for the local treatment of primary breast 

carcinoma, this multi-center prospective study used RFA as the sole local 

treatment of breast tumors � 1.5cm in size on ultrasound and MRI. 

Exclusion criteria include receiving of preoperative chemotherapy, or the 

presence of invasive lobular carcinoma or invasive ductal carcinoma with 

suspicious EIC. After confirmation that the standard baseline core biopsy 

for diagnosis and measurement of tumors markers (ER, PgR, HER-2/neu 

expression and the presence of the Ki-67 proliferative marker) have been 

obtained, consent will be obtained and the patient scheduled RFA. All 

patients received adjuvant radiation therapy. The use and choice of 

systemic therapy will be based on the information from the baseline core 

biopsy and imaging studies. The first primary endpoints of this study is 

successful tumor ablation, as evidenced by negative findings on vacuumassisted 

or core biopsies and imaging studies after RFA. The second 

primary endpoints is the incidence of procedure related adverse events. 

Forty patients with small tumors that are clearly identifiable and measurable 

by ultrasound and MRI were enrolled. The response to ablation was 

evaluated with both vacuum-assisted or core biopsies and imaging studies 

every 3 months during the first year. The long-term outcomes were assessed 

using quality of life measurement scales and imaging studies every 6 

months thereafter through year 5. 


86s Cancer Prevention/Epidemiology 

1500 Oral Abstract Session, Mon, 8:00 AM-11:00 AM 

A phase III prevention trial of low-dose tamoxifen in HRT users: The HOT 

trial. Presenting Author: Bernardo Bonanni, European Institute of Oncology, 

Milan, Italy 

Background: Primary prevention trials have shown that tamoxifen (T) lowers 

ER� breast cancer (BC) incidence, but adverse events are a barrier to its 

broad use. The Italian Tamoxifen Prevention Trial showed a positive 

risk/benefit ratio in the subgroup of hormone replacement therapy (HRT) 

users in the T arm, with fewer BC and no cardiovascular disease (CVD) 

excess. In a dose-ranging study, T 5 mg/day showed a favorable biomarker 

modulation in HRT users. We conducted a multicentre, phase III, BC 

prevention trial in current or de novo HRT users, randomized to either T 5 

mg/day or placebo (P) for 5 yrs, with 5yrs follow-up. Methods: The study was 

powered to detect a 40% decrease of BC on T from an annual rate of 

4/1000 on P with 20% dropout and 5y recruitment. All analyses were 

performed on ITT basis. The cumulative incidence of events was determined 

using Kaplan-Meier methods. The two treatment groups were 

compared by using the log-rank test. Hazard ratios (HRs) and 95% 

confidence intervals were obtained using Cox proportional regression 

model. All P values were two-sided. Results: Due to the WHI-HRT trial 

results, recruitment was lower than anticipated, with a total of 1884 

subjects being randomized (946 P and 938 T arm, respectively). 79% were 

�50 years old at study entry. 66% were normal weight, 21% were 

hysterectomized; 80% were already on HRT at baseline, 53% were on 

trasdermal route and 28% had 5y-Gail risk�1.5%. At 7.7y mean follow-up, 

43 BC were diagnosed, 24 (annual rate 4.1/1000) on P and 19 (3.3/1000) 

on T (HR 0.80, 95%CI 0.44-1.46). The efficacy of T was greater in 

luminal-A type (HR�0.32, 95% CI, 012-086). CVD events were rare 

(including 1 DVT on T), with no statistical difference between arms. A HR of 

4.74 (95% CI, 1.96-11.5) was observed for benign endometrial polyps, 

but no increase of uterine cancers (3 on P vs 1 on T). Menopausal 

symptoms were more frequent on T, whereas headache was less frequent on 

T. Conclusions: The combination of low-dose T and HRT is safe and provides 

a promising way to retain the benefits while reducing the risks of either 

agent. While the insufficient power of our study prevents firmer conclusions, 

it supports further studies of low-dose T in the prevention setting. 


BMI, long-term changes in BMI, and risk of cancer mortality in a large 

cohort study. Presenting Author: Niloofar Taghizadeh, Department of 

Epidemiology, University Medical Center Groningen, Groningen, Netherlands 

Background: There are indications of an association between Body Mass 

Index (BMI) and risk of different cancer types. There is dispute whether this 

association differs between males and females. Methods: We studied the 

association of BMI at the first survey with risk of mortality from the most 

common types of cancer (lung, colorectal, breast and prostate cancer) in a 

large general population-based cohort study (Vlagtwedde-Vlaardingen, 

1965-1990) with follow-up on mortality status until 2009. Additionally, 

we assessed this association based on tertiles of the annual change in BMI 

(defined as the difference between BMI at last survey and first survey 

divided by the time between last and first survey). We used 3 categories of 

BMI (� 25 kg/m2 , 25-30 kg/m2 , and � 30 kg/m2 ) and changes in BMI 

(� 0.02 kg/m2 /yr, 0.02-0.2 kg/m2 /yr, and � 0.2 kg/m2 /yr) in the analyses. 

The multivariate Cox regression model was adjusted for age, smoking, 

gender. Analyses were additionally stratified by gender and smoking. 

Results: Among all 8645 subjects, 1194 died due to cancer (lung cancer: 

275; colorectal cancer: 134; breast cancer: 117; prostate cancer: 83). 

Mortality from all types of cancer was significantly increased in subjects 

with BMI � 30 kg/m2 (HR (95 % CI)) � 1.22 (1.00-1.48)), especially in 

females (1.38 (1.06-1.81)) and in never smokers (1.39 (1.02-1.90)). 

Prostate cancer mortality was significantly increased in males with BMI 

25-30 kg/m2 (2.04 (1.90-3.83)) and � 30 kg/m2 (2.61 (1.02-6.67)). This 

association between prostate cancer mortality and BMI was higher in 

smokers. Lung cancer mortality risk was decreased in subjects with BMI 

25-30 kg/m2 (0.71 (0.54-0.93)) and � 30 kg/m2 (0.82 (0.50-1.32)), 

especially in males, in smokers, and in smoking males. There were no 

significant associations between BMI and colorectal or breast cancer 

mortality nor between change in BMI and mortality from all analyzed types 

of cancer. Conclusions: We show that an increase in BMI is associated with 

an increased risk of mortality from all types of cancer in females and with 

an increased mortality risk from prostate cancer in males but with a 

decreased lung cancer mortality risk, especially in males. More research is 

needed into the biological mechanisms that link BMI to cancer. 


Estrogen plus progestin (E�P) and breast cancer incidence and mortality. 

Presenting Author: Rowan T. Chlebowski, Los Angeles Biomedical Research 

Institute at Harbor-UCLA Medical Center, Torrance, CA 

Background: In the WHI clinical trial, E�P increased both breast cancer 

incidence and breast cancer mortality (JAMA 2010;304:1684). In contrast, 

breast cancers associated with E�P use in most observational studies 

have a more favorable prognosis. To address differences, a cohort of WHI 

Observational Study participants with characteristics similar to the WHI 

clinical trial was identified to examine E�P association with invasive breast 

cancer incidence and outcome. Methods: 41,449 postmenopausal women 

with no prior hysterectomy and mammogram negative for breast cancer � 2 

years before who either were not hormone users (25,328) or were using 

E�P (16,121) were identified. Breast cancers were verified by centralized 

medical record review. Adjusted Cox proportional hazard regression was 

used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). 

Additional analyses adjusted for breast cancer screening, censoring participants 

for incidence analyses who had a � 2 year interval without a 

mammogram. Results: After a mean (SD) follow-up 11.3 (3.1) years, 2,236 

breast cancers were diagnosed. Breast cancer incidence was higher in E�P 

users (0.60% vs 0.42%, annualized rate, respectively: HR 1.55, 95% CI 

1.41-1.70, P�0.001). Screening adjusted analyses had stronger breast 

cancer association (0.63% vs 0.39%, HR 1.72, 95% CI 1.54-1.93; 

P�0.001). Survival following breast cancer, measured from diagnosis 

date, was similar in E�P users and non-users (HR 0.95, 95% CI 

0.74-1.23). Breast cancer mortality, analyzed from cohort entry date, are 

shown in the table. Conclusions: E�P use is associated with increased 

breast cancer incidence. As breast cancer prognosis following diagnosis on 

E�P is similar to that of nonusers, the higher incidence with E�P leads to 

increased breast cancer mortality. 

Deaths from breast cancer HR (95% CI) P values 

Screening adjusted* 

No 1.32 (0.90-1.93) 0.15 

Yes 1.54 (1.00-2.39) 0.052 

Deaths after breast cancer diagnosis 

Screening adjusted * 

No 1.65 (1.29-2.12) �0.001 

Yes 2.21 (1.66-2.94) �0.001 

* Censored for breast cancer diagnosis when time w/o mammogram � 2 yrs. 


Long-term therapy with thiazolidinediones and the risk of bladder cancer: A 

cohort study. Presenting Author: Ronac Mamtani, Perelman School of 

Medicine at the University of Pennsylvania, Philadelphia, PA 

Background: The US Food and Drug Administration and other regulatory 

agencies recently warned prescribers that use of pioglitazone, a thiazolidinedione 

(TZD), may increase the risk of bladder cancer. France and Germany 

removed the drug from their markets, although the rest of Europe did not. 

However, no information was available about the risk from alternative TZDs. 

We aimed to compare bladder cancer risk over time with use of TZDs 

relative to sulfonylureas (SUs), and between pioglitazone and rosiglitazone. 

Methods: We conducted a cohort study of patients with type 2 diabetes who 

initiated treatment with a TZD or SU using The Health Improvement 

Network (2000-2010), a UK general practitioner medical record database. 

Incident cancers within the database were identified. We computed hazard 

ratios (HRs) of bladder cancer for TZDs in comparison to the reference 

group of SU users. Results: There were 60 incident diagnoses of bladder 

cancer in the TZD cohort (n�18,459) and 137 in the SU cohort 

(n�41,396). There was no significant difference in bladder cancer risk 

between the cohorts (HR 0·93, [95% CI 0·68-1·29]), but most use was 

short-term use. In contrast, the risk of bladder cancer increased with 

increasing time since initiation of TZD versus SU therapy (HRs 1·15, 1·40, 

and 1·72 for 3-4, 4-5, and � 5 years, respectively; P-trend�0·033). 

Bladder cancer risk also increased with increasing time since initiation of 

pioglitazone (P-trend�0·001) and rosiglitazone (P-trend�0·006). Direct 

comparison of pioglitazone to rosiglitazone did not demonstrate significant 

differences in cancer risk with increasing time since initiation (Ptrend�0·12) 

or duration of therapy (P-trend�0·75). Conclusions: Longterm 

TZD therapy is associated with an increased risk of bladder cancer, 

which appears to be a class effect. 



Dexrazoxane exposure and risk of secondary acute myeloid leukemia in 

pediatric cancer patients. Presenting Author: Dana Marie Walker, Children’s 

Hospital of Philadelphia, Philadelphia, PA 

Background: Dexrazoxane (DXZ) is an effective cardioprotectant in children 

with leukemia and solid tumors. However, the potential risk of secondary 

acute myeloid leukemia (AML) limits DXZ use. We compared the incidence 

of secondary AML in pediatric cancer patients with and without DXZ 

exposure to estimate the risk of DXZ-associated secondary AML. Methods: 

We conducted a retrospective cohort study of anthracycline exposed 

pediatric cancer patients (excluding de novo AML) hospitalized from 

January 1999 to March 2011 in 43 freestanding children’s hospitals in the 

Pediatric Health Information System (PHIS) database. Secondary AML was 

defined as an ICD9 code for AML that occurred at least 90 days after first 

anthracycline exposure. Proportions of patients with secondary AML were 

compared between patients with and without an exposure to DXZ after the 

initial anthracycline exposure. Results: During the study period of interest, 

15,532 pediatric cancer patients were exposed to anthracycline, of which 

1404 (9.04%) subsequently received DXZ. Secondary AML was identified 

in 235 (1.51%) patients. Patients � 10 years of age, black patients, 

patients in New England and the Midatlantic regions, and those with bone 

tumors were significantly more likely to have received DXZ. The unadjusted 

incidence of secondary AML in the DXZ exposed and unexposed patients 

did not differ significantly (1.21% v. 1.54%, p�0.3308). After adjusting 

for these variations in demographics, the incidence of secondary AML still 

did not significantly differ between DXZ exposed and unexposed patients 

(p�0.6224). Conclusions: Our findings suggest that DXZ exposure does not 

lead to an increased risk of secondary AML in children. These data are 

important given the conflicting results from individual clinical trials about 

the risk of DXZ-associated secondary AML. While subject to well-known 

limitations of administrative database analyses, these data represent the 

largest cohort of DXZ exposed patients with available data on the occurrence 

of secondary AML. Additional multivariate analyses of chemotherapeutic 

covariates and time to secondary AML are ongoing. 


Sensitivity of clinical BRCA1 testing compared with linkage analysis. 

Presenting Author: Payal D. Shah, University of Pennsylvania, Philadelphia, 

PA 

Background: Specific clinical interventions in BRCA mutation carriers 

reduces the risk of breast and ovarian cancers and may improve survival; 

thus,identification of mutation carriers is important. The sensitivity of 

current BRCA mutation testing is unclear as a “gold standard” test is 

lacking. We assessed the BRCA1 mutation detection rate with current 

comprehensive clinical testing using linkage analysis as the comparator. 

Methods: 26 families with linkage analyses results available were included 

in this analysis. BRCAPRO, BOADICEA, and other risk estimation models 

were applied. Maximum-likelihood linkage analyses were performed to 

compute two-point and multipoint LOD scores using previously described 

BRCA1 –linked genetic markers; scores were classified as linked, not 

linked, or suggestive. At least one individual from each family underwent 

comprehensive testing. Results: Of 26 families analyzed, 9 demonstrated 

linkage and 4 demonstrated suggestive linkage to BRCA1. Of these 13 

families, 12 were found to have BRCA1 mutations: a detection rate of 

92.3%. In 3 of these 12 families, genetic mutation testing performed prior 

to large genomic rearrangement (LGR) testing was negative, demonstrating 

an improved detection rate with LGR testing which in this series was 23%. 

The 12 families with higher LOD scores and positive mutation testing had 

high mean prior probabilities by all models. Families which were not linked 

and who tested negative for mutations had lower mean prior probabilities. 

In one family, disease demonstrated linkage with a two-point LOD score of 

1.59 and multipoint LOD of 0.85 and all risk estimation models yielded 

high prior probabilities. Despite this, mutation testing was negative by full 

sequencing and MLPA analysis. Conclusions: When evaluated in a sample 

of families from high-risk clinics, current comprehensive testing compares 

well to linkage data. The inclusion of LGR testing has improved the 

mutation detection capability of clinical testing; however, some mutations 

may still be missed. Negative mutation testing results should be interpreted 

in the context of family history and prior probability during 

counseling. Despite recent advances, further improvements in genetic 

testing are warranted. 


87s 

CRA1505 Oral Abstract Session, Mon, 8:00 AM-11:00 AM 

Quality of cancer family history and referral for genetic counseling and 

testing among oncology practices: A pilot test of quality measures as part of 

the ASCO Quality Oncology Practice Initiative (QOPI). Presenting Author: 

Marie Wood, University of Vermont, Burlington, VT 








The APC I1307K polymorphism as a significant risk factor for CRC in 

average-risk Ashkenazi Jews. Presenting Author: Ben Boursi, Sheba Medical 

Center, Ramat Gan, Israel 

Background: The I1307K adenomatous polyposis coli gene variant, prevalent 

among Ashkenazi Jews, may increase risk for colorectal neoplasia. We 

studied the clinical importance of screening for this polymorphism in 3305 

Israelis undergoing colonoscopic assessment. Methods: Blood samples and 

risk factor information were collected from individuals undergoing colonoscopic 

examination at our medical center. Germline genetic analysis for the 

APC I1307K variant was performed using real-time PCR for DNA extracted 

from peripheral mononuclear cells. Results: The overall prevalence of the 

I1307K polymorphism was 8.0% (10.1% among Ashkenazi while only 

2.7% among Sephardic Jews, p�0.001). The overall adjusted odds ratio 

(OR) for CR neoplasia among carriers was 1.51(95% CI, 1.16 –1.98). 

Among average risk Ashkenazi Jews, the OR was 1.76 (95% CI 1.26-2.45). 

On the contrary, among Sephardi subjects the OR was 0.996 (95% CI, 

0.51-1.93). A multiplicative interaction was identified between Ashkenazi 

ethnicity and APC I1307K carrier status (PINTERACTION�0.055). The 

histopathological features of adenomas and cancers did not differ between 

carriers and non-carriers. Conclusions: The APC I1307K gene variant is an 

important risk factor for CRC in average risk Ashkenazi jews and should be 

considered for screening in this population. 




Use of PTEN protein dosage to predict for underlying germ-line PTEN 

mutations among patients presenting with thyroid cancer and Cowden-like 

phenotypes. Presenting Author: Joanne Y. Y. Ngeow, Genomic Medicine 

Institute, Cleveland Clinic, Cleveland, OH 

Background: Thyroid cancer is a major component of Cowden Syndrome 

(CS), a heritable syndrome characterized also by breast, uterine and kidney 

cancers. CS patients with an underlying germline PTEN mutation have a 

70-fold increased risk of developing epithelial thyroid cancer. In contrast, 

�1% of sporadic epithelial thyroid cancer harbor a germline PTEN 

mutation. Thus, cost-efficient markers capable of shortlisting thyroid 

cancers for CS genetic testing would be clinically useful. Here, we analyzed 

the relationship of patient PTEN protein levels in predicting the presence of 

germline PTEN mutations. Methods: We conducted a 5-year, multi-center 

prospective study of 2792 CS and CS-like patients, all of whom had 

comprehensive PTEN analysis done. Analysis of PTEN and downstream 

proteins by immunoblotting was performed on total protein lysates from 

patient-derived lymphoblast lines. We compared PTEN protein expression 

levels between patients with pathogenic PTEN mutations (PTENmut� ), and 

those with variants of unknown significance (VUS) or wildtype PTEN. PTEN 

immunohistochemistry (IHC) was performed on available thyroid samples. 

Results: Of 2792 CS/CS-like patients, 722 had thyroid cancer. PTEN 

germline pathogenic mutations were present in 36/722 (5%) patients. 

PTEN mut� 

cases presented at an earlier age (35 vs 42 years; p�0.02). PTEN 

frameshift and truncation mutations accounted for 55% of mutations. 95% 

(19/20) of PTENmut� patients had blood-PTEN protein levels in the lowest 

quartile as compared to 27% (90/330) of PTEN wildtype/PTEN VUS 

patients (p�0.001). Low blood-PTEN levels predicted for PTENmut� cases 

with a 99.6 % NPV (95%CI 97.7- 99.9) and a positive test likelihood ratio 

of 3.5 (95%CI 2.8-4.3). Affected thyroid tissues (n�22) from PTENmut� cases showed loss of PTEN protein by IHC, correlating with patient blood 

PTEN levels (r2�0.30, p�0.016). Conclusions: Our study shows that 

PTEN protein dosage could serve as a molecular correlate predicting for 

germline PTEN mutation in CS and CS-like presentations of thyroid cancer. 

The clinical utility of PTEN IHC in identifying thyroid cancer patients for 

germline PTEN testing should be further explored. 

1510 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM 

Meta-analysis of cancer risk among users of insulin glargine. Presenting 

Author: Alice Koechlin, International Prevention Research Institute, Lyon, 

France 

Background: The association between diabetes, its risk factors and treatments, 

and cancer risk and death is now high on the clinical and research 

agenda. Methods: All data regarding cancer risk and use of insulin glargine 

has been assembled and meta-analyses performed using state-of-the-art 

statistical methodology. Glargine is the most studied insulin in this regard. 

A random effects model was employed with tests for heterogeneity (I2 ) and 

publication bias. These meta-analyses are based on reports from epidemiological 

studies involving a total of 907,008 diabetic subjects and 2,597,602 

person-years of observation. Results: Based on independent estimates from 

14 studies, the Summary Relative Risk (SRR) for all forms of cancer was 

(SRR�0.90, 95% CI (0.82, 0.98)) and for breast cancer SRR�1.14 (95% 

CI (1.00, 1.29)). For new users of glargine, from 7 studies, the SRR for 

breast cancer was SRR�1.20 (95% CI (0.90, 1.58)). Based on independent 

estimates for 9 studies, for colorectal cancer the SRR was 0.73 (95% 

CI (0.59, 0.91)) and for prostate cancer SRR�1.16 (95% CI (1.03, 

1.30)). Overall, the risk of developing cancer among users of insulin 

glargine is reduced compared to the risk of users of other insulins. 

Similarly, the risk of colorectal cancer is reduced among users of glargine. 

While above unity, the risks of breast cancer and prostate cancer are 

increased marginally. Potential limitations to this meta-analysis include 

that the comparison group was not the same in all studies but this could 

also be seen as a strength. This is not likely to invalidate the findings of this 

analysis nor would the fact that different adjustments were made in the 

individual studies. Conclusions: The current evidence gives no support to 

the hypothesis that insulin glargine is associated with an increased risk of 

cancer as compared to other insulins and should give reassurance to 

physicians and their patients. Given the short exposure time possible to 

glargine (less than 5 years maximum), it is not biologically plausible to have 

a causal link to common forms of cancer. 


Diabetes, related factors, and breast cancer risk. Presenting Author: Peter 

Boyle, International Prevention Research Institute, Lyon, France 

Background: Diabetes and breast cancer are both common conditions in 

women and may share common risk factors. Methods: To shed clarification 

on the potential association between diabetes, related factors and breast 

cancer risk, a comprehensive literature review and formal meta-analysis 

was carried out, planned, conducted and reported following PRISMA 

guidelines regarding meta-analysis of observational studies. Variables 

studies in relation to breast cancer risk were adiposity, physical activity, 

glycaemic load, glycaemic index, diabetes, IGF-1, fasting glucose, fasting 

insulin and C-peptide, adiponectin, metformin and glargine use. The 

Summary Relative Risk (SRR) and the corresponding 95% Confidence 

Interval (CI) was calculated. Results: For breast cancer at all ages, the 

calculated risks were as follows: diabetes (SRR�1.23 95% CI (1.12, 

1.34); physical activity (SRR�0.88, 95% CI (0.85, 0.92)); glycaemic load 

(SRR�1.05, 95% CI (1.00, 1.10)); glycaemic index (SRR�1.05, 95% CI 

(1.00, 1.09)); fasting glucose (SRR�1.14, 95% CI (0.94, 1.37)); serum 

insulin (SRR�1.26, 95% CI (0.86, 1.84)); c-peptide (SRR�1.29, 95% CI 

(0.91, 1.82)); adiponectin (SRR�1.16, 95% CI (0.93, 1.46)); metformin 

(SRR�0.97, 95% CI (0.82, 1.16)); and glargine (SRR�1.10, 95% CI 

(0.94, 1.30)). An increase of 5 units in Body Mass Index (a weight increase 

if 14.5 kg in a person 1.70 metres tall) was associated in post-menopausal 

breast cancer (SRR�1.12, 95% CI (1.08, 1.16)) but not at premenopausal 

ages (SRR�0.83, 95% CI (0.72, 0.95)). Serum insulin was 

associated with breast cancer at post-menopausal ages but not at premenopausal 

ages whereas with c-peptide there was a significant association 

at pre-menopausal ages but not post-menopausal. For IGF-1, Hodge’s 

Standardised Mean Difference (HSMD) was calculated and there was no 

significant association with breast cancer at all ages (HSMD�-0.026, 95% 

CI (-0.031, 0.084)), at post-menopausal ages (HSMD�0.007, 95% CI 

(-0.068, 0.082)) or at pre-menopausal ages (HSMD�-0.065, 95% CI 

(-0.009, 0.140)). Conclusions: Key risk factors for breast cancer appear to 

be adiposity and physical activity which are both related to the risk of 

developing diabetes. 


Changes in glucose, insulin, and insulin resistance from presurgery to post 

adjuvant treatment for breast cancer. Presenting Author: Emer M. Guinan, 

Trinity College Dublin, Dublin, Ireland 

Background: Elevated fasting insulin levels at breast cancer diagnosis are 

associated with increased risk of recurrence and reduced survival. (Goodwin 

PJ, et al. JCO. 2012;30:164-171) Weight gain related to adjuvant 

treatment coupled with sedentary activity habits may further alter insulinrelated 

measures for breast cancer survivors. We present results from a 

prospective longitudinal study examining changes in insulin-related markers 

from pre breast cancer surgery to post adjuvant treatment. Methods: 

Subjects were recruited from St. James’s hospital, Dublin, Ireland at the 

time of breast cancer diagnosis (stage I-III). Fasting pre-surgery blood 

samples were drawn to measure insulin, glucose and glycosylated haemoglobin 

A1c (HBA1C). Insulin resistance was calculated using the homeostatic 

model assessment (HOMA). Subjects with no evidence of active 

cancer completed the same measurements 2-5 years later. Paired sample 

t-tests were used to measure changes from pre-surgery to post-adjuvant 

treatment. Statistical significance was set at P � .05. Results: Forty-four 

subjects (n � 22 postmenopausal) completed both measurements (mean 

� SD age 54.1�8.6 years). Mean time since diagnosis to follow-up 

measures was 3.4�0.8 years. Adjuvant therapy included chemotherapy 

(n�37), radiotherapy (n�36), biological therapy (n�8) and concurrent 

hormonal therapy (n�37). There was a statistically significant increase in 

insulin (mean � SD change 2.8�4.1mU/L, P�.000), insulin resistance 

(0.54�1.0, P�.001) and HBA1C (0.1�0.2 %, P� .003). Fasting glucose 

levels did not change (P � .06). Conclusions: Results indicate that patients 

with breast cancer experience significant increases in insulin, insulin 

resistance and HBA1C from pre-surgery to post adjuvant treatment. 

Elevated post-treatment insulin levels may further contribute to risk of 

breast cancer recurrence and mortality, while also predisposing to the 

development of cardiovascular disease and type 2 diabetes mellitus. 

Exercise and diet interventions are warranted in this population to improve 

markers of insulin resistance as a surrogate for improving breast cancer and 

overall health outcomes. 


1512 Poster Discussion Session (Board #1), Sun, 8:00 AM-12:00 PM and 

11:30 AM-12:30 PM 

Routine universal screening for Lynch syndrome in colorectal cancer 

patients in the community setting. Presenting Author: Jeffrey M. Goldberg, 

Norton Cancer Institute, Louisville, KY 

Background: Identification of colorectal cancer (CRC) cases that are due to 

Lynch Syndrome (LS) is important to prevent secondary malignancies or 

development of additional malignancies among relatives. Utilization of 

clinical criteria to select CRC patients for laboratory testing fails to identify 

a significant proportion of patients whose CRC is due to LS. Therefore, 

universal screening for LS among CRC patients has been advocated by the 

Evaluation of Genomic Applications in Practice and Prevention Working 

Group. However, the feasibility of routine universal screening has not been 

evaluated in a community-based, non-research setting. We implemented a 

universal screening protocol for LS as part of routine care of CRC at Norton 

Healthcare, a multi-institutional community-based healthcare organization. 

Methods: Beginning in October 2009, all resected CRC tumors 

automatically underwent immunohistochemistry analysis (IHC) for Lynch 

Syndrome-associated mismatch repair gene (MMR) expression. Selected 

patients who underexpressed MLH1 also underwent testing for the BRAF 

V600E mutation. Patients who had a BRAF V600E mutation were considered 

to have sporadic CRC. All other patients with abnormal IHC were 

automatically referred for genetic counseling. We retrospectively reviewed 

the outcomes of genetic counseling in all patients referred through this 

universal screening protocol. Results: Between October 2009 and December 

2011, 388 patients underwent resection of CRC, all of whom had IHC 

for MMR expression. Seventy patients were identified as having abnormal 

IHC. Sixty-two had MLH1/PMS2 underexpression, of which 18 underwent 

BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6 

underexpression. Nine patients have been confirmed to have LS, 31 have 

been found not to have LS, and 19 are in the process of evaluation. Seven 

patients declined genetic counseling, and 4 died before they could be 

adequately evaluated. Conclusions: Universal screening for CRC due to LS, 

using IHC with select BRAF V600E mutation testing and automated 

referral for genetic counseling, is feasible in the community setting. 

Funded in part with federal funds: NCI, NIH, Contract No. 

HHSN261200800001. 


11:30 AM-12:30 PM 

Use of clinical history (CH) for Lynch syndrome (LS) risk assessment: An 

economic decision analysis. Presenting Author: Sarmad Sadeghi, Cleveland 

Clinic Taussig Cancer Institute, Cleveland, OH 

Background: Previous studies comparing screening strategies (STs) for LS 

concluded that immunohistochemistry (IHC)-based STs are most cost effective. 

However, these analyses generally exclude clinical history (CH)-based criteria 

due to concerns for reliability, e.g. Amsterdam (Ams), Bethesda (Beth), MMRpro 

(Mpro), MMRpredict (Mpre) and PREMM (PRE). We conducted a comprehensive 

comparison of all STs. Methods: Using assumptions from published reports we 

performed a cost effectiveness analysis (CEA) with a societal viewpoint using 

TreeAge software. 20 STs for proband (Pd) and general population (GP) 

screening in a cohort of 100,000 assumed a 3% LS prevalence (Prev) in Pd and 

0.23% in GP, 5 first degree relatives (FDRs) per LS diagnosis (Dx), 50% LS Prev 

in FDRs, and 90% genetic testing (GT) compliance in Pds and GP and 52% in 

FDRs. We used the number of LS Dxs as effectiveness measure (EM). Sensitivity, 

accuracy, and incremental cost effectiveness ratios (ICERs) were calculated. 

Results: The ST of Mpro followed by GT is highly sensitive and has an accuracy of 

.997. Assuming 1-1.4 life years saved per Dx based on prior studies, this 

strategy is also cost effective. Strategies with greater sensitivity were dominated 

or not cost effective. Table shows results in order of increasing cost per Dx. 

Conclusions: This comprehensive comparison suggests that Mpro is an appropriate 

first step in screening for LS in Pds, and its routine use may be considered as 

a quality measure in the management of colorectal cancer. IHC � BRAF, GT 

should be reserved for Pds where CH is incomplete. 

ST Sensitivity LS in Pds LS in FDRs ICER 

No screening 0 0 0 - 

Ams, IHC, GT .17 493 641 - 

Ams, GT .2 594 772 - 

Mpre, IHC, GT .55 1,546 2,010 - 

Mpro, IHC, GT .72 1,994 2,593 $4.9K 

Beth, IHC, GT .66 1,838 2,389 - 

Mpre, GT .67 1,863 2,422 - 

PRE, IHC, GT .73 2,017 2,622 - 

Mpro, GT .88 2,403 3,124 $21.6K 

Beth, GT .8 2,214 2,878 - 

PRE, GT .89 2,430 3,159 $513K 

IHC � BRAF, GT .82 2,241 2,913 - 

IHC, GT .82 2,241 2,913 - 

MSI, GT .84 2,295 2,983 - 

PRE GP 4, GT age > 35 .89 110 144 - 

PRE GP 3, GT age > 30 .89 120 156 - 

PRE GP 2, GT age > 25 .89 129 168 - 

PRE GP 1, GT age > 20 .89 138 179 - 

MSI � IHC, GT .89 2,430 3,159 - 

MSI � IHC � BRAF, GT .89 2,430 3,159 - 

Up-front GT 

- � dominated. 

1 2,700 3,510 $1,053K 


89s 


11:30 AM-12:30 PM 

An alternative approach to identify women at risk for colorectal cancer. 

Presenting Author: Amanda S. Bruegl, University of Texas M. D. Anderson 


Background: Hereditary colorectal cancer (CRC) is preventable; however, 

identification of individuals at sufficiently high risk to warrant heightened 

surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer 

syndrome due to germline mutation in a DNA mismatch repair gene. For 

women with LS, the lifetime risk of endometrial cancer (EC) is 64% and 

CRC is 54%. Fifty percent of women with LS will present with EC or ovarian 

cancer prior to CRC. Therefore, women with LS associated EC represent an 

ideal group for CRC prevention. The optimal method to identify women with 

LS associated EC is not known. The purpose of this study was to determine 

the utility of Amsterdam II and Society of Gynecologic Oncology (SGO) 

Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in 

identifying women with LS associated EC. Our ultimate goal is to identify 

women at increased risk of CRC. Methods: Immunohistochemistry (IHC) for 

DNA mismatch repair proteins and MLH1 methylation analyses were used 

to identify LS associated EC among 388 women. EC was designated as LS 

if there was loss of mismatch repair protein expression. Absence of MLH1 

methylation was required to confirm LS in tumors with MLH1 protein loss. 

Results: Fifty-nine (15.2%) of the EC patients tested had LS. These 

patients are summarized in the table. Conclusions: Clinical criteria to detect 

LS identify 17/59 (29%) - 44/59 (74%) of women who present with EC 

first. EC with MSH2 loss is most likely to occur in younger women and 

women with positive family history of EC and CRC, features classically 

associated with LS. In general, the MSH6 mutation is associated with older 

age at diagnosis and fewer familial CRCs, however, we found a large 

number of MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than 

50 years with no family history of CRC. Our data suggest that classic 

clinical screening criteria are inadequate to detect patients with LS who 

present with EC, potentially missing up to 25% of these patients. 

Gene MLH1 MSH2 MSH6 PMS2 Total 

Total number 14 27 11 7 59 

Median age at diagnosis (range) 52 44 56 66 50 

(42-79) (33-81) (31-76) (45-87) (31-87) 

Diagnosis at greater than 50 years 7 8 9 6 30 

FH CRC 3 16 4 3 26 

Amsterdam criteria 3 13 0 1 17 

SGO criteria 11 22 7 4 44 


11:30 AM-12:30 PM 

Next-generation sequencing to identify candidate gene for hereditary mixed 

polyposis syndrome. Presenting Author: Michele Caroline Gornick, University 

of Michigan, Ann Arbor, MI 

Background: Rare monogenic disorders are often due to mutations that are 

highly penetrant, extremely rare, and strongly disrupt normal biology. 

Hereditary mixed polyposis syndrome (HMPS, OMIM ID %601228), is 

characterized by a mixture of atypical juvenile polyps, hyperplasic polyps, 

sessile serrated adenomas and an increased risk of colorectal cancer. 

Polyps appear to be inherited in an autosomal dominant fashion. The 

putative susceptibility locus initially mapped to 15q13-14, however, the 

genetic basis of this syndrome is not well understood, and no mutation or 

associated variants have been identified. Methods: Germline DNA from four 

individuals from a family with clinically and pathologically confirmed 

HMPS was subjected to massively parallel sequencing (Illumina GAII). 

Affected individuals had an average of 30x coverage of their exome and 10x 

coverage of their genome. Sequence calls were filtered using the criteria of 

� 4x coverage, quality score over depth � 50, depth of coverage � 360, 

allele balance � 0.75, number or MAPQ zero reads at locus � 4. Common 

variants were filtered out by excluding variants found in dbSNP (build131), 

1000 Genomes Project, the Exome Variant Server or 80 unaffected 

controls sequenced by hybrid capture and whole exome sequencing. 

Polyphen2 and SIFT were used to predict pathogenicity of the novel, shared 

variants, and validated by Sanger sequencing. Expression levels of novel 

variants were examined in available tumor samples using qRT-PCR. 

Results: From the 32 previously unidentified nonsense, missense or splice 

site variants shared by the family members whose whole genomes were 

sequenced, only 5 (4 missense, 1 nonsense) were predicted to be 

damaging, leading to a small subset of novel candidate genes including 

ZNF426, which may be responsible for HMPS within this family. 

Conclusions: HMPS extremely difficult to accurately diagnosis and the 

genetic basis is unknown. Using next-generation sequencing we were able 

to detect previously unidentified low frequency allelic variants including a 

novel candidate locus. 




11:30 AM-12:30 PM 

PTEN germline mutations in patients first tested for other hereditary cancer 

syndromes: Would use of risk assessment tools have reduced health care 

costs? Presenting Author: Jessica Mester, Genomic Medicine Institute, 

Cleveland Clinic, Cleveland, OH 

Background: PTEN Hamartoma Tumor Syndrome (PHTS) includes patients 

with Cowden (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) with 

germline PTEN mutation. Breast, colon, endometrial cancer and GI 

polyposis are associated, creating overlap with Hereditary Breast and 

Ovarian Cancer (HBOC), Lynch (LS) and adenomatous polyposis syndromes 

(APS). We reviewed our PHTS patient series to find how often testing 

criteria for these syndromes were met or testing was pursued before PTEN. 

Methods: Patients were prospectively recruited by relaxed International 

Cowden Consortium criteria or presence of known germline PTEN mutation; 

mutations were identified by mutation scanning or MLPA analysis and 

confirmed by sequencing or quantitative PCR, respectively. Families were 

excluded if diagnosed with CS or BRRS before 1998, family history was 

unavailable, or proband was �18 yrs. Pedigree, genetic testing reports, and 

medical records were reviewed to determine if patients met HBOC testing 

criteria, Amsterdam II or Bethesda 2004 criteria, or had adenomatous 

polyps. Risk assessment was conducted for BRCA1/2 via the BRCAPRO, 

Myriad II, and Penn II models; for MLH1/MSH2/MSH6 via the PREMM1,2,6 

and MMRPro models; and for PTEN via the Cleveland Clinic (CC) PTEN 

Risk Calculator. Results: 115 PTEN mutation-positive adult probands were 

identified among 3,405 patients. 53 (46.1%) met testing criteria for HBOC 

or LS and 34 (29.6%) underwent previous testing for HBOC, LS or APS. 

Average risk for BRCA1/2 and MLH1/MSH2/MSH6 mutations in tested 

patients were 7.5-16.9% and 33.1-41.4%, respectively; whereas PTEN 

mutation risks were 35.9% and 79.7%. No patient tested for APS (average 

PTEN mutation risk 73%) had �5 adenomas. An estimated $89,700 was 

spent on negative analyses for HBOC, LS and APS among patients 

ultimately found to have germline PTEN mutations. Conclusions: PHTS 

should be part of the differential diagnosis for patients referred for question 

of HBOC, LS or APS. Pathology review is key for patients with polyposis. 

Using the CC PTEN risk calculator enables clinicians to understand when 

PTEN mutation risk is high, allowing testing to proceed in a step-wise and 

cost-saving manner. 


11:30 AM-12:30 PM 

Pathologic findings at risk-reducing salpingo-oophorectomy among women 

at increased ovarian cancer risk: Results from GOG-199. Presenting 

Author: Phuong L. Mai, National Cancer Institute, Rockville, MD 

Background: Although risk-reducing salpingo-oophorectomy (RRSO) is a 

standard management option for women with BRCA1/2 mutations, the lack 

of large, prospective cohort studies makes estimating the prevalence of 

cancer at RRSO problematic. Methods: GOG-199 is a large, nonrandomized 

multi-center trial which enrolled women at high-risk (due to 

BRCA mutations or strong family history) of ovarian cancer, comparing 

surgery at enrollment with serial transvaginal ultrasound and CA-125 

screening. RRSO specimens were processed according to a standardized 

tissue processing protocol including 2-3mm sectioning of both ovaries and 

tubes. Results: 2,605 participants were accrued to GOG-199. Of the 1 030 

enrolled in the baseline RRSO cohort, 28 were ineligible and 36 declined 

surgery after enrollment, resulting in 966 baseline RRSO. Pathology review 

demonstrated 4 tubal intraepithelial carcinoma and 20 serous pelvic 

cancers, of which 12 were identified only microscopically. Among the 20 

serous cancers, the predominant or exclusive site of involvement was ovary 

in 10, fallopian tube in 5, and peritoneum in 5 cases. In addition, 6 

endometrial cancers (among the 515 undergoing concomitant hysterectomy) 

and 3 adenocarcinomas suggestive of metastasis were identified. The 

serous pelvic cancer prevalence was: entire cohort�2.1% (20/966), all 

BRCA mutation carriers�3.2 (18/558), BRCA1 mutation carriers�3.7% 

(12/325), BRCA2 mutation carriers�2.6% (6/231), and mutationnegative�0.5% 

(2/402). Compared to those without cancer, women with 

serous pelvic cancer were older at surgery (p� .001), and more often 

menopausal (vs pre-menopausal, p� .002), nulliparous (vs parous, p�.04) 

and never users of tamoxifen (vs ever users, p� .04). Serous pelvic cancers 

were more frequent in BRCA mutation carriers (vs no mutation, p� .004), 

and among carriers, more common in those with BRCA1 mutations (vs 

BRCA2 mutation, p� .02). Conclusions: The prevalence of serous pelvic 

cancers in this cohort was 3.2% among carriers vs 0.5% among the 

mutation-negative but with a strong family history. Our data will be useful 

when counseling women at increased ovarian cancer risk who are contemplating 

risk-reducing surgery. 


11:30 AM-12:30 PM 

Risk-reducing salpingo-oophorectomy and prophylactic mastectomy among 

BRCA mutation “previvors.” Presenting Author: Laura L. Holman, University 


Background: We prospectively evaluated the timing and uptake of riskreducing 

surgery in a cohort of female BRCA mutation carriers that have no 

personal cancer history (“previvors”). Methods: Patients at high risk of 

breast and ovarian cancer were enrolled between 2007 and 2011 and 

followed in a high-risk ovarian cancer screening clinic. Women were offered 

risk-reducing salpingo-oophorectomy (RRSO) and/or prophylactic mastectomy 

(PM) per guidelines. Their clinical data were recorded and analyzed 

using descriptive statistics. Results: Of 260 BRCA mutation carriers 

enrolled, 73 have no personal history of cancer and are “previvors.” 

Patients have been followed for a median of 26.5 months (1-50 months). 

The median age is 38 years, 81.1% are white, 16.2% are Ashkenazi 

Jewish, and 79.7% are premenopausal. BRCA1 carriers account for 43.2% 

of participants and 55.4% have a BRCA2 mutation. The majority of 

patients (77.6%) presented for ovarian cancer screening �1 year after 

their BRCA testing. In all, 60.8% of women underwent prophylactic 

surgery: 28.4% chose RRSO, 18.9% chose PM, and 13.5% chose both 

procedures. Postmenopausal women were more likely to choose RRSO, 

while uptake for both procedures was common for premenopausal women 

(Table, p�0.04). RRSO was also more likely in parous than nulliparous 

premenopausal women (35.2% vs 9% p�0.001). PM was not associated 

with parity (p�0.79). Of women that had both surgeries, 20% had them 

concurrently and 20% had PM first. Of the 60% that underwent RRSO first, 

all had their second surgery within 14 months. Conclusions: BRCA mutation 

“previvors” have a high overall uptake of prophylactic surgery. Premenopausal 

women are more likely to choose PM than postmenopausal women; 

reasons for this are unclear. “Previvors” that choose RRSO and PM typically 

have both surgeries within a fairly short timeframe. With the growing 

population of “previvors” in the US, further study of patient preferences 

regarding preventative surgery and long-term consequences is needed. 

Surgery choices of pre- versus postmenopausal women. 

None RRSO PM RRSO�PM 

Premenopausal 35.6% 23.7% 22% 16.9% 

Postmenopausal 20% 46.7% 0% 6.7% 


11:30 AM-12:30 PM 

A multi-institution study of the accuracy of BRCAPRO in predicting 

BRCA1/BRCA2 mutations in women with ovarian cancer. Presenting 

Author: Molly S. Daniels, University of Texas M. D. Anderson Cancer 


Background: 10-15% of ovarian cancer patients have a germline BRCA1 or 

BRCA2 mutation, with significant management implications for both 

patients and relatives. Genetic testing decisions are guided in part by the 

estimated likelihood of identifying a mutation. The BRCAPRO model uses 

personal and family history of breast and ovarian cancer to calculate the 

likelihood of a BRCA1/2 mutation. This study’s purpose was to assess the 

ability of BRCAPRO to accurately determine this likelihood. Methods: 

BRCAPRO scores were calculated using CancerGene v5.1 for 589 ovarian 

cancer patients referred for genetic counseling at three institutions. The 

study population was divided into quintiles by BRCAPRO score, with 

cutpoints chosen such that each quintile represented 20% of the sample. 

Chi-square goodness-of-fit test was used to compare observed BRCA1/2 

mutations to the number predicted. ANOVA models were used to assess 

factors impacting BRCAPRO accuracy. Results: 180/589 (31%) ovarian 

cancer patients tested positive for a BRCA1/2 mutation. At BRCAPRO 

scores under 40%, more mutations were observed than expected (93 

observed vs. 34.1 expected, p�0.001). If patients with BRCAPRO scores 

�10% had not been offered genetic testing, almost one-third of mutations 

(51/180, 28%) would have been missed. Multivariate analysis demonstrated 

that BRCAPRO underestimated risk for high grade serous ovarian 

cancers but overestimated risk for other histologies (p�0.0001), underestimation 

increased as age at diagnosis decreased (p�0.02), and model 

performance varied by institution (p�0.02). Conclusions: Ovarian cancer 

patients classified as low risk by BRCAPRO are more likely to test positive 

than predicted, therefore the BRCAPRO prediction could falsely reassure 

patients considering genetic testing. BRCAPRO performance could be 

improved by incorporating factors such as ovarian cancer histology. 

Alternatively, given the high prevalence of BRCA1/2 mutations in high 

grade serous ovarian cancer and the apparent limitations of using family 

history to predict mutation probability, BRCA1/2 genetic testing could be 

offered to high grade serous ovarian cancer patients regardless of family 

history. 



11:30 AM-12:30 PM 

Alcohol and breast cancer risk in postmenopausal women: The PLCO 

experience. Presenting Author: Roni Falk, Division of Cancer Epidemiology 

and Genetics, National Cancer Institute, Rockville, MD 

Background: Moderate alcohol consumption is an established breast cancer 

(BC) risk factor. Invasive BC is a heterogeneous disease comprised of 

several histological subtypes with distinct biological features that suggest 

etiologic differences. Several studies show the alcohol link may be stronger 

for estrogen receptor-positive tumors (ER�/PR� and ER�/PR-) and for 

lobular BC. Few have evaluated the role of alcohol consumption by BC 

histology and hormone receptor status combined. Methods: We evaluated 

the risk of BC by baseline alcohol consumption in the Prostate, Lung, 

Colorectal and Ovarian Cancer Screening Trial cohort (54649 participants, 

1786 incident invasive breast cancers) by histology and hormone receptor 

status. Histologic subtype-specific associations were evaluated using a 

recently developed Cox proportional hazards model to calculate multivariate 

hazards ratios (HR) and 95% confidence intervals (CI). Results: 1444 

ductal (81%), 233 lobular (13%) and 109 mixed ductal lobular (6%) cases 

were identified. The majority were ER�/PR� (ductal: 959 ER�/PR�, 136 

ER�/PR-, 229 ER-/PR-; lobular: 179 ER�/PR�,37ER�/PR-, 6 ER-/PR-; 

mixed ductal/lobular: 88 ER�/PR�, 6ER�/PR-, 5 ER-/PR-). For ductal 

and lobular BC, risks for alcohol consumption were modestly elevated; 

compared to never drinkers, women consuming 7-14 drinks/week had a 

40% increase in HR in both histologic subtypes. Risks for mixed ductal 

lobular cancer were significantly higher, particularly for women consuming 

7-14 drinks per week (HR�3.0; 95% CI�1.5, 6.1). For all histologies 

combined, alcohol risks were confined to ER�/PR� cancers with HR�1. 6 

(95% CI�1.3, 2.1) for women consuming 7-14 drinks/ week; p 

trend�0.0005. Similarly, for each histologic subtype, the risk for alcohol 

consumption was limited to ER�/PR� tumors, and notably, very few cases 

with pure lobular or mixed ductal lobular cancer were either ER�/PR- or 

ER-/PR-. Conclusions: Moderate alcohol consumption is associated with 

risk of ER�/PR� BC in each of the predominant histologic subtypes, but 

not with hormone receptor-negative cancer. Unlike other studies, we did 

not find a link between alcohol consumption and ER�/PR- BC. 


11:30 AM-12:30 PM 

Genetic polymorphisms of the OPG gene associated with breast cancer. 

Presenting Author: Gunter Assmann, University Medical School of Saarland 

and Jose Carreras Research Center, Homburg, Germany 

Background: The receptor activator of NfkappaB (RANK) and osteoprotegerin 

(OPG) cascade system have been reported to play a role in the 

pathogenesis of breast cancer (BC). Genetic variations in the genes coding 

for RANK, RANK ligand (RANKL), and OPG are supposed to play a role in 

the susceptibility of breast cancer. Methods: In the present case-control 

study genomic DNA was obtained from 307 BC patients (age: median 56) 

and 396 healthy female controls (healthy blood donors, HC; age median: 

45). We studied six single nucleotide polymorphisms (SNPs) in the genes 

coding for RANK (2 SNPs, rs1805034, rs35211496), OPG (2 SNPs, 

rs3102735, rs2073618), and RANKL (2 SNPs, rs9533156, rs2277438) 

using TaqMan assay-guided PCR for the respective SNPs. The genotype 

and allelic frequencies comparing BC with HC were analyzed with �2 test 

for 2x3 and 2x2 tables, respectively. Results: The genotype distributions as 

well as the allelic frequencies of the SNP rs3102735 in the OPG gene 

differed significantly (p�0.006 and p�0.019, respectively) between BC 

patients and HC; the genotypes containing the minor allele were more 

frequent in BC patients (table). In the OPG SNP rs2073618 the minor 

allele C was significantly less frequent in BC patients compared to HC 

(43.8 vs. 49.7%; OR: 0.788; p�0.031). In addition, BC patients carried 

less frequently the homozygous genotype of the minor allele compared to 

major allele (18.6 vs. 23.9%, p�0.083). No significant risk was detected 

for the other SNPs investigated in this study. Conclusions: This is the first 

study reporting a significant association of the SNP rs3102735 in the OPG 

gene with the susceptibility to develop BC in the Caucasian population. The 

minor allele C of OPG SNP rs2073618, however, seems to be protective 

against BC disease. The impact of the OPG SNP rs3102735 (location: 

5�near region, chromosome 8q24) and of the OPG SNP rs2073618 (a 

missense SNP, leading to amino acid exchanges Leu3Asn) on the pathogenesis 

of BC are unclear. 

SNP 

Allele / 

genotypes 

Breast 

cancer 

Healthy 

females 

OR 

(95% CI) p value 

OPG rs3102735 n�614 (%) n�784 (%) 

Allele minor C 113 (18.4%) 102 (13.0%) 1.508 0.006 

Major T 501 (81.6%) 682 (87.0%) (1.127-2.018) 

n�307 (%) n�392 (%) 

Genotype CC 10 (3.3%) 5 (1.3%) 0.019 

CT 93 (30.3%) 92 (23.5%) 

TT 204 (66.4%) 295 (75.3%) 


91s 


11:30 AM-12:30 PM 

Contribution of TP53 p.R337H mutation to breast cancer prevalence in 

Brazil. Presenting Author: Patricia Ashton-Prolla, UFRGS/HCPA, Porto 

Alegre, Brazil 

Background: The exact contribution of TP53 germline mutations, associated 

with Li Fraumeni Syndrome, to the overall burden of cancer is still only 

partially known. Studies in Southern and Southeastern Brazil have shown 

that a specific germline mutation at codon 337 (c.1010G�A; p.R337H), 

has incomplete penetrance and may be present in a significant number of 

subjects (estimated frequency at the populational level of 1:300 individuals). 

In an exploratory approach, the aim of the study is to assess the 

frequency of the p.R337H mutation in women from different Brazilian 

regions, diagnosed with breast cancer (BC) before 46 and after 55 years of 

age, and unselected for family history of cancer. Methods: Formalin-fixed 

paraffin-embedded (FFPE) non-tumoral tissue (lymph nodes or normal 

breast) of women diagnosed with BC between 2000 and 2010 in 3 

pathology laboratories from the Brazilian cities of Porto Alegre, São Paulo 

and Barretos were obtained retrospectively and analyzed after anonimization. 

Genomic DNA was isolated with standard methods and genotyping 

performed in duplicates by qPCR (TaqMan assay). Confirmation of all 

mutation-positive and a sample of mutation-negative cases were done by 

TP53 exon 10 sequencing or by a second independent qPCR analysis. 

Results: Analysis of 515 BC-affected women identified the p.R337H 

mutation in the germline of 70 (8,6%) cases: 49/403 (12,1%) diagnosed 

before 46 years and 21/412 (5,1%) diagnosed after 55 years. BC occurred 

earlier in p.R337H mutation carriers than in non-carriers (p�0.001). 

Conclusions: Preliminary analysis in a sample of women with BC indicates 

that p.R337H founder mutation is present in a high proportion of cases, 

especially those diagnosed at a young age. Regional genetic background 

and recruitment strategies may account for the different mutation frequencies 

observed in the centers of study. The occurrence of this mutation at 

such a high frequency in a particular geographic region has important 

implications for disease management and cancer risk counseling for these 

patients and families. This mutation likely contributes to a significant 

proportion of the health burden associated with BC in Brazil. Financial 

support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline. 


11:30 AM-12:30 PM 

Breast cancer intrinsic subtypes by PAM50 in older women. Presenting 

Author: Emily Oldham Jenkins, University of North Carolina Lineberger 

Comprehensive Cancer Center, Chapel Hill, NC 

Background: Breast cancer (BC) incidence dramatically increases with age 

and the number of older BC patients (pts) in the U.S. is rising. Although 

immunohistochemical (IHC) data confirm that the incidence of luminal BC 

increases with age while the incidence of triple negative (TN) BC decreases, 

age-specific data on the frequency of BC subtypes defined by gene 

expression is limited. We characterized the incidence of BC intrinsic 

subtypes using gene microarrays according to age. Methods: Data from 

2,150 pts were pooled from publicly available microarray datasets to 

determine the incidence of PAM50 breast cancer intrinsic subtypes 

(Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basallike 

[Basal] and Normal-like [Norm]) by age. Adjuvant treatment data 

(none, chemotherapy, endocrine therapy or both) were available for 1,741 

samples. Relapse-free (RFS) and overall survival (OS) differences were 

determined using the Kaplan-Meier method. Results: PAM50 intrinsic 

subtypes by age are tabulated below. The incidence of luminal (A, B, A�B) 

tumors increased with age (p�0.01, p�0.0001, p�0.0001, respectively), 

while the percentage of basal tumors decreased (p�0.0001). Basal tumors 

represented 13% of pts aged � 70 years (yrs); of the 70% with available 

IHC data, 74% were TNBC. Age as a continuous variable was not associated 

with RFS (p � 0.37). Subtype alone (n�2031), and after controlling for 

treatment (n�1645), was significantly associated with RFS (both 

p�0.0001). The addition of age to a multivariate analysis added no 

prognostic information. Conclusions: Though more favorable subtypes 

increase with age, older BC pts still have a substantial percentage of 

high-risk subtypes. Age alone was not a significant factor in outcome. 

Tumor biology as defined by intrinsic subtype is an important clinical 

predictor. 

PAM50 intrinsic subtypes by age. 

Age (total n�2150)



11:30 AM-12:30 PM 

Cost-effectiveness of the 21-gene recurrence score assay in the setting of 

multifactorial decision making for chemotherapy in early-stage breast 

cancer. Presenting Author: Shelby D. Reed, Duke Clinical Research 

Institute, Durham, NC 

Background: The objective of this study was to incorporate evidence from 

two recently-published studies to reevaluate the cost-effectiveness of the 

21-gene Recurrence Score (RS) assay (Oncotype DX) in the context of 

multifactorial decision making to guide the use of chemotherapy for 

node-negative, estrogen receptor–positive breast cancer in the United 

States from the societal and healthcare system perspectives. Methods: We 

developed a decision-analytic model to first cross-classify hypothetical 

patients by clinicopathologic characteristics according to the Adjuvant! 

using risk groups and RS risk groups. We generated estimates of long-term 

costs, survival, and quality-adjusted survival for the RS-guided and 

non–RS-guided strategies using a probabilistic state transition model. In 

addition to costs for the 21-gene assay, we assigned attributable costs for 

chemotherapy, hormonal therapy, monitoring for disease recurrence, and 

distant recurrence. For the societal perspective, we also considered 

incremental patient time costs. Costs and survival were discounted at 3% 

annually. Results: With the RS-guided strategy, 40.4% of patients were 

expected to receive chemotherapy relative to 47.3% in the non–RS-guided 

strategy. Targeted use of chemotherapy in the RS-guided strategy was 

expected to increase survival by 0.19 years (95% CI, 0.09 to 0.32) and 

0.16 QALYs (95% CI, 0.08 to 0.28). Lifetime direct medical costs were 

expected to be $2692 (95% CI, 1546 to 3821) higher with the RS-guided 

strategy. The incremental cost-effectiveness ratios (ICERs) were $14,059 

per life-year saved (95% CI, $6840-$28,912) and $16,677 per QALY 

(95% CI, $7613-$37,219). When incorporating lower indirect costs of 

$950 per patient, the ICERs were $9095 per life-year saved (95% CI, 

dominant-$23,397) and $10,788 per QALY (95% CI, $6840-$30,265). 

In probabilistic sensitivity analysis, more than 99% of the ICERs were less 

than $50,000 per life-year saved and per QALY. Conclusions: Our updated 

cost-effectiveness estimates are supportive of the economic value of the 

21-gene RS assay in the setting of node-negative, estrogen receptor– 

positive breast cancer. 


11:30 AM-12:30 PM 

Associations between allergies and risk of hematologic malignancies: 

Results from the Vitamins and Lifestyle (VITAL) cohort study. Presenting 

Author: Mazyar Shadman, University of Washington, Seattle, WA 

Background: Several case-control studies have suggested a reduced risk of 

hematologic malignancies (HMs) for individuals with allergies, but results 

have been inconsistent, and prospective cohort studies have not confirmed 

this association. Herein, we used the large prospective VITAL study to 

examine this association. Methods: 64,847 men and women, aged 50-76, 

completed a baseline questionnaire in 2000-2002 and reported on their 

current allergies and history of physician-diagnosed asthma. Individuals 

with prior cancer other than non-melanoma skin cancer were excluded from 

this analysis. Incident HMs were identified through December 2009 by 

linkage to the SEER registry; those with a diagnosis of a non-HM during 

follow-up were censored at the time of that diagnosis. Multivariable Cox 

proportional hazards models were built with adjustment for sex, race/ 

ethnicity, education, smoking, self-rated health, physical activity, history 

of anemia in the year before baseline, vegetable use and family history of 

leukemia or lymphoma. Results: Our analysis included 64,839 participants, 

among whom 681 (1.03%) incident HMs were found (MDS [69], 

AML (41], myeloproliferative disorders [60], mature B-cell neoplasms 

[262], chronic lymphocytic leukemia [107], plasma cell disorders [83], 

Hodgkin lymphoma [23], T-cell/NK-cell neoplasms [22], and others [14]). 

In multivariable analyses, a history of any allergy was associated with 

increased risk of HM (HR�1.21; 95% CI 1.02-1.43, p�0.02). This 

association was seen for current allergies to plants/grass/trees (HR 1.27 

[1.06-1.52], p�0.001) but not for allergies to mold/dust, animals, insects, 

food, or medications. We did not find an association between a history of 

asthma and incident HMs (HR�0.95 [0.72-1.26]). Conclusions: Our study 

indicates a moderately increased risk of HMs inindividuals with a history of 

allergy, especially to plant, grass or trees. While no causality can be 

inferred, this may suggest a possible carcinogenic role for chronic stimulation 

of the immune system. However, further mechanistic investigations 

focusing on the biochemical markers of immune system as well as on 

possible gene effect modifiers are needed. 


11:30 AM-12:30 PM 

Racial disparities in treatment patterns and clinical outcomes in patients (pts) 

with HER2� metastatic breast cancer (MBC). Presenting Author: Adam Brufsky, 

University of Pittsburgh School of Medicine, Pittsburgh, PA 

Background: Data examining prognosis and treatment outcomes for black pts 

with HER2� MBC are limited. Methods: registHER is a large, observational 

cohort of pts (N�1,001) with HER2� MBC diagnosed w/in 6 mos of enrollment 

and followed until death, disenrollment, or 6/09 (median follow-up 27 mos). 

Demographics, treatment patterns, and clinical outcomes were described for 

black (n�126) and white pts (n�793). Progression Free Survival (PFS) and 

Overall Survival (OS) were examined. Multivariate analyses adjusted for baseline 

and treatment factors. Results: Black pts were more likely to be obese (BMI � 

30), have diabetes, and a history of cardiovascular disease (CVD) than white pts 

(Table). Black pts were less likely to have estrogen receptor (ER)/progesterone 

receptor (PR)� disease and more likely to present with stage IV MBC. In 

trastuzumab (T)-treated pts, incidence of cardiac safety events (grade �3) was 

higher in black (13/119 [10.9%]) than white pts (59/746 [7.9%]). Unadjusted 

median OS (mos) was significantly lower (blacks: 27.1, 95%CI 23.2-32.1; 

whites: 37.3, 95%CI 34.6-41.1) and median PFS (mos) was lower (blacks: 7.0, 

95%CI 5.7-9.7; whites: 10.2, 95%CI 9.3-11.2) in black than white pts. The 

adjusted OS hazard ratio (HR) for black vs. white was 1.32 (95%CI 1.04, 1.69); 

the adjusted PFS HR was 1.31 (95% CI 1.07, 1.61). Conclusions: These 

population-based data show poorer prognostic factors and independently worse 

clinical outcomes in black vs. white pts, and represent the largest database to 

date with black pts with HER2� MBC. Further research is needed to explore the 

basis for the differences noted in this hypothesis-generating analysis. 

Demographic and clinical characteristics of black and white pts. 

Black 

White 

Variable (%) 

(n�126) 

(n�793) 

Age (y), median (min, max) 

BMI (kg/m 

50 (20,90) 54 (22,92) 

2 ) 

- 

- 

30 

50.8 

32.4 

ER/PR status 

- 

- 

ER� or PR� 

42.1 

54.7 

ER- and PR- 

54.8 

41.5 

Unknown 

3.2 

3.8 

Stage, initial diagnosis 

- 

- 

IV 

31.0 

26.6 

I-III, MBC 12 mos 

50.8 

61.0 

Baseline CVD 30.2 15.8 

Diabetes 13.5 6.5 

T-based 1st-line regimens 

(n�102) 

(n�670) 

C only 

77.5 

65.4 

HT only 

4.9 

6.3 

C and HT 

11.8 

20.6 

T alone 

5.9 

7.8 

Abbreviations: BMI, body mass index; C, chemotherapy; HT, hormone therapy. 


11:30 AM-12:30 PM 

Outcomes from an electronic medical record (EMR)-based standardized 

tobacco assessment and cessation program in a NCI-designated comprehensive 

cancer center. Presenting Author: Graham Walter Warren, Roswell Park 

Cancer Institute, Buffalo, NY 

Background: Tobacco assessment and cessation is advocated by ASCO and 

national clinical oncology guidelines, but there is little information on large 

scale clinically efficient models to assess tobacco use and provide 

cessation in a structured evidence based manner. Automation through the 

electronic medical record (EMR) could reduce subjective interpretation by 

clinicians and assist in increasing data tracking accuracy to enhance 

meaningful use initiatives. Methods: A standard set of evidence based 

tobacco assessment questions were incorporated into an annotated fixedvariable 

response system in the EMR delivered by nursing at initial consult 

and at follow-up. A logic based EMR referral system was developed to 

determine patient eligibility for mandatory automated referral to a dedicated 

tobacco cessation service. An evidence based institutional clinical 

cessation program was developed to provide cessation support to referred 

patients. The evidence based screening and referral algorithms will be 

presented. Results: Over 13 months, 677 patients were referred and 529 

patients were successfully contacted to date for cessation support. In the 

529 patients, 21 (3.9%) were inappropriate referrals (never smokers or 

long term former smokers), 48 patients (9.1%) did not want to enroll, but 

wanted to discuss cessation at a later date. Notably, only 18 patients 

(3.4%) refused any intervention. In a total of 415 patients enrolled in the 

cessation program, 104 patients (25.1%) were thinking about quitting 

(contemplation), 134 patients (32.3%) were preparing to quit, 169 

patients (40.7%) were quitting (action phase), and 8 patients (1.9%) have 

relapsed. Tobacco assessments and automated referrals through the EMR 

took a median of 4 minutes to complete. Conclusions: A large volume of 

patients were screened and referred to a dedicated cessation program with 

low patient refusal for intervention without impeding physician workflow. 

These data suggest that this nursing driven EMR based assessment is a 

highly efficient clinical model for tobacco assessment and cessation. 



11:30 AM-12:30 PM 

Potential risk of asbestos exposure among Japanese general population: 

Japanese general screening study for asbestos-related diseases (JGSARD). 

Presenting Author: Nobuhiko Seki, Teikyo University School of Medicine, 

Tokyo, Japan 

Background: The number of patients with pleural mesothelioma and lung 

cancer associated with asbestos exposure has recently been increasing in 

Japan. The aim of this study was to evaluate the results of screening for 

asbestos-related diseases in a group of Japanese general population. 

Methods: This prospective study was approved by the institutional review 

board. From 2006 to 2008, 9810 subjects (5283 men and 4527 women; 

mean age, 57 years) underwent chest radiography and low-dose CT 

examinations in 26 institutions in Japan. Among them, 6286 (64.1%) 

subjects underwent subsequent CT examinations after 2 years of interval. 

Clinical information such as histories of smoking and asbestos exposure 

was reviewed. Images were interpreted independently by 15 experienced 

pulmonologists or chest radiologists. Results: The history of asbestos 

exposure was definitely present in 1253 (12.8%) subjects, possibly 

present in 2058 (21.0%), and absent in 6499 (66.2%). On chest 

radiograph, pleural plaque and thickening were seen in 61 (0.6%) and 65 

(0.6%) subjects, respectively. On low-dose CT, pleural plaque and thickening 

were identified in 264 (2.7%) and 245 (2.5%) subjects, respectively, 

and non-calcified pulmonary nodule/mass was seen in 1003 (10.2%). 

Furthermore, lung cancer was identified in 29 (0.3%) subjects. The history 

of asbestos exposure was not confirmed in 77 out of 264 subjects (29.2%) 

having pleural plaques on low-dose CT. Based on the logistic regression 

analysis, pleural plaque on low-dose CT was significantly correlated with 

male, age more than 60 years, smoking, and a history of asbestos exposure. 

Especially, total residential period in asbestos factory area as well as 

asbestos exposure work period showed significantly increased relative risk 

every 10 years. Similarly, lung cancer was significantly correlated with age 

more than 60 years, a history of asbestos exposure, and presence of pleural 

plaques. Conclusions: Our results indicate the presence of pleural plaques 

on low-dose CT among Japanese general population is closely associated 

with potential risk of asbestos exposure. However, about 30% of such 

subjects are not aware of a history of asbestos exposure. 


11:30 AM-12:30 PM 

Clinical characteristics and natural history of patients with squamous cell 

lung carcinoma with FGFR1 amplification. Presenting Author: Marc Bos, 

Lung Cancer Group Cologne, Department I of Internal Medicine and Center 

for Integrated Oncology, University Hospital Cologne, Cologne, Germany 

Background: FGFR1 amplifications have been described as a promising 

oncogenic target in squamous cell lung cancer. Here we aimed at 

describing the clinical characteristics and natural history of FGFR1amplified 

squamous cell lung cancer patients. Methods: From 01/2011 to 01/2012 

we screened 553 squamous cell lung cancer patients in our Network for 

Molecular Screening of Lung Cancer for the presence of FGFR1 amplifications 

by FISH analysis in accordance with the local ethics committee. 

FGFR1 was defined as amplified if the ratio of FGFR1 copies to centromeric 

copies was above 2 or if more than 50% of tumor cells showed 5 copies or if 

more than 15% of tumor cells demonstrated clusters of FGFR1. Clinical 

data were collected by extracting information from medical records, the 

local cancer registry and by questioning treating physicians and patients. 

Results: FGFR1FISH analysis could be performed in 95% of the cases and 

was amplified in 16%. Of the amplified cases 75 % were male and 25% 

female without significant enrichment for male or female. The median age 

of the patients at diagnosis was 67 yrs (range 46 - 82). Stage at 

presentation was: 16% I; 17.3% II; 26.7% IIIa, 40% IIIb/IV. 97,3% of the 

patients were former or active smokers with a median of 40 pack years. The 

median progression free survival of patients with stage IIIb/IV disease was 

11 months (95% CI 8-14; n�14). The median overall survival was not yet 

reached after a median follow-up time of 14 months (95% CI 11 - 17; 

n�24). We further screened for co-existing genetic lesions such as 

mutations in EGFR, BRAF, KRAS, PIK3CA as well as translocations of ALK 

and amplifications of ERBB2. Two patients demonstrated co-occurring 

PIK3CA mutations and one a BRAFmutation. Conclusions: Screening for 

FGFR1 is feasible under routine clinical conditions. By implementation of a 

regional molecular screening network the ability to screen for FGFR1 

amplification was successfully expanded to non-academic centers and 

private practices. FGFR1 amplifications in squamous cell cancer of the 

lung are frequent (16%) and associated with smoking history. Screening for 

FGFR1 might pave the way for the application of new FGFR1 directed 

targeted drugs in squamous cell lung cancer. 


93s 


11:30 AM-12:30 PM 

Never-smoking women with lung cancer from the Spanish WORLD07 

database. Presenting Author: Dolores Isla, Hospital Lozano Blesa, Zaragoza, 

Spain 

Background: Gender differences in lung cancer (LC) have been reported, 

but with many unresolved issues yet. Tobacco causes the majority of 

women lung cancer (WLC), although the rate of never-smoking WLC is 

higher than in men. Several factors may play etiologic roles, and an 

in-depth understanding is needed. Methods: WORLD07 is a Spanish 

prospective, multicenter, epidemiologic female-specific LC database sponsored 

by ICAPEM, a professional association committed with WLC research. 

In order to improve the knowledge on never-smoking WLC, 

information has been extracted from WORLD07 database. Results: From 

October/2007 to October/2011, 1371 newly diagnosed WLC were included 

in an e-database from 32 centers, 539 (39.3%) never-smoking. 

Patient (p) characteristics: median age 71.1 years(y); median age of 

menarche 13y.; motherhood 91.2% (median 2.3 children, median age at 

first child 26.4y); oral contraceptive use 11.9%; postmenopausal 88.9% 

(median age of menopause 49y); HRT 5.2%; second-hand smokers 40% 

(work-exposure 17.1%, home-exposure 88.8%); obesity 16.3%; familiar 

history of cancer 39.9% (LC 29.8%); previous history of cancer 13% 

(breast/lung/cervix: 41.4/5.7/2.9%); current LC histology(%): adenocarcinoma/SqCC/LCC/SCLC: 

83.4/6.2/5.5/3.9; EGFR mut� (268 p analyzed): 

55.5% (exon 19/20/21(%): 61.1/7.4/36.9); TNM NSCLC I/II/III/IV(%): 

14/3.3/19.8/60.3. Treatment: EGFR-TKI in p EGFR mut�, stage IV(1st-/ 2nd-line)(%): 51.7/15.4; stage IV NSCLC (1st-line/2nd-line): platinumbased 

CT 42.5%, EGFR-TKI 33.5%, combinations with bevacizumab 

2.9% / EGFR-TKI 15.8%. Overall survival: median 27 months(m), 1/2y(%) 

74.8/55.2; stage IV NSCLC: median 20.5m, 1/2-y(%) 67/46; 

EGFR-mut� p: median 27.3m, 1/2-y(%) 75/54.3. Conclusions: According 

to our e-database, WLC showed high rates of never-smokers (39.3%), and 

of relatives diagnosed with malignant tumours (39.9%, �1/3 LC). Adenocarcinoma 

was the most frequent histology (76.1%), and more than half of 

the cases analyzed harboured EGFR mutations. Although 40% were 

second-hand smokers, further investigations are warranted. Survival outcomes 

remain satisfactory, as expected from this selected subgroup of p. 

Additional epidemiologic and treatment data will be presented. 


11:30 AM-12:30 PM 

Molecular epidemiological prospective study of EGFR mutations from 

Asian patients (pts) with advanced lung adenocarcinoma (PIONEER). 

Presenting Author: Pan-Chyr Yang, National Taiwan University Hospital, 

College of Medicine, Taipei, Taiwan 

Background: The epidemiological, multicenter prospective study 

(NCT01185314; PIONEER) assessed EGFR mutation (M) rates in pts from 

Asia with newly diagnosed advanced lung adenocarcinoma (ADC). Influence 

of demographic and clinical factors on EGFR M rates was investigated. 

Methods: Pts were aged �20 years, with treatment naïve stage 

IIIB/IV lung ADC. Tumor sample (biopsy, surgical specimen, cytology) 

EGFR M status (primary endpoint; positive [M�], negative [M-], undetermined 

[MU]) was determined using Scorpion ARMS (Therascreen EGFR 

RGQ kit). EGFR M frequency was calculated and compared between 

demographic/clinical factor subgroups (chi-square/Fisher’s exact test). 

Factors with p�0.05 in the univariate analysis were further analyzed by 

multivariate logistic regression at 1% significance level to take the large 

dataset into consideration. Results: Of 1482 pts from 7 Asian countries, 

43.4% were female, mean age was 60 years (range 17-94), and 52.6% 

were never-smokers. EGFR M status was evaluated in 1450 patients (32 

[2.2%] were MU): 746 (51.4%) were M�, 704 (48.6%) were M-. Country, 

gender, ethnicity, smoking status, pack years, metastasis, (all p�0.001) 

and disease stage (p�0.009) correlated significantly with EGFR M status. 

EGFR M� rate by country: Vietnam 64.2% (77/120), Taiwan 62.1% 

(108/174), Thailand 53.8% (63/117), Philippines 52.3% (34/65), China 

50.2% (372/741), Hong Kong 47.2% (76/161), India 22.2% (16/72). 

EGFR M� rates were 61.1% in females, 44.0% in males, 60.7% in never 

smokers, and 31.4% in heavy smokers (�50 pack years). EGFR M� rates 

were 37.5% in male regular smokers (113/301), 34.8% in female regular 

smokers (8/23), 56.5% in male never smokers (104/184) and 62.0% in 

female never smokers (358/577). Ethnic group (p�0.001) and pack years 

(p�0.001) were identified as important factors by logistic regression; 

gender was not significant when adjusted for smoking status. Conclusions: 

The overall EGFR M� rate in unselected ADC was 51.4%. Ethnicity and 

pack years were found to have a statistically significant association with 

EGFR M rates. There was no association between gender and EGFR M rates 

when adjusted for smoking status. 




11:30 AM-12:30 PM 

Genetic sequence variant (GSV) in TERT-CLPTM1L (5p15.33 locus) and 

survival in platinum-treated stage-IV non-small cell lung cancer (NSCLC). 

Presenting Author: Abul Kalam Azad, Ontario Cancer Institute, Princess 

Margaret Hospital, Toronto, ON, Canada 

Background: Lung cancer is a leading cause of cancer-related mortality in 

North America. Besides tobacco smoking, inherited genetic factors can 

also influence the development of lung cancer. These genetic factors may 

lead to biologically distinct subsets of cancers that have different outcomes. 

We evaluated whether GSVs associated with lung cancer risk are 

also associated with overall survival (OS) and progress free survival (PFS) in 

platinum-treated stage-IV NSCLC patients. We chose this subset of 

patients with lung cancer because they are uniformly treated and followed 

up at our institute (Princess Margaret Hospital). Methods: A total of 32 

candidate GSVs in 21 genes previously reported to be associated with lung 

cancer risk were genotyped in 188 platinum-treated NSCLC stage-IV 

patients. Illumina Custom GoldenGate Genotyping Panel was used for the 

genotyping assay platform. Multivariate Cox proportional hazard models 

adjusted for the potential clinical prognostic factors were generated for OS 

and PFS. Results: Median age is 60 yr (range: 31-81); 73% with 

adenocarcinoma. Median follow-up time is 27 mo; median OS is 16 mo and 

PFS is 8 mo. The top significant GSV was rs4975616 (g.1315660G�A) in 

telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 

1-like (CLPTM1L) gene on chromosome 5p15.33. The adjusted 

hazard ratio (aHR) for OS was 0.76 (95% CI: 0.58-0.99; p�0.04) and for 

PFS aHR was 0.70 (95% CI: 0.55-0.90; p�0.005) for each protective 

allele, respectively. This GSV has previously been associated with lung 

cancer risk in genome-wide association study (PMID: 19654303). 

Conclusions: The TERT-CLPTM1L:rs4975616 GSV is not only a risk factor 

for lung cancer but also is associated with survival in patients with stage-IV 

NSCLC treated with platinum based chemotherapy. GSVs may be able to 

define subsets of patients with different risk and prognosis of NSCLC. 

Future studies should evaluate whether this GSV is predictive or prognostic. 

1537 General Poster Session (Board #1A), Sat, 1:15 PM-5:15 PM 

Correlation of breast cancer risk in European BRCA2 mutation carriers with 

birth cohort. Presenting Author: Muy-Kheng Maria Tea, Medical University 

of Vienna, Department of OB/GYN, Division of Senology, Vienna, Austria 

Background: Mutations in the Breast Cancer Gene 1 (BRCA1) and Breast 

Cancer Gene 2 (BRCA2) lead to an elevated risk of developing breast (BC) 

and ovarian cancer (OC). However, risk estimates vary, depending on the 

study population. Furthermore, there are indications that birth cohort can 

influence the cancer risk. We investigated the risks for BC and OC 

associated with BRCA2 mutations in a cohort of female mutation carriers of 

a genetically heterogeneous central European population who were identified 

by molecular genetic testing in our institute. Methods: This study 

included 171 Caucasian women from Austria who underwent genetic 

counseling and where molecular genetic analysis identified a mutation in 

the BRCA2 gene at the Medical University of Vienna, Division of Senology, 

in Austria. A total of 57 healthy and 114 affected BRCA2-carriers were 

detected. The risk was estimated using the product limit method. The log 

rank test was used to compare different strata. Results: The risk of 

developing cancer to age 70 was found to be 85% for BC (95% CI 

77–93%) and 31% for OC (95% CI 16–46%) in our BRCA2 study 

population. Female BRCA2-carriers born in 1958 or later were at a 

significantly higher risk of developing BC (p�0.001; 88% vs. 46% to age 

40) but not of OC (p is not significant; 0% vs. 2% to age 40) compared to 

mutation carriers born earlier. Conclusions: We conclude that female 

BRCA2 mutation carriers should also be counseled about their cohortdependent 

cancer risk, especially for breast cancer. Further research about 

variables that may affect cancer risk like lifestyle-related factors should be 

considered. 


11:30 AM-12:30 PM 

Second malignant neoplasms (SMN) among 18,627 testicular cancer 

survivors (TCS) after chemotherapy (CHEM) or surgery (SURG). Presenting 

Author: Chunkit Fung, James P. Wilmot Cancer Center, University of 

Rochester School of Medicine and Dentistry, Rochester, NY 

Background: Increased risks of SMN after radiotherapy (RT) for testicular 

cancer (TC) are well established. Few population-based studies, however, 

have focused on SMN risk among a contemporary group of TCS managed 

initially with non-RT approaches, including CHEM. Methods: Standardized 

incidence ratios (SIR) of SMN stratified by site and time since TC diagnosis 

were calculated for 18,627 TCS reported to the SEER program (1980- 

2008) who initially had CHEM (n�8,058) or SURG (n�10,569) alone 

without RT, with each cohort accruing 65,398 and 92,681 person-years 

(PY) of follow-up respectively. Results: After CHEM, significantly increased 

risks of solid cancers (n�154; SIR 1.3; 95% CI 1.1-1.5; absolute excess 

risk (AER) 5.4 per 10,000 PY) and leukemias (n�18, SIR 3.9; 95% CI 

2.3-6.1; AER 2.0) were observed. Solid cancer risk remained elevated for 

� 20 yrs, whereas excess leukemias were concentrated within 10 years 

after diagnosis. SIRs for solid cancers during the �1, 1-4, 5-9, 10-14, 

15-19, and 20� yr periods were 2.0 (95% CI 1.03-3.5), 1.4 (95% CI 

0.97-2.0), 0.8 (95% CI 0.5-1.2), 1.3 (95% CI 0.9-1.8), 1.6 (95% CI 

1.05-2.2), and 1.5 (95% CI 0.95-2.2) respectively (P-trend 0.5) whereas 

SIRs for leukemia were 3.2, 9.9 (P�0.05), 2.6, and 2.3 respectively, with 

no cases reported in the latter 2 intervals. Median latencies to the 

development of solid cancers and leukemia were 12.5 yr (0.1-28) and 2.5 

yr (0.1-14) respectively. Increased site-specific risks were apparent for 

cancers of liver (SIR 1.9; 95% CI 0.6-4.4); pancreas (SIR 2.1; 95% CI 

0.8-4.6); soft tissue (SIR 4.9; 95% CI 2.1-9.7); bladder (SIR 1.9; 95% CI 

1.02-3.3); kidney (SIR 2.6; 95% CI 1.4-4.3); brain/CNS (SIR 1.8; 95% CI 

0.7-3.7), and thyroid (SIR 3.9; 95% CI 2.1-6.6). Secondary leukemias 

included 16 non-lymphocytic and 2 lymphocytic leukemias. In contrast, 

among TCS managed initially with SURG alone, no excess solid cancers 

were observed (n�198; SIR 1.0; 95% CI 0.8-1.1), albeit an increased risk 

of leukemia (n�15; SIR 1.9; 95% CI 1.1-3.2, AER 0.8) was seen. 

Conclusions: Future analytic studies should further evaluate the sitespecific 

risks of SMN after modern CHEM for TC and the baseline risk 

among patients managed with non-cytotoxic approaches. 

1538 General Poster Session (Board #1B), Sat, 1:15 PM-5:15 PM 

Identification of new susceptibility genes in familial breast cancer by 

exome sequencing. Presenting Author: Henry T. Lynch, Creighton University, 

Omaha, NE 

Background: Familial breast cancer was described in the early 1970s with 

its syndromy confirmed by the discovery of BRCA germline mutations in the 

1990s. BRCA mutations account for less than 10% of affected families. 

Efforts made in the past two decades have resulted in limited results in 

identifying additional susceptibility genes for familial breast cancer. 

Methods: Using exome sequencing, we analyzed eight members in a 

BRCA1-, BRCA2-, p53- and PTEN-negative breast cancer family; five with 

breast cancer and three unaffected. Mutation candidates were idenified by 

bioinformatics analysis, experimentally validated by Sanger sequencing 

and their damaging effect was predicted by the SIFT program. Validated 

mutations were also tested in 42 additional breast cancer samples from 

BRCA-negative breast cancer families. Results: We identified 55 nonsynonymous 

germline mutations affecting 49 genes in multiple members 

of this family, 20 of 22 selected mutations predicted to cause damaging 

effects were validated. As an exemplar, two mutations in the MYST4 gene 

were detected at the C terminal (p.D1516Y and p.R1577C), validated, and 

predicted to cause damaging consequences. MYST4 is a histone acetyltransferase 

(Champagne, N. et al. JBC. 274, 28528-28536,1999). It contains 

a C2HC-type finger and a PHD-type zinc finger. Its N-terminal is involved in 

transcriptional repression while its C-terminal is involved in transcriptional 

activation and interacts with important transcriptional regulators RUNX1 

and RUNX2. MYST4 is involved in DNA replication, transcriptional regulation, 

and epigenetic modification of chromatin structure. A translocation 

t(10;16)(q22;p13) between CREBBP and MYST4 was identified in acute 

myeloid leukemia. The 20 validated germline mutations were tested by 

Sanger sequencing in 42 additional breast cancer cases from 26 BRCAnegative 

families. None of the 20 mutations were detected. Conclusions: 

Results show that remaining unknown susceptibility genes are likely 

family-specific and can be detected in each affected family using genome 

sequencing approaches. These results may be the first reported in an exome 

sequencing study of BRCA-negative breast cancer families. 


1539 General Poster Session (Board #1C), Sat, 1:15 PM-5:15 PM 

Evaluation of genes associated with undescended testes as predictors of 

TGCT susceptibility. Presenting Author: Ariela Marshall, Hospital of the 

University of Pennsylvania, Philadelphia, PA 

Background: Testicular germ cell tumors (TGCTs) are highly heritable. 

Cryptorchidism (undescended testes; UDT) is a strong risk factor for TGCT, 

with increased risk to both the ipsilateral and contralateral testes. However, 

recent genome-wide association studies (GWAS) identifying genetic variants 

associated with TGCT susceptibility have not found differences in 

genotype carriage between TGCT patients with and without UDT. We 

investigated the role of potential risk variants for UDT as risk factors for 

TGCT. Methods: 1300 SNPs in and around 25 gene regions with published 

associations with UDT were evaluated in 474 TGCT cases (45 with UDT) 

and 919 controls. Genotype information was available from the Affymetrix 

Genome-Wide Human SNP Array 6.0. Statistical analysis was performed 

using PLINK, and statistical significance was assessed by Fisher’s Exact 

test. Results: Comparing TGCT cases with and without UDT, variants in the 

region of four genes (EPHB2, ESR1, SEMA3C, TGFBR3) were suggestively 

associated with UDT. When TGCT cases with UDT were compared with 

unaffected controls, the associations all met the required level of significance 

(p � 4x10-5 ). Only variation at ESR1 approached significance 

(P�0.0004) when TGCT cases and unaffected controls were compared. 

Conclusions: We identified variants at three genetic loci - SEMA3C, 

TGFBR3 and EPHB2 - that were significantly associated with UDT, but not 

with TGCT. The association of variation in EPHB2 and SEMA3C with UDT 

are novel findings. While associated with UDT, variation at ESR1 is also 

potentially associated with TGCT risk. These data continue to suggest that 

genetic risk factors for UDT are largely independent of those for TGCT. 

Thus, screening for TGCT could be targeted in a UDT population to those 

with genetic risk factors. Further studies should be done to investigate the 

genetic link between UDT and TGCT. 

1541 General Poster Session (Board #1E), Sat, 1:15 PM-5:15 PM 

Clinical characteristics of patients with malignant pleural mesothelioma (MPM) 

harboring somatic BAP1 mutations. Presenting Author: Marjorie Glass Zauderer, 

Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Efforts to elucidate tumorigenic mutations in MPM are essential to 

advance therapy. We reported a 23% incidence of somatic mutations in 

BRCA1-associated protein-1 (BAP1) in 53 patients with MPM (Bott et al. Nat 

Genet 2011). Germline BAP1 mutations were also reported in two families with a 

predisposition to mesothelioma and uveal melanoma (Testa et al. Nat Genet 

2011). While BAP1 somatic mutations are more common in poor prognosis uveal 

melanoma (84% class 2, 4% class 1; Harbour et al. Science 2010), the 

significance of these mutations in MPM is unknown. Therefore, we analyzed the 

clinical characteristics of patients with somatic BAP1 mutations in order to 

describe this newly identified subpopulation. Methods: We reviewed the charts of 

121 patients with tumors tested for somatic BAP1 mutations. Results: Patient 

characteristics are in the Table. Twenty percent harbored somatic BAP1 

mutations. Other than the percent of current or former smokers (75% BAP1 

mutations, 42% BAP1 wild-type, p�0.006), no other clinical feature was 

significantly different among those with and without BAP1 mutations. Among 53 

samples analyzed for NF2 mutation and p16 deletion, no correlation was seen 

with BAP1 mutation. Conclusions: Somatic BAP1 mutations occur in about 20% 

of MPM tumors. Aside from smoking history, no other differences in clinical 

characteristics or outcomes were noted in the BAP1 mutated cases. Similar 

efforts are needed to describe the features of germline mutations in order to 

define this new cancer predisposition syndrome. We are planning a prospective 

trial to further evaluate the prevalence of germline BAP1 mutations, and we are 

also exploring the therapeutic implications. 

BAP1 mutants 

(N�24) 

BAP1 wild-type 

(N�97) p value 

Gender (M � male) M: 79% M: 68% 0.33 

Median age at diagnosis 65 63 0.31 

Histology 

E: 71% E: 77% 0.28 

E � epithelial 

M: 25% M: 12% 

M � mixed 

S � sarcomatoid 

S: 4% S: 10% 

Stage I: 13% 

I: 5% 0.43 

II: 25% II: 27% 

III: 33% III: 45% 

IV: 29% IV: 22% 

Known asbestos exposure 54% 46% 1 

Smoking (former or current) 75% 42% 0.006 

Surgery 

EPP: 54% EPP: 55% 1 

EPP � extrapleural pneumonectomy Other: 38% Other: 35% 

None: 8% None: 10% 

Median overall survival from 

diagnosis (months) 

14.8 15.3 0.78 


95s 

1540 General Poster Session (Board #1D), Sat, 1:15 PM-5:15 PM 

MEN1 gene mutations with different phenotypic presentations in two 

families: Is it a time to grade MEN1 mutations as high-risk and low-risk? 

Presenting Author: Alexander L. Shifrin, Jersey Shore University Medical 

Center, Neptune, NJ 

Background: MEN1 syndrome results from MEN1 gene mutations and is 

characterized by primary hyperparathyroidism (PHPT), pancreatic endocrine 

tumors (PET), pituitary adenomas, thymic and other tumors. About 

600 different mutations have been reported on Human Gene Mutation 

Database and 30 of them presented as Familial Isolated Hyperparathyroidism 

(FIHP); however, no genotype-phenotype correlations have been 

identified. Methods: We characterized 2 independent families with newly 

diagnosed MEN1. Mutation analyses were performed in Dept of Genetics 

Yale University. Diagnostic tests, surgical treatment were implemented. 

Results: Family 1 has 21 members. 5 presented with early onset of PHPT 

and no other tumors. 3 ½ parathyroidectomies were performed. A proband 

had direct sequencing that showed a mutation in Exon 7, consisting of 

single base insertion in codon 319 (TAC to TTAC)(c1065_1066insT). 

There were no deaths in the family. Family 2 has 20 members. 7 were 

tested and showed a mutation in Exon 2, consisting of single base deletion 

in codon 103 (CTG to _TG)(c417delC). One 1st generation member died 

from PET at age 79, three 3rd generation members had multifocal 

metatstatic malignant gastrinomas (ages 32, 39, 41). The proband had 

total pancreatectomy at age 32. Five members had PHPT, angiofibromas. 

Three 2nd generation members had thymic carcinomas (ages 20, 54, 60). 

Conclusions: Phenotypic presentation of MEN1 syndrome may vary with the 

same mutation suggesting a lack of genotype-phenotype correlation and 

the effect of modifying factors. On the other hand, these two families—one 

with a mutation predicted to truncate the menin protein close to its 

terminus and the other with a truncating mutation early in the coding 

sequence—have dramatically different severity of the syndrome. Our 

findings suggest that the exon 7 mutation has a milder effect on protein 

function resulting in FIHP. The management may be heavily influenced by 

the predicted clinical phenotype, we are proposing the development of a 

grading system for MEN1 gene mutations as low-risk and high-risk and to 

attempt to identify other modifying genetic and environmental factors to 

improve screening and timing for surgery. 

1542 General Poster Session (Board #1F), Sat, 1:15 PM-5:15 PM 

Genetic testing referral, uptake, and results in a program for women age 40 

or younger with breast cancer. Presenting Author: Asma Ali, Sunnybrook 

Health Sciences Centre, University of Toronto, Toronto, ON, Canada 

Background: PYNK: Breast Cancer Program for Young Woman is a novel 

program started in 2008 at our center to optimize management and 

promote research for women � age 40 newly diagnosed with breast cancer. 

Clinical and epidemiological data including cancer family history (FH) is 

prospectively collected on each consenting patient. As Toronto’s population 

is uniquely multiethnic we sought to determine BRCA testing eligibility, 

uptake and results for PYNK patients. Methods: Of the 145 consecutive 

patients, data were available for 109, of whom 2 had testing prior to 

diagnosis. Our provincial BRCA testing criteria are age � 35 at diagnosis; 

suspicious FH; or Ashkenazi Jewish (AJ) and age � 50 at diagnosis. Results: 

Of the 107 previously untested patients, 40 were � 35 at diagnosis. In 5 of 

the other 67 testing eligibility could not be assessed. 66 of the 102 (65%) 

were eligible and of those 65 (98%) were offered referral for counseling. 

One declined counseling, 9 were not yet seen, 2 declined testing, and 53 

were tested. Test results are available for 47 as follows: 30 (64%) no 

mutation, 4 (8%) variant of uncertain significance (VUS), 7(15%) BRCA1 

mutations and 6 (13%) BRCA2 mutations including 1 of the 4 AJ women. 

Ethnicity of the other 12 mutation carriers was: 1 Hispanic, 2 European, 2 

African, 4 Asians, 1 mix, 1 unknown and 1 not recorded. Two (15%) of the 

mutation carriers had no FH of breast or ovarian cancer. Four additional 

women opted for counseling and testing despite ineligibility and none had 

mutations. Conclusions: A specialized program for young women facilitates 

appropriate referral for genetic testing and encourages high testing uptake, 

which is important given the high prevalence of mutations (28% of tested 

women). Further research is necessary to assess the psychological and 

management impact of having a VUS on young women compared to their 

older counterparts. 



1543 General Poster Session (Board #1G), Sat, 1:15 PM-5:15 PM 

Breast cancer in Irish families with Lynch syndrome. Presenting Author: 

Emmet Jordan, Mater Misericordiae University Hospital, Dublin, Ireland 

Background: Breast cancer is not among the recognised malignant manifestations 

of Lynch Syndrome which include colorectal, endometrial, gastric, 

ovarian and upper urinary tract tumours. In this study we report the 

prevalence of breast cancer in Irish Lynch Syndrome families and determine 

immunohistochemical (IHC) expression of mismatch repair proteins 

(MMR) in available breast cancer tissue. Methods: Breast cancer prevalence 

was determined among Lynch Syndrome kindreds from two institutions in 

Ireland. One kindred was omitted due to a biallelic MMR and BRCA1 

mutation.The clinicopathological data that was collected on breast cancer 

cases included age of onset, morphology, and hormone receptor status, and 

a genotype phenotype correlation was investigated. Immunohistochemical 

staining was performed for MLH1, MSH2, MSH6, and PMS2 on all 

available breast cancer tissue from affected individuals. Results: The 

distribution of MMR mutations seen in sixteen pedigrees were as follows; 

MLH1 (n�5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal 

cancer and 14 cases of endometrial cancer were seen. Seven breast 

cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of 

ductal carcinoma in situ were reported in 7 pedigrees. This compared with 

4 cases of prostate cancer. Of the 7 LS kindreds containing breast cancer, 

6 MSH2 mutations and 1 MSH6 mutations were identified. Median age of 

breast cancer diagnosis was 49 years (range 38-57). Hormone receptor 

status is available on 3 breast cancer cases at time of abstract submission; 

all were ER positive and HER 2 negative. All cases had grade 2 or 3 

tumours. 5 samples were available for IHC evaluation. 3 out of 5 cases 

showed loss of MMR expression, all showed loss of MSH2 and MSH6 

expression. One of the two cases with normal IHC expression in breast 

tissue belonged to a kindred where 3 siblings with colorectal cancer and 

documented deleterious mutations demonstrated no IHC loss. Conclusions: 

Breast cancer occurred at an early age and was more common than prostate 

cancer in Irish Lynch Syndrome pedigrees. All identified breast cancer were 

in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer 

screening may be warranted in certain Lynch Syndrome kindreds. 


BRCA carrier status as an independent prognostic factor associated with 

earlier biochemical relapse in local prostate cancer. Presenting Author: 

Elena Castro, The Institute of Cancer Research and The Royal Marsden 

NHS Foundation Trust, London, United Kingdom 

Background: Biochemical relapse after local treatment for prostate cancer 

(PCa) indicates recurrent disease and is associated with shorter survival. 

Germline BRCA mutations are associated with worse PCa outcomes. BRCA 

carriers are currently treated with the same protocols used for non-carriers. 

We analyzed biochemical-progression free survival (bPFS) after conventional 

treatment for localized PCa in a cohort of BRCA patients (pts). 

Methods: In this retrospective case-control study, each BRCA carrier (9 

BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external 

beam radiotherapy (RT) was matched with 3 non-carriers (NC) by age at 

diagnosis (�5 yrs), TNM stage, Gleason score, presenting PSA, local 

treatment , androgen-deprivation therapy (ADT) and year of treatment (�3 

yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical 

failure was reviewed according to ASTRO and NCCN criteria. The Kaplan- 

Meier method and a multivariate Cox regression model adjusted by 

matching factors were employed. Results: 172 pts were included. Median 

follow-up was 76 months (ms). Median age at diagnosis was 58 yrs 

(43-75). Tumour stages were I 11%, IIA 19%, IIB 28%, III 28%, IV 14%. 

80 pts received RT (18 BRCA2, 5BRCA1, 57NC) and 85% also received 

ADT (70% for �6 months). 92 pts underwent RP (16 BRCA2, 4 BRCA1 

and 72 NC), and 9% of them received ADT (�6months). Overall, median 

bPFS was 71ms. For those treated with RT, median bPFS was 65ms in NC 

vs 39ms in BRCA carriers (p�0.023). bPFS was not affected by ADT 

duration. Median bPFS after RP was 65ms in BRCA carriers. No difference 

was observed in 3yrs-bPFS between BRCA carriers and NC (73% vs 76%). 

The adjusted MVA confirmed the independent prognostic value of tumour 

stage (p�0.004) and BRCA status (p�0.032) for bPFS. Among BRCA 

carriers, the risk was greater when the analysis was limited to BRCA2 pts 

(p�0.013, HR 2.1,.95%CI 1.2-3.7). Conclusions: Our results suggest that 

BRCA carriers with PCa have worse local disease control than NC when 

treated with RT, regardless of ADT duration. No differences in bPFS were 

observed in pts treated with RP after �6 yrs median follow-up. These 

results may have implications for tailoring clinical management for these 

patients. 


Cost sharing and hereditary cancer risk: Predictors of willingness-to-pay for 

genetic testing. Presenting Author: Jennifer Madeline Matro, Fox Chase 

Cancer Center, Philadelphia, PA 

Background: The increasing availability of genetic testing (GT) in cancer 

(CA) care has been paralleled by increasing cost-sharing practices by 

payors that are intended to reduce overuse of health care services. Patients 

referred for hereditary CA risk assessment may be subject to financial 

deterrents such as high out-of-pocket (OOP) costs. Little is known about 

what factors may influence high-risk patients’ willingness-to-pay (WTP) for 

GT. Methods: The Gastrointestinal (GI) Tumor Risk Assessment Registry 

includes individuals referred for evaluation of genetic CA risk based on 

personal and/or family hx. At enrollment, participants complete a survey 

collecting detailed demographic, CA hx, and psychosocial items related to 

CA risk. Baseline data on 406 participants were available; 21 who did not 

respond to WTP items were excluded. WTP items included intention for: GT 

only if paid by insurance; GT even if paid by self; and amount WTP (7 levels, 

$25 to $2000). Multivariable models examined predictors of WTP (self vs 

only if paid by insurance) (model 1, logistic), and predictors of amount WTP 

(model 2, ordinal logistic, 5 levels). All statistical tests are two-sided 

(��0.05). Results: Most participants were women (73%), white (92%) and 

aged 45-64 (58%). 51% had � 4 yr college degree; 22% had household 

income �$75,000; 42% had hx of GI CA; 56% had � 11st degree relative 

(FDR) with colorectal CA (CRC). Overall, 82 (21.3%) were willing to have 

GT only if paid by insurance, and 303 (78.7%) were WTP OOP. Of those 

WTP, 271 (89%) stated an amount. Independent predictors of WTP (model 

1) were: 1) expectation of positive result, 2) confidence to control CA risk, 

3) fewer perceived barriers to CRC screening and 4) benefit of guiding 

screening (all p�0.05). Subjects WTP a higher amount (model 2) were 

male, more educated, and had greater CA worry, fewer FDR with CRC (all 

p�0.05), and more positive attitudes toward GT (p�0.01). Conclusions: 

Patients who are WTP some OOP costs for GT anticipate benefits to control 

of CA risk afforded by GT. Women and less educated patients may face 

greater barriers from high co-pays. Identifying patient-level factors associated 

with WTP for genetic services is increasingly important as GT is 

integrated into routine CA care. 


Comparison of BRCA1/2-positive and -negative women diagnosed with 

metachronous breast and ovarian cancers. Presenting Author: Amanda C. 

Brandt, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: After a primary breast cancer (BC) or ovarian cancer (OC) 

diagnosis, women have a risk to develop a second primary cancer, 

significantly more so in women with a BRCA gene mutation. The objective 

was to evaluate characteristics of BRCA positive and negative women 

diagnosed with metachronous BC and OC. Methods: Women with metachronous 

BC and OC were identified at the University of Texas MD Anderson 

Cancer Center. BRCA test results, age at diagnosis of both BC and OC, first 

degree relatives (FDR) with BC and/or OC, total relatives affected, and 

histopathologic tumor features were obtained from a prospectively maintained 

research database. Univariate and logistical regression analyses 

were performed. Results: A total of 64 women with metachronous primary 

cancers underwent BRCA genetic testing. Of the 45 BRCA positive women, 

36 (80%) were diagnosed with BC (mean 40 years) prior to OC and 9 (20%) 

were diagnosed with OC first (mean 47 years). Of the 19 BRCA negative 

women, 10 (53%) were diagnosed with BC first (mean 63 years), and 9 

(47%) diagnosed with OC first (mean 48 years). Women diagnosed with BC 

first were more likely to be BRCA positive than women diagnosed with OC 

first (p�0.03). Patients with a FDR with BC were more likely BRCA positive 

than women without family history (p�0.0062). Patients with PR negative 

BR (p�0.0199) or triple negative (TN) BC (p�0.0139) were more likely to 

test BRCA positive. High grade ovarian carcinomas approached significance 

(p�0.053) in BRCA positive when compared to BRCA negative 

cohort. Ethnicity, total number of affected relatives with BC or OC, ER 

status, Her2 status, and nuclear grade were not statistically significant 

between the two groups. Conclusions: Women with OC preceding their BC 

with lack of family history of BC and OC are significantly less likely to test 

BRCA positive. BC is often the sentinel cancer in women with a BRCA 

mutation compared to BRCA negative women with metachronous BC and 

OC. This should be considered during the risk assessment to more 

accurately estimate the chance of identifying a BRCA mutation in women 

with metachronous BC and OC. 



Features of familiality in a cohort of patients (pts) with sarcoma. Presenting 

Author: Georgios Lypas, Dana-Farber Cancer Institute, Boston, MA 

Background: Sarcomas occur in a number of cancer predisposition syndromes, 

yet genetic evaluation is rarely recommended for sarcoma pts. We 

broadly reviewed the family cancer histories of unselected pts in a tertiary 

center sarcoma clinic to explore the potential relevance of genetic assessment. 

Methods: Between 2005 and 2008, 397 pts (median age 52 years) 

with documented sarcoma who consented to research use of medical 

records and tissues also completed a family history questionnaire. Patient 

and family histories were reviewed for features suggesting hereditary risk 

(e.g. early age at diagnosis or familial clustering of certain associated 

diagnoses). Results: A family history of malignancy was noted in 301 of 397 

pts (76%). Seventy-six pts (19%) were diagnosed with 99 additional 

malignancies, most frequently breast cancer (n�23), prostate cancer (12), 

melanoma (12), thyroid cancer (6) or a second sarcoma (10). Sarcoma was 

diagnosed prior to or synchronously (within 6 months) with another 

malignancy in 20 pts and metachronously in 56 pts. In 18 pts, sarcoma 

arose within a prior radiation field. Thirty-seven pts (9%) had a sarcoma 

subtype associated with a recognized syndrome: desmoid fibromatosis 

(n�16), malignant peripheral nerve sheath tumor (11), PEComa/ 

angiomyolipoma (6), retinoblastoma (3), and GIST with paraganglioma (1). 

Based on additional features, the associated syndromes were confirmed in 

6 of them (1.5% of the cohort): familial adenomatous polyposis (n�1), 

neurofibromatosis type 1 (2), familial retinoblastoma (2), and Carney- 

Stratakis dyad (1). Thirty-three pts (8% of the cohort, or 16% of pts age 

�50) fulfilled TP53 testing criteria (Chompret, Birch or classical Li- 

Fraumeni Syndrome [LFS] criteria). Another 147 pts (37% of the entire 

cohort) did not fulfill LFS testing criteria, but were diagnosed with sarcoma 

before age 50 and had at least one first or second degree relative with a 

diagnosis of malignancy before age 50. Conclusions: Sarcomas are rare and 

diverse cancers. Given the potential association with cancer predisposition 

syndromes, genetic evaluation should be strongly considered in sarcoma 

pts based on age at diagnosis, histology, and family cancer history. 


Predictors of contralateral prophylactic mastectomy among patients with 

ductal carcinoma in situ (DCIS) who underwent evaluation for BRCA 

genetic testing. Presenting Author: Nisreen Elsayegh, University of Texas 


Background: Patients with DCIS are at increased risk for developing 

contralateral breast cancer (CBC). Therefore, an increasing number of 

women with DCIS are electing for contralateral prophylactic mastectomy 

(CPM). In a previous study involving 2072 women with DCIS, 13.5% chose 

CPM. In this study, we aimed to evaluate factors associated with CPM in 

patients with DCIS who underwent genetic counseling for BRCA. Methods: 

165 women with pure DCIS, who underwent genetic counseling, were 

included in the study. Patients’ characteristics were obtained from a 

prospectively maintained research database at UT M.D. Anderson Cancer 

Center. Univariate and multivaraite logistic regression analysis were used to 

determine predictive factors associated with CPM. Patients’ characteristics 

included age, marital and educational status, tumor markers, nuclear 

grade, family history with breast (BC) and ovarian cancer (OC), race, 

Ashkenazi Jewish ancestry, and BRCA genetic test results. Results: Out of 

165 patients, 17(10.3%) were found to have a BRCA deleterious mutation. 

44(26.7%) underwent CPM. Younger patients (median � 45 yr) were more 

likely to elect for CPM than older patients (p� 0.0098). Patients who 

tested positive for a BRCA mutation were more likely to elect for CPM than 

those who tested negative or were not tested (p� 0.0001). Patients who 

had a family history of OC (15 (57.7%) were more likely to choose CPM 

than those who did not (p� 0.0004). These three factors remained 

significant in the multivariate model (p �0.008). Marital and educational 

status, tumor markers, nuclear grade, and family history of breast cancer 

were not significant predictors of CPM. Conclusions: The rate of CPM in 

patients with DCIS is high. Factors associated with increased likelihood of 

undergoing CPM include family history of OC, age, and BRCA positivity. 

Further studies are needed to evaluate patients perception of CBC risk, and 

if this may play a role in the high number of CPM. 


97s 


Analysis of mutations in formalin-fixed paraffin-embedded (FFPE) tumor 

samples from two phase II clinical trials using a Sequenom-based approach. 

Presenting Author: Maria Orr, AstraZeneca, Macclesfield, United 

Kingdom 

Background: Analysis of tumour samples for biomarker discovery, personalised 

health care and disease stratification is becoming increasingly 

important. Methods to detect somatic mutations are often limited by the 

requirement for a significant amount of input DNA, low sensitivity or low 

sample throughput. The aim of this work was to obtain a comprehensive 

mutation profile of tumour samples taken from patients enrolled on two 

Phase II clinical trials. A Sequenom based approach was used to determine 

mutation profiles for the samples so that these could be correlated with 

response at some future date. Methods: After successfully piloting the 

Sequenom MassArray 4 platform on formalin fixed paraffin embedded 

(FFPE) tumour samples and tumour cell line admixes, we ran an exploratory 

analysis of 177 melanoma and 230 non small cell lung cancer (NSCLC) 

FFPE samples collected from two phase II clinical trials. DNA was extracted 

from the FFPE samples using the QIAmp DNA FFPE Tissue Kit (Qiagen). 

We designed a panel of 86 assays in 14 genes covering approximately 

160� mutations. Mutations were chosen based on mutation frequency and 

biological significance in these tumour types. Results: Using this approach 

we were able to detect concomitant mutation profiles in a significant 

percentage of samples using only approximately 20uL of FFPE DNA (500 

copies/�L average). Mutation status concordance was over 97% in BRAF 

and KRAS when compared to data generated via other approaches 

(sequencing, ARMS). Conclusions: Using Sequenom to screen tumour 

material, collected during clinical trials, is a feasible, rapid and comprehensive 

approach. Such an approach can be used to identify mutation profiles 

which correlate with patient response, potentially identify further patient 

stratification and help generate new hypotheses for further exploration. 


Profiling uptake of single site testing (SST) for familial cancer (CA) risk in an 

administrative genetic testing database. Presenting Author: Michael J. Hall, Fox 

Chase Cancer Center, Philadelphia, PA 

Background: Among the anticipated social and cost-saving benefits to identifying 

a mutation in a CA predisposition gene in an individual is the subsequent 

opportunity to perform SST in close relatives to confirm risk status and to guide 

risk-reducing interventions. Despite ample research into uptake of primary 

genetic testing for Lynch syndrome (LS) and hereditary breast ovarian syndrome 

(HBOS) among moderate- and high-risk individuals, few studies have focused on 

the resultant cascade of SST that is predicted to follow in families. Methods: 

Administrative data on 2,631 consecutive single-site mutation tests performed 

over a 3-month interval (12/1/10-2/28/11) were obtained from a commercial 

genetic testing database maintained by Myriad Genetic Laboratories. 14 

subjects (29 tests) were excluded due to multiple entries. Demographic, 

personal/family history (hx), and provider data are collected on a Test Requisition 

Form included in kits. All statistical tests are 2-sided (��0.05). Results: Women 

had SST more often than men (HBOS 82.8%; LS 65.5%). Mean age at time of 

SST was 42.7 yrs, and was higher for HBOS than LS (p�0.01). Among subjects 

with hx of CA, mean age at CA diagnosis (dx) was similar (HBOS 48.6; LS 48.7 

yrs). Subjects reported CA in �1 relatives (range 1-16) with a mean age at dx 

40.1 yrs. Compared to HBOS, those tested for LS were more likely to report CA in 

a 1st degree relative (81.3 vs 74.4%, p�0.001) and a lower age of youngest CA 

dx in the family (p�0.001). Non-European ancestry was more common for 

HBOS SST than LS (30.0 vs 24.8%) (p�0.05). SST positive test rate was no 

different by syndrome or ancestry, but was higher for men (47.5 vs 42.0%, 

p�0.02). Conclusions: Uptake of commercial SST in high-risk families is uneven 

by age, sex, ancestry and CA syndrome. While between-syndrome variability in 

CA risks may explain some differences, more research is needed to understand 

barriers to uptake of SST among at-risk individuals if CA prevention goals are to 

be realized. 

Characteristics of 2,602 subjects undergoing SST for familial CA risk. 

% 

Sex F 79.5 

M 20.5 

Cancer Hx Y 19.9 

N 71.6 

Unreported 8.5 

Ancestry European 70.5 

Other 29.5 

Syndrome (genes) HBOS (BRCA1/2) 82.7 

LS (MLH1/MSH2/MSH6) 13.1 

Other 4.2 




NAD(P)H: Quinone oxidoreductase 1 (NQO1) C609T polymorphism and 

lung cancer risk: A meta-analysis. Presenting Author: Yuqing Lou, Department 

of Pulmonary, Shanghai Chest Hospital, Jiaotong University, Shanghai, 

PR China, Shanghai, China 

Background: No clear consensus has been reached on the NAD(P)H: 

quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung 

cancer risk. We performed a meta-analysis to summarize the possible 

association. Methods: We conducted a computer retrieval of PUBMED and 

EMBASE databases prior to January 2012. References of retrieved articles 

were also screened. According to the inclusion criteria, 24 articles (31 

studies) were finally included. The fixed-effects model and the randomeffects 

model were applied for dichotomous outcomes to combine the 

results of the individual studies. Results: There was no statistical association 

between C609T polymorphism and lung cancer risk in overall, East 

Asians, African-Americans or Hispanics. In Caucasians, significant association 

was found in allele comparison model (T vs. C) (P�0.04, OR�1.09, 

95%CI [1.00–1.19], Pheterogeneity�0.24, fixed-effects model). In Hawaiians, 

significant association could be found in dominant genetic model 

((TT�CT) vs. CC) (P�0.04, OR�0.52, 95%CI [0.28–0.96], fixed-effects 

model). In the subgroup of squamous cell carcinoma, a borderline 

significance could be found in the dominant genetic model ((TT�CT) vs. 

CC) (P�0.05, OR�1.20, 95%CI [1.00–1.43], Pheterogeneity�0.65, fixed-effects model). Significant association could also be found in 

allele comparison (T vs. C) (P�0.03, OR�1.21, 95%CI [1.01–1.44], 

Pheterogeneity�0.68, fixed-effects model). In the subgroup of small cell lung 

cancer risk, significant association were found in allele comparison (T vs. C) 

(P�0.03, OR�1.68, 95%CI [1.05–2.68], Pheterogeneity�0.10, randomeffects 

model) and in the homozygote comparison (TT vs. CC) (P�0.02, 

OR�2.79, 95%CI[1.14–6.85], Pheterogeneity�0.72, fixed-effects model). 

No association was observed in adenocarcinoma subgroup. Conclusions: 

NQO1 C609T polymorphism might associate with lung cancer risk in 

Caucasians and Hawaiians. NQO1 C609T polymorphism might also associate 

with squamous cell carcinoma and small cell lung cancer risk. 


Why do breast cancer programs fail to refer patients to genetic counseling 

upon obtaining family history? Presenting Author: Julia R. Trosman, Center 

for Business Models in Healthcare, Chicago, IL 

Background: Women with personal or family history suggestive of susceptibility 

to hereditary breast or ovarian cancer should be referred to genetic 

counseling (US Preventive Services Task Force, Ann Intern Med. 2005). 

Our goal is to examine whether this guideline is followed by breast cancer 

programs providing screening and treatment in a large urban area; and if 

not followed, why. Funded by Susan G. Komen for the Cure. Methods: Using 

the framework approach of qualitative research, we conducted interviews 

with 130 providers of breast cancer screening and treatment at 26 

institutions in Chicago (18 community, 4 academic and 4 public hospitals). 

We interviewed radiologists, mammography technologists, nurses, 

surgeons, oncologists, internists, and patient navigators. Interviews were 

transcribed and coded; theme analysis was conducted; simple frequencies 

and Fisher’s exact test were calculated. Results: While all 26 programs 

collect patient personal and family history, only one program has both a 

protocol for referral to genetic counseling and a genetic counseling service. 

All six interviewees from that program (6/130, 5%) report referring 

appropriate patients to genetic counseling, compared to none from other 

programs (p�0.0001). 90% of interviewees (118/130) did not perceive 

any role in raising patient awareness or referring them to genetic counseling. 

Among the 124 interviewees not referring to genetic counseling, 51 

(41%) have genetic counseling available, but only 12% (6/51) of them view 

referring or making patients aware of genetic services as their responsibility; 

while none of the interviewees without genetic counseling services view 

this their responsibility (p�0.0001). None of the interviewees noted 

reimbursement of genetic counseling as a barrier to referral. Conclusions: 

The lack of accountability by care providers is a barrier to referring patients 

with personal or family history of breast or ovarian cancer to genetic 

counseling, even when the service is available. A comprehensive approach 

addressing access to genetic counseling, adoption of referral protocols and 

clear assignment of referral responsibilities is needed to ensure that women 

appropriately receive genetic assessment. 


Ethnic difference of driver mutation frequencies and correlations between 

driver mutations and histologic subtypes in lung adenocarcinoma. Presenting 

Author: Yuki Yamane, Division of Thoracic Oncology, National Cancer 

Center Hospital East, Kashiwa, Chiba, Japan 

Background: The frequencies of known driver mutation in lung adenocarcinoma 

from patients in the United States have been reported by the NCI’s 

Lung Cancer Mutation Consortium (LCMC), indicating driver mutations 

were detected in 54% (280/516) of tumors. In this report, mutations 

found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, 

MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK 

rearrangements 7%. However little is known about ethnic difference of 

driver mutation frequencies and correlations between driver mutations and 

histological subtypes in lung adenocarcinoma. Methods: Known driver 

mutations in tumors from 97 Japanese patients with lung adenocarcinoma 

who underwent surgical resection between 1999 and 2003 in National 

Cancer Center Hospital East were analyzed by next-generation sequencing 

and confirmed by Sanger sequencing. Correlations between driver mutations 

and histological subtypes were also assessed. Results: Driver mutations 

were detected in 72% of tumors. Mutations found: EGFR 57%, 

KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, 

MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement 

detection by exon-sequencing, ALK rearrangements were not analyzed. 

Compared with the report by LCMC, the frequency of EGFR mutations was 

high and that of KRAS mutations was low in the present study. All 

mutations were mutually exclusive. The number of predominant histological 

subtypes of tumors harbored EGFR mutations were papillary 28, acinar 

3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 

2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. 

Two tumors harbored PIK3CA mutations showed both histological acinar 

pattern. Each of BRAF mutation and MET amplification showed lepidic and 

papillary pattern, respectively. Conclusions: It was suggested that there 

should be ethnic difference of driver mutation frequencies in lung adenocarcinoma 

between Asian and non-Asian patients, although the details of 

ethnic distribution included in LCMC study has not been opened. In 

addition, each driver mutations did not correspond to specific histological 

subtypes of lung adenocarcinoma. 


Breast cancer prognosis in BRCA1/2 mutation carriers: A case control 

study. Presenting Author: Grazia Arpino, Medical Oncology, Endocrinology 

and Oncology Department, University Federico II of Napoli, Napoli, Italy 

Background: We evaluated the clinical impact of germ-line BRCA1/2 

mutations and variants of unknown clinical significance (VUS) for BRCA1/2 

in patients (pts) with early breast cancer (BC). Methods: Twenty-eight 

BRCA-positive (BRCA�) BC pts with germ-line BRCA1 /2 mutations and 

16 VUS BC pts were selected from our database and matched (1:3) with 

154 nonhereditary BC controls (sporadic controls, SC, defined by no 

associated personal history of breast cancer and no family history of breast 

and ovarian cancer or an uninformative BRCA mutation test) for stage, 

histologic subtype, age, and year of diagnosis. Clinical characteristics, 

recurrence (rec) pattern, disease free survival (DFS) and overall survival 

(OS) were analyzed. Results: Compared with VUS and SC, BRCA� pts were 

less likely to express estrogen receptor (64% vs. 89% vs. 54% respectively 

p�.005) and progesterone receptor (64% vs. 86% vs. 59% respectively 

p�.005) but more likely to be triple negative (0 vs. 3.4% vs 47.4% 

respectively p�.005). Compared with VUS and SC, BRCA� pts were more 

likely treated by radical mastectomy (37.5% vs. 26.4% vs. 59.3% % 

respectively p�.005). Pattern of rec was also different. Compared with 

VUS and SC, BRAC� pts developed more second tumors (11% vs. 6.3% vs. 

1.9% respectively p�.0001) but less local or distant rec (31% vs. 2.6 vs. 

0% for local rec and 12% vs. 16% vs. 11% for distant rec respectively 

p�.0001). Controlateral BC was more frequent in VUS compared to the 

BRAC� and SC pts (12% vs. 7% vs. 1% respectively, p�.0001). At a 

median follow up of 88 months, at univariate analysis, BRAC� but not VUS 

pts had worse OS compared to SC (p�.006). No difference in DFS was 

observed for VUS or BRAC� when compared to SC pts. After adjustment for 

age, stage, grade, nodal status, hormone receptors, adjuvant therapy and 

year of diagnosis, BRCA� pts continued to have and increased risk of death 

compared to SC (HR 5.9, 95% CI 1.9-18.1, p�.002). Most of the deaths 

observed in BRAC� pts were not cancer related. Conclusions: Despite 

decrease incidence of local or distant recs, BRAC� pts seems to be more 

likely to die compared to SC. Development of second cancers and unknown 

effects of BRCA1/2 mutations on nonneoplastic diseases that cause death 

may account for this findings. 



Variants of uncertain significance in BRCA testing: Impact on risk perception, 

worry, prevention, and counseling. Presenting Author: Tracy Graham, 

Sunnybrook Hospital, Toronto, ON, Canada 

Background: Genetic testing for BRCA1 and BRCA2 is an instrumental tool 

in clinical decision-making. Variants of uncertain significance (VUS) can 

occur in up to 25% of individuals and pose clinical challenges. We 

compared i) result recall ii) risk perception iii) worry and iv) risk modifying 

behaviours in individuals with VUS, a pathogenic mutation (PM) or an 

uninformative result (UR). Care provider attitudes to VUS were also 

studied. Methods: A questionnaire was mailed to women testing positive for 

a VUS, PM or UR. Items included demographics, time from disclosure, 

result recall and cancer worry using the validated Trask score. Likelihood of 

risk modifying behaviours or intensified screening was evaluated by 5 point 

Likert scale. 9 regional genetic counselors and 11 referring physicians were 

surveyed on VUS management. Responses were evaluated by chi square 

and ANOVA. Results: All groups had similar age, marital status and 

education. Failure to correctly identify a result as uninformative occurred in 

32% of VUS; 90% had low economic status. 87% (VUS) and 44% (PMC) 

had personal history of breast cancer. Perceived risk increased after 

disclosure in 29% (VUS), 70%(PM) and 10% (UR) (p�0.001). Mean 

Trask scores were 7.6 (VUS) and 9.8 (PMC) (p�0.006, t-test). In affected 

patients, mastectomy was 22% (VUS) and 55% (PMC) (p�0.01), oophorectomy 

39% (VUS) and 85% (PMCs) (p�0.001) with75% and 95% 

intensified screening 75% in unaffected VUS and PM (p�0.16). 3% (VUS) 

and 6% (PMC) agreed with chemoprophylaxis (p�NS). Genetic counselors 

unanimously reported low comprehension in VUS vs PM. VUS was 

disclosed only 75% of the time with poor comprehension, perceived anxiety 

and negative family history as reasons. Referring physicians recommended 

predictive testing for relatives of VUS carriers (100%). Conclusions: Nearly 

1/3 of patients fail to recall their VUS as uninformative. Perceived risk was 

increased after VUS disclosure but lower than PMC. Worry scores showed 

impact on daily functioning. Uptake of prophylactic surgery was lower in 

affected VUS vs PMC carriers with similar rates of intensified screening if 

unaffected. Patients with low economic status or anxiety are at particular 

risk of incomplete counseling. 


A comparison of simple single-item measures and the NCI Common 

Toxicity Criteria version 3.0 measure of peripheral neuropathy. Presenting 

Author: Suneetha Puttabasavaiah, Mayo Clinic, Rochester, MN 

Background: Peripheral neuropathy (PN), a common and intrusive side 

effect of chemotherapy in clinical trials, has been assessed via the 

clinician-rated common terminology criteria for adverse events (CTCAE) 

and/or patient-reported outcome (PRO) measures (Morton, ASCO, 2005). 

We assessed the relative sensitivity of CTCAE and PRO measures for 

evaluating interventions for preventing and ameliorating CIPN. Methods: 

Data from285 patients in two prevention trials (N05C3, N04C7) and 432 

patients from three intervention trials (N00C3, N01C3, N06CA) were 

analyzed separately. CTCAE version 3.0 item for neuropathy was compared 

to 2 NCCTG numerical analogue CIPN items, 6 EORTC CIPN20 individual 

items, 2 McGill Pain Questionnaire items, and one Brief Pain Inventory 

item. The sample size provided over 80% power to detect a true Spearman 

rank correlation of 0.15 assessed the relationship between CTCAE and PRO 

measures. Results: Results from both the prevention and treatment trials 

were similar in terms of the relationship between the CTCAE and PRO 

measures. No correlation coefficients between the CTCAE and any of the 

PRO items at baseline were above 0.35, with the majority around 0.2. 

Higher scores for the numbness items were observed than for the CTCAE in 

47% of the patients at baseline and 39% during treatment in the treatment 

trials. Many patients had severe numbness PRO scores but mild CTCAE 

scores (12%) at baseline and (8%) during treatment in the treatment trials. 

Results for the numbness and tingling PRO measures were redundant. The 

correlations of the CTCAE with pain were weak, all below 0.35 at baseline 

with differences as much as 29 points on average on a 0-100 transformed 

scale. Conclusions: The CTCAE and PRO measures of PN measure different 

constructs. The CTCAE includes both functional and ADL/motor aspects 

which may or may not be related to the singular constructs of pain, 

numbness, tingling, or adjectival characteristics of pain assessed by the 

PRO measures. The two measures cannot be used in place of each other. 


99s 


Differential effects of light at night and shift rotation pattern on the 

circadian system in night workers. Presenting Author: Pedram Razavi, 

Department of Medicine, University of Southern California, Los Angeles, 

CA 

Background: Light at night as in shift work suppresses nocturnal secretion 

of melatonin, a pineal hormone with oncostatic properties. Several studies 

have associated night shift work with higher risk of cancer, leading WHO in 

2007 to classify rotating night shift work as “probably carcinogenic”. We 

conducted one of the most comprehensive studies, to date, to evaluate the 

effects of light and night shift work on melatonin measurements in the 

field. Methods: Study participants were 130 active nurses (84 current 

rotating night shift workers and 46 day shift workers) participating in 

NHS2. Each nurse wore a head-mounted light- and accelerometer for a 

3-day study period, during which each spontaneous urine was collected for 

repeated urinary 6-sulfatoxymelatonin (melatonin) measurements. In addition, 

nurses were asked to fill out paper questionnaires and diaries. We 

used mixed models to evaluate the influence of light, activity and night shift 

work on urinary melatonin level adjusting, for age, lifestyle, and occupational 

history. We log-transformed main variables and report geometric 

means (GM [standard deviation]). Results: Greater levels of light were 

associated with lower melatonin (P � 0.0001), independent of activity 

level. An increase in light intensity from 10 to 100 lux was associated with 

a 12% decrease in geometric mean of melatonin level; however, this 

inverse association was only significant at night (Ptrend � 0.01). At night, 

each hour increase in exposure to � 20 lux light lowered melatonin level by 

5.7% (Ptrend � 0.0001). A single night shift affected the circadian system 

by lowering melatonin peak by 22% (day shift: GM � 17.57 [2.73]; night 

shift: GM � 13.64 [2.54]) and induced a phase shift (PS) of 0.9 hours, 

-changes that reset to normal by the next day. Two consecutive night shifts 

had a similar effect as a single shift. However, the effect was worse after 

three consecutive night shifts (GM � 10.11 [2.77]; PS � 2.2 hours). 

Conclusions: We found significant inverse associations of intensity and 

duration of exposure to light at night with urinary melatonin, independent 

of activity level. Three consecutive night shifts affected the circadian 

system more strongly than two consecutive, or a single night shift. 

1558 General Poster Session (Board #3H), Sat, 1:15 PM-5:15 PM 

Association of CYP19A1 gene variants with differences in disease progression 

in breast cancer patients from different racial/ethnic backgrounds. 

Presenting Author: Reina Villareal, University of New Mexico and New 

Mexico VA Health Care System, Albuquerque, NM 

Background: Polymorphisms in the aromatase (CYP19A1) gene result in 

differences in the risk for breast cancer and response to treatment. We 

hypothesize that allele frequencies in the CYP19A1 gene vary according to 

race and may result in differences in progression of breast cancer among 

women from different racial backgrounds. The objectives of this study are: 

1) to determine the allele/genotype frequencies in the CYP19A1 gene 

among women with breast cancer from different racial backgrounds, and, 

2) to determine the association between disease progression and CYP19A1 

gene variants. Methods: Clinical data and stored DNA from 327 patients 

participating in the Expanded Breast Cancer Registry (EBCR) program at 

the University of New Mexico were analyzed. These patients were followed-up 

for a period of 1 to 6 years. Comprehensive genotyping for 

CYP19A1 gene single nucleotide polymorphisms (SNPs) was performed 

using microarray (Illumina). Results: Data from 164 non-Hispanic white 

and 119 Hispanic women were analyzed. Four SNPs (rs1259269, 

rs17703883, rs16964211, rs28757101) were associated with differences 

in genotype/allele frequencies between the 2 racial groups. Furthermore, 

3 SNPs (rs4646, rs17647478, and rs6493486) were associated 

with differences in disease progression. The rare allele (G) for the 

rs17647478 (G/T) is associated with poor progression compared those 

without the allele (41.7% vs. 17.1%, p�0.04). Similarly the minor (A) 

allele for the rs4646 (A/C) and the rs6493486 (A/G) is also associated with 

a greater chance of worsening disease (23.2% vs. 12.4%, p�0.02 and 

23.4% vs. 12.4%, p�0.02, respectively). A significant percentage of 

women carrying the A allele for both rs4646 and rs6493486 and the T 

allele for the rs17647478 have more advanced disease at the time of 

presentation. None of the SNPs analyzed result in racial differences in 

breast cancer progression. Conclusions: Polymorphisms in the CYP19A1 

gene influence overall disease progression in breast cancer patients but 

have no impact on the racial differences of disease behavior. Women 

carrying the risk alleles present at a more advanced stage and are also at 

greater risk of progression. 




Public perception of cancer risk. Presenting Author: Lisa Burns, University 

College Cork, Cork, Ireland 

Background: The public’s knowledge of cancer risk factors has rarely been 

studied in Ireland. An understanding of this can help inform cancer 

prevention programs. Methods: An online surveywas used to assess the 

public’s perception of cancer risk. Results: 525 people completed the 

survey. Mean age was 40yrs (range:18-74), 82% were female and 36% had 

college degrees. 81% were concerned about developing cancer, however 

20% believed if cancer was in their family there was nothing they could do 

about personal cancer risk. 20% did not know that cancer risk increased 

with age, 27% believed that �50% of cancers are inherited, and 54% 

believed 10-20% of cancers are inherited. The top 5 risk factors listed by 

respondents were: smoking 85%, diet 74%, alcohol 44%, genetics 38%, 

and environment 31%. Only 32% were aware that obesity is a risk factor for 

cancer and 33% did not think the location of fat was important for cancer 

prevention. When given a list of potential behaviours relevant to cancer risk 

33% believed wearing a tight bra and 49% believed a blow to the breast 

could increase cancer risk. 87% believed genetics ‘strongly’ increased risk, 

85% stress, and 86% believed cell phones increased risk. 12% believed 

‘luck’ was important in avoiding cancer, 35% thought ‘detox’ diets and 

61% believed organic food reduced risk. Only 33% agreed with the 

statement that ‘frozen vegetables/fruit are as good as fresh’, 40% were 

unaware of the link between red meat and cancer. The following foods were 

thought to increase risk: cheese (29%), soy (9%), milk chocolate (30%), 

red wine (25%), and eggs (11%). Aerosol use (71%), cleaning agents 

(73%), smoking (99%), cooking methods (68%), processed meat (86%), 

food irradiation (77%), and genetically modified foods (81%) were believed 

to increased risk. The majority were aware that berries, green tea, garlic, 

brassica vegetables and physical activity of 30 minutes a day can reduce 

cancer risk. Conclusions: There is a sizable portion of the population who 

are misinformed about cancer risk. Most are aware of classic risk factors 

(e.g. smoking, poor diet). Many overestimate risk attributable to genetics, 

environment, stress, and underestimate age, obesity and sunlight. One in 5 

believes lifetime risk of cancer is non-modifiable. 


Clinical and genetic predictors of weight gain in patients diagnosed with 

breast cancer. Presenting Author: Sangeetha M. Reddy, Northwestern 

University Feinberg School of Medicine, Chicago, IL 

Background: Obesity and weight gain in breast cancer patients has been 

associated with decreased quality of life, decreased response to chemotherapy, 

increased cancer recurrence, and higher all-cause mortality. Our 

study was designed to identify factors that contribute to this weight gain. 

Methods: Chart review was conducted on 565 breast cancer patients to 

obtain weights and BMIs over an 18 month period from diagnosis, tumor 

characteristics (ER/PR/Her2 status, grade, presence of LN metastases, 

stage), demographics (age, race), clinical factors (menopausal status), and 

treatment regimens (chemotherapy, hormone therapy, radiation). Blood 

samples were genotyped for polymorphisms in FTO (fat mass and obesityassociated 

protein) and the adiponectin pathway, two pathways found to be 

associated with obesity and breast cancer risk. Results: See table. For 

genetic analysis, one statistically significant epistatic and three gene x 

environmental interactions were detected for adiponectin SNPs: rs822396d 

x BMI at diagnosis (effect size 8.65), rs2232853a x age (2.75), 

rs1501299a x BMI at diagnosis (3.63), and rs266729d x rs7539542d 

(6.40). Conclusions: We have identified multiple clinical and genetic 

variables that are likely predictors of weight gain in breast cancer patients. 

We are conducting a prospective study of 200 breast cancer patients to 

validate the findings of this retrospective study. By identifying a high risk 

patient population, we hope to target them for aggressive lifestyle interventions 

to prevent weight gain and thereby improve their mortality and 

morbidity. 

OR for statistically significant clinical variables. 

Univariate analysis 

Multivariate 

Variable 

6 mo 1 yr 18 mo analysis 

Chemotherapy 0.75** 0.88** 0.88** 

Hormone therapy 1.28** 1.18** 1.18** 1.20** 

Stage (3 or 4) 0.78** 0.86** 0.87** 0.85** 

Postmenopausal status at diagnosis 0.87* 0.91** 

LN metastases 0.84** 0.91* 0.91** 

ER status 1.37** 1.18** 1.18** 1.22** 

PR status 1.23** 1.11* 1.13** 

Grade (2 or 3) 0.80* 0.87* 0.89** 

African American vs. white 0.88* 0.90** 

Hispanic vs. white 1.43* 1.17* 

Asian vs. white 

*p � 0.05 

** p � 0.01 

0.79* 0.87* 


The effects of BR-DIM (BioResponse 3, 3’-Diindolylmethane) administered 

pre-prostatectomy on the androgen receptor (AR). Presenting Author: 

Elisabeth I. Heath, Karmanos Cancer Institute, Wayne State University, 

Detroit, MI 

Background: Consumption of cruciferous vegetables is associated with 

decreased risk of prostate cancer (PCa). 3,3’-diindolylmethane (DIM), an in 

vivo active compound formed after consumption of cruciferous vegetables, 

down-regulates the AR, and causes its nuclear exclusion which results in in 

vitro growth arrest and apoptosis of PCa cells. We conducted a biomarker 

trial evaluating BR-DIM in pre-prostatectomy patients with the primary 

objective of measuring DIM levels in prostate tissue and in plasma. 

Methods: Patients with organ-confined PCa who were candidates for surgery 

were treated with BR-DIM at a dose of 225 mg orally twice daily for a 

minimum of 14 days. Patients did not receive any androgen deprivation 

therapy. Patients received their last dose of BR-DIM the day before surgery. 

Blood samples for DIM levels were collected pre-treatment and just prior to 

surgery. DIM concentration was measured in the plasma and in prostate 

tissue specimens using a validated high-performance liquid chromatographic 

method with tandem mass spectrometric detection. AR was 

evaluated by immunohistochemistry (IHC). Results: 36 patients were 

treated at 2 institutions. The 26 evaluable patients had median age of 60 

years (range 41 - 76), 14 were Caucasian, and 10 were African American. 

Reasons for inevaluability included change in surgery date (n�4), inadequate 

BR-DIM treatment (2), withdrawal from study (2), canceled surgery 

(1), and other (1). Toxicity was minimal; only two patients with grade 3 

headache. Post dosing, DIM was found at a mean trough level of 10.2 ng/ml 

(range, 0.5 to 24.7) and 12.3 ng/gm of tissue (range, 0.0 to 26.8) in 

plasma and in prostate tissue, respectively. PSA levels had a slightly 

downward trend after BR-DIM treatment. In 18 of 20 evaluable PCa 

specimens, IHC showed nuclear exclusion of AR. Conclusions: BR-DIM was 

well tolerated, and DIM was detected in both plasma and prostate tissues at 

~12 h post dosing. Nuclear exclusion of AR was found in 90% of PCa 

specimens post BR-DIM dosing, suggesting in vivo inactivation of AR 

activity. PSA levels were slightly reduced overall. Accrual is ongoing and 

nearly complete. Additional studies with BR-DIM in PCa are warranted. 


Breast cancer risk reduction among patients with DCIS. Presenting Author: 

Melanie R. Palomares, City of Hope, Duarte, CA 

Background: The incidence of ductal carcinoma in situ (DCIS) has dramatically 

increased with widespread mammographic screening. Although risk of 

recurrence of DCIS is low, it is associated with a higher risk for subsequent 

contralateral breast cancer (CBC), for which preventive measures are 

available. We evaluated the uptake of surgical and pharmacologic interventions 

to reduce CBC risk at our institution and investigated factors that may 

influence treatment choices for DCIS. Methods: City of Hope (COH) DCIS 

patients were identified using two sources, the Circulating Breast Tumor 

Marker (BrTM) Registry and the National Comprehensive Cancer Network 

(NCCN) database. Datasets were linked together, and treatment variables 

were cross-tabulated with patient and tumor characteristics. Results: Of 

782 patients with breast malignancy diagnosed since 1997, 370 were 

excluded due to concurrent or prior invasive disease, 8 due to suspected 

misclassification based on therapies received, and 4 due to treatment on 

protocol. Of the remaining pure DCIS patients, treatment choices were 

recorded for 289. Of those, 40 (14%) chose bilateral risk reduction 

mastectomy (BRRM), 82 (28%) unilateral mastectomy, 165 (57%) lumpectomy, 

and 2 had no surgery. Hormonal therapy (HT) was recorded for 215 

individuals who did not pursue BRRM: 124 (57%) took tamoxifen, 3 of 

whom switched to raloxifene, 5 (2%) started with raloxifene, and 7 (3%) 

took an unspecified hormonal agent, for a total HT uptake of 55%. This 

included 8 of 29 women with ER-negative DCIS who chose HT for CBC risk 

reduction. Younger age at diagnosis was associated with BRRM (24% of 

women diagnosed before age 50, 10% of those diagnosed 50-64, and 5% 

of women 65� had BRRM, p�0.001) and HT (59% of women �65 chose 

HT compared to 40% of women 65�,p�0.009). Within ethnic minorities, 

more Asian women chose BRRM (22% vs 7% of other minorities, p�0.08). 

Interestingly, fewer high grade DCIS women opted for HT (39% vs 55% for 

low to intermediate grade, p�0.06). Conclusions: Young women tend to 

pursue surgical prophylaxis. Among women who keep their breasts, HT 

uptake was high across all age and ethnic groups, except for those older 

than 65 at diagnosis. It is unclear if this is due to patient choice or reflects 

age bias in physician recommendation. 



Risk perception and knowledge of breast and colon cancers in a diverse 

population. Presenting Author: Katherine Lang, Virginia Commonwealth 

University, Richmond, VA 

Background: The accuracy of cancer risk perception has implications for 

preventive behaviors. Studies show that despite receiving personalized 

breast and colon cancer risk information, people continue to overestimate 

their numeric risks. It is still not fully understood why this occurs. Breast 

cancer, especially, is highly visible in the media so an individual may hear 

more about breast cancer, increasing general knowledge but potentially 

inflating risk perceptions. This study explores relationships between 

general knowledge and numeric risk perceptions for breast cancer (BC) and 

colon cancer (CC) among women. We hypothesize that general knowledge 

of BC will be high relative to CC, but risk perception for BC will be less 

accurate. Methods: Data was obtained from the first 369 (final N�490) 

patients recruited for the Kin Fact study from a Women’s Health Clinic. Kin 

Fact is a randomized controlled trial examining effects of an intervention to 

increase cancer risk communication in families. Women complete baseline 

surveys including knowledge and numeric risk perception measures for BC 

and CC. We use CA Gene software to calculate actual lifetime risk for BC 

and CC. Correlations, t-tests and linear regressions were used for the 

analysis. Results: Women averaged 33 years old, and 58% were African 

American. Average lifetime risk was 3% for CC and 11% for BC. Women 

overestimated their numeric risk for both BC and CC, but the mean 

overestimation for BC (24%) was significantly larger than for CC (19%) 

(p�0.001). Average scores for BC knowledge were also significantly higher 

than for CC (p�0.001). Compared to knowledge about CC, women who had 

greater knowledge of BC also were more inaccurate in terms of their 

perceived numeric risk (r� -0.131, p�0.016). This finding remained 

significant controlling for age, race and genetic literacy. Conclusions: 

Results endorse an apparently paradoxical effect that compared with CC, 

women with increased knowledge of BC have less accurate risk perception 

for BC. Inaccuracies in perceived risk can affect psychosocial well-being 

and adherence to screening and prevention recommendations. Findings 

reveal a need for increasing knowledge about cancer without adversely 

impacting the accuracy of risk perceptions. 


Factors and trends in cancer screening in the United States from 2004 to 

2010. Presenting Author: Thanyanan Reungwetwattana, Mayo Clinic, 

Rochester, MN 

Background: Understanding the prevalence of cancer screening in the US 

and the factors associated with its accessibility is important for public 

health promotion. Methods: The 2004 and 2010 Behavioral Risk Factor 

Surveillance Systems were used to ascertain cancer screening rates among 

populations indicated for each test by age, gender, and the American 

Cancer Society recommendation for cancer screenings [fecal occult blood 

test (FOBT) or endoscopy for colorectal cancer (CRC) screening, digital 

rectal examination (DRE) or prostate specific antigen (PSA) for prostate 

cancer screening, clinical breast examination (CBE) or mammogram for 

breast cancer screening, and Papanicolaou (Pap) test for cervical cancer 

screening]. Results: Over this period, CRC and breast cancer screening rates 

significantly increased (15.9%, 13.9%) while prostate and cervical cancer 

screening rates significantly decreased (1.2%, 5.2%). Race/ethnicity 

might be an influence in CRC and cervical cancer screening accessibility. 

Prostate cancer screening accessibility might be influenced by education 

and income. The older-aged populations (70-79, �79) had high prevalence 

of CRC, prostate and breast cancer screenings even though there is 

insufficient evidence for the benefits and harms of screenings in the 

older-aged group. Conclusions: The disparities in age, race/ethnicity, health 

insurance, education, employment, and income for the accession to cancer 

screening of the US population have decreased since 2004. The trajectory 

of increasing rates of CRC and breast cancer screenings should be 

maintained. To reverse the trend, the causes of the decreased rate of 

cervical cancer screening and the high rates of screenings in older-aged 

populations should, however, be further explored. 

Proportion of cancer screenings in year 2004 and 2010 (weighted %). 

Screenings 2004 2010 Absolute difference P value 

CRC 

FOBT 

17.52 18.25 

�0.73 0.001 

Sigmoidoscope/colonoscope 49.66 59.90 �10.24 0.000 

Total 

49.74 65.62 �15.88 0.000 

Prostate cancer 

DRE 

64.35 59.89 

-4.46 0.000 

PSA 

65.87 66.71 

�0.84 0.080 

Total 

77.40 76.24 

-1.16 0.008 

Breast cancer 

CBE 

63.26 82.99 �19.73 0.000 

Mammogram 

74.06 74.88 

�0.82 0.004 

Total 

74.06 87.94 �13.88 0.000 

Cervical cancer 

Pap 76.06 70.83 -5.23 0.000 


101s 


First report on screening an asymptomatic population for cancer: The yield 

of an integrated cancer prevention center. Presenting Author: Tal Sella, 

Sheba Medical Center, Ramat Gan, Israel 

Background: Cancer is a leading cause of mortality worldwide. Screening is 

a key strategy for reducing cancer morbidity and mortality. We aimed to 

evaluate the utility of cancer screening in an asymptomatic population at 

an integrated cancer prevention center. Methods: One-thousand consecutive 

asymptomatic, apparently healthy adults, aged 20-80 years, were 

screened for early detection of 11 common cancers by routine screening 

tests. Results: Malignant and benign lesions were found in 2.4% and 7.1% 

of the screenees, respectively. The most common malignant lesions were in 

the gastrointestinal tract and breast followed by gynecological and skin. 

The compliance rate for the different screening procedures was considerably 

higher than the general Israeli population – 78% compared to 60% for 

mammography (p�0.001) and 39% compared to 16% for colonoscopy 

(p�0.001). Advanced age, family history and certain lifestyle parameters 

were associated with increased risk for cancer. Moreover, polymorphisms in 

the APC and CD24 genes indicated high cancer risk. When two of the 

polymorphisms existed in an individual, the risk for a neoplastic lesion was 

extremely high (OR 2.3 [95% CI 0.94-5.9]). Conclusions: A significant 

number of neoplastic lesions were diagnosed at an early stage. Polymorphisms 

in the APC and CD24 genes may identify individuals at an 

increased risk for cancer. Cancer may be diagnosed at an early stage using 

the screening facilities of a multidisciplinary outpatient clinic. 


Sun exposure profile in the French population: Results of the EDIFICE 

melanoma survey. Presenting Author: Bruno Sassolas, CHRU Brest, Brest, 

France 

Background: The main environmental risk factor for melanoma is related to 

UV-exposure. Our objective was to evaluate in a survey the profile of sun 

exposition in the French population as well as the level of knowledge about 

UV risk and UV protection. Methods: “Edifice Melanoma” a nationwide 

observational survey was conducted in France via phone interviews among a 

representative sample of 1502 subjects aged � 18, using the quota 

method. The survey took place shortly after the summer (September 28th to 

October 20th , 2011). Results: From the total population of 1502 subjects, 

330 (22%) denied any sun exposition. Among those declaring being 

exposed to the sun (1172), 62% affirmed using a photoprotection method 

(clothes, sun protective cream). The opportunities for sun exposure arose 

during holidays (85%), sport (79%) or professional activities (23%), with 

an annual average exposure of 113 days. 902 subjects (77%) declared 

avoiding sun exposure between 12 and 4 PM. The main sociodemographic 

characteristics of subjects exposed to the sun, compared to non-exposed 

ones are as followed (p�0,05): men, aged �40, with no children or with 

children aged �15, from high social and occupational group, with at least a 

2-years university degree. The analysis of sociodemographic characteristics 

of subjects declaring to use sun protective measures are (p�0,05): women 

from high social and occupational group, with at least a 2-years university 

degree, with high income levels. We explored additional risk behavior in the 

population studied. Subjects who declared having sun exposure were more 

likely (p�0,05) to be : smokers, alcohol users and/or alcoholic, tanning bed 

users before the age of 30, and have a high number of nevi (�50). On the 

other hand, prior history of cancer was associated with a non-exposure 

behavior. Conclusions: These data provide important new information about 

sun behavior in the French population and might give important clues in 

the field of public health and education to increase the effectiveness of 

melanoma primary prevention campaigns. A better knowledge of the target 

to improve would provide better results for public health benefit. 




Cancer screening: Source of information and level of trust. Presenting 

Author: Jean F. Morere, Oncology Department, Hôpital Avicenne, Bobigny, 

France 

Background: Providing public information is critical for cancer control. 

EDIFICE surveys were conducted to provide a better understanding of the 

participation of the French population in cancer screening programs 

(colorectal, breast) or individual cancer screening (prostate). To evaluate 

sources of information in the general population and their level of trust, 

specific questions were addressed in the EDIFICE 3 survey. Methods: This 

third nationwide observational study, EDIFICE 3, was conducted by phone 

interviews among a representative sample of 1603 subjects aged between 

40 and 75 years old, using the quota method. Questions on the source of 

information were: Concerning cancer screening, what are all your means of 

information? What level of trust (quoted from 1 to 10) do you have on the 

following media of information; your own general practitioner, physicians in 

general, patient associations, national health insurance system, health 

authorities, your close circle, radio and television, lay press, internet. 

Results: In the overall population, the most frequently quoted means of 

information for cancer screening were: radio and television (61%), general 

practitioners (52%), lay press (33%), institutional letters (19%) and 

internet (18%). People under 50 years old named significantly more often 

radio and television (66% vs 58%) and internet (24% vs 15%), while older 

people above 50 years old (target population for screening programs) more 

frequently named institutional letters (26% vs 7%). In a trust scale from 0 

to 10, the best level of trust was achieved by general practitioners (8.2), 

patient associations (6.8), national health insurance system (6.6) and 

health authorities (6.2). In contrast, radio and television (5.7), lay press 

(5.2) and internet (4.6) were mistrusted. Overall, women and younger 

subjects were more trustful. Conclusions: Radio and television are the most 

frequently quoted source of information but paradoxically they are not 

highly trusted. The general practitioner appears to be the best option 

(trusted and used) for providing cancer screening information. As institutional 

letters were frequently quoted and highly trusted, they might be 

useful for informing the population even before the age of recommended 

screening. 


Patient perceptions of stool-based DNA testing across racial groups. 

Presenting Author: Lily Huang, Case Western Reserve University, Cleveland, 

OH 

Background: Despite the widespread acceptance of colonoscopy as the gold 

standard for Colorectal Cancer (CRC) screening, compliance rates with 

recommended CRC screening lag far behind screening for breast and 

cervical cancers. Patients often delay or forgo screening colonoscopy due to 

associated discomfort, inconvenience, anxiety, and high cost. In addition, 

recent data have casted doubt on its effectiveness, especially in detecting 

right-sided colon neoplasia. Stool-based DNA (sDNA) testing is an emerging 

CRC screening tool that is convenient, noninvasive, and effective in 

detecting both right and left sided colon cancer. The goal of this study was 

to evaluate patient attitudes towards sDNA testing, identify preferences in 

CRC screening tools, and assess racial differences in these attitudes and 

preferences. Methods: In a colonoscopy-based case-control study, 100 

patients of average CRC risk were asked to complete (1) sDNA testing 

(LabCorp ColoSure test), (2) screening colonoscopy, and (3) a patient 

satisfaction survey. Results: Eighty patients completed the study, including 

55 (69%) White, 22 (27%) African American, and 3 (4%) Others. Overall, 

patients rated sDNA testing favorably in all preparation and test related 

features, except for perceived accuracy. Patients reporting a preferred 

screening method favored sDNA testing (78%) to FOBT (12%) or colonoscopy 

(10%), and 83% of all patients reported that they are likely to repeat 

sDNA testing. Non-Caucasians rated sDNA testing less favorably than 

Caucasians – reporting more discomfort (ANOVA, p�0.004), more anxiety 

(ANOVA, p�0.001), and less suitability (Chi-Squared, p�0.0035). Of 

those patients reporting a preferred screening test, 82% of Caucasians and 

64% of non-Caucasians selected sDNA testing. Conclusions: Although 

sDNA testing was ranked less favorably by non-Caucasians, it was well 

received overall as the preferred CRC screening test, as compared to FOBT 

and colonoscopy. The differences between racial groups may reflect the 

generally lower uptake of CRC screening among non-Caucasians, regardless 

of the test. In conclusion, sDNA testing may be an effective means to 

increase CRC screening in African Americans, hence preventing CRC and 

closing the racial disparity gap. 


Cancer screening in France: 3rd edition of the EDIFICE survey. Presenting 

Author: Jérôme Viguier, CHRU Trousseau, Tours, France 

Background: The EDIFICE survey program started in 2005 and was aimed at 

providing a better understanding of the participation of the French 

population in cancer screening programs and assess the evolution over 

time. The EDIFICE 3 survey was conducted in 2011, following EDIFICE 1 

(2005) and EDIFICE 2 (2008), and focused on colorectal, breast and 

prostate cancer. Methods: This third nationwide observational study, 

EDIFICE 3, was conducted by phone interviews among a representative 

sample of 1603 subjects aged between 40 and 75 years, using the quota 

method. The analysis focused on the target population of the national 

screening programs for breast and colorectal cancer (50-74 years). The 

same population was analysed for prostate cancer screening behaviours. 

Results: For breast cancer, the rate of women attending at least one 

screening test was 93%/94%/95% in 2005/2008/2011 respectively. A 

mammography had been performed as recommended within the last two 

years for 75%/83%/83% among them. We observed an increase in timing 

compliance between 2005 and 2011, significant for women aged 65-74. 

For colorectal cancer, the rate of subjects attending at least one screening 

test was 25%/38%/59%. A fecal test or colonoscopy had been performed 

according to the recommended timing for NA/30%/51% among them. 

Colorectal cancer screening has increased significantly in all age groups, 

especially between 65 and 69 years, and for both genders. For prostate 

cancer, the rate of men having performed at least one screening test (PSA 

and/or rectal examination) was 36%/49%/50%.This rate have significantly 

decreased in men aged 50-59 between 2008 and 2011(44% vs 37%, 

p�0.05). Conclusions: For National Programs, the attendance rate remains 

high for breast cancer screening and is improving for colorectal cancer 

screening. However, the European guideline objective rate of participation 

for colorectal cancer screening has not yet been reached. Despite the 

absence of recommendations, prostate cancer screening is frequently 

carried out and stable overall. 


On-line breath analysis of volatile organic compounds as a method for 

colorectal cancer detection. Presenting Author: Francisco Zambrana Tevar, 

Department of Medical Oncology, Hospital Infanta Sofía, Madrid, Spain 

Background: Analysis of exhaled volatile organic compounds (VOCs) in 

breath is an emerging approach for cancer diagnosis, but little is known 

about its potential use as a biomarker for colorectal cancer (CRC). We 

investigated whether a combination of VOCs could distinct CRC patients 

from healthy volunteers. Methods: In a pilot study, we prospectively 

analyzed breath exhalations of 38 CRC patient and 43 healthy controls all 

scheduled for colonoscopy, older than 50 in the average-risk category. The 

samples were ionized and analyzed using a Secondary ElectroSpray 

Ionization (SESI) coupled with a Time-of-Flight Mass Spectrometer (SESI- 

MS). After a minimum of 2 hours fasting, volunteers deeply exhaled into the 

system. Each test requires three soft exhalations and takes less than ten 

minutes. No breath condensate or collection are required and VOCs masses 

are detected in real time, also allowing for a spirometric profile to be 

analyzed along with the VOCs. A new sampling system precludes ambient 

air from entering the system, so background contamination is reduced by 

an overall factor of ten. Potential confounding variables from the patient or 

the environment that could interfere with results were analyzed. Results: 

255 VOCs, with masses ranging from 30 to 431 Dalton have been identified 

in the exhaled breath. Using a classification technique based on the ROC 

curve for each VOC, a set of 9 biomarkers discriminating the presence of 

CRC from healthy volunteers was obtained, showing an average recognition 

rate of 81.94%, a sensitivity of 87.04% and specificity of 76.85%. 

Conclusions: A combination of cualitative and cuantitative analysis of VOCs 

in the exhaled breath could be a powerful diagnostic tool for average-risk 

CRC population. These results should be taken with precaution, as many 

endogenous or exogenous contaminants could interfere as confounding 

variables. On-line analysis with SESI-MS is less time-consuming and 

doesn’t need sample preparation. We are recruiting in a new pilot study 

including breath cleaning procedures and spirometric analysis incorporated 

into the postprocessing algorithms, to better control for confounding 

variables. 



The effect of family history on adherence to breast cancer screening 

guidelines. Presenting Author: Lauren Marie Hibler, Yale University, New 

Haven, CT 

Background: A family history of breast cancer increases the risk of 

developing this disease. We sought to determine the effect of a family 

history of a first degree relative with breast cancer (FDFHx) on adherence to 

mammography (MMG) and clinical breast examination (CBE) guidelines. 

Methods: The National Health Interview Survey (NHIS), conducted annually 

by the Centers for Disease Control, is designed to be representative of the 

US population. The 2010 NHIS data was used to evaluate the effect of 

FDFHx on the likelihood that women aged � 30 had MMG and/or CBE 

within the past year. Results: Of the 12,320 women aged � 30, 1276 

(10.7%) had a FDFHx; 1263 (99.0%) of female breast cancer and 13 

(1.0%) of male breast cancer. Overall, 4573 (38.4%) of women reported 

having had MMG within the past year; 5377 (46.3%) had CBE within the 

past year. FDFHx was associated with use of MMG and CBE within the past 

year (58.0% vs. 36.0%, p�0.001, and 57.5% vs. 45.0%, p�0.001, 

respectively). Women with a FDFHx of male breast cancer were no more 

likely to have MMG (72.5% vs. 57.9%, p�0.313) nor CBE (66.8% vs. 

57.4%, p�0.518) within the past year than those with a FDFHx of female 

breast cancer. On multivariate analysis controlling for age, race, personal 

history of breast cancer (PHx), income, insurance, education and region, 

FDFHx was associated with a higher likelihood of having MMG (OR�1.75; 

95% CI: 1.48-2.06, p�0.001) and CBE (OR�1.48; 95% CI: 1.26-1.74, 

p�0.001) within the past year. Region was not associated with adherence 

to either MMG or CBE screening guidelines. Conclusions: FDFHx, along with 

age, race, PHx, income, insurance, and education, is an independent 

predictor of adherence to screening MMG and CBE guidelines. Still, only 

58% of women with a FDFHx had MMG and CBE in the past year. Further 

efforts are warranted to improve screening in this population at increased 

risk. 

Multivariate analysis. 

Factor 

MMG 

p value 

CBE 

p value 

FHx �0.001 �0.001 

Age �0.001 �0.001 

Race 0.018 �0.001 

PHx �0.001 �0.001 

Income �0.001 �0.001 

Insurance �0.001 �0.001 

Education 0.005 �0.001 

Region 0.700 0.196 


Esophageal cancer incidence gender disparity. Presenting Author: Luckson Noe 

Mathieu, Sidney Kimmel Comphrehensive Cancer Center at Johns Hopkins 

Hospital, Baltimore, MD 

Background: Over the past 30 years, esophageal cancer incidence has been 

increasing more rapidly than any other solid neoplasm in the Western world. 

Globally, there is a large male predominance in both esophageal squamous and 

adenocarcinoma. The reasons for this gender difference and the possible role of 

estrogen are unclear. The objective of this study is to determine if estrogen 

exposure is consistent with the male predominance observed in esophageal 

cancer incidence. Methods: A database assessment of esophageal cancer 

incidence rates (age-adjusted) from 1975 to 2008 was conducted in the 

National SEER 9 Database and the Maryland Cancer Registry. Rates by gender 

and age were calculated. Gender-specific incidence rate ratios were compared 

across age groups. Annual percentage change (APC) was compared for each 

gender-age group. Results: In both national and state, male and female, adeno 

and squamous cell histologies, incidence rates increase with patient age. SEER 

data trends revealed the 50-64 aged female cohort as the only gender-age cohort 

APC decreasing between 1975-2008. Furthermore, a significant increase in 

incidence for females is observed in the 65� age groups; whereas among males, 

the rates are rising in all age groups. Conclusions: Using age as a proxy for 

estrogen exposure, our findings suggest a hormonal component in the declining 

male: female esophageal cancer incidence rate ratios with increasing age and 

confirm gender differences in incidence long observed in esophageal cancer. 

Histological features may be predictive of a lower rate ratio. (Bodelon et al. 

2011) Estrogen exposure may play a protective role in esophageal cancer which 

dissipates with time after age 60-69. Our data suggest possible future roles of 

estrogen as a chemopreventive agent in esophageal cancer (Barone et al. 2011). 

Esophageal cancer annual percentage change, 1975-2008, SEER 9. 

Age 50-64 Age 65-74 Age 75� 

Males �1.2 �1.4 �1.9 

Females -1.5 �0.3 �0.7 

The M: F incidence ratio decreases with age in the nation (SEER) and in Maryland. 

Male to female incidence ratio, SEER, 1975-2008 and MD Registry 1992- 

2008. 

Age 40-49 Age 50-59 Age 60-69 Age 70-79 Age 80-89 

SEER 9.0 7.6 7.9 5.7 4.3 

MD 6.0 6.0 5.4 4.2 3.3 


103s 


ABO blood group and the risk of breast cancer: Multicenter, case-control, 

observational study. Presenting Author: Yuksel Urun, Department of 

Medical Oncology, Ankara University School of Medicine, Ankara, Turkey 

Background: The role of genetic factors in the development of cancer is 

widely accepted. ABO blood type is an inherited characteristic and previous 

studies have observed an association between ABO blood group and risk of 

certain malignancies, including pancreatic and gastric cancer. The data on 

the role of ABO blood group and Rh factor in breast cancer is inconclusive. 

Methods: All patients who had breast cancer (BC) and treated between 

2000-2010 at the Departments of Medical Oncology of both Ankara and 

Hacettepe Universities (Ankara, Turkey) with defined ABO blood type and 

Rh factor were included in our retrospective reviews of tumor registry 

records. A group of volunteer healthy women donors of Turkish Red 

Crescent between 2004-2011 were identified as a control group, without 

any matching factors. The relationship of ABO blood types and Rh factor 

with various prognostic factors such as age at diagnosis, menopausal 

status, family history of breast cancer, and ER/PR/HER2 status were 

evaluated from 1740 BC patients. We compared the distributions of ABO 

blood types, Rh factors among 1740 patients and 204,553 healthy 

controls. Among BC patients, differences between each of aforementioned 

ABO blood groups and Rh factors with respect to various prognostic factors 

were explored, respectively. Results: Overall distributions of ABO blood 

groups as well as Rh factor were comparable between patients (44% A, 8% 

AB, 16% B, 32% O, 88% Rh�) and controls (41% A, 8% AB, 16% B, 35% 

O, 87% Rh�). However, there were statistically significant differences 

between patients and controls with respect to A vs. nonA (p�0.019) and 

marginal significance (p�0.051) for O vs. nonO. Among patients, there 

were statistically significant differences between A and nonA with respect 

to HER2 (p�0.0421), M stage (p�0.0447), T stage (p�0.0020). Only T 

stage (p�0.0337) were significantly different between O vs nonO. Grade 

(p�0.0227) and M stage (p�0.0107) were significantly different between 

Rh factors. Conclusions: In our study sample, ABO blood type was 

statistically significantly associated with breast cancer. Additional studies 

are necessary to determine the mechanisms by which ABO blood type may 

influence the risk of breast cancer. 


Study KBP-2010-CPHG: Characteristics and management of 7,051 new 

cases of lung cancer managed in French general hospitals in 2010. 

Presenting Author: Chrystele Locher, Saint-Faron Hospital, Meaux, France 

Background: An initial epidemiologic study was performed in 2000 by the 

French College of General Hospital Respiratory Physicians (Study KBP- 

2000-CPHG). Over the last 10 years, lung cancer management changed: 

new drugs such as targeted therapies appeared; new diagnostic techniques 

such as exploration for genetic mutations in the tumour have been 

developed; a new TNM classification has been drawn up. The aims of this 

study were to describe patient characteristics, first-line management, 1, 4 

and 5-year survival rates and to compare the results with those of Study 

KBP-2000-CPHG. Methods: A prospective multi-centre study included all 

patients �18 years presenting with a new case of primary lung cancer, 

histologically or cytologically diagnosed between 1 January and 31 December 

2010 and managed by one of the participating centers. A standardised 

form was completed for each patient. A steering committee checked the 

exhaustivity of data’s collection. Results: 7,610 patients from 119 general 

hospitals were included between 1 January and 31 December 2010. The 

main patient characteristics were: mean age 65.5 years (�/-11.3); 24.3% 

female; 10.9% non-smokers, 39.9% ex-smokers, 49.2% current smokers; 

68.9% performance status 0 and 1; 9.1% of patients had lost �10 kg 

within the previous 3 months. The main tumour characteristics were: 

13.7% small-cell lung cancer; 46.2% adenocarcinoma, 26.8% squamouscell 

carcinoma; EGFR mutation, explored in 30.5% of cases, were found in 

10.5% of cases; 16.4% stage IA to IIB, 13.4% stage IIIA, 10.2% stage 

IIIB and 60.0% stage IV. First-line treatments were: curative surgery, 

16.6%; chemotherapy, 63.4%; radiotherapy alone, 17.8%; combined 

radio-chemotherapy, 8.8%; and supportive care, 11.1%. Targeted therapy 

was used in 6.6% of patients treated by chemotherapy. Conclusions: In 10 

years, characteristics of lung cancer patients changed with an significantly 

increase of women, non-smokers, adenocarcinoma histology and stage IV at 

diagnosis. 




Hepatitis B reactivation risk in patients with solid tumors receiving 

single-agent capecitabine versus doxorubicin-based chemotherapy. Presenting 

Author: Winnie Hui Yee Ling, National University Cancer Institute, 

Singapore 

Background: Reactivation of hepatitis B virus (HBV) in cancer patients on 

chemotherapy is a challenge especially in Asia where HBV infection is 

endemic. Risk of HBV reactivation differs according to cancer type, 

chemotherapy regimen, and concomitant use of steroids. The United 

States Centre for Disease Control and Prevention recommends universal 

screening for chronic HBV infection for all patients before chemotherapy 

although screening for low-risk chemotherapy regimens may not be cost 

effective. Methods: We sought to assess and compare HBV reactivation risk 

and effectiveness of prophylactic anti-viral therapy in preventing HBV 

reactivation in patients receiving a ‘high-risk’ (doxorubicin-based) chemotherapy 

regimen for which prophylactic anti-viral therapy for hepatitis B 

carriers is generally accepted versus a ‘low-risk’ (single agent capecitabine) 

chemotherapy regimen for solid tumours at a tertiary cancer centre. The 

electronic medical records of eligible patients were reviewed between 

January 2007 and December 2010. Results: A total of 708 patients were 

identified, including 434 and 274 who received doxorubicin-based chemotherapy 

and single agent capecitabine respectively. HBV screening rate was 

42.6% (51% for doxorubicin-based chemotherapy, 30% for single agent 

capecitabine, p�0.0001). 15/302 (5%) screened patients were found to 

be hepatitis B carriers (6 on doxorubicin, 9 on capecitabine). Overall, 

3/708 patients (0.4%) developed HBV reactivation (all from the unscreened 

doxorubicin group, 3/214 (1.4%) compared to 0/192 (0%) 

unscreened patients in the capecitabine group, p�0.0001). All 15 

identified hepatitis B carriers received prophylactic anti-viral therapy (14 

received lamuvidine, 1 had entacavir) and none had HBV reactivation. 

Conclusions: Not all chemotherapy regimens are associated with risk of HBV 

reactivation. Routine hepatitis B screening and prophylaxis for low-risk 

chemotherapy regimens such as single agent capecitabine may add 

morbidity and may not be cost effective. 


Assessing a prognostic model for predicting VTE occurrence in cancer 

patients. Presenting Author: Deesha Sarma, Princeton University, Princeton, 

NJ 

Background: Venous thromboembolism (VTE) poses a significant health risk 

to cancer patients and is one of the leading causes of death among this 

population. The most effective way to prevent VTE and reduce its 

prominence as a public health burden is by identifying high-risk patients 

and administering prophylactic measures. In 2008, Khorana et al. developed 

a model that classified patients by risk based on clinical factors. 

Methods: We conducted a retrospective study to test this model’s efficacy, 

on 150 patients with cancer receiving chemotherapy at an outpatient 

oncology clinic between January 1 and August 1, 2011. We aggregated 

data and assigned points based on the five factors in the Khorana model: 

site of cancer with 2 points for very high-risk site and 1 point for high-risk 

site, 1 point each for leukocyte counts more than 11 x 109 /L, platelet 

counts greater than 350 X 109 /L, hemoglobin levels less than 100 g/L 

and/or the use of erythropoiesis-stimulating agents, and BMI greater than 

35 kg/m2 (Khorana et al., Blood 2008). Based on this scoring system, 

patients with 0 points were grouped into the low-risk category, those with 

1-2 points were considered intermediate-risk, and those with 3-4 points 

were classified as high-risk. Results: As shown in the table, VTE incidence 

for the low-risk group was 1.9%, intermediate-risk group was 3.9%, and 

high-risk group was 9.1%. Conclusions: High-risk patients were about 4.5 

times more likely to develop a VTE than low risk patients. These results 

provide valuable insight in determining which patients might benefit from 

prophylaxis and in motivating the design of prospective clinical trials that 

assess the VTE predictive model in various ambulatory cancer settings. 

Risk level 

Number of 

patients 


patients with VTE 

VTE incidence 

(%) 

Low risk (score�0) 52 1 1.9 

Intermediate risk (score�1-2) 76 3 3.9 

High risk (score�3�) 22 2 9.1 

Total: 150 6 4 


Predictors of pediatric and adult fibrosarcoma survival: Analyses of the 

Surveillance, Epidemiology, and End Results (SEER) program, 1973- 

2008. Presenting Author: Simona Ognjanovic, Biothera, Eagan, MN 

Background: Fibrosarcoma (FS) is the second most common group of soft 

tissue sarcomas in children, however, most FS are diagnosed in adults. The 

goal of this study was to compare clinical features and outcomes of children 

and adults diagnosed with FS and identify predictors of survival. Methods: 

We have analyzed data from 569 children (� 19 years) and 5,508 adults 

(�19 years) diagnosed between 1973 and 2008 with FS (ICCC category 

IXb) available in the SEER database. Survival estimates were determined 

using survival time with end point death from any cause. Results: Comparison 

of two diagnostic periods, 1973-1989 vs. 1990-2008 showed that 

5-year survival rates have improved in adults (48.4% vs 60.9%, P�0.0001), 

but not in children (72.3% vs. 73.9%, P�0.16). Children with FS had 

significantly better outcome compared to adults (5-year survival rates were 

73.4% � 2%, and 56.7% � 0.7%, respectively, P�0.0001). Sites with 

survival rates higher than the median 5-year survival were grouped as 

favorable (extremities, head and neck, and genitourinary site); trunk, 

abdomen, and other sites were grouped as unfavorable. Cox proportional 

hazard regression model identified diagnosis in childhood, fibromyxosarcoma 

histologic subtype (ICD-O3 code 8811/3), favorable site, and 

localized stage as positive predictors of survival. Compared to fibromyxosarcoma, 

other histologic types had hazard ratio (HR) of 11.6 (95% CI� 

1.6-83.2, P�0.01) in children, and HR of 1.8 (95%CI�1.5-2.1, 

P�0.0001) in adults. Diagnosis at unfavorable site was associated with 

HR�1.9 (95%CI�1.4-2.6) in children and HR�1.4 (95%CI�1.3-1.5) in 

adults. Compared to localized, distant disease had HR�4.2 in children and 

HR�5.1 in adults, both highly significant (P�0.0001). Conclusions: 

Adults diagnosed with FS had worse survival than children. Predictors of 

good outcome, including histiologic subtype, primary site, and stage, were 

valid in both children and adults. 


Incidence of bone metastases among children with cancer in Denmark. Presenting 

Author: Rohini Khorana Hernandez, Center for Observational Research, 

Amgen Inc, Thousand Oaks, CA 

Background: There are no published population-based studies on the incidence 

of bone metastases (BM) among children with cancer. The current literature is 

limited to small case series or case reports. Methods: We used the Danish Cancer 

Registry (DCR) to identify children �18 years old diagnosed with cancer 

between 1/1/1994 and 12/31/2009. Patients were followed from cancer 

diagnosis to BM, emigration, death, or end of study (1/1/2011). DCR data were 

linked to (1) Danish Civil Registration System to obtain information on death and 

emigration, and (2) Danish National Registry of Patients to identify ICD-10 

codes for BM. We estimated incidence rates (IRs) of BM and mortality rates 

overall and stratified by gender, calendar year, age, and primary tumor type. 

Results: During the study period, 2,652 children were identified with a first-time 

diagnosis of cancer, of whom 35 (1.3%) developed BM (mean follow-up of 7.0 

years). The IR of BM was 1.9 per 1,000 person-years (95% CI: 1.4 – 2.6); the 

highest rates occurred in children aged 12 – 17 years and among those with 

osteosarcoma (Table). Twenty-one (60%) children with BM died during followup, 

yielding a mortality rate of 192 per 1,000 person-years (95% CI: 125 – 

295). The median time from cancer diagnosis to BM was 221 days and from BM 

to death was 283 days. Conclusions: This study represents the first comprehensive 

examination of BM in children and reveals that BM is a rare event, with 

median survival of less than one year from diagnosis. 

IR of BM among children 0-17 years diagnosed with cancer in Denmark, 

1994-2009. 

Characteristic N 

N 

with BM 

IR of BM 

per 1,000 person-years 

(95% CI) 

Overall 

Gender 

Female 

Male 

Age at cancer diagnosis 

0–27days 

28 days – 23 months 

2 – 11 years 

12 – 17 years 

Calendar year of cancer diagnosis 

1994 – 1997 

1998 – 2001 

2002 – 2005 

2006 – 2009 

Tumor type 

Leukemia 

Lymphoma 

Brain / other CNS tumors 

Neuroblastoma 

Nephroblastoma 

Osteosarcoma 

Other tumors 

NA � Not Applicable. 

2,652 

1,163 

1,489 

38 

392 

1,314 

908 

642 

649 

691 

670 

827 

156 

378 

20 

115 

154 

1,002 

35 

14 

21 

0 

1 

18 

16 

3 

13 

8 

11 

1 

0 

1 

1 

1 

12 

19 

1.9 (1.4 - 2.6) 

1.7 (1.0 - 2.9) 

2.0 (1.3 - 3.1) 

NA 

0.37 (0.05 - 2.6) 

1.9 (1.2 - 3.1) 

2.6 (1.6 - 4.2) 

0.43 (0.14 - 1.3) 

2.3 (1.3 - 4.0) 

2.0 (1.0 - 4.0) 

6.0 (3.3 - 11) 

0.17 (0.02 - 1.2) 

NA 

0.45 (0.06 - 3.2) 

8.7 (1.2 - 62) 

1.0 (0.15 - 7.4) 

14 (8.0 - 25) 

2.4 (1.5 - 3.8) 



Compliance of recommendations with French clinical practice in the management 

of thromboembolism in patients with cancer: The CARMEN study. 

Presenting Author: Marie-Antoinette Sevestre, Service de Medecine Vasculaire, 

Amiens, France 

Background: Long-term treatment with low-molecular-weight heparin (LMWH) is 

recommended for treatment of venous thromboembolism (VTE) in cancer 

patients. Few data are available on compliance in this population. Our study 

measured whether the management of VTE in patients with cancer was 

consistent with French recommendations. Methods: Compliance with recommendations 

(CR�) was analysed according to malignancy and VTE from a 500patient 

cross-sectional observational study run between May and October 2010. 

CR� was defined as the compliance to initial 10-day treatment followed by 

long-term LMWH for at least 3 months, avoiding LMWH in patients with renal 

insufficiency (SRI). All inpatients with a diagnosis of cancer and VTE of less than 

6 months were included in the study. Results: Of 500 patients included in 47 

centers, 242 (49%) were male, 81 (18%) had local (T�), 83 (18%) had 

loco-regional (N�) and 287 (64%) had metastatic malignancies. Malignancies 

were gastro-intestinal (25%), gynaecologic (23%), pulmonary (21%), haematological 

(14%), urologic (10%) or other (8%). Twelve patients had SRI. Overall, 

treatment was CR� in 289/500 patients (58% [95% CI 53%-62%]). Out of 12 

patients with SRI only 3 (25%) were treated long-term with vitamin K 

antagonists (VKA), as usually recommended. Tumour site influenced CR� 

(p�0.02). Treatment for haematological malignancy was poorly compliant with 

recommendations (32%) while patients with lung malignancy had the best 

compliance (68%). TNM stage and VTE location had no influence on treatment 

compliance. Conclusions: In French practice, treatment of cancer-related VTE is 

CR� in 58% of cases. TNM stage and VTE location do not influence compliance 

which remains insufficient, especially in patients with haematological malignancy. 

Characteristics N (%) CR� (%)* 

Primary tumor Gastrointestinal 92 (18) 56 

Gynaecologic 52 (10) 65 

Haematological 67 (13) 37 

Pancreas 32 (6) 50 

Lung 106 (21) 68 

Breast 63 (13) 57 

Urologic 48 (10) 65 

Other 40 (8) 72 

TNM stage T� 81 (18) 63 

N� 83 (18) 59 

M� 287 (64) 61 

VTE Pulmonary embolism 149 (30) 60 

Deep vein thrombosis 315 (63) 61 

Superficial thrombosis 16 (3) 25 

Other 18 (4) NA 

*Rate of compliance with recommendations. 


Age, race/ethnicity, and the ER/PR/HER2 subtypes in breast cancer. 

Presenting Author: Carol Parise, Sutter Institute for Medical Research, 

Sacramento, CA 

Background: The association of age and ER/PR/HER2 subtype in African- 

American (AA) and Hispanic women with breast cancer has been reported. 

This study examines the association of age and subtype among 12 

self-reported race/ethnicity categories. Methods: Using the California Cancer 

Registry 2000-2010, we examined 136,175 cases of first primary 

female invasive breast cancer. Race/ethnicity was stratified into 12 

categories. The distribution of age and race/ethnicity among the 8 

ER/PR/HER2 subtypes was examined. Age was stratified into �40, 40-69, 

and 70� years. For each age strata, odds ratios (OR) and 95% confidence 

intervals (CI) were computed to assess the association of race/ethnicity with 

ER-/PR-/HER2�, ER-/PR-/HER2- (TN), and ER�/PR�/HER2� (TP) when 

compared with the ER�/PR�/HER2- subtype. Results: The % of each race 

was: White 66.8; AA 6.0; Hispanic 15.9; Pacific Islander (PI) 0.3; 

Southeast Asian (SEA) 2.5; Indian Continent (IC) 0.7; American Indian; 

0.2; Chinese 2.5; Japanese 1.2; Filipino 3.1; Korean 0.7; Hispanic/nonwhite 

0.3. All AA women had increased ORs of the ER-/PR-/HER2�, TN 

and TP. Hispanic women mimicked the AA population except for young 

women with TP. Chinese (OR�0.53; 95%CI�0.37-0.76) Japanese 

(OR�0.51; 95%CI�0.28-0.96), and Filipino (OR�0.45; 95%CI�0.31- 

0.67) women �40 were less likely to have TN subtype. For women 40-69, 

SEA, Chinese, Filipino, and Korean women had increased ORs for TP, and 

ER-/PR-/HER2�. The Japanese had increased ORs for the TP (OR�1.23; 

95%CI�1.00-1.49) but decreased odds for the TN (OR�0.72; 

95%CI�0.57-0.90). IC women had increased odds for the TN (OR�1.38; 

95%CI�1.10-1.72). Korean women 70� were more likely to have the TP 

and ER-/PR-/HER2�. SEA had increased ORs for ER-/PR-/HER2� and TN, 

IC only had increased ORs for TN (OR�2.03; 95%CI�1.26-3.27). 

Chinese and Filipino women only had increased ORs for the ER-/PR-/ 

HER2�. Conclusions: AA and Hispanic women of all ages are at increased 

risk of the TN, and ER-/PR-/HER2� subtypes. AA women of all ages and 

Hispanic women over age 40 are at increased risk of the TP subtype. The 

diversity of Asian women with regard to breast cancer necessitates 

accurately defining this population. 


105s 


Castration resistance and high-risk disease among nonmetastatic (M0) 

prostate cancer (PC) patients on androgen deprivation therapy (ADT). 

Presenting Author: Melissa Pirolli, SDI Health, Plymouth Meeting, PA 

Background: Prostate-specific antigen (PSA) is a well-known PC biomarker. 

In the M0 setting, rising PSAs despite ADT is an indication of the 

development of castration-resistant prostate cancer (CRPC). In this disease 

state, men are at risk for developing bone metastasis (BM), which is 

associated with significant morbidity and may negatively affect survival. 

Using real-world data, we explored PSA-based criteria to identify patients 

who develop CRPC while on ADT and the subsets that may be at increased 

risk of BM. Methods: We used the Oncology Services Comprehensive 

Electronic Records (OSCER) database, which includes electronic medical 

record (EMR) data on cancer patients from 328 urology and oncology 

clinics in the US. Eligible patients were adult men with M0 PC with �1 PSA 

recorded between 3/1/2010 and 2/28/2011 and currently receiving ADT 

(gonadotropin-releasing hormone agonists or bilateral orchiectomy) for �6 

months (mos). We defined CRPC as two sequential PSA rises while on ADT 

and high risk for BM as any PSA �8 ng/mL or PSA doubling time (DT) �10 

mos, as described by Smith MR et al, Lancet 2012. We explored subsets of 

CRPC patients who may be at even higher risk of BM using PSA thresholds 

(�8 ng/mL and �20 ng/mL) and DT (�4, 6, 8, and 10 mos). Results: Of 

1,818 men with M0 PC receiving ADT �6 mos, 36% (N�646) met the 

CRPC definition, of whom 80% (N�517) had PSA �8 ng/mL and/or PSA 

DT �10 mos (high risk). PSA DT alone explained 63% (44% / 70%) to 

93% (65% / 70%) of subgroup eligibility (Table), and emerged as a main 

driver in defining increased risk of BM for CRPC subsets. Conclusions: In 

this analysis of EMR data, over one-third of men with M0 PC on ADT met 

criteria for CRPC, and most CRPC patients (80%) may be considered at 

high risk for BM. Requiring �3 PSAs to define CRPC may be a limitation; 

however, because PSAs are closely monitored in patients on ADT, these 

definitions of CRPC and high risk may be useful in practice. These data 

suggest that PSA DT may be a more clinically meaningful measure of 

defining CRPC subsets than absolute PSA thresholds. 

CRPC subsets PSA >8 ng/mL PSA >20 ng/mL No PSA threshold (PSA < 8 ng/mL) 

DT



Impact of response shift on time to quality-of-life scores deterioration in 

patients with breast cancer. Presenting Author: Zeinab Hamidou, Biostatistics 

and Epidemiology Unit, Medical Information Department, Centre 

Georges-François Leclerc and EA4184, College of Medicine, Dijon, France 

Background: Time to quality of life (QoL) score deterioration (TD) is a 

method of longitudinal QoL data analysis that has been proposed for breast 

cancer (BC) patients (Hamidou et al Oncologist 2011). As for RECIST 

criteria, the optimal definitions dealing with reference should be explored. 

This study aims to study the impact of changes in internal standards (CIS) 

of response-shift (RS) and the influence of baseline QoL expectancies on 

TD. Methods: A prospective multicenter study including all women hospitalized 

for a primary BC was conducted. The EORTC-QLQ-C30 and BR-23 

questionnaires were used to assess the QoL at baseline, at the end of 1st hospitalization, and 3 and 6 months after. CIS was investigated by the 

then-test method. QoL expectancy was assessed at baseline using Likert 

scale. Deterioration was defined as a decrease in QoL scores reaching at 

least the mean difference identified as minimal clinically important 

difference (MCID) using Jaeschke’s transition question. Sensitivity analyses 

were done using the then-test score as reference score, and considering 

5 and 10 points as MCID. TD was estimated using Kaplan-Meier method. 

Cox regression analyses were used to identify factors influencing TD. 

Results: From February 2006 to February 2008, 381 women were included. 

For role functioning dimension, the median TD increased from 3.2 

months [95% CI: 3.1-3.36] to 4.76 months [3.3-6.2] when adjusting on 

CIS. For body image when adjusting on CIS, sentinel lymph node biopsy 

became significantly associated with longer TD (HR: 0.64[0.43-0.94]) as 

compared to axillary lymph node dissection, radiotherapy to a shorter TD 

(HR: 0.63[0.42-0.95] and the type of surgery had no effect on TD. For 

global health, cognitive and social functioning dimensions, patients expecting 

deterioration in their QoL had a significantly shorter TD. For fatigue and 

breast symptom scales, patients expecting no change had a significantly 

shorter TD, as compared to patients expecting an improvement. Sensitivity 

analyses using a MDCS of 5 or 10 confirmed these results. Conclusions: Our 

results suggest that it would be more accurate to take into account CIS 

component of RS as well as QoL expectancies to estimate TD of QoL scores 

in patient with BC. 


Outcomes of male breast cancer in the United States: A SEER database 

analysis from 1973 to 2008. Presenting Author: Akm Mosharraf Hossain, 

Ellis Fischel Cancer Center, Missouri University School of Medicine, 

Columbia, MO 

Background: Male breast cancer (MBC) is rare compared to female breast 

cancer (FBC). There has been no systemic study to examine the epidemiology 

of MBC in USA in the past decade. Methods: We examined 6,157 cases 

of MBC reported in SEER database from 1973-2008 (released 2011). We 

performed rate, frequency and survival sessions to examine age, sex, stage, 

grade, treatment modalities and survival using the SEER*Stat Software 

7.0.5. These variables were compared with that of 877,885 FBC cases 

reported in SEER 1973-2008. Results: The incidence rate was 1.3 (MBC) 

and 124 (FBC) per 100,000, respectively. Median age of diagnosis was 

higher in MBC compared to FBC (72 vs. 61 yrs. P�0.001). 18% of MBC 

were seen at age less than 60 years compared to 32% in FBC (p�0.001). 

FBC tend to be more hormone receptor positive (74% vs. 61%; p�0.001). 

There were 5,145 Caucasians (WH), 701 African Americans (AA), 258 

Hispanics and 42 Asian patients. Stage III and IV, Grade III and IV 

histologies were more common in MBC. Staging and Grading did not differ 

among the different ethnicities except for Grade IV histology in AA 19%, 

Asians 20% when compared to WH 13% (p�0.001). Treatment modalities 

included, surgery (MBC 78% vs. FBC 93%; p�0.001), chemotherapy 

(MBC 82% vs. FBC 43%; p�0.001) and radiation therapy (MBC 19% vs. 

36% FBC; p�0.001). Treatment modalities were similar among WH and 

AA. Survival was higher in FBC compared to MBC (table) but improved over 

time in MBC. AA and Asians had lower 1-5 year survival compared to WH. 

Conclusions: MBC presents at a later age, higher stage and grade, 

predominantly requiring chemotherapy with an overall poor survival compared 

to FBC. But 1-5 year survival improved over time in MBC. This can be 

explained by early diagnosis, better treatment and other factors. Further 

studies should be performed in this regard. 

Comparison of survival between male and female breast cancer patients 

reported in SEER database from 1973 to 2008. 

Variable Male (N�6,157) Female (N�877,885) p value 

1 year (%) 91.3 (91.6 – 93) 96.1 � 0.001 

2 years (%) 85.9 (84.9 – 86.9) 90.1 � 0.001 

3 years (%) 79.9 (78.7 – 81.1) 85.1 � 0.001 

4 years (%) 73.5 (72.2 – 74.8) 80.7 � 0.001 

5 years (%) 67.9 (66.6 – 69.3) 76.7 � 0.001 


An exploratory study to determine if BRCA1 and BRCA2 mutation carriers 

have higher risk of cardiac toxicity. Presenting Author: Roohi Ismail-Khan, 

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 

Background: Anthracycline related cardiac toxicity (CT) is a concern in 

treating women with breast cancer. The prevalence of heart failure (HF) 

affects 2% of the population, less so in women. Patients receiving 

anthracycline based therapy (ABT) have a dose-dependent risk of reduction 

in ejection fraction. Recent work by Dr. Verma suggests that BRCAdeficient 

mice manifest increased levels of cardiac failure. We sought to 

explore the risk for CT and evaluate the association between ABT and HF in 

female BRCA mutation carriers. Methods: An online survey was developed 

to collect information about breast cancer treatment (including HF) in 

BRCA mutation carriers through the national BRCA patient advocacy 

organization FORCE via their 2011 conference and their website as well as 

the Moffitt-based Inherited Cancer Registry (ICARE). The prevalence of CT 

and HF was calculated in both BRCA 1 and 2 breast cancer patients and 

compared to general population risks. Data from those that received ABT 

was compared to published HF rates from ABT. Results: Our sample 

included 227 BRCA1 carriers and 164 BRCA2 carriers in whom 6.4% 

reported cardiac toxicity (i.e., either HF and/or CT). This included similar 

proportions in BRCA1 vs BRCA2 carriers (i.e., 6.6% and 6.1%, respectively). 

These proportions are significantly higher than the published rate of 

2% (all p-values � 0.001). Specifically regarding ABT, 112 mutation 

carriers had doxorubicin (Adriamycin) for treatment of whom 8% reported 

HF, similar to the 11 who had Epirubicin (11 patients), of whom 9% 

reported HF. Conclusions: Our data suggests that BRCA mutation carriers 

may have an increased risk of CT compared to the general population. In 

particular, women with BRCA mutations treated with ABT also appear to 

have a higher risk of developing CT and/or HF. This exploratory study 

provides the basis upon which larger retrospective and prospective studies 

are currently being planned. The high percentage of CT observed in this 

study requires confirmation as they could inform recommendation for 

cardiac screening and review of the current standard for ABT use in this 

population. 


Evaluation of perioperative therapy for stage II and III rectal cancer in 

California, 1994-2009. Presenting Author: Myung Mi Cho, Loma Linda 

University School of Public Health, Department of Epidemiology and 

Biostatistics, Loma Linda, CA 

Background: Surgical treatment of stage II and III rectal cancer changed 

little during the past two decades, while ancillary therapies have undergone 

two evolutionary changes. We sought to evaluate changes in chemoradiation 

(chemoRT) practices for patients receiving radical operations for stage 

II and III rectal cancer in California, 1994-2009. Methods: We extracted 

age, sex, race/ethnicity (R/E), socioeconomic status (SES) (demographic 

variables) and chemoRT variables for stage II and III rectal cancer cases in 

California. We used unconditional logistic regression to compute independent 

odds ratios of receiving preoperative chemoRT (PreOP Tx) to postoperative 

chemoRT (PostOP Tx) during Early (1994-1999), Middle (2000- 

2003), and Late (2004-2009) time-periods using the late time-period as 

the referent group. Results: Logistic regression analyses assessing timeperiod 

and demographic variables reveal trends and odds ratios with 95% 

confidence intervals (OR; CI) for chemoRT variables. Our findings showed a 

stepwise increase in the odds of PreOP Tx to PostOP Tx across 

Early, Middle, to Late time-periods (OREarly/Late�0.11; 0.10, 0.13, 

ORMiddle/Late�0.36; 0.32, 0.40). Age �40 and 40-49, independently 

predicted higher odds of PreOP Tx than PostOP Tx compared to age 50-74, 

while the findings for subjects age 75� were similar to those seen in the 

age 50-74 group (OR�40/50-74�1.63; 1.30, 2.05, OR40-49/50-74�1.18; 1.03, 1.36, OR75�/50-74�1.04; 0.90, 1.18). Females showed lower odds 

of PreOP Tx to PostOP Tx than males (ORFemale/Male�0.85; 0.77, 0.93). 

Odds of PreOP Tx to PostOP Tx were significantly lower among Asian/Other 

(A/O) and Hispanic relative to Non-Hispanic White (NHW), while findings 

were similar to NHW for Non-Hispanic Black (NHB) (ORA/O/NHW�0.85; 0.74, 0.98, ORHispanic/NHW�0.84; 0.73, 0.96, ORNHB/NHW�0.92; 0.73, 

1.15). SES did not predict odds of PreOP Tx versus PostOP Tx. Conclusions: 

These findings depict independent increases in PreOP Tx across the three 

time-periods among stage II and III rectal cancer patients receiving radical 

operations. Further analyses will evaluate survival characteristics predicted 

by changes in perioperative therapies for stage II and III rectal cancer 

patients. 



Second primary gynecologic neoplasms among breast cancer survivors. 

Presenting Author: Maria Pilar Barretina Ginesta, Institut Catala d’Oncologia 

Hospital Universitari Josep Trueta, Girona, Spain 

Background: Excess of risk of several second primary malignancies after 

treatment for breast cancer (BC) has been reported. This risk can be related 

with shared risk factors, cancer susceptibility genes or prior treatments 

received. Hormonal factors and hormone therapy are known to be risk 

factors for both BC and some gynecological malignancies. The aim of this 

study was to asses gynecological cancer risk as a second neoplasm among 

BC patients in our population. Methods: Patients diagnosed with invasive 

BC (CIE10: C50.0-C50.9) and registered in the Girona Cancer Registry 

from 1980 to 2006 were included in our study. We analyzed their 

incidence of second gynaecological malignancies except for contralateral 

BC. Standardized Incidence Ratios (SIR) and absolute excess of risk (AER) 

of these patients compared to general population were calculated. Results: 

6.209 patients were diagnosed of invasive BC in this period, with median 

age at diagnosis 62 years, median follow-up 4 years. 84 of them developed 

a second malignancy of gynaecological origin (SIR 1,98 CI 95% 1,59- 

2,44; AER 104,01/100.000 person-year). We observed 4 uterine cervix 

(SIR 0.64 IC95% 0,20-1,54), 3 vulvar-vaginal (SIR 0,96 IC95% 0,24- 

2,60), 13 ovarian (SIR 1,13 IC95% 0,63-1,89) and 63 uterine corpus 

neoplasms (UC), as well as 1 genital female tract neoplasm unspecified. 

High and statistically significant SIR was observed for gynecological 

malignancies in general and specifically for UC(SIR 3.14 IC 95% 2,44- 

4,00). With this finding, histology of UC cases was reviewed. 12 out of 63 

were malignant histologies, not otherwise specified. Among the remaining 

51, there were 8 type II (1 clear cell and 7 serous adenocarcinoma, 

15.7%), 34 type I (endometrioid adenocarcinoma, 66.7%) and 6 carcinosarcomas 

(11.8%). There were also 2 adenosarcomas (3.9%) and 1 

mucinous adenocarcinoma (1.9%). Conclusions: Women with previous BC 

have an elevated risk of developing a second primary gynecological 

malignancy compared with general population, particularly for UC. These 

patients should be followed up for its early detection. We detected a slight 

increase in unfavourable uterine carcinoma histologies respect to the 

general population. Further investigation of this finding is warranted. 


Renal impairment after chemotherapy in lung (LC), colorectal (CRC), and 

breast cancer (BC) patients (pts) from the Henry Ford Health System 

(HFHS) tumor registry. Presenting Author: Laura Chu, Genentech, South 

San Francisco, CA 

Background: Renal impairment is a common comorbidity in cancer pts. It 

can delay excretion and alter metabolism of anticancer drugs leading to 

further renal toxicity. The objective of this study was to determine the 

proportion of pts with renal impairment, defined as the presence of 

proteinuria (PR), acute kidney injury (AKI), or chronic kidney disease 

(CKD), after chemotherapy (chemo) initiation. Methods: LC, CRC, and BC 

pts newly diagnosed between 2000 and 2007 (regardless of prior renal 

status) were identified using the HFHS tumor registry, with follow-up 

through Mar 2009. AKI was defined based on RIFLE (severity categories 

only) using lab data within 1 to 7 days after chemo initiation. CKD was 

defined based on NKF-KDOQI criteria and lab data up to 1 year after chemo 

initiation. Proteinuria was defined as protein/creatinine �30 mg/g within 3 

months after chemo initiation. Descriptive statistics include proportions 

stratified by renal impairment status (yes, no) at cancer diagnosis. Results: 

We identified 1,896 LC, 1,088 CRC, 1,611 BC chemo treated pts. Median 

age for all pts was 66 years. For LC and CRC, 56% and 51% were men, 

respectively. The proportion of pts with renal impairment after chemo by 

tumor type was the following: LC (AKI�23.4%; CKD�48.2%; PR�0.4%); 

CRC (AKI�20.3%; CKD�55.7%; PR�0.1%); BC (AKI�7.8%; 

CKD�63.9%; PR�0.6%). Pts with pre-existing renal impairment at 

cancer diagnosis were more likely to have impairment after chemo (Table). 

Conclusions: In LC, CRC, and BC pts, the proportion of pts with renal 

impairment after chemo initiation was high. Extent of renal impairment, 

especially AKI, appears to be associated with tumor type. Older age, as in 

this HFHS cohort, is associated with higher prevalence of CKD. Renal 

function should be closely monitored, particularly among pts with preexisting 

renal impairment, and preventive measures implemented to 

minimize further toxicity after treatment. 


107s 


The influence of prognostic factors on metastatic breast cancer survival 

over time. Presenting Author: Margaret Quinn Rosenzweig, University 

of Pittsburgh School of Nursing, Pittsburgh, PA 

Background: Recent evidence suggests that survival in metastatic breast 

cancer is slowly improving associated with the use of better adjuvant and 

metastatic chemotherapeutic and targeted agents. Patient and clinical 

factors such as age, estrogen status, non-white race, Her 2 status, disease 

free interval and sites of metastatic breast cancer involvement indicate 

worse clinical outcome after recurrence. This analysis focused on the 

influence of these factors on metastatic breast cancer survival over time. 

Methods: Subjects were women with metastatic breast cancer from one 

large urban practice, of the University of Pittsburgh Cancer Institute Breast 

Cancer Program followed from 1999 through December, 2008. Patients 

were dichotomized into two time categories: A) 1999 through 2004 and B) 

2005 through 2008. Outliers of long term survivors (n �72) with survival 

extending beyond 6 years were excluded. Log rank tests were conducted for 

assessing the relationship between prognostic factors and survival. Results: 

Cohorts included patients diagnosed with metastatic breast cancer in 1999 

through 2004, (n�284) and 2005 through 2008, (n�332). They were 

followed up to December, 2011. Median survival improved over time 

(p�0.053). Estrogen negativity remained significant for worse survival 

across both time periods (p�0.0001). Age, presence of brain metastasis 

and Her 2 status were not significant for influence on survival at either time 

interval. Shorter disease free interval (p� 0.02), higher number of 

metastatic sites (p�.001) and presence of visceral metastasis at diagnosis 

(p�0.003) became significant for worse survival in the 2005-2008 

intervals but had not been in the earlier time period. African American race 

was highly significant (�0.001) for worse survival in 1999-2004 but lost 

significance in 2005 through 2008 with dramatic survival increase 

(median survival - 12.5 months to 35 months). Conclusions: It is important 

for clinicians to clarify the prognostic features associated with worse 

outcomes in metastatic breast cancer. With newly emergent therapies and 

sensitivity toward specific patient factors these features evolve over time. 


Treatment patterns and comorbidities in a population-based cohort of 

glioblastoma patients diagnosed 1997-2008. Presenting Author: Susan A. 

Oliveria, EpiSource, Newton, MA 

Background: Glioblastoma multiforme (GBM) is one of the most common, 

most malignant and rapidly progressive forms of brain cancer. Published 

reports of GBM in non-trial populations are limited. The purpose of this 

study was to assemble a population-based cohort of GBM patients with 

comprehensive clinical and demographic information and to define treatment 

patterns and outcomes in this population. Methods: GBM patients 

served by Henry Ford Health System (HFHS), a major GBM referral center, 

were identified using ICD-O and histology codes from the HFHS tumor 

registry. Eligible patients were newly diagnosed with GBM between 1997 

and 2008. Comprehensive, population-based data were compiled using 

tumor registry data (including histology and mortality) with linkages to 

pharmacy data (including infusion), outpatient and inpatient encounter 

data, and laboratory results. Results: Overall, 812 GBM patients were 

identified; mean age was 54 years (standard deviation 15.8). The cohort 

was 63% male and 84% white. Among the most common post-diagnosis 

comorbidities/complications, 14% of patients had venous thromboembolism 

(95% confidence interval [CI] 12-17), 16% had seizures (95% CI 

14-19), and 6% had central nervous system hemorrhage (95% CI 4-7). 

Arterial thromboembolism occurred in 3% of patients (95% CI 2-4), while 

7% experienced infections such as candidiasis, herpes simplex, and 

pneumocystis pneumonia (95% CI 5-9) and 2% experienced wound 

dehiscence (95% CI 1-3). 94% (95% CI 93-96) of the cohort received 

some form of treatment with 81% undergoing surgery (95% CI 78-84), 

75% receiving radiation therapy (95% CI 72-78), and 67% receiving 

chemotherapy (95% CI 64-70). Median overall survival after diagnosis was 

1.4 years (95% CI 1.3-1.5) among all patients, and 1.6 years (95% CI 

1.4-2.0) among those diagnosed 2005-2008. Conclusions: This study 

presents a well-characterized population-based cohort of GBM patients. 

Understanding treatment patterns and comorbidities outside the clinical 

trial setting is important in informing and evaluating real-world treatment 

decisions. Additional results exploring time trends in systemic cancer 

therapy and Kaplan-Meier survival curves will be presented. 




Secondary breast cancer (s-BC) after hematopoietic cell transplantation 

(HCT) for leukemia: Role of total body irradiation (TBI). Presenting Author: 

Can-Lan Sun, City of Hope, Duarte, CA 

Background: s-BC after conventional chest radiation for histologically 

distinct cancer is well-recognized, and has resulted in radiologic screening 

recommendations by American Cancer Society. However, risk of s-BC after 

TBI is not well-defined. Methods: We determined the risk of s-BC in 648 

consecutive females transplanted for leukemia (ALL [19%], AML/MDS 

[57%], CML [24%]) between 1976 and 2008 with a post-HCT survival of 

�2 years. The study was restricted to leukemia to understand the role of 

TBI without the influence of pre-HCT chest radiation. Near-complete 

ascertainment of s-BC was assured by combining institutional follow-up 

with California Cancer Registry data. Results: Median age at HCT was 38 

years (range, 0-71); 14% had received autologous HCT, 64% related and 

22% unrelated donor HCT; 70% had received TBI for myeloablative 

conditioning. After 5,675 person-years of observation, 16 patients developed 

s-BC (14 after TBI). Median latency from HCT to s-BC was 16y 

(2-27). Median age at s-BC was 50y (29-66). Cumulative incidence of s-BC 

was 6% at 20y after HCT, contributed to largely by TBI (s-BC incidence 

after TBI: 5.7%). Among TBI-exposed, 8.6% were projected to develop 

s-BC by age 65y (1.6% among non-TBI-exposed, p�0.03). TBI-exposed 

patients were 2.4 times more likely to develop s-BC compared with general 

population (p�0.001); non-TBI exposed were not at increased risk 

(SIR�0.9, p�0.9). Multivariate analysis (adjusted for age at HCT, follow-up 

and primary diagnosis) revealed a 4.7-fold (p�0.068) increased 

risk of s-BC among TBI-exposed. Conclusions: Risk of s-BC after TBI as the 

sole source of radiation to breast is increased. Nearly 9% of those exposed 

to TBI will develop s-BC by age 65y. Identification of vulnerable subpopulations 

among the TBI-exposed patients is underway to create targeted 

screening strategies for early detection of s-BC. 


Association of a history of autoimmunity or hypersensitivity with overall 

survival in breast cancer. Presenting Author: Hakan Lars Olsson, Departments 

of Oncology and Cancer Epidemiology, Lund University, Lund, 

Sweden 

Background: Antibody therapy of malignant melanoma with ipilimumab is 

associated with the development of an autoimmune disease. The aim was 

to investigate if preexisting autoimmune disorders or hypersensitivities, 

similar to the side effects of immunotherapy in malignant melanoma, gave 

a better overall survival for breast cancer (BC) patients, compared with 

patients without these disorders. Methods: A consecutive clinical material 

consisting of 1,705 breast cancer patients diagnosed between 1980 and 

2010 was used. The patients were grouped according to preexisting 

autoimmune disease or hypersensitivities. The remaining BC patients were 

used as a reference group. All analyses were adjusted for age at diagnosis, 

T, N, M-status of the tumor, and ever-use of HRT simultaneously. A p value 

of less than 0.05 was considered significant. Results: One hundred and 

twenty-five (7.3%) patients had a history of autoimmunity and 72 (4.2%) 

patients had a history of hypersensitivity prior to BC diagnosis. Our main 

finding was that BC patients with a preexisting autoimmune disease or 

hypersensitivities with ER-negative tumors had a longer overall survival 

compared to patients without, HR 0.55, 95% CI 0.31-0.97. The risk was 

specifically low in BC patients with hypersensitivity and ER-negative 

tumors, HR 0.39, 95% CI 0.16-0.96. The risk was nonsignificantly lower 

in the autoimmune group, HR 0.78, 95% CI 0.37-1.61. Stratifying both on 

ER-status and menopausal status, similar results were seen in premenopausal 

BC patients with hypersensitivity. Postmenopausal BC patients with 

an ER-negative tumor and an autoimmune disease had a longer nonsignificant 

overall survival, HR 0.3, 95% CI 0.07-1.26. Conclusions: BC patients 

with an ER-negative tumor and/or diagnosed before menopause had a 

longer overall survival when previously diagnosed with hypersensitivity. For 

BC patients with an autoimmune disease, the prognostic benefit was seen 

when diagnosed postmenopausally with an ER-negative BC. Preexisting or 

induced autoimmunity or hypersensitivity may prolong life in breast cancer 

especially in young patients and those with ER-negative tumors. 


Effect of sunlight exposure on survival in patients with lymphoma: Results 

from the prospective Singapore Lymphoma Study. Presenting Author: Yin 

Leng Lee, National Cancer Center, Singapore 

Background: Recently, several studies evaluating the effect of ultraviolet 

light exposure on the risk of developing lymphoma have yielded conflicting 

results, in part due to seasonal and latitude variation. Further, most of 

these studies also lack long term follow up and could not systemically 

address the influence of sunlight exposure on survival. In this prospective, 

epidemiological study, we explored the relationship between past sunlight 

exposure and survival in lymphoma patients in tropical Singapore, where 

sunlight exposure is constant throughout the year. Methods: Singapore 

Lymphoma Study was established in 2005. A total of 384 patients with 

histologically confirmed lymphoma were followed from date of diagnosis 

through November 2011. Interviewers were trained to conduct in-person 

interviews to collect detailed information, including every occupational 

period that lasted at least 1 year and number of hours worked outdoor from 

9am to 5pm using a structured questionnaire. Descriptive, multivariate and 

survival analysis (Kaplan Meier; age, gender, race and education level 

adjusted) were performed. Results: Among all lymphoma subtypes, the 

most prevalent was diffuse large B cell lymphoma, 47.7%, followed by 

Hodgkin lymphoma, 14.6%, follicular lymphoma, 12.2% and T cell 

lymphoma, 6.5%. 97.1% had black or brown eye color and 49.6% had fair 

skin. Overall survival of lymphoma and NHL subtype decreased significantly 

with increasing lifetime occupational hours (ptrend�0.01 and 

0.03). Chinese was associated with longer survival with increasing daily 

sunlight exposure during childhood and adolescent years, whether at 

school or outdoor leisure (ptrend�0.04) and there were no evidence for 

non-Chinese (Malays or Indians). Patients with lighter eye color results in 

shorter survival (HR�2.91, 95% CI: 1.15-7.34, p�0.02). Conclusions: We 

found leisure sunlight exposure during childhood and adolescent years to 

be beneficial to the survival of Chinese lymphoma patients and increasing 

lifetime cumulative occupational exposure is associated with increasing 

risk of death. This data contributes to the growing research on the effects of 

sunlight exposure on lymphoma patients. 


The evolution of breast cancer screening in the Medicare population: 

Clinical and economic implications. Presenting Author: Brigid K. Killelea, 

Yale University School of Medicine, Yale Comprehensive Cancer Center, 

New Haven, CT 

Background: Breast screening has evolved as newer approaches to mammography, 

ultrasound, and MRI have diffused into clinical practice. The use of 

these technologies and their impact on screening-related costs and 

outcomes remain undefined, particularly among older women. Methods: 

Using the Surveillance Epidemiology and End Results – Medicare linked 

database, we identified women aged 66 and older without a diagnosis of 

breast cancer. We constructed two cohorts (2001 vs. 2006) and followed 

each for two years. We assessed changes in imaging technology, screeningrelated 

costs (defined as costs for screening and subsequent imaging and 

testing, adjusted to 2009 USD), and stage at diagnosis between the two 

cohorts. Results: There were 136,845 women in the 2001-2002 (earlier) 

cohort and 137,733 in the 2006-2007 (later) cohort. The mean age was 

76.9 and 77.2 respectively, (p�.001). The proportion of women receiving 

any screening mammogram was 42.5% in the earlier cohort and 43.4% in 

the later cohort, (p�.001). The use of digital mammography for screening 

increased from 2.2% to 15.0%, (p�.001). The use of any computer aided 

detection (CAD) increased from 3.2% to 29.3% (p�.001). MRI use 

increased from 0.03% to 0.2%, and ultrasound use from 4.0% to 4.5% (p 

�.001 for both). Average screening-related cost increased 31%, from 

$101 to $132 (p�.001). There was no significant difference in early stage 

at diagnosis over time (58.1% of women were in situ/stage I in early period 

vs. 57.2% in later period, p�.65). Conclusions: The use of digital 

mammography and CAD increased substantially between 2001 and 2007, 

contributing to a 31% increase in screening-related costs for women in the 

Medicare program. The increased cost of screening and downstream testing 

must be evaluated in context of an absence of benefit in terms of stage at 

diagnosis. 



ABO blood group and the risk of lung cancer: Multicenter, case-control, 

observational study. Presenting Author: Gungor Utkan, Ankara University 

School of Medicine, Ankara, Turkey 

Background: The role of genetic factors in the development of cancer is 

widely accepted. Previous studies have observed an association between 

ABO blood group and risk of certain malignancies, including pancreatic 

and gastric cancer. The data on the role of ABO blood group and Rh factor 

in lung cancer is limited. Methods: All patients who had Lung cancer (LC) 

and treated between 2000-2011 at the involved centers with defined 

ABO/Rh were included in our retrospective reviews of tumor registry 

records. A group of volunteer healthy blood donors of Turkish Red Crescent 

between 2004 and 2011 were identified as a control group. The relationship 

of ABO/Rh with clinical features such as age at diagnosis, histological 

subtype and sex were evaluated. We compared the distributions of ABO/Rh 

among 1954 patients and 3,022,883 controls. Among LC patients, 

differences between each of aforementioned ABO/Rh groups with respect 

to various clinical features were explored, respectively. Results: Of these 

patients the median age was 62 (range: 17-90). The 84% of patients were 

male. Overall distributions of ABO blood groups as well as Rh factor were 

statistically different between patients (43.6% A, 8.3% AB, 17.3% B, 

30.8% O, and 86.3% Rh�) and controls (42.2% A, 7.6% AB, 16.3% B, 

33.9% O, and 87.7% Rh�) (p�0,03). In addition, there were statistically 

significant differences between patients and controls with respect to O vs. 

nonO (p�0.004) and marginal significance for A vs. nonA (p�0,065), B vs. 

nonB (p�0,076), and Rh� vs. Rh- (p�0,057). Among patients, there 

weren’t statistically significant differences between blood group with 

respect to sex and age. However there was statistically significant difference 

between blood group with respect to histology (p�0,001). Although 

the distribution of A and O were similar according to histology, patients with 

squamous histology had antigen B more frequently than other histological 

sub types (p�0,009). Conclusions: In the study populations, ABO blood 

type was statistically significantly associated with the LC and having blood 

type other than O increases the risk of LC. Further studies are necessary to 

define the mechanisms by which ABO blood type may influence breast 

cancer risk. 


Analyzing excess mortality from cancer among individuals with mental 

illness. Presenting Author: Jackson S. Musuuza, Department of Population 

Health Sciences, University of Wisconsin School of Medicine and Public 

Health, Madison, WI 

Background: Previous studies have documented higher cancer-related 

mortality in individuals with mental illness, compared to their healthier 

counterparts. The aim of this study was to identify the anatomic cancer 

sites for which mortality is higher in individuals with mental illness. 

Methods: We used a linked dataset comprised of death certificate data for 

the state of Ohio for the years—2004-2007 and data from the publicly 

funded mental health system in Ohio. Decedents with mental illness were 

those identified concomitantly in both data sets. We used age-adjusted 

standardized mortality ratios (SMRs) in race- and sex-specific strata to 

estimate excess deaths for each of the anatomic cancer sites. Results: 

Overall, there was excess mortality from cancer associated with having 

mental illness in Non-Black men and women (SMR: 1.14 (95% confidence 

interval [CI] � 1.05-1.22), and 1.13 (95% CI� 1.05-1.20, respectively), 

but lower mortality in Black men, likely due to premature mortality from 

other causes (0.71 (95% CI� 0.61-0.83). In Black women, we observed 

no excess mortality from cancer that was associated with having mental 

illness. There was excess mortality from hepatobiliary cancer in Non-Black 

men (SMR� 1.65; 95% CI �1.15-2.29), but not in any other sex- and 

race- stratum. In addition, we observed excess mortality from lung and 

laryngeal cancers among Non-Black men and women (SMRs for lung 

cancer of 1.28 (95% CI� 1.13-1.45), and 1.45 (95% CI� 1.29-1.62), 

respectively; and for laryngeal cancer (2.01 (95% CI� 1.19-3.18 for men, 

and 2.47 (95% CI� 1.08-4.89) for women). Black women experienced 

excess mortality from cancer of the kidney and renal pelvis (SMR� 2.91; 

95% CI �1.53-5.06), while Non-Black women experienced excess mortality 

from urinary bladder cancers (SMR�1.89; 95% CI�1.15- 2.92). 

Conclusions: Compared to the general population in Ohio, individuals with 

mental illness experienced excess mortality from certain cancers. In part, 

this excess mortality may be mediated by a higher prevalence of smoking or 

substance abuse in individuals with mental illness. Further investigation is 

needed to explain the observed racial variation in cancer mortality, and to 

examine mortality for specific cancers based on severity of mental illness. 


109s 


Association of p53 Arg72Pro polymorphism and HPV status with the 

initiation, progression, and development of cervical cancer (CC): A metaanalysis. 

Presenting Author: Steven Habbous, Princess Margaret Hospital, 


Background: CC develops through progression from normal cervical epithelium 

through squamous intra-epithelial lesions (SILs) to cancer. CC is 

classically associated with oncogenic human papillomavirus (HPV). Yet, 

not all CC patients demonstrate HPV infection at diagnosis. HPV� and 

HPV– subsets of CC patients may thus represent distinct entities. HPV 

binds to P53, promoting its degradation; the Arg variant of p53 Arg72Pro 

binds more ardently to HPV than the Pro variant. Although there have been 

meta-analyses of Arg72Pro in CC risk, none has evaluated the relationship 

between Arg72Pro and HPV status together. We hypothesize that p53 

Arg72Pro modifies aspects of the carcinogenic process in HPV� (but not 

HPV-) subsets of CC. Methods: Pubmed/Embase databases identified 1494 

potential studies; 51 were eligible and included. Separate analyses were 

performed to evaluate CC risk (CC vs normal), initiation of cancer (SIL vs 

normal), and progression towards cancer (CC vs SIL), by HPV status. Pooled 

odds ratios (pOR) were generated using RevMan 5.1 software. Results: p53 

Arg72Pro was not associated with CC risk in either HPV� or HPV- patient 

subsets (pORs 0.92; 95%CI, 0.6-1.3 and pORs 1.07; 95%CI, 0.7-1.7, 

respectively). Similarly, there was no association with the initiation of 

disease (SIL vs normal): pORs 0.96; 95%CI, 0.7-1.3 (HPV� subset); 

1.11; 95%CI, 0.9-1.4 (HPV- subset). There was no association with 

disease progression from SIL to CC in the HPV- subset (pOR, 0.98; 95%CI, 

0.7-1.4). However, in the HPV� subset, comparing the progression from 

SIL through to CC, there was strong and significant association: pOR, 1.37; 

95%CI, 1.2-1.6 (p�4.0x10E-4), with no evidence of heterogeneity (I2 � 

0%) or bias (by funnel plot). Sensitivity analyses demonstrated similarly 

significant results, even after taking into account differing quality of 

methodological designs and type of biological sample analyzed (tumour vs. 

blood) of the underlying studies. Associations were mainly restricted to 

Caucasian studies. Conclusions: In this meta-analysis, the Arg variant of 

p53 Arg72Pro was associated with progression of SIL to CC only in HPV� 

subsets, but not to disease initiation or risk of CC. 


Analysis of KRAS and BRAF mutant colorectal cancers in a multiracial 

population. Presenting Author: Jared David Acoba, University of Hawaii 

Cancer Center, Honolulu, HI 

Background: We previously demonstrated racial disparities in colorectal 

cancer (CRC) survival despite adjustments for tumor and socioeconomic 

factors. Molecular differences in breast and lung tumors contribute to 

racial survival inequality, yet in CRC, molecular tumor characteristics have 

not been studied extensively in a racially diverse cohort. We performed a 

comprehensive evaluation of KRAS and BRAF mutations in a multiracial 

population to determine the prevalence in CRC and the degree to which 

these molecular traits impact survival. Methods: A retrospective cohort 

study of patients diagnosed with CRC between 2008 and 2011 from 

hospital tumor registries was performed. The prevalence of KRAS and 

BRAF mutations was determined for the study population and individual 

racial groups. Multivariable Cox proportional hazards regression models for 

survival were built for KRAS and BRAF mutation status while adjusting for 

age at diagnosis, race, and stage of disease. Results: Of 706 patients 

diagnosed with CRC, KRAS mutational analysis was performed on 148 

subjects. 14% of subjects were white (W), 64% Asian (A), and 21% Native 

Hawaiian/Pacific Islander (NH). KRAS mutation was identified in 48 

subjects (32%). The prevalence of mutant tumors among racial groups was 

W 33%, A 36%, and NH 30%. Analysis for KRAS G13D mutations revealed 

a prevalence of W 11%, A 9%, and NH 7%. When compared to published 

datasets of predominantly white patients, our multiracial cohort had a 

significantly higher rate of KRAS G13D mutant tumors, p�0.039. Of 74 

subjects tested for the BRAF mutation, two mutant tumors were detected 

(3%). The prevalence of the BRAF mutation by race was 10% W, 3% A, and 

0% NH (p�0.18). BRAF and KRAS G13D mutations were adverse 

prognostic factors in a multivariate analysis, although the odds ratios failed 

to meet statistical significance. Conclusions: The prevalence of BRAF and 

KRAS mutations in this multiracial cohort is similar to what has been 

previously reported. However the rates of KRAS G13D and BRAF mutant 

tumors in our cohort are higher than prior reports. Furthermore, KRAS 

G13D which has been postulated to be a favorable prognostic factor for 

CRC, may adversely impact survival of minority patients. 



1600^ General Poster Session (Board #9B), Sat, 1:15 PM-5:15 PM 

Correlation of high body mass index and circulating tumor cell positivity in 

patients with early-stage breast cancer. Presenting Author: Uta Ortmann, 

Heinrich Heine University , Duesseldorf, Germany 

Background: The prognostic relevance of both body mass index (BMI) and 

circulating tumor cells (CTC) has been confirmed in different trials for 

patients with early breast cancer. This analysis evaluates the correlation 

between high BMI and CTC positivity as risk factors for reduced disease free 

and overall survival. Methods: Data of 3658 patients of the SUCCESS A trial 

have been analyzed. CTC count and BMI were documented before (N � 

2026) and after (N � 1504) chemotherapy. Within this trial patients with 

early breast cancer were randomized to two chemotherapy regimens and 

received either 3 cycles of fluorouracil, epirubicin and cyclophosphamide 

followed by 3 cycles of docetaxel (FE100C-Doc) or 3 cycles of fluorouracil, 

epirubicin and cyclophosphamide followed by 3 cycles of docetaxel and 

gemcitabine(FE100C-DG). In addition, patients were randomized to zoledronic 

acid either for 2 or 5 years. CTC were analyzed using the CellSearch 

System (Veridex, USA). Different groups of bodyweight were classified 

according to the WHO’s international definition: Underweight (BMI � 18,5 

kg/m2 ), normal range (BMI � 18,5- � 25), overweight (BMI �25- � 30), 

obesity (BMI � 30). Correlation between CTC count and BMI was analyzed 

using frequency-table methods. Results: At study entry 24 (1.2%) patients 

were underweight, 952 (47%) patients were normal weight, 658 (32.5%) 

patients were overweight and 392 (19.4%) patients were obese. Before the 

start of chemotherapy, CTC were detected in 435 (21.5%) patients. We did 

not find a correlation between CTC positivity and BMI (p�0.94). After 

chemotherapy CTC were detected in 330 (16,3%) patients. Again, there 

was no statistically significant correlation between BMI and CTC positivity 

(p�0.86). In particular, CTC positivity was not observed more frequently in 

obese patients neither before (p�0.70) nor after chemotherapy (p�0.95) 

compared to patients with a BMI � 30 kg/m2 . Conclusions: As compared to 

patients with normal BMI, there was no significant difference in the 

prevalence of CTC in underweight, overweight and obese patients, respectively, 

neither before nor after chemotherapy. The risk factors obesity and 

prevalence of CTC seem to be independent prognostic factors. 


Correlation of BMI with tumor stage in early breast cancer patients (pts): 

Pooled analysis of the German SUCCESS A, B, and C trials. Presenting 

Author: Carola Anna Melcher, Department of Gynecology and Obstetric, 

Heinrich Heine University, Duesseldorf, Germany 

Background: Independent from known prognostic factors, e.g., tumor size 

and nodal status, obesity is a risk factor for poor disease free, distant 

disease free, and overall survival in breast cancer. The aim of this analysis 

was to examine the correlation of the body mass index (BMI) with tumor 

characteristics in early breast cancer. Methods: We analyzed the data of 

7,997 pts with early, node positive or high risk node negative primary 

breast cancer treated with adjuvant taxan-based chemotherapy within the 

German multicenter phase III SUCCESS A, B, or C trials. The pts’ tumor 

stage at primary diagnosis was classified according to the UICC tumor-nodemetastasis 

(TNM) classification. Additionally, the tumor’s hormonereceptor 

status and HER2/neu status were determined. Before enrollment 

into the study each patient was grouped according to the WHO global 

database on BMI. Contingency table methods were used to analyze the 

correlation of BMI and tumor characteristics. Results: Among the 7,997 pts 

100 (1.3%) pts were underweight, 3,556 (44.5%) pts were normal weight, 

2,569 (32.1%) pts were overweight and 1,772 (22.2%) were obese. Of all 

pts 4,508 pts (56.4%) suffered from a pT2-4 tumor, 4830 (60.4%) 

showed lymph node involvement (pN1-3) and 7509 (93.9%) had G2-3 

tumors. 5839 pts (73.0%) showed positivity for ER or PR and 935 (11.7%) 

for HER2/neu. Overweight and obese pts had significantly larger tumors 

compared to pts with normal BMI (p�0.0001; p�0.0001). Furthermore, 

overweight and obesity were associated with a significantly higher rate of 

lymph node involvement (p�0.0001; p�0.0003) respectively. In contrast 

neither grading, tumor histology, ER/PR-status nor HER2/neu-overexpression 

were correlated with BMI. Conclusions: These data are the first to show 

in a large number of pts that both obese and overweight women suffering 

from primary breast cancer have significantly larger tumors and more often 

positive axillary lymph nodes. As there are no differences in tumor biology, 

the advanced tumor stage might be due to more difficult and delayed 

detection of breast cancer and lymph node lesions in these women. 


Evolution and landscape of clinical trials for breast cancer patients. 

Presenting Author: Semih Dogan, Institut Gustave Roussy, Villejuif, France 

Background: Recent advances in cancer research are expected to have 

dramatically changed the way clinical trials are being done. In an effort to 

outline new trends of clinical research in the breast cancer area, we have 

evaluated the evolution of clinical trials started between 2006 and 2011. 

Methods: 622 clinical trials, started during the first semester 2006, the 

second semester 2008 and the first semester 2011, were analyzed. The 

data source was Clinicaltrials.gov. 30 items were included in the database. 

Results: The overall number of patients included in prospective clinical 

trials increased over these periods (n�67,820, n�91,429, n�98,417). 

However, when large epidemiological cohorts are excluded, a significant 

fall in the number of patients is seen (n�67,820, n�44,554, n�37,417). 

The absolute number of therapeutic trials also decreased during this time 

(n�93, n�99, n�78), mainly related to the dramatic fall in the number of 

trials testing conventional treatments (n�40, n�24, n�20). In the 

meantime, the number of trials testing targeted agents remained similar 

(n�46, n�67, n�50). Interestingly, in the same time, the number of trials 

testing a targeted agent in a population defined by a biomarker increased 

(n�1, n�6, n�14). At the opposite, prospective studies aimed at 

validating biomarkers did not increase, and remained only driven by large 

consortiums. As illustration, when we exclude RxPONDER trial, the 

biomarker-validation studies opened in 2011 planned to include only 2 

493 patients, representing 2% of the breast cancer research field. 

Prospective trials testing social sciences and supportive care (n� 70, 

n�72, n�70) tend to become as important as therapeutic trials. Finally, 

large epidemiological cohorts opened in 2011 will represent more than 

60% of the patients included in clinical trials. Conclusions: The part of 

cohorts and social sciences in breast cancer research is increasing and 

represents now the majority of the clinical research activity. When the 

analysis focuses on therapeutic trials, the breast cancer field recently 

shifted to targeted agents and early data suggest that therapeutic research 

is increasingly incorporating companion biomarker. Analysis on all 2,762 

clinical trials done between 2006 and 2011 will be presented. 


Effect of gender on age-specific effects for ulcerated malignant melanomas. 

Presenting Author: Blakely S. Richardson, University Hospitals Case 

Medical Center/Case Western Reserve University School of Medicine, 

Cleveland, OH 

Background: Gender, age at diagnosis, and ulceration are all independent 

prognostic factors for melanoma. The purpose of this study was to further 

examine the interactions among gender, age, and melanoma ulceration. 

Methods: Using the NCI’s SEER 17 Registries Database (2004-2008), we 

assessed ulceration status among White men and women with malignant 

melanoma, stratified by younger (ages 10-39 years) and older (ages 40-84 

years) ages at diagnosis as well as by tumor depth. The analysis was 

restricted to melanomas common to both age groups, i.e. superficial 

spreading, nodular, and unclassified melanomas. There were 2905 older 

men, 301 younger men, 1624 older women and 276 younger women that 

fit our criteria. Relative risks were expressed as incidence rate ratios (IRR) 

with 95% confidence intervals (CI). Results: At every tumor depth, IRRs for 

ulcerated melanomas were significantly higher for older than younger 

persons (IRR�1.0). The trend, however, was different in men as compared 

to women. In men, the IRR (older to younger) rose continuously with 

increasing depth [�1.0mm: IRR 7.81 (CI 6.18-9.98), 1.01mm-�2.0mm: 

IRR 9.71 (CI 7.55-12.68), 2.01mm-�4.0mm: IRR 11.04 (CI 8.78- 

14.06); and �4.01mm: IRR 12.26 (CI 9.60-15.87)]. On the other hand, 

in women, IRR (older to younger) was stable for all depths �4.0mm then 

nearly doubled for melanomas �4.01mm [�4.01mm: IRR 8.00 (CI 

5.85-11.20)]. The IRR trend analysis was statistically significant for men 

(p � 0.01) but not for women (p � 0.34). Conclusions: Our study confirms 

that older age at diagnosis is associated with higher incidence rates of 

ulcerated malignant melanomas. This large-scale population-based analysis 

also shows an effect modification by gender and tumor thickness, 

suggesting different biologic behavior in melanoma in younger and older 

men and women. Future studies should further investigate tumor biology 

differences in these populations and the interactions among gender, age at 

diagnosis, and ulceration in melanoma. 



Long-term survival and prognostic factors in neuroendocrine tumors: 

Results from a large multicenter study. Presenting Author: Antongiulio 

Faggiano, Department of Molecular and Clinical Endocrinology and Oncology, 

Federico II University, Naples, Italy 

Background: The clinical behavior of neuroendocrine tumors (NET) is highly 

variable, but the only data available in literature on large series are mainly 

based on retrospective register data collected in 3-5 decades, focusing on 

short-term follow-up. These are clearly insufficient due to the frequent 

evolution in classification criteria, diagnostic techniques and the scarcity of 

clinical data. Methods: Data from a total of 1659 NET patient were 

collected from 12 Italian referral centers. A specific software was developed 

for the study. Only patients with histological diagnosis revised 

according to the WHO Classification in active long term follow-up in the 

period 1990-2010 were included in the study. Patients with incomplete 

diagnostic work-up, without clinical data or lost at follow-up were excluded. 

Cumulative survival were analyzed according to site of origin, histotype, 

grading, ki67 score, secreting pattern (functioning or not functioning) and 

staging. Results: At 2 yr cumulative survival do not differ between 

pancreatic (pNET 94.9%), gastrointestinal (GINET 94.4%) and lung NET 

(TNET 94.6%), functioning (93.5 %) and non functioning (93.9%), while 

was significantly different between T1N0M0 (98%), T1N1M0 (92.9%), 

T1N1M1 (90.2%) and grading (G1 98%, G2 96.8%, G3 84.1%). At 5, 10 

and 15 yr, cumulative survival were respectively 90.9, 77.1, 62.7% for 

pNET, 88.7, 83.5, 62.7% for GINET 90.3, 80.2, 67.9% for TNET. 88.4, 

77.0, 59.0% in functioning and 89.8, 79.1, 64.6% in not functioning. 

96.1, 89.5 and 77.0% for T1N0M0, 88.2, 83.5, 70.4 for T1N1M0 and 

82.0, 55.8 and 43.9 for T1N1M1, 93.1, 82.3, 75.4% for G1, 87.8, 64.8, 

48.6% for G2, 81.4, 75.2, 40.1% for G3. Conclusions: Brief (2y) and very 

long term (15y) survival do not significantly differ between different site of 

NET origin. Functioning tumors have the same survival rate at 2 y but lower 

at 15 y. Staging and grading appear as the most significant prognostic 

factors particularly at 10 and 15 y. Long-term cumulative survival in NET 

results significantly higher than in historical series, probably due to the 

anticipation of the diagnosis and the availability of new therapeutic 

strategies. 


Breast cancer survival: Is the Asian population homogenous? Presenting 

Author: Vincent Caggiano, Sutter Institute for Medical Research, Sacramento, 

CA 

Background: Study of the ER-/PR-/HER2- (TN) subtype has generated 

interest in race/ethnicity with respect to breast cancer. Poor survival of 

African-American (AA) women with breast cancer has been reported. Less 

is known about the Asian population. This study examines survival of four 

ER/PR/HER2 subtypes among 10 self-reported race/ethnicity categories 

Methods: Using the California Cancer Registry 2000-2010, we examined 

136,175 cases first primary female invasive breast cancer. For stages 1 

and 2, Kaplan-Meier survival and the Log-Rank test were computed by 

stage and race for the ER�/PR�/HER2-, ER-/PR-/HER2�, ER�/PR�/ 

HER2� (TP) and TN subtypes. Results: When the Asian population is 

combined into the category Asian/Pacific Islander (API): ER�/PR�/ 

HER2-: AAs had worse 5-year survival than whites in stages 1 and 2 but 

Hispanics and APIs had better survival in both stages; ER-/PR-/HER2�: 

AAs and Hispanics were no different from whites in stage 1 but APIs had 

better 5-year survival (0.96 vs 0.89, p�0.001). For stage 2, there were no 

differences in survival among the races. ER�/PR�/HER2�: AAs had worse 

and APIs had better survival in both stages; Hispanics had better survival 

only in stage 1 (0.93 vs 0.92, p�0.03) and were no different from whites in 

stage 2. ER-/PR-HER2-: AAs and Hispanics were no different from whites 

in stage 1 but APIs had better survival (0.93 vs 0.88, p� .003); AAs had 

worse survival than whites in stage 2 (0.71 vs 0.75, p� 0.04) Hispanics 

were no different, and APIs had better survival (0.81, p � 0.001). When 

the Asian population was expanded into 7 categories, Pacific Islanders and 

Koreans were no different than whites in stages 1 or 2 for all four subtypes 

examined. For Stage 1, Southeast Asians had better survival for all 

subtypes except for the TN whereas Filipinos had better survival for all 

subtypes except for TP. For the ER�/PR�/HER2- subtype, women from the 

Indian Continent had better survival in stage 1 (0.98 vs 0.92, p�0.003) 

and in stage 2 (0.94 vs 0.88, p�.001) and better survival for stage 1 of the 

TN subtype (1.00, vs 0.88, p �0.04). Conclusions: There is heterogeneity 

among the Asian population, but regardless of how categorized, Asians 

have either the same or better 5-year survival than whites for all subtypes in 

stages 1 and 2. 


111s 


Survival of elderly Medicare patients after standard chemotherapy for 

advanced lung and gastrointestinal cancers in the real world. Presenting 

Author: Elizabeth B. Lamont, Massachusetts General Hospital Cancer 

Center, Boston, MA 

Background: Elderly cancer patients are under-represented on clinical trials 

that determine standards of treatment, thus survival of such patients 

following standard treatment in the real world is not known. We describe 

unadjusted survivals for site, stage, and treatment-specific cohorts of 

elderly Medicare cancer patients who were treated in usual care settings. 

Methods: From SEER-Medicare data, we identified elderly Medicare patients 

with advanced lung or GI cancers who received specific standard 

chemotherapy regimens within six months of diagnosis. Of the 108,386 

patients with the cancer sites and stages of interest, 39% (42,570/ 

108,386) received some form of chemotherapy within six months of 

diagnosis. Only 32% (13,689/42,570) received one of the specific 

standard regimens we studied. Results: Median survival times and interquartile 

ranges (IQRs) varied according to cancer site, stage, and treatment. For 

598 stage IV CRC patients on FOLFOX, the median survival was 19.4 mos 

(IQR 9.3-43.0); this is comparable to PRIME Study patients (19.7 mos). 

For 130 stage IV CRC patients on FOLFIRI, the median survival was 16.1 

mos (IQR 5.6-30.0), which is lower than BICC-C Study patients (23.1 

mos). For 3,815 advanced pancreatic cancer patients on gemcitabine, the 

median survival was 4.3 mos (IQR 2.0-8.7), which is slightly lower than 

CALGB 80303 patients (5.8 mos). For 8,040 stage IV NSC lung cancer 

patients on carboplatin and paclitaxel, the median survival was 7.0 mos 

(IQR 3.2-14.2); this is comparable to ECOG 1594 patients (7.8 mos). For 

1,104 extensive stage SCLC patients on cisplatin and VP16, the median 

survival was 8.5 mos (IQR 4.7-12.9), which is slightly lower than CALGB 

9732 patients (10.0 mos). Conclusions: The observed survival of cancer 

site, stage, and treatment-specific cohorts of elderly Medicare patients with 

advanced lung or GI cancers who were treated in real world settings with 

standard chemotherapy was, in general, similar to that of patients treated 

with nominally identical regimens on trials. Further analyses should explore 

the shorter survival for elderly Medicare patients with stage IV CRC treated 

with FOLFIRI in the usual care setting compared to patients treated on 

trials. 


Impact of obesity and overweight in the prognosis of women diagnosed with 

non metastatic breast cancer in a Mexican cohort. Presenting Author: José 

Luis Aguilar, Instituto Nacional de Cancerología, Mexico City, Mexico 

Background: Mexico positions right up at the top with U.S. in worldwide 

rankings of the most obese countries. In addition, breast cancer (BrCa) is 

the main type of cancer among women in this country. Studies have shown 

inconsistent results regarding obesity as a prognostic factor for worse 

outcome. Methods: Our aim is to identify if overweight and obesity confer 

poor prognosis in non-metastasic BrCa patients (pts). We identified 1799 

Hispanic women with newly diagnosed BrCa who attended the National 

Cancer Institute in Mexico from 2004-2008 and compared clinical and 

pathological features and overall survival (OS) between pts with a body 

mass index (BMI) � or � than 25. Results: The median age at diagnosis was 

51 years. A BMI�25 was found in 71% of pts. Postmenopausal women 

comprised 52%, and had a greater proportion of cases with a BMI�25 than 

premenopausal pts (75% vs. 67%, p�0.0001). Pts with BMI�25 presented 

with more advanced TNM stages and nodal involvement than their 

counterparts (73% vs. 67%, p�0.005 and 76% vs. 71%, p�0.017; 

respectively). Overall prevalence of hormone-receptor (HR), triple-negative 

(TN) and HER2 positive disease was 62%, 23%, and 27%, respectively. 

Differences according to receptor status between pre and postmenopausal 

pts and BMI are shown in table. There was no difference in disease-free 

survival and OS according to overweight and obesity in the overall 

population, but when menopausal status was considered, premenopausal 

pts with BMI�25 had a worse OS compared to pts with BMI�25 (HR 1.6, 

p�0.037). This difference was not seen in the postmenopausal group. 

Conclusions: Obesity may influence BrCa outcomes via several hormonal 

and inflammatory mechanisms. In this study, overweight and obesity confer 

a poor prognosis in premenopausal patients, possibly related to excess 

estrogen availability and higher prevalence of TN BrCa. Therefore, overweight 

and obesity deserve additional attention to assess possible causal 

relationships that potentially could be modified to improve outcomes in 

premenopausal patients. 

Premenopausal Postmenopausal 

25 (%) p 25 (%) p 

HR - 34 41 0.028 45 34 0.003 

� 66 59 55 66 

TN - 79 73 0.043 76 81 0.079 

� 22 27 24 1 

HER2 - 71 76 0.094 65 73 0.010 

� 29 24 35 27 




American BRCA outcomes and utilization of testing (ABOUT) study. 

Presenting Author: Rebecca Sutphen, Epidemiology Center, University of 

South Florida Morsani College of Medicine, Tampa, FL 

Background: An estimated 100,000 individuals currently undergo genetic 

testing for hereditary susceptibility to breast and ovarian cancer annually in 

the U.S., yet little is known about their characteristics, testing experience 

or outcomes. Research in this high-risk group has been limited to patients 

recruited at academic medical centers where case ascertainment, health 

services delivery, decision-making and, quite likely, outcomes are different 

from those in the community setting where the majority of individuals 

currently receive healthcare services. Methods: Eligible subjects include 

10,000 consecutive individuals requesting BRCA testing through the 

nation’s third-largest health insurer, Aetna, beginning in December, 2011. 

De-identified data are analyzed from each test request form submitted by 

the ordering provider. Each eligible subject is mailed a study packet 

inviting them to complete a questionnaire (by mail, online or telephone) 

designed to investigate informational and healthcare services, test results, 

knowledge, risk perception and medical intentions. Results: Of 442 

subjects contacted during the first two weeks of accrual, 143 (32%) have 

completed the questionnaire to date. Similar to Aetna member demographics, 

7% are African-American and 7% report Hispanic ethnicity. Based on 

Chi-Square tests, there were no differences between respondents and 

non-respondents with regard to age (51% under age 50), race, ethnicity or 

personal history of cancer (58%). Among respondents, deleterious mutations 

were identified in 8%. Testing for a known familial mutation was 

performed in 8%. Among women with breast cancer, 13% were undergoing 

testing prior to initial surgical treatment. Updated results from 3000 

eligible subjects will be presented. Conclusions: This innovative, academicindustry 

collaboration enables an unprecedented investigation of significant 

issues surrounding individuals at increased risk for hereditary breast 

and ovarian cancer and undergoing genetic testing in the U.S. The results 

will guide the development and dissemination of more targeted decisionsupport 

tools and strategies to improve medical outcomes for such 

individuals. 


Health and quality of life (QOL) issues in four groups of lung cancer 

patients: Low-dose computed tomography (LDCT) screened, chest x-ray 

detected, incidentally found, and routinely diagnosed. Presenting Author: 

Ping Yang, Mayo Clinic, Rochester, MN 

Background: Low dose computed tomography (LDCT) scans have reduced 

lung cancer deaths by 20.3% in high risk populations, although there is an 

unknown balance between the benefits and harms of LDCT scans as a 

screening tool. Our purpose was to compare health-related QOL issues 

among lung cancer patients who were initially detected by LDCT scans; 4 

comparison groups included: lung cancer diagnosed by a screening chest 

X-ray, as an incidental finding from procedures taken for other medical 

reasons, or based on symptoms indicative for lung cancer and routinely 

diagnosed, and individuals who were LDCT screened but found no lung 

cancer (controls who participated in Mayo’s lung cancer CT screening trial). 

Methods: A total of 1,658 lung cancer patients (cared at Mayo Clinic) in the 

4 groups (37, 151, 389, and 1081 respectively) and 488 controls were 

compared on following patient-reported outcomes (collected via validated 

tools): overall QOL, four symptoms (cough, pain, dyspnea, fatigue), mental/ 

physical/ emotional/ social/ spiritual QOL, and other concerns (e.g., family/ 

friends/ financial/ legal). A clinically significant deficit was defined as at 

least 10-points in difference (or �50 points) on a 0-100 scale. The rates of 

deficits were compared via Fisher’s exact tests and average QOL values via 

Kruskal-Wallis tests. Results: Overall QOL and individual symptoms were 

significantly worse (p�0.05) in all lung cancer groups than in controls, 

except for pain. LDCT-screened patients reported the greatest deficit 

among the 4 lung cancer groups in physical (41%), emotional (24%), 

social (38%), and spiritual QOL (24%); whereas chest X-ray detected 

patients had the least deficit in overall QOL (22%) and pain (32%). All 4 

lung cancer groups experienced much worse fatigue (52-64%) than the 

controls (32%). Conclusions: Our preliminary results suggest that LDCTscreening 

detected lung cancer patients reported a different QOL profile 

from other lung cancer patients and non-lung cancer controls. The clinical 

course, smoking behavior, and QOL related health issues associated with 

LDCT screening for lung cancer warrant thorough investigation. 


Association between age, gender, residential region, and prevalence of 

subependymal giant cell astrocytoma among patients with tuberous sclerosis 

complex: A U.S. Healthcare Claims Database study. Presenting Author: 

Michael Kohrman, University of Chicago, Chicago, IL 

Background: Subependymal giant-cell astrocytomas (SEGA) are slow growing 

non-cancerous tumors that can occur in patients with tuberous sclerosis 

complex (TSC). The objectives of this study were to examine SEGA 

prevalence among TSC patients in a real world setting, and to ascertain the 

relationships between SEGA prevalence and age groups, genders, or 

residential regions. Methods: We conducted a retrospective cohort study 

based on a large US commercial healthcare claims database. Patients with 

a TSC claim between 2000 and 2009 and with 12-month continuous 

enrollment after their first TSC claim were included into the study. SEGA 

was identified based on ICD-9CM codes in inpatient or outpatient claims. 

Patients’ genders, residential regions and ages of their first TSC claim and 

/or their first SEGA claim (if they had SEGA) were extracted from enrollment 

files respectively. SEGA prevalence was assessed with subgroup analyses of 

genders, age groups of first TSC claim, and residential regions. Two-sample 

t tests and Chi-square tests were used to explore the relationships between 

SEGA prevalence and age groups, genders, or residential regions. Results: 

The study had 2,767 patients with a mean age of 28.5 years on their first 

observed TSC claim, and 55.3% were female. Among these TSC patients, 

7.7% had SEGA with variations by age groups of their first TSC claim (5.9% 

for age�1 year, 12.6% for age 1-5 years, 11.0% for age 6-10 years, 11.0% 

for age 11-18 years, 7.6% for age 19-25 years, and 5.1% for age 26 years 

or more), by genders (8.7% for males vs. 6.9% for females), and by 

residential regions (6.0%-11.0%). The associations between SEGA prevalence 

and age groups, genders or residential regions were all statistically 

significant with p�0.05. Conclusions: In a real world setting, and by the 

end of the first post-TSC year, 7.7% TSC patients had an observed SEGA 

diagnosis. This prevalence varied by age groups, genders, residential 

regions. Further research is needed to explore the factors that results into 

these variations. 


A retrospective analysis of all non-AIDS defining cancers (NADC): A subset 

analysis of the County Hospital AIDS Malignancy Project (CHAMP). 

Presenting Author: Shweta Gupta, John H. Stroger Jr. Hospital of Cook 

County, Chicago, IL 

Background: County Hospital (CCH) with its HIV clinic, the CORE Center 

(CC) is the largest provider for HIV patients (pts) in Chicago, treating over 

5,500 HIV pts yearly. There is paucity of data on characteristics of HIV� 

cancers (ca) in the inner city. The CHAMP cohort is a retrospective study of 

all HIV associated cancers at CC and CCH over past 14 years (yrs). We 

analyzed all of the NADC from this cohort. Methods: All HIV pts with NADC 

were identified from the CHAMP cohort and retrospectively reviewed for 

HIV and cancer characteristics, overall survival (OS), and pt demographics. 

Statistics: Survival data was analyzed using Kaplan-Meier analysis and Cox 

Proportional Hazards model. Results: Of 438 pts identified, 157 were 

NADC representing 21 ca. The average (ave) age was 48 yrs (range 44-57), 

with prostate ca having highest age presentation. Over the past 10 yrs, the 

number of NADC has risen from 10 to over 20 each yr. Unlike historical 

controls (HC) where lung ca is most common, anal ca (21%) was most 

frequent followed by lung ca (17%). Prostate, head and neck (HNSCC), 

liver, and colorectal ca were seen in 9, 9, 8, and 7% respectively. 65% of 

pts were African Americans (AA) and 18% Caucasians. 78% of all NADC 

were men. 45% of anal ca present with stage IIIa/b disease, moderately to 

poorly differentiated ca in 48%, with a median OS of 34 mo. CD4 count did 

not alter OS but stage predicted better outcomes. 86% lung ca presented 

as stage III/IV disease with ave CD4 count 204. Histologically, 36% were 

SCC, 28% adenosquamous and 20% adenocarcinoma. OS was 5.5 mo and 

did not change by histology, CD4, or age. 68% HNSCC present with stage 

IVa/b but no IVc. Ave age was 48 yrs with an OS of 18mo. 50% were 

oropharyngeal compared to 22% in HC. Conclusions: Based on data by 

Sheilds et. al, CCH treats just over 1% of the country’s NADC population. 

We demonstrate a higher incidence of NADC over time, dominated by a 

younger, AA and male population. Each ca presents with advanced stage 

45-86% and poorly differentiated tumors ranging from 15-30%. The OS of 

each cancer is consistent with HC with exception of HNSCC. As HIV pts age 

becoming prone to cancers of elderly, education and screening of inner city 

HIV pts will help improve cancer rates. 


TPS1612 General Poster Session (Board #10F), Sat, 1:15 PM-5:15 PM 

The MIRACLE trial: A randomized, controlled trial comparing green tea 

extract versus placebo for the prevention of metachronous colon adenomas 

in a screening population. Presenting Author: Thomas Ettrich, Department 

of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle, 

Germany 

Background: Prevention of colorectal cancer is a major health care issue. 

After polypectomy there is an increased risk of polyp recurrence and various 

means of chemoprevention have been tried to prevent this. NSAIDs have 

been shown to be effective but confer side effects such as gastrointestinal 

bleeding. Nutraceuticals such as polyphenols from tea plants have demonstrated 

remarkable therapeutic and preventive effects in molecular, epidemiological 

and some clinical trials. However, their value in preventing 

colorectal polyps has not been demonstrated in a large, randomized trial. 

The beneficial safety profile of decaffeinated green tea extract and 

accumulating evidence of its cancer preventive potential justify and 

require, in our view, a validation of this compound for the nutriprevention of 

colorectal adenoma. Good accessibility and low costs might render this 

neutraceutical a top candidate for wider use as nutritional supplement in 

colon cancer prevention. Methods: Randomized, double blinded, placebocontrolled, 

multicenter trial. After a one month run-in period with verum, 

2534 patients (age: 50-80 years) who have undergone polypectomy within 

the last 6 months will be randomized to receive either decaffeinated green 

tea extract (containing 150 mg epigallocatechin gallate (EGCG) two times 

daily) or placebo over a period of three years. 2028 patients are expected to 

complete the whole study course. Primary outcome: Incidence of metachronous 

colorectal adenomas (tubulovillous, tubular, villous, serrated lesions) 

at the 3 year follow-up colonoscopy Secondary outcomes: Occurrences, 

number, localization, size and histological subtypes of adenomas, frequency 

of colorectal carcinoma. In addition, genetic and biochemical 

biomarkers in blood samples and genetic alterations (e.g. K-ras, B-raf, 

specific microRNAs) in tissue samples of adenomas will be analyzed 

(biobanking subprojects). Additionally, nutrikinetics and nutrigenetics of 

EGCG and other catechins will be assessed in healthy volunteers. Patient 

recruitment has started in November 2011. We expect the last patient out 

in fall 2017. (Trial identifier: NCT01360320) 

TPS1614 General Poster Session (Board #11B), Sat, 1:15 PM-5:15 PM 

Trial of exercise in ovarian cancer survivors. Presenting Author: Melinda 

Irwin, Yale University, New Haven, CT 

Background: Physical activity (PA) has been associated with improved QOL 

and survival in breast and colorectal cancer survivors, yet no study has 

examined the effect of exercise on ovarian cancer outcomes. The purpose of 

our NCI-funded trial is to examine, in 230 women diagnosed with Stage I-IV 

ovarian cancer, the impact of exercise vs. attention control on: QOL, body 

composition, and serum markers associated with ovarian cancer. This 

abstract presents preliminary recruitment and adherence results. Methods: 

Women are being recruited via Connecticut Tumor Registry and Yale Cancer 

Center into the Women’s Activity and Lifestyle Study in Connecticut 

(WALC). We are also recruiting patients nationally via self-referral and 

collaboration with medical oncologists at DFCI and Summa Akron City 

Hospital. Women are randomly assigned to exercise (n � 115) or attention 

control (n � 115). Both groups receive weekly telephone calls for six 

months from a certified health educator to discuss ovarian cancer health 

topics. In addition, the exercise group receives PA counseling to participate 

in 150 min/wk of aerobic exercise (primarily brisk walking) for six months. 

Results: Study recruitment began in March, 2010 and will be ongoing 

through December, 2013. As of December 31, 2011, we have identified 

556 potentially eligible women. Of these, 145 are recently diagnosed and 

are awaiting screening, 115 were unable to be contacted, and 296 have 

completed the telephone screening. Of the 270, 46% were ineligible (e.g., 

already exercising, physical limitations); 30% were not interested, 24% (n 

� 66) have been randomized, and 9% (n � 24) are undergoing baseline 

visits. On average, women are 62 years old, diagnosed 1.8 years in the past, 

with primarily stage III disease. Thirty-three patients have completed the 

trial, with high adherence among women randomized to exercise (average 

141 min/wk of exercise reported and 75% of exercisers participating in at 

least 150 min/wk of exercise). Conclusions: Women are interested in and 

able to participate in exercise after an ovarian cancer diagnosis. Our trial 

could suggest a unique and important role for exercise in ovarian cancer 

care given that physical and functional aspects of QOL are often the most 

compromised in ovarian cancer patients. 


TPS1613 General Poster Session (Board #11A), Sat, 1:15 PM-5:15 PM 

Mitigation of iatrogenic risk in young women Hodgkin’s survivors, acceptability 

of a structured information process. Presenting Author: François 

Eisinger, Institut Paoli Calmettes, Marseille, France 

Background: Long term follow up of cancer survivors uncovers iatrogenic 

risk. Higher risk for second cancers should be mainly observed for cancer 

with a high rate of therapeutic efficacy, using aggressive therapeutic and for 

cancers occurring in young people. Hodgkin lymphoma fits all these 

criteria. Consistent data about higher risk for breast cancer in these women 

had been published. However, risk management is not yet often carried out. 

Methods: We plan to carry out a national program aiming both at offering 

counselling and screening protocol and to assess key parameters allowing 

to better estimate risk, and offering acceptable and effective risk management 

option. Our National program will start in January 2013. We are now 

in a pilot phase in a single medical institution in which we offered women 

previously affected with an Hodgkin lymphoma to have access to risk 

analysis and information and if they agree to a specific breast cancer 

screening program. We present some of our psychosocial questionnaire 

analysis based on 27 women (aged 19-50 years old) fulfilled at the end of 

the information consultation and one month latter. Results: There was few 

or no negative assessment: no one stated that they express regrets to have 

been informed, nor they better ignore some delivered information, no one 

feel that risk management description is unsatisfying and no one will advice 

an other women against that kind of consultation. Only 4 out 27 i.e. 15% 

stated that there was in delivered information a source for anxiety. However 

positive assessment was only fairly high and not stable after one month. 

Information process to inform women survivors from Hodgkin lymphoma of 

their higher risk of being affected with a breast cancer and the current 

recommendation for earlier breast cancer screening reach a high level of 

satisfaction at the initial stage of the process. However it could decrease 

with time and thus, need to be monitored. 

At the end of 

the consult 

113s 

One month 

later 

No induced anxiety 11/27 (41%) 8/27 (30%) 

No regrets 17/27 (63%) 13/27 (48%) 

Nothing better to ignore 18/27 (67%) 13/27 (48%) 

Risk management clear and fine 17/27 (63%) 11/27 (41%) 

Advise other women to undergone such consult 16/27 (59%) 12/27 (44%) 

TPS1615 General Poster Session (Board #11C), Sat, 1:15 PM-5:15 PM 

Statin polyp prevention trial in patients with resected colon cancer: NSABP 

protocol P-5. Presenting Author: Bruce M. Boman, National Surgical 

Adjuvant Breast and Bowel Project and Helen F. Graham Cancer Center, 

Newark, DE 

Background: HMG-CoA reductase inhibitors (statins) are effective lipidlowering 

agents that are used for treating hyperlipidemia. Results from cell 

culture, animal experiments, and epidemiologic studies indicate that 

statins may be active chemopreventive agents against colorectal cancer 

(CRC). However, the clinical studies come largely from retrospective, 

observational studies originally designed to investigate lipid-lowering or 

cardiovascular endpoints rather than tumor endpoints. Methods: NSABP 

P-5 is a randomized, prospective placebo-controlled, double-blind study of 

rosuvastatin (10 mg per day x 5 years) or placebo for the prevention of 

adenomatous polyps of the colon or rectum, metachronous colorectal 

carcinoma, and colon cancer recurrence. Additional secondary endpoints 

include the size, number and features of the colorectal adenomas as well as 

health-related quality of life and self-reported symptoms. Selected Eligibility: 

(1) Patients who have undergone complete resection of AJCC Stage I or 

II colon cancer within 1 year before randomization. (2) Colonoscopy within 

180 days before randomization. Selected Ineligibility: (1) Hyperlipidemia, 

(2) Familial Adenomatous Polyposis, (3) Lynch Syndrome. Sample Size: 

1,740 patients will be entered, and as of January 23, 2012, 163 (9.37%) 

have been randomized. The study is open at NSABP and CTSU sites in 

North America. Funded by NCI PHS grants U10-CA-37377 and U10-CA- 

6974, with additional funding from AstraZeneca Pharmaceuticals, LP. 



TPS1616 General Poster Session (Board #11D), Sat, 1:15 PM-5:15 PM 

O6-benzylguanine (BG) and temozolomide (TMZ) therapy of glioblastoma 

multiforme (GBM) with infusion of autologous lentiviral transduced 

P140KMGMT� hematopoietic progenitors to protect hematopoiesis: A 

phase I study. Presenting Author: Andrew E. Sloan, University Hospital 

Case Medical Center, Cleveland, OH 

Background: The administration of radiation therapy (RT) and concomitant 

and adjuvant temozolomide (TMZ) for the treatment of newly-diagnosed 

glioblastoma (GBM) is associated with modestly prolonged survival. However, 

the benefit of concurrent therapy is restricted to a subgroup of 

patients whose tumor exhibits methylation of the promoter for methylguanine-DNA-methyltransferase 

(MGMT). Promoter methylation silences the 

expression of DNA alkyltransferase (AGT), the product of the MGMT gene 

which functions to repair alkylated DNA. Unfortunately, the majority of 

GBMs have non-methylated MGMT promoters and do not appear to benefit 

from adding TMZ to radiotherapy. Two potential strategies for targeting 

MGMT-induced chemoprotection in gliomas include depletion of tumor 

MGMT, and dose escalation of TMZ accomplished by minimizing TMZinduced 

bone marrow toxicity. In this study, we propose to combine the 

irreversible MGMT inhibitor O6-benzylguanine (BG) with infusion of autologous 

hematopoetic stem cells (HSCs) transduced with lentiviral P140K- 

MGMT, an MGMT mutant which is highly resistant to inactivation by BG, 

with the intent to reduce or prevent the myelosuppressive effects of TMZ. 

The primary objective is to assess the safety and feasibility of combining 

these two strategies in patients with newly-diagnosed GBM. Methods: This 

is a three cohort, Phase I study for patients with newly resected supratentorial 

GBM. There will be at least four evaluable patients per cohort. Cohort 1 

will receive standard RT and concomitant TMZ prior to infusion of 

autologous lentiviral P140K-MGMT transduced HSCs, followed by adjuvant 

TMZ. Cohort 2 will receive an induction dose of TMZ�BG followed by 

infusion of autologous LV-P140K-MGMT HSCs prior to concomitant RT 

�TMZ and adjuvant TMZ. Cohort 3 will include intra-patient dose escalation 

of TMZ in patients who exhibit detectable levels of P140K-MGMT 

marked cells in vivo, using the design (i.e. cohort 1 or 2) proven to be safest 

and most effective. The study is open and has accrued the first patient. 



MGMT promoter methylation as a predictive biomarker for response to 

radiotherapy versus chemotherapy in malignant astrocytomas in the elderly: 

The NOA-08 trial. Presenting Author: Wolfgang Wick, University 

Hospital Heidelberg, Heidelberg, Germany 

Background: In a few years more than half of the patients with glioblastoma 

will be older than 65 years of age and thus be classified as elderly. The 

current standard of care in elderly patients with glioblastoma (GB) or 

anapestic astrocytoma (AA) is resection or biopsy followed by involved-field 

radiotherapy (RT). The role of primary chemotherapy is poorly defined. The 

NOA-08 trial compared efficacy and safety of RT to temozolomide (TMZ) in 

patients with newly diagnosed AA or GB. Methods: Patients (N�412; 39 

AA, 373 GB) � 65 years with a Karnofsky performance score � 60 were 

randomized to receive RT or TMZ. The primary endpoint was overall survival 

(OS). The trial sought to demonstrate the non-inferiority of TMZ compared 

with RT. Results: Patient characteristics in the intention-to-treat population 

[N�373 (178 patients RT, 195 patients TMZ)] were balanced. All 

histologic diagnoses (11% AA and 89% GB) were centrally confirmed. 

Median OS [HR�1.09 (95% CI: 0.84-1.42)] and event-free survival (EFS) 

[hazard ratio (HR)�1.15 (0.92-1.43)] of TMZ versus RT did not differ 

between both arms. Non-inferiority of TMZ compared with RT was significant 

(p�0.05). Extent of resection, but not age or diagnosis of AA were 

associated with prolonged EFS and OS. DNA repair protein O6-methylgua nine DNA-methyltransferase (MGMT) promoter methylation in tumor tissue 

was associated with prolonged OS [HR�0.67 (0.38-1.29)]. Patients with 

MGMT promoter methylation had longer EFS when treated with TMZ (8.4 

months [5.5-11.7] versus RT (4.6 [4.2-5] months) whereas patients 

without MGMT promoter methylation had longer EFS when treated with RT 

(4.6 [3.7-6.3] versus 3.3 [3-3.5] months). This effect persisted for OS. 

Conclusions: NOA-08 demonstrates the non-inferiority of TMZ compared 

with RT in the treatment of elderly patients with malignant astrocytoma. 

MGMT promoter methylation is a strong predictive biomarker for the choice 

between RT and TMZ. 


The NF�B pathway as a key mediator of the glioblastoma mesenchymal 

subtype in glioblastoma stem cells and human tumors. Presenting Author: 

Brian D. Vaillant, The Methodist Hospital, Houston, TX 

Background: The mesenchymal (MES) subtype of glioblastoma (GBM) is 

associated with worse prognosis and increased treatment resistance. 

Several transcription factors driving the MES phenotype have been identified, 

including STAT3, CEBP-�, and WWTR1/TAZ. However, the key 

signaling pathways driving this transcriptional program remain unknown. 

Methods: Expression profiling analyses was performed on multiple GBM 

stem cell (GSC) lines derived from individual human tumors. Three large 

GBM tumor gene expression datasets (TCGA, Rembrandt, Erasmus) were 

also used in the analyses to identify pathways activated in MES tumors and 

GSCs. Intracranial GSC xenograft models were used for in vivo validation. 

Results: We found that GSCs with a MES phenotype also demonstrated 

upregulation of a gene cassette associated with NF�B activation. Analysis 

of multiple large expression data sets also demonstrated a tight correlation 

between the MES phenotype and NF�B activation in human tumors. To 

determine the effect of NF�B activation in GSCs, we stimulated NF�B by 

addition of the inflammatory cytokine TNF�. This was accompanied by 

increased expression of the MES transcription factors (STAT3, CEBP-�, 

TAZ), and MES markers including CD44. Conversely, blockade of NF�B 

signaling in GSCs by I�B-� was sufficient to prevent TNF-induced MES 

transition. Investigation of potential source of NF�B activation suggested a 

role of microglia. Indeed, addition of supernatant from activated microglia 

was sufficient to activate NF�B and MES transition in GSCs that could be 

blocked by I�B-�. To test the role of microglia and NF�B activation on 

treatment resistance in vivo, treatment with minocycline, an inhibitor of 

microglia activation, led to a reduction of tumor grade and down-regulation 

of MES markers in intracranial GSC xenografts. Conclusions: NF�B appears 

to play an important role in induction of the MES phenotype in GBM and 

GSCs. Furthermore, activation of microglia is a potential source of NF�B 

activation in these tumors. These data suggest that blockade of NF�B 

and/or inhibition of microglia activation may be attractive therapeutic 

approaches for downregulating MES transition and overcoming treatment 

resistance in GBM. 



A revised RTOG recursive partitioning analysis (RPA) model for glioblastoma 

based upon multiplatform biomarker profiles. Presenting Author: 

Arnab Chakravarti, Arthur G. James Cancer Center, The Ohio State 

University, Columbus, OH 

Background: The Radiation Therapy Oncology Group (RTOG) recursive 

partitioning analysis (RPA) model, which relies on clinical variables, has 

been used worldwide to establish distinct prognostic classes of patients 

(pts) with malignant glioma as well as eligibility criteria for clinical trials. In 

the present study, we have updated the RPA to include additional 

molecular variables, specifically for glioblastoma (GBM) patients treated in 

the temozolomide (TMZ)-era, to make the model more relevant, contemporary, 

and discriminatory. Methods: The dataset utilized was from RTOG 

0525, a phase III study examining radiation (RT) with concurrent TMZ, 

followed by adjuvant standard dose vs. dose-dense TMZ in pts with 

newly-diagnosed GBM. 162 pts from RTOG 0525 had available tissues for 

profiling of key signaling molecules using the AQUA platform. Results: 

pAKT, c-met, and MGMT protein were each found to be significantly 

associated with adverse outcome on multivariate analysis. These variables 

were combined with clinical and genetic biomarkers (e.g., MGMT promoter 

methylation, IDH1 mutation, mRNA profiling) previously found to be of 

significance (MCP model, ASCO, 2011) to generate an even more robust, 

discriminatory RTOG RPA model. The explained variation for these three 

classification models was found to be 41.7 (Current RPA), 19 (MCP), and 

14.9% (Clinical RPA), respectively, with higher values indicating better 

separation of prognostic groups (see table). Conclusions: The current RTOG 

RPA classification model, based upon incorporation of multi-platform 

biomarker analysis, holds promise for RT�TMZ-treated GBM patients; 

further validation of this model is planned. Financial Support: NCI grants 

U10 CA21661, U10 CA37422, U24 CA114734, 1RC2CA148190, 

1RC2CA148190, RO1CA108633, and BTFC grant. 

Clinical RPA Current RPA 

Model class 

Median 

survival 

(months) 

Lower 95%> 

confidence 

limit (CL) 

Upper 

95% CL 

No. 

cases 

(%) 

Model 

class 

Median 

survival Lower 

(months) 95% CL Upper 

95% CL 

115s 

No. 

cases 

(%) 

III 33.3 16.8 -na- 32 (19.6) III -na- 23.5 -na- 17 (10.5) 

IV 16.3 13.4 19.9 89 (55.9) IV 22.4 15.5 33.3 33 (20.4) 

V 13.1 7.9 16.6 41 (25.3) V 15.7 12.9 17.0 101 (62.4) 

VI 5.2 2.2 13.6 11 (6.8) 

Abbreviation: na, not reached. 


Randomized phase II 8-arm factorial study of adjuvant dose-dense (dd) 

temozolomide (TMZ) with permutations of thalidomide (Thal), isotretinoin 

(CRA), and/or celecoxib (Cel) for newly diagnosed glioblastoma (GBM). 

Presenting Author: Mark R. Gilbert, University of Texas M. D. Anderson 


Background: Concurrent radiation and TMZ followed by 6-12 months of 

adjuvant TMZ (d 1-5 of a 28d cycle) is the current standard of care for 

patients with newly diagnosed GBM. The addition of cytostatic or signal 

transduction agents may enhance efficacy without a significant increase in 

toxicity. A phase I trial (Neuro-oncology 2009) established the safety of 

ddTMZ with 2 or 3 of the cytostatic agents. Methods: This randomized 

phase II study was conducted by the Brain Tumor Trials Collaborative 

(BTTC) and the MDACC CCOP. The primary objectives: determine if 

specific cytostatic agents added to ddTMZ alters outcomes (PFS, OS) and 

compare triplet with doublet therapy. Eligibility criteria: centrally confirmed 

newly diagnosed GBM, age �18, KPS�60, stable or improved after 

chemoradiation (pseudoprogression allowed), adequate hematologic, renal 

and hepatic function. Pts were randomly assigned to 12 treatment cycles 

(28 d/cycle) in 8 arms: ddTMZ alone (150 mg/m2/day, 7-d on, 7-d off) or 

TMZ-containing doublet, triplet and quadruplet combinations with Thal, 

CRA, or Cel. Results: The study enrolled 155 eligible patients from 

11/2005 to 9/2010 to the 8 arms of the factorial design. Median age was 

53 (18-84) and median KPS, 90 (60-100). Compared with TMZ alone, the 

TMZ�CRA doublet had worse PFS (10.5, 6.5 mo; p�0.043) and OS 

(21.2, 11.7 mo; p�0.037). Trends were also seen for worse outcome (PFS, 

OS) for CRA-containing regimens, improved OS for Cel containing arms and 

no impact of Thal. A strong trend for OS improvement was seen for triplet 

compared with doublet regimens (20.1, 17.0 mo; p�0.15), but no 

difference for PFS. Treatment was well tolerated with expected high rates of 

grade 3/4 lymphopenia, and overall a modest toxicity rate. Conclusions: The 

results indicate that the addition of CRA to ddTMZ may be detrimental in 

patients with newly diagnosed GBM. This study demonstrated the utility of 

the factorial design in efficiently testing drug combinations, the impact of 

individual agents in these combinations as well as doublet vs. triplet 

regimens and supports its utility in testing combinations of targeted agents. 


116s Central Nervous System Tumors 


Relationship between overall survival and progression-free survival for 

recent NCCTG glioblastoma multiforme trials. Presenting Author: Wenting 

Wu, Mayo Clinic, Rochester, MN 

Background: With the approval of novel agents for glioblastoma (GBM) 

treatment, reliable historical outcome data for the common phase II 

endpoint of progression free survival (PFS) is not available. In particular, 

the association between progression and overall survival (OS) has not been 

evaluated after temozolomide (TMZ) became the standard therapy for 

newly diagnosed GBM. Methods: Datasets from 5 TMZ-including NCCTG 

clinical trials in newly diagnosed GBM (n�325, 2005-2011, 1 phase I 

only and 4 phase I and single arm phase II trials) were pooled and analyzed 

to evaluate the individual level correlation between PFS and OS using 

correlation coefficient, landmark analyses, and time-dependent variable 

analyses. A historical control group was constructed by pooling datasets 

from 12 pre-TMZ era NCCTG clinical trials in the same patient population 

(n�1359, 1980-2004). Each of the 5 newer trials was compared to the 

control group to estimate the treatment effect (hazard ratio) on PFS and 

OS, which were analyzed to evaluate the trial level correlation between PFS 

and OS using correlation coefficient and weighted linear regression. 

Results: The estimated correlation coefficient between PFS and OS at 

individual patient level is 0.75 (95%CI, 0.7 to 0.8). The estimated hazard 

ratios of death in the landmark analysis at 4 and 6 months are 2.15 

(95%CI, 1.47 to 3.15) and 2.17 (95%CI, 1.57 to 3.12), respectively, and 

the estimated hazard ratio of death is 10.1 (95%CI, 6.6 to 15.4) when 

progression is treated as a time-dependent variable. For trial level correlation 

(against the historical control group), the estimated correlation 

coefficient between HRos and HRpfs is 0.51 (95%CI, -0.67 to 0.96), with 

moderate prediction: the predicted HRos is very close to the observed HRos in 4 of 5 cases, however the predicted HRos is significantly different from 1 

in only 2 out of 5 cases due to small sample size in other 3 cases. 

Conclusions: PFS and OS are highly associated at the individual patient 

level but only moderately at the trial level, the latter possibly due to small 

sample size in some of the trials. Additional validation in other trials could 

support use of PFS as a primary endpoint for randomized phase II trials in 

GBM. 


Consolidation reduced dose whole brain radiotherapy (rdWBRT) following 

methotrexate, rituximab, procarbazine, vincristine, cytarabine (R-MPV-A) 

for newly diagnosed primary CNS lymphoma (PCNSL): Final results and 

long-term outcome. Presenting Author: Richard Charles Curry, Memorial 


Background: After promising early results in the pilot phase (N� 30) 

reported by Shah 2007, we report on final results of a multicenter phase II 

study (N�52) in newly diagnosed PCNSL combining R-MPV-A and rdW- 

BRT, expanded to address long-term disease control and cognitive outcomes 

in pts who actually received rdWBRT. Methods: Pts received 5 cycles 

of R-MPV (MTX dose: 3.5g/m2). Those with partial response (PR) received 

additional 2 cycles. Pts with a complete response (CR) after 5-7 cycles 

received rdWBRT (23.4 Gy), otherwise standard WBRT was offered (45 

Gy). Consolidation cytarabine was given to all pts. Primary end-point was 

2-y progression-free survival (PFS) in pts receiving rdWBRT (n�30 pts in 

CR required). Exploratory end-points included comprehensive neuropsychological 

testing, white matter changes (WMC) analysis (Fazekas scale) and 

apparent diffusion coefficient (ADC) on MRI. Results: Accrual was completed 

(N�52; 22 women); median (med) age� 60 (30-79); med KPS� 

70 (50-100). In total, 31 (59%) pts were assessable for the primary 

endpoint (achieved a CR after induction and received rdWBRT). The 2-y 

PFS for this group was 78% (95% ci: 64%- 92%); med PFS� 7.7 y; the 

med OS was not reached (med follow-up� 6y); 3y-OS� 88% (ci 70-95); 

5y-OS� 81% (ci 62-91). Cognitive testing showed improvement in 

executive function (P � 0.01) and verbal memory (P � 0.05) following 

induction chemotherapy; follow-up scores remained stable across the 

various domains. Minimal WMC developed in long term survivors: 36% of 

pts showed no change in Fazekas’ scores, 64% of pts developed scores 1 or 

2 and no pt showed scores 3-6. The intent-to-treat (n�52) med PFS was 

3.3y; med OS� 6.6 y. Differences in ADC values did not predict response 

(p�0.15), PFS (p�0.41) or OS (p�0.48). Conclusions: Consolidation 

rdWBRT is a highly effective and safe treatment for newly diagnosed 

PCNSL. Long term follow-up showed robust PFS and OS, comparable or 

superior to full dose WBRT, with excellent cognitive outcomes and no 

significant WMC over time. An RTOG randomized trial has been initiated 

comparing R-MPV-A with vs without rdWBRT. 


Bayesian adaptive randomized trial design for patients with recurrent 

glioblastoma. Presenting Author: Brian Michael Alexander, Dana-Farber 

Cancer Institute/Brigham and Women’s Cancer Center, Boston, MA 

Background: Bayesian-based trial design has the ability to utilize accumulating 

data in real time to alter the course of the trial, thereby enabling 

dynamic allocation to experimental arms and earlier dropping of ineffective 

arms. This flexibility results in a potentially more efficient trial framework 

by increasing the probability of enrollment to arms that show evidence of 

efficacy. In this study we considered a hypothetical scenario in which 

patients who have been previously treated on several separate experimental 

protocols at the Dana-Farber/Harvard Cancer Center and the University of 

California, Los Angeles were instead enrolled in a single multi-arm protocol 

utilizing a Bayesian adaptively randomized trial design. The purpose was to 

determine whether similar scientific results could have been accomplished 

more efficiently. Methods: We generated an adaptive randomization procedure 

that was retrospectively applied to primary patient data from four 

separate phase II clinical trials in patients with recurrent glioblastoma. We 

then compared AR to more conventional trial designs using realistic 

hypothetical scenarios consistent with survival data reported in the literature. 

Our primary endpoint is the number of patients needed to achieve a 

desired statistical power. Results: If our phase II trials had been a single 

multi-arm AR trial, bevacizumab would have been identified as an 

efficacious therapy, and 30 fewer patients would have been needed 

compared to a multi-arm balanced randomized (BR) design. More generally, 

Bayesian AR trial design for patients with glioblastoma would result in 

trials with fewer overall patients with no loss in statistical power, and in 

more patients randomized to effective treatment arms. For a trial with a 

control arm, two ineffective arms and one effective arm with hazard ratio 

0.6, a median of 47 patients would be randomized to the effective arm 

compared with 35 in a BR design. Conclusions: Given the desire for control 

arms in phase II trials, an increasing number of experimental therapeutics 

for patients with glioblastoma, and a relatively short time for events, 

Bayesian adaptive designs are attractive for clinical trials in glioblastoma. 


Elderly patients with primary CNS lymphoma: Results from the G-PCNSL- 

SG-1 trial. Presenting Author: Patrick Roth, University Hospital Zurich, 

Zurich, Switzerland 

Background: Age is the most important therapy-independent prognostic 

factor in patients with primary central nervous system lymphoma (PCNSL). 

Here we aimed at providing an analysis of the impact of higher age on 

response to therapy, toxicity, and survival in the largest PCNSL trial ever 

performed to date. Methods: Response to therapy, toxicity and survival of 

PCNSL patients enrolled in the G-PCNSL-SG-1 trial evaluating the role of 

radiotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy 

were monitored. Subjects aged 70 or more were compared to younger 

patients. Results: Of all eligible patients (n�526), 126 (24%) were aged 

70 or more. In the per protocol population, 66 of 318 patients (21%) were 

at least 70 years old. Among the eligible patients, the rate of complete and 

partial responses (CR�PR) to HD-MTX-based chemotherapy was 44% in 

the elderly compared to 57% in the younger patients (p�0.016). A higher 

rate of grade III/IV leukopenia was observed in the elderly (34% versus 

21%, p�0.007). Also, death on therapy was more frequent (18% versus 

11%; p�0.027) in these patients. In contrast, there was no other major 

age-dependent toxicity. Survival analyses revealed shorter progression-free 

survival (PFS) (4.0 versus 7.7 months, p�0.014) and overall survival (OS) 

(12.5 versus 26.2 months, p�0.001) in the elderly population. The PFS of 

CR patients was 35.0 months in younger patients compared to 16.1 in the 

elderly (p�0.024). Salvage therapy was used less commonly in elderly 

patients. When salvage WBRT was applied in patients who had failed on 

HD-MTX-based chemotherapy, there was no association between age and 

survival (p�0.633). Conclusions: Elderly PCNSL patients have a lower 

response rate and higher mortality on HD-MTX-based chemotherapy. Their 

PFS is shorter and they receive less salvage therapy which may contribute 

to the poor prognosis. 



Rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) 

followed by consolidation high-dose chemotherapy (HDC) and autologous 

stem-cell transplant (ASCT) for newly diagnosed primary CNS lymphoma 

(PCNSL). Presenting Author: Antonio Marcilio Padula Omuro, Memorial 


Background: In our previous study in newly diagnosed PCNSL, induction 

chemotherapy with MTX and cytarabine followed by consolidation HDC 

(carmustine, etoposide, cytarabine, melphalan [BEAM]) with ASCT without 

radiotherapy resulted in only 50% of pts transplanted, reflecting low 

efficacy of induction chemotherapy, and short intent-to-treat (ITT) median 

PFS (�6m). In this phase II trial, we sought to optimize this strategy by 

utilizing a more effective induction regimen (R-MPV) and a more aggressive 

HDC regimen (Soussain et al). Methods: Pts received 5-7 cycles of R-MPV 

(MTX: 3.5g/m2) and if a partial or complete response was achieved, HDC 

with thiothepa, cyclophosphamide and busulfan was given, followed by 

ASCT and no radiotherapy. The primary endpoint was ITT 1 year event-free 

survival (promising: 75%, non-promising: 50%; 90% power, significance�0.05). 

Follow-up included comprehensive neuropsychological evaluation. 

Results: Accrual has been completed (N�32 pts, median age 57 

[range 23-67], median KPS�80). Following R-MPV, 17 pts achieved a CR, 

13 pts a PR and two pts progressed. A total of 25 (78%) pts were 

transplanted; the reasons for not receiving transplant were progressive 

disease (N�2), poor performance status/ physician’s decision (N� 2), 

mobilization failure (N�1) and consent withdrawn (N� 2). One pt who 

withdrew consent relapsed and received HDCASCT for salvage. Two (8%) 

pts died from early complications of ASCT (Stevens-Johnson: one, sepsis: 

one) and one pt experienced a fatal late colitis of unknown etiology. In the 

ITT population, the median EFS and OS have not been reached after a 

median follow-up of 22 months. The 1 year EFS was 78% (95%CI 58-90) 

and the 2y OS was 76% (95% CI 54-89). No pt has developed delayed 

neurotoxicity. Conclusions: R-MPV induction regimen resulted in improved 

response rates, allowing 78% of pts to receive HDC-ASCT. Although more 

toxic, this regimen resulted in excellent disease control and survival in the 

ITT population, far exceeding the efficacy of our previous transplant study. 

The primary endpoint was met, warranting further investigation. 


Effects of cediranib, a VEGF signaling inhibitor, in combination with 

chemoradiation on tumor blood flow and survival in newly diagnosed 

glioblastoma. Presenting Author: Elizabeth Robins Gerstner, Massachusetts 

General Hospital, Boston, MA 

Background: Anti-angiogenic therapy is hypothesized to synergize with 

radiation and chemotherapy by improving tumor blood flow. We evaluated 

the tolerability, efficacy and potential mechanism of action of radiation, 

temozolomide, and cediranib in newly diagnosed glioblastoma patients. 

Methods: Newly diagnosed glioblastoma patients were treated with radiation, 

temozolomide, and cediranib followed by monthly temozolomide for 6 

cycles and daily cediranib until tumor progression or toxicity as part of an 

IRB-approved, Phase Ib/II clinical trial. MRI scans including measurement 

of cerebral blood flow were performed at baseline, weekly during the 6 

weeks of chemoradiation and then monthly. Radiographic response was 

determined by RANO criteria. Results: Six patients were enrolled in the 

phase Ib part of the study with cediranib 30 mg daily in combination with 

temozolomide and radiation. No dose-limiting toxicities were identified. 

Forty patients were enrolled in the phase II part of the study. Among the 

entire cohort of 46 patients, median age was 57 (range 35-74), median 

KPS was 90% (60-100), 36 patients underwent a subtotal resection and 

10 underwent biopsy. 26/30 patients taking corticosteroids were able to 

taper corticosteroids during chemoradiation. Off study reasons included 

toxicity (14), disease progression (18), and patient preference (2). Five 

patients remain on study without disease progression and 20 patients have 

died. Median duration on study was 158 days. Median progression free 

survival was 288 days (95%CI 240,�) and median overall survival was 786 

days (95%CI 411 ,�). Best radiographic response in patients who completed 

chemoradiation was CR in 2 patients, PR in 20 patients, and SD in 

15 patients. Patients with increased tumor perfusion during chemoradiation 

survived nearly 1 year longer (mean OS�611 days) than patients with 

decreased perfusion (mean OS�269 days). Conclusions: Cediranib was 

well tolerated and led to improved PFS and OS compared to historical 

controls, particularly in those with improved perfusion. This combination is 

being evaluated in an ongoing randomized trial (RTOG 0837). 


117s 

2008b Oral Abstract Session, Sun, 8:00 AM-11:00 AM 

Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with 

anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase 

III study. Presenting Author: J. Gregory Cairncross, University of Calgary, 

Calgary, AB, Canada 

Background: Anaplastic oligodendrogliomas, pure (AO) and mixed (AOA), 

are chemosensitive tumors, especially if co-deleted for chromosomes 1p 

and 19q, but whether addition of CT to RT prolongs overall survival (OS), is 

unknown. Methods: In the RTOG 9402 Phase III trial, patients (pts) with 

AO/AOA were randomly assigned to PCV [procarbazine, CCNU (lomustine) 

and vincristine] followed by immediate RT vs. immediate RT alone. Early 

analysis showed no OS benefit for the PCV�RT group but combined therapy 

was associated with a longer progression-free survival (PFS). It also showed 

that the finding of 1p/19q co-deletion was associated with a longer OS 

independent of treatment. The current analysis has a median follow up of 

11.3 years (yrs). Results: Two hundred ninety-one patients were randomized, 

148 to PCV�RT and 143 to RT. PCV�RT was associated with longer 

PFS [2.5 vs. 1.7 yrs, hazard ratio (HR) 0.68, 95% confidence interval (CI) 

(0.53, 0.88), P � 0.003] and the 1p/19q co-deletion with a longer Median 

Survival Time (MST) [8.7 vs. 2.7 yrs, HR 0.41, 95% CI (0.30, 0.55), P � 

0.001]. For the entire cohort, there was no difference in MST by treatment 

[4.6 yrs for PCV�RT vs. 4.7 yrs for RT, HR 0.79, 95% CI (0.60, 1.04), P � 

0.1]. However, patients with 1p/19q co-deleted tumors lived much longer 

after PCV�RT (n � 59) than after RT (n � 67) [14.7 vs. 7.3 yrs, HR 0.59, 

95% CI (0.37, 0.95), P � 0.03]. There was no difference in MST by 

treatment in pts without the 1p/19q co-deletion [n�137; 2.6 vs. 2.7 yrs, 

HR 0.85, 95% CI (0.58, 1.23), P � 0.39]. Re-operation rates upon 

progression were similar between treatment arms in co-deleted pts (43%, 

PCV�RT vs. 54%, RT) but salvage CT rates were higher in the RT arm [57% 

vs. 81% (P � 0.04)]. Conclusions: PCV followed by immediate RT was a 

highly effective therapy for patients with 1p/19q co-deleted AO/AOA. In 

this setting, 1p/19q co-deletion was both prognostic and predictive, and 

the early PFS benefit in co-deleted cases was a harbinger of their longer OS. 

[This work was supported by RTOG grants U10 CA21661 and U10 

CA32115, NCCTG grant U10 CA25224, ECOG grants CA17145 and 

CA21115, SWOG grant CA32102, and CCOP grant U10 CA37422 from 

the National Cancer Institute (NCI)] 


Effect of antiangiogenic therapy on tumor-associated macrophages in 

recurrent glioblastoma. Presenting Author: Christine Lu-Emerson, Massachusetts 


Background: Antiangiogenic therapy is associated with increased radiographic 

responses in glioblastoma (GBM), but tumors invariably recur. 

Tumor associated macrophages (TAMs) have been proposed as a mechanism 

of resistance to anti-angiogenic therapy in preclinical models. To 

examine the role of TAMs in recurrent GBM, we analyzed autopsy 

specimens from patients with or without history of antiangiogenic therapy. 

Methods: We compared autopsy brain specimens from 17 recurrent GBM 

patients who received anti-angiogenic treatment and chemoradiation 

(AAT�) to 7 patients who received chemotherapy and/or radiotherapy 

without anti-angiogenic therapy, or no treatment (AAT-). TAMs were 

morphologically and phenotypically identified with flow cytometry and 

immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 

markers. All specimens were obtained from the Department of Pathology at 

Massachusetts General Hospital and clinical information gained through 

review of the patients’ records. Results: Using flow cytometry, we observed 

an increase in CD11b�CD14� cells in the AAT� patients compared to 

AAT- patients. Using IHC analysis, we observed a significant increase in 

CD68� macrophages in the tumor bulk (p�0.01) and infiltrative areas 

(p�0.05) in AAT� versus AAT- patients. We also observed a significant 

increase in CD11b� myeloid cells in the tumor bulk (p�0.01) and a 

significant increase in CD163� cells in the infiltrative areas (p�0.05) in 

the AAT� group. Finally, we noted a trend toward an increase in CD163� 

cells in the tumor bulk (p�0.087) in the AAT� versus the AAT- patients. 

Conclusions: Patients with recurrent GBM after antiangiogenic therapy 

showed a significant increase in CD68� TAMs and in CD11b� cells in the 

tumor bulk. Additionally, antiangiogenic treatment induced an increase in 

CD68� and CD163� TAMs in the infiltrative region. These data indicate 

that TAMs may participate in escape from antiangiogenic therapy and may 

represent a future therapeutic target in recurrent GBM. 




Modulation of antiangiogenic resistance: Targeting the JAK/STAT3 pathway 

in glioblastoma. Presenting Author: John Frederick De Groot, University 


Background: Determining the mechanism of treatment failure of antiangiogenic 

therapies would provide insight into either potential combination 

approaches or salvage therapies. Methods: Tumor and monocyte expression 

of phosphorylated-signal transducer and activator of transcription 3 (p- 

STAT3) was compared between recurrent glioblastoma patients treated 

with either conventional chemotherapy or bevacizumab (BEV), and secondarily 

validated in murine model systems of intracerebral glioma treated with 

either BEV or cediranib. The JAK/STAT3 inhibitor AZD1480 alone and in 

combination with cediranib was evaluated in immunocompetent mice 

bearing intracerebral GL261 xenografts to evaluate therapeutic synergy. 

Results: Human glioblastoma patients failing BEV have an increase in 

intratumoral p-STAT3- expression with a mean number of p-STAT3 

expressing cells of 36.5 � 8.6% (n�7) compared to a mean of 20.2 � 4% 

(n�5) in patients never receiving antiangiogenic therapy. In a separate 

cohort of recurrent glioblastoma patients, the up-regulation of p-STAT3 

was detected in monocytes within 24 hours after initial BEV administration. 

In intracranial xenograft models, both BEV and cediranib extended 

median animal survival time, but during treatment failure BEV increased 

the mean percentage of p-STAT3-expressing cells to 24.6 � 6.4% 

(P�0.0011), and cediranib increased this to 16.2 � 1.8% (P�0.0125) 

relative to 9.0 � 4.4% in controls. Administration of the JAK/STAT3 

inhibitor AZD1480 alone and in combination with cediranib reduced tumor 

hypoxia and infiltration of VEGF inhibitor-induced p-STAT3 macrophages. 

The combination reduced tumor volume by 80% compared to untreated 

controls, and by 65% compared to cediranib or AZD1480 treatment alone. 

Microvascular density and tumor de-differentiation were reduced, indicating 

that up-regulation of the STAT3 pathway can mediate resistance to 

antiangiogenic therapy. Conclusions: Cumulatively, these data suggest that 

a prominent mechanism of failure of anti-VEGF therapy in malignant 

glioma patients involves up-regulation of the STAT3 pathway, and resistance 

to antiangiogenic therapy can be modulated with inhibitors of the 

JAK/STAT pathway. 

2013 Poster Discussion Session (Board #1), Fri, 1:00 PM-5:00 PM and 

4:30 PM-5:30 PM 

Phase I safety and pharmacokinetic (PK) study of veliparib in combination 

with whole brain radiation therapy (WBRT) in patients (pts) with brain 

metastases. Presenting Author: Minesh P. Mehta, Northwestern University, 

Chicago, IL 

Background: Veliparib is an oral PARP-1 and -2 inhibitor that enhances the 

antitumor activity of DNA damaging agents including radiation therapy in 

vivo. In pre-clinical models, veliparib crosses the blood-brain barrier. This 

ongoing phase I dose-escalation study evaluates the safety, PK, and 

provides preliminary antitumor activity of veliparib in combination with 

WBRT in pts with brain metastases. Methods: Pts with brain metastases 

from non-CNS primary solid malignancy, adequate organ function, RPA 

Class 2, and KPS �70 were treated with WBRT (37.5 Gy in 15 fractions or 

30 Gy in 10 fractions) QD with veliparib BID with every fraction of WBRT in 

escalating doses of 10, 20, 30, 50, 100, 150, and 200 mg; the final WBRT 

fraction was followed by 1 extra day of veliparib. Safety, PK, and tumor 

response by RECIST were assessed. Results: At the time of reporting 59 pts 

(M/F, 21/38; median age 57 y) had been treated. Baseline KPS was 70, 

80, 90, and 100 in 6.8, 32.2, 40.7, and 20.3% pts, respectively; primary 

tumor types were breast (n�20), NSCLC (n�20), melanoma (n�9), 

colorectal (n�2), and others (n�8); 71.2% pts had multiple lesions; and 

18.6% had prior brain SRS. Grade 3/4 treatment-emergent adverse events 

(TEAEs; �5%) were fatigue (6.8%), anemia (5.1%), hyponatraemia 

(5.1%), and thrombocytopenia (5.1%); other TEAEs (�20%) were fatigue 

(57.6%), headache (42.4%), nausea (40.7%), alopecia (28.8%), vomiting 

(22%), radiation skin reactions (22%), and decreased appetite (22%). PK 

of veliparib were approximately dose-proportional, with oral clearance of 

21.6 � 14.2 L/h (mean � SD, n�45), minimal drug accumulation at day 

15, and no significant effect of food on bioavailability. Tumor response was 

evaluable in 48 pts. Best tumor response and median survival were 37.5% 

and 10 months (m) for NSCLC, and 52.9% and 12.5 m for breast cancer 

(excluding pts with leptomeningeal disease). Conclusions: Addition of 

veliparib up to 200 mg BID was well tolerated with concurrent WBRT and 

dose escalation ongoing. The PK of veliparib was dose proportional with no 

food effect. Preliminary antitumor activity is encouraging and informative 

for the design of more definitive trials. 


Effects of cediranib (VEGF signaling inhibitor) on edema in newly diagnosed 

glioblastoma patients during initial chemoradiation. Presenting 

Author: Pavlina Polaskova, Martinos Center for Biomedical Imaging, 

Massachusetts General Hospital, Charlestown, MA 

Background: A significant benefit of antiangiogenic therapy is control of 

brain edema. We evaluated the impact of adding cediranib to standard 

chemoradiation (CRT) on peritumoral edema in patients with newly 

diagnosed glioblastoma(GBM) during the initial 6 weeks of CRT. Methods: 

Two cohorts of patients were enrolled in two clinical trials. The control 

group (N�13) received radiation for 6 weeks plus temozolomide. The 

cediranib (CED) group received standard CRT plus daily cediranib (N�34). 

MRIs were performed at baseline and weekly during CRT. Volumes of 

interest (VOIs) were drawn outlining the enhancing tumor on T1-weighted 

post contrast images and the abnormal FLAIR hyperintensity. ADC (apparent 

diffusion coefficient) maps were calculated from diffusion-weighted 

images and histograms of the distribution of ADC values created for each 

visit using the baseline FLAIR VOI to characterize the peritumoraledema. 

Patients were on stable or decreasing doses of steroids. Results: In the CED 

group, T1 and FLAIR VOI decreased during CRT vs controls where T1 VOI 

did not change and FLAIR VOI increased. By the end of CRT, the mode of 

the ADC histogram in the CED group shifted to the left while the mode of 

the controls shifted to the right. The skewness, a measure of asymmetry of 

the distribution, increased in the CED group and decreased in controls. 

Conclusions: In patients with newly diagnosed GBM treated with CRT and 

cediranib, tumor volume decreased on T1 and FLAIR images whereas the 

FLAIR volume significantly increased in the control group suggesting 

increased edema. The shift of mode to the right and decreasing skewness in 

controls (indicating an increase in the proportion of very high ADC values) 

suggests that adding cediranibprevented the development of edema and 

contributed to the resolution of existing edema. Preventing the edema by 

adding anti-VEGF treatment may improve the tolerability of CRT for GBM 

patients. 

T1 VOI 

(ml) 

FLAIR VOI 

(ml) 

ADC histogram mode 

(x10 -4 �m 2 /ms) 

ADC histogram 

skewness 

Baseline 6 wks Baseline 6 wks Baseline 6 wks Baseline 6 wks 

CED 18.0 11.5 36.0 32.9 10.8 10.1 2.64 2.97 

Control 14.8 14.5 25.9 57.1* 9.5 11.8* 2.62 2.42 

* Significant difference between CED and controls (p � .05). 


4:30 PM-5:30 PM 

FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS 

met): Potential predictors of patient outcome. Presenting Author: Nooshin 

Hashemi Sadraei, Cleveland Clinic Foundation, Cleveland, OH 

Background: Patients with CNS met have a poor outcome with significant 

variation in overall survival. No marker to predict survival exists. Rb1 is a 

negative regulator of the cell cycle, and FiP200 is an upstream signaling 

node that is distributed between the nucleus and cytoplasm. Nuclear 

FIP200 inhibits cell proliferation by promoting expression of Rb1, whereas 

cytoplasmic FIP200 promotes cell survival through autophagy. Previously 

FIP200 deletion/mutation has been reported in 20% of primary invasive 

breast cancer [BR ca] patients. FIP200 cellular localization and genetic 

alterations have not been examined in CNS met. Methods: A retrospective 

analysis of BR ca and CNS met was performed based on tissue availability 

from 2 institutions. FIP200 and Rb1 expression and localization was 

evaluated by immunohistochemistry. Genetic alterations were evaluated by 

DNA array analysis. Results: 80 patients (42 BR ca and 38 CNS met) were 

identified. Overall CNS met samples had significantly higher levels of 

cytoplasmic FIP200 as compared to BR ca (52% vs 24% respectively, 

p�0.0002) and increased expression of FIP200 around areas of hypoxia/ 

necrosis, consistent with increased autophagy. There was also a significant 

increase in expression of nuclear FIP200 and Rb1 in the CNS met 

compared to BR ca (p�0.0007 and p�0.0055 respectively). Median 

survival from development of CNS met was longer in the group with high 

levels of nuclear Rb1; 14 (3-27) vs 20 (12-33) months (low expression � 

20% vs high � 20%, p�0.1). The same finding was observed with FIP200, 

longer survival was observed with high nuclear expression; 16 (7-33) vs 19 

(0.4-27) months (low expression �20% vs high � 20%, p�0.2). Our DNA 

analysis for copy number variation and LOH in CNS met revealed no 

deletion in Rb1 or FIP200. Conclusions: The pattern of expression of Rb1 

and FIP200 in CNS met is different from BR ca. Notably, cytoplasmic 

FIP200 which promotes cell survival is highly expressed in CNS mets vs BR 

ca. This suggests metastatic breast cancer cells utilize autophagy as a 

survival mechanism. In addition, there is a trend to better survival of those 

patients with CNS met who express high nuclear FIP200 and Rb1, both of 

which have anti-proliferative roles in the nucleus. 



4:30 PM-5:30 PM 

Intraventricular (IVe) topotecan for women with neoplastic meningitis (NM) 

associated with �responsive� malignancies. Presenting Author: Kurt A. 

Jaeckle, Mayo Clinic, Jacksonville, FL 

Background: A prior study of intra-CSF topotecan (TOPO) for unselected pts 

w/ NM reported PFS 6 mo of 19%, and OS of 15 wks (Groves, NeuroOncol 

2008;10:208). We postulated that greater activity might occur in pts w/ 

malignancies considered sensitive to topoisomerase inhibitors. Methods: 

We reviewed outcome of women with NM and adenocarcinoma of the 

breast, ovary or lung receiving IVe TOPO (0.4 mg 2x/wk x 4wk, Q wk x 4, Q 

2wk x 2, Q mo x 3, Q 2mo x 3, and Q 3mo x 4) until progression (PROG) or 

adverse events (AE). All had baseline CSF cytology, and MRI of brain and 

spine. CSF cytology was obtained at each treatment (Rx), and brain/spine 

MRI Q 3mo. Neuro-specific PROG was defined as recurrent � CSF cytology; 

PROG of NM on MRI; all-cause neurologic worsening; pt refusal; or death. 

PFS/OS were measured from 1st TOPO Rx. All pts signed consent; the study 

was IRB approved. Results: 17 women (breast -12; lung-3; ovary - 2) were 

treated via Ommaya reservoirs; 7 (41%) had VP shunts w/ valves, adjusted 

for Rx. Median (med) age was 53 (41-79), and KPS 70 (50-90). At 

presentation, 11(65%) had � CSF cytology and 14 (82%) had NM on MRI 

[brain-11 (65%); spine-10 (59%)]. 15 (88%) had no prior intrathecal Rx. 

13 pts (76%) received focal RT for CNS disease, and 8 (47%), chemotherapy 

for extracranial disease. Med.number of Rx were 13/pt (range, 

3-50); med. duration of TOPO Rx was 14 wks (range, 1-109). Med. 

neuro-specific PFS was 13 wks; PFS6 was 41%, and PFS12, 29 %. Med. 

OS was 33 wks (range, 5-180), w/ 4 alive at 13�, 30�, 33�, and 180� 

wks. 4 pts (24%) lived � 95 wks. Of 11 w/ baseline � CSF cytology, 7 

(64%) cleared CSF of malignant cells (med. duration clear � 47 wk (range, 

9-104). AE included arachnoiditis (18%), leukoencephalopathy (18%), 

and Ommaya infections (12%). Rx was stopped for neuro PROG (29%); 

systemic PROG (23%); refusal (18%); AE (12%); or persistent negative 

CSF (6%); 12% are still on Rx. Conclusions: Promising activity of IVe TOPO 

was observed in women with NM from breast, lung and ovarian cancer. PFS 

6 and 12, OS and cytologic response were twice that noted in prior studies 

of NM pts w/ unselected malignancies. This data supports our plan for a 

phase II study targeting this select cohort. 


4:30 PM-5:30 PM 

Modeling radiation dose to circulating lymphocytes during brain tumor 

treatment: Effects of target volume, dose rate, and treatment technique. 

Presenting Author: Susannah G. Yovino, Johns Hopkins University School 

of Medicine, Baltimore, MD 

Background: Severe treatment-related lymphopenia (TRL) occurs in 40% of 

glioblastoma patients despite minimal radiation (RT) doses to bone marrow 

or nodal sites. In glioblastoma, TRL is associated with decreased survival. 

To explain the lymphopenia, we sought to estimate radiation doses received 

by circulating lymphocytes during partial brain RT. Methods: An in-house 

computer program linked to treatment planning software was used to 

calculate the mean radiation dose to circulating blood (DCB) and the 

fraction of blood receiving �0.5 Gy. The model also studied the impact of 

different target volumes (PTV), dose rates (DR), and delivery techniques 

(IMRT, 3D-CRT). Results: The mean DCB for a 60-Gy course (8-cm 

diameter PTV, dose rate 600 MU/minute) was 2.2 Gy. With this the entire 

blood pool receives a lymphotoxic dose of �0.5 Gy. DCB is correlated with 

fraction number, PTV size, and DR. Regardless of dose rate or delivery 

technique, the percent of circulating blood receiving �0.5 Gy approached 

100% as the number of fractions increased. Changing dose rate had 

minimal effects on mean DCB (3.1Gy for 300 MU/min vs 2.2 Gy for 1200 

MU/min). Smaller PTV size reduced the percent of blood receiving �0.5 Gy 

(15% for 2-cm diameter PTV vs 100% for 8-cm PTV). Conclusions: 

Standard RT for brain tumors delivers a lymphotoxic radiation dose to 

circulating blood. Altering dose rate may initially affect DCB, but advantages 

disappear over the course of 30 fractions. Marked reductions in target 

size appear to be the best way to avoid radiation injury to normal circulating 

lymphocytes. Other novel approaches are needed to limit radiation exposure 

to circulating lymphocytes given evidence associating lymphopenia 

with poorer outcomes in cancer patients. 


119s 


4:30 PM-5:30 PM 

Addition of upfront whole-brain radiotherapy to surgery or stereotactic 

radiosurgery versus surgery or stereotactic radiosurgery alone for treatment 

of brain metastases: A systematic review and meta-analysis. Presenting 

Author: Yu Yang Soon, National University Cancer Institute, Singapore 

Background: The benefits of adding upfront whole-brain radiotherapy 

(WBRT) to surgery or stereotactic radiosurgery (SRS) when compared to 

surgery or SRS alone for treatment of brain metastases are unclear. We 

performed a systematic review and meta-analysis of published randomized 

controlled trials (RCT) to determine the efficacy and safety of additional 

upfront WBRT. Methods: We searched MEDLINE, EMBASE, CENTRAL 

from date of inception and annual meeting proceedings of ASCO and 

ASTRO from 1999 to September 2011 for RCTs comparing surgery or SRS 

plus WBRT with surgery or SRS alone for treatment of brain metastases. 

The primary outcome was overall survival (OS). Secondary outcomes 

include progression free survival (PFS), local and distant intracranial 

disease progression, neurocognitive function (NF), quality of life (Qol) and 

neurological toxicity. Hazard ratios (HR), confidence intervals (CI), p values 

(p) were estimated with random effects models using Revman 5.1. Results: 

We found five RCTs including 663 patients with one to four brain 

metastases. Adding upfront WBRT decreased the one-year incidence of any 

intracranial disease progression from 73-76% to 22 - 47% but did not 

improve OS (HR 1.11, 95%CI 0.83 - 1.48, p � 0.47) and PFS (HR 0.76, 

95%CI 0.53 - 1.10, p � 0.14). Subgroup analyses showed that the effects 

on overall survival are similar regardless of types of focal therapy used, 

number of brain metastases, dose and sequence of WBRT. The effects of 

upfront WBRT on NF, Qol and neurological toxicity were variable. 

Conclusions: Adding upfront WBRT to surgery or SRS significantly decreased 

any intracranial disease progression at one year but did not improve 

overall and progression free survival and produced variable effects on 

neurocognitive function, quality of life and neurological toxicity when 

compared with surgery or SRS alone. Future research should focus on 

developing more effective approaches to characterize and ameliorate the 

potential neurological toxicity of WBRT. 


4:30 PM-5:30 PM 

Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery 

(SRS) in patients with 1-3 newly diagnosed brain metastases. Presenting 

Author: David M. Peereboom, Cleveland Clinic, Cleveland, OH 

Background: For patients with 1-3 brain metastases, standard therapy after 

SRS is adjuvant whole brain radiotherapy (WBRT). SRS without WBRT 

carries a higher rate of brain relapse. Due to concerns about neurologic 

sequelae of WBRT, however, many patients and physicians opt to defer 

WBRT until the time of central nervous system (CNS) progression. This trial 

used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. 

Sunitinib inhibits vascular endothelial growth factor signaling, and we 

hypothesized that it would prevent growth of microscopic brain metastases 

presumed to be present. The objective was to use adjuvant sunitinib after 

SRS to prevent the emergence of new or progressive disease in the brain or 

at the site of SRS and to preserve neurocognitive function. Methods: 

Eligible patients had 1-3 newly diagnosed brain metastases, RTOG RPA 

class 1-2, and started sunitinib � 1 month after SRS and baseline 

neuropsychological testing (NPT). Patients with controlled systemic disease 

were allowed to continue chemotherapy for their primary disease 

according to a list of published regimens (therapy � sunitinib) included in 

the protocol. Patients received sunitinib 37.5 or 50 mg/d days 1-28 every 

42 days until CNS progression. NPT and MRIs were obtained every 2 

cycles. The primary endpoint was the rate of CNS progression at 6 months 

(PFS6) after SRS. Results: Fourteen patients enrolled. The median age was 

59 (range 46-80). Main histologies: lung 36%, breast 21%, melanoma 

14%. Toxicities: Grade 4: neutropenia [ANC] (1 pt); Grade 3: fatigue (5), 

ANC (2), rash (1). Dose reduction due to toxicity: 1 pt (to 37.5 mg/d). The 

CNS PFS6 and PFS12 were 50% � 13% and 43% � 13%, respectively. 

The median PFS was 6.6 months (95% C.I. 1.5-19). NPT results will be 

reported at the meeting. Conclusions: Sunitinib after SRS for 1-3 brain 

metastases was well tolerated with a PFS6 of 50%. The use of novel agents 

to prevent progressive brain metastasis after SRS requires the incorporation 

of chemotherapy regimens to control the patient’s primary disease. 

Future trials should continue to explore the paradigm of secondary 

chemoprevention of brain metastases after definitive local therapy (surgery 

or SRS). 




4:30 PM-5:30 PM 

IDH1 status and survival benefit from surgical resection of enhancing and 

nonenhancing tumor in malignant astrocytomas. Presenting Author: Daniel 

P. Cahill, Massachusetts General Hospital, Boston, MA 

Background: The value of maximal safe resection for malignant astrocytic 

gliomas (AA, WHO Grade III anaplastic astrocytoma and GBM, WHO Grade 

IV glioblastoma) has sometimes been controversial, because of confounding 

between measures of surgical resection and other prognostic factors. 

IDH1 gene mutations are associated with improved survival in glioma 

patients, and are thought to identify tumors with a distinct molecular 

evolutionary origin. We sought to determine the prognostic impact of 

surgical resection on survival after controlling for IDH1 status in malignant 

astrocytomas. Methods: Clinical parameters including preoperative and 

postoperative MRI-based tumor volume were recorded prospectively on 

407 malignant astrocytoma patients – AA (n�157) and GBM (n�250). 

IDH1 status was assessed by sequencing and R132H-specific immunohistochemistry. 

Results: The measures of surgical resection associated with 

longer survival differed between IDH1 wild-type and mutant tumors. In 

multivariate analyses of IDH1 wild-type tumors (controlling for age, 

Karnofsky performance score, tumor location, and tumor grade), residual 

postoperative enhancement was associated with a median survival of 9.9 

mo vs. 17.4 mo with no enhancement (HR�1.73, 95% CI, 1.19-2.52, 

p�.004). Residual non-enhancing disease, however, was not associated 

with survival (scored as continuous volumetric cc, 95% CI 0.99-1.01, 

p�.608). These results are consistent with prior studies of GBM, which are 

largely IDH1 wild-type lesions (Lacroix et al., J Neurosurg 95:190-8, 

2001). In contrast, in IDH1 mutant tumors, both residual enhancing 

(HR�7.93, 95%CI 1.14-55.22, p�.037) and non-enhancing (HR�1.03, 

95% CI 1.01-1.05, p�.005) postoperative tumor burden were associated 

with worse survival. Conclusions: These data suggest surgical resection in 

malignant astrocytic gliomas may be individualized based on IDH1 genotype. 

IDH1 mutant tumors have a better baseline overall prognosis, 

therefore more aggressive surgery and tolerance of temporary peri-operative 

neurologic deficits can be weighed in an attempt to gain the additional 

survival benefit that appears to be associated with reducing non-enhancing 

tumor burden. 


4:30 PM-5:30 PM 

MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and 

FISH. Presenting Author: Kimary Kulig, National Comprehensive Cancer 

Network, Fort Washington, PA 

Background: GBM, the most common and lethal malignant primary brain 

tumor in adults, has an overall one-year life expectancy of 33.7%. 

Personalized medicine on the basis of predictive biomarkers remains 

elusive in GBM; however a recent case report showed clinical improvement 

after treatment with a mesenchymal-epithelial transition (MET) inhibitor. 

The authors of that report ascribe clinical response to the MET inhibitor, 

but the drug is also an inhibitor of anaplastic lymphoma kinase (ALK). We 

explored the co-expression, gain, or amplification of both MET and ALK by 

IHC and FISH in GBM. Methods: A convenience sample of 56 available 

tumors from gross-resected GBM cases within the Duke Brain Tumor tissue 

bank was stained for MET using clone 8F11 (Leica) and for ALK using clone 

5A4 (Novocastra). FISH employed the LSI ALK (2p23) breakpointspanning 

dual-color DNA probe and the LSI D7S486 (MET)/CEP 7 dual 

color DNA probe (Vysis). Results: Of 56 GBM cases, MET was expressed in 

69.6% and ALK in 17.9% by IHC. By FISH, gain or amplification was found 

in 100% of cases for MET and in 48.2% for ALK. Co-expression of MET and 

ALK by IHC was 14.3% and 48.2% by FISH. Co-expression by either IHC or 

FISH was also 48.2%. OS estimation for this cohort is premature, with 

77% of patients still alive. Conclusions: MET and ALK are (co-)expressed in 

a significant proportion of GBM. IHC detection of MET and ALK did not 

correlate well with FISH results, suggesting that gene gain or amplification 

does not necessarily lead to abnormal MET and ALK protein expression or 

that IHC methods or antibodies used can be optimized. Prior studies 

reported MET amplification in GBM as low as 4%. Our study indicates that 

MET gain/amplification and protein expression may be much higher, having 

implications for MET-targeted therapy. Additionally, co-expression of ALK 

and MET has implications for dual inhibitors of these signaling pathways as 

well as resistance mechanisms. Our continued work will explore significance 

of MET and ALK as predictors of therapeutic response, with careful 

control for clinically relevant patient and disease characteristics. 

Biomarker IHC � 

FISH � 

(gain or amplification) IHC- FISH- 

MET 39 56 17 0 

ALK 10 27 46 29 

MET � ALK 8 27 15 0 


4:30 PM-5:30 PM 

Genomic characterization of meningiomas. Presenting Author: Priscilla 

Kaliopi Brastianos, Dana-Farber Cancer Institute, Boston, MA 

Background: Understanding the genetic alterations in cancer has lead to 

groundbreaking discoveries in targeted therapies. Meningiomas are among 

the most common primary brain tumors, with approximately 18,000 new 

cases diagnosed annually. Though certain genes have been associated with 

the development of meningiomas, most notably the tumor suppressor gene 

neurofibromatosis 2 (NF2), the genetic changes that drive meningiomas 

remain poorly understood. Our objective was to comprehensively characterize 

the somatic genetic alterations of meningiomas to gain insight into the 

molecular pathways that drive this disease. Methods: Fresh frozen specimens 

and paired blood were collected from 16 consented patients. DNA 

was extracted from regions of high tumor purity determined by evaluation of 

H&E slides. Whole-genome sequencing from 10 tumor-normal pairs and 

whole-exome sequencing from 6 tumor-normal pairs was carried out. We 

performed an unbiased screen for point mutations, insertions-deletions, 

rearrangements and copy-number changes across the exomes and genomes. 

Recurrent (potential driver) events were then analyzed with 

additional algorithms for statistical significance. Results: Alterations in the 

NF2 gene were present in 9 of 16 patients. Multiple novel rearrangements 

and recurrent non-NF2 mutations were also identified in the cohort. 

Massive genomic rearrangement termed chromothripsis was observed in 

chromosome 1 in one sample, which has never previously been described in 

meningiomas, and represents a potentially new mechanism of malignant 

transformation in this tumor type. Conclusions: While NF2 mutations 

appear to drive a majority of these tumors, our analysis has uncovered 

additional potential driver genes in meningiomas, particularly in those 

tumors negative for NF2 alterations. To our knowledge, this is the first study 

to comprehensively characterize the totality of somatic genetic alterations 

in meningiomas, and brings us closer to the development of new therapeutic 

targets for this disease. 


4:30 PM-5:30 PM 

Pilocytic astrocytomas in adults: A retrospective study of 125 patients. 

Presenting Author: Brett James Theeler, University of Texas M. D. Anderson 


Background: Pilocytic astrocytomas (PAs) are rare primary brain tumors in 

adults. The natural history is poorly defined with the largest published 

series including only 30-40 patients. To better define clinical characteristics 

of adult PAs, we present an analysis of adult PAs at MD Anderson 

Cancer Center. Methods: We conducted an IRB-approved, retrospective 

chart review of patients �18 years diagnosed with PAs from 1990-2011 at 

our institution. Results: We identified 125 patients with a median age of 29 

(range 18-72y), female to male ratio of 1.7:1, and median follow-up of 62 

months. The most common anatomic locations were brainstem 22%, 

cerebellum 14%, intraventricular 14%, and cortical/lobar 14% (36% other 

locations). 21% of cases had an initial pathologic diagnosis discordant with 

neuropathologic review at our institution. Comorbidities included neurofibromatosis 

type 1 (5 pts) and a history of asthma or autoimmune disease 

(14%). 38 patients had a gross total (GTR), 55 a sub-total resection (STR) 

and the remainder a biopsy. 62 patients were treated with radiotherapy 

(RT): 45 as adjuvant (adj), 17 at recurrence; 2 received RT in both adj and 

recurrent settings. 73 (58%) patients were stable after initial treatment 

(surgery �/- adj RT). Median progression free survivals (mPFS) based on 

upfront treatment as follows: GTR only (n�30) - not been reached, STR 

only (n�32) 226.6 months, GTR plus adj RT (n�8) 13.2 months, STR plus 

adj RT (n�23) is 52.4 months (p�0.026, logrank test for trend). At last 

follow-up, 77% of all patients were stable and 13% were deceased. 

Conclusions: This is the largest series of adult PAs reported to date. 

Extracerebellar location, slight female predominance, and history of 

allergic/autoimmune disease were associations found in this cohort. 

Neuropathologic review is essential to avoid misdiagnosis. A significant 

subset of adult PAs behave more aggressively than expected for a grade I 

tumor with over 40% of patients experiencing recurrence after initial 

treatment. Adj RT following GTR or STR did not improve PFS, and a trend 

towards worse PFS with adj RT was observed although these analyzed 

subgroups were small. These results may help provide a framework for 

prospective studies in this tumor type. 



4:30 PM-5:30 PM 

Recurrent genetic alterations in primary central nervous system lymphoma 

of immunocompetent patients. Presenting Author: Alberto Gonzalez, APHP, 

UPMC, CRICM, UMR975, Hopital Pitié-Salpêtrière, Paris, France 

Background: Little is known about the molecular pathogenesis of primary 

central nervous system lymphoma (PCNSL) in immunocompetent patients. 

Our objective was to identify the genetic changes involved in PCNSL 

oncogenesis and evaluate their clinical relevance. Methods: Twenty nine 

and four newly diagnosed, HIV-negative PCNSL patients were investigated 

using high-resolution single nucleotide polymorphism (SNPa) arrays (Infinium 

Illumina Human 610-Quad SNP array-Illumina; validated by realtime 

quantitative polymerase chain reaction) and whole-exome sequencing 

respectively. Molecular results were correlated with prognosis. Results: All 

PCNSLs were diffuse large B-cell lymphomas, and the patients received 

high-dose methotrexate-based polychemotherapy without radiotherapy as 

an initial treatment.SNPa analysis revealed recurrent large and focal 

chromosome imbalances that target candidate genes in PCNSL oncogenesis. 

The most frequent genomic changes were (i) 6p21.32 loss (79%), 

corresponding to the HLA locus; (ii) 6q loss (27-37%); (iii) CDKN2A 

homozygous deletions (45%); (iv) 12q12-q22 (27%); (v) chromosome 

7q21 and 7q31 gains (20%). Sequencing of matched tumor and blood 

DNA samples identified novel somatic mutations in MYD88 (L265P hot 

spot mutation) and TBL1XR1 in 38% and 14% of the cases, respectively. 

The correlation of genetic abnormalities with clinical outcomes using 

multivariate analysis showed that 6q22 loss (p�0.006 and p�0.01), and 

CDKN2A homozygous deletion (p�0.02 and p�0.01) were significantly 

associated with shorter progression free survival and overall survival. 

Conclusions: Our study identified novel genetic alterations in PCNSL, such 

as MYD88 and TBL1XR1 somatic mutations, which would both contribute 

to the constitutive activation of the NFkB signaling pathway and represent 

potential promising targets for future therapeutic strategies. 


4:30 PM-5:30 PM 

Impact of adjuvant anti-VEGF therapy on treatment-related pseudoprogression 

in patients with newly diagnosed glioblastoma receiving chemoradiation 

with or without anti-VEGF therapy. Presenting Author: Marco C. Pinho, 

Martinos Center for Biomedical Imaging, Massachusetts General Hopital, 

Boston, MA 

Background: Chemoradiation (CRT) can significantly modify the appearance 

of glioblastoma (GBM) on MRI, especially within the 3-month window 

after CRT. Pseudoprogression (PsP) is an increasingly recognized phenomenon 

in this scenario, and is thought to be secondary to increased 

permeability of the tumor vessels from irradiation, possibly enhanced by 

temozolomide (TMZ). We sought to determine if the addition of a VEGF 

signaling inhibitor (cediranib) during and after CRT had an impact on the 

frequency of PsP, by comparing two groups of patients with newly 

diagnosed GBMs. Methods: Two groups of patients enrolled in IRBapproved 

trials underwent serial MRIs at baseline, weekly during CRT and 

monthly thereafter. The control group received radiation plus TMZ, while 

the other group (CED) also received cediranib until progression (which was 

defined by RANO criteria) or toxicity. Patients that progressed up to 3 

months after CRT were considered to have apparent progression (AP) and 

kept on treatment. Lesions that subsequently stabilized/regressed were 

classified as PsP, while those that maintained growth despite treatment 

were classified as true early progression (EP). Results: Forty patients were 

enrolled in CED and 11 as controls. Ten patients from CED and three 

controls were excluded due to treatment discontinuation before 3 months 

(drug-related toxicity and enrollment in post-CRT trials respectively). Three 

patients in CED (6%) had AP (all confirmed as EP) and no patients fulfilled 

criteria for PsP. Six patients from control (54%) had AP; 3 (27%) were 

eventually classified as EP and 3 (27%) as PsP. The frequency of PsP was 

significantly higher in the control group (p�0.0086). Conclusions: The 

addition of a VEGF inhibitor as part of adjuvant treatment in this cohort of 

glioblastoma patients prevented the development of early treatmentrelated 

effects (PsP). Suppressing the edema and mass effect that 

accompanies PsP may improve the tolerability of treatment. Additionally, 

this effect may be exploited as a strategy to make chemoradiation feasible 

in patients with large, unresectable tumors and/or poor baseline performance 

status. 


121s 


4:30 PM-5:30 PM 

Blood alterations preceding clinical manifestation of glioblastoma. Presenting 

Author: Aysegul Ilhan-Mutlu, Medical University of Vienna, Vienna, 

Austria 

Background: Glioblastoma is the most common and aggressive primary 

brain tumour in adults. There is lack of knowledge on biochemical blood 

alterations prior to clinical diagnosis of glioblastoma. We had the rare 

opportunity to investigate selected blood markers from plasma samples 

taken 12, 42 and 72 months before tumor manifestation in a glioblastoma 

patient. This index patient was enrolled in the longitudinal population 

based Vienna Transdanube Aging Study (VITA), which prospectively collects 

blood plasma from 600 participants at baseline (age 75), 30 and 60 

months thereafter. Methods: We determined plasma levels of S100B, 

neuropeptide Y (NPY), secretagogin (SCGN), microRNA-21, microRNAlet7, 

microRNA-128, and microRNA-342-3p in all three blood samples 

from our index patient and in consecutive blood samples from five male and 

five female controls from the VITA cohort. These proteins and microRNAs 

were previously shown to be relevant for the pathobiology of glioblastomas. 

None of the controls had a malignant or neurological disease. Protein 

markers were analysed using commercially available ELISAs and microR- 

NAs were quantified using RT-qPCR. Results: Compared to baseline values, 

we found a significant increase of microRNA-21 (up to 4-fold) and 

microRNA-let7 (up to 7-fold) levels in the blood samples of our index 

patient, whereas control samples showed almost stable levels of these 

markers. There was no significant difference in S100B, NPY, SCGN, 

microRNA-128, and microRNA-342-3p plasma levels between the index 

patient and controls. Conclusions: Increases of microRNA-21 and microRNAlet7 

plasma levels may be associated with pre-clinical development of 

glioblastoma. 


4:30 PM-5:30 PM 

A single-institution phase II trial of radiation (RT), temozolomide (TMZ), 

erlotinib, and bevacizumab for initial treatment of glioblastoma (GBM). 

Presenting Author: Jennifer Leigh Clarke, University of California, San 

Francisco, San Francisco, CA 

Background: Standard treatment for GBM includes surgery followed by RT 

and TMZ, rarely a curative treatment. Both the EGFR and VEGF pathways 

are frequently overactive in GBM; we previously added erlotinib, an EGFR 

inhibitor, to RT and TMZ, with modest improvement in survival. The present 

study combined bevacizumab, a VEGF inhibitor, and erlotinib with RT and 

TMZ, with the goal of improving overall survival (OS). Methods: Treatment 

consisted of fractionated RT to 60 Gy with daily TMZ at 75 mg/m2/d and 

erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzymeinducing 

antiepileptic drugs [EIAEDs]). Bevacizumab was given at 10 

mg/kg every 2 wks, starting � 4 wks after surgery. After RT, adjuvant TMZ 

was given at 200 mg/m2/d x 5d per 28d cycle, with unchanged erlotinib 

and bevacizumab doses. Treatment was continued until progression or for 

12 mo, with an option to continue for up to 24 mo. OS and progression-free 

survival (PFS) from initial diagnosis were compared against institutional 

historical controls (recent prior up-front clinical trials including RT and 

TMZ). Results: 59 pts were enrolled; 12 were receiving EIAEDs. Median age 

was 54 yrs; median KPS was 90. 33% underwent gross total resection and 

53% subtotal resection. 16 pts had tumors with methylated MGMT 

(mMGMT), 26 with unmethylated MGMT (umMGMT), and 17 with unknown 

status. The most frequent related grade 3/4 AEs were lymphopenia 

(68%) thrombocytopenia (24%), neutropenia (10%), diarrhea (14%), 

weight loss (14%), and fatigue (12%). 1 pt died of aspergillosis. Median 

OS and PFS were 19.8 mo and 13.5 mo, respectively, vs. 18 mo and 8.6 

mo for the historical control. The hazard ratio (adj for age, KPS, and extent 

of surgery) for PFS was 0.7 (95% CI 0.49-0.99, p�0.04). Median OS in 

pts with mMGMT was 20.9 mo, vs. 17.5 mo in pts with umMGMT; median 

PFS was 14 mo vs. 12.4 mo, respectively. Conclusions: The combination of 

bevacizumab, erlotinib, TMZ, and RT showed improved PFS but not OS vs. 

historical controls. Though the numbers were small, PFS and OS for pts 

with umMGMT were not significantly different from pts with mMGMT, 

suggesting that this combination may be more effective than standard 

therapy alone for pts with unMGMT tumors. 




4:30 PM-5:30 PM 

Vorinostat, temozolomide, and bevacizumab for patients with recurrent 

glioblastoma: A phase I/II trial. Presenting Author: Katherine B. Peters, 

Duke University Medical Center, Durham, NC 

Background: Prognosis for recurrent glioblastoma (GBM) remains poor with 

median survival between 3 to 6 months. Use of anti-vascular endothelial 

growth factor inhibitor, bevacizumab (BEV), has advanced this area of 

research, but continued studies have focused on whether the addition of 

other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a 

small molecule inhibitor of histone deactylase (HDAC), has anti-tumor 

activity directly through HDAC inhibition and indirectly by promoting 

anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile 

make it a promising additive agent to standard therapy. Thus, we evaluated 

the efficacy of vorinostat in combination with BEV and daily temozolomide 

(TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single 

arm study in recurrent GBM patients. Primary endpoint was 6-month 

progression free survival (PFS). Secondary endpoints were safety/ 

tolerability, radiographic response, PFS, and overall survival of recurrent 

GBM patients treated with BEV plus daily TMZ and vorinostat. Chief 

eligibility criteria included age � 18 years, KPS � 70, time interval � four 

weeks from previous treatment, and maximum of 2 prior progressions. 

Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 

mg/m2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 

28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of 

those patients receiving a vorinostat dose of 400 mg. Most common grade 2 

and above toxicities were leukopenia (36%), neutropenia (29%), fatigue 

(24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 

toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation 

and intracranial hematoma) and 1 patient expired on day of informed 

consent due to pulmonary embolism (grade 5). With a median follow-up of 

11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% 

(95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete 

responses, 17 partial responses, 20 stable responses, and 1 radiographic 

progression. Conclusions: In summary, combination of BEV, daily TMZ, and 

vorinostat has promising efficacy on recurrent GBM with reasonable 

toxicity/safety. 

2029^ Poster Discussion Session (Board #17), Fri, 1:00 PM-5:00 PM and 

4:30 PM-5:30 PM 

Bevacizumab versus bevacizumab plus vorinostat in adults with recurrent 

malignant glioma: Results of a phase I part of a phase I/II trial. Presenting 

Author: Jing Wu, University of North Carolina at Chapel Hill, Lineberger 

Comprehensive Cancer Center, Department of Neurosurgery, Chapel Hill, 

NC 

Background: Antiangiogenic therapy using bevacizumab (Bev) has shown 

promising activity against recurrent glioblastoma (GBM). However, most 

patients have disease progression after striking but transient responses. 

Salvage therapies have been uniformly ineffective, suggesting development 

of resistance mechanisms including upregulation of other proangiogenic 

factors and increased activity of hypoxia inducible factors (HIF)-1a. 

Vorinostat, a histone deacetylase (HDAC) inhibitor has single agent activity 

against recurrent GBM and downregulates HIF-1a and other proangiogenic 

and invasive factors. We hypothesized that HDAC inhibition combined with 

Bev would result in improved clinical outcome. We report the results of the 

Phase I portion of the study preceding the initiation of the 2-arm adaptive 

randomized Phase II study. Methods: Adults with recurrent malignant 

glioma, KPS � 60, normal hepatic, renal and marrow organ function and no 

prior exposure to Bev or Vorinostat were enrolled to the combination therapy 

after the confirmation of recurrent GBM. A conventional 3�3 Phase I 

design was used to determine the maximum tolerated dose (MTD) and the 

toxicity profile of the combination of Bev and Vorinostat. The starting dose 

was Bev at 10mg/kg administered on days 1 and 15 intravenously and 

Vorinostat 400 mg/day orally on days 1 to 7, and days 15 to 21 with each 

cycle being 28 days. Results: A total of 6 patients were enrolled and all 6 

patients were evaluable. Three patients were enrolled in the first cohort at 

the starting dose of the combination and completed the first cycle. One 

patient experienced a grade 3 ALT elevation and grade 3 hyperglycemia, 

which were designated as possibly related to vorinostat and constituting a 

dose-limiting toxicity (DLT). No grade 4 toxicities were noted. The cohort 

was expanded by 3 more patients with none of these patients experienced a 

DLT in the first cycle. The starting dose level of Bev and vorinostat was 

declared the Phase II dose. Conclusions: Combination of Bev (10 mg/kg q 2 

weeks) and of vorinostat (400 mg on days 1 to 7 and 15 to 21) has tolerable 

toxicity profile. This will be followed by a multicenter Bayesian adaptive 

randomized Phase II study. 


4:30 PM-5:30 PM 

Bevacizumab for recurrent WHO grade III anaplastic glioma (AG). Presenting 

Author: Anna Maria Delios, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: Salvage treatment with bevacizumab (BEV) has been increasingly 

used in grade III AG, but limited data are available, with conflicting 

results reported. Because of differences in molecular characteristics, 

angiogenesis mechanisms, growth rate and chemosensitivity, results observed 

in glioblastoma (GBM) treated with BEV may not apply to AG, and 

may differ between anaplastic astrocytomas (AA) and oligodendrogliomas 

(AO). Methods: IRB approved retrospective review of all pts with recurrent 

WHO grade III AG treated with BEV at MSKCC. Response and progression 

were determined by RANO criteria. Results: BEV was given to 39 pts with 

recurrent grade III AG (AA: 26; AO: 10; anaplastic oligoastrocytoma [AOA]: 

3); median (med) age: 49 (range 20-75); med KPS: 80 (60-100). MGMT 

promoter methylation was determined in 17 pts (methylated 8, unmethylated 

9). Amongst AO/AOA, 1p/19q co-deletion was present in 6 and absent 

in 5. IDH1/ IDH2 mutations were present in 3/5 tested tumors. Med time 

from diagnosis of AG to BEV treatment was 11.5m (3 – 112.5). The med 

number of previous recurrences was 1 (range 1-4). BEV was given as single 

agent to 16 pts and combined with a cytotoxic agent in 23. Objective 

response rate (ORR) was 41% (complete response: 5; partial: 11). The med 

progression-free survival (PFS) was 4.8m (6-m PFS: 35% [95% CI 

20-50]). The med overall survival (OS) was 11.5 m (1y-OS: 45% [95% CI 

29-61]). In pts achieving ORR, med OS was 13 m vs 4minptswith 

stable/progressive disease (P�0.02). Pts at first recurrence fared better 

than pts with more than one recurrence (med PFS: 6 vs 3.4 months, 

P�0.04). AO/AOA tended to fare worse than AA (med PFS 3 vs 5.5 m, 

P�0.07). There were no differences in PFS (P�0.8) or OS (P�0.4) 

between single agent vs BEV � cytotoxic agent. Toxicity included one grade 

4 brain hemorrhage. Conclusions: In this relatively large series, BEV was 

associated with higher ORR and PFS as compared to historical controls, 

although improvements in those endpoints were of a lower magnitude than 

in GBM. While ORR predicted OS, improvements in OS were not apparent; 

results in AO were particularly disappointing. The use of BEV in this 

population requires reappraisal in a randomized study with adequate 

stratification for histology and number of previous recurrences. 


4:30 PM-5:30 PM 

Differences in outcome due to bevacizumab (BEV) discontinuation versus 

BEV failure in adults with glioblastoma. Presenting Author: Mark Daniel 

Anderson, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: BEV is approved for use in recurrent glioblastoma. Patients 

(pts) who benefit from BEV therapy are often treated until tumor progression 

but fail to respond to salvage therapy suggesting that BEV may alter 

tumor biology. In a subset of pts who benefit from BEV, treatment is 

discontinued for reasons other than disease progression; the characteristics 

and outcomes of this subset are poorly defined. Methods: In this IRB 

approved retrospective study, our neuro-oncology longitudinal database 

was screened for pts treated with BEV for � 6 months (mo) between 

2005-2010 and 18 pts were identified in whom BEV was discontinued for 

reasons other than disease progression (BEV-D group). A cohort of 72 pts 

who received BEV until treatment failure due to progression was used as 

comparator (BEV-F group). Results: In the BEV-D group, 5 pts completed a 

planned treatment course and 13 stopped BEV due to toxicity; in this 

group, progression free survival at 12 mo (PFS12) was 83.3% (95% CI, 

56.8-94.3) and median time to progression (TTP) 27.6 mo. Median TTP 

after BEV discontinuation was 7.0 mo. In contrast, in the BEV-F group, 

PFS12 was 24.6% (95% CI, 13.9-36.2) and median PFS 9.7 mo. Length 

of BEV therapy was not significantly different between the groups with a 

median time to discontinuation of 10.2 and 12 mo. In 12/18 pts in the 

BEV-D group who subsequently had tumor recurrence a predominantly 

local pattern of progression was seen unlike those in the BEV-F group who 

had more infiltrative or distant failures. Salvage therapy yielded a PFS-6 of 

28.6% (95% CI, 4.1-61.2) with a median PFS of 17.1 wk compared with 

6.8% (95% CI, 1.2-19.8) and 9 wk in the comparator group. Conclusions: 

Among pts who benefit from BEV therapy, the BEV-D group did not 

experience an immediate progression suggesting continued benefit after 

BEV cessation. This cohort also had a less invasive pattern of recurrence 

and a possibly improved response to salvage therapy compared with BEV-F 

group. Our results suggest that planned cessation of BEV therapy could 

potentially change patterns of progression and response to subsequent 

therapy. This strategy warrants further evaluation in prospective studies 

given the absence of effective salvage therapy after BEV failure. 



4:30 PM-5:30 PM 

NCCTG N057K phase II trial of everolimus, temozolomide, and radiotherapy 

in patients with newly diagnosed glioblastoma: A North Central 

Cancer Treatment Group trial. Presenting Author: Daniel Ma, Mayo Clinic, 

Rochester, MN 

Background: The mammalian target of rapamycin (mTOR) functions within 

the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical 

studies in GBM indicate that the combination of mTOR inhibitors, such as 

everolimus (RAD001), with either radiation therapy (RT) or temozolomide 

(TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM 

pts were eligible for the study. RAD001 was dosed orally at 70 mg/week 

weekly, starting 1 week prior to RT/TMZ, and continued throughout 

RT/TMZ, adjuvant TMZ and then until progression. This was a single arm 

phase II design powered to detect a true overall survival at 12 months 

(OS12) of 73% (vs 58% in historical controls). Secondary endpoints were 

toxicity, response rate, and time to progression (TTP). A subgroup of 

patients with measurable residual disease were eligible for the PET imaging 

component of the study, consisting of an 18FLT-PET/CT scan performed 

before and after the initial two doses of RAD001 but before the first dose of 

RT or TMZ. Results: 103 patients were accrued to phase II of which 100 

were evaluable. The median age was 60.5 years (23-81), median ECOG PS 

was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at 

diagnosis. Treatment tolerance was acceptable: 17% patient had at least 

one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic 

toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% 

had at least one grade 4 non-heme toxicity. No increased incidence of 

infectious complications was observed and there were no treatment related 

deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients 

progression free. Mature OS data will be available at the meeting. MGMT 

methylation status analysis is ongoing. Of the pts who had evaluable 

FLT-PET data, three of eight (37.5%) had a drop in SUVmax �25% after 

two treatments of RAD001. Conclusions: RAD001 with standard of care 

chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for 

evaluating drug-induced changes in tumor proliferation following RAD001. 

Final outcome data and association of MGMT status with outcome will be 

reported at the meeting. 


4:30 PM-5:30 PM 

Final results of a randomized phase III trial of nimotuzumab for the 

treatment of newly diagnosed glioblastoma in addition to standard radiation 

and chemotherapy with temozolomide versus standard radiation and 

temoziolamide. Presenting Author: Manfred Westphal, Department of 

Neurosurgery, UKE Hamburg, Hamburg, Germany 

Background: The receptor for epidermal growth factor (EGF-R) has consistently 

been found expressed or overexpressed in human malignant glioma 

disease. Therapeutic targeting of the EGF-R has shown mixed responses 

which appear to be restricted by specific features of the tumor cells.Nimotuzumab 

binds preferentially to highly over expressing cells, a phase III trial 

was initiated to test efficacy in glioma. Methods: Nimotuzumab was tested 

in an open label, randomized, multicenter Phase III trial in patients with 

histologically confirmed, newly diagnosed glioblastoma. 12 consecutive 

weekly infusions of 400mg during standard radiotherapy with Temozolomide 

followed by biweekly infusions of 400mg arm A was randomized 

against standard radio chemotherapy alone arm B. Primary endpoint was 

PFS as determined by centralized neuro-imaging review. OS as secondary 

endpoint with quality of life, safety as additional parameters.MGMT and 

EGF-R were assessed where sufficient materials could be retrieved as well 

as tumor hypoxia. Results: Between 2007 and 2010, 149 patients were 

randomized and 142 were available for analysis. Stratification according to 

resection status resulted in 40 pts in the treatment arm and 41 in the 

control arm with residual tumor and 31 vs 30 pts without residual tumor. 

PFS: 12 month was 25.5% arm A vs 20.3% in arm B (p � 0.78) and OS: 

679 days vs 596 days. For non - methylated MGMT the difference was most 

notable: OS arm A 28 pats: 19.6 months vs arm B 28 pats 15.0 months 

EGF-R amplification, gave no clear signal, neither was there a statistically 

significant treatment effect between with or without residual tumor. Tumor 

hypoxia does not appear to have predictive value in the overall group but 

possibly in subgroups.AEs and SAEs did not reveal a new specific toxicity 

profile beyond the known side effects from glioma treatment with current 

standard. Conclusions: Nimotuzumab shows a clear trend towards efficacy 

in MGMT non-methylated glioblastoma patients. Safety profile and indications 

for subgroup efficacy potentially justify focused evaluation of antibody 

therapy against glioblastoma. 


123s 


4:30 PM-5:30 PM 

Phase I/randomized phase II trial of either dasatinib or placebo combined 

with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme 

(GBM): Final results of phase I study. Presenting Author: Nadia N. 

Laack, Mayo Clinic, Rochester, MN 

Background: Dasatinib is a potent oral ATP competitive multi-targeted 

kinase inhibitor of multiple members of the Src kinase family, known to be 

involved in gliomagenesis and invasion. N0877 is a phase I/randomized 

phase II trial evaluating the combination of dasatinib, radiation (RT) and 

temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has 

been completed and is the focus of this report. Methods: A cohorts-of-3 

design was used to assess the safety of dasatinib in combination with RT 

and concomitant TMZ, and establish the phase II dose of the combination. 

Dasatinib was given orally for 42 days, beginning with the first day of RT 

(total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest 

(cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for 

DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of 

dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of 

TMZ � dasatinib, pts stay on dasatinib only (28 day cycles) until 

progressive disease. Results: Phase I component is complete with 13 

patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One 

patient in dose level 1 had to be replaced due to the development of 

unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 

1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was 

observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was 

determined to be 150mg daily. Most common adverse events throughout 

the entire study period were hematologic with the most common toxicity 

being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other 

toxicities attributed to treatment and occurring in � 10% of patients 

included anemia (31%), neutropenia (15%), and fatigue(15%). Best 

response was stable disease in 10 patients, progressive disease in 1 

patient, and not evaluable in 2. Conclusions: MTD for dasatinib in 

combination with TMZ and RT in newly diagnosed GBM patients is 150mg 

daily. Toxicity was primarily hematologic with minimal non-hematologic 

events. This dose is currently being used in the ongoing placebo-controlled, 

randomized phase II trial. 


4:30 PM-5:30 PM 

APG101_CD_002: A phase II, randomized, open-label, multicenter study 

of weekly APG101 plus reirradiation versus reirradiation in the treatment of 

patients with recurrent glioblastoma. Presenting Author: Martin Bendszus, 

Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, 

Germany 

Background: Preclinical data indicate antiinvasive activity of APG101, an 

intravenous CD95 ligand-binding fusion protein, as well as synergistic 

activity together with radiotherapy in glioblastoma. Methods: Patients with 

recurrent glioblastoma after prior standard radiochemotherapy with temozolomide 

(� 1 second-line chemotherapy) were considered for re-irradiation 

provided a tumor diameter 1-4 cm and time since the end radiotherapy � 8 

months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5 

times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat 

dose to be continued until progression. Radiotherapy plans were centrally 

evaluated. Primary endpoint was 6-months progression free survival (PFS- 

6). MRIs were performed every 6-weeks and centrally read. Sample size of 

the investigational treatment arm according to a two-stage design of Simon 

required 55 patients. A control arm of 28 patients was implemented to 

validate the assumptions on PFS-6 in a cohort of patients treated with 

reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25 

centers were randomized and treated, preliminary data of the current report 

are available on 71 patients (49 APG01 � irradiation, 22 irradiation 

alone). Median age was 57 years, median KPS 90%. The maximal tumor 

diameter was � 2-5 cm in 34 patients and � 2.5 cm in 37 patients. No 

SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101 

arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is 

the first trial evaluating CD95-mediated pathway inhibition as a therapeutic 

strategy. This trial is also the prospective trial on reirradiation in 

glioblastoma. Side effects of the combination were minimal, and treatment 

could be delivered as planned. The experimental arm met the primary 

endpoint. The approach to block rather than stimulate the CD95 system is 

breaking a paradigm. Our data suggest that CD95 inhibition by APG101 

should be evaluated in the management of newly diagnosed glioblastoma in 

combination with standard radiochemotherapy. Further molecular data and 

updated results will be presented. 




4:30 PM-5:30 PM 

A phase II trial evaluating tumor penetration of bortezomib in patients with 

recurrent malignant gliomas treated prior to surgery and then treated with 

bortezomib and temozolomide postoperatively. Presenting Author: Jeffrey 

J. Raizer, Northwestern University, Feinberg School of Medicine, Chicago, 

IL 

Background: NF-Kappa B is one of the mechanisms of resistance for 

malignant gliomas. A few trials have assessed bortezomib in the treatment 

of malignant gliomas with limited activity. This may in part be due to 

limitations in dose escalation from peripheral neuropathy. We performed a 

phase II trial with the goal of measuring bortezomib in tumor tissue and also 

its effects on NF-Kappa B. Methods: Patients felt to be surgical candidates 

were enrolled after signing an IRB approved consent. They were treated 

with bortezomib 1.7 mg/m2 IV on day 1, 4 and 8 and then had surgery on 

day 8 or 9. Approximately, 14 days post operatively, patients were started 

on temozolomide 75 mg/m2 PO on days 1-7 and 14-21; on day 7 and day 

21 they received bortezomib 1.7 mg/m2 (1 cycle was 1 month). Treatment 

continued until progression. If �1 patient had a PFS at 6 months the trial 

would be stopped. Results: 10 patients were enrolled (8 M and 2 F). Median 

age and KPS were 50 (42-64) and 90% (70-90). All but 1 patient went to 

surgery, one had an intracranial hemorrhage. The median number of cycles 

post operatively was 2 (1-4), with two patients discontinuing for wound 

infection (post 3 cycles, not restarted due to prolonged delays) and 

meningitis (post 2 cycles then withdrew from trial). Six patients are 

deceased. Trial was stopped as no patient had a PFS-6. PK analysis 

revealed measurable drug levels in tumor tissue. Conclusions: Post operative 

treatment with temozolomide and Bortezomib did not have any activity. 

Bortezomib can achieve measurable drug levels in tumor but may not be 

sufficient for anti-tumor activity. Tissue will be assessed for bortezomib 

effects on NF-Kappa B. 


4:30 PM-5:30 PM 

Phase II trial of dose-dense temozolomide as initial treatment for progressive 

low-grade oligodendroglial tumors: A multicentric study of the Italian 

Association of Neuro-Oncology (AINO). Presenting Author: Roberta Ruda, 

Division of Neuro-Oncology, University Hospital San Giovanni Battista, 

Turin, Italy 

Background: Standard temozolomide has been shown to be active in 

progressive low grade gliomas after surgery, whereas few data are available 

on the impact of dose dense regimens. Thus, we developed a phase II single 

arm multicenter study to evaluate the efficacy and toxicity of a regimen of 

dose dense temozolomide in progressive low grade oligodendroglial tumors. 

Methods: The inclusion criteria of the study were as follows: 1)biopsyproven 

supratentorial WHO grade II oligodendroglioma and oligoastrocytoma; 

2)progressive disease, clinically (epileptic seizures)or radiologically; 

3)measurable disease on MRI (at least 1 cm); 4)age �18 years; 5)Karnofsky 

Performance Status �70. Temozolomide was administered at 

150mg/m2 1 week on/1 week off up to a maximum of 18 cycles or 

unacceptable toxicity. The primary end-point was response rate (RR) 

according to RANO criteria, whereas secondary end-points were clinical 

benefit in terms of reduction of epileptic seizures �50%, progression-free 

survival (PFS), quality of life and toxicity. Results: From January 2005 until 

December 2010 60 patients (median age 39 and median KPS 80) have 

been accrued and are now evaluable for response. Response rates on 

T2/FLAIR images were as follows: CR 0/60, PR 21/60 (35%), MR 14/60 

(23%), SD 21/60 (35%) and PD 4/60 (7%). The clinical benefit was 

significant in 29/34 patients (85%). As for toxicity 5/60 (8%) patients 

stopped treatment for lymphopenia grade IV, whereas 11/31 patients 

(35%) were switched to the standard regimen of temozolomide. PET with 

methionine was added to MRI in 17 patients: in 10/17 (59%) a disappearance 

or a significant reduction of uptake was observed, being the reduction 

of seizures better correlated with the response on PET rather than that on 

MRI. 1p/19q codeletion was not associated with either the response or the 

clinical benefit, whereas the analysis of MGMT methylation and IDH1 

mutations are ongoing. Thirty-nine (65%) patients are still free of tumor 

progression. Conclusions: Dose-dense TMZ seems to be active, especially in 

terms of clinical benefit, but the myelotoxicity could be a concern. 


4:30 PM-5:30 PM 

Lenalidomide and irinotecan in adults with recurrent malignant gliomas: 

Phase I results of the phase I/II trial. Presenting Author: Vinay K. Puduvalli, 


Background: Patients with recurrent malignant gliomas have limited treatment 

options. We previously reported promising results using 6 month 

progression free survival [PFS6] endpoint combining irinotecan and thalidomide 

compared to historical controls. In this study, we tested the 

tolerability and efficacy of Irinotecan combined with Lenalidomide, a more 

potent thalidomide analogue with unique antiangiogenic and immunomodulatory 

properties. Methods: This phase I portion of the phase I/II study 

aimed to determine the maximum tolerated doses (MTD) of irinotecan and 

lenalidomide. Eligible patients were adults (��18 y) with recurrent WHO 

Grade 3 or 4 gliomas who were not on EIAED, had failed prior radiation 

therapy, had a KPS��60, had adequate marrow, renal and hepatic organ 

function, no major medical illnesses and no other concurrent malignancies. 

Each cycle was designated as 4 weeks in duration. Results: Two of the 4 

patients enrolled at the starting dose level of Lenalidomide 10 mg/day on 

days 1-21 and irinotecan 200 mg/m2 q2 weeks developed rash as dose 

limiting toxicity (DLT). The trial was restarted with no change in irinotecan 

dose but with a lowered Lenalidomide dose of 7.5 mg/day for cycle 1 with 

escalation to 10 mg/day for cycle 2 and beyond. Of 3 eligible patients 

enrolled, no DLTs were noted even after cycle 2. The dose was hence 

escalated to Lenalidomide 10 mg/day with unchanged irinotecan dose. 

Only 1/6 patients experienced a DLT (pulmonary embolism); however, it 

was noted that 4/6 patients required dose reduction of irinotecan to 150 

mg/m2 after cycle 1. One patient died during cycle 2 of unknown causes 

(autopsy declined) without reports of preceding toxicities. Non DLT 

toxicities included neutropenia, leukopenia, hypokalemia, diarrhea, fatigue 

and nausea/vomiting. Lenalidomide pharmacokinetic data, obtained by 

serial blood draws initially after one dose of the drug on day 0 and 

subsequently after irinotecan and lenalidomide dose on day 1 to examine 

drug interactions, will be presented. Conclusions: Based on these results, 

the maximum tolerated dose was Lenalidomide 10 mg/day on days 1-21 

and irinotecan 150 mg/m2 q 2 weeks every 28 days which will be used in 

the phase II study that will open shortly. 


Does pilocytic astrocytoma (PA) in adults have a different prognosis than 

PA in children? Presenting Author: Daniel Fernandes Marques, Instituto do 

Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, 

Brazil 

Background: Pilocytic astrocytoma (PA) accounts for up to 25% of all brain 

tumors in children. A 75% progression-free survival rate at 5 years and 

overall survival rates of 95.8% at 10 years have been reported after a 

complete resection. However, the incidence in adults is low and the 

outcome less well characterized. We conducted a retrospective analysis of 

adult PAs identified in order to review the clinical characteristics and 

outcome of this neoplasm in this age group. Methods: A descriptive, 

cross-sectional study was undertaken in patients over 16 y.o., diagnosed 

with PA between January 1990 and December 2010 at our center. Clinical 

characteristics, date and extent of surgery, tumor location, postoperative 

treatment, complications and recurrences were collected from hospital 

records. Results: From May, 1990 to December, 2010, 18 eligible adult 

patients (pts) with the diagnosis of PA were identified. Median age was 

25,5 (16-52) years, 72,2% female and 83,3% had an ECOG performance 

status � 2. The most frequent tumor sites were the cerebellum (44,4%), 

followed by the cerebral hemispheres (38%). All patients underwent 

surgery as primary treatment, 72% had a complete macroscopic resection 

(CMR) and 28% had a partial resection (PR). Two patients received 

postoperative radiotherapy: one following a PR and the other after tumor 

relapse following a CMR. Two patients relapsed five months and 44 months 

after initial complete gross resection. Salvage surgery achieved CMR in 

both. With a median follow-up of 89 months, all patients are alive, except 

for one who died in the postoperative period due to fungal meningitis. Of 

note, none of 5 pts undergoing a partial resection progressed and 3 are alive 

for more than 10 years. Conclusions: As it occurs in the pediatric 

population, PA in adults seems to carry a similarly favorable prognosis. It is 

conceivable that after initial surgical resection a watch and wait type of 

approach is appropriate, even following partial resection. The role of 

upfront radiotherapy is uncertain and it should probably be left for 

progressive tumors. 



Use of a non-coplanar half-beam block on the lower spinal field to decrease 

the maximum bowel and cumulative dose in craniospinal irradiation. 

Presenting Author: Madeera Kathpal, University of Medicine and Dentistry 

of New Jersey, New Brunswick, NJ 

Background: To develop and compare a non-coplanar half beam block 

technique that can be used in both prone and supine treatment positions 

with conventional beam matching for craniospinal irradiation (CSI) in order 

to decrease the maximum cumulative dose and dose to the bowel, while 

maintaining the therapeutic dose to the spinal axis. Methods: Ten treatment 

plans from five patients who underwent CSI were analyzed. The bowel was 

contoured en bloc for each patient on their simulation cat scan. Two 

different geometric techniques for each patient were planned and analyzed. 

The first technique consisted of the conventional method for CSI 

utilizing two coplanar beams to cover the entire spinal axis. The other 

technique used a non-coplanar half beam block on the lower spinal beam to 

exactly match the upper spinal beam’s divergence. Four “featherings” 

between the two spinal beams for each technique were still necessary to 

minimize under and overdosing which occur at abutting beam fields. 

Maximum doses for the plan and the bowel were compared between the two 

techniques on the same patient. Results: The maximum bowel dose was 

decreased between 10 to 35 percent when the non-coplanar half beam 

block was used. The maximum doses for the conventional technique were 5 

to 35 percent higher than the plans using a non-coplanar half beam block. 

The homogeneity of the dose to the spinal axis was not altered with the use 

of the non-coplanar half beam block. Conclusions: Use of a non-coplanar 

half beam block to match the two spinal fields in craniospinal irradiation 

significantly reduces the maximum dose to the bowel and of the entire plan 

possibly resulting in reduced gastrointestinal toxicity while maintaining 

therapeutic dose to the spinal axis. 


Toxicity profile of temozolomide in the treatment of 300 malignant glioma 

patients in Korea. Presenting Author: Chae-yong Kim, Department of 

Neurosurgery, Seoul National University College of Medicine, Seoul National 

University Bundang Hospital, Seoul, South Korea 

Background: Toxicity of temozolomide itself has been rarely reported in the 

field of neuro-oncology. In an attempt to explore the toxicity profiles of 

temozolomide we investigated the records of 300 glioma patients in two 

institutions in Korea. Methods: We reviewed the records of 300 glioma 

patients who were treated with temozolomide between Jan 2004 and May 

2010 at two hospitals of our university at two medical centers in Seoul 

National University, Korea. The age range of patients was 17 ~ 84 years old 

with its median of 49 years old. Their pathologies were glioblastoma, 

anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, 

gliomastosis cerebri, gliosarcoma and others. Temozolomide 

was used as only concurrent manner with radiotherapy in 46 patients, as 

both concurrent and adjuvant manner in 93 patients, and as only adjuvant 

or palliative manner in 161 patients. We classified the side effects by 

Common Terminology Criteria for Adverse Events version 3.0(CTCAE). 

Results: We found 603 events of side effects of temozolomide. Nonhematolgic 

toxicities were most common (n�482). Especially, nausea(n�135), 

vomiting(n�110), and anorexia(n�40) were common among all kinds of 

toxicities. Hematologic adverse events(n�121), for example, thrombocytopenia(n�43), 

anemia(n�33), and neutropenia(n�20) were the second 

common toxicities. Some patients suffered from fatigue(n�31). None of 

our patient presented fatal Pneumocystis jiroveci pneumonitis. In our 

series, 512 cases(84.9%) of toxicity were grade 1 or 2, and 91 

cases(15.1%) were grade 3 or 4. Grade 3 or 4 toxicity were 140 

cases(15.1%). Only 27 cases(2.9%) presented grade 4 toxicity. There was 

no mortality due to temozolomide. Only 4 patients (1.3%) presented 

leukopenia, which is different pattern compared with the incidence 

reported in prior studies from western countries. Conclusions: Temozolomide 

had many kinds of toxicities. However, most of the toxicity was 

tolerable. This profile could be used to prevent toxic reactions more 

effectively and improve the patient’s quality of life. Furthermore, we could 

use these lessons for education of patients during the treatment with 

temozolomide. 


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Relationship of cognitive function, quality of life (QOL), and neuroimaging 

in primary CNS lymphoma (PCNSL) survivors. Presenting Author: Nancy 

Diane Doolittle, Oregon Health & Science University, Portland, OR 

Background: Delayed treatment-related neurotoxicity in PCNSL is a significant 

problem since improved treatments have increased survival. The study 

purpose is to describe and correlate neuropsychologic (NP), QOL and 

neuroimaging outcomes as neurotoxicity indicators. Methods: Four centers 

in Germany and U.S. prospectively evaluated PCNSL patients (pts) in 

complete remission (CR) for 2 yrs or more, treated as shown in the Table. 

NP tests evaluated attention/executive function, verbal memory, motor 

skills, and QOL (Correa, Ann Oncol 2007). Brain MRI was obtained; the 

size of T2 abnormalities was determined using two perpendicular linear 

measurements where hyperintensities were largest and the sum of the 

measurements was calculated. Differences in total T2 among treatments 

were compared using analysis of variance; correlations between total T2 

and NP or QOL results were assessed using Pearson’s correlation coefficient 

(r). Results: From Feb 2009 to Feb 2011, 80 pts were evaluated (43 

male; median age, 59; median KPS, 80). Median follow-up from diagnosis 

to evaluation was 5.5 yrs. Total T2 abnormalities were significantly 

different among treatments (p � 0.0006). The mean area of total T2 in pts 

treated with WBRT was significantly higher and more than twice the mean 

of any of the other 3 treatments. Total T2 abnormalities were negatively 

associated with NP results ie. attention/executive function, r � -0.38 (p � 

0.0006), verbal memory, r � -0.23 (p � 0.042), motor skills, r � -0.28 (p 

� 0.016), composite score, r � -0.34 (p � 0.002); and functional/global 

QOL (higher total T2 associated with lower QOL). Conclusions: This large 

PCNSL series in long-term (LT) CR reveals higher total T2 abnormalities in 

pts treated with WBRT, which are associated with poorer cognitive 

performance and lower QOL at LT follow-up. Enhanced chemotherapy 

results in exciting LT survival and function. 

Treatment No. pts Follow-up (median, yrs) 

High-dose methotrexate (HD MTX)-based 

32 4.5 

chemotherapy (CHT) alone 

MTX-based intra-arterial CHT with blood-brain 

25 12.3 

barrier disruption alone 

HD MTX-based CHT f/b HDT/autologous stem cell 

8 4.5 

transplantation (ASCT) alone 

HD MTX-based CHT (with/without HDT/ASCT) and WBRT 15 5.6 


The oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor 

LY2157299 plus lomustine in patients with treatment-refractory malignant 

glioma: The first human dose study. Presenting Author: Analia Azaro, 

Medical Oncology, Vall d’Hebron, Barcelona, Spain 

Background: Activated TGF-b signaling has been associated with poor 

survival in several tumors, including glioma. TGF-b inhibitors are expected 

to improve outcome. Part B of this Phase I trial assessed safety, pharmacokinetics, 

pharmacodynamics, and antitumor activity of the intermittent 

treatment with LY2157299 in combination with lomustine. Methods: After 

evaluating safety of LY2157299 monotherapy in part A of the study, 2 

cohorts of patients were treated with LY2157299 at 160 or 300 mg/day 

with intermittent dosing (each cycle�14 days on followed by 14 days off) 

in combination with lomustine at standard dose (100 to 130 mg/m2 every 6 

weeks) for �2 cycles. Toxicity was assessed using the Common Terminology 

Criteria for Adverse Events, version 3. Results: Twenty-six patients with 

glioma (18 WHO Grade IV; 5 Grade III; 3 unspecified grade) were treated 

with LY2157299 and lomustine (160 mg/day, n�15; 300 mg/day, n�11). 

There were no dose-limiting toxicities. No clinically meaningful cardiotoxicities 

were observed. Twenty-one SAEs occurred in 10 patients, all 

considered to be related to lomustine and none to LY2157299. Of the 26 

patients, 7 had thrombocytopenia (27%), and recovery around weeks 4 to 6 

was not impacted by the second cycle of LY2157299. Two patients taking 

160 mg/day were treated for �6 cycles, with 1 of the 2 patients showing an 

unconfirmed partial response. At the 300 mg/day dose, no responses were 

observed; 2 patients were treated for �6 cycles. Co-administration of 

lomustine did not alter LY2157299 exposure. Observed exposure of 

LY2157299 increased with dose escalation between the 2 cohorts. On Day 

7, the variability estimates (coefficients of variation) of exposure and 

maximum concentration were slightly higher in presence of lomustine 

(58%) when compared with LY2157299 alone (47%) and then again 

reduced on Day 14 (53%). Pharmacodynamic results will be reported at a 

later date. Conclusions: The 14 days on/14 days off treatment with 

LY2157299 did not increase the known lomustine toxicity. Given the 

overall safety profile and antitumor effect, LY2157299 is being investigated 

in Phase II studies. 




Expression of CXCR7, CXCR4, CXCR3 and their chemokine ligands in 

glioblastoma. Presenting Author: Robert D. Berahovich, ChemoCentryx, 

Inc., Mountain View, CA 

Background: The chemokine receptors CXCR4 and CXCR7, and their shared 

ligand CXCL12/SDF-1, have been implicated in multiple aspects of 

tumorigenesis, including tumor cell proliferation, angiogenesis, vasculogenesis, 

and metastasis. Recently, a role for CXCR4 and CXCR7 has been 

postulated in the control of glioblastoma growth and vasculogenesis. We set 

out to define the expression patterns of these proteins on primary 

glioblastoma tumors and associated vasculature. Methods: First, a tumor 

microarray containing grades 1, 3, and 4 glioma samples were analyzed by 

immunohistochemical techniques for the expression of CXCR7. Second, 

two glioblastoma microarrays were analyzed by the same technique for 

CXCR7, CXCR4, and their shared chemokine ligand CXCL12. The same 

microarrays were also probed for the expression of the additional CXCR7 

ligand, CXCL11/ITAC, as well as the chemokine receptor CXCR3, which is 

also a receptor for CXCL11. Tissues were scored in a blinded fashion by a 

certified neuropathologist for both the intensity of signal and location of 

signal for all proteins tested. Results: CXCR7 expression was largely 

dependent on tumor grade, as the receptor was usually absent on most 

grade 1 gliomas but was moderately-to-highly expressed in the majority of 

anaplastic astrocytomas and glioblastomas. CXCR7 expression on tumorassociated 

vasculature was seen in all samples and its expression level also 

increased with glioma grade. In contrast to CXCR7, CXCR4 expression in 

glioblastoma was usually limited to the glioma cells, with only infrequent 

expression on the vasculature. Conversely, CXCL12 expression in glioblastoma 

was usually limited to the vasculature. CXCR3 was detected in a 

subset of glioblastomas, and only on the glioma cells. The CXCR7 and 

CXCR3 ligand CXCL11 was, like CXCR7, expressed on both the glioma cells 

and vasculature. Conclusions: These results, in light of prior evidence for 

CXCR7 in tumor growth, suggest a positive role for CXCR7 in the 

development of glioblastoma. Because CXCR7 colocalizes with its ligands, 

CXCL12 and CXCL11, as well as their other receptors, CXCR4 and CXCR3, 

the function of CXCR7 in glioblastoma may lie in the regulation of both the 

CXCR4/CXCL12 and CXCR3/CXCL11 axes. 


A phase II multicentric study of sunitinib administered as upfront therapy 

in glioblastoma: A study by the GEINO group. Presenting Author: Carmen 

Balana, Institut Catala d’Oncologia Badalona, Barcelona, Spain 

Background: Sunitinib is a multitargeted tyrosine kinase inhibitor that has 

direct antitumor and antiangiogenesis activity through targeting VEGFR 

1-2, PDGFR �-�, c-kit, bFGF, (CSF-1), FLT3 and RET. Experimental 

studies in GB mice showed angiogenic activity, prolonged survival and 

synergy with irradiation Methods: Eligible pts were �75 years with GB not 

amenable to resection, PS�2, MMS �25. Treatment was sunitinib 

37.5mg daily for 8 w before radiotherapy, during radiotherapy (60Gy, 6 w) 

and after radiotherapy until disease progression. Primary endpoint was 

overall response (OR) (RANO criteria) after 8wofsunitinib treatment 

before radiotherapy. Secondary endpoints were % pts free of neurological 

deterioration before radiotherapy, % pts who completed radiotherapy, PFS, 

OS and 1-year survival. We used a Simon 2-stage design (12 ¡20) based 

on OR to calculate the number of patients needed to detect at least 10% of 

responses with � error of 0.05 and � error of 0.10. Twelve patients were 

included in the first phase and one response was needed to continue study 

accrual. Results: 12 pts were enrolled: 7 males, median age 65 years, 

PS�1: 8pts, median MMS 26.5. Neurological deficit: 5pts, DXM treatment 

10/12, non-EIDS 3/12. Treatment: 5 pts completed 8woftherapy, 2pts 

completed 7 w, 4 pts � 6w. Toxicity G3 and 4: diarrhea (1pt), asthenia 

(2pts), skin and EDDPP (2), mucositis (2), fatal CNS hemorrhage (1), 

hypercholesterolemia and hypertriglycemia (1). OR was 1/12 SD, 11/12 P; 

radiological response was SD in 5 pts but 4 pts progressed neurologically. 

Only 2 pts completed radiotherapy plus sunitinib. The only SD received 

treatment for 18 w. Median PFS was 7.5w (CI 95% 5.8-9.2), OS 16w (CI 

95% 0.5-23.7), 1year OS: 0%. Conclusions: the trial was closed after the 

first stage due to lack of response. Sunitinib is an inactive agent in 

glioblastoma. 


Use of tumor-targeting salmonella typhimurium to eradicate human glioma 

in an orthotopic model in nude mice. Presenting Author: Masashi Momiyama, 

AntiCancer Inc., San Diego, CA 

Background: Prognosis remains poor for glioma and therefore requires new 

approaches. We have previously developed a genetically-engineered strain 

of Salmonella typhimurium, A1-R, that targets tumors without overt toxicity 

in mouse models (Proc. Natl. Acad. Sci. USA 102, 755-760, 2005; Cancer 

Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 

10170-10174, 2007; Expert Opinion on Drug Discovery 7, 73-83, 2012). 

In the present study, we demonstrated that Salmonella typhimurium A1-R 

can inhibit and eradicate human glioma in an orthotopic nude mouse 

model. Methods: S. typhimuirum A1-R was administered by injection 

through a craniotomy open-window or intravenously in nude mice. To 

establish the model, 2�105 U87 human glioma cells, expressing red 

fluorescent protein (RFP), were injected stereotactically into the mouse 

brain through the craniotomy open window. Two weeks after glioma-cell 

implantation, mice were treated with S. typhimurium A1-R (2�107 CFU / 

200 �l intravenous injection [i.v.] or 1�106 CFU / 1 �l intracranial 

injection [i.c.]) once a week for 3 weeks. Results: Brain tumors were 

observed by fluorescence imaging through the craniotomy open window 

over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor 

growth 7.6-fold compared with untreated mice (p � 0.009) and improved 

survival 73% (p � 0.001). Two of ten mice had their tumors eradicated. 

Intravenous administration of S. typhimurium A1-R was not effective. 

Conclusions: The results of the present study demonstrate that bacterial 

therapy of glioma is a novel, effective and safe treatment strategy in a 

highly treatment-resistance cancer in an orthothopic model, a first step 

toward clinical development. 


Neuraxis imaging in leptomeningeal metastasis: A retrospective case 

series. Presenting Author: Marc C. Chamberlain, Fred Hutchinson Cancer 

Research Center, Seattle Cancer Care Alliance, Seattle, WA 

Background: (and Objective) Leptomeningeal metastasis (LM) is a central 

nervous system metastatic complication of cancer that affects the entire 

neuraxis. Quantify imaging (brain and spine MRI and radio-isotope cerebrospinal 

fluid [CSF] flow study) abnormalities in a retrospective case series of 

patients with LM. Methods: 240 adult patients with LM (125 non-brain 

solid tumor patients with positive CSF cytology; 40 non-brain solid tumor 

patients with negative CSF cytology; 50 lymphoma and 40 leukemia 

patients with positive CSF flow cytometry) underwent prior to treatment 

brain and entire spine MRI and radio-isotope CSF flow studies (FS). Results: 

Neuraxis MRI in pathologically defined patients was more often normal in 

hematologic tumors (80-84%) compared to solid tumors (60%). Similarly, 

FS was more often normal in hematologic tumors (90-92%) compared to 

solid tumors (72-75%). However, neuraxis MRI and FS abnormalities (i.e. 

CSF flow obstruction; nodular subarachnoid or parenchymal disease; 

hydrocephalus) altered therapy by requiring CSF diversion, site specific 

radiotherapy, systemic chemotherapy or recommending no further therapy 

in one third of CSF cytology positive solid tumors and 15% of CSF flow 

cytometry positive hematologic tumors. Conclusions: Notwithstanding less 

frequent imaging abnormalities in hematologic tumors, similar to solid 

tumors imaging abnormalities frequently result in treatment alteration for 

patients with LM. Consequently, neuraxis imaging is recommended in both 

tumor categories in patients being considered for LM-directed and in 

particular intra-CSF chemotherapy treatment. 



The effect of the addition of chemotherapy to radiotherapy on cognitive 

function in patients with low-grade glioma: Secondary analysis of RTOG 

98-02. Presenting Author: Roshan Sudhir Prabhu, Winship Cancer Institute, 

Emory University, Atlanta, GA 

Background: The addition of PCV chemotherapy to radiotherapy (RT) for 

patients with WHO grade II glioma improves progression free survival (PFS) 

and overall survival (OS), for patients surviving at least 2 years (Shaw, J Clin 

Oncol 26: 2008). The effect of therapy intensification on cognitive function 

(CF) remains a concern in this population with substantial long term 

survival. Methods: 251patients with WHO grade II glioma and age � 40 

with any extent of resection, or age � 40 with subtotal resection/biopsy 

were randomized to RT (54Gy) or RT � PCV. 111 patients with age � 40 

and gross total resection were observed. CF was assessed by mini-mental 

status exam (MMSE)at baseline and years 1, 3, and 5 for patients without 

progression. Change in MMSE score from baseline of � 3 points was 

considered clinically significant. Results: Overall, very few patients experienced 

significant decline in MMSE score, with a median follow-up time of 

9.7 years for alive patients. There were no significant differences in the 

proportion of patients experiencing MMSE decline between study arms at 

any time point. The table below summarizes MMSE change from baseline 

over time. Neither baseline MMSE score nor change in MMSE at year 1 

significantly predicted for OS or PFS, but there was a trend towards worse 

OS for patients with MMSE loss of � 2 points [HR 1.73, 95% CI (0.86, 

3.47), p�0.12]. Conclusions: The MMSE is a relatively insensitive tool that 

has not been validated in patients receiving cranial RT, and subtle changes 

in CF may have been missed. However, the addition of PCV to RT for low 

grade glioma did not result in significantly higher rates of MMSE decline 

than RT alone or observation. There was a trend towards an MMSE decline 

of � 2 points at year 1 predicting for worse OS. 

Observation (%) RT (%) RT � PCV (%) 

Significant MMSE decline 

Year 1 0 / 62 (0) 5 / 74 (6.8) 2 / 51 (3.9) 

Year 3 0 / 44 (0) 1 / 48 (2.1) 0 / 43 (0) 

Year 5 

No MMSE change 

0/27(0) 0/22(0) 2/25(8) 

Year 1 60 / 62 (96.8) 66 / 74 (89.2) 44 / 51 (86.3) 

Year 3 44 / 44 (100) 45 / 48 (93.8) 38 / 43 (88.4) 

Year 5 

Significant MMSE gain 

27 / 27 (100) 21 / 22 (95.5) 20 / 25 (80) 

Year 1 2 / 62 (3.2) 3 / 74 (4.1) 5 / 51 (9.8) 

Year 3 0 / 44 (0) 2 / 48 (4.2) 5 / 43 (11.6) 

Year 5 0 / 27 (0) 1 / 22 (4.5) 3 / 25 (12) 


Predictive role of MGMT status in recurrent glioblastoma (GBM) patients 

(PTS) treated with antiangiogenic drug (AD) plus temozolomide (TMZ) or 

CPT-11. Presenting Author: Giuseppe Lombardi, Medical Oncology 1, 

Istituto Oncologico Veneto-IRCCS, Padua, Italy 

Background: Methylation and silencing of MGMT promoter is a favourable 

predictive factor in PTS with GBM treated with single alkylating agent such 

as TMZ. Yet, MGMT is an important resistance determinant to CPT-11 

activity. AD can be administered in second line treatment as single agent or 

in combination to cytotoxic drugs. We analyzed the predictive role of MGMT 

status in PTS treated with AD plus TMZ or CPT-11 as second line 

treatment. Methods: Retrospectively, 55 PTS were analyzed: 36 (65%) with 

unmethlyated MGMT, 19 (35%) with methylated MGMT; 3 (5%) PTS with 

IDH1 mutations. 17 (31%) PTS performed a reoperation before the second 

line treatment and MGMT status was changed in 2 (18%) PTS, IDH1 status 

was unchanged in all PTS. 32 PTS were treated with sorafenib 800mg/die 

plus TMZ 40mg/m2/die, 23 with bevacizumab 10mg/Kg plus irinotecan 

every two weeks. Tumor response was evaluated by clinician assessment 

and by MRI according to RANO criteria every two months or when clinically 

indicated. Results: Among all PTS, median PFS was 2.7 months (95%CI 

1.5-3.5), median OS from start of AD was 7.3 months (95%CI 6.02-8.5), 

6-month PFS was 32%; no significant differences were observed and 

MGMT status was balanced between the two AD groups (p�0.05). 

Analyzing MGMT status at first surgery, according to univariate analyses 

there were no significant differences in terms of PFS (3.5ms vs 2.1ms; 

p�0.2), OS (6.5ms vs 7.2ms; p�0.1) and 6-PFS (HR�0.2, CI95% 

0.05-1.07) between PTS with unmethylated and methylated MGMT, 

respectively. On multivariate analysis, adjusted for performance status, age 

and cytotoxic drug, MGMT status was not statistically significant in terms of 

PFS (p�0.8) and OS (p�0.1). Yet, no significant differences emerged with 

MGMT status at second surgery as well as analyzing the two AD groups, 

separately. Conclusions: MGMT status might not be a predictive factor in 

recurrent GBM patients treated with AD plus TMZ or CPT-11 as second line 

treatment, although MGMT status may change in some PTS between first 

and second surgery. In conclusion, the outcome of patients with recurrent 

GBM receiving AD plus TMZ or CPT-11 is not significantly influenced by 

MGMT methylation status. 


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First results of radiotherapy after hyperbaric oxygenation with temozolomide 

for high-grade gliomas. Presenting Author: David Hamid Khelif, 

Service de Radiothérapie Groupe Hospitalier sud Reunion, Saint Pierre, 

Reunion 

Background: The outcome of patients with high-grade gliomas remains poor 

despite modern therapeutic arsenal. The objective of this study was to 

assess the feasibility and efficacy of radiotherapy (RT) given immediately 

after hyperbaric oxygenation (HBO) with Stupp protocol. Methods: All 

patients with histologically confirmed high-grade gliomas from 2008 till 

2011 coveraged at GHSR hospital were enrolled. Patients underwent 

Stupp protocol consisting in 60 Gy RT with a daily dose of 2 Gy for 5 days 

per week administrated immediately after HBO. Temozolomide (TMZ) was 

administrated at the daily dose 75 mg/m², 7 days per week followed by 6 

cycles of TMZ 150 to 200 mg/m² for 5 days each 28 day-cycle. HBO 

schedule was approximately 15 min of compression with air, 60 min of 

100% oxygen inhalation and 10 min of decompression with oxygen. 

Results: A total of 21 patients were diagnosed and histologically confirmed 

high grade gliomas. Five were excluded because of HBO contraindications. 

Twelve patients (75%) had undergone debulking surgery. The time interval 

from completion of decompression to start of irradiation was less than 15 

minutes (mean 14.25, range 8-18). Twelve patients (75%) received the 

complete dose of RT and TMZ. HBO was completed for 7 (43.75%). Five 

(31.25%) were temporarily stopped and 4 (25%) were definitively stopped. 

One patient (6.25%) suffered from pancytopenia with grade 4 thrombopenia 

and grade 3 neutropenia. The median follow up was 46.95 weeks 

(range 5.7-108.3). Nine patients (56.25%) are still alive. Four (25%) have 

a survival more than 16 months. Conclusions: HBO with Stupp protocol is 

feasible and promising but requiring a large multicentric study. 


Phase II trial of sunitinib malate and lomustine in patients with temozolomide 

refractory recurrent low-grade and anaplastic gliomas. Presenting 

Author: Johnny Duerinck, UZ Brussel, Brussels, Belgium 

Background: Recurrent low-grade and anaplastic gliomas eventually transform 

to a higher grade that is characterized by neo-angiogenesis. Sunitinib 

inhibits multiple tyrosine kinase receptors (including VEGFR, PDGFR and 

c-Kit) but has no meaningful activity as a mono-therapy for recurrent 

glioblastoma when given at a daily dose of 37,5 mg (Neyns et al. J 

Neurooncol. 2011). We investigated sunitinib in combination with lomustine 

(CCNU) for the treatment of patients (pts) with temozolomide (TMZ) 

refractory recurrent low-grade or anaplastic glioma. Methods: Pts received a 

daily dose of 25 mg sunitinib for 28 consecutive days followed by a 14 days 

treatment-free interval. CCNU was administered as a single dose (80 

mg/m²) on day 14 of a 6w cycle. T1 � Gd and T2/FLAIR weighted MRI 

images were obtained q6 wks. 18FET-PET was performed at baseline and 

reassessed in responding pts. Results: 13 pts were enrolled (mean age 40 

[range 33-49]; M/F 8/5; KPS 80-90/70-60: 8/5 pts). All pts had PD 

following surgery, RT and TMZ. In 7 pts, treatment was initiated at 2nd 

recurrence, in 4 pts at 3rd recurrence and in 2 pts at the 4th recurrence. 

Most frequent AEs where fatigue (gr 2: n� 3; gr 3: n� 1), thrombopenia (gr 

2: n� 1gr3:n�3 gr4: n� 1), neutropenia (gr 2: n� 2; gr3: n� 2; gr4: n� 

2) and lymphopenia (gr 2: n�1; gr 3: n�2; gr 4: n�1). In 5/13 pts CCNU 

had to be discontinued because of AEs. Treatment with sunitinib was 

continued in these cases without reoccurrence of AEs. BOR according to 

RANO criteria: 1 CR, 1 PR (not-confirmed) and 2 SD (DCR: 4/13� 31%). 

In the patient with CR, FET-PET indicated a complete metabolic response. 

After a mean FU of 7 mths (range 2 -19), 5 pts are alive. The 6-month PFS 

is 23% (3/13 pts); median PFS is 1,8 mths (95%CI 1.0 - 2,7). A durable 

disease control was obtained in 3 pts (TTP respectively 14.8, 11.8� and 

19.2� mths). Conclusions: in this heavily pretreated population with 

recurrent low-grade and anaplastic glioma the combination of sunitinib and 

CCNU is associated with acceptable toxicity and offers a durable progressionfree 

survival in a subgroup of pts. Molecular predictive factors identifying 

the sensitive population would be needed to justify further clinical 

investigation of this combination. 




Phase II study of PX-866 in recurrent glioblastoma. Presenting Author: 

Marshall W. Pitz, CancerCare Manitoba, University of Manitoba, Winnipeg, 

MB, Canada 

Background: Glioblastoma (GBM) is the most aggressive malignancy of the 

central nervous system. The majority of GBM have genetic changes that 

increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal 

transduction pathway, critical for cell motility, proliferation, and survival. 

We present the interim results of PX-866, an oral PI3K inhibitor, in patients 

(pts) with recurrent GBM. Methods: Pts with histologically confirmed GBM 

at first recurrence after treatment with chemoradiation and adjuvant 

temozolomide are given PX-866 8 mg daily on this single-arm phase II 

study. MRI and clinical exam are done every 8 weeks to determine 

treatment response. The trial has a 2-stage design with dual endpoints of 

objective response and early progression (within 8 weeks). In Stage I, 15 

pts are evaluated and if 0 responses and 10 or more early progressions are 

seen, enrolment will stop. Otherwise, Stage II will enrol another 15 pts for 

efficacy analysis. Tumour tissue is collected for analysis of potential 

markers of PI3K inhibitory activity (PTEN, EGFRvIII, PIK3CA mutations). 

Results: Seventeen pts have been enroled to date: 14 evaluable for response 

and 15 for toxicity. Median age was 54 years (range 35-70), with 7 females 

and 10 males. No pts had received treatment for recurrent GBM, and 

median time between initial diagnosis and study enrolment was 300 days 

(range: 113-447 days). Pts have received a median of one 8-week cycle of 

PX-866 (range: 1-4). Twelve pts have discontinued therapy, 9 due to 

disease progression and 3 due to grade 3/4 liver enzyme abnormalities. 

Other adverse effects have included fatigue (10 pts/1 grade 3), diarrhea (6 

pts/3 grade 3), nausea (7 pts/0 grade 3), vomiting (6 pts/0 grade 3), 

lymphopenia (14 pts/3 grade 3). Stage I response data are premature; it is 

not yet known if the trial will continue to Stage II. Archival tissue is 

available on all patients and is undergoing analysis. Conclusions: This is one 

of the first trials of a PI3K inhibitor in pts with recurrent GBM. PX-866 has 

been relatively well tolerated. Stage I response data are premature; while it 

is not yet known if the criteria will be met to continue to Stage II, prolonged 

SD has been observed in some pts. The correlative biomarker assays 

underway will be important to understand this observation. 


Correlation of large brain edema with favorable prognosis in patients with 

single brain metastases. Presenting Author: Matthias Preusser, Department 

of Medicine I and Comprehensive Cancer Center CNS Tumours Unit, 

Medical University of Vienna, Austria, Vienna, Austria 

Background: The sub-cohort of brain metastases (BM) patients (pts) with 

single BM has relatively favorable survival times, but novel prognostic 

factors are needed to individualize patient management. Methods: We 

retrospectively evaluated pre-operative magnetic resonance images in 

patients, who underwent neurosurgical resection of a single BM. The 

localization and largest diameter of the BM was recorded. The extent of 

brain edema (BE) was graded on contrast-enhanced T1, T2 and fluidattenuated 

inversion recovery (FLAIR) images as follows: BE �1cm, BE �1 

cm without affection of the contralateral hemisphere, BE �1cm with 

affection of the contralateral hemisphere. Further, immunohistochemically 

assessed expression of hypoxia-induced factor 1 alpha (HIF1a) was 

analyzed in each BM tissue specimen. Results: 159 pts were studied (81 

male, 78 female; age range 24 to 80 years, median 58). The primary 

tumors were lung carcinoma in 74, breast cancer in 26, kidney cancer in 

13, colorectal cancer in 11, melanoma in 9 and other tumor types in 26 

cases. At univariate analysis, we found a significant positive correlation of 

overall survival time (OS) with young age, Karnofsky index �80, nonmelanoma 

histology, and, surprisingly, large BE (p�0.05, log-rank test). At 

multivariate analysis, pts age, histological diagnosis and extent of BE 

remained independent prognostic parameters (Cox regression model, 

p�0.05). We found a significant positive correlation of extent of BE with 

expression of HIF1a (Mann-Whitney-U test, p�0.003). Conclusions: Large 

BE positively and independently correlates with favorable prognosis in pts 

operated for single BM. Peritumoral BE correlates with HIF1a expression, 

indicating a possible role of tumor hypoxia in its formation. 

Parameter n 

Median 

OS/days 

(95% CI) 

p value 

(univariate) 

p value 

(multivariate) 

Age � 60 years 90 435 (334-536) 0.02 0.014 

�60 years 69 263(121-405) 

Karnofsky index �80 29 179 (37-321) 0.047 0.242 

�80 110 443(344-542) 

Histological diagnosis Non-melanoma 150 423 (329-517) �0.001 �0.001 

Melanoma 9 130 (95-165) 

Extent of BE �1cm 26 209(137-281) 0.004 0.008 

�1cm, only ipsilateral 

hemisphere 

105 435 (334-536) 

�1cm, ipsi- and 

contralateral hemisphere 

28 575 (235-915) 


Concurrent intrathecal methotrexate and liposomal cytarabine for the 

treatment of leptomeningeal metastasis from solid tumors. Presenting 

Author: Brian J. Scott, University of California, San Francisco, San 

Francisco, CA 

Background: Leptomeningeal metastasis (LM) from solid tumors is typically 

a late manifestation of disease with a median survival of weeks to a few 

months. Treatment is palliative, with no widely accepted standard of care. 

Options include intrathecal (IT) or systemic chemotherapy, radiation 

therapy or ventriculoperitoneal shunting. Randomized trials comparing 

single agent IT methotrexate to liposomal cytarabine have shown similar 

efficacy and tolerability. There is limited data, however, on the use of 

combination IT chemotherapy in solid tumor LM. Methods: We conducted a 

retrospective cohort study of 19 subjects treated for LM from solid tumors 

at a single institution. In addition to therapies directed at active solid tumor 

sites, each subject received IT liposomal cytarabine plus IT methotrexate 

injections every two weeks. Survival data and treatment-related toxicities 

were determined by systematic chart review. Results: LM was diagnosed by 

CSF cytology in 12/19 (63%), while the remainder were diagnosed by 

clinical and MRI findings. The most common cancer types were breast 

7(37%), glioblastoma 6(32%) and lung 3(16%). The majority 18(95%) 

had active systemic or parenchymal brain disease at the time of treatment, 

requiring systemic chemotherapy 18(95%) or radiation therapy 13(68%). 

The median number of IT treatments was 4(range 1-9). Treatment was 

interrupted due to toxicity in 3(17%), while 7(37%) experienced � CTCAE 

grade III toxicities, most commonly meningitis 3(16%). Treatment was 

stopped in 7/19(37%) following complete cytologic response 6/11(55%) 

or radiographic clearance 1/7(14%). The median overall survival was 96 

days(n�6; range 29-158), median time to neurologic progression was 46 

days (n�9; range 6-101) and the most common cause of death was 

progression of systemic disease 4(67%). Conclusions: Combination IT 

chemotherapy was reasonably well-tolerated, even in a population also 

receiving chemotherapy for progressive systemic disease. IT-related adverse 

events occurred at rates similar to previously reported single agent 

trials. Prospective evaluation is necessary to determine whether there is a 

survival benefit compared to single agent IT chemotherapy. 


Management of primary intraocular lymphoma (PIOL): Results from the 

prospective German PIOL registry (PIOL-R). Presenting Author: Kristoph 

Jahnke, Hematology and Oncology, Charité Campus Benjamin Franklin, 


Background: Primary intraocular lymphoma (PIOL) is a very rare disorder, 

and the optimal treatment is yet to be defined. Here, we report clinical 

characteristics and outcome of patients with PIOL enrolled in the prospective 

German PIOL registry (PIOL-R). Methods: Patient data in this prospective, 

non-interventional multicenter study were compiled by standardized 

questionnaires sent to Ophthalmology and Hematology/Oncology centers in 

Germany. All histologically or cytologically confirmed immunocompetent 

PIOL patients were eligible. Results: Fifteen patients (8 female, median age 

66 years, median Karnofsky performance status 90%) from 4 centers were 

included between August 2008 and January 2012. Median follow-up was 7 

months. Median time from first occurrence of symptoms to PIOL diagnosis 

was 5 (range, 1-11) months. All PIOL were of diffuse large B-cell histology. 

Eight patients had concomitant (n�3), prior (n�2) and/or subsequent 

(n�4) parenchymal brain involvement. First-line treatment included methotrexate 

(MTX)-, rituximab- and/or ifosfamide-based systemic chemotherapy 

in 12 (including high-dose chemotherapy [HDCT] with autologous stem cell 

transplantation [ASCT] in 2), intraocular (i.o.) chemotherapy with MTX 

(n�2) and/or rituximab (n�6) in 7, and ocular radiation in one patient(s). 

Two patients received prophylactic intrathecal (i.th.) treatment with MTX 

and none had whole-brain irradiation. The PIOL remission rate was 100% 

(complete remission in 11/14 evaluable patients and partial remission in 3 

patients). Four patients relapsed in the brain after 5, 6, 21 and 23 months 

and received salvage treatment with MTX and/or ifosfamide (n�3) and 

HDCT with ASCT (n�1). No ocular or systemic relapses were observed. 

Median progression-free survival was 23 (95% confidence interval, 19-26) 

months. All patients are alive. Conclusions: Although the awareness of PIOL 

and diagnostic possibilities have improved over the past 2 decades, time 

from symptom presentation to diagnosis seems to remain at previously 

reported levels. There appears to be a shift from local ocular treatments and 

radiation to systemic therapy as compared to anecdotal data with promising 

response and survival rates. 



Effect of the integrin inhibitor cilengitide on TGF-beta signaling. Presenting 

Author: Michael Weller, University Hospital Zurich, Zurich, Switzerland 

Background: Glioblastoma is the most malignant form of intrinsic brain 

tumors. One of its characteristic features, angiogenesis, is mediated by the 

expression of integrins �v�3 and �v�5 on tumor-associated vasculature. 

Cilengitide is a synthetic peptide which inhibits ligand binding to the �v�3 

and �v�5 integrins. The addition of cilengitide to the standard treatment 

regimen of radiochemotherapy in patients with newly diagnosed glioblastoma 

demonstrated promising results without significant toxicity which led 

to the initiation of a randomized phase registration III trial. Besides other 

functions, av-integrins can be involved in the activation of the cytokine 

transforming growth factor (TGF)-� which contributes to the malignant 

phenotype of glioma cells. Methods: Integrin expression was examined by 

immunohistochemistry and flow cytometry. The effects of cilengitide on 

TGF-� signaling in glioma cells were investigated by PCR, immunoblot and 

ELISA. Further assessments included reporter assays and glioma xenografts 

in nude mice. Results: The target integrins of cilengitide are 

expressed in glioblastoma blood vessels and tumor cells. Exposure to 

cilengitide results in detachment and reduced phosphorylation of Smad2 

in most glioma cell lines, including stem-like glioma cells. Furthermore, 

exposure of glioma cells to cilengitide is associated with reduced TGF-�mediated 

reporter gene activity. Smad2 phosphorylation, but not attachment, 

can be rescued by co-exposure to recombinant TGF-�. Cilengitide 

results in decreased TGF-�1 and TGF-�2 mRNA and protein expression and 

loss of transcriptional activity of the TGF-� promoter. Blocking antibodies 

to integrins �v, �v�3 or�v�5, or silencing of integrins �v, �3, �5 or�8 by 

RNA interference mimics the effects of cilengitide on TGF-� expression. 

Intracranial LN-308 glioma xenografts in nude mice display reduced 

pSmad2 levels in response to cilengitide. Conclusions: This study demonstrate 

a novel mechanism which may in part mediate anti-glioblastoma 

activity of cilengitide. These anti-TGF-� properties of cilengitide might be 

exploited in future clinical trials. 


Natural history of glioblastoma in the modern era: Longitudinal results from 

a large prospective Italian register. Presenting Author: Alba Ariela Brandes, 

Medical Oncology Department, Bellaria-Maggiore Hospital, Azienda USL of 

Bologna, Bologna, Italy 

Background: The role of temozolomide (TMZ) concurrent with and adjuvant 

to radiotherapy (RT) in the treatment of glioblastoma (GBM) has been 

demonstrated by the EORTC 22981/26981-NCIC CE.3 (EORTC/NCIC) 

randomized trial, and has been widely accepted as the standard treatment. 

The impact of RT/TMZ in the general patient population was assessed in 

the context of the Registry of the Project of Emilia-Romagna Region in 

Neuro-Oncology (PERNO), that represents the first italian prospectic 

observational population-based study in neuro-oncology. Methods: Approvals 

from local Ethical Committees were obtained by 8 participating centres. 

Patients (pts) who met the following inclusion criteria were evaluated: age 

�18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant 

non glial tumoral disease, resident in Emilia Romagna region. The data 

were prospectively collected. Results: From January 2009 to January 2011, 

194 GBM pts were enrolled. The median age was 62.5, with 26% of pts 

over 70 years. After surgery pts received RT/TMZ (73%), RT alone (19%), 

TMZ alone (5%) or no further treatment (3%); 22% were included in 

clinical trials. Median overall survival (OS) was 12.9 months. Pts �70 

years received RT/TMZ in 85% of cases. In this group of pts mOS was 17 

months (95%CI: 15.4–18.6). Interestingly, pts �70 years included in 

experimental clinical trials showed a significant OS improvement (p�0.04). 

In multivariate analysis, only extent of surgery (p�0.047), KPS (p�0.01) 

and RT/TMZ (p�0.001) were associated with OS in pts �70 years. 

Conclusions: Our population data reproduces the beneficial effect of 

RT/TMZ from the EORTC/NCIC randomized trial, confirming how this 

successful approach as been widely incorporated in daily practice. Interestingly, 

our data suggest that the survival of GBM pts treated with RT/TMZ 

could be greater than patients treated with RT/TMZ in the EORTC/NCIC 

trial at the beginning of this century. 


129s 


Impaired expression of ketone metabolizing enzymes in malignant gliomas: 

Implication for ketogenic diet therapy. Presenting Author: Howard T. 

Chang, Michigan State University, East Lansing, MI 

Background: Malignant glial cells may have altered expression of mitochondrial 

enzymes that are key for deriving energy from ketones. The novel 

strategy of treating malignant gliomas with a ketogenic diet has been tested 

in animal models with promising results. To evaluate the applicability of 

these findings to human patients we tested the hypothesis that high grade 

human gliomas may lack or have decreased expression of mitochondrial 

enzymes that are important for metabolizing ketones. Methods: We evaluated 

the expression of 2 key mitochondrial enzymes involved in ketone 

metabolism in 22 patients (17 males and 5 females, mean age 55,range 

30-85) with either glioblastoma (GBM, WHO grade IV) or anaplastic glioma 

(WHO grade III) (Table). Immunohistochemistry reactions were performed 

on formalin-fixed paraffin-embedded sections from brain biopsies, using 

antibodies raised against succinyl CoA: 3-oxoacid CoA transferase (OXCT1) 

and 3-hydroxybutyrate dehydrogenase 1 (BDH1). Immunoreactivities were 

graded using a semi-quantitative scale based on the percentage of positive 

cells: negative (NEG) � 5%; intermediate (INT) 5-20%; and positive (POS) 

more than 20%. Focal non-neoplastic “normal” brain tissue present within 

the specimens expressed both enzymes and served as an internal positive 

control. Results: Either absent or marked decreased expression of OXCT1 

and BDH1 were observed in most GBM and anaplastic glioma. Concordance 

for absent or marked decrease expression of both OXCT1 and BDH1 

was observed in 14 of the 17 (82%) GBM’s, and 1 of 5 (20%) anaplastic 

gliomas. Conclusions: These data support the rationale for a pilot clinical 

study investigating the therapeutic utility of a ketogenic diet in selected 

glioma patients. Malignant gliomas with diminished expression of key 

enzymes (e.g., OXCT1, BDH1) may benefit from the ketogenic diet therapy, 

whereas those with positive expression of these enzymes likely will not. 

OXCT1 BDH1 

N NEG INT POS NEG INT POS 

GBM 17 10 4 3 11 6 0 

Anaplastic glioma 5 0 1 4 1 3 1 


Quality of life in patients with malignant brain tumors. Presenting Author: 

Ali Choucair, Norton Neuroscience Institute, Louisville, KY 

Background: A positive quality of life (QOL) serves as an important outcome 

priority in patients with malignant brain tumors whose survival is limited by 

tumor resistance to treatment. The FDA and ASCO have designated QOL as 

an outcome secondary in importance to survival. We conducted a prospective 

longitudinal collection of QOL measures (EORTC QLQ-C30, EORTC 

QLQ-BN20, and Hospital Anxiety and Depression Scale [HADS]) coupled 

with clinical standards of care (brain MRI and clinical history and physical 

examinations) in patients with newly diagnosed primary brain tumors 

(PBT). We also examined the QOL measures over time as related to tumor 

progression. Methods: Under an IRB-approved protocol, we reviewed the 

validated QOL measures and standard clinical measures from patients who 

were newly diagnosed with PBT. The patients were followed every 3 months 

over 2 years. No proxies were allowed. A total of 52 patients were enrolled 

in the study. Survey responses were compared between two tumor groups of 

patients: patients with tumor recurrence and/or died and patients without a 

recurrence (n�26 each group). A total of 17 patients succumbed to a 

tumor-related death. Statistical analysis utilizing non-parametric t-tests 

and Wilcoxon sign tests assessed QOL responses. Results: Significant group 

differences were noted in the questions of the QOL measures surveys with 

more negative responses in the recurrence group. The questions with 

significant group differences on the EORTC QLQ-C30 ranged from symptoms 

of dyspnea (p�.05) and difficulty sleeping (p�.05) as well as a poor 

QOL (p�.005) and pain interfering with daily activities (p�.05). Significant 

group differences of questions on the EORTC QLQ-BN20 included 

weakness of the legs (p�.05), coordination difficulties (p�.005), and 

unsteady gait (p�.05). Significant group differences of questions on the 

HADS reflected a patient who is �slowed down� (p�.01) and �frightened� 

(p�.05). Conclusions: Our analysis of questions answered by patients with 

newly diagnosed PBT may shed light on the impact of cancer and its 

treatment and potential recurrence on a patient’s QOL. Further research is 

warranted to incorporate QOL measurements into improvement of patient 

care and their use in clinical trials and as a prognostic indicator. 




Tolerance and feasibility of chemotherapy by procarbazine, lomustine, and 

vincristine (PCV) for oligodendroglial anaplastic gliomas (OAG). Presenting 

Author: Marine Davos, University Hospital Timone, Marseille, France 

Background: Chemosensitivity of OAG has been documented although their 

role as part of adjuvant treatment combined to radiotherapy is debated. 

Beside temozolomide still under investigation, several studies have underlined 

activity of PCV regimen in this setting. However, significant toxicity 

has been described and dose intensity and schedule duration are not 

clearly reported. Methods: This monocentric retrospective analysis included 

all pts with OAG treated with at least 1 cycle of PVC (lomustine 110mg/m2 

every 6 weeks) at our institution from August 2007 to August 2011 

(pharmacy charter). Toxicities data were collected from clinical observations 

and blood investigations. Results: 40 pts were identified (M/F: 23/17). 

Median age was 45y (20 – 72). At the time of analyses, 32 pts were still 

alive. Histologies were oligodendroglioma (73%) or oligoastrocytoma (27%). 

Codeletion 1p19q was observed in 30 % of pts. PCV was administered in 

first or second line of chemotherapy for 60 % and 40 % of pts respectively. 

Seventy five percent and 52.5% of pts completed at least of 4 and 6 cycles 

respectively. Discontinuation of PCV occurred in 45% of pts for toxicity 

(10%), progression (30%), or other reason (5%). Because of toxicity 

38/196 (19%) PCV cycles were delayed. Dose was adapted for 73% of pts 

and decreased under 60% of theoretical dose in 30% of pts at cycle 4 and 

in 57% of pts at cycle 6 (table1). Grade III or IV toxicity occurred in 28% of 

pts and only grade I-II in 50%. Neuropathies occurred in 43 % of pts. 

Conclusions: Despite activity of PCV regimen, significant toxicity is associated 

to this schedule, that impact feasibility and compliance. PVC 

schedule should be redefined taking into account dose intensity applied in 

toxicity observed. 

Cycles 

Cumulative number (nb) 

of pts under PCV 

Nb of pts per dose 

% of theoretical dose of lomustine 

90–100% 70–80% 50–60% < 50 % 

Total nb of 

pts per cycle 

1 40 (100%) 23 (57.5%) 13 (32.5%) 3 (7.5%) 1 (2.5%) 6 (15%) 

2 34 (85%) 18 (53%) 11 (32%) 4 (12%) 1 (3%) 2 (5%) 

3 32 (80%) 12 (38%) 12 (38%) 6 (18%) 2 (6%) 2 (5%) 

4 30 (75%) 10 (33%) 11 (37%) 6 (20%) 3 (10%) 3 (7.5%) 

5 27 (32.5%) 8 (30%) 8 (30%) 6 (22%) 5 (18%) 6 (15%) 

6 21 (52.5%) 4 (19%) 5 (24%) 7 (33%) 5 (24%) 21 (52.5%) 


The association of pretreatment neutrophil to lymphocyte ratio with overall 

survival in patients with glioblastoma multiforme (GBM). Presenting 

Author: Richard Martin Bambury, Department of Medical Oncology, Cork 

University Hospital, Cork, Ireland 

Background: GBM is the most common and aggressive primary brain tumor. 

The neutrophil to lymphocyte ratio (NLR) gives a measure of systemic 

inflammatory response and lymphopenia, both of which are poor prognostic 

factors in many malignancies. No published study has assessed the 

prognostic impact of NLR in GBM. Methods: Patients treated for GBM at our 

regional referral centre with assessable complete blood count at first 

presentation (prior to corticosteroid therapy or surgery) were identified. 

Medical notes were reviewed to extract demographic and treatment data. 

Survival curves were estimated via Kaplan-Meier method and compared via 

log-rank method. Multivariate analysis was performed via Cox proportional 

hazards regression modelling. Results: A total of 86 patients were identified, 

of which 65(76%) were male. Median age at diagnosis was 58 years 

(range: 18–76). At the time of analysis all patients still alive had � 2 years 

follow-up. Median overall survival (OS) was 9.3 months (range: 1-82). 57% 

completed the standard adjuvant Stupp protocol and 43% discontinued 

early due to disease progression or treatment toxicity. Median OS was 11.2 

months in patients with NLR�4 and 7.5 months in patients with NLR�4 

(HR 0.59, p�.04). Other significant prognostic factors based on univariate 

analysis were consistent with published data (Table). After correcting for 

known prognostic factors NLR remained a significant predictor of survival 

(Table). Conclusions: Recent advances in immunotherapy have highlighted 

the importance of the immune system in the treatment and prognosis of 

cancer patients. Many GBM patients are on corticosteroids for a significant 

proportion of their disease course which may abrogate the effects of host 

immunity on outcome. Nevertheless, we have shown that NLR at diagnosis 

is an independent predictor of survival in GBM patients. Investigation of 

therapies which harness the immune response are warranted in this 

disease. 

Univariate Multivariate 

Hazard ratio p value p value 

NLR (4) 0.59 0.01 0.01 

Age (60) 0.47 �0.01 0.01 

Surgery (debulking vs biopsy) 0.60 0.01 0.01 

Stupp protocol (complete vs incomplete) 0.21 �0.01 �0.01 


Anaplastic gliomas at first recurrence: Outcome analysis. Presenting 

Author: Enrico Franceschi, Medical Oncology Department, Bellaria- 

Maggiore Hospital, Azienda USL of Bologna, Bologna, Italy 

Background: Although anaplastic gliomas show a more favorable response 

to postsurgical therapy than glioblastoma, when recurs, salvage therapies 

offer only temporary benefit. Moreover, due to the rarity of these entities, no 

study exists to evaluate the clinical outcomes of anaplastic gliomas at first 

recurrence. Methods: A retrospective analysis was made using a database 

on 249 anaplastic glioma patients (pts) followed prospectively between 

01/2000 and 12/2011. Eligibility criteria: age �18 years; PS 0-2; 

histological diagnosis at first surgery of anaplastic astrocytoma (AA), 

anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA); 

first recurrence after postsurgical treatments. Results: 163 pts (recurrent 

AA:52%, AOA:23%, AO: 25%, mean age: 45 years, range: 21–74) were 

enrolled. 1p deletion and MGMT methylation were found in 23% and 56% 

of evaluable specimens, respectively. At time progression, second surgery 

was performed in 51 pts (31%). Chemotherapy was delivered in 128 pts: 

temozolomide in 96 pts (75%), PCV regimen in 11 pts (9%), and other 

cytotoxic treatments in 21 pts (16%). Median PFS was 7.1 months (95% 

CI: 5.8–8.5), being PFS-6 57.8% (95%CI: 49.8%–65.8%), mOS: 18.3 

months (95% CI: 13.9–22.8) and OS-12: 63% (95%CI: 55.4%-70.6%). 

1p status was not significantly associated with PFS and OS measured from 

first recurrence to second progression or death, respectively (p�0.12 and 

p�0.08). In the Cox proportional hazard model, PFS at recurrence was 

significantly correlated with OS measured at the first disease recurrence 

(p�0.00001). Conclusions: our data represent the largest series that 

evaluated the outcome of anaplastic gliomas at first recurrence. In this 

setting, PFS should be considered as a worthy endpoint, being significantly 

correlated with OS. 


Illness intrusiveness and subjective well-being in patients with glioblastoma 

multiforme. Presenting Author: Linda Coate, Princess Margaret 

Hospital, Toronto, ON, Canada 

Background: Glioblastoma multiforme (GBM) is the most common adult 

CNS malignancy. The quality-of-life (QOL) impact of its neurological 

sequelae and poor prognosis is poorly understood. In this study we 

examined relations between disease severity and mood in GBM patients. 

Methods: GBM patients (n�73) completed validated questionnaires examining 

depression (CESD), positive affect (ABS), illness intrusiveness (II), 

and health-related QOL (EORTC-QLQ30, BN-20). Median age was 53 years 

(range 26-75), median time since diagnosis was 1.1 years (range 0.1- 

12.4). 88% were on temozolomide. Questionnaire scores were compared to 

normative data from GI, GU, Breast, Head and Neck, Lymphoma, and Lung 

cancer groups using t-tests. Hierarchical multiple regression analyses 

tested the impact of disease severity indicators (ECOG; Symptoms, derived 

from QLQ30, BN20) and potential moderators on mood and whether II 

mediates those effects. Results: GBM patients reported less positive affect, 

more depression and greater II than other cancer patients (p�.05). 

Increase in symptoms correlated with greater II (��.59; 95% CI [.31, .87], 

p�.0001) and depression (��.37; 95% CI [.20, .55], p�.0001) and less 

positive affect (��-.04; 95% CI [-.08, -.01], p�.02). Surprisingly, higher 

ECOG (i.e., poorer performance status) was associated with less II 

(��-3.58; 95%CI [-7.06, -.10], p�.04) and depression (��-2.20; 95%CI 

[-4.21, -.19], p�.03). II partially mediated the relations between disease 

severity and mood, evidenced by the change in the disease severity 

coefficient when II was added to the models (mean change measured by 

bootstrap sampling: CESD�.23, 95% CI [.06, .43]; ABS�.21, 95%CI 

[.02, .44]). The occurrence of other stressful life events was associated 

with II (��2.73; 95% CI [.43, 5.02], p�.02), but there was no evidence of 

a moderating effect on this or any other relationship (p�.05). Conclusions: 

GBM patients are more distressed than other cancer patients. GBMinduced 

lifestyle disruptions partially mediate the association between 

disease severity and subjective well-being. Efforts to engage patients in 

valued activities and interests, despite the constraints, can help to preserve 

QOL. 



Impact of duration of bevacizumab (Bev) treatment in the prognosis of 

adults with recurrent malignant gliomas. Presenting Author: Mohamed Ali 

Hamza, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Bev is the standard treatment for patients with recurrent 

glioblastoma (GB) but is also used in treating recurrent anaplastic gliomas 

(AG). Differences in outcome between these groups and optimal duration of 

treatment with Bev in pts with recurrent malignant gliomas are not well 

defined. We examined the relationship between the duration of Bev 

treatment and the outcome in pts with GB and AG. Methods: In this 

retrospective chart and data review derived from our longitudinal database, 

we identified pts with recurrent AG and GB who were treated with Bev alone 

or Bev-containing regimens between 2005 and 2009; the data was 

analyzed to determine the overall survival (OS) and the progression free 

survival (PFS). Results: A total of 261 patients with recurrent malignant 

gliomas (196 with GB and 65 with AG) were identified. There was no 

significant difference between the median length of treatment between AG 

and GB (5.81�0.66 months vs. 6.77�0.52 months, p�0.32). PFS6 was 

34.2% (95% CI, 27.8-41.3) for patients with GB and 44.2% (95% CI, 

32.5-56.7) for patients with AG. Patients with GB who were treated �6 

months had a significantly higher OS (29.13 months vs. 20.16 months, p� 

0.001) compared to those treated �6 months, and a significantly higher 

PFS compared to those treated �6months (11.33 months vs. 3.7 months, 

p�0.0001). For patients with AG, although treatment �6 months had a 

significantly higher PFS (13.93 months vs. 3.53 months, p�0.0001), OS 

was not significantly different (months 38.6 vs. 52.5 months, p�0.6) 

compared with those treated �6 months. Conclusions: Length of treatment 

�6 mo with Bev or Bev-containing regimen was associated with improved 

PFS in both AG and GB but only the GB subgroup showed improved OS. 

These results suggest equivocal survival benefit in patients with AG with 

longer duration of bevacizumab treatment, which requires further study in 

prospective trials. 


A preclinical study on the combined treatment of nimotuzumab and 

sirolimus in glioblastoma. Presenting Author: Chee Kian Tham, National 

Cancer Centre, Singapore 

Background: The human epidermal growth factor receptor (EGFR) is an 

ideal therapeutic target for inhibiting glioblastoma (GBM) growth as the 

signaling pathway is highly dysregulated in GBM. However, trials so far with 

EGFR inhibitors have not shown clinically meaningful improvement in 

response rates and survival. One of the postulated mechanisms of resistance 

is the constitutive activation of the downstream, PI3K/AKT/mTOR 

pathway, independent of the upstream EGFR activation status. Hence, the 

dual blockage of the pathways with an anti-EGFR agent and mTOR inhibitor 

is postulated to have synergistic anti-tumour effects. We aim to investigate 

the anti-tumour effect of combined nimotuzumab (anti-EGFR monoclonal 

antibody) and sirolimus (mTOR inhibitor) in a GBM preclinical model. 

Methods: Primary human GBM cells were derived from surgical GBM 

specimens. The endogenous expressions of glial-fibrillary acidic proteins 

and EGFR were determined by IHC staining and Western Blot analysis. Cell 

viability assays were then carried out in these GBM cells and immortalized 

human normal astrocytes (iHNA) using a range of concentrations of 

nimotuzumab alone, sirolimus alone or combined treatment. Results: GBM 

cells treated with nimotuzumab showed a dose- dependent cell kill and the 

optimal concentration was determined to be 2 �g/ml. Treatment of the 

GBM cells with sirolimus showed that the drug was capable of inducing cell 

death at varying levels and the optimal level was determined to be 0.1 mM. 

Combined treatment with nimotuzumab (2�g/ml) and rapamycin (0.1 mM) 

showed a dose dependent cell kill in GBM cells which was not observed in 

iNHA cells. The combined treatment resulted in only 10% of residual 

gliomas at 24 h post treatment. Single treatment with rapamycin has no 

cytotoxic effect whereas treatment with nimotuzumab alone exerts a 

cytotoxicity effect of 33%. Taken together, we observed an additive effect 

of cell kill when rapamycin is used together with nimotuzumab in human 

glioma cells. Conclusions: In this study, combined treatment of nimotuzumab 

and sirolimus resulted in a greater cytocidal effects in GBM cells 

than either agent alone. We will further examine this combination regimen 

in a subsequent phase I clinical trial. 


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Rising incidence of glioblastoma and meningioma in the United States: 

Projections through 2050. Presenting Author: Derek Richard Johnson, 

Mayo Clinic, Rochester, MN 

Background: In the absence of proven environmental or behavioral risk 

factors, patient age and sex remain the most important predictors of 

primary brain tumor risk. In coming years, an increasing incidence of brain 

tumors in the United States can be anticipated based on shifts in the 

demographic structure of the population. This study provides estimates of 

glioblastoma and meningioma incidence through 2050. Methods: Groupspecific 

glioblastoma and meningioma incidence rates based on age 

(eleven categories) and sex were calculated from National Cancer Institute 

(NCI) Surveillance, Epidemiology, and End Results (SEER) data for the 

period 2004-2008. United States Census projections based on data from 

the 2000 census were used to compute the size of the twenty-two 

demographic subpopulations of interest in 2010, 2020, 2030, 2040, and 

2050. The estimated number of new glioblastoma and meningioma 

diagnoses for each of these years was calculated from the defined 

incidence rates and population size. Results: Crude annual tumor incidence 

rates were 3.13 per 100,000 persons for glioblastoma and 6.81 per 

100,000 persons for meningioma. While the overall size of the population 

is expected to increase only 42% between 2010 and 2050, the number of 

Americans over 65 years of age, the group at highest risk of glioblastoma 

and meningioma, is expected to increase by 120%. We estimate that the 

number of new glioblastoma diagnoses will rise from 10,688 in 2010 to 

18,466 in 2050, a 72% increase. Likewise, the number of new meningioma 

diagnoses will rise from 22,946 to 40,680 over the same period, a 

77% increase. Conclusions: The number of new glioblastoma and meningioma 

diagnoses will increase substantially in the future. This analysis, which 

assumes a fixed incidence rate, may underestimate the true magnitude of 

the coming change given reports suggesting that incidence rates of 

glioblastoma and meningioma are rising over time. 


Bevacizumab failure in glioblastomas. Presenting Author: Ghazaleh Tabatabai, 

Department of Neurology, University Hospital Zurich, Zurich, Switzerland 

Background: Bevacizumab has been approved for the treatment of recurrent 

glioblastoma in various countries. The phase III registration trial assessing 

the addition of bevacizumab to standard chemoradiotherapy in newly 

diagnosed glioblastomas has completed recruitment. Salvage treatment of 

glioblastoma patients after bevacizumab failure, however, is commonly not 

successful. In the present study, we aimed at characterizing histological 

and molecular characteristics associated with glioma recurrence after 

bevacizumab. Methods: Paired tissue samples from primary and recurrent 

tumors obtained from 12 patients with glioblastoma (n�11) or anaplastic 

astrocytoma (n�1) before and after bevacizumab treatment, and 14 

non-bevacizumab-treated patients as a reference group, were analyzed for 

histological features as well as molecular markers. Clinical records and 

magnetic resonance images were reviewed. Results: Histologically, recurrent 

tumors after bevacizumab showed more commonly a decreased blood 

vessel density and reduced glomeroloid microvascular proliferations when 

compared to recurrent tumors after conventional radiochemotherapy. In 

contrast, tumor cellularity and proliferation rate were similar. Distant 

relapse was more common in bevacizumab-treated patients. Molecular 

genetic studies of the respective tissue specimens are currently under way. 

Conclusions: Histological and molecular analyses of tumor tissue samples 

from glioma patients before and after bevacizumab treatment, combined 

with thorough clinical and radiological correlates, may provide hints for 

therapy escape mechanisms that can then be validated in preclinical 

models. 




Effect of electrochemotherapy with IV bleomycin on complete response in a 

preclinical brain tumor study. Presenting Author: Birgit Agerholm-Larsen, 

Department of Oncology, C*EDGE at Glostrup Research Institute, Glostrup, 

Denmark 

Background: Electrochemotherapy (ECT) describes enhanced chemotherapeutic 

drug uptake after cell membranes have been made transiently 

permeable due to application of an electric field to the tumor. ECT is 

routinely used to treat skin metastases, with high response rates after 

once-only treatment. We have developed an electrode for use in the brain, 

both a rodent model and an electrode for clinical use. The aim of the 

present study was to evaluate ECT using intravenous (iv) bleomycin in a rat 

brain tumor model. Methods: Sprague Dawley male rats (7-11 week old) 

were inoculated with rat glial cell derived tumor cells (N32) through a burr 

hole in the skull. When tumors appeared on MRI, animals were allocated to 

ECT (iv bleomycin and local electric pulses), iv bleomycin only, iv 

bleomycin with placement of electrodes (no pulses), or no treatment. 

Bleomycin was injected iv in the tail vein (600�L, 3 IU/�L) and electrode 

deployment was made through the burr hole into the brain tissue. 

Electrochemotherapy parameters were 32 pulses, 100V, 100�s, 1Hz. 

Tumor size was determined based on contrast enhanced area from MR 

scans. Kaplan-Meyer events were defined as termination due to extensive 

tumor progression prior to end of the three independent experiments 

performed. Immuno-histo-pathology was performed after termination to 

verify MRI findings. Results: In 88% of the animals (14 of 16) treated with 

electrochemotherapy we found complete response (no tumor), validated by 

MRI and immuno-histo-pathology, whereas bleomycin only, bleomycin and 

electrodes, and no treatment showed progression in 11 out of 13 control 

animals. A Kaplan-Meier plot showed a pronounced improved survival for 

the ECT group as compared to controls within 3 weeks from treatment 

(p�0.001). Treatment was well tolerated. Conclusions: The present data 

suggest that electrochemotherapy with iv injection of bleomycin is a new 

promising treatment for brain tumors. In a clinical study using iv bleomycin 

and electrochemotherapy for brain metastases (www.clinicaltrials.gov, 

ID:NCT01322100) the first patient has just been treated successfully with 

ECT, indicating feasibility of the approach in the clinical setting. 


Health-related quality of life (HRQOL) in patients with glioblastoma (GBM) 

and their caregivers in the end-of-life phase: A retrospective study. 

Presenting Author: Birgit Flechl, Medical University of Vienna, Vienna, 

Austria 

Background: Glioblastoma multiforme (GBM) still harbours an inevitably 

fatal prognosis. The specially course of this disease poses unique challenges 

in care provision to the relatives. We still lack data about the 

end-of-life phase of GBM patients to improve counseling and supporting 

GBM patients and their proxies. Methods: In this retrospecitve study we 

included 52 caregivers of deceased GBM patients treated in two hospitals 

in Vienna, Austria. We used a specially developed questionnaire by the 

Medical University of Amsterdam to explore and document the last three 

months of living of GBM patients. Results: Most of the included caregivers 

were the partners of the patients (88%) and two thirds were female. The 

most common symptom in GBM patients was fatigue (87%), followed by 

reduced consciousness (81%) and aphasia (77%). 22% of the patients 

were bedbound during their last three months increasing to 80% in the last 

week of life. 30% of the caregivers told that they felt incompletely informed 

for their task and about the illness of their loved one. They stated the quality 

of life (QOL) of the patients with 2.2 and their own with 2.8 on a scale of 1 

to 7 whereas 7 displays the best possible answer. The majority of the 

patients (46%) died in hospitals and 38% at home, which was the most 

often expressed wish for place of death (45%)by patients. Regarding the 

caregivers´ symptoms, sadness (90%), fear (69%), burnout (60%), less 

interest in others (54%) and irritation (42%) were the leading ones and did 

not differ significantly in-between the places of death. Conclusions: The 

end-of-life phase of GBM patients is different from that of patients dying 

from other cancers. Most alarmingly, one thirds of their caregivers feels 

poorly informed. About two thirds of the caregivers fell overstrained and 

stresses thereby the urgent need for support and dedicated educational 

programs. 


Prospective follow-up of a cohort of 112 patients with leptomeningeal 

metastases of breast cancer recruited from 2007 to 2011: Prognostic 

factors. Presenting Author: Fahed Zairi, CHRU, Lille, France 

Background: Around 5% of patients with breast cancers (BC) will develop 

leptomeningeal metastasis (LM). The incidence may increase. Methods: We 

reported the description and outcome of 112 consecutive BC patients 

diagnosed with LM in our institution from 2007 to 2011. Correlations 

between characteristics and overall survival (OS) were analyzed using usual 

statistical methods (Kaplan Meier, Log-rank, Cox model). Results: BC were 

invasive ductal carcinoma in 69.7%. Estrogen and progesterone receptors 

were detected in respectively 61.6 and 44.6%. HER2 expression was 

observed in 26%. 23% were triple negative. Median time between BC 

diagnosis and LM diagnosis was 44 months. At LM diagnosis, median age 

was 54 and median Performance Status (PS) was 2. CSF cytology and 

cerebrospinal MRI were positive in respectively 72,5% and 87%. 103 

(92%) LM patients received IT liposomal cytarabine as 1st line of 

treatment (ventricular device in 47%). IT therapy could be associated with 

systemic treatment in 58% of the cases and cerebral radiotherapy for LM in 

14% of the cases. Clinical response after 1st line treatment was observed 

in 57%, CSF response in 30,5%, MRI response in 62,5%. 24 patients 

received a 2nd line of IT thiotepa, 6 a 3rd line of IT methotrexate. The more 

significant prognostic factors (p�0,0001) were initial PS, associated 

systemic treatment and triple negative BC status. Other significant predictors 

of OS were thiotepa as 2nd line treatment (p�0,0004), intracranial 

hypertension at LM diagnosis (p�0,019), associated cerebral radiotherapy 

(p�0,02), progesterone receptor status (p�0,04). Median OS of the 103 

treated patients was 3,8 months (4,75 months for 0-2 PS and 1,6 months 

for 3-4 PS patients). Conclusions: Median OS was consistent those of other 

recent cohorts of BC LM. Our results confirm the role of a very early 

diagnosis, before the degradation of the general status. The association 

with systemic treatment or cerebral radiotherapy is indicated when possible. 


Pediatric glioblastoma: Results with adjuvant chemoradiation using temozolomide. 

Presenting Author: Nikhil Purushottam Joshi, All India Institute 

of Medical Sciences, New Delhi, India 

Background: Paediatric glioblastoma patients are underrepresented in 

major trials for this disease. The value of concurrent and adjuvant 

temozolomide is not known in this subset of patients. Methods: We 

retrospectively analysed our database between 2004 and 2010. All 

patients were treated with maximally safe surgical resection. This was 

followed by a uniform treatment schedule of post-operative radiation 

according to RTOG guidelines with concurrent daily temozolomide at 75 

mg per meter square. The radiation dose was 60 Gy in 30 fractions planned 

by 3 dimensional conformal radiotherapy. 4 weeks later, adjuvant temozolomide 

was started at 150 mg per meter square, day 1 to 5 every 28 days 

and escalated to 200 mg per meter square if well tolerated. Log-rank test 

was used to compare survival distribution. The data was analysed using 

SPSS 16. Results: 23 patients were analysed. The median age was 11 years 

(range: 5 to 19 years). 15 males and 8 females were noted. 4 patients had 

seizures at presentation while 19 did not. 13 patients underwent a gross 

total resection while 10 underwent a subtotal resection. 5 patients received 

only concurrent temozolomide while 18 received concurrent and adjuvant 

temozolomide. The median number of adjuvant temozolomide cycles were 

6 (range 2 to 12). The median follow up was 11.9 months (range: 1.6 to 

30.1 months). 6 patients were dead and 17 were alive at the time of 

analysis. The median overall survival was not reached. The median survival 

for patients receiving only concurrent temozolomide was 13 months while 

that for patients receiving concurrent and adjuvant temozolomide was not 

reached and the difference was statistically significant (p�0.0009). The 

overall survival was not statistically different for age less or more than 10 

years, gender, and type of surgery or the number of adjuvant cycles of 

temozolomide (less or more than 6). Conclusions: Temozolomide may have 

a role in paediatric Glioblastoma. Both concurrent and adjuvant temozolomide 

seem to be important for superior overall survival in this group of 

patients. 



Bevacizumab use and central nervous system (CNS) hemorrhage. Presenting 

Author: Nathalie LeTarte, Centre Hospitalier de l’université de Montreal 

(CHUM), Montreal, QC, Canada 

Background: Bevacizumab is widely used and may cause life-threatening 

bleeding, usually at sites of disease involvement such as the CNS. We 

attempted to identify clinical characteristics associated with CNS hemorrhage 

in a broad population. Methods: We did a retrospective review of the 

FDA Medwatch database of adverse events reported with bevacizumab from 

11/1997 to 5/2009. Results: We searched the database for keywords 

bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, 

hemorrhagic stroke, and brain. 17,466 reports were included in the 

database: 154 described CNS hemorrhage in 99 patients, and 1041 

reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage 

was the most frequent event reported (n�39), followed by intracranial 

hemorrhage (n�20) and subarachnoid hemorrhage (n�18). Median age 

was 62 years; 54% of patients were female. Primary cancer was colorectal 

(42%), glioma (13%), and breast cancer (10%). Patients received a 

median of three (1-36) doses of bevacizumab prior to the bleed. 54% of 

patients received myelosuppressive chemotherapy, and 30% had documented 

history of hypertension. Sixteen patients with CNS hemorrhage 

were reported to have CNS metastases. For 70 patients, information on 

CNS involvement was not reported. Death was reported as a complication of 

hemorrhage in 48% of patients. Nine patients with brain metastases died 

and CNS hemorrhage was the cause of death in seven. Six patients with 

glioma died, and CNS hemorrhage was the cause in three. One patient with 

brain metastases, and one patient with glioma also experienced a non-CNS 

bleed. Five patients in each group had received heparin, warfarin or 

NSAIDs. Low platelet counts were reported in 3 patients with CNS 

metastases and 2 patients with glioma. The most common factor associated 

with CNS hemorrhage was medication predisposing to bleeding, 

followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage, 

was reported in 4 patients with brain metastases, and 2 patients with 

glioma. Conclusions: In this database, 154 of 1195 reports of bleeding 

associated with bevacizumab described a CNS bleed. Although CNS bleeds 

were not common, they were the reported cause of death in more than half 

of the cases. 


Phase II trial of bevacizumab and fotemustine in recurrent grade III 

gliomas. Presenting Author: Riccardo Soffietti, Division of Neuro-Oncology, 

University Hospital San Giovanni Battista, Turin, Italy 

Background: Bevacizumab (BV) has shown activity in recurrent grade III 

gliomas, and few data are available on the combination of BV and 

nitrosoureas. Fotemustine (FTM) is a nitrosourea with elevated lipophilic 

properties. Methods: In this phase II study patients with grade III gliomas 

recurrent after surgery, radiation therapy and concomitant/adjuvant temozolomide 

were eligible. The treatment consisted of an induction phase with 

BV at 10mg/kg intravenously on day 1 and 15 and FTM at 75mg/m2 

intravenously on day 1 and 8, followed after a 3 week interval by a 

maintenance phase with BV 10mg/kg and FTM 75mg/m2 every 3 weeks 

until tumor progression or unacceptable toxicity. Patients had undergone 

clinical and MRI assessment 1 month after the start of treatment and 

thereafter every 2 months. The primary endpoint was progression-free 

survival at 6 months (PFS-6), whereas secondary end-points were response 

rate (RR), based on RANO criteria, progression-free survival (PFS), overall 

survival (OS), and safety. Results: From May 2008 to September 2011, 32 

patients (males 23, females 9, median age 46) were enrolled. PFS-6, PFS 

-12 and median PFS were 31%, 7% and 5 months (range: 1-43�), 

respectively. OS-6, OS-12 and median OS were 78%, 37.8% and 8.6 

months (3.5-43�), respectively. Response rates were as follows: 4 CR 

(12.5%), 12 PR (37.5%), 14 SD (44%) and 2 PD (6%). A significant 

neurological improvement was observed in 48% of symptomatic patients, 

being steroids reduced or withdrawn in 83% of patients. 29/32 (91%) 

patients have progressed and patterns of tumor progression were local in 20 

(69%), multicentric in previous multicentrinc tumors in 5 (17%), gliomatosis-like 

in 3 (10%) and local plus leptomeningeal seeding in 1 (4%). 23/29 

patients had salvage treatment after failure. Toxicities after BV were as 

expected; 5 patients interrupted FTM for grade III-IV myelotoxicity. We did 

not observe any additional toxicity from the combination. Conclusions: The 

combination of bevacizumab and fotemustine in grade III gliomas recurrent 

after standard treatment seems to have some activity. 


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2074^ General Poster Session (Board #16E), Sat, 1:15 PM-5:15 PM 

Phase II study to evaluate the efficacy and safety of rilotumumab and 

bevacizumab (BEV) in subjects with recurrent malignant glioma (MG). 

Presenting Author: Mary Lou Affronti, Duke University Medical Center, 

Durham, NC 

Background: Prognosis of recurrent MG remains poor with a median survival 

of 3-9 months. Few evidence based treatments are available and response 

rates have been � 20% with 6 month progression–free survival (PFS) of � 

9-16%. Poor prognosis is linked to the MG’s ability to induce vascular 

proliferation and invasion. MG’s have an abundance of neo-vascularization 

and high levels of vascular endothelial growth factor (VEGF). BEV, an 

antibody to VEGF, is the most active agent tested for recurrent MG with an 

overall response rate of 21.2%. Rilotumumab is a human monoclonal 

antibody that blocks human hepatocyte growth factor (HGF) and its 

receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity 

inducing angiogenesis and expression of additional angiogenic autocrine 

factors such as VEGF. The novel combination of rilotumumab (C-Met 

inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and 

tumor proliferation may demonstrate synergistic tumor growth inhibition. 

Methods: A two-stage design is used to assess radiographic response rate 

with � 3 responses required for the first stage. Secondary endpoints were 

PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve 

MGs received rilotumumab at 20 mg/kg in combination with BEV at 10 

mg/kg every two weeks � 28 days after the last surgical procedure. A brain 

MRI was obtained after each 6-week cycle. Results: 15 of the 19 patients 

required for the first stage have been accrued. 10(67%) were male and � 

50 years. 73% received � 2 prior regimens and 46% had � 2 prior 

progressions. Best tumor response included 1(7%) complete response, 2 

(13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive 

disease with 20% (3/15) non-evaluable due to early termination secondary 

to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month 

PFS of 25.4% (95% CI: 6.4, 50.5) and 6-month OS of 68.3% (95% CI: 

34, 87.1). Toxicities are listed below. Maximum average weight increase 

over all cycles was 6.3 % (SD � 6.09). Conclusions: Rilotumumab in 

combination with BEV is an active regimen in MG. Toxicity will need to be 

closely monitored. 

Toxicity Grade 3 Grade 4 Grade 5 

Prolonged QTc interval 1 (7%) 

Hypotension 1 (7%) 

Hypokalemia 1 (7%) 

DVT/PE 1 (7%) 2 (13%) 1 (7%) 


Adult low-grade gliomas: The Cleveland Clinic experience. Presenting 

Author: Lizbeth Robles Irizarry, Cleveland Clinic, Cleveland, OH 

Background: Low-grade gliomas account for 10-20% of all primary brain 

tumors. There is limited data on specific prognostic factors for patients with 

low-grade gliomas. Methods: After obtaining IRB approval, the Cleveland 

Clinic Brain Tumor and Neuro-Oncology Center’s database was used to 

identify patients with histologically confirmed grade 2 glioma at the time of 

diagnosis. Multivariable analysis was conducted with use of a Cox proportional 

hazards model and a stepwise selection algorithm that used p�0.10 

as the criteria for entry and p�0.05 as retention in the model to identify 

independent predictors of survival. Results: Chart records of 478 patients 

(54% of whom were men) diagnosed between 1991 and 2010 were 

included for analysis. The median age at presentation was 41 years (range, 

18-83 years). 42% of patients had biopsy only, 27% had gross total 

resection, 6% had near total resection, and 25% had subtotal resection. 

22% of patients were initially treated with radiation, 30% with adjuvant 

chemotherapy, and 7% with concurrent chemotherapy. Median progression 

free survival and median overall survival (OS) were 5.1 years and 12.8 

years, respectively. On multivariate analysis, independent of additional 

therapy, five factors were identified as independent predictors of OS: age at 

diagnosis (p�0.002), Karnofsky performance status (KPS, p�0.0001), 

histology (astrocytoma vs. other, p�0.001), hemispheric location (left or 

bilateral involvement vs. right, p�0.02) and gender (male vs. female, 

p�0.0003). Conclusions: Older age, male gender, poor performance 

status, astrocytic histology, and left hemispheric or bilateral involvement 

are associated with higher mortality. 

Risk factors for mortality: Multivariable Cox proportional hazards analysis. 

Factor1 Hazard ratio (95% C.I.) p2 KPS (55 vs. 50-55 vs.



Utility of iron oxide nanoparticles in the radiographic diagnosis of CNS 

lymphoma and inflammatory diseases. Presenting Author: Brian T. Farrell, 

Oregon Health & Science University, Portland, OR 

Background: Ferumoxytol, an ultrasmall superparamagnetic iron oxide 

nanoparticle (USPIO), is approved for intravenous treatment of iron 

deficiency in chronic renal failure. The package insert warns of potential 

alterations of magnetic resonance imaging (MRI). Our initial animal studies 

provided evidence of USPIO uptake by macrophages and lymphoreticular 

cells suggesting its potential in CNS lymphoma (CNSL), post transplant 

lymphoproliferative disease, or CNS inflammation (i.e. multiple sclerosis). 

The mechanism of USPIO enhancement differs from gadolinium-based 

contrast agents (GBCA), which optimally image areas of increased vascular 

permeability. Methods: USPIO was administered as an MRI contrast agent 

to 20 patients with presumptive or de facto diagnosis of CNSL or CNS 

inflammation. Seventeen of 20 patients underwent both USPIO- and 

gadolinium-based MRI. Three patients received only USPIO due to risk of 

nephrogenic systemic fibrosis (NSF) with GBCA exposure. In the pilot 

phase of the study, patients were given the USPIO ferumoxtran-10 and 

subsequent patients were given a successor USPIO (ferumoxytol) which 

has improved pharmaceutical properties. All patients were monitored for 

adverse reactions. MRI scans were subsequently reviewed by a neuroradiologist. 

Results: No significant toxicities were seen. Thirteen of 17 patients 

who received both contrast agents showed equal numbers of enhancing 

lesions on postcontrast images. USPIO-based contrast revealed additional 

areas of enhancement in three of 17 patients that were not visible when 

GBCA was administered. In three patients more lesions were seen with 

GBCA. Examples of ferumoxytol utility include 1) improved targeting for 

surgical biopsy; 2) avoidance of NSF; 3) demonstrating enhancement 

related to macrophages within lesions; 4) correlating cerebral blood volume 

and CNS inflammation; 5) demonstrating pitfalls such as prolonged 

imaging changes (3 months) in one case due to intensive inflammation, 

which can simulate hemorrhage. Conclusions: These studies provide data 

about the utility and value of USPIO-based contrast imaging in CNSL and 

inflammatory CNS lesions that support a dual role for these agents beyond 

iron replacement. 


Tegwondo-CCNU: A novel combination of protracted, near-continuous 

temozolomide and CCNU with activity in recurrent malignant gliomas. 

Presenting Author: Herwig Matthias Strik, University of Marburg, Marburg, 

Germany 

Background: Recent data have been raising doubt if dose-dense temozolomide 

is more efficient against malignant gliomas than with conventional 

dosing. We report here updated results of combined near-continuous 

temozolomide, aimed at depleting anti-alkylating MGMT, with once weekly 

application of low-dose lomustine (CCNU) at first or second relapse of 

malignant gliomas. Methods: 25 consecutive patients with recurrent 

malignant gliomas (12 anaplastic gliomas WHO III, 13 glioblastomas or 

gliosarkomas WHO IV) were treated: 15 males (60%), 10 females (40%); 

mean age at start of chemotherapy was 52 (20-78) years; Eight patients 

were treated at first, 15 at second and two at third recurrence. All patients 

were pretreated with temozolomide. Four patients received fractionated, 

stereotactically guided re-irradiation (FSRT). The treatment regimen consisted 

of near-continuous temozolomide 50mg/m2 day 1-5/7 and low-dose 

CCNU 40mg absolute dose day 6/7. In cases of bone-marrow depression, 

temozolomide was reduced in steps of 20mg total dose or – in more severe 

cases – chemotherapy was interrupted until normalization of blood counts. 

Results: In total, 89 cycles (months) of chemotherapy were applied. The 

combination was well tolerated in terms of nausea and fatigue. Blood 

counts usually decreased continuously, enabling a gradual dose adaptation. 

Hematological WHO grade 3�4 toxicity occurred in 5/25 patients 

(20%), two of them were symptomatic. Three patients had prolonged 

elevation of liver enzymes. Best responses after � 3 months (23 patients) 

were: 2 complete and 1 partial remissions (13%, ), 13 stable diseases 

(57%), and 7 progressive diseases (30%). Progression-free survival at six 

months from start of chemotherapy of the 16 patients treated � 6 months 

or deceased (PFS 6) was 37%, median overall survival 6.3 months. 

Conclusions: Although some hematotoxicity was observed, the regimen 

presented here is well tolerated and safe if carefully controlled. The 

objective responses and considerable rate of stable diseases indicate that 

this combination is active in malignant gliomas after pretreatment with 

temozolomide alone. The results have to be controlled in a prospective trial. 


MRI-based vessel function maps for high-resolution differentiation between 

tumor and nontumoral tissues in brain tumor patients. Presenting 

Author: Leor Zach, Sheba Medical Center, Ramat-Gan, Israel 

Background: Changes in enhancement seen in post treatment brain MRIs in 

primary and secondary brain malignancies often mimic tumor progression 

(pseudoprogression, radiation necrosis). Conventional MRI cannot differentiate 

tumor progression from treatment related effects resulting in suboptimal 

patient management. Methods: The application of delayed contrast 

extravasation MRI for depicting unique vessels characteristics with high 

resolution and high sensitivity to subtle BBB disruption is demonstrated in 

17 GBM and 15 brain metastases patients undergoing standard chemoradiation 

and radiosurgery respectively. Results: 2 primary vessel function 

populations were defined: a slow population where contrast clearance from 

the tissue was slower than accumulation, and a fast population where 

clearance was faster than accumulation. Ten stereotactic biopsies acquired 

from GBM patients showed complete correlation with the maps, confirming 

the discrimination between fast population regions, reflecting morphological 

active tumor and slow regions reflecting necrosis/treatment-induced 

changes. Typical fast population vessel morphology consisted of proliferating 

endothelial cells, dilated lumen, peri vascular fibrosis and glumeroloid 

vessels, while slow regions consisted of necrotic vessels, in agreement with 

the observed MRI vessel function. The fast component volume 3 weeks post 

treatment was significantly correlated with the fast volume 4 (r2�0.84, p�0.0005) and 6 months (r2�0.84, p�0.01) later, suggesting early 

prediction of response. Brain metastases histology showed similar results: 

5 brain metastases with a fast population component were confirmed 

histologically to contain morphologically active tumor. One metastasis 

consisting of the slow population only significantly decreased in volume in 

the following MRIs. Conclusions: These results demonstrate the feasibility 

of applying our delayed contrast extravasation high resolution function 

vessel maps for improving patient management by clearly depicting tumor 

and non-tumoral tissues in patients with primary and secondary brain 

malignancies undergoing standard chemoradiation or radiosurgery. 


Retrospective analysis of glioblastoma patients treated with bevacizumab 

who presented with multifocal disease at diagnosis. Presenting Author: 

Jethro Lisien Hu, Cedars-Sinai Medical Center, Los Angeles, CA 

Background: Glioblastoma patients who present with multifocal disease 

have an extremely poor prognosis – a recent analysis at our institution 

demonstrated a median survival of 6 months, versus 11 months for a cohort 

of unifocal glioblastoma patients matched for age, extent of resection, and 

KPS. Bevacizumab is frequently used to treat patients with recurrent or 

progressive glioblastoma. However, its benefit in the setting of multifocal 

disease is unproven, particularly in light of the concern that antiangiogenic 

treatment may promote a more invasive, multifocal, and potentially 

treatment-resistant phenotype. Methods: Between 2004 to 2010, 368 

patients were diagnosed with glioblastoma at our institution. We identified 

46 patients with multifocal disease on initial presentation, and retrospectively 

reviewed their clinical course and treatment history. Kaplan-Meier 

estimates and Wilcoxon tests were used to assess survival distribution. 

Results: Of the 46 patients with multifocal disease, 12 were treated with 

bevacizumab (7 upfront and 5 at first recurrence). All 12 bevacizumabtreated 

patients received external beam radiation therapy, and 11 received 

temozolomide. In the bevacizumab-treated cohort, median age at the time 

of surgery was 59 years, and median KPS was 80. For the 34 patients with 

multifocal disease who did not receive bevacizumab, median age was 69 

years, and median KPS was 75. Median survival for the bevacizumabtreated 

patients was 12.9 months, with 12-month survival of 58.3%. By 

comparison, median survival for patients with multifocal disease who did 

not receive bevacizumab was 5.8 months, with 12-month survival of 

20.6%. The difference in survival between the two groups was statistically 

significant, with p-value of 0.045 by the Wilcoxon test. Conclusions: This 

single-institution retrospective analysis suggests that bevacizumab treatment 

is associated with a survival benefit for glioblastoma patients who 

present with multifocal disease. One can infer that the clinical benefit of 

bevacizumab in this setting outweighs any potential concerns regarding the 

ability of bevacizumab to promote an invasive, treatment-resistant tumor 

phenotype. 



The impact of bevacizumab on the occurrence and recurrence of intracranial 

brain metastases in non-small cell lung cancer (NSCLC) patients. 

Presenting Author: Mohamed E. Salem, Karmanos Cancer Institute, Wayne 

State University School of Medicine, Dertoit, MI 

Background: Patients (pts) with brain metastases (BM) have a poor 

prognosis and limited treatment options. Approximately 40-50% of pts 

with NSCLC will develop BM during the course of their disease. A better 

understanding of the pathobiology of BM and the development of targeted 

agents hold promise for improved prophylaxis and therapy of BM which 

could have significant impact on disease progression and pt’s survival. 

Vascular Endothelial Growth Factor has been implicated in setting up a 

metastatic niche allowing cells to seed and grow in the brain parenchyma. 

Inhibition of this signaling has been studied and shown to be effective in 

reducing BM in animal models. Methods: The objective of this retrospective 

study was to determine whether bevacizumab decreases the incidence and 

or the recurrence of BM in pts with NSCLC. We retrospectively identified 

NSCLC pts with and without BM treated with bevacizumab. The primary 

endpoint was the proportion of patients who developed BM on or after 

bevacizumab therapy. Secondary endpoints were rate of local or regional 

recurrence after stereotactic radiosurgery (SRS). Occurrence of BM was 

evaluated by retrospectively reviewing MRI and or CT scans. Results: A total 

of 30 pts with stage IV non-squamous NSCLC who had no BM at diagnosis 

treated with bevacizumab (Non-BM group, NBMG) and 85 pts with 

non-squamous NSCLC who had BM and underwent SRS (BM group, BMG) 

were studied (46%M; median age 60 years (range 32-84). In the NBMG, 

28% of pts developed BM. Median time to development of BM was 10.5 

months. In the BMG, 4 pts were treated with bevacizumab following SRS. 

Of these 4 pts, 3 pts (75%) had no recurrence while 1 pt (25%) developed 

local then regional recurrence at 7 and 9 months, respectively. Of the 

remaining 81 pts who underwent SRS but never received bevacizumab, 

27% of pts had local recurrence and 41% had regional recurrence at 

median time of 4 and 4.5 months, respectively. Conclusions: Bevacizumab 

may have a role in the treatment of NSCLC in regards to development and 

recurrence of brain metastases. These results support the need for further 

prospective investigation in a larger patient population with matched 

controls. 


Plasma levels of IL-8 and g-CSF in high-grade gliomas treated with 

bevacizumab. Presenting Author: Marica Eoli, Fondazione IRCCS Istituto 

Neurologico Carlo Besta, Milan, Italy 

Background: Bevacizumab, an anti-VEGF antibody, has shown significant 

activity in high grade gliomas (HGG). However, tumor recurrence inevitably 

occurs. Methods: We treated 63 recurrent HGG patients with poor prognostic 

factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 

mg/m2 ) every 2 weeks, and investigated IL-12, IL-13, IL-17, FGF basic, 

G-CSF, MIP-1b, PDGF-beta, plasma levels before starting treatment and 

every 8 weeks by Bioplex. Ten age- and sex-matched healthy controls were 

used for comparison. Results: After a median follow-up of 27 weeks, 

median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 

months were 32% and 12%, respectively. OS at 6 months was 60%. 

Toxicity was mild. Baseline higher amounts of IL-13 (48�174 pg/ml vs 

3.44�0.9 pg/ml, p�0.0001) and lower amounts of MIP-1b (35.3�20.9 

pg/ml vs 67.2�18.8 pg/ml, p�0.0002), PDGF-beta (1585.5�1585 

pg/ml vs 7098�1585 pg/ml, p�0.0001) and VEGF (27�39.8 pg/ml vs 

54.5�32 pg/ml, p�0.001) were detected in patients than in healthy 

controls. In a cohort of 15 non-responders (patients who progressed 8 

weeks after treatment onset), baseline IL-8 (15.7�10.8 pg/ml vs 10.9�9.4 

pg/ml, p�0.03) and G-CSF (113.3�54 pg/ml vs 84.9�59.2 pg/ml, 

p�0.03) were significantly higher than in patients responding to treatment. 

In the same cohort no significant reduction of VEGF and other 

cytokines was observed after 8 weeks of treatment, while a decrease of 

plasma VEGF was observed in the remaining patients (26�32 pg/ml vs 

13.3�28.5 pg/ml, p�0.001). Furthermore, in a cohort of 22 long-term 

responders (patients who progressed after more than 18 weeks of treatment), 

levels of VEGF decreased after 8 weeks of treatment when compared 

to baseline, whereas no difference was observed in baseline levels 

(23.9�22.6 pg/ml vs 9.8�9.4 pg/ml, p�0.001). Conclusions: Data 

suggest that high levels of IL-8 and G-CSF at baseline associated with a 

lack of VEGF decrease after 8 weeks of treatment identify patients who are 

resistant to bevacizumab. This hypothesis should be tested in a large 

number of patients. 


135s 


Relationship between IDH1 mutation status and magnetic resonance 

imaging features in WHO grade II and III oligodendroglial tumors. Presenting 

Author: Frederique Toulgoat, Neuroradiologie CHU Nantes, Nantes, 

France 

Background: In gliomas, relationship between radiological characteristics 

and several biomarkers was the subject of numerous publications. Mutations 

in the isocitrate dehydrogenase 1 (IDH1) gene have been identified 

recently to play a key role in these tumors occuring in up to 75% of 

low-grade diffuse (WHO grade II) and anaplastic (WHO grade III) astrocytic, 

oligodendroglial and mixed oligodendroglial neoplasms. However, the 

correlation with magnetic resonance imaging (MRI) features has been little 

studied. Methods: Patients treated for WHO grade II and III oligodendroglial 

tumors between 2005 and 2011 were retrospectively identified. Each case 

has been reviewed by the same neuropathologist. IDH1 and IDH2 mutations 

were available. Preoperative MRI, including T1 weighted, T2 weighted, 

T1 contrast enhanced, FLAIR, T2* weighted, diffusion weighted (ADC 

ratio), perfusion weighted (CBV ratio) and MR spectroscopy, were analyzed 

by two radiologists blinded from molecular data. Logistic regression 

analysis and Fisher’s test were used to develop predictive models of genetic 

profile from imaging. Results: Sixty eight patients, WHO grade II (n� 37) 

and grade III (n�31) patients were identified. Mean age at diagnosis was 

46 years; ratio male/female was 40/28. IDH1 mutations were identified in 

42 patients (62 %), IDH2 in 4 patients (6 %). Analysis of tumor location, 

size, borders, morphological aspect, and signal did not shown any significant 

difference between IDH1 mutated group and IDH1 non mutated group 

neither in grade II nor in grade III oligodendroglial tumors. In the same way, 

MR spectroscopy (Choline/NAA ratio and detection of lipid and lactate) was 

not relevant to discern the two groups. As well, ADC ratio (1,5 versus 1,4; 

p�0,35) and CBV ratio (3,4 versus 4,2; p� 0,46) did not reveal any 

difference between mutated group and non mutated group. Conclusions: In 

our study, IDH1 mutations were not correlated with MRI features available 

during routine MRI. Nevertheless, recent studies suggest the ability of MR 

spectroscopy to detect 2-hydroxyglutarate as an MRI marker of IDH1 

mutated tumors, which encourage carrying on research in molecular 

imaging. 


The final report of a phase I trial of surgical resection with biodegradable 

carmustine (BCNU) wafer placement followed by vaccination with 

dendritic cells pulsed with tumor lysate for patients with glioblastoma. 

Presenting Author: Jeremy Rudnick, Neuro-Oncology Program, Cedars- 

Sinai Medical Center, Los Angeles, CA 

Background: Our prior immunotherapy trials demonstrated efficacy in 

generating a tumor specific immune response in malignant glioma and the 

potential for high tumor-specific toxicity and sustained tumoricidal activity. 

Immunotherapy may synergize with chemotherapy and biodegradable 

carmustine (BCNU) wafers and have a modest impact to extend overall 

survival. We exploited this synergistic effect to maintain a cytotoxic 

environment around the tumor milieu, and this is a presentation of the final 

results of our clinical trial. Methods: Patients with glioblastoma were 

eligible after maximal resection with biodegradable carmustine (BCNU) 

wafer placement. Screening leukapheresis was used to isolate mononuclear 

cells which were differentiated into dendritic cells, pulsed with tumor 

lysate, and then 3 intradermal vaccines administered at 2-week intervals. 

Patients continued systemic chemotherapy after vaccine or at progression. 

Results: Twenty three patient with glioblastoma received therapy including 

8 with newly diagnosed disease (35%) and 15 with recurrent disease 

(65%) were evaluable. Immune response data is available for 20/23 

patients although survival data is present for all. One grade 3 SAE of fever 

and chills was noted otherwise therapy was well tolerated. Within the newly 

diagnosed GBM cohort the median overall survival (OS) was 25.5 months 

(15,31�), and within the recurrent GBM cohort, the median OS was 16 

months (8,23�). Among the recurrent GBM an increase of �1.5 X baseline 

interferon gamma production post vaccination was associated with a 

prolonged median OS 22 months (8,40) in 4/12 patients versus 17 months 

(9,27) in 8/12 patients. Conclusions: We were able to generate an immune 

response in 25% of patients which is lower than what we have seen in 

previous trials and suggests a limited synergy with local control. However, 

within the recurrent GBM cohort we did find prolonged survival in both 

groups with an increased survival noted in immune responders demonstrating 

the potential for this therapy. 




The role of fluorescence-guided surgical resection in the combined treatment 

of malignant glioma. Presenting Author: Carmine Maria Carapella, 

Neurosurgery, Cancer Institute Regina Elena, Roma, Italy 

Background: Malignant glioma represents a relevant therapeutic issue and 

the value of extensive surgical resection remains debated; recent evidence 

suggests that radical removal is associated with better survival. An 

interesting tool for identifying tumor tissue and increasing the extent of 

surgery is represented by fluorescence-guided resection, taking advantage 

of metabolic and structural changes induced by a natural precursor of heme 

biosynthetic pathway, 5-amino-levulinic acid (ALA). Methods: The present 

experience is related to 32 patients affected by malignant glioma (18 newly 

diagnosed: 16 glioblastoma (GBM), 2 anaplastic oligodendroglioma; and 

14 recurrent GBM) eligible for fluorescence-guided resection, operated on 

in our Institute since fall of 2009. All patients underwent preoperative and 

early postoperative MRI, showing contrast enhancing lesions. An oral dose 

of 20 mg 5-ALA /kg bw was administered to each patient. Microsurgical 

resection was performed by an operating microscope enabled to visualize 

the fluorescence. All the patients, as first line treatment, have been 

submitted to radiotherapy and chemotherapy; second and in some cases 

third line treatments were utilized in recurrent cases. The patients 

follow-up ranged from 2 years to 6 months. Results: In more than 90% of 

patients tumor tissue showed intraoperative red fluorescence; mainly in 

recurrent GBM, when MRI documented heterogeneous lesions with enhancing 

areas mixed with non enhancing gliotic scars, fluorescence-guided 

surgery allowed a better definition of active tumor, with net margins from 

perilesional “healthy” brain. Early postoperative MRI confirmed gross total 

resection without contrast enhancement in 80 % of patients. In the present 

experience the procedure did not determine any relevant additional 

neurological deficit. Considering overall survival of recurrent patients we 

obtained a median extension of at least 9.0 months (3 – 16� months). 

Conclusions: Fluorescence-guided surgery improves tumor detection and 

allows extended resection of malignant glioma, without any relevant impact 

on neurological status, resulting helpful mainly in the recurrent setting with 

a consistent effect on overall survival. 


Correlation of survival with tumor antigen expression in patients with newly 

diagnosed glioblastoma receiving a multi-epitope pulsed dendritic cell 

vaccine. Presenting Author: Surasak Phuphanich, Neuro-Oncology Program, 

Cedars-Sinai Medical Center, Los Angeles, CA 

Background: This study evaluated the safety and immune responses to an 

autologous dendritic cell vaccine pulsed with class I peptides from tumor 

associated antigens (TAA) expressed on gliomas and overexpressed in their 

cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2, 

HER2 and AIM-2, are also overexpressed on glioblastoma multiforme 

(GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2, 

gp100, MAGE-1, IL13R�2, and AIM-2. HLA-A1 and/or HLA-A2 positive 

glioblastoma (GBM) patients with gross total resection were eligible. 

Mononuclear cells from leukapheresis were differentiated into dendritic 

cells, pulsed with TAA peptides, and administered intradermally three 

times at two-week intervals in the axilla region after a standard treatment 

with concurrent temozolomide (TMZ) and radiation therapy for newly 

diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17 

ND-GBM and three recurrent GBM patients and one brainstem glioma. 

Immune response data on 15 newly diagnosed patients showed 33% 

responders. TAA expression by qRT-PCR showed all patient tumors 

expressed at least three TAA with 75% expressing all six. Correlations of 

increased PFS and quantitative expression of MAGE1, AIM-2, gp100 and 

HER2 were observed. A decrease or absence of CD133 expression was seen 

in five patients who underwent a second resection. As of February 1, 2012, 

six of 16 ND-GBM patients showed no evidence of tumor recurrence 

(44-63 months). Median progressive free survival (PFS) in newly diagnosed 

patients was 16.9 months with a two-year PFS rate was 43.8% 

(95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4 

months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions: 

Expression of four ICT-107 targeted antigens in the pre-vaccine tumors 

correlated with prolonged overall survival and PFS in ND-GBM patients. 

The goal of targeting tumor antigens highly expressed on glioblastoma 

cancer stem cells is supported by the observation of decreased or absent 

CD133 expression in the recurrent areas of gadolinium-enhanced tumor. 


An investigator-initiated monocentric phase I dose escalation trial of 

temsirolimus and irinotecan (TEMIR) in patients with relapsing glioblastoma 

multiforme (reGBM). Presenting Author: Max E. Scheulen, Department 

of Medical Oncology, West German Cancer Center, University of 

Duisburg-Essen, University Hospital Essen, Essen, Germany 

Background: Deregulation of the PI3K/AKT pathway has been preclinically 

involved in the pathophysiology of GBM. The mammalian target of 

rapamycin (mTOR) is an important downstream mediator of PI3K/AKT 

signalling. The mTOR-inhibitor temsirolimus (Tem) achieves significant 

drug levels in brain. Thus, Tem may be effectively combined with irinotecan 

(Iri) which has shown promising results in combination with bevacizumab 

in patients (pts) with reGBM refractory to temozolomide (Tmz) in phase II. 

Exposure to Tem as well as Iri is substantially reduced in pts receiving 

CYP3A4 enzyme-inducing anticonvulsants (CYP3A4-Ind). Methods: TEMIR 

is a phase I trial of escalating doses of Tem in combination with Iri in pts 

with reGBM refractory to Tmz depending on the cotreatment with CYP3A4- 

Ind. In pts without CYP3A4-Ind dose escalation of Tem was performed 

according to the “3�3 protocol” from 15 via 20 to 25 mg iv wkly together 

with 85 mg/m2 Iri iv wkly. In pts with CYP3A4-Ind the doses of Tem were 

30, 40 and 50 mg iv wkly together with 170 mg/m2 Iri iv wkly, respectively. 

The determination of the pharmacokinetics (PK) of Tem and its influence 

on the PK of Iri and its active metabolite SN38 was performed by validated 

RP-HPLC methods with fluorescence detection. Results: Up to now, 14 pts 

[4 female and 10 male, median age 47 yrs (range 41-65 yrs), 9 without and 

5 with CYP3A4-Ind] have been treated. All 9 pts without CYP3A4-Ind (3 

pts on 15, 20 and 25 mg Tem each) are evaluable for safety with only mild 

toxicity [highest CTC-grade �2 (gr) per pt]: diarrhea 4 (gr2) and 1 (gr3), 

neutropenia 1 (gr3), thrombopenia 1 (gr2), anemia 1 (gr2), pneumonia 2 

(gr2), rash 1 (gr2). PK parameters of Iri and SN38 were in agreement with 

previously published studies and there was no significant effect of 15 to 25 

mg Tem combined with 85 mg/m2 Iri on the PK of Iri and SN38. In 7 pts 

evaluable for efficacy there was no remission (RECIST) and median time to 

symptomatic and/or MRT progression was 10 wks (7, 9�, 10, 10�, 11, 

15, 20 wks). Conclusions: The combination of Tem in standard dose of 25 

mg iv wkly with 85 mg/m2 Iri wkly is safe in pts with reGBM without 

CYP3A4-Ind. Tem has no significant effect on the PK of Iri and SN38. 


High-dose chemotherapy (HDC) followed by autologous stem cell transplant 

(ASCT) for recurrent/progressive CNS lymphoma. Presenting Author: 

Mary Roberta Welch, Memorial Sloan-Kettering Cancer Center, New York, 

NY 

Background: In two reports by Soussain et al, promising efficacy was 

observed in recurrent primary CNS lymphoma with induction cytarabine/ 

VP-16 (CYVE) followed by HDC-ASCT (busulfan, thiotepa and cyclophosphamide 

[BTC]), but significant toxicity, mainly from CYVE, has limited 

widespread use. We report our experience with HDC-ASCT with alternative 

induction regimens. Methods: Retrospective review of pts with recurrent/ 

refractory non-Hodgkin lymphoma (NHL) with CNS involvement treated 

with HDC-ASCT (2000-present). Results: Seventeen pts met inclusion 

criteria: med age� 58 (41-65); 9 were women; med KPS prior to 

transplant� 90 (range 70-100). At initial presentation, 10 had primary 

CNS lymphoma (ocular: 1); 7 had systemic NHL without CNS involvement; 

1 had both systemic and CNS disease. Pts had been heavily pre-treated. 

Among those with PCNSL, high dose MTX was used in all pts and WBRT in 

4. Two pts had received a previous HDC-ASCT. Among systemic NHL pts, 

various regimens were used, mostly R-CHOP(4), but also R-EPOCH (1), 

CVP (1), ICE (1) and CODOX-M (1). At CNS recurrence, pts received various 

induction regimens prior to HD-ASCT: high-dose methotrexate (MTX)based 

chemotherapy (N� 13), cytarabine-based regimens (N�2), and 

other (N� 2). All pts achieved a CR or near CR prior to HDC-ASCT. 

Harvesting was obtained with G-CSF alone in 9 pts; 8 required plerixafor. 

Two pts failed mobilization N�15 received HDC-ASCT. The HDC consisted 

of BTC (N�13); 1 received BEAM and 1 received reduced intensity 

fludarabine, melphalan and alemtuzumab. Eight pts experienced a grade 

III or IV toxicity – most commonly fatigue, febrile neutropenia, and 

infection. One previously transplanted pt died from sepsis. With a med 

follow-up of 11 months, post-transplant med-PFS has not been reached. 

The 12m PFS was 92% (95% CI 56-98). Because no patient has 

progressed, the OS was identical to PFS. Conclusions: HDC-ASCT was a 

highly effective salvage approach in this population of recurrent/refractory 

CNS lymphoma. To reduce the risk of harvesting failure at the time of 

recurrence, harvesting stem cells at the time of initial treatment could be 

considered in pts with high risk for relapse. 



The addition of bevacizumab to temozolomide and radiation therapy 

followed by bevacizumab, temozolomide, and oral topotecan for newly 

diagnosed glioblastoma multiforme (GBM). Presenting Author: Henry S. 

Friedman, Duke University Medical Center, Durham, NC 

Background: The prognosis for newly-diagnosed GBM is dismal. The 

addition of temozolomide to radiation therapy improved the median overall 

survival (OS) to 14.6 months (mos). GBM’s have the highest levels of 

vascular endothelial growth factor (VEGF). Hypoxia inducing factor-1 alpha 

(HIF-1 alpha) is an important regulator of VEGF, and topotecan may inhibit 

HIF-1 alpha. Methods: We performed a phase II trial in newly diagnosed 

GBM by adding bevacizumab and topotecan to standard therapy. 80 newly 

diagnosed GBM patients were enrolled between January 2010 and January 

2011. Patients received standard radiation therapy and temozolomide. 

Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks 

post-op. Two weeks after radiation therapy was completed, 12 monthly 

cycles of temozolomide at 150 mg/m2 /d days 1-5, oral topotecan at 1.5 

mg/m2 for patients not on an enzyme inducing anti-epileptic drug (EIAED) 

and 2.0 mg/m2 for patients on an EIAED days 2-6, and bevacizumab at 10 

mg/kg on days 1 and 15. Results: The addition of bevacizumab to standard 

radiation therapy and daily temozolomide was safe. Of the 80 patients, 76 

completed radiation therapy. Four patients did not complete radiation, two 

with clinical decline, one each with a bone flap infection, and a pulmonary 

embolus. Fifteen patients came off study for toxicity, five with recurrent 

grade IV thrombocytopenia, three with grade III fatigue, two each with 

grade 2 CNS hemorrhage, and wound dehiscence requiring surgery and one 

each with GI perforation, pulmonary embolism and an aortic thrombus. Of 

the 80 patients, 56 have progressed and 37 have died. The median 

progression-free survival (PFS) and OS are 11.1 mos (95% CI: 9.4-13.6) 

and 17.2 mos (95% CI: 15.2) at a median follow-up of 18.4 months. The 

two year OS is 45.3%. Conclusions: The addition of bevacizumab to 

temozolomide and radiation followed by temozolomide, bevacizumab and 

oral topotecan is tolerable. The median PFS and OS are encouraging. The 

randomized phase III trials with bevacizumab for newly diagnosed GBM 

patients are essential. 


Primary central nervous system lymphoma: The Cleveland Clinic experience. 

Presenting Author: Manmeet Singh Ahluwalia, Cleveland Clinic, 

Cleveland, OH 

Background: Primary central nervous system lymphoma (PCNSL) is an 

uncommon variant of extranodal non-Hodgkin lymphoma that involves the 

brain, leptomeninges, eyes, or spinal cord without evidence of systemic 

disease. Untreated PCNSL has a rapidly fatal course, with survival of 

approximately 1.5 months from the time of diagnosis. In this study, we 

sought to describe the demographics, diagnoses, management, and outcomes 

of patients with PCNSL at a single institution. Methods: After 

obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro- 

Oncology Center’s database was used to identify patients with histologically 

proven PCNSL at the Cleveland Clinic between 1986 and 2010. Data were 

subjected univariate and multivariate analysis followed by recursive partitioning 

analysis in order to generate a prognostic model. Results: 153 

patients were diagnosed with PCNSL with a median age of 61 and 

Karnofsky performance status (KPS) of 70. The progression-free survival 

(PFS) was 9.3 months; the overall survival (OS) was 27 months. The 

treatment regimen included methotrexate-based chemotherapy (MTX) or a 

combination of methotrexate-based chemotherapy and whole brain radiation 

therapy (WBRT). Patients treated with the MTX regimen had an OS of 

65 months; those treated with the MTX � WBRT regimen had an OS of 74 

months. The Cox proportional hazards regression identified age and KPS as 

the only prognostic indicators to OS and PFS. Recursive partitioning 

analysis categorized the patients into three groups according to these 

prognostic factors. Patients with KPS � 70 had a favorable outcome 

compared to patients with KPS � 70. This held true especially for patients 

age 60 and younger, whose median OS was 100 months. Conclusions: The 

survival and prognostic indicators approximate those reported previously 

and provide independent validation for a simple yet powerful prognostic 

model that uses age and KPS to predict survival. 

PFS and OS of patients in different groups based on age and performance 

status. 

Outcome PFS (months) OS (months) 

All patients 9.3 27 

Group 1 17 100 

Group 2 18 41 

Group 3 2.3 6.0 

Group 1: age � 60 years and KPS � 70; group 2: age � 60 years and KPS � 70; 

group 3: KPS � 70 (p � 0.0001). 


137s 


Comparison of fractionated and single session radiosurgery for radiation 

resistant brain metastases. Presenting Author: Eric Karl Oermann, University 

of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: Melanoma and renal cell carcinoma are commonly called 

radiation resistant tumors due to the decreased response rate to traditional 

radiation (1.8-2 Gy /Fraction). Large brain metastases from radioresistant 

primaries are clinical challenges. This study examines the impact of 

fractionation on the treatment of intracranial metastases from radiation 

resistant tumors. Methods: Patients with a primary diagnosis of melanoma 

or renal cell carcinoma and intracranial metastases who completed 

treatment at The University of North Carolina with frameless robotic 

radiosurgery between 2007-2011 were retrospectively analyzed. Patients 

were treated with either single or 3-5 fractions depending on volume. The 

study’s primary endpoints were overall survival (OS) and local control (LC), 

and its secondary endpoint was patient steroid requirements. Outcomes 

data and pre-treatment variables were analyzed for significance using 

appropriate non-parametric tests. Results: 25 patients were included in the 

single fraction arm and 13 patients in the multi-fraction arm, and both had 

equivalent pre-treatment characteristics with the exception of tumor 

volume which was larger in the multi-fraction arm (p�0.01). At a median 

follow-up of 4.7 months (range, 1.8-11.6), the median OS for all patients 

was 6.2 months. One year survival was 35.1% and 5 patients (13%) had 

local failures at a median time to local failure of 5.5 months. Patients in the 

multi-fraction arm failed at a higher rate (10.5%) than patients in the 

single fraction arm (2.6%) (p�0.04), but there was no difference in OS 

(p�0.34). There was no difference between pre-treatment and posttreatment 

steroid requirements between the two arms (p�0.351). 

Conclusions: Fractionation is intended to facilitate radiosurgery in large 

tumors by limiting high doses of radiation to a large portion of normal brain. 

In our study of radioresistant intracranial metastases, large tumors receiving 

multi-fraction radiosurgery had decreased local control with no difference 

in toxicity or OS. These results suggest a need for either dose 

escalation, or combination therapy designed to reduce tumor size (resection 

or aspiration) in order to facilitate single fraction treatment. 


Low-grade gliomas in older patients. Presenting Author: Adewale Alade 

Fawole, Fairview Hospital, Cleveland, OH 

Background: Low grade gliomas account for 10-20% of all primary brain 

tumors. The outcomes of older patients with low-grade glioma (LGG) are not 

well known. Methods: After obtaining IRB approval, the Cleveland Clinic 

Brain Tumor and Neuro-Oncology Center’s database was used to identify 

older patients defined as those �55 years of age with histologically 

confirmed grade 2 glioma at the time of diagnosis. Multivariable analysis 

was conducted with use of a Cox proportional hazards model and a stepwise 

selection algorithm that used p�.10 as the criteria for entry and p�0.05 as 

retention in the model to identify independent predictors of survival. 

Results: Chart records of 61 patients diagnosed between 1991 and 2010 

were included for final analysis. In contrast to patients �55 years, older 

patients are more likely to be male (p�.06), have poorer performance 

status at presentation (p�.0001), more comorbid conditions (p�.0001), 

present with more neurologic symptoms (p�.0001), have a prior history of 

cancer (p�.0001). They are more likely to have astrocytic histology 

(p�.008) and present with multifocal tumors more frequently (p�.001). 

Older patients received radiation (RT) upfront more frequently (p�.07) and 

undergo gross total resection less frequently (p�.003). Median Progression 

free survival (PFS) and median overall survival (OS) was 1.9 and 4.3 years, 

respectively in these patients. On univariate analysis, patients with poor 

performance status have worse PFS (p�.01) and OS (p�.003). Patients 

with memory impairment have worse PFS (p�.009) and OS (p�.0001). 

Patients treated with adjuvant chemotherapy had better OS (p�.01). 

Tumor related characteristics associated with poor survival included, �pure� 

or mixed astrocytoma histology (OS, p�.06), multifocal tumors (OS, 

p�.08), left-sided tumors (p�.07). In multivariable analysis, performance 

status was the only independent predictor of either PFS or OS. Conclusions: 

Older patients with low grade gliomas have less favorable outcomes as 

compared to younger patients. They have more comorbid conditions and 

symptoms at presentation. Use of chemotherapy in this patient group was 

associated with improved survival. Performance status was the only 

independent predictor of either PFS or OS. 



2094^ General Poster Session (Board #19A), Sat, 1:15 PM-5:15 PM 

Safety and efficacy of the addition of bevacizumab to temozolomide and 

radiation therapy followed by bevacizumab, temozolomide, and irinotecan 

for newly diagnosed glioblastoma multiforme. Presenting Author: James J. 

Vredenburgh, Duke University Medical Center, Durham, NC 

Background: Glioblastoma (GBM) has a very poor prognosis, and the 

majority of patients die within 2 years of diagnosis. GBMs have high 

concentrations of vascular endothelial growth factor (VEGF), and the more 

VEGF, the worse the prognosis. Bevacizumab is a humanized antibody to 

VEGF and is active in recurrent GBMs. The study aims to improve the 

survival of newly diagnosed GBM patients by incorporating an antiangiogenic 

agent with radiation and temozolomide, and adding a topoisomerase 

I inhibitor, and an anti-angiogenic agent to temozolomide postradiation 

therapy. Methods: Patients received standard radiation and 

temozolomide at 75 mg/m2 /day, with bevacizumab at 10 mg/kg every 14 

days beginning a minimum of 28 days post-operatively. Following the 

completion of radiation therapy, patients received 6-12 cycles of bevacizumab, 

temozolomide and irinotecan. Each cycle was 28 days. Bevacizumab 

was given at a dose of 10 mg/kg days 1 and 15, temozolomide 200 

mg/m2 days 1-5 and irinotecan on days 1 and 15 at 125 mg/m2 for patients 

not on an enzyme inducing anti-epileptic (EIAED) and 340 mg/m2 for 

patients on an EIAED. The statistical design was a goal of 60% overall 

survival at 16 months. Results: 125 patients were enrolled between 8/07 

and 3/09. All the patients have completed therapy. Nine patients had 

thromboembolic complications (DVT or PE). Two patients had wound 

dehiscence, one bowel perforation, one secondary AML and two pneumocystis 

carinii pneumonias (PCP). Seventeen had grade 4 hematologic toxicity 

requiring dose decrements. There were 4 toxic deaths, one each with a 

myocardial infarction PCP, PE and sepsis. At a median follow-up of 40 

mos, the median overall survival was 20.9 mos, the median progressionfree 

survival was 13.8 mos and the 2-year overall survival was 42.4%. 

Conclusions: Adding bevacizumab to temozolomide and radiation therapy 

followed by bevacizumab, temozolomide with irinotecan is tolerable and 

efficacious. 


Prognostic nomogram in elderly patients with glioblastoma. Presenting 

Author: Mital Patel, Cleveland Clinic, Cleveland, OH 

Background: Glioblastoma (GBM) is the most common malignant primary 

brain tumor. More than half the cases occur in patients aged �65 years; 

however, there is limited data on specific prognostic factors in these 

patients and there is a lack of easy to use nomograms in elderly GBM 

patients to provide them prognostic information. Methods: The Cleveland 

Clinic Brain Tumor and Neuro-Oncology Center’s database was used to 

identify elderly patients with GBM ( �65 years at the time of diagnosis). 

Multivariable analysis was conducted to identify independent predictors of 

survival using a Cox proportional hazards model and a stepwise selection 

algorithm with p�.10 as criteria for entry and retention. �Points� were 

assigned to each of these poor prognostic features and prognostic groups 

were formed based on the total number of calculated points. Results: 512 

GBM patients with a median age of 73 years (range 65-96, 54% male) were 

included in the final analysis. On multivariable analysis six factors were 

identified as having an independent impact on overall survival after 

controlling for non-surgical treatment related factors like chemotherapy 

and radiation: age at diagnosis (p�.0001), surgery (p� .0001), multifocal 

disease (p�.0008), seizure at presentation (p�.02), hypertension (p�.05) 

and Karnofsky Performance Status (p�.0001). Prognostic groups were 

developed as summarized in the table. 28% of the patients had the most 

favorable profile which was associated with 56% one year survival and a 

13.2 months median survival. In contrast, almost all patients in the least 

favorable group (27%) died within one year. Conclusions: This is an easy to 

use nomogram in elderly GBM patients to provide them prognostic 

information. 

Prognostic groups in elderly patients (> 65 years) with glioblastoma. 

Prognostic group No. of “points” 1 N (%) 

1-yr survival 

(%) 

Median survival 

(months) 

Favorable 0-4 123 (28%) 56% 13.2 

Intermediate 5-8 196 (45%) 19% 6.5 

Unfavorable �8 117 (27%) 1% 2.8 

1 Lack of seizure, HTN � 1 point; multiple tumors, age 70-79, KPS 70-80 � 2 

points; biopsy only � 3 points; age �80, KPS �70 � 4 points. 

2095^ General Poster Session (Board #19B), Sat, 1:15 PM-5:15 PM 

Phase II study of bevacizumab plus irinotecan and carboplatin for recurrent 

WHO grade 3 malignant gliomas with no prior bevacizumab failure. 

Presenting Author: Annick Desjardins, Duke University Medical Center, 

Durham, NC 

Background: No standard treatment exists for recurrent WHO grade 3 

malignant glioma patients. Bevacizumab (BV) with irinotecan has significant 

anti-tumor activity for recurrent glioblastoma. Carboplatin has antiglioma 

activity and can potentiate the cytotoxicity of irinotecan. We 

evaluated the progression-free survival (PFS) of BV in combination to 

irinotecan and carboplatin in recurrent WHO grade 3 malignant gliomas, as 

well as its safety. Methods: Adult patients with measurable recurrent WHO 

grade 3 malignant glioma, �12 weeks after radiation therapy, �4 weeks 

after chemotherapy, with adequate organ function, KPS �70%, no prior 

failure or grade �3 toxicity to the agents, and no contraindications to BV 

were eligible for study. Patients received BV at 10 mg/kg with irinotecan on 

days 1 and 15 of a 28-day cycle. The dose of irinotecan was 125 mg/m2 for 

patients not on enzyme inducing anti-epileptics (EIAEDs) and 340 mg/m2 

for patients on EIAEDs. All patients received carboplatin at an AUC of 4 on 

day 1 of each cycle. MRIs were obtained every 8 weeks. Results: As 

planned, 39 WHO grade III malignant glioma patients were enrolled on 

study. Median age was 47 (range, 26-71). At a median follow up of 14 

months, the 6-month PFS is 69% and the median PFS is 11 months. A 

median of 8 cycles were given. Seven patients completed the planned 

course of treatment (12 cycles) with hypometabolic PET scan and nine 

patients remain on study. Fifteen patients came off study due to disease 

progression and eight due to toxicity. As of 1/25/2012, 22 patients are still 

alive and 17 have died. Grade 3-4 toxicities included: neutropenia (grade 

3, n�12; grade 4, n� 1), thrombocytopenia (grade 3, n�6; grade 4, n�4), 

nausea (grade 3, n�7), diarrhea (grade 3, n�2), deep venous thrombosis 

(grade 3, n�2), febrile neutropenia (grade 3, n�1; grade 4, n�1), fatigue 

(grade 3, n�8; grade 4, n�1), cerebral infarction (grade 4, n�3), 

intracranial hemorrhage (grade 4, n�1), posterior reversible encephalopathy 

syndrome (grade 3, n�1). Conclusions: The combination of bevacizumab, 

irinotecan and carboplatin for WHO grade 3 malignant glioma 

patients is effective and with no more than expected toxicity. 


Poor prognostic factors of post-CNS recurrence survival in breast cancer 

patients. Presenting Author: Carlos Castaneda Altamirano, Instituto Nacional 

de Enfermedades Neoplásicas, Lima, Peru 

Background: Survival after the onset of metastases in the central nervous 

system is very short. However, some variables could indicate subsets of 

worse prognosis. Our aim was to determine the value of clinicopathological 

characteristics and prognostic scores in the post-SNC recurrence survival. 

Methods: We evaluated a retrospective cohort of 2597 breast cancer 

patients treated at the Instituto Nacional de Enfermedades Neoplasicas 

(Lima-Peru) between 2000-2005. Clinicopathological data was retrieved, 

RPA and GPA brain metastases prognostic scores were constructed and 

phenotypes were categorized according to the IHC expression in 

[HR�,HER2-], [Any HR, HER2�] and Triple Negative. Survival was 

calculated according to the Kaplan Meier methodology and cases were 

stratified by variables evaluated. The log-rank or Breslow tests were used 

when appropriate and multivariate analysis was done by the cox regression. 

AP�0.05 was considered statistically significant. Results: One hundred 

and fifty seven cases developed CNS metastasis, from which 23 developed 

leptomeningeal metastases. The post recurrence CNS survival was 0.405 

years. There were not differences according to phenotype (P�0.102), 

histological grade (P�0.647), number of brain metastases (P�0.695) and 

metastases volume (P�0.155). We found statistic differences in regard to 

leptomeningeal carcinomatosis (present, 0.249ys vs absent 0.436ys; 

P�0.033); CSF infiltration (present, 0.115ys vs absent, 1.044ys; 

P�0.022); status of primary tumor (controlled, 0.501ys vs uncontrolled, 

0.263ys; P�0.001); ECOG performance status (�2, 0.504ys vs �2, 

0.288ys; P�0.030); and time from BC diagnosis to SNC metastases (�8 

moths, 0.115 vs �8 months, 0.425ys; P�0.023). Cox regression identifies 

to CSF infiltration as statistically significant (HR�9.77; P�0.025). In 

regard to Prognostic scores, we found differences when cases were 

stratified according to RPA score (Class I, 0.564ys vs Class II, 0.455ys vs 

Class III, 0.288ys; P�0.049) and GPA score (0-1, 0.26ys vs 1.5-3, 

0.455ys vs 3.5-5, 0,564; 0.048). Conclusions: RPA and GPA scores are 

more accurate to identify poor survival subsets in this group of patients than 

other tumor features (phenotype or histology). 



Effects of lazaroid U-74389G liposomes in a glioblastoma mouse model. 

Presenting Author: Fady Ibrahim, University of British Columbia, Vancouver, 

BC, Canada 

Background: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has 

radioprotective effects against radiation-induced lipid peroxidation. Also in 

vitro antiproliferative effects have been reported against glioblastoma cell 

lines. The aim of this study was to use a liposomal formulation to evaluate 

LAZ radioprotective and antiproliferative effects in a glioblastoma mouse 

model. Methods: LAZ PEGylated liposomes (Lipo G) were developed at the 

University of Houston, College of Pharmacy. Glioblastoma cell line U87expressing 

firefly luciferase reporter gene (100,000 cells in 2 �L) was 

injected intracranially in each male SCID hairless outbred mouse. There 

were 4 treatment groups (n�8-9, each): brain model (M) without treatment 

(control), radiation 2Gy weekly (M�R), Lipo G at 5 mg/kg dose IP twice per 

week (M�L) and radiation with Lipo G (M�R�L). Treatment lasted three 

weeks. Tumor size was monitored using non-invasive bioluminescence 

imaging (BLI), in each mouse. Mice were sacrificed after 3 weeks. Brain 

was harvested for immunohistochemistry examinations. Lipid peroxidation 

of brain tissues was quantified by measuring malondialdehyde (MDA) as a 

surrogate biomarker. Survival was evaluated using Kaplan Meier analysis at 

P� 0.05. Results: The relative BLI intensity was 4002.03�1737.67, 

2034�737.72, 1387.36�684.53 and 2498.89�2521.32 % for M, 

M�R, M�L and M�R�L, respectively. The tumor size of the M�L group 

was reduced by 65% compared to control . For the radiation treated groups 

(M�R and M�R�L), there was no significant difference in tumor size 

compared to control group. MDA brain concentration in M�L and M�R�L 

groups was significantly less than in M�R group (8.27�0.78 and 

10.37�3.30 �M/gm vs. 23.09� 3.79 �M/gm). The survival mean was 

22.67, 25.33, 25.22 and 27.13 days for M, M�R, M�R�L and M�L 

groups, respectively. Mean survival of LAZ treated groups (M�L and 

M�R�L) was significantly longer than that of the control group Conclusions: 

LAZ liposomal formulations administered at 5 mg/kg dose reduced tumor 

growth by 65%. LAZ also protected brain tissue from radiation-induced 

lipid peroxidation by reducing MDA concentration by 50%. These provocative 

data warrant further investigation of LAZ as a radiation protectant and 

chemotherapeutic agent. 


Anaplastic oligodendroglial tumors: The Cleveland Clinic experience. 

Presenting Author: Neda Hashemi-Sadraei, Cleveland Clinic, Cleveland, 

OH 

Background: Anaplastic oligodendroglial tumors include both anaplastic 

oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA), histological 

categories of WHO grade 3 gliomas. There is limited data on specific 

prognostic factors for patients with these tumors. Methods: After obtaining 

IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology 

Center’s database was used to identify patients with histologically confirmed 

AO and AOA at the time of diagnosis. Multivariable analysis was 

conducted with use of a Cox proportional hazards model and a stepwise 

selection algorithm that used p�0.05 both as the criteria for entry and 

retention in the model to identify independent predictors of survival. 

Results: Chart records of 139 patients, 52% of whom were male, diagnosed 

between 1992 and 2009 were included for analysis. Median age at 

presentation was 47 years (range, 18-83 years). 22% of patients had 

biopsy only, 35% had gross total resection, 43% had near total resection or 

subtotal resection. Following surgery, 30% of patients were treated with 

chemotherapy (CT) alone, 14% were treated with radiotherapy (RT) and 

47% received both CT and RT. Median progression free survival and 

median overall survival (OS) were 29.0 and 58.7 months respectively. On 

multivariate analysis, four factors were identified as independent predictors 

of OS: age at diagnosis (�50 vs. �50, p�0.004), Hypothyroidism 

(p�0.009), multifocal disease (p�0.005) and 1p 19q co-deletion 

(p�0.001). Choice of initial therapy did not impact survival in this cohort 

of patients. Conclusions: Older age, hypothyroidism and multifocal disease 

were associated with higher mortality. 1p, 19q co-deletion was associated 

with lower mortality. 

Risk factors for mortality: Multivariable Cox proportional hazards analysis. 

Factor Hazard ratio (95% C.I.) p2 Age at diagnosis, years 

(>50 vs.



Correlation between CD4 lymphocytes count and the opportunistic infections 

in treated glioblastoma. Presenting Author: Marie Josee Begin, 

University of Montreal, Montreal, QC, Canada 

Background: Less than 200 CD4 lymphocytopenia happens frequently with 

temozolomide treatment of glioblastoma. This immunosuppression is 

associated with many opportunistic infections and antibiotic prophylaxis is 

given in some centers to prevent Pneumocystis pneumonia. Methods: We 

analyzed the association between documented culture-proved infections 

and CD4 lymphocytes level in 140 patients treated with temozolomide in 

first-line glioblastoma in Notre-Dame Hospital from 2006 to 2009. 

Demographic and treatment data were collected and analyzed with Kaplan- 

Meier survival plots and Log Rank tests. Results: The cohort of infected 

patients was represented by 31 patients who developed 49 culture-proved 

infections: 21 urinary origin, 8 pulmonary (1 Pneumocytis and 2 Aspergillosis), 

5 brain, 5 bacteremia and 2 other. The infected cohort (n�31) had 

similar demographs, but also similar outcome compared to our control non 

infected glioblastoma treated patients cohort (n�109) with a 2 year 

survival of 40.8% vs 50.2% (p�). The median CD4 lymphocytes level was 

260, but clearly infections were associated with less than 200 CD4 

lymphocytes. During their infection, 20 patients had a CD4 level less than 

200, compared with 11 patients with more than 200 CD4 lymphocytes 

count. Conclusions: CD4 lymphocytopenia less than 200 is associated with 

increase in number of documented culture-proven infections in patients 

treated with temozolomide, but the survival is not altered by the infection. 


A phase III randomized controlled trial of short-course radiotherapy with or 

without concomitant and adjuvant temozolomide in elderly patients with 

glioblastoma (NCIC CTG CE.6, EORTC 26062-22061, TROG 08.02, 

NCT00482677). Presenting Author: James R. Perry, Sunnybrook Health 

Sciences Centre, Toronto, ON, Canada 

Background: The EORTC (26981-22981)/NCIC CTG (CE.3) RCT in newly 

diagnosed GBM found improved survival with concomitant and adjuvant 

temozolomide (TMZ) added to radiotherapy (RT). Study pts were 18-71 

(median 56) years; however a sub-group analysis noted a trend of 

decreasing benefit from the addition of TMZ with increasing age, such that 

for age 65-71, the hazard ratio of 0.8 did not reach statistical significance 

(p�0.340). Recent RCTs in elderly GBM found improved survival with RT 

compared to supportive care alone and detected non-inferiority of 40 Gy/15 

vs. a 60 Gy/30 RT regimen. Based upon these results short-course 

hypofractionated RT is often recommended for elderly pts. However, 

whether the addition of TMZ to RT confers a survival advantage in elderly 

pts remains unanswered. Methods: Patients �65 yrs of age with histologically 

confirmed newly diagnosed glioblastoma, ECOG 0-2, are randomized 

1:1 to receive 40Gy/15 RT vs. 40Gy/15 RT with 3 weeks of concomitant 

temozolomide plus monthly adjuvant TMZ until progression or 12 cycles. 

Stratification is by centre, age (65-70, 71-75, or 76�), ECOG 0,1 vs 2, and 

biopsy vs resection. For 90% power to detect a 25% reduction in the 

primary outcome of overall survival (increased MST from 6 to 8 months) 

between arms, using a two-sided 5% alpha, a minimum of 520 deaths 

must be observed prior to analysis; total sample size is 560 patients. The 

trial is open in Canada (NCIC CTG), Europe (EORTC), Australia and New 

Zealand (TROG), and Japan. As of Jan 25, 2012, 361 (65%) of the target 

560 pts were randomized (147 Canada, 144 Europe, 64 Australasia, 6 

Japan). Median age of randomized patients is 73 (65-88) years. A planned 

futility analysis after 120 events by the independent DSMB resulted in a 

recommendation that the trial continue.Accrual is expected to be complete 

in 2013. A comprehensive molecular companion analysis, including 

MGMT promoter methylation, is planned. 


REACT: A phase II study of rindopepimut (CDX-110) plus bevacizumab 

(BV) in relapsed glioblastoma (GB). Presenting Author: David A. Reardon, 

Dana-Farber Cancer Institute, Boston, MA 

Background: EGFRvIII is a constitutively active tumorigenic deletion mutation 

of EGFR. It is expressed in ~30% of primary GB where it is linked to 

poor long-term survival (Pelloski 2007). The investigational vaccine rindopepimut 

consists of the unique EGFRvIII peptide sequence conjugated to 

keyhole limpet hemocyanin (KLH), delivered intradermally (500ug with 

150ug GM-CSF as an adjuvant). Remarkably consistent and promising 

results across 3 phase II studies in newly diagnosed, resected EGFRvIII� 

GB (Lai 2011) represent a statistically significant improvement over a 

historical control cohort matched for major eligibility criteria (median 

overall survival [OS] � 24.4 - 24.6 vs. 15.2 months from diagnosis [m] and 

median progression-free survival [PFS] � 12.3 - 15.3 vs. 6.4 m). ACT IV, a 

phase III trial in this population, is ongoing. The immunosuppressive 

influence of residual/advanced GB presents a challenge to activation of 

efficacious antitumor immune responses. Anecdotal evidence (compassionate 

use cases, Sampson 2008) suggests that rindopepimut may induce 

specific immune responses and regression in multifocal and bulky residual 

tumors. Rindopepimut with BV, which inhibits VEGF and its immunosuppressive 

properties (including impaired maturation of dendritic cells and 

disruption of tumoral T cell infiltration [Johnson 2007, Shrimali 2010]) 

may further optimize EGFRvIII-specific immune response and antitumor 

activity. Methods: ReACT is a Phase II study of rindopepimut plus BV in 

patients (pts) with 1st or 2nd relapse of EGFRvIII� GB. BV-naïve pts will be 

enrolled to Group 1 (n�70: randomized 1:1 to BV plus either rindopepimut/ 

GM-CSF or control injection [low-dose KLH]) while BV-refractory patients 

will enter Group 2 (n�25: to receive BV plus open-label rindopepimut/GM- 

CSF). Concurrent with BV (10 mg/kg, q 2 wks), blinded treatment or 

open-label vaccine is given in priming phase (days 1, 15 and 29), then 

monthly until PD. Tumor response is assessed every 8 weeks, and patients 

are followed for survival after PD. Objectives are PFS at 6 months (primary), 

objective response rate, PFS, OS, safety, immunogenicity and elimination 

of EGFRvIII. ReACT opened to accrual in December 2011 (NCT01498328). 


Bevacizumab plus radiotherapy for elderly patients with glioblastoma 

(ARTE). Presenting Author: Ghazaleh Tabatabai, Department of Neurology, 

University Hospital Zurich, Zurich, Switzerland 

Background: The standard of care for patients with newly diagnosed 

glioblastomas after surgical resection is radiotherapy with concomitant and 

adjuvant temozolomide chemotherapy. Yet, inclusion into the pivotal trial 

was limited to patients up to the age of 70, and subgroup analyses 

suggested that older patients did not gain benefit from combined modality 

treatment. Further, the efficacy of radiotherapy has been confirmed in a 

randomized trial comparing best supportive care versus radiotherapy alone. 

Of note, hypofractionated radiotherapy is equieffective in patients aged 

65-70 years and more. Two randomized trials in elderly patients (NOA-08, 

Nordic Trial) indicated smilar efficacy of primary temozolomide chemotherapy 

alone compared with radiotherapy alone. Combined radiochemotherapy 

is compared with radiotherapy alone in an ongoing NCIC-CTG 

EORTC TROG Japanese group trial 26062-22061. Thus, radiotherapy 

alone is the standard of care for newly diagnosed glioblastoma of elderly 

patients. These clinical data justify the exploration of new, temozolomidefree 

first-line treatment strategies in elderly patients. Methods: The ARTE 

trial will therefore investigate bevacizumab when added to a short course of 

radiotherapy and bevacizumab maintenance therapy until progression. The 

translational research program shall include blood and urine biomarker 

analysis and FET-PET in addition to MRI for monitoring the course of the 

disease. This trial is an explorative randomized, non-comparative phase II 

trial aiming at recruiting 60 patients in Switzerland. Elderly patients (� 65) 

will be randomized 2:1 either to the experimental arm (bevacizumab plus 

radiotherapy) or the standard arm (radiotherapy). The primary endpoint is 

median overall survival. Secondary endpoints include overall survival at 6 

months, overall survival at 12 months, median progression-free survival, 

progression-free survival at 6 months, median time to treatment failure. 


TPS2106 General Poster Session (Board #20E), Sat, 1:15 PM-5:15 PM 

Phase III trial of tumor-treating fields (TTFields) together with temozolomide 

compared with temozolomide (TMZ) alone in patients with newly 

diagnosed glioblastoma multiforme (NCT00916409). Presenting Author: 

Santosh Kesari, University of California, San Diego, San Diego, CA 

Background: TTFields therapy is a novel, non-invasive, anti-mitotic treatment, 

inhibiting tumor growth by interfering with the metaphase to 

anaphase transition during mitosis (Lee et al., 2011). TTF therapy was 

recently approved by the FDA for recurrent GBM following a prospective, 

randomized trial. Preclinical studies have shown TTFields and TMZ to have 

an additive inhibitory effect on glioma cell proliferation. The design for the 

current study was supported by results from a pilot study with TTFields 

therapy and TMZ in patients with newly diagnosed GBM demonstrating 

favorable safety, tolerability and promising efficacy (Kirson et al., 2009). 

Methods: The hypothesis of the current study is that the addition of 

TTFields therapy to maintenance TMZ will increase progression free 

survival (PFS) of newly diagnosed GBM patients. Secondary endpoints 

include overall survival (OS), radiological response, quality of life and 

safety. Eligible patients will be randomized (2:1) to continuous TTFields 

therapy (200 kHz) in combination with maintenance TMZ versus maintenance 

TMZ alone. Maintenance TMZ will be administered as per the Stupp 

Protocol for 6 courses (Stupp et al., 2005). TTFields therapy may be 

administered for up to 24 months. Patients will be stratified based on: 

extent of resection and MGMT methylation status. Eligibility criteria 

include: pathological diagnosis of GBM; Karnofsky � 70; previous chemoradiotherapy 

per Stupp Protocol; no progressive disease at baseline. 

Patients with infratentorial tumor or implanted electronic devices are 

excluded. The sample size of 700 patients will have 80% power to detect a 

2 month (9 vs 7 months) improvement in PFS using log-rank test with an 

overall 5% 2-sided type I error. The trial is also powered to detect a 4.5 

month increase in median OS in NovoTTF-100A/TMZ patients. Patients 

will be followed clinically monthly and with bimonthly MRI to assess tumor 

progression and additional endpoints. 221 patients have been enrolled at 

the time of abstract submission. The DMC last reviewed the trial in October 

2010 and recommended that the trial continue as designed. 


141s 


A randomized, double-blind, controlled phase IIb study of the safety and 

efficacy of ICT-107 in newly diagnosed patients with glioblastoma multiforme 

following resection and chemoradiation. Presenting Author: Elma S. 

Hawkins, Immunocellular Therapeutics, Ltd., Woodland Hills, CA 

Background: Tumor stem cells have been correlated with recurrence and 

clinical outcome in glioblastoma multiforme (GBM). ICT-107 is an autologous 

vaccine consisting of the patient’s dendritic cells pulsed with 6 

synthetic peptide CTL epitopes targeting the GBM tumor and tumor-stem 

cell associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100 and 

IL-13R�2. Phase I results showed a good safety profile and interesting 

clinical potential (ASCO, 2010, abs#2097 and ASCO, 2011, abs#2042) 

in 16 newly diagnosed GBM patients with a median progression-free 

survival (PFS) of 16.9 months (measured from surgery) and a median 

overall survival (OS) of 38.4 months. Methods: In this Phase II study eligible 

patients have newly diagnosed GBM and complete surgical resection or 

minimum residual tumor � 1cm3 , are HLA-A1 and/or HLA-A2 positive, 

older than 18, have Karnofsky Performance Score (KPS) of � 70% and 

have adequate hematologic and chemistry parameters. Patients with a 

serious immune or autoimmune disorder or other systemic disease are 

excluded. Patients undergo apheresis to isolate peripheral blood mononuclear 

cells (PBMCs) to be used for preparation of study treatment (ICT-107 

and Control). Pre-study treatment consists of 6 weeks of concurrent 

temozolomide (TMZ) and radiation. After stratification by site and age, 

patients are randomized 2:1 to receive either ICT-107 or its matching 

control (autologous, unpulsed dendritic cells). Patients then receive 

induction ICT-107 or control once a week for four weeks. All patients 

subsequently receive maintenance TMZ for 5 days per month for 12 

months. Booster vaccinations occur at Cycles 1, 3, 6 and 10, and every six 

months thereafter. The primary endpoint is OS and secondary endpoints 

include PFS, rates of OS and PFS at 6 months after surgery and every 3 

months thereafter, safety and tolerability of ICT-107, immune response to 

ICT-107 and predictors of response. 120 patients have been enrolled in 

this ongoing trial. It is expected that approximately 200 patients will be 

enrolled for screening with the intention to randomize at least 102 patients. 

The trial significance is alpha�0.025 one-sided. 


142s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy 

2500^ Oral Abstract Session, Mon, 3:00 PM-6:00 PM 

Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 

2,3-dioxygenase 1 (IDO1), in advanced cancer patients. Presenting 

Author: Robert Charles Newton, Incyte Corporation, Wilmington, DE 

Background: The ineffectiveness of the immune system to control tumor 

growth is, in part, a result of immunosuppression imposed by negative 

regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme 

that catabolizes the first and rate-limiting step in the degradation of 

the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been 

shown preclinically to play an important role in tumor-mediated immunosuppression. 

In cancer patients (pts), elevated IDO1 levels are associated 

with poor prognosis and shortened survival in a number of tumor types. 

Here we describe the pharmacodynamic (PD) assessment of INCB024360, 

a novel inhibitor of IDO1. Methods: Plasma samples were obtained from 

consented pts in study INCB 24360-101, a phase I dose-escalation study 

in patients with advanced malignancies. Trp and Kyn levels in plasma were 

determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells 

was also monitored. Results: Using anti-IDO1 specific antisera and archived 

tumor samples, we found IDO1 expression in various human tumors, 

including ovarian, colorectal, breast and prostate. Consistent with this 

result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were 

detected in archived plasma samples from pts, indicative of higher IDO1 

activity in cancer pts. To date, 23 pts have been treated with the selective 

IDO1 inhibitor INCB024360. When plasma samples from patients were 

collected pre- and post-INCB024360 treatment, significant dosedependent 

reductions in plasma Kyn/Trp ratios and Kyn levels were 

detected. As an additional biomarker measurement, whole blood samples 

collected from pts at various times after dosing were stimulated ex vivo with 

interferon-� and lipopolysaccharide to increase IDO1 activity and also 

showed dose-dependent decreases in IDO activity. With the current dose 

regimens and assays we have successfully achieved sustained inhibition of 

�90% at a well tolerated dose of INCB024360. Conclusions: This is the 

first demonstration of PD activity of an IDO1-specific inhibitor in cancer 

pts. Our study also confirms that IDO1 is frequently activated in cancer pts. 

The methods described will be used to establish a phase II dose. 

2502 Oral Abstract Session, Mon, 3:00 PM-6:00 PM 

Isolation of human anti-MICA antibody from cancer patients responding to 

immunotherapies. Presenting Author: Kenneth F. May, Dana-Farber Cancer 


Background: Immunotherapy is a promising modality for the treatment of 

cancer, and elucidating the mechanism of action is crucial to guiding 

patient selection and developing future immunotherapeutic strategies. 

Engagement of the immune molecule NKG2D by the cancer antigen MICA 

is important for immune surveillance of many cancers. Tumors can evade 

immune surveillance by shedding cell surface MICA, which leads to 

dampening of anti-tumor immunity. Investigations by our laboratory revealed 

that patients responding to immunotherapy can mount antibody 

responses targeting MICA, which permits re-engagement of immunity. 

Methods: Patients with advanced cancer treated at our institution with 

immunotherapies (tumor cell vaccination, ipilimumab) were identified, 

including several with long-term clinical remissions. Plasma was analyzed 

for MICA reactivity to three distinct MICA alleles, and rare memory B cells 

reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin 

heavy and light chain variable domains were sequenced with single 

cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma 

from patients treated with immunotherapy revealed considerable interpatient 

variation in reactivity to MICA. Patients with marked plasma 

reactivity (including several with sustained clinical remissions) were 

selected for isolation of rare memory B cells reactive to MICA. From these 

cells, we have generated a recombinant fully-human MICA-reactive monoclonal 

antibody that exhibits binding to a variety of MICA alleles. Conclusions: 

We have developed novel methods to analyze anti-MICA antibody responses 

and isolate rare memory B cells from cancer patients who gained significant 

clinical benefit from immunotherapy. This has facilitated the generation of 

fully human recombinant anti-MICA monoclonal antibody. To our knowledge, 

this is the first example of a specific antibody reactive to a cancer 

antigen isolated from a cancer patient responding to immunotherapy. As 

these antibody responses likely played a role in tumor destruction, these 

results inform the development of new antibody-based immunotherapies 

targeting the NKG2D-MICA pathway. 


A phase I study of 1-methyl-D-tryptophan in patients with advanced 

malignancies. Presenting Author: Hatem Hussein Soliman, H. Lee Moffitt 

Cancer Center & Research Institute, Tampa, FL 

Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create 

immune suppression and unresponsiveness to tumor antigens in tumorbearing 

hosts. 1-methyl-D-tryptophan (1-MT) is an oral inhibitor of the IDO 

pathway, currently in development as an immune adjuvant for anti-tumor 

vaccines and chemotherapy. The primary goal of this trial is to determine 

the MTD and toxicity for oral 1-MT. Secondary endpoints include response 

rates, PK, serum tryptophan catabolites, circulating T-reg cells, and C 

reactive protein (CRP) levels. Methods: This phase I study utilizes a 3�3 

design comprised of ten dose levels (200, 300,400,600,800,mg QD, 600, 

800,1200,1600,2000mg BID). Inclusion criteria: patients with measurable 

metastatic solid malignancy, age �18, life expectancy �4 months, 

and adequate organ/marrow function. Exclusion criteria: chemotherapy in 

the past 3 weeks, untreated brain metastases, active autoimmune disease, 

or malabsorptive GI disease. Continuous toxicity monitoring early stopping 

rules were used. Results: At submission, 48 out of the planned 50 patients 

were accrued. MTD was not reached at 2000mg BID. At 200mg QD dose, 3 

patients previously treated with active immunotherapy (ipilimumab, n�2, 

CD40-mAb, n�1) developed an autoimmune hypophysitis. Since IDO is 

closely linked to both CTLA-4 and CD40/CD40L pathways this was 

considered on-target effect. Subsequently, patients with prior immunotherapy 

were excluded and no additional treatment related G3-5 adverse 

events were observed. Five patients showed SD�6 months (2 melanoma, 2 

sarcoma 1 colon) as well as some mixed responses were seen in some 

patients including regression of a liver visceral metastases. 1-MT plasma 

PK AUC and Cmax were proportional with dose. Cmax (~40 �M at 2000mg 

BID) is at 2.9 hours and the t1/2 is at 10 hours. Elevations in CRP levels 

and declines in T-reg cell counts were seen across multiple dose levels. 

Additional correlative data analysis is ongoing. Conclusions: The treatment 

was well tolerated and orally bioavailable. Biologic activity in terms of 

prolonged disease stabilization, induction of hypophysitis, and changes in 

T-reg levels and CRP were observed. Trials combining 1-MT with docetaxel 

and a dendritic cell vaccine are ongoing. 

2503^ Oral Abstract Session, Mon, 3:00 PM-6:00 PM 

Durability of complete remission by moxetumomab pasudotox (HA22 or 

CAT-8015) assessed by clone-specific real-time quantitative PCR (RQ- 

PCR). Presenting Author: Robert J. Kreitman, Laboratory of Molecular 

Biology, NCI, NIH, Bethesda, MD 

Background: The anti-CD22 recombinant immunotoxin moxetumomab 

pasudotox, also known as HA22 or CAT-8015, was recently reported in 

phase I testing to achieve complete remissions (CRs) in 13 (46%) of 28 

patients with relapsed/refractory hairy cell leukemia (HCL); 3 of 13 

patients have relapsed. Methods: To complete this trial, 20 additional 

patients received the highest dose level (50 �g/Kg every other day x 3 

doses); none of the 48 HCL patients had dose-limiting toxicity (DLT). 

Results: Of the first 42 patients with �6 mo of follow up off-treatment, 23 

(55%) had CRs, with an overall response rate of 88%. Of the 23 CRs, 21 

were evaluable for minimal residual disease (MRD) using flow cytometry of 

blood and immunohistochemistry of the bone marrow biopsy, and 17 

(81%) were negative. Of these 17 patients, 11 (65%) were negative by 

bone marrow aspirate (BMA) flow cytometry. PCR using consensus primers 

for the heavy chain immunoglobulin (IgH) rearrangement was less specific 

than flow cytometry of blood, since IgH rearrangements of normal B cells, 

which recovered rapidly after immunotoxin treatment, were also amplified. 

For better MRD detection in blood, patient IgH sequences were cloned and 

sequence specific primers and probes designed for real-time quantitative 

PCR (RQ-PCR). RQ-PCR of blood was negative in 6 (100%) of 6 patients 

achieving flow-negativity in both blood and BMA and positive in 3 (100%) 

of 3 patients flow-negative in blood but not BMA (p�0.01). No relapses 

from CR have been observed in 10 patients who became RQ-PCR-negative 

in blood or flow-negative in BMA, with 5-38 (median 11) mo of follow-up. 

Conclusions: We conclude that clone-specific RQ-PCR is the most sensitive 

blood test for MRD in our HCL patients after moxetumomab pasudotox, and 

could be used to assess the possibility of long-term molecular remissions. 

We believe these results, including durable CRs without DLT, support a 

pivotal trial in which moxetumomab pasudotox is compared with alternative 

therapy. Note: this summary contains investigator reported data. This study 

was funded by MedImmune, LLC, and supported by NCI’s Intramural 

Research Program and the Hairy Cell Leukemia Research Foundation. 




A phase I study of EpCAM/CD3-bispecific antibody (MT110) in patients 

with advanced solid tumors. Presenting Author: Walter M. Fiedler, Medical 

Clinic II, University Medical Center Hamburg-Eppendorf, Center of Oncology 

(Hubertus Wald Tumorzentrum), Hamburg, Germany 

Background: MT110 is a bispecific T cell engaging antibody construct 

(BiTE) that directs CD3 expressing T cells to kill target cells that express 

EpCAM, which is widely found on solid tumors. Methods: Safety, tolerability, 

pharmacokinetics and anti-tumor activity of MT110 in patients (pts) 

with advanced solid tumors were studied using a 3�3 design. Continuous 

IV infusions for at least 28 days of doses ranging from 1 to 48 �g/d have 

been tested. Stepwise intra-patient dose escalations within cycle 1 or at 

start of cycle 2 have been explored. Results: 51 pts (6 gastric cancers, 32 

CRC, 2 SCLC, 5 NSCLC, 3 HRPC, 1 ovarian cancer) have been treated in 

12 dose cohorts. The maximally administered dose includes day 1 dose of 3 

�g/d escalated up to 48 �g/d. The maximum tolerable dose (MTD) has not 

yet been established. Diarrhea and elevations in liver function tests have 

been reported as dose limiting toxicity (DLT) for individual patients. 

Transaminase elevations were fully reversible and mitigated by dexamethasone 

at initiation or escalation of dose. Other adverse events of grade 3 or 

higher included transient lymphopenia, increase in lipase or amylase, 

nausea, vomiting, and hypoalbuminaemia. No CNS safety signal was 

observed. The mean serum half-life of MT110 was 4.5 hours. Mean steady 

state serum concentrations of MT110 were linear with dose across 

treatment cycles. At 48 �g/d, the mean Css was 3.2 ng/mL. This compares 

to preclinical EC90 of 1.35 – 3.85 ng/ml in CRC cell lines. Sixteen pts who 

received a dose of � 24 �g/d were evaluable for anti-tumor response. Best 

response of SD was reported in 38%; median duration was 155 days (95% 

CI 92; 161). Anti-tumor activity was demonstrated on biopsy of liver 

metastases in one patient. Following at least 1 week of MT110 treatment at 

48 �g/d, a decrease in circulating tumor cells was observed with a median 

nadir 74% below baseline. Conclusions: The use of stepwise dose escalation 

and concomitant dexamethasone resulted in improved tolerability. A 

dose of 48 �g/d appears tolerable. Tumor biopsy evaluation on treatment 

and pharmacodynamic evidence of anti-tumor activity are encouraging. 

Additional dose cohorts will seek to identify the recommended phase II 

dose and further evidence of anti-tumor activity. 


WT1-targeted dendritic cell vaccination as a postremission treatment to 

prevent or delay relapse in acute myeloid leukemia. Presenting Author: Zwi 

N. Berneman, Antwerp University Hospital, Edegem, Belgium 

Background: Vaccination with tumor antigen-loaded dendritic cells (DC) 

holds promise for the adjuvant treatment of cancer. Methods: In a phase I/II 

trial, we investigated the effect of autologous DC vaccination in 17 patients 

with acute myeloid leukemia (AML) in remission but at very high risk of full 

relapse. Wilms’ tumor 1 protein (WT1) was chosen as immunotherapeutic 

target and introduced into the DC by mRNA electroporation. We are 

continuing a phase II trial, which is still recruiting. Results: Two out of 3 

patients, who were in partial remission with chemotherapy-refractory 

disease, were brought into complete remission following 4 biweekly 

intradermal injections of WT1 mRNA-electroporated DC. In those 2 

patients as well as in 6 other patients who were in complete remission but 

who had molecularly demonstrable residual disease, there was a return to 

normal of the AML-associated WT1 mRNA tumor marker following DC 

vaccination, compatible with reaching clinical and molecular remission in 

8/17 patients. Among the 8 responders, there have been 2 relapses and 2 

deaths. Of the 9 non-responders, 8 have relapsed and 7 have died. Of the 2 

patients in partial remission who were brought into complete remission by 

DC vaccination, 1 has died following relapse. Median overall survival was 6 

months in non-responders and 52 months in responders (p�0.0007). 

Median relapse-free survival was 3 months in non-responders as compared 

to 47 months in responders (p�0.0001). Clinical responses overall were 

correlated with elevated levels of activated natural killer (NK) cells 

post-vaccination. Long-term clinical responses, lasting for at least 3 years, 

were significantly correlated with an increase in polyepitope WT1-specific 

tetramer� CD8� T-cell frequencies. Conclusions: DC-based immunotherapy 

elicits both innate (NK) and adaptive (T cells) cellular responses 

correlated with clinical benefit. WT1 mRNA-transfected DC emerge as a 

feasible and effective strategy to control residual disease in AML, in 

particular as a post-remission treatment to prevent full relapse. 

143s 


Anti-CD3 immunotoxin to induce remissions in cutaneous T-cell lymphoma 

patients. Presenting Author: Arthur E. Frankel, Scott and White Hospital, 

Temple, TX 

Background: The anti-CD3 immunotoxin, AdmDT390bisFv(UCHT1), composed 

of the catalytic and translocation domains of diphtheria toxin 

(DT390) fused to two anti-CD3 sFvs showed selective cytotoxicity to normal 

and malignant human T cells in vitro and in vivo and was prepared for a 

phase I clinical study (Woo, Protein Exp Purif 58, 1, 2008). FDA approval 

(BB IND#100712), and IRB approval was obtained. Methods: Nineteen T 

cell lymphoma patients were screened, and 12 patients treated. Median 

age was 62 years (range, 39-84 years) with 6 males and 6 females. Disease 

was previously treated with one (6), two (3), three (1) or four (2) systemic 

therapies. One patient had stage IV PTCL and the other patients had CTCL 

(stage IB in 5, IIB in 4, IIIB in 1, and IV in 1). Six patients were treated with 

2.5�g/kg x 8; five patients were treated with 5�g/kgx5-8andonepatient 

treated with 7.5�g/kg x 8. Results: Drug-related toxicities were mild in 

11/12 patients and were not dose dependent with transient fevers, chills, 

lymphopenia, transaminasemia, CMV and/or EBV viremia, and hypoalbuminemia. 

One 69 year old male with pre-existing heart failure treated at the 

5�g/kg x 5 suffered severe vascular leak syndrome and heart failure. 

Immunotoxin Cmax was 1 – 60ng/mL, and mean half-life was 42min. Four 

patients had pre-treatment anti-immunotoxin titers �10�g/mL, and the 

others had lower pre-treatment antibody levels. All evaluable patients 

except two had increases of antibody titer between day 12 to 30 of 4 – 

2000-fold. Among 10 evaluable patients, there were 2 complete remissions 

(CRs) of 17 and 41� months durations and 4 partial remissions (PRs) 

of 1� -32�months. Conclusions: The immunotoxin has exciting clinical 

efficacy in this heavily pretreated group of patients. Dose escalation is 

proceeding. 


Phase IB study on combined intradermal (ID) and intravenous (IV) 

administration of autologous mRNA electroporated dendritic cells (DC) as a 

single-agent cellular immunotherapy or combined with ipilimumab. Presenting 

Author: Bart Neyns, UZ Brussel, Brussels, Belgium 

Background: Autologous monocyte-derived DC electroporated with synthetic 

mRNA encoding CD40 ligand, a constitutively active TLR4, and 

CD70 (TriMix-DC) have superior T-cell stimulatory capacity. In a pilot 

clinical trial, ID administration of TriMixDC-MEL (a mixture of TriMix-DC 

co-electroporated with mRNA encoding a fusion of DC.LAMP and 1 of 4 

melanoma associated antigens) was immunogenic but resulted in limited 

anti-tumor activity in patients (pts) with advanced melanoma. Ipilimumab 

(IPI) is a CTLA-4 blocking mAb with established activity in pts with 

advanced melanoma. Methods: TriMixDC-MEL by the IV and ID-route was 

investigated as a single-agent or in combination with IPI (10 mg/kg q3wks 

x4, allowing for maintenance with IPI-alone q12wks in pts PFS at �24 

wks). Ratio of ID/IV administered DC: Cohort-1: 20.106 /4.106 DC [2pts], 

-2: 12.106 /12.106 DC [3pts], -3: 4.106 /20.106 [6pts], and -4: 0/24.106 DC [4pts]; DC were administered 4x q2w, and a 5th administration on w16. 

in cohort-5, DC (4.106-ID/20.106-IV) were first administered alone and 2w 

thereafter in combination with IPI for a total of 4 administrations [6pts]. 

Results: Local skin reactions (gr1-2) were observed in all pts receiving DC 

ID, flu-like symptoms (� gr2) were observed in 12/21 pts, post IV-infusion 

chills (gr2) in 7/21 pts. Cytokines release (including a �2-fold rise in the 

serum levels of IL-1RA, IL-6, IL-8, IL-17, G-CSF, IFN-g, MIP-1a, MIP-1b, 

TNF-a) was documented during chills. Best objective tumor response: 2x 

PR � 2x CR (by RECIST) out of 15 pts (27%) treated with DC-only (ongoing 

after 10�, 14�, 19�, and 20� mths) and 3 PR out of 6 pts (all stage 

IV-M1c) treated with DC�IPI (ongoing after 5�,5�,6�mths). Conclusions: 

ID/IV-administration of TriMixDC-MEL as a single-agent cellular immunotherapy 

or combined with IPI is associated with distinct but manageable 

side-effects and has clinical activity against pretreated advanced melanoma. 

Activity compares favorably with TriMixDC-MEL by ID-administrationonly. 

Combined ID/IV administration of TriMixDC-MEL with IPI is currently 

under further evaluation in a phase II trial. 




From bench to bedside: The use of the li-Key technology to improve helper 

peptides for clinical use in cancer vaccines. Presenting Author: Timothy J. 

Vreeland, San Antonio Military Medical Center, Ft. Sam Houston, TX 

Background: Work involving peptide vaccines has shown that peptides 

containing MHC Class II epitopes, which elicit CD4� T cell responses, may 

play a role in potentiating an immune response. The Ii-Key peptide (amino 

acids 77-80 of the immune-regulatory Ii protein), when covalently linked to 

an MHC Class II epitope, can induce conformational change in the epitope 

binding groove, increasing CD4� T cell stimulation up to 250 fold. Here we 

present an update of results from clinical trials evaluating this novel 

technology in an adjuvant breast cancer vaccine targeting HER2/neu. 

Methods: We reviewed our trials investigating AE37, a hybrid peptide 

created by the addition of the Ii-Key peptide (LRMK) to AE36 (GVGSPYVS- 

RLLGICL), an MHC Class II-binding peptide from the intracellular domain 

of the HER2 protein. We have completed a phase I study and are currently 

conducting a randomized phase II trial of the AE37 peptide � GM-CSF in 

the adjuvant treatment of disease-free breast cancer patients with any level 

of HER2 expression (IHC 1-3� or FISH�1.2). Results: Phase I data showed 

the vaccine to be safe and effective in raising anti-HER2 immunity. 

Importantly, even the cohort of patients given AE37 without GM-CSF 

showed significant increases in both in vivo and in vitro immune responses. 

To date, we have enrolled 201 patients to our phase II trial (Vaccine 

(VG)�103, Control (CG)�98). Toxicity has been minimal (99% of local 

and systemic toxicities grade �2). VG patients have shown significant 

increases in both in vivo and in vitro responses to both AE36 and AE37, 

with consistently stronger responses to the AE37 hybrid peptide than the 

native AE36. With a median f/u of 22 months, Kaplan Meier projections 

estimate recurrence rates of 10.3% in the VG compared to 18% in the CG; 

a 43% risk reduction. Conclusions: The AE37 peptide vaccine appears to be 

effective in eliciting a strong immune response and possibly preventing 

breast cancer recurrence. These results provide an important proof of 

concept and suggest that additional studies evaluating Ii-Key hybrid 

peptide vaccines are warranted, whether in the field of immunotherapy or 

more traditional vaccines. 


PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and 

clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with 

solid tumors. Presenting Author: Scott S. Tykodi, Fred Hutchinson Cancer 

Research Center, Seattle, WA 

Background: Blocking the interaction between programmed death-1 (PD- 

1), a co-inhibitory receptor expressed by activated T cells, and its ligand 

PD-L1 may enhance T-cell function. Here we describe the safety and 

activity from the first clinical study of BMS-936559 in patients (pts) with 

advanced solid tumors, further validating the importance of the PD-1/ 

PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was 

given Q2 wk IV in a 6-wk cycle at doses of 0.3�10.0 mg/kg during dose 

escalation and/or cohort expansion; pts could receive up to 16 cycles (48 

doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL, 

n�53), non-small-cell lung (NSCLC, n�50), colorectal (n�18), renal cell 

(RCC, n�17), ovarian (n�17), and pancreatic (n�7) cancer were treated. 

Median therapy duration was 11 wks (max 99 wks). Common related 

adverse events (rAEs; �5% pts) included fatigue, diarrhea, infusion 

reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs 

was 8.6%. AEs of special interest included hypothyroidism, hepatitis, 

sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drugrelated 

deaths. Clinical activity was observed in MEL, RCC, and NSCLC. 

Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated 

pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting �1 

yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data 

lock. Several pts had prolonged stable disease. Some pts had a persistent 

reduction in overall tumor burden in the presence of new lesions but were 

not categorized as responders. In NSCLC, ORs were observed irrespective 

of histology. Conclusions: BMS-936559 was active and generally well 

tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from 

anti-PD-1/BMS-936558 trials, this study concurrently validates the importance 

of the PD-1/PD-L1 pathway for cancer immunotherapy and supports 

further clinical development of anti-PD-1/PD-L1 directed therapy. 

Dose 

(mg/kg) 

MEL RCC NSCLC 

N a OR uPR b RR c (%) N a OR uPR b RR c (%) N a OR uPR b RR c (%) 

1 18 1 1 11 0 - - - 11 0 0 0 

3 17 5 1 35 0 - - - 13 1 0 8 

10 17 3 0 18 17 2 1 18 25 4 3 28 

a response evaluable pts 

b unconfirmed PR 

c response rate ([OR � uPR] � N) 

CRA2509 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM 

Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: 

Clinical activity, safety, and a potential biomarker for response. 

Presenting Author: Suzanne Louise Topalian, The Johns Hopkins University 

School of Medicine, Baltimore, MD 


abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 




be printed in the Saturday edition of ASCO Daily News. 


Costimulatory effect of agonistic 4-1BB antibody on proliferation and 

effector phenotype of tumor-infiltrating lymphocytes in melanoma. Presenting 

Author: Amod Sarnaik, H. Lee Moffitt Cancer Canter & Research 

Institute, Tampa, FL 

Background: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) 

is a promising form of immunotherapy with a 20-30% durable response 

rate. Its widespread implementation is limited by the relatively long time 

needed to establish TIL in vitro and the lack of effective tumor reactivity. 

Our objective was to incorporate co-stimulation with 4-1BB agonism to 

optimize TIL growth preparation time and tumor reactivity to improve 

outcomes. Methods: 7 metastatic melanoma patients were consented to an 

IRB-approved tissue procurement protocol. For each specimen, TIL were 

propagated in vitro from 4 melanoma tumor fragments per condition with 

standard 6000 IU/mL of IL-2 and either 10 ug/mL of 4-1BB agonistic 

antibody (BMS-663513) or its isotype control. After 3 weeks, TIL were 

counted and phenotyped using flow cytometry. TIL were re-stimulated with 

HLA-matched melanomas and assessed for interferon-� (IFN�) release by 

ELISA. Statistical comparisons involved the 2-tailed, paired t test using 

GraphPad Prism software. Results: 4-1BB treatment yielded a median 

4.3x10 7 TIL (range 1.1x10 7 -8.4x10 7 ) compared to a median 2.3x10 7 

cells in the control (range 1.5x10 6 -5.3x10 7 ,p� 0.009). This is clinically 

significant as the initial minimum target number for TIL generation is 

3x10 7 . On phenotypic analysis compared to control, 4-1BB treatment 

resulted in a 1.5X higher CD8 � cell numbers (p�0.02), a 6X lower CD4 � 

cell numbers (p�0.02), and 5.5X lower CD4 � CD25 � FoxP3 � Treg cell 

numbers (p�0.09). A paired sample was re-stimulated in triplicate with 

HLA-matched tumor target, and ELISA of the supernatant treated with 

4-1BB yielded 1.6 fold higher IFN� (p�0.05). A paired sample was then 

assayed for known markers of T cell cytolytic activity: EOMES and perforin. 

4-1BB treatment resulted in 34.5% EOMES and perforin double positive 

TIL compared to 18.8% in the control group. Conclusions: 4-1BB agonism 

is associated with enhanced kinetics of TIL proliferation, increased yield of 

CD8 � TIL, lower Treg numbers, increased markers of cytolysis, and 

enhanced IFN� release upon tumor re-stimulation. 4-1BB agonism may be 

a useful adjuvant in the generation of TIL in future clinical trials. 




Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients 

with advanced solid tumors. Presenting Author: Amita Patnaik, South 

Texas Accelerated Research Therapeutics, LLC, San Antonio, TX 

Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that 

may lead to suppression of antitumor immunity. MK-3475 is a humanized 

monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown 

antitumor activity in multiple tumor types. This first-in-human phase I trial 

explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An 

open-label, dose escalation study was conducted in patients with advanced 

malignancy refractory to standard therapy. Cohorts of 3-6 patients were 

enrolled (3�3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following 

an initial dose and 28-day Cycle 1, patients were allowed to subsequently 

receive multiple doses given every 2 wks. Radiographic assessment was 

conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 

at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). 

Patients had non–small cell lung cancer (NSCLC, n�3), rectal cancer (n�2), 

melanoma (MEL, n�2), sarcoma (n�1), or carcinoid (n�1). To date, a total of 

63 doses were administered (median 7/patient; max 12) without DLT. 

Drug-related adverse events (AEs) across all doses included Grade 1 fatigue 

(n�3), nausea (n�2), diarrhea (n�1), dysgeusia (n�1), breast pain (n�1), 

and pruritus (n�1). One drug-related Grade 2 AE of pruritus was reported. No 

drug-related AEs � Grade 3 were observed. PK data are shown in the table. 

Based on RECIST, 1 patient with MEL on therapy �6 mths had a partial 

response, and preliminary evidence of tumor size reduction (stable disease) 

was observed in 3 additional patients with advanced cancer. Conclusions: 

MK-3475 was well-tolerated without DLT across 3 tested dose levels. 

Evidence of antitumor activity was observed. Enrollment continues to obtain 

additional safety, PK, and efficacy data; updated data will be presented at the 

meeting. 

Mean (CV%) PK parameter values of MK-3475 following single IV dose of 

1, 3, or 10 mg/kg in cycle 1. 

Dose (mg/kg) N Cmax (·g/mL) AUC (0-28day) (�g·day/mL) a t1/2 (day) 

1 4 6.8 (23) 163 (20) b 15.1 (41) b 

3 3 109 (26) 990 (23) 21.7 (11) 

10 2 337 (8) 2,640 (30) 13.6 (28) 

aPK sampling up to 28 days following first IV administration; therefore t1/2 not 

fully characterized. 

bN�3 due to subject discontinuation. 

2515 Poster Discussion Session (Board #3), Sat, 8:00 AM-12:00 PM and 

12:00 PM-1:00 PM 

Radiotherapy plus the anti-EGFR mAb nimotuzumab or placebo for the 

treatment of high-grade glioma patients. Presenting Author: Maria Teresa 

Solomon, Calixto García Hospital, Havana, Cuba 

Background: Despite remarkable advances in multimodal therapy, high 

grade glioma (HGG) patients still face a poor prognosis. EGFR is well 

validated as a primary contributor of HGG initiation and progression. 

Nimotuzumab is a humanized monoclonal antibody (mAbs) that recognizes 

the EGFR extracellular domain. While it has similar preclinical and clinical 

activity when compared to other anti-EGFR mAbs, it does not induce skin 

toxicity or hypomagnesemia. Methods: A randomized, double blind, multicentric 

clinical trial was conducted in 70 anaplastic astrocytoma (AA) and 

glioblastoma multiforme (GBM) patients that received radiotherapy (RT) 

plus nimotuzumab or placebo. Patients received 6 weekly doses of 

nimotuzumab or placebo together with radiotherapy. Treatment was maintained 

every 3 weeks, until completing 1 year of treatment. GBM patients 

did not receive temozolomide since the drug cannot be sold to Cuba. The 

objectives of this study were to assess the overall survival, progression free 

survival (PFS), response rate, immunogenicity and safety in both treatment 

groups. Results: Seventy patients were included in the study: 41 AA and 29 

GBM. The median cumulative dose was 3600 mg of nimotuzumab and the 

median antibody number of doses was 16. The combination of nimotuzumab 

and radiotherapy was very safe. The most prevalent related adverse 

events included grade 1-2 nausea, fever, tremors and anorexia. There was 

no increasing toxicity with repeated drug exposure. No anti-idyotipic 

response was detected. The mean and median survival time for subjects 

treated with nimotuzumab and RT was 31.06 and 17.76 months while the 

mean and median survival time for controls was 21.07 and 12.63 months, 

respectively. For the evaluable patients of the AA stratum, the median 

survival time was 44.56 months (active drug) vs. 14.6 months (control). 

For the evaluable patients in the GBM cohort, the median survival time was 

16.06 months (nimotuzumab arm) vs. 8.36 months (placebo arm). Median 

PFS was 18.23 vs. 6.25 months. Conclusions: In this randomized trial, 

nimotuzumab continues showing an excellent safety profile and positive 

efficacy results in patients with high grade glioma in combination with 

irradiation. 

145s 


12:00 PM-1:00 PM 

Effect of stimulation of natural killer cells with an anti-CD137 mAb on the 

efficacy of trastuzumab, cetuximab, and rituximab. Presenting Author: 

Holbrook Edwin Kohrt, Stanford Cancer Center, Stanford, CA 

Background: Antibody-dependent cell-mediated cytotoxicity (ADCC), mediated 

by natural killer (NK) cells, plays an important role in the efficacy of 

monoclonal antibodies (mAb)s. CD137 is a costimulatory molecule expressed 

on immune cells following activation, including NK cells. We 

hypothesize that as the antitumor efficacy of mAbs is due to ADCC, their 

activity can be enhanced by stimulation of NK cells with an anti-CD137 

agonistic mAb. Methods: Upregulation of CD137 on NK cells was assessed 

using CD20�lymphoma, HER2�breast, and EGFR�head and neck cell 

lines and primary patient samples. NK cell degranulation, cytokine release 

and cytotoxicity were assessed by CD107a mobilization, IFN-� secretion, 

and chromium release. Mechanism of synergy was explored by cell 

depletion in an immune competent mouse model. Xenotransplanted 

models were used to demonstrate anti-tumor activity and sufficiency of an 

innate immune response. Results: NK cells in human primary patient 

samples do not express CD137 at baseline, however CD137 is highly 

upregulated when encountering mAb-coated tumor cells. MAb-induced NK 

cell degranulation and cytotoxicity are enhanced by anti-CD137 agonistic 

mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances 

anti-tumor activity of anti-CD20 mAb leading to complete tumor 

resolution and prolonged survival. NK cell depletion completely abrogates 

the therapeutic effect. In seven xenotransplant models, sequential administration 

of rituximab, trastuzumab or cetuximab plus anti-CD137 mAb 

provided superior reduction in tumor burden and prolonged overall survival. 

In a phase 0 biomarker study, level of CD137 expression on circulating and 

intratumoral NK cells was influenced by disease burden, prior treatment, 

Fc�RIII polymorphism, and time since mAb therapy. Conclusions: Our 

results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting 

mAb by stimulation of mAb-activated NK cells with anti-CD137 mAb to 

enhance ADCC. These results support a novel, sequential antibody approach 

against CD20�B cell, HER2�breast, and EGFR�head and neck 

malignancies by targeting first the tumor and then the host immune system. 


12:00 PM-1:00 PM 

Safety of the antimyostatin monoclonal antibody LY2495655 in healthy 

subjects and patients with advanced cancer. Presenting Author: Gayle S. 

Jameson, Virginia G. Piper Cancer Center/Translational Genomics Research 

Institute, Scottsdale, AZ 

Background: Skeletal muscle wasting (cachexia) is a prevalent and not 

readily managed condition in advanced cancer patients. LY2495655 is a 

humanized monoclonal antibody to myostatin, which has demonstrated 

positive effects on cachexia measures in animal models. We present phase 

I trial data on use of LY2495655 in healthy volunteers (Study 1) and 

interim data from an ongoing phase I study in patients with advanced 

cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, 

blinded, single-dose, parallel, dose-escalation study evaluating the safety 

and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an 

ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics 

(PKs) of LY2495655 in patients with advanced cancer not 

receiving chemotherapy. Dose cohorts (2 mg-700 mg, �3 patients per 

cohort) were to be treated until the maximum tolerated dose (MTD) was 

met, or the highest dose (700 mg) cohort was completed. Final locked data 

from Study 1 and interim data from the dose escalation phase of Study 2 

were used in the analyses. Results: In Study 1, 64 healthy volunteers were 

enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had 

received treatment with LY2495655 at the time of the analysis. In both 

studies, all doses of LY2495655 were well tolerated (no DLTs were 

observed and MTD was not reached), and nonlinear PKs were observed 

(most evident in lower dose levels). In Study 1, thigh muscle volume 

generally increased with LY2495655. In Study 2, increased muscle 

volume was observed only at 21-mg and 70-mg doses. Consistent increases 

in hand grip strength and improvements in functional tests were observed 

at doses �21 mg. Conclusions: There were no unusual safety concerns in 

healthy subjects or cancer patients. PK results were consistent between the 

2 studies. Increases in muscle volume were observed in both studies, with 

concomitant improvement in functional measures. However, there is no 

clear trend in dose-dependent efficacy, possibly due to extremely small 

sample sizes and patient heterogeneity. Enrollment in Study 2 continues 

with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic 

cancer patients. 




12:00 PM-1:00 PM 

A phase I safety study of NPC-1C: A novel, therapeutic antibody to treat 

pancreas and colorectal cancers. Presenting Author: Philip M. Arlen, 

Neogenix Oncology, Rockville, MD 

Background: NPC-1C (NEO-101; Ensituximab) is a chimeric monoclonal 

antibody being developed as a novel biological treatment for pancreatic and 

colorectal cancers. This antibody was selected from a panel of hybridomas 

generated from mice immunized with semi-purified membrane-associated 

proteins derived from biologically screened, pooled human allogeneic colon 

cancer tissues. The NPC-1C target appears to be a variant of MUC5AC that 

is expressed specifically by human colon and pancreatic tumors with 

minimal cross-reactivity to normal GI tract tissues. Methods: A phase I open 

label, multi-center dose escalation clinical trial with NPC-1C has completed 

accrual of subjects with advanced pancreatic and colorectal cancer 

refractory to standard therapy. The primary objectives are to determine 

safety and tolerability of escalating doses of NPC-1C and to assess 

pharmacokinetics (PK) and select immune responses to the antibody at 

each dose level. Secondary objectives are to evaluate evidence of clinical 

benefit and to explore immunologic correlates Results: Three cohorts of 

subjects have been treated with NPC-1C at escalating dose levels of 1, 1.5, 

and 2 mg/kg IV every two weeks. All 15 subjects (10 colorectal, 5 

pancreatic) have enrolled on study (5/15 non-evaluable). No DLT was noted 

at the 1mg/kg dose level with 2 of 3 patients showing stable disease at 

completion of Course 1. At the 2 mg/kg dose level, one patient demonstrated 

stable disease after course 1. At escalating rates of infusion, 3 

subjects experienced mild to moderate hemolysis that resolved without 

intervention. All 6 patients who have received 1.5 mg/kg at a constant rate 

of infusion have been evaluated, with no dose limiting toxicity. One of 5 

patients re-staged thus far in the 1.5 mg/kg cohort showed stable disease 

on scans after completing the first course of treatment (4 doses), and 

continued to receive additional doses. Preliminary data show no drug 

induced antibody responses in treated subjects. PK, HAMA and cytokine 

evaluation is ongoing. Conclusions: NPC-1C is tolerated well at the current 

dose level of 1.5 mg/kg every 2 weeks without producing any DLT We plan 

to continue accrual in the Phase 2A to evaluate clinical responses and 

additional safety data. 


12:00 PM-1:00 PM 

Assessment of a novel immunological biomarker SNP panel from a phase 

III trial of Bacillus Calmette-Guérin (BCG) adjuvant treatment in stage III 

melanoma patients. Presenting Author: Connie Ging Ting Chiu, Department 

of Molecular Oncology and Division of Surgical Oncology, John Wayne 

Cancer Institute, Santa Monica, CA 

Background: Melanoma is an immunogenic cancer, whereby immunotherapy 

in stage III patients has shown some success. However, there are no 

effective immune biomarker tests to identify patients most likely to benefit 

from immunotherapy. BCG (Bacillus Calmette-Guérin) therapy is a form of 

immunomodulation. The objective was to assess the predictive clinical 

effect of a single nucleotide polymorphism(SNP) immune biomarker panel 

in stage III resected melanoma patients treated with BCG. Methods: 

MMAIT-III was a phase III prospective randomized international multicenter 

trial of BCG�melanoma vaccine vs BCG�placebo after complete 

resection of stage III melanoma patients (NIH #NCT00052130). 120/292 

patients with palpable disease treated with resection and BCG�placebo 

had lymphocytes(PBL) from USA sites available for analysis. Endpoints 

were overall survival(OS) and disease-free survival(DFS), with a 10-yr 

follow-up. PBL DNA was assessed by MassARRAY MALDI-TOF for 28 SNPs 

associated with macrophage/monocyte-related immune response pathways 

to BCG/tuberculosis. A pilot study(n�34) from phase II BCG trial confirmed 

presence of the SNPs. A logistic regression determined a SNP score, 

and a cutoff was identified by ROC and used as a predictor in a Cox 

proportional hazard model in a verification study(n�120). Results: 9 SNPs 

in 6 genes had prognostic value: NRAMP1 and CD14, 18, 195, 209, 282. 

The 9-SNP panel distinguished patients in 2 survival groups(OS median 

4.9-yrs vs 1.5-yrs, p�0.0008), AUC�0.77. SNP biomarker positivity 

demonstrates significant association with 10-yr OS (59.7% vs 15.7%; HR 

1.97, CI 1.11-3.50, p�0.018) and DFS (47.2% vs 12.3%; HR 2.35, CI 

1.43-3.92, p�0.0007). In Cox model, the SNP panel was a significant 

predictor of OS(HR 2.69, CI 1.56-9.00, p�0.0052) and DFS(HR 2.33, CI 

1.49-5.16, p�0.0003) independent of known melanoma prognostic 

factors. Conclusions: The 9-SNP panel identified patients with an exceptionally 

favourable disease outcome, and may represent a stratifying predictive 

SNP panel for identifying patients that are inherently responsive to BCG 

therapy and potentially other immunomodulating agents in melanoma. 


12:00 PM-1:00 PM 

Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab 

at 10mg/kg to predict for overall survival in patients with metastatic 

melanoma. Presenting Author: Shigehisa Kitano, Memorial Sloan- 


Background: Ipilimumab, an antibody that blocks the function of the 

immune inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4), 

significantly prolongs survival in patients with metastatic melanoma. 

Approximately 30% of patients derive clinical benefit from therapy. 

Defining biomarkers of response to ipilimumab therapy would enable 

selection of patients more likely to respond and is relevant for both 

practicing clinicians and for clinical trial design. We performed a pilot 

correlative study evaluating myeloid derived suppressor cells (MDSC), a 

population of immune suppressive monocytic cells, as a biomarker of 

clinical outcome. Methods: Peripheral blood from 26 patients with stage IV 

melanoma treated with ipilimumab 10mg/kg every 3 weeks for 4 doses at 

our center, as part of an expanded access program (BMS CA184-045) was 

assessed for MDSC quantity (%CD14� ,HLA-DRlow/- cells) pre-treatment, at 

week 7, week 12, and week 24 by flow cytometry. MDSC ability to inhibit T 

cell proliferation was tested using an in vitro suppression assay. Results: We 

found that lower MDSC quantity pre-treatment predicted for improved 

overall survival (Hazard ratio 1.07 (1.03, 1.11) p�0.002) and trended 

toward associating with clinical benefit measured at week 24 imaging 

(p�0.09). This effect was independent of pre-treatment or week 7 absolute 

lymphocyte counts (ALC) and pre-treatment LDH when evaluated in a 

multivariate model with ALC and MDSC quantity HR 1.10; 95% CI 1.04, 

1.17 p�0.0006 and LDH and MDSC quantity HR 1.06; 95% CI 1.01, 

1.11 p � 0.013. Furthermore, a general trend of increasing MDSC number 

by week 24 from the pre-treatment baseline was associated with patients 

that did not achieve clinical benefit. MDSC suppressed peripheral blood T 

cell proliferation as measured by CFSE dilution in response to anti-CD3 

antibody stimulation. Conclusions: Pre-treatment MDSC quantity may 

predict clinical response following ipilimumab therapy. Further studies 

evaluating MDSC as a biomarker of ipilimumab therapy are warranted both 

retrospectively and prospectively in a broader group of patients. 

2520^ Poster Discussion Session (Board #8), Sat, 8:00 AM-12:00 PM and 

12:00 PM-1:00 PM 

Investigating genes and pathways that play a role in immune responses 

mediated by anti-CTLA-4 therapy. Presenting Author: Jianjun Gao, University 


Background: Blockade of the inhibitory T cell molecule CTLA-4 with a 

monoclonal antibody has led to enhanced anti-tumor immune responses 

and clinical benefit. Ipilimumab, an anti-CTLA-4 antibody (BMS), was 

recently FDA-approved for the treatment of metastatic melanoma. Only a 

subset of patients benefit from anti-CTLA-4. In order to identify genes and 

pathways that are induced by anti-CTLA-4, which may be used in future 

studies for potential correlation with clinical outcomes or provide additional 

targets for therapy, we purified and analyzed CD4 T cells from 

patients treated with anti-CTLA-4 for changes in gene expression profile. 

We also obtained tumor tissues from treated patients for similar studies. 

Methods: On an IRB-approved Phase Ia pre-surgical clinical trial, 6 patients 

with localized bladder cancer were treated with two doses of Ipilimumab at 

10 mg/kg at weeks 1 and 4. Blood was collected pre-therapy and 

post-therapy (3 weeks after each dose). CD4 T cells were enriched from 

peripheral blood by using the CD4 T cell isolation kit from Miltenyi Biotec 

(Auburn, CA). Total RNA was isolated from purified CD4 T cells using 

Qiagen RNeasy kit for Affymetrix microarray analyses. Microarray data were 

then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR, RPPA 

and Western blot were used to confirm significant changes in genes or 

pathways identified in microarray analyses. Results: Ipilimumab treatment 

resulted in modulation of differentially expressed genes (DEGs). After dose 

#1, Ipilimumab only modulated 16 DEGs �2-fold (p�0.05) in CD4 T cells. 

After two doses of treatment, Ipilimumab significantly changed expression 

of a total of 100 DEGs. Further pathway analyses indicated that Ipilimumab 

induced a variety of pathways involved in cell cycle control, cell proliferation, 

apoptosis, and immune modulation. Specifically, these pathways 

include PI3K/AKT, MAP/ERK, IFN/JAK-STAT, granzyme, and protein 

ubiquination. Conclusions: Ipilimumab treatment results in modulation of 

multiple genes and pathways, which likely play important roles in antitumor 

immune responses and need to be considered for future optimization 

of anti-CTLA-4 therapy and design of combination immunotherapy strategies. 




12:00 PM-1:00 PM 

The immunological impact of the RAF inhibitor BMS908662: Preclinical 

and early clinical experience in combination with CTLA-4 blockade. 

Presenting Author: Margaret Callahan, Memorial Sloan-Kettering Cancer 


Background: Two new approaches to treat advanced melanoma have 

transformed the standard of care: the CTLA-4 blocking antibody, ipilimumab, 

and the targeted inhibitor of mutated BRAF, vemurafenib. These 

agents are mechanistically unique and combination therapy is a promising 

next step. We evaluated the combination of BMS908662 (662), a pan RAF 

inhibitor, with CTLA-4 blockade in preclinical studies and report first-inhuman 

clinical experience with this combination. Methods: 1) We tested 

the impact of 662 on T cells in vitro, using cultured human T cells, and in 

vivo, using OT-1 transgenic mice. T cell activation and MAPK pathway 

signaling were assessed in parallel. 2) Preclinical studies measuring the 

anti-tumor activity of combination therapy were performed in CT-26 and 

SA1N tumor models. 3) Three pts with BRAF mutant stage IV melanoma 

were treated at MSKCC on CA206005, an IRB-approved protocol, receiving 

ipilimumab (3 mg/kg) and 662 (25 mg bid) (NCT01245556). Two pts 

consented to an IRB-approved protocol permitting immune monitoring. 

Results: 1) In vitro studies demonstrate that 662 can potentiate T cell 

activation after stimulation. This corresponds with increased MAPK pathway 

signaling, consistent with paradoxical activation of the MAPK pathway 

in wild type cells, a class effect of RAF inhibitors. In vivo, enhanced 

expansion of OT-1 cells after ovalbumin challenge was seen in mice treated 

with 662. T cell expansion was greatest in mice treated with a combination 

of CTLA-4 blockade and 662 (p�0.05). 2) Both preclinical models 

demonstrate superior anti-tumor activity with combination therapy compared 

to monotherapy (p�0.05). 3) All pts treated on protocol CA206005 

tolerated combination therapy. New keratoacanthomas and SCCs, likely 

related to 662, were identified. One pt has an ongoing response at 10 mos 

(-85%), one had stable disease for 24 wks (-19%) and a third had disease 

progression. Enhanced MAPK signaling in PBMCs after treatment with 662 

was detected ex vivo. Conclusions: RAF inhibitors may potentiate T cell 

activation in vitro and in vivo, offering one explanation for the enhanced 

anti-tumor activity seen in combination with CTLA-4 blockade in preclinical 

models. 


12:00 PM-1:00 PM 

Cyclin-A1 expression in acute myeloid leukemia stem cells and its 

representation as an immunogenic antigen that can be targeted by 

cytotoxic T cells. Presenting Author: Sebastian Ochsenreither, Department 

of Hematology and Medical Oncology, Charité, CBF, Berlin, Germany 

Background: Targeted T-cell therapy represents a more specific and less 

toxic alternative to allogeneic stem cell transplantation for providing a 

cytotoxic anti-leukemic response to eliminate the leukemic stem cell (LSC) 

compartment in acute myeloid leukemia (AML). The aim of this study was 

to identify a leukemia-associated antigen that is both immunogenic and 

exhibits selective high expression in AML LSCs. Methods: Expression 

microarrays of leukemic and normal cells were used to identify suitable 

candidate genes. Cyclin-A1 appeared to be differentially expressed, and 

was further analyzed by quantitative RT-PCR, intracellular FACS staining, 

and immunofluorescence microscopy. T-cell clones specific for cyclin-A1 

were generated by stimulation in vitro with an overlapping peptide library, 

followed by cloning of responding cells. Specificity of the clones was 

documented by intracellular IFNg and tetramer staining. Cytotoxicity was 

determined by chromium release and caspase-3 cleavage assays. Results: 

To identify target candidates with a suitable expression pattern, microarray 

data from LSCs, hematopoietic cells and healthy tissues were compared. 

Cyclin-A1 was found to be selectively expressed in LSCs of �50% of AML 

patients, but minimally expressed in normal tissues with exception of 

testis. Using dendritic cells and monocytes pulsed with a cyclin-A1 peptide 

library, T-cells were generated against eight cyclin-A1 oligopeptides. Two 

HLA A2-restricted epitopes were further characterized, and specific T-cell 

clones recognized both peptide-pulsed target cells and the HLA A2-positive 

AML line THP-1. Furthermore, cyclin-A1-specific CD8 T-cells lysed primary 

AML cells. Conclusions: Cyclin-A1, known to be important in meiosis, 

is expressed in AML LSCs and testis and can be targeted by T-cells. Thus, 

cyclin-A1 is the first prototypic LSC-associated leukemia-testis-antigen. 

Cyclin-A1 already has been shown to be leukemogenic in mice and to 

promote proliferation and survival in AML blasts. This pro-oncogenic 

activity, together with high expression levels and a multitude of immunogenic 

epitopes, make it a promising target for T-cell based therapy 

approaches. 

147s 


12:00 PM-1:00 PM 

Immune responses and association with clinical outcome of advanced 

colorectal cancer patients treated with the multi-peptide vaccine IMA910. 

Presenting Author: Sabrina Kuttruff, Immatics Biotechnologies GmbH, 

Tuebingen, Germany 

Background: IMA910 is a novel multi-peptide cancer vaccine consisting of 

10 HLA class I and 3class II tumor-associated peptides (TUMAPs), which 

were selected based on natural presentation on colorectal tumors by the 

XPRESIDENT antigen discovery platform. Methods: 92 HLA-A*02� advanced 

colorectal cancer (aCRC) patients (pts) with stable or responding 

disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled 

in this phase I/II trial. After pre-treatment with cyclophosphamide (300 

mg/m2 ), patients were immunized intradermally with IMA910 plus the 

immune modulator GM-CSF without (cohort 1; n�66) or with (cohort 2; 

n�26) topically applied imiquimod, another immune modulator acting via 

toll-like receptor 7 on antigen presenting cells. T-cell responses to 

individual IMA910 peptides were analyzed by HLA multimer and intracellular 

cytokine staining (ICS) assays. Results: IMA910 elicited immune 

responses towards multiple class I (43%) and class II TUMAPs (65%). 

34% of pts responded to multiple class I and class II TUMAPs. Pts that 

received imiquimod were more often multi-peptide class I responders in the 

ICS assay (p�0.016) and showed an approx. 2x higher frequency of T-cell 

response (p�0.12). Responses to multiple class I and class II TUMAPs 

were associated with higher disease control rate at all time points (all 

p�0.02), increased time to progression (p�0.006), progression-free 

survival (p�0.009) and OS (p�0.088, HR�0.53). Baseline characteristics 

of multi vs. non-multi responders were overall well comparable. In a 

prospectively defined, blinded matched-pair analysis with patients in arm C 

of the COIN trial, multi-peptide responder patients showed a prolonged 

survival vs. corresponding COIN patients (p�0.04), while the non-multi 

responder patients had comparable survival. Conclusions: IMA910 is 

immunogenic. Imiquimod increases the quality of immune responses. 

Responses to multiple TUMAPs are associated with better clinical outcome. 

Several observations indicate that this association is not a reflection 

of better prognosis of the immunologically responding subset of patients. 

These results suggest further development of IMA910. 


12:00 PM-1:00 PM 

Adjuvant dendritic cell (DC)-based vaccine therapy of melanoma patients. 

Presenting Author: Natalia N. Petenko, N. N. Blokhin Cancer Research 

Center, Russian Academy of Medical Sciences, Moscow, Russia 

Background: Earlier DC vaccine therapy demonstrated clinical benefit in 

some patients (pts) with advanced melanoma although the effect was seen 

only in pts with minimal tumor burden (ASCO2007 abstract No: 3077). As 

there is no effective treatment for high risk resected melanoma we 

conducted an exploratory trial to assess the effectiveness of DC vaccine in 

stage III and IV melanoma pts after radical surgery in comparison with 

observation. Methods: 108 stage III and IV melanoma pts were enrolled in 

two comparative arms. The arms were well balanced in respect with 

demographic and prognostic factors. The vaccine was based on mature 

autologous monocyte-derived DC primed with autologous tumor lysate, 

administered intradermally every 2-6 weeks until the disease progression. 

Disease free survival (DFS) and overall survival (OS) were evaluated with 

Kaplan-Meier method and compared between the two arms using the log 

rank test. Safety of DC vaccine was also monitored. Results: The vaccine 

arm included 56 pts (stage III – 46, stage IV – 10 pts) who were surgically 

rendered free of disease and treated with DC vaccine. 52 pts were enrolled 

in the control arm (stage III – 47, stage IV – 5 pts), they were treated 

surgically and observed afterwards. At a median follow-up of 22 months, 

the HR (DC vs observation) for DFS was 0.45 (p � 0.05; 95%CI 

0.29-0.69) and for OS was 0.71 (p�0.23; 95%CI 0.40-1.25). 60% of pts 

in the DC arm remained alive at this time point. Risk reduction significantly 

correlated with the strong delayed type hypersensitivity reaction induced by 

vaccine in 31 (55%) out of 56 vaccinated pts. The vaccine was safe and 

well tolerated although vitiligo was registered in 4 cases which was 

associated with more durable time to progression and OS. Conclusions: The 

immunotherapy with DC vaccine is safe and significantly improves DFS 

compared with observation in the adjuvant treatment of stage III and IV 

melanoma. 




12:00 PM-1:00 PM 

CD40 ligand/interferon-� matured DC immunization with gp100 antigen 

HLA class I A *0201 restricted peptides in patients with newly diagnosed 

metastatic melanoma. Presenting Author: Gerald P. Linette, Washington 

University, St. Louis, MO 

Background: CD40L/IFN-� matured Dendritic Cells (DCs) produce IL-12 

and are potent antigen-presenting cells for naïve resting T cells. We sought 

to determine the magnitude and kinetics of CD8� T cell growth in patients 

receiving autologous CD40L/IFN-� matured DC and identify biomarkers 

associated with clinical outcome. Methods: A phase I clinical trial 

(NCT00683670) incorporating CD40L/IFN-� for the ex vivo maturation of 

autologous DCs pulsed with three well characterized gp100 melanoma 

antigen derived peptides (G154, G209-2M, G280-9V) was initiated with 

enrollment from 2008-11 at a single center. HLA-A*0201� individuals 

with treatment naïve metastatic melanoma were immunized every 3 weeks 

by intravenous infusion for six doses after a single dose of cyclophosphamide 

(300 mg/m2 iv). CT imaging was performed at baseline, week 9 

and 18 for clinical assessment using RECIST. Responding patients were 

eligible for maintenance doses every 2-4 months. PBMC were taken weekly 

for immune monitoring by tetramer analysis and functional assays. DC 

preparations were characterized to assess for biomarkers of response. 

Results: 10 patients were screened. Among the 7 treated patients, there 

were 3 confirmed responses (independently verified), including one durable 

CR �3 years and 2 PR. Three patients had rapid disease progression 

and received only 3 doses. Four patients (1 CR, 2 PR, 1 PD) received 6 or 

more vaccine doses. No SAEs were noted. There was no correlation between 

tumor volume and response. Using pre-specified immune response criteria, 

6 (86%) treated patients developed CD8� T cell immunity to all three 

peptides as assessed by tetramer analysis. The vaccine-induced T cells 

from all 6 individuals were polyfunctional and killed gp100�, HLA-A2� 

human melanoma targets in a standard 51Cr release assay. IL-12 production 

by DCs correlated with TTP (p�0.0198, likelihood ratio test) but not 

OS (p�0.08). Conclusions: Weekly immune monitoring reveals the rapid 

onset of CD8� T cell immunity against gp100 among the responder 

patients. This is the first DC vaccine clinical trial in melanoma to 

demonstrate a correlation of IL-12 production and TTP. 


12:00 PM-1:00 PM 

EGF-based cancer vaccine for advanced NSCLC: Results from a phase III 

trial. Presenting Author: Tania Crombet Ramos, Center of Molecular 

Immunology, Havana, Cuba 

Background: The prognosis of patients with advanced non small cell lung 

cancer (NSCLC) remains dismal. Epidermal Growth Factor Receptor 

(EGFR) is overexpressed in epithelial tumors and its role in the development 

of NSCLC is widely proven. The EGF vaccine is a therapeutic cancer 

vaccine composed by recombinant Epidermal Growth Factor (EGF) conjugated 

to a carrier protein, P64K from Neisseria Meningitides and Montanide, 

as adjuvant. The vaccine is intended to induce antibodies against 

self EGF that would block EGF-EGFR interaction. Methods: A multicentric, 

randomized Phase III trial was designed to assess the efficacy, immunogenicity 

and safety of the EGF cancer vaccine in advanced NSCLC patients. 

Patients older than 18 years with histology or cytology proven NSCLC at 

stage IIIB and IV were enrolled in the trial. All patients received no less than 

4 platinum-based cycles and achieved at least stable disease, before 

entering the trial. A low-dose of cyclophosphamide was administered 3 

days before the first immunization. Then, patients received 4 quarterly 

immunizations followed by monthly re-immunizations. Control patients 

received best supportive care. Results: In total, 405 patients bearing stage 

IIIB/IV NSCLC were recruited in 21 sites. The vaccine was very well 

tolerated. The most frequent adverse events consisted in grade 1/2 

injection site pain, fever, headache, vomiting and chills. The vaccine was 

immunogenic. Antibody titers against EGF significantly increased with 

vaccination and on the contrary, EGF concentration in sera showed a fast 

reduction after immunization. There was an inverse correlation between the 

anti-EGF antibody titers and the EGF concentration in sera. Baseline EGF 

concentration was a worse prognostic factor for the control patients and a 

predictive factor for vaccinated subjects. The overall survival was significantly 

better for vaccinated patients as compared to controls. There was a 

direct correlation between the antibody titers and survival. Conclusions: The 

EGF cancer vaccine was very well tolerated and significantly increased 

overall survival of the vaccinated patients. Baseline EGF concentration 

predicted survival benefit. The EGF vaccine is a new therapeutic option for 

advanced NSCLC patients. 


12:00 PM-1:00 PM 

Interim analysis of a phase II randomized clinical trial of samrium-153 

(Sm-153) with or without PSA-TRICOM vaccine in metastatic castrationresistant 

prostate cancer after docetaxel. Presenting Author: Christopher 

Ryan Heery, Medical Oncology Branch, National Cancer Institute, National 

Institutes of Health, Bethesda, MD 

Background: A prior randomized, placebo-controlled, multi-center phase 2 

trial of PSA-TRICOM (PROSTVAC) demonstrated an overall survival benefit. 

Sm-153 is a radiopharmaceutical that targets osteoblastic bone lesions. 

Preclinical data indicated that Sm-153 could alter tumor phenotype, 

causing upregulation of Fas, MHC Class I, and tumor-associated antigens, 

making tumor cells more amenable to immune-mediated killing. Methods: 

This is a phase 2 multi-center trial design intended to randomize 68 

patients (pts) to Sm-153 with or without PROSTVAC. Eligibility included 

castrate resistant prostate cancer bone metastases, no visceral disease, 

prior docetaxel, ECOG �2, and normal organ function. Sm-153 was given 

at 1mCi/kg IV on day 8 and then every 12 weeks. PROSTVAC was given on 

days 1, 15, 29, then every 4 weeks. The 1° endpoint is a comparison of 

progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA 

criteria. 68 patients will provide 80% power to detect a difference of 15% 

vs. 40% without progression at 4 mo with a one-tailed alpha � 0.10 

assuming Fisher’s exact test comparing these fractions as the primary 

method of analysis. 2° endpoints are OS, ORR, PSA changes, immunologic, 

toxicity, and palliation. Reported here is the result of a pre-specified 

interim analysis, which required �20% conditional power to detect 15% 

vs. 40% without progression at 4 months for the trial to continue. Results: 

Of 37 enrolled pts, 3 were not evaluable for PFS. PFS and PSA findings are 

found below. Hematologic toxicities (anemia, thrombocytopenia, neutropenia, 

or lymphocytopenia) are most common, with grade 3 or 4 thrombocytopenia 

occurring in 22% and 26% of treatment cycles on Arms A and B, 

respectively. The conditional power for the comparison of fractions without 

progression at 4 mo is 77%. Conclusions: This interim analysis suggests the 

combination of PROSTVAC and Sm-153 is well tolerated with similar 

toxicity profile to Sm-153 alone. The early indication of improved TTP 

warrants continued study accrual. 

Sm-153 

(A) 

Sm-153 � PROSTVAC 

(B) 

PFS 

At4mo 2/17 (11.8%) 5/17 (29.4%) 

Median PFS days 60 117 

Pt # confirmed PSA decline 

> 30% 0 4 

> 50% 0 2 


12:00 PM-1:00 PM 

Association of idiotype vaccine-induced T-cell response with improved 

survival and time-to-next treatment (TTNT) in untreated mantle cell 

lymphoma (MCL). Presenting Author: Kieron Dunleavy, Metabolism Branch, 

National Cancer Institute, National Institutes of Health, Bethesda, MD 

Background: Murine models show Id-vaccines induce antitumor responses, 

possibly through Th1/Tc1 cytokines. We report an 11-year follow-up of 

Id-vaccine following DA-EPOCH-Rituximab in 26 untreated MCL patients. 

Methods: DA-EPOCH-R was administered q3 weeks � 6, followed 12 weeks 

later by 5 cycles of Id-vaccine. Id protein was made by hybridoma 

technology, conjugated to keyhole limpet hemocyanin (KLH) and administered 

with GM-CSF. Pre- and post-vaccine immune responses (IR) were 

tested in parallel: anti-Id and anti-KLH humoral responses (ELISA); 

anti-KLH cellular responses (intracellular cytokine assay); and anti-tumor 

cellular responses (cytokine induction, IFN� ELISPOT). Results: Characteristics: 

median age 57 (r 22-73), blastoid variant 15%, and MIPI (low-65%; 

intermediate-16%; high-19%). With 122 mo median follow-up (r 111- 

132), the median PFS is 24 mo and OS is 104 mo. MIPI was associated 

with OS (p�0.0002); median OS: low (not reached), intermediate (84 mo) 

and high (44 mo). We found no association between OS and anti-KLH IR, 

anti-Id humoral response, IFN� ELISPOT, or antitumor TNF� or IFN� 

responses. Normalized antitumor T-cell GM-CSF response (median �4.3 

vs. �4.3) was associated with OS of 79 mo vs. not reached, respectively 

(p�0.015 (unadj.) and p�0.045 (adj.)). MIPI (p�0.02) and GM-CSF 

(p�0.057) were independently associated with OS. TTNT (based on 

disease activity), correlated with antitumor GM-CSF response (p�0.018) 

but not MIPI and was independent of MIPI (GM-CSF; p�0.041). Correlation 

of pre-and post-treatment GM-CSF production suggested a priming 

effect. Tumor proliferation by GEP did not correlate with OS (n�14). 

Conclusions: Antitumor GM-CSF response was significantly associated with 

OS and TTNT, suggesting antitumor cellular immune response significantly 

delayed tumor growth. Antitumor GM-CSF response may serve as a 

surrogate biomarker for vaccine efficacy. Our results are consistent with 

recent data that T-cell GM-CSF production is required for breaking 

tolerance against self-antigens. Id vaccines may prolong survival of MCL 

following rituximab-based chemotherapy and should be further evaluated. 




12:00 PM-1:00 PM 

Safety and long-term maintenance of anti-HER2 immunity following 

booster inoculations of the E75 breast cancer vaccine. Presenting Author: 

Raetasha Sheavette Dabney, Brooke Army Medical Center, San Antonio, TX 

Background: We have completed accrual and are in the follow up portion of 

phase I/II clinical trials evaluating the E75 HER2 peptide vaccine. E75 has 

been proven safe, capable of stimulating HER2 immunity, and effective in 

decreasing breast cancer recurrence rates. During the conduct of this trial, 

it was noted that E75-specific immunity waned after the Primary Vaccine 

Series (PVS) which corresponded with late recurrences. To maintain 

long-term immunity, a voluntary booster program was started. Here we 

present analysis of the booster inoculations. Methods: The trial enrolled 

node-positive or high-risk, node-negative breast cancer patients (pts) with 

tumors expressing any level of HER2 (IHC 1-3�). HLA-A2/A3� pts 

comprised the vaccine group (VG), HLA-A2/A3- pts were followed as the 

control group (CG). The VG received 4-6 monthly inoculations of E75�GM- 

CSF. Volunteer booster program pts (BG) received inoculations every 6 

months after the PVS. Pts were monitored for toxicities, in vivo responses by 

local reactions (LR) and DTH, and in vitro responses measured by 

enumeration of E75 specific cytotoxic T lymphocytes. Results: 53 pts 

received at least 1 booster, 34 received 2, 24 three, 20 four, 12 five, and 8 

at least 6. 24% of pts had no local toxicity, 73% Grade 1 (G1), 3% G2. 

74% had no systemic toxicity, 35% G1, 1% G2. LRs increased significantly 

from the initial vaccine (R1) during PVS to each booster (B) (R1: 59.5�3.1 

v B1: 89.2�3.3, p�0.001; v B2: 95.15�5, p�0.001; v B3: 86.63�5.5, 

p�0.001; v B4: 83.26�4.6, p��0.001; v B5: 80.67�6.7, p�0.006; v 

B6: 78.75�9.4, p�0.04). Dimer values increased from the end of PVS to 

each post-booster value (pre B1:1.29�0.25 v post B1: 1.46�0.38; post 

B2: 1.41�0.4; post B3: 1.84�0.35; post B4: 2.23�0.4; post B5: 

1.94�0.31; post B6: 2.73�0.09, p�0.02). At median 60 months, the 

recurrence rate for BG was 3.8% vs 18.9% in the CG (p�0.01). 

Conclusions: Booster inoculations are well-tolerated and appear to assist in 

the maintenance of long term peptide-specific immunity. Boosted pts have 

improved recurrence rates. Based on the success of this program, we have 

incorporated the practice of booster inoculations in our current cancer 

vaccine trials. 


12:00 PM-1:00 PM 

Response to epidermal growth factor vaccine in patients with metastatic 

non-small cell lung cancer (NSCLC) after progressing to first-line therapy. 

Presenting Author: Diego Venegas, Universidad Peruana Cayetano Heredia, 

Lima, Peru 

Background: A direct correlation between anti–epidermal growth factor 

(EGF)antibody titers and survival was demonstrated in vaccinated patients 

with novel NSCLC advanced in Phase II studies. We show the results of 

treatment with anti-EGF vaccine in a cohort of patients with metastatic 

NSCLC after progressing to first line therapy. We evaluated immunogenicity, 

safety, treatment response and effect on survival. Methods: 12 patients 

with metastatic NSCLC after progressing to first-line therapy received anti 

EGF-vaccine alone or in combination with chemotherapy. Results: From 

October 2009 until August 2011, 12 patients started treatment with anti 

EGF vaccine; mean age 56.5 (42-79 y); 66.7% male; ECOG 0 and 1: 

41.7% and 58,3% respectively. Adenocarcinoma (50%), bronchioloalveolar 

(33.3%), adenosquamous (16.7%). Metastatic sites: lung (41.7%), 

pleura (25%), CNS (16.7%), Kidney (8.3%). In addition to chemotherapy 

previous used: radiotherapy (50%), surgery (41.7%), erlotinib (41.7%), 

bevacizumab (25%). The 50% patients received vaccine alone. The 83.3% 

of patients had titers 1/4000 sera dilutions or more (good responders). 

According to RECIST 1.1: CR: 8.3%, PR: 16.7%, SD: 41.7%, PD 25%. 

Median overall survival was 18.8 months (95% CI: 13.3- 24.4 m). Median 

progression-free survival was 7.3 months (95% CI: 6.4 -8.2 m). We found 

no statistically significant differences in OS and PFS when comparing 

vaccine alone or combined (p � 0.181 and p � 0.801). 75% of patients 

had adverse effect: more frequently were: 42.4% application site pain, 

15.1% fever and 10.38% chills, none of them serious. Conclusions: 

Vaccination anti EGF in patients with metastatic NSCLC after progressing 

to first line, alone or in combination, was safe and provoked an increase in 

anti-EGF antibody titers, produced clinical benefit, improved overall 

survival and progression free survival. 


12:00 PM-1:00 PM 

Phase I clinical trial of a genetically modified and oncolytic vaccinia virus 

GL-ONC1 with green fluorescent protein imaging. Presenting Author: Jesus 

Corral Jaime, Royal Marsden Hospital and Institute of Cancer Research, 

Sutton, United Kingdom 

Background: GL-ONC1 is a genetically engineered vaccinia virus attenuated 

by insertion of the RUC-GFP (Renilla luciferase and Aequorea green 

fluorescent protein fusion gene), beta-galactosidase (lacZ) and betaglucuronidase 

(gusA) reporter genes into the F14.5L, J2R (thymidine 

kinase) and A56R (hemaglutinin) loci. A phase I clinical trial of iv GL-ONC1 

was pursued to evaluate safety, tolerability, tumour delivery, neutralizing 

antibody development and anti-tumour activity. Methods: GL-ONC1 was 

administered to patients with advanced solid tumours at escalating doses 

(1�105 ,1�106 ,1�107 ,1�108 ,1�109 ,3�109 plaque-forming units 

(pfu) on day 1; 1.667�107 and 1.667�108 pfu on day 1-3 of a 28-day 

cycle) using a 3�3 dose escalation design. Green fluorescent protein (GFP) 

imaging was performed on skin rash and mucosal tumour lesions at 

baseline and after each cycle. Optional tumour biopsies were obtained for 

pharmacodynamic and viral delivery evaluation. Results: 27 patients (21 

males, median age 60 years) were treated. One of six patients at the 1x109 pfu dose level developed a dose-limiting, grade 3 rise in aspartate 

transaminase levels after a single infusion. Other reported adverse events 

(grade 1/2) included pyrexia (21), musculoskeletal pain (9), fatigue (8), 

nausea (7), and vomiting (4). Two patients developed skin rash during the 

first week of treatment, which appeared green by GFP and were positive to 

viral plaque assay (VPA). VPA of blood, urine, stool and sputum were 

negative for viral shedding in all but one patient who had positive shedding 

for 11 days. Increased neutralizing antibody titres were detected in all 

tested patients apart from one. Best response by RECIST was stable 

disease at 48 weeks (1), 24 weeks (3) and 8-12 weeks (5). A patient with 

squamous cell carcinoma of the tongue had a biopsy after 4 cycles which 

showed positive IHC staining of vaccinia virus. This is the first time that a 

virus is shown to be delivered to solid tumour after iv delivery. Conclusions: 

GL-ONC1 administered iv is well tolerated, with documented colonisation 

in patient tumour, and preliminary evidence of anti-tumour activity. 


12:00 PM-1:00 PM 

Association of breast cancer in men with exposure to 5-� reductase inhibitors: A 

RADAR report. Presenting Author: Steven M. Belknap, Department of Dermatology, 

Northwestern University Feinberg School of Medicine, Chicago, IL 

Background: Breast cancers in men (BCM) account for �1% of all breast 

cancers. Dihydrotestosterone (DHT) inhibits proliferation of normal and neoplastic 

mammary tissue and constrains the effect of estrogens. Finasteride (F) and 

dutasteride (D) are 5-� reductase inhibitors (5-�RIs) that reduce systemic and 

local dihydrotestosterone and cause gynecomastia in 1–3% of men. The package 

inserts for F and D state, “the relationship between long-term use of (finasteride/ 

dutasteride) and male breast neoplasia is currently unknown.” F and D are 

marketed for treatment of symptomatic benign-prostatic hyperplasia. F is 

marketed for treatment of androgenetic alopecia. Methods: To detect disproportionality 

in the FDA MedWatch dataset, we calculated the empiric Bayes 

geometric mean (EBGM) for association of BCM with F or D. We also calculated 

the attributable risk of BCM exposed to F or D among men at an urban academic 

hospital (Northwestern Memorial Hospital) and at a rural healthcare system 

(Marshfield Clinic). Results: In the MedWatch dataset, we identified 33 reports of 

F-associated BCM and 5 reports of D-associated BCM. For F–associated BCM, 

the EBGM was 58.95 (95% CI 24.47-81.76; p�0.0001). For D-associated 

BCM, the EBGM was 15.79 (95% CI 4.57-35.49; p�0.0001). The mean age 

for BCM after 5-�RI exposure was 70�11 years; 11/38 (29%) had gynecomastia. 

There were 38 cases of BCM associated with 5-�RI in the combined 

Northwestern and Marshfield cohort (see table below). Conclusions: We found a 

highly significant association between BCM and 5-�RI exposure in each of 6 

separate analyses (3 sources X 2 drugs), with an estimated 1 extra BCM per 564 

men exposed to 5-�RIs. We now plan to assess BRCA status and other risk 

factors. Given that 5-�RIs are marketed for control of lower urinary tract 

symptoms or for cosmetic purposes, it is not immediately obvious that use of 

finasteride or dutasteride for their labeled indications would provide any net 

benefit. 

Risk of breast cancer in men with 5-�RI exposure. 

Breast cancer 

Risk/ 

Yes No Total 1,000 

5-�RI exposure 38 17,161 17,199 2.21 

No 5-�RI exposure 576 1,319,183 1,319,759 0.436 

Total 614 1,336,344 

95% CI 

1,336,958 

Attributable risk per 1.77 (1.07–2.48) 

1,000 men 

Risk ratio 5.1 (3.6–7.0) 

Number needed to harm 564 

Chi-square 116.3 

p value p � 0.00001 


149s



12:00 PM-1:00 PM 

Effect of age on the pharmacokinetics of busulfan (Bu): An alliance study. 

Presenting Author: Jan Hendrik Beumer, University of Pittsburgh Cancer 

Institute, Pittsburgh, PA 

Background: Older acute myeloid leukemia (AML) and myelodysplastic 

syndrome (MDS) patients (pts) have been excluded from myeloablative 

regimens including agents such as busulfan because of the potential for 

non-disease related morbidity and mortality. Busulfan, often used as part of 

myeloablative regimens, is cleared in part by glutathione–S-transferase and 

CYP3A4. We hypothesized that busulfan clearance (BuCL) in the elderly 

(� 60 years) would be reduced compared to that in young patients 

(� 60 years), thus potentially explaining differences in tolerability. 

Methods: AML and MDS pts in three CALGB bone marrow transplant studies 

across a wide age range (17-74) were treated with a conditioning regimen 

using IV busulfan, dosed at 12.8 mg/m2 in CALGB studies 10503 and 

19808 and 6.4 mg/m2 in CALGB 100103. Blood samples were collected 

for determination of busulfan plasma pharmacokinetics (PK). Plasma 

busulfan was quantitated by LC-MS. BuCL was determined using noncompartmental 

modeling, and normalized to actual (ABW), ideal (IBW) and 

corrected (CBW) body weight (kg). Differences between age groups were 

examined using the Wilcoxon rank sum test. Results: A total of 185 pts were 

accrued and signed consent, of which 174 provided useable PK data. 

Twenty-nine pts �60 years old (median age 66.3) had a significantly higher 

mean BuCL vs those � 60 years old (median age 49.8); BuCL 263 vs 186 

mL/min, p�0.0002; BuCL/ABW 3.22 vs 2.34 mL/min/kg, p�0.0001; 

BuCL/IBW 3.63 vs 2.91 mL/min/kg, p�0.0035; BuCL/CBW 3.50 vs 2.70 

mL/min/kg, p�0.0005. Inter-patient variability in clearance (CV%) was up 

to 47% in the elderly and up to 48% in young patients. Phenytoin use, a 

potential confounder, did not affect BuCL, regardless of weight normalization 

(p�0.74). Conclusions: Contrary to our hypothesis, BuCL is significantly 

higher in pts �60 years old compared to younger patients and does 

not explain the previously reported increase in Bu toxicity observed in the 

elderly. 


12:00 PM-1:00 PM 

Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus 

epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced 

or metastatic gastric or esophagogastric junction (G/EGJ) cancer. 

Presenting Author: Min Zhu, Amgen Inc., Thousand Oaks, CA 

Background: R is an investigational, fully human monoclonal antibody to 

hepatocyte growth factor/scatter factor (HGF/SF), the only known MET 

receptor ligand. In a double-blind, placebo-controlled, phase 2 trial of 121 

pts with G/EGJ cancer, R (7.5 or 15 mg/kg) � ECX showed trends for 

improved overall survival (OS) and progression-free survival (PFS) compared 

to ECX alone (placebo, P). Methods: E-R analyses were performed 

using pharmacokinetic (PK), biomarker, efficacy, and safety data. A 

population PK model was used to evaluate covariate effects (eg, demographics, 

ECX, and MET status) on R PK and predict individual R exposure 

(trough steady-state Cmin [C]). The effect of C on OS/PFS was evaluated 

with Kaplan-Meier estimates and Cox proportional hazards models. Covariate 

effects for OS/PFS were evaluated with multivariate analysis. The 

relationships between adverse events of interest (AEs), lab values, and C 

were analyzed with descriptive statistics and linear regression models. 

Results: R showed linear PKs that were unaffected by ECX or MET levels. 

Pts who received R � ECX were divided into low C (C L ) and high C (CH ) 

groups by the median C (94 �g/mL). Median PFS was 4.2, 4.5, and 6.9 

months in the P, CL , and CH groups; median OS was 8.9, 9.5, and 13.3 

months. Improved OS/PFS in CH and improved PFS in CH and CL groups (vs 

P) were seen after adjusting for baseline covariates. Pts with tumors that 

expressed high MET levels (METHigh : � 50% cells positive) showed greater 

improvement in OS in the CH vs CL group. No improvement in OS was seen 

in METLow pts (CH and CL groups) compared to placebo (see Table). No 

relationship was seen between R exposure and AEs or lab values. 

Conclusions: Higher R exposure was associated with improved OS/PFS in 

METHigh pts without increased toxicity, supporting further study of R � ECX 

in G/EGJ cancer. 

C group N 

Median OS - 

mo (80% CI) 

Adjusted HR 


METHigh P 11 5.7 (4.5,10.4) - - 

CL 14 9.3 (8.0, 11.1) 0.50 (0.18, 1.39) 0.183 

CH 13 13.4 (13.3, NE) 0.12 (0.03, 0.45) 0.002 

METLow P 17 NE (8.5, NE) - - 

CL 15 8.6 (4.9, 9.9) 2.39 (0.90, 6.33) 0.081 

CH 20 11.6 (7.8, 12.5) 1.52 (0.59, 3.95) 0.389 

NE: Not estimable. 


12:00 PM-1:00 PM 

A first-in-human, phase I safety and pharmacokinetic study of genz- 

644282, a non-camptothecin topoisomerase I inhibitor, in patients with 

advanced solid tumors. Presenting Author: Hyo S. Han, H. Lee Moffitt 

Cancer Center & Research Institute, Tampa, FL 

Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and 

topotecan) are camptothecin derivatives. The lactone ring structure of 

camptothecins negatively impacts their clinical potential.Genz-644282 is 

a novel non-camptothecin that induces TopI-DNA cleavage complexes at 

similar as well as unique genomic positions; that are more persistent. This 

study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) 

model to predict the maximum tolerated dose (MTD). Methods: A PK-PD 

relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, 

Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 

patients received 3 weekly doses of Genz-644282 on a 28 day schedule 

starting with 0.5 mg/m2 . After MTD on the 28 day schedule was exceeded, 

21 day schedule was initiated. Results: 49 patients (N�44 data available: 

26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small 

cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from 

the PK-PD model 8 cohorts were evaluated on the 28 day schedule before 

defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and 

21 day schedules, respectively. Dose limiting toxicities that determined the 

MTD were: gr 4 thrombocytopenia (n�2); gr 2 thrombocytopenia (n�1) 

and gr 4 neutropenia (n�1) both of which resulted in �72h delays in 

initiating cycle 2. Treatment emergent adverse events (�10%) were 

nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting 

(23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), 

hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) 

and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 

minor response;1 complete response), and 2 patients (breast, gastric) with 

stable disease (� 6 months). PK data show a Genz-644282 half-life of 

approximately 50 h, a linear dose-exposure relationship, and no accumulation 

in between doses. Conclusions: Genz-644282 is a non-camptothecin 

TopI inhibitor in phase I development with ongoing expansion phase. The 

emerging pk, efficacy and safety data are suggestive of a distinct clinical 

profile of Genz-644282 from the camptothecins. 


12:00 PM-1:00 PM 

Pharmacological interactions of TKIs with the P-gp drug transport protein. 

Presenting Author: Sandra Roche, NICB, Dublin City University, Dublin, 

Ireland 

Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug 

transport proteins. P-gp is a transporter with two important roles in cancer 

drug therapy. If overexpressed in tumour cells it can cause drug resistance. 

However, P-gp, expressed in tissues as part of normal drug clearance 

mechanisms, is also involved in termination of drug action. Hence, 

TKI-mediated interactions with P-gp have significant therapeutic consequences. 

Methods: P-gp over-expressing cancer cell lines were used to 

determine the inhibitor or substrate status of tyrosine kinase inhibitors 

(erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). 

Cell proliferation assays in combination with a potent P-gp inhibitor, or 

P-gp substrate were also employed. Findings were augmented using 

LC-MS-based quantitation of cellular levels of target drugs. Results: We 

summarise our findings of four distinct interactions with P-gp among 

various TKIs. Some agents have little interaction at conventional doses; 

others can act as P-gp inhibitors without being substrates; substrates 

without being inhibitors or substrates which also prevent the actions of the 

transporter.Eachof the investigated TKIs has a distinct relationship with 

P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is 

a substrate but not an inhibitor, while pazopanib has little interaction with 

P-gp. Other agents also have an effect on or are affected by P-gp to varying 

amounts with some of these interactions likely to be suprapharmacological. 

Conclusions: P-gp protein has important roles both in resistance and drug 

toxicology, hence, a clear understanding of the interaction of emerging 

drugs with this transporter is vital. Agents which are inhibitors of P-gp may 

have applications in drug resistance circumvention but may also greatly 

exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; 

conversely the activity of P-gp substrate TKIs may be reduced by 

tumour overexpression of the transporter. Hence in vitro screening of 

TKI-transporter interactions may identify putative TKI resistance mechanisms, 

help guide the development of combination schedule trials and/or 

reducing unwanted treatment side effects. 




12:00 PM-1:00 PM 

Pharmacogenetic study in metastatic colorectal cancer (CRC) patients 

receiving third-line panitumumab-irinotecan: A GERCOR ancillary study. 

Presenting Author: Marie-Christine Etienne-Grimaldi, Centre Antoine- 

Lacassagne, Nice, France 

Background: Test the predictive value of gene polymorphisms potentially 

linked to panitumumab and irinotecan pharmacodynamics. Methods: 45 

patients with metastatic CRC refractory to standard therapy were enrolled 

in this ancillary pharmacogenetic study as part of a phase II trial that 

included 63 patients. Inclusion required wild-type KRAS tumor status 

(codons 12-13, analyses performed in each center). After inclusion, central 

KRAS re-assessment was performed (codons 12-13-59-61) and 9 patients 

over 45 were found to carry a KRAS mutation. Patients received panitumumab 

(6 mg/kg, day 1) associated with irinotecan (180 mg/m2 , day 1), 

Q2W until disease progression or unacceptable toxicity. Analyzed polymorphisms 

on blood DNA were : EGFR (CA repeats in intron 1, -216G�T, 

-191C�A), EGF (61A�G), CCND1 (870A�G), UGT1A1 (*28). Results: 

Cutaneous toxicity imputable to panitumumab i.e. folliculitis and paronychia 

was not linked to EGFR, EGF or CCND1 polymorphisms. Diarrhea 

(12 grade 1, 13 grade 2, 8 grade 3) was linked to CCND1 polymorphism: 

22% grade 2-3 in AA patients vs 63% in AG�GG patients (p � 0.007). As 

expected, neutropenia (6 grade 1, 4 grade 2, 5 grade 3) was more frequent 

in patients bearing the *28 allele of UGT1A1 gene (33% grade 2-3 vs 5% 

in *1/*1, p � 0.020). In these 45 patients, response rate, progression-free 

survival and overall survival (OS) were only significantly related to reassessed 

KRAS status. Of note, a tendency for a longer OS was observed in 

patients bearing the *28 allele of UGT1A1 gene (p � 0.091, analysis 

adjusted for KRAS). Interestingly, the frequency of KRAS mutation was 

higher in patients with long CA repeats in EGFR gene intron 1: 54.5% i.e. 6 

mutated patients among the 11 patients with both alleles �17 vs 10.5% 

i.e. 2 mutated patients among the 19 patients with intermediary alleles vs. 

6.7% i.e. 1 mutated patient among the 15 patients with both alleles �17 

(p � 0.004). Conclusions: Present data indicate that A870 allele of CCND1 

gene (40% AA patients) may protect from diarrhea induced by panitumumab-irinotecan. 

Also, these results report an original relationship 

between EGFR polymorphism in intron 1 and KRAS mutation status that 

merits further confirmation. 

2539 General Poster Session (Board #1B), Mon, 8:00 AM-12:00 PM 

Phase Ib study of plitidepsin (APL) with gemcitabine (GEM) in refractory 

solid tumors and lymphoma patients. Presenting Author: Mark N. Stein, 

Cancer Institute of New Jersey, New Brunswick, NJ 

Background: Combination chemotherapy (CT) regimens may improve the 

outcome of patients with advanced metastatic disease. APL (a marinederived 

cyclodepsipeptide) is a cytotoxic agent that induces apoptosis by 

JNK-pathway activation and increased oxidative stress; it has also shown 

anti-angiogenic properties in vitro. GEM has a different mechanism of 

action and toxicity profile from APL, making this combination appropriate 

for clinical testing. Moreover, APL has been shown pre-clinically to 

potentiate the anti-tumor effect of GEM. Methods: Patients with ECOG-PS 

� 1 received escalating doses of APL/GEM (1.8/750, 1.8/1000, 2.4/1000 

and 3.0/1000 mg/m2 ) on days 1, 8 and 15 every four weeks. The primary 

objective was to determine of the maximum tolerated dose (MTD) and the 

recommended dose (RD) for APL/GEM. Secondary objectives included 

characterization of safety profile, pharmacokinetics (PK) and anti-tumor 

activity of APL/GEM. Results: 34 patients were included and 33 treated (23 

solid tumors and 11 lymphomas) with a median age of 59 years (r: 28–86), 

median prior CT lines 3 (r:1-7) and a median of 2 cycles (r:1-12). Relative 

dose intensity was 66.7% (r: 37.7-85.7%) and 80.9% (r: 56.1-100.6%) 

for APL and GEM, respectively. The MTD was 3.0/1000 mg/m2 ,as2/6 

patients experienced dose limiting toxicities (DLTs) [grade (G) 4 thrombocytopenia 

and 2 missed doses due to G2 ALT/AST]. The RD was 2.4/1000 

mg/m2 , with no patients experiencing DLTs. Adverse events (AEs) were 

mainly G 1-2 anemia, thrombocytopenia and ALT/AST increase. Six 

patients with solid tumors had stable disease (SD) � 3 months, one patient 

with NK T-cell lymphoma had a complete response, a patient with Hodgkin 

disease (HD) had a partial response and three other patients with HD had 

SD � 3 months with tumor decrease at the RD. No relevant drug-drug 

interaction was observed for the dose levels tested. Conclusions: APL/GEM 

at the RD can be safely combined. Objective responses were observed in 

patients with HD and NK T-Cell lymphoma. Further studies of this 

combination in lymphoma are warranted. 

151s 

2538 General Poster Session (Board #1A), Mon, 8:00 AM-12:00 PM 

A mismatch between methods and objectives in phase I drug development: 

Statistical limitations and personalized medicine—A California Cancer 

Consortium (CCC) study. Presenting Author: Paul Henry Frankel, City of 

Hope, Duarte, CA 

Background: Patient variation in drug response and toxicity impacts all 

phases of drug development. While detailed sample-size calculations and 

analysis based on statistical methodology are critical for addressing 

variation in late stage trials, phase I studies pose unique and largely 

unsolved challenges related to variability. Changes in patient selection 

during the study, small sample-sizes and large patient variation in toxicity 

are exactly the kind of problems that statistical methods cannot address in 

small, isolated phase I studies, regardless of apparent mathematical rigor. 

We have documented these problems via a physician survey. Methods: A 

10-question anonymous survey was sent to 670 oncologists at National 

Comprehensive Cancer Network (NCCN) and CCC institutions via an online 

survey. 19 % (126/670) of the oncologists polled responded. 78/126 

(62%) specialized in Medical Oncology. The number of years in practice 

varied from 2-45 yrs with a median of 17 yrs. Results: a) 66% of all 

respondents stated that non-DLT toxicities on one dose level would impact 

their patient selection on the following dose level, conflicting with the 

assumption of random patient selection implicit in simulations used in 

evaluating statistical designs. b) Only 13% stated a desire to target a 

non-heme toxicity as high as 20% grade 3, while 87% desired a 10% or 

less grade 3 rate; c) More than half the respondents would prefer not to 

escalate if 3/3 patients experienced grade 2 LFTs; d) 82% of the 

respondents thought the appropriate target toxicity differed for patients 

depending on their potential for becoming a surgical candidate, furthering 

the need for personalized dosing. Conclusions: Statistical methods in phase 

I trials are unable to address many of the salient features of phase I study 

conduct and investigator goals. We will present several approaches we have 

initiated to address these limitations, and present future plans to help 

produce a more reliable estimate of a recommended dose. Supported in 

part by NCI grants U01CA062505, N01-CM-62209, and NCCN data 

collection assistance. 

2540 General Poster Session (Board #1C), Mon, 8:00 AM-12:00 PM 

Prediction of early death among patients (pts) enrolled in phase I trials: 

Development and validation of a new model based on platelet count and 

albumin level. Presenting Author: Anne Ploquin, Centre Oscar Lambret, 

Lille, France 

Background: Selecting pts with “sufficient life expectancy” for phase I 

oncology trials remains challenging. The Royal Marsden Model (RMM; 

Arkenau, JCO 2009) identified high-risk pts as those with �2 of: albumin 

(ALB) �35g/l; LDH �ULN; more than 2 metastatic sites. The RMM was 

assessed in 1845 pts treated in phase I trials by members of the European 

New Drug Development Network (ENDDN). The present study aimed to 

develop an alternative prognostic model using a different methodology and 

to compare its performance with the RMM. Methods: The primary endpoint 

was 90-day mortality rate (90-DMR). The new model was developed from 

the ENDDN database using CHAID, an exploratory non-parametric data 

analysis method evaluating the relationship between a dependent variable 

(90-DMR) and possible predictive variables through a decision-tree analysis. 

The ROC characteristics and calibration of both methods were then 

validated in the independent EORTC Database (n�341 pts). Results: The 

CHAID method identified low and high-risk groups with 90-DMR of 9.5% vs 

37.5%. High-risk pts had ALB�33g/L or ALB�33g/L but platelet count 

�400.000/mm3 . Applying both models to the validation dataset; the rates 

of correctly-classified pts were 0.86 [CI-95% 0.82-0.90] vs. 0.67 [CI-95% 

0.60-0.74], with the CHAID model and RMM respectively. The CHAID 

model had higher specificity (0.90 vs. 0.65), but lower sensitivity (0.36 vs. 

0.93) than the RMM. Discriminative slopes were similar for the CHAID 

model and RMM (19.4% and 19.3%, respectively). The negative predictive 

value (NPV; correct identification of pts surviving 90 days) was similar for 

the CHAID model and RMM (0.94 [0.91-0.97] and 0.99 [0.94-1.00] 

respectively). Calibration, assessed by the Brier score, was slightly better 

with the CHAID model (0.001 and 0.098, respectively). Conclusions: In 

selecting pts for phase I trials arguably an important criterion is NPV; the 

CHAID model and RMM provided a similar high level of NPV but the CHAID 

model gave a better rate of correctly-classified patients. Both models 

improved the screening process and reduce the attrition rate in phase I 

trials. 



2541 General Poster Session (Board #1D), Mon, 8:00 AM-12:00 PM 

Relationship of variability in tumor measurement and response assessment. 

Presenting Author: Binsheng Zhao, Department of Radiology, Columbia 

University Medical Center, New York, NY 

Background: RECIST is widely used to evaluate anti-cancer therapy efficacy. 

This study explored variability in reporting tumor change and 

response to therapy due to both target lesion selection and measurement. 

Methods: 2256 measurements were performed in CT scans of chest, 

abdomen and pelvis from 30 patients retrospectively taken from a multicenter 

Phase II/III colorectal clinical trial. Using RECIST, three radiologists 

interpreted baseline, 6-wk and 12-wk scans in the following manner: (1) 

Radiologists independently selected and measured target lesions, (2) one 

radiologist’s target lesions were re-measured by the other two and (3) one 

radiologist re-measured the same scans in the above manner at an interval 

of greater than a month to prevent memory recall. Measurement variability 

in total tumor burden (TTB) on relative changes at 6-wk and 12-wk from 

baseline was analyzed for inter- and intra-reader target lesion selection, 

inter- and intra-reader measurement using Bland-Altman method, and 

agreements on RECIST categorical responses were assessed by kappa 

coefficient. Results: When the same target lesions were used, inter- and 

intra-reader variability in TTB on relative changes at 6-wk and 12-wk from 

baseline were similar; all had 95% limits of agreement within (-15%, 

15%). Kappa coefficients for RECIST were 0.74 (6-wk) and 0.87 (12-wk) 

for inter-reader and 0.64 (6-wk) and 0.88 (12-wk) for intra-reader to report 

responses. When radiologists independently selected and measured target 

lesions, variability in relative changes was within (-17%, 16%) at 6-wk and 

(-24%, 23%) at 12-wk for inter-reader and (-16%, 16%) at 6-wk and 

(-14%, 18%) at 12-wk for intra-reader interpretations. Kappa coefficients 

were 0.66 (6-wk) and 0.75 (12-wk) for inter-reader and 0.63 (6-wk) and 

0.80 (12-wk) for intra-reader to report responses. Conclusions: Differences 

exist in measuring tumor change. The magnitude of change in categorical 

RECIST response is quantifiable. The largest differences are when radiologists 

independently select and measure target lesions, the smallest when 

one radiologist repeats measurements on identical target lesions. The 

variability may impact the reporting of categorical responses and trial 

results, especially in a single arm study. 

2543 General Poster Session (Board #1F), Mon, 8:00 AM-12:00 PM 

Clinical importance of including new and nontarget lesion assessment of 

disease progression (PD) to predict overall survival (OS): Implications for 

randomized phase II study design. Presenting Author: William Leonard 

Mietlowski, Novartis Oncology, Florham Park, NJ 

Background: Fridlyand (2011) retrospectively compared PFS vs. change in 

tumor burden as a primary endpoint in phase II non-small cell lung cancer 

(NSCLC) trials to inform phase III decision making and found the use of 

PFS was superior. Since the classic tumor burden model only uses 

measurements of target lesions, we investigated whether the model could 

be strengthened by incorporating new and non-target lesion progression. 

The ability to use a strong tumor burden model has the benefit of potentially 

earlier decision making and considerable timeline savings. Methods: We 

analyzed five phase III trials of combination chemotherapy � targeted 

therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, 

-2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line 

ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards 

model to OS using the covariates of baseline tumor burden, 1st tumor 

assessment percentage change from baseline, new lesions, and non-target 

PD. Results: See table. Conclusions: We show that predictive models for OS 

should consider new and non-target lesions for PD, as well as target lesion 

tumor burden, findings independently corroborated by Suzuki (2011). We 

propose a longitudinal rank-based randomized phase II design, ranking a 

patient’s risk of death, differentially weighting PDs by type and time of PD, 

and percentage change in tumor burden. This may be more informative for 

phase II decision making for phase III trials based on OS, than PFS which 

only uses time of PD. Further studies with other tumor types and treatment 

modalities are warranted. 

Study 

Baseline 

tumor burden* 

Estimated hazard ratio (Wald test p value) 

% change 

from baseline* New lesion 

Non-target 

lesion PD 

ATTRACT-1 1.36 (p�0.001) 1.37 (p�0.001) 3.37 (p�0.001) 1.95 (p�0.001) 

ATTRACT-2 1.21 (p�0.001) 1.49 (p�0.001) 3.91 (p�0.001) 1.19 (p�0.332) 

EPO906A2303 1.09 (p�0.053) 1.12 (p�0.046) 2.20 (p�0.001) 1.67 (p�0.001) 

CONFIRM-1 1.31 (p�0.001) 1.38 (p�0.001) 3.02 (p�0.001) 1.40 (p�0.087) 

CONFIRM-2 1.41 (p�0. 001) 1.47 (p�0.001) 2.54 (p�0.001) 1.81 (p�0.001) 

* Unit of measurement is one standard deviation. 

2542 General Poster Session (Board #1E), Mon, 8:00 AM-12:00 PM 

A multicenter phase II neoadjuvant trial of bevacizumab combined with 

docetaxel plus carboplatin in the treatment of triple-negative breast cancer: 

Korean Cancer Study Group (KCSG-BR 0905, NCT 01208480). Presenting 

Author: Hye Ryun Kim, Division of Medical Oncology, Department of 

Internal Medicine, Yonsei University College of Medicine, Seoul, South 

Korea 

Background: Triple negative breast cancer (TNBC) is dismal disease that is 

ineligible for endocrine or anti-HER2 therapy. We have conducted a phase 

II neoadjuvant trial to evaluate efficacy and tolerability of bevacizumab 

combined with docetaxel plus carboplatin in TNBC. Methods: Women with a 

histologically confirmed stage II or III TNBC were eligible. Hormone 

receptors and HER2 negativity were confirmed by immunohistochemistry 

and/or fluorescence in situ hybridization. Patients received 6 cycles of 

docetaxel 75 mg/m2 , carboplatin AUC 5, and bevacizumab 15 mg/kg on 

day1 every 21 days. Bevacizumab was omitted in the last cycle to avoid 

wound complication. The primary endpoint was pathologic complete 

response (pCR) rate in both breast and axillary lymph node and secondary 

endpoints were clinical response rate, toxicity profiles, and breast conserving 

surgery (BCS) rate. Results: Forty-five TNBC patients were recruited 

from 7 institutes in the Korean Cancer Study Group (KCSG) between 

October 2010 and August 2011. The median age of the patients was 45 

years (30-72 years). The T1, T2, and T3 were 4.4 %, 68.9 %, and 26.7 %, 

respectively and axillary lymph node was positive in 80% by breast MRI. 

Among 45 patients, 44 patients completed 6 cycles of therapy followed by 

surgery and one patient was withdrawn due to patient’s refusal of further 

therapy after 3rd cycle. The pCR rate was 42.2 % (19/45) and clinical 

response rate was 95.5 % (43/45) (CR, n� 6; PR, n�37; SD, n�1; not 

evaluable, n�1) based on RECIST criteria 1.1. BCS was undertaken in 

77.7 % (35/45). The grade 3 or 4 adverse events were neutropenia (38), 

febrile neutropenia (4), vomiting (3), nausea (2), anemia (1), thrombocytopenia 

(1), stomatitis (1), gastrointestinal bleeding (1), and increased ALT 

(1). Only one patient experienced delayed wound healing after breast 

surgery. Conclusions: Bevacizumab in combination with docetaxel and 

carboplatin as neoadjuvant treatment provided an encouraging pCR rate 

(42.2 %) and a negligible wound healing problem after surgery. The 

adverse events were manageable. 

2544 General Poster Session (Board #1G), Mon, 8:00 AM-12:00 PM 

How to run survival-endpoint phase II trials with 25% to 40% fewer 

patients. Presenting Author: Michael J. Schell, H. Lee Moffitt Cancer 

Center & Research Institute, Tampa, FL 

Background: New molecular information, whether arising from expression 

profiling, identification of key mutations, or proteomic analyses is making 

the personalization of therapy increasingly feasible. This leads to the 

fragmentation of common disease entities into multiple molecular subtypes. 

Having sufficient numbers of patients to demonstrate the effectiveness 

of novel targeted therapies for each subtype has therefore become 

challenging, essentially impeding progress. Methods: Use of sample size 

determination software allows for comparison of phase II trials with a target 

survival proportion at a given time T based upon Kaplan-Meier versus 

exponential survival methods. Results: The use of exponential survival 

fitting methods, in lieu of the currently implemented trial designs, to single 

arm phase II studies can routinely reduce patient numbers by 25-40% 

(Table) without compromising the statistical power. The biggest advantage 

is that survival information both before and after time T reduces the 

variability for the exponential fit estimate. This approach will lead to the 

saving of financial and patient resources for researchers. Moreover, the 

time saved will accelerate the approval of agents making the proposed trial 

designs ethically attractive. However, this approach is only applicable if the 

exponential distribution assumption behind the approach is valid. 

Conclusions: The exponential survival fitting method should replace the 

current standard approach in all instances unless the exponential distribution 

assumption is known to be false. Detailed examples and analysis will 

be presented. 

Percent savings obtained by using the exponential fit approach. 

(T,T*) 

HR (1,1) (2,2) (3,3) (4,4) (1,1.5) (1,2) (2,3) (2,4) 

2.0 5 15 25 36 30 41 31 38 

1.83 8 15 26 40 31 42 30 36 

1.67 9 12 28 38 32 42 28 33 

1.50 6 16 23 38 30 40 30 36 

Avg. 7 14 26 38 31 41 30 36 

T is scaled so T�1 is the median survival time; T* is the time through which the 

exponential fit is used; HR is the ratio of the alternative to null hypothesis 

median survival times. 




Feasibility and safety of sequential research-related tumor core biopsies in 

clinical trials with anti-angiogenic and targeted therapies. Presenting 

Author: Jung-min Lee, Medical Oncology Branch, Center for Cancer 

Research, National Cancer Institute, Bethesda, MD 

Background: There has been increasing interest in serial/paired research 

biopsies (bx) in studies of molecularly targeted therapies. Definition of 

optimal target tissue and patient characteristics for safe and feasible 

research tumor bx in the era of anti-angiogenic and targeted therapies is 

needed. Methods: IRB-approved review of retrospective clinical data 

including patient demographics, pre-and post-procedure and recovery 

notes, and radiographic bx images. The cohort consisted of 142 pts 

scheduled for serial bx enrolled in phase 1 (5) and phase 2 (1) studies. 

Tumor core bx were obtained percutaneously under local anesthesia using a 

16 or 18g needles under US or CT visualization by interventional radiologists. 

Results: Paired tumor core bx were collected in 96 pts (68%) and 

baseline only in 42 pts (32%). Bx were aborted in 4 pts due to cystic mass 

(3) and safety (1). 132 pts were female and 10 pts were male, median age 

56 yrs (27-78), median BMI 25.8 (14.4-46.2), ECOG PS 0-2, and normal 

end-organ function. All pts had recurrent metastatic cancers (gynecologic 

121, breast 6, sarcoma 5, melanoma 4, colon 2, adrenal 1, mesothelioma 

1, RCC 1, papillary thyroid ca 1). 67 pts (51%) were on bevacizumab 

(bev)-based therapy at the time of their 2nd /3rd bx (bev � sorafenib; bev � 

dasatinib); others received gefitinib (27), imatinib (23), vandetinib (9), or 

olaparib � carboplatin (16). Median tumor size was 2.7cm (1-14.5cm). Bx 

sites were abd/pelvic masses 42, liver 40, lymph nodes 42, abd/chest wall 

12, lung 4 (3 pleural, 1 parenchymal), and psoas muscle 1. Minor 

complications were observed in four pts (3%; uncomplicated liver subcapsular 

hematoma [1]; vasovagal syncope responding to fluids [2]; uncomplicated 

pneumothorax without intervention [1]) and there were no major 

complications. The median number of tumor cores was 3 (1-6) at the 

baseline, 2nd (during or at the end of the first cycle) and 3rd time point 

(during cycle 2). Conclusions: Core needle bx of deep internal lesions such 

as intra-abdominal masses and retroperitoneal lymph nodes can be 

obtained percutaneously under imaging guidance. Sequential tumor bx are 

feasible and safe for pts on anti-angiogenic and chemotherapeutic agents. 


Predictive model for survival and toxicity in early-phase trials in hematology. 

Presenting Author: Rahima Jamal, University of Montreal, Montreal, 

QC, Canada 

Background: Strict criteria are used to limit toxicity for patients (pts) 

enrolled in phase I/II clinical trials, but the ability to survive beyond 12 

weeks, a common inclusion criterion, is subjective and error-prone. A 

prognostic score with 3 variables was designed and validated as an 

independent predictor of OS in pts with solid tumors included in phase I 

trials (Arkenau, JCO 2009). We examined the ability of objective measures 

to predict OS and risk of grade �3 toxicity in pts with hematologic 

malignancies enrolled in early-phase trials. Methods: A retrospective 

analysis was conducted on 290 pts in Phase I (79 pts) and II (211 pts) 

trials from the NCIC - Clinical Trials Group and our institution from 1995 to 

2009. Only pts with survival data up to 90 days were included. Univariate 

model (UVA) was used to identify factors significantly associated with OS. A 

Cox proportional hazards model (MVA) included all factors identified from 

the UVA. Six prognostic factors were identified in the MVA, and each 

assigned a score of 0 or 1. Pts were categorized as high or low risk based on 

the total scores that they received, �3 were assigned to the high risk group, 

and a �2 to the low risk group. Kaplan-Meier method was used to generate 

the survival distribution for the high and low risk groups. Multivariate 

logistic regression was used to identify the risk factors for grade �3 toxicity. 

Results: The overall median survival was 238 days (95% CI 237 to 331), 

and 27% of pts had grade � 3 toxicity. In the MVA, albumin (alb), alkaline 

phosphatase (ALP), lactate dehydrogenase (LDH), lymphocytes, platelets 

(plts) and diagnosis were significantly associated with OS. Pts in the low 

risk group had a median survival of 10.6 months, relative to 2.4 months 

among pts in the high risk group. Survival at 90 days was 80% in lower risk 

vs. 36% in the high risk group. In addition, the MVA for toxicity showed that 

alb, ALP, LDH, plts and performance status were significantly associated 

with grade �3 toxicity. Conclusions: Our model predicts OS, 90 day survival 

and risk of grade � 3 toxicity among pts with hematologic malignancies 

entered in Phase I/II trials. Future work will include a linear predictor score 

based on MVA to refine the prediction model. The model will also be 

validated using another dataset. 

153s 


Phase I immunotherapy trial using glioblastoma apoptotic body-pulsed 

dendritic cells. Presenting Author: Christopher L. Moertel, University of 

Minnesota, Minneapolis, MN 

Background: We recently reported that tumor cell vaccines cultured in 5% 

oxygen (O2) had enhanced the immunogenicity relative to those grown in 

standard atmospheric O2. In order to develop an “off-the-shelf” source of 

whole cell antigen we screened a panel of primary glioblastoma (GBM) cell 

lines, leading to identification of (GBM6) as an ideal candidate. GBM6 was 

extensively characterized and shown to express glioma-associated antigens 

(IL13Ra2, Sox2, Epha2, etc.). A Phase I clinical trial was initiated to 

evaluate the safety and feasibility of a vaccine consisting of dendritic cells 

(DC) pulsed with apoptotic bodies from GBM6 grown in 5% O2. Methods: 

Patients ranging from 3 to 71 years with recurrent GBM (n�6) or 

ependymoma (n�1) were enrolled. Monocytes were collected via apheresis, 

matured into DC and pulsed with apoptotic bodies derived from GBM6. 

The first three patients received escalating doses of DC (5x106 , 10x106 , 

and 15x106 ), the remainder received 15 x 106 DC. Pulsed dendritic 

cellswere injectedsubcutaneously into the supra-scapular region. Imiquimod 

cream was applied at the injection site just prior to vaccination and 

24 hours later. The vaccine schedule dictated administration every 2 weeks 

for 8 weeks (total of 5 doses) then monthly to progression or a total of 52 

weeks. Prior to each vaccination, patients met eligibility parameters and 

had no progression on MRI. Patients were imaged monthly and blood was 

drawn to evaluate toxicity and immune response. Results: No vaccinerelated 

toxicity has been reported. Time to progression ranges from 6.5 

weeks for the patient treated at the first dose level to 35 weeks for one 

patient receiving 15 x 106 DC. The latter patient experienced a partial 

response at 20 weeks. Two patients have stable disease at 18.5 and 28 

weeks, respectively. One patient was not evaluable. Flow cytometric 

analysis demonstrated expansion of central memory T cells amidst declining 

effector memory cells following vaccination in three patients at a dose 

of 15x106 DC. Conclusions: Apoptotic body-pulsed DC vaccination was well 

tolerated and preliminarily demonstrated clinical activity but a minimum of 

15x106 DC was required for a modulation of central memory T cells. 


Difference between duration of treatment (DOT) and progression-free 

survival (PFS) as a marker of unbalanced censoring. Presenting Author: 

Laleh Amiri-Kordestani, National Cancer Institute, National Institutes of 

Health, Bethesda, MD 

Background: In the conduct of randomized trials Kaplan and Meier 

envisioned rates of censoring as similar between arms, providing accurate 

assessment of clinical trial results. Censoring is used when patients 

withdraw consent, leave study due to toxicity, or reach data cut-off without 

disease progression or death. Censoring can lead to erroneous conclusions 

as it can be either beneficial or detrimental to the arm under study. Such 

censoring can also explain how a statistically valid difference in PFS 

“disappears” when overall survival (OS) is examined. We hypothesized that 

censoring, especially that due to toxicity, would lead to a discrepancy 

between DOT and PFS since two different patient populations would be 

scored. Methods: We reviewed all phase III randomized studies of drugs 

approved by FDA since 2005 for pts with metastatic solid tumors, looking 

for DOT and PFS. We used standard statistical analyses using SAS. Results: 

We identified 55 Phase III studies conducted with abiraterone, axitinib, 

bevacizumab, cabazitaxel, cetuximab, eribulin, erlotinib, everolimus, ipilimumab, 

ixabepilone, lapatinib, panitumumab, pazopanib, sorafenib, 

sunitinib, temsirolimus and vandetinib. DOT was not provided in 27%. 

Forty-four comparisons (88 arms) were included in the analysis. The 

median PFS, DOT, delta PFS (difference in PFS between experimental and 

control arms) and delta DOT were: 161, 126, 51 and 36 days, respectively. 

The slopes of PFS vs DOT and delta PFS vs delta DOT were 1.16 and 1.03, 

respectively close to the ideal of 1.0. Five trials fell above the 90% CI 

boundary with delta PFS/delta DOT of 3 to 36, including two everolimus 

studies (PNET and breast cancer) two sunitinb studies (RCC and PNET) 

and one bevacizumab study (E2100, breast cancer). Conclusions: PFS and 

DOT as well as delta PFS and delta DOT should be concordant. The most 

likely explanation for a discordance between these values is toxicity-driven 

censoring and its occurrence raises concerns regarding the degree of 

efficacy. A greater utilization of “Time to Treatment Failure”, an endpoint 

that includes toxicity in its definition would be valuable in oncology trials, 

particularly those with high levels of toxicities. 




Recommendation of dose banding of cytotoxics according to pharmacokinetic 

criteria. Presenting Author: Etienne Chatelut, Institut Claudius 

Regaud, Toulouse, France 

Background: Dose-banding has been recently suggested in order to optimize 

chemotherapy preparation. Ranges (or bands) of body surface area (BSA) 

are predefined. The individual dose of a particular patient is calculated 

according to a single BSA value per band, usually the mid-point of the BSA 

band in which the actual BSA of the patient lies. Thanks to this simple 

procedure, chemotherapy provision can be rationalized and chemotherapies 

can be prepared in advance for drugs with sufficient long-term drug 

stability. The primary purpose of dose-banding is to reduce patient waiting 

time and improve capacity planning of the pharmacy production, but 

additional benefits can also be found, such as reduced potential for 

medication errors, reduced drug wastage, and prospective quality control of 

preparations. The objective of this analysis was to compare dose-banding to 

individual BSA-dosing (current practice) according to pharmacokinetic 

(PK) criteria. Methods: Dose-banding was defined according to three bands 

of BSA: BSA�1.7m², 1.7m²�BSA�1.9m², and BSA�1.9m² for which the 

values of 1.55m², 1.80m², and 2.05m² were allocated, respectively. By 

using individual actual values of clearance of six drugs (cisplatin, docetaxel, 

paclitaxel, doxorubicin, topotecan, and irinotecan) from a total of 

1,206 adult cancer patients, the AUCs corresponding to the two dosing 

methods were compared to a target value of AUC for each drug. Results: 

Over all 6 drugs, by using dose-banding the percent change of individual 

dose in comparison with BSA dosing ranged between -14% and �22%. In 

terms of capacity to attain the target AUC, there was no significant 

difference in precision when using dose-banding as compared to BSAdosing 

for all drugs except paclitaxel (precision of 23.2% versus 21.8%, 

respectively). For all drugs including paclitaxel, distributions of AUC values 

were very similar with both dosing methods. Conclusions: For these 6 drugs 

and maybe others, dose-banding may be implemented without any risk of 

increasing interindividual plasma exposure. Dose-banding would make it 

possible to anticipate chemotherapy preparation and analytical control 

without any delay for the patients. 


Thymidylate synthase genotype specific dosing of capecitabine: Proof of 

concept phase I study. Presenting Author: Ross A. Soo, National University 

Cancer Institute, Singapore 

Background: Thymidylate synthase (TYMS) is the target of fluoropyrimidines 

(FP). TYMS 3R3R is the predominant genotype in East Asian (EA) patients 

and is associated with increased TYMS expression, reduced FP related 

toxicity and relative FP resistance. Dose finding studies for FP were 

developed in Caucasians, a population that typically harbors TYMS 2R2R 

and 2R3R genotypes. We hypothesize the recommended phase II dose 

(RP2D) of capecitabine is higher in 3R3R and similar for 2R allele carriers 

compared to the FDA approved dose. Objectives 1) To determine the 

maximal tolerated dose (MTD) and RP2D of capecitabine in EA patients 

with advanced stage malignancy 2) To determine the safety and toxicity of 

this regimen and 3) To perform plasma pharmacokinetics (PK) of capecitabine 

and its metabolites. Methods: EA patients with advanced stage 

cancer were prospectively allocated into two cohorts: Group A (3R3R) and 

Group B (2R3R, 2R2R). In each cohort, dose escalation followed a 

standard phase I 3�3 design. Additional patients were treated at the R2P2 

dose level (DL). Initial dose was 1250/m2 bd for 14 days q3w (DL 1) with 

125 mg/m2 bd increments subsequently. Pharmacokinetics (PK) of capecitabine 

and its metabolites were performed using a LC-MS/MS method. 

Results: 23 patients (Group A�18; group B�5) received 94 cycles (median 

2.5, range 1-8). Median age was 58 (range 34-74) years. Median 

turnaround time for TYMS genotyping was 1 day. In group A, grade 3-4 

DLTs were seen in 3 patients: diarhoea, neutropenic fever, hand-foot 

syndrome, and mucositis. MTD was at DL 4 (1625mg/m2 bd) and the RP2D 

was 1500mg/m2 bd (DL 3). DL 3 was expanded to n�9. At DL 3, day 1 

mean (� SD) capecitabine and 5FU Cmax was 12.3 � 9.9 and 0.91 � 0.73 

�g/mL, respectively and AUC0 – twas 9.84 � 5.53 and 1.21 � 0.54 

h*�g/mL, respectively. Compared with DL1, Cmax for capecitabine and 5FU 

was 2 and 2.02 fold higher and AUC 0-t was 1.49 and 1.59 fold higher at 

DL3. Accrual in group B was ceased at DL2 due to lack of patient 

enrolment; no DLT was seen. By ROC analysis, day 1 5FU AUC0–tof 1.74 

h*�g/mL predicted for DLT (p�0.022, sensitivity 100%, specificity 90%). 

Conclusions: In EA patients with TSER 3R3R, the RP2D was 1500 mg/m2 bd. The D1 5FU AUC0–tat RP2D was 59% more than the FDA approved 

dose (DL1). 


Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in 

patients with advanced solid tumors. Presenting Author: Serena Marchetti, 

Netherlands Cancer Institute, Amsterdam, Netherlands 

Background: ModraDoc001 is a novel oral formulation containing docetaxel 

as a solid dispersion. Oral administration of docetaxel is feasible in 

combination with the CYP3A4 inhibitor ritonavir. Objectives were to 

determine the safety, maximum tolerated dose (MTD) and pharmacokinetics 

(PK) of weekly oral docetaxel (as ModraDoc001) in combination with 

ritonavir. Methods: Patients with advanced solid tumors, WHO PS � 2, no 

concomitant use of MDR or CYP3A modulating drugs, adequate bone 

marrow (ANC � 1.5x109 /L), liver (bilirubin � 1.5xULN, ALAT/ASAT � 

2.5xULN) and renal function (creatinine � 1.5xULN or clearance � 50 

ml/min) were eligible. Docetaxel (ModraDoc001 10mg capsule) and 

ritonavir (Norvir 100mg) were simultaneously given once weekly in a ‘3�3 

cohort’ dose escalation design. MTD was defined as the highest dose 

resulting in �1/6 probability of causing a dose limiting toxicity in the first 4 

weeks of treatment. This cohort was expanded with 6 patients. PK was 

determined on days 1 and 8. Results: 40 patients (25 male, 35 evaluable 

for safety) were enrolled in 6 dose levels (30/100, 40/100, 60/100, 

80/100, 60/200 and 80/200 mg docetaxel/ritonavir). Common treatment 

related adverse events in the 4 highest dose levels were diarrhea (68%), 

nausea (62%) and fatigue (62%), mostly CTC grade 1-2 (80%, 95% and 

73% respectively). Five patients experienced a DLT (grade 3 diarrhea (4), 

elevated ASAT/ALAT (1), grade 4 dehydration and grade 3 mucositis (1), 

grade 3 fatigue (2)). The MTD was 60 mg/200 mg docetaxel/ritonavir. 

Partial remission was seen in 4 patients (CUP, NSCLC, gastric and mamma 

ca) and sustained stable disease in 15 patients (6x NSCLC). Both drugs 

were rapidly absorbed after oral administration. Mean Tmax was 2.0 hours 

(CV�73%) for docetaxel. Cmax and AUC of docetaxel increased less than 

proportionally with dose to 162 ng/ml (CV� 67%) and 1615 ng/ml*hr 

(CV� 81%), respectively, in 15 patients at the MTD. Conclusions: At the 

MTD (once weekly 60 mg docetaxel and 200 mg ritonavir) ModraDoc001 is 

safe, well tolerated and shows encouraging antitumor activity. The exposure 

of docetaxel with this regimen is comparable to weekly intravenous 

administration of 35 mg/m2 docetaxel. Phase II studies in solid tumors are 

planned. 


A phase Ib dose-escalation study of eribulin mesylate in combination with 

capecitabine in patients with advanced/metastatic cancer. Presenting 

Author: Muhammad Yaser Nasim, Medical Oncology, The Beatson West of 

Scotland Cancer Centre, Glasgow, United Kingdom 

Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by 

FDA for patients (pts) with metastatic breast cancer after treatment with at 

least two prior chemotherapeutic regimens. This Phase Ib, open-label doseescalation 

study determined the maximum tolerated dose (MTD) of eribulin in 

combination with capecitabine. Methods: Pts with advanced solid malignancies 

refractory to standard therapies, adequate organ function and ECOG 

performance status �2 received eribulin mesylate (2–5-min IV) by Schedule 1 

(1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on 

Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each 

schedule where �1/6 pts experienced dose-limiting toxicity (DLT). Safety and 

pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 

(53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% 

male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were 

enrolled in Schedules 1 and 2, respectively. Most common tumor types were 

large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are 

shown in the table; there were no unexpected toxicities with the combination. 

The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, 

respectively, in combination with capecitabine 1000 mg/m2 twice-daily. 

Eribulin PK were dose proportional and independent of schedule or capecitabine 

co-administration. Combination with eribulin had no effect on the 

disposition of capecitabine and its metabolites. Although sample size was 

small, preliminary signs of efficacy were observed. Conclusions: The combination 

of eribulin and capecitabine was well tolerated with no unexpected safety 

findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose 

intensity of eribulin than Schedule 1 and was selected for evaluation in an 

ongoing Phase II breast cancer study. 

Summary of DLTs. 

Schedule 

Dose 

mg/m2 DLT 

n (%) DLT DLT grade 

1(N�19) 1.2 1 (5.3) Febrile neutropenia 3 

1.6 1 (5.3) Neutropenia 4 

2.0 2 (10.5) 1x Fatigue 3 

1x Lethargy 3 

2(N�15) 0.7 0 (0) NA NA 

1.1 1 (6.7) Neutropenic sepsis 4 

1.4 1 (6.7) Neutropenia 3 

NA, not applicable 




Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of 

intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced 

malignancies. Presenting Author: Susan Elaine Bates, Center for Cancer 

Research, National Cancer Institute, Bethesda, MD 

Background: DMS612 is a dimethane sulfonate compound that was 

identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines 

in a chemical screen of the NCI-60 panel. DMS612 has bifunctional 

alkylating activity in vitro. Objectives of this first-in-human phase I study 

included determining the dose-limiting toxicity (DLT), maximum tolerated 

dose (MTD), recommended phase 2 dose (RP2D), PK and PD of DMS612 

administered by 10 minute intravenous infusion on day 1, 8 and 15 of a 28 

day cycle. Methods: Eligibility criteria included adults with advanced solid 

malignancies or lymphoma with ECOG performance status 0-2, life 

expectancy � 3 months and adequate organ and marrow function. Patients 

were enrolled using a standard “3�3” dose escalation scheme. Plasma PK 

of DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD 

was assessed by �-H2AX immunofluorescence. Results: 35 subjects were 

enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor 

types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses 

administered were 1.5, 3, 5, 7, 9 and 12 mg/m2 . The MTD was determined 

to be 9 mg/m2 , with only one DLT of grade 4 thrombocytopenia in 12 

subjects enrolled. The maximum administered dose of 12 mg/m2 was 

considered to be intolerable after 1 of 3 subjects had grade 4 neutropenia 

and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia 

in later cycles was observed in other subjects, including one patient 

naïve to prior cytotoxic chemotherapy. One subject with RCC had a 

confirmed partial response at 7 mg/m2 . DMS612 was rapidly converted into 

carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides, 

some of which retained alkylating activity in vitro. Dose-dependent pharmacodynamic 

evidence of DNA damage induced by DMS612 in vivo was 

observed by �-H2AX immunofluorescance in both peripheral blood lymphocytes 

and plucked scalp hairs. Conclusions: The MTD of DMS12 administered 

by intravenous infusion on day 1, 8 and 15 of a 28-day cycle was 9 

mg/m2 . Pre-clinical and clinical observations suggest that further study of 

DMS612 in RCC is warranted. 


Phase I development of a weekly dosing schedule for the oral taxane 

tesetaxel. Presenting Author: Amy Lang, South Texas Accelerated Research 

Therapeutics, LLC, San Antonio, TX 

Background: Tesetaxel (TST) has anticancer activity in patients (pts) with 

metastatic breast cancer (MBC) and gastric cancer when administered 

orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not 

cause hypersensitivity reactions, and may be associated with less neurotoxicity. 

The maximally tolerated dose (MTD) on the Q3W schedule is 27 

mg/m2 , and neutropenia is dose-limiting. Since taxane activity may be 

schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation 

of TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2; 

adequate organ function. TST was given once weekly for 3 weeks in a 

28-day cycle, beginning at a total flat dose of 25 mg/cycle with progressive 

increases in total dose up to 75 mg/cycle. Subsequently, dosing was 

converted to a weight-based regimen at weekly doses of 12.5, 15, and 17.5 

mg/m2 (i.e., total per cycle dose up to 52.5 mg/m2 ). Serial plasma samples 

were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The 

MTD was 15 mg/m2 /wk (total cycle dose, 45 mg/m2 ). With repeated cycles, 

constitutional symptoms (fatigue and anorexia) rather than neutropenia 

proved dose-limiting at 17.5 mg/m2 /wk. Only 1 pt (at 12.5 mg/m2 /wk) 

developed grade 3 neutropenia; no other episodes of Grade 3-4 myelotoxicity 

were observed. One pt with MBC (who had progressed after 2 prior 

taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained 

prolonged reduction of PSA (� 57%). PK analyses showed low but 

progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 

days after each succeeding dose, which was consistent with the prolonged 

T½ of this drug (~180 hrs). There was no substantial drug accumulation 

over multiple cycles. Conclusions: Weekly oral TST is safe, provides 

long-term low-level drug exposure, and increases the total delivered dose 

over 12 wks by 25%. Interestingly, this regimen is not associated with 

significant myelosuppression. Thus, weekly TST dosing provides a highly 

convenient, “dose-dense”, taxane regimen that is not associated with 

neutropenia, which should facilitate its integration into multiple chemotherapy 

regimens. An ongoing study is evaluating efficacy of weekly TST 

dosing in MBC. 

155s 


Phase I and pharmacokinetic (PK)/pharmacodynamic (PD) study of 

LY2334737, an oral gemcitabine prodrug, in patients (pts) with advanced 

solid tumors. Presenting Author: Sandrine J. Faivre, Department of Medical 

Oncology, Beaujon University Hospital, Clichy, France 

Background: LY2334737 is a valproic acid-bound carboxylesterasesubstrate 

prodrug of gemcitabine that can be given orally. The primary 

objective was to define the recommended phase II doses and schedules 

(sch) of administration of LY2334737 in 28-day cycles. Methods: Eligible 

pts (ECOG�2) had adequate hematologic, renal, and hepatic functions. In 

sch-A, LY2334737 was given every other day for 21 days. In sch-B, 

LY2334737 was given daily every other week. Dose escalation (3�3) was 

based on CTCAE V3 toxicities. Secondary objectives were PKs (LY2334737, 

dFdC, dFdU), PD biomarkers (dFdC DNA incorporation, Cytokeratin 18 - 

M30), and antitumor activity. Results: 57 pts (38 males, 19 females, 

median age 60 yrs) were treated using 7 dose-levels (40–100 mg/day). Pts 

received a median of 2 cycles. Dose limiting toxicities (DLTs) at cycle 1 

(any dose level) consisted of diarrhea (2pt), AST elevation (1pt), lower 

extremity edema (1pt), QTC prolongation (1pt), and general deterioration 

(1pt). A total of 2/7pts treated with 100mg in sch-A and 1/4pts treated with 

90mg in sch-B had DLTs. During dose escalation most frequent toxicities 

were 1) Sch-A (28 pts): nausea (10pts), pyrexia (9pts), vomiting (8pts), 

mucositis (6pts), anorexia (6pts), ALT elevation (5pts), asthenia (5pts), 

anemia (5pts), fatigue (4pts), chills (4pts), and lymphopenia (4pts). 2) 

Sch-B (29 pts): pyrexia (13pts), nausea (8pts), diarrhea (6pts), vomiting 

(5pts), chills (6pts), anemia (5pts), asthenia (6pts), AST elevation (6pts), 

ALT elevation (5pts), and fatigue (4pts). Nine pts had stable disease (3pts 

completed �6 cycles). PKs showed a dose-proportional increase in 

exposure of LY2334737 and dFdC with no accumulation after repeated 

dosing. dFdC is detected in the DNA of peripheral blood mononuclear cells 

(increasing amount with dose and over time after repeated cycle). In sch-A, 

we observed a significant increase in cytokeratin 18 M30 relative to 

baseline. Conclusions: LY2334737 displayed linear PK and acceptable 

safety profile in both schedules. The dose of 90mg given every other day is 

the recommended dose for phase II trials with LY2334737 (dose expansion 

is ongoing). 


Effect of dexrazoxane on doxorubicin-induced testicular toxicity. Presenting 

Author: Irit Ben-Aharon, Davidoff Center, Rabin Medical Center, Petach 

Tikva, Israel 

Background: Seminal advances in anti-cancer therapy result in growing 

numbers of young male cancer survivors for whom treatment-induced 

infertility represents a major late-term concern. Doxorubicin (DXR) has 

been previously shown to exert toxic effect on the testicular germinal 

epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), 

we aimed to study its potential effect to reduce DXR-induced testicular 

toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg 

DXR or 100mg/kg DEX or the combination of both and scarified at one 

month post treatment. Saline-injected mice served as controls. Testes were 

excised, weighed and further processed. For oxidative stress determination 

glutathione assay was performed on testes’ lysates and P38 protein levels 

were determined by western blot analysis. Bax levels were used to assess 

apoptosis. Immunohistochemistry and confocal microscopy were used to 

study the effect of DXR, DEX and their combination, on the testis histology 

as well as on the spermatogonial reserve. Results: One month after DEX and 

DXR treatment, a striking decline in testicular weight was observed 

(decrease by 60% compared with control values; decrease of 54% in 

DXR-only treated mice; p�0.05). DEX prevented DXR-induced oxidative 

stress. However, DEX enhanced DXR-induced apoptosis within the testes 

and furthermore, the combination depleted the spermatogonial reserve one 

month after treatment. Conclusions: DEX activity in the testis may differ 

from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate 

DXR-induced testicular toxicity. 




First-in-human phase I and pharmacokinetic study of DTS-108 in patients 

with advanced carcinomas. Presenting Author: Romain Coriat, Cochin 

Teaching Hospital, AP-HP, Paris Descartes University, Paris, France 

Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite 

of irinotecan, where the SN38 moiety is covalently linked to a 20AA 

peptide through a specific cross-linker that releases SN38 by esterase bond 

cleavage. DTS-108 was designed to achieve therapeutic levels of SN38, 

while reducing diarrhea. Methods: This trial identified the pharmacokinetics, 

the adverse event (AE) profile (NCI-CTCv3 criteria), the dose limiting 

toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the 

recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours) 

every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas, 

ECOG:0-1, and adequate hepatic, marrow, and kidney functions. 

Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 

3-416 mg/m2). All grade AEs were asthenia (43%), nausea (43%), 

diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia 

(21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%). 

Grade 3 diarrhea was only reported in two pts with either partial bowel 

obstruction or recent history of a total colectomy. Neutropenia was the dose 

limiting toxicity of DTS-108. Neutropenia started to be observed at doses 

�56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Infusion 

related reactions (itching urticaria) were observed with increasing frequency 

and severity at doses �75 mg/m2 and required antihistamine 

premedications. At 313 mg/m2 and 416 mg/m2, infusion skin reactions 

were 2/6 pts and 6/6 pts, respectively. Fluorescence HPLC was initially 

used to quantify DTS-108 and its metabolites (SN-38 and SN-38G). 

Sample stability analysis of this method showed that SN38 values were 

inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood 

collection, plasma storage, and/or sample extraction. New processes and 

analytical LC/MS/MS methods for testing SN-38 were implemented. At the 

dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%) 

were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor 

stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts. 

Conclusions: DTS induced neutropenia and infusion skin reactions but no 

dose-limiting diarrhea. The MTD was 416 mg/m2 and the RD was 313 

mg/m2 q2w. 

2559 General Poster Session (Board #3H), Mon, 8:00 AM-12:00 PM 

Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined 

with allogeneic tumor antigen as a novel vaccine for metastatic lung 

adenocarcinoma. Presenting Author: Ben C. Creelan, H. Lee Moffitt Cancer 


Background: We created a vaccine in which irradiated allogeneic lung 

adenocarcinoma cells are combined with a bystander K562 cell line 

transfected with hCD40L and hGM-CSF. By recruiting and activating 

dendritic cells, we hypothesized the vaccine would induce tumor regression 

in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was 

given every 14 days x3, followed by monthly x3. Cyclophosphamide (300 

mg/m2 IV) was administered before 1st and 4th vaccines to deplete 

regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after 

1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood 

mononuclear cells (PBMCs) were collected at baseline and after each 

vaccination. T-cell activation profiles were analyzed by ELISpot assay and 

tested by generalized Wilcoxon for correlation to survival. Results: 24 

participants were accrued at a single center from 10/2006 to 6/2008, with 

median age 64 and median of 3 previous lines of chemotherapy prior to 

entry. 20 were former smokers and 4 had brain metastases. A total of 101 

vaccines were administered. Common toxicities of any grade were joint pain 

(79%) and fatigue (75%). Significant adverse events included a grade 3 

hypotension and a grade 3 acute respiratory distress. No confirmed 

complete or partial radiologic responses were observed. Median overall 

survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-toprogression 

was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred 

reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p�0.02) and 

trend to improved OS (HR 0.59, p � 0.06). Of 14 participants with 

evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell 

activation after vaccination. Ex vivo peptide immune response correlated 

with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p � 

0.04). Conclusions: Vaccine administration was feasible and tolerable in a 

heavily pretreated population of metastatic lung cancer. These data 

suggest the vaccine has clinical activity in the subset with peptide-induced 

T-cell immune responses and warrants further investigation. A randomized 

trial of the vaccine is currently in development. 


Human papillomavirus type 16 (HPV16) E6/E7-specific cytotoxic T lymphocytes 

(CTL) for immunotherapy of HPV-associated cancer (Ca). Presenting 

Author: Carlos Almeida Ramos, Baylor College of Medicine, Houston, TX 

Background: Vaccines prevent HPV-associated Ca, but their benefits in 

established Ca are disappointing: although these tumors express viral E6 

and E7 antigens (Ags) immune responses are limited even after vaccination, 

likely due to negative environmental cues that block tumor recognition 

and T cell (TC) activation in vivo. We postulated that ex vivo stimulation of 

TCs in an immunologically favorable milieu would allow us to reactivate 

tumor-directed CTLs from Ca patients and benefit the recipients on 

reinfusion. Methods: We studied 68 patients with HPV� Ca. To detect 

HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFN� 

ELISpot responses of TCs stimulated by monocyte-derived dendritic cells 

(DCs) loaded with pepmixes (peptide libraries of 15-mers overlapping by 

11 aa) spanning E6/E7. Because HPV-TCs from these patients may be 

anergized by their tumors, potent Ag presenting strategies might be 

required for reactivation, and thus we stimulated these cells in the 

presence of IL-6, -7, -12 and -15, as we have shown that these can induce 

responses to poorly immunogenic Ags. Results: We successfully reactivated 

HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We 

could expand these HPV-TCs to clinically useful numbers by using patient 

B-cell blasts (BBs) as APCs. Stimulation of DC-stimulated HPV-TCs by 

E6/E7 pepmix-loaded BBs further expanded (3.8 � 1.5�/round) HPV-TC 

lines, which phenotypically are almost exclusively composed of TCs (98 � 

3% CD3�), with a variable proportion of mostly effector memory (CD45RA–, 

CD45RO�, CD62L– and CCR7–) CD4� and CD8� cells (37 � 28% and 

49 � 27%, respectively). The viral/tumor associated epitopes recognized 

mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87. 

The expanded cells from patients killed E6/E7� targets (specific lysis up to 

45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have 

developed a system that allows the robust generation of HPV-directed CTLs 

from patients with HPV16� Ca, which recognize specific epitopes in 

tumor-associated Ags. Our lines have the potential to be used for adoptive 

cellular immunotherapy of HPV� Ca. 


Where to look for sentinel node in breast cancer? Presenting Author: Anton 

J. Scharl, Klinikum St Marien, Amberg, Germany 

Background: It has been observed, that the caudal Axilla on the border to 

pectoralis muscle is predicive for the sentinel node. The sono-morphology 

of lymph nodes has been the subject of multiple publications, usually 

dealing with malignant melanoma. In the context of sentinel lymph node 

biopsy (SLNB) in breast cancer patients, the following study examines the 

feasibility of the sonographic differentiation of the Sentinel lymph node 

(SLN) from neighboring non-SLNs and whether sentinel-ultrasound-needle 

localization (SUN) is a useful addition or alternative to current methods of 

“lymphatic mapping”. Methods: During a prospective study performed from 

1/2003 to 9/2005 including 404 breast cancer patients (Tis-T4), the 

SLNB was performed using patent blue�/- 99Tc-Nanocoll. In addition to 

and independent of this method, the axilla was sonographically examined 

for “reactive” lymph nodes n�180 pt. (Siemens Elegra 7.5 MHz). The 

“reactivity” of the nodes was quantified using an index , which allowed the 

comparison of adjacent nodes. The most “reactive” lymph node in the 

caudal axilla was identified as the “Ultrasound-Sentinel-Node”(US-SLN) 

and has been marked with a wire. Results: In 180 patients the SLN was 

localized using the standard methods as well as (SUN). The was no 

difference in detection rates of US-SLN and the standard methods in 

tumor-free nodes(SLN-). However, for patients with axillary metastases 

(SLN�) SUN provided superior detection rate (99,1%). The false-negativerate 

was reduced from 10,7 % to 1,3%. This was attributed to the 

embolization of lymph vessels afferent to the metastasized (SLN�) node 

causing a bypass of the “lymphatic mapping” and inhibiting detection. 

Conclusions: The SUN–Method is comparable to “lymphatic mapping” in 

tumor free nodes (SLN -). If SLN is metastasized (SLN�) - SUN is superior 

to the standard methods in sensitivity and specificity (80%) and the 

false-negative-rate can be reduced. Systematic axilla sonography is an 

effective method for the SLN-Localisation, and offers an excellent method 

for quality control during SLNB. 




A randomized pilot phase I study of modified carcinoembryonic antigen 

(CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine (CEA-vac) in patients 

(pts) with pancreatic adenocarcinoma (PC). Presenting Author: 

Daniel M. Geynisman, University of Chicago, Chicago, IL 

Background: CEA is expressed in �90% of PC and may be an appropriate 

immunotherapy target. CEA is poorly immunogenic due to immune tolerance; 

CAP1-6D, an altered peptide ligand can help bypass tolerance. We 

conducted a pilot randomized phase I trial in PC pts to determine the 

appropriate CEA-vac peptide dose required to induce an optimal cytotoxic T 

lymphocyte (CTL) response. Methods: Eligible pts, PS 0-1, expressed 

HLA-A2 and had CEA-expressing, histologically-confirmed, previouslytreated 

PC. Randomization: 10 �g (arm A), 100 �g (arm B) or 1000 �g 

(arm C). CEA-vac was given Q 2 weeks until disease progression (amended 

4/09 to a 24 dose maximum). Results: From 2/06-9/09 66 pts were 

screened for HLA-A2; 19 pts randomized to Arms A/B/C 5/8/6 are evaluable 

for toxicity; 14 pts (5/5/4) who received at least 3 doses of CEA-vac are 

evaluable for the primary immunologic endpoint. Median age: 60 (range 

27-86), female: 68%, PS 0: 58%. Disease stage: metastatic (M) 74%, 

locally advanced (LA) 5%, resected (R) 21%. Cycles: median 4 (range 

1-81). Mean CTL response by ELISPOT (spots per 104 CD8� cells, Arm 

A/B/C): 37/126/248. (A vs. C, p�0.037). CTL responses developed in 

20%/60%/100% of pts in Arms A/B/C. 1 LA pt in Arm C had a complete 

radiologic response, a strong CTL response, and remains alive at 71 mo. 1 

M pt in Arm B had SD for 11 mo, a strong CTL response, and is alive at 39 

mo. Toxicity: no grade 3/4 toxicities, 58% grade 1/2 skin toxicity. 

Conclusions: CTL response was dose-dependent in this randomized phase I 

trial; the 1 mg peptide dose elicited the most robust CTL response. Clinical 

activity was demonstrated at the higher doses. Further evaluation of 1 mg 

CEA-vac with stronger adjuvants, combined with agents to overcome 

immune inhibitory pathways, may be warranted in PC pts. Supported by 

UCCCSG P30CA14599. 


Evaluation of immune activation following neoadjuvant sipuleucel-T in 

subjects with localized prostate cancer. Presenting Author: Nadeem A. 

Sheikh, Dendreon Corporation, Seattle, WA 

Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy 

for men with asymptomatic or minimally symptomatic metastatic 

castrate resistant prostate cancer (mCRPC). NeoACT (Study P07-1) was 

undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects 

with localized prostate cancer. Methods: In this open-label, phase 2 study 

(NCT00715104), subjects with localized prostate cancer received 3 

infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 

weeks prior to radical prostatectomy (RP). Following RP, subjects were 

randomized 1:1 to receive / not receive a sipuleucel-T booster infusion 12 

weeks post-RP. Cellular composition, antigen presenting cell (APC) activation, 

cytokines, and T and B cell activation were profiled before and after 

each culture with PA2024, the fusion protein containing prostatic acid 

phosphatase used to generate sipuleucel-T. Results: Of the 42 enrolled 

subjects (median age: 61 years; 98% Caucasian), 38 received all 3 

infusions of sipuleucel-T, and 15 subjects received a booster infusion. 

Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC activation) 

was greater at the second and third infusions relative to the first 

(p�0.001). The expression of early T cell activation markers (CD134, 

CD137, CD278 and CD279) were increased in pre-culture cells obtained 

after the first infusion, and further increased after culture. Activated 

mature B cells (CD20�CD27�IgD�CD86�) increased following culture 

in all 3 products (p�0.01); memory B cells (CD20�CD27�IgD-CD86�) 

were progressively increased following the first infusion (p�0.05 third vs. 

first product). TNF-�, IFN-�, IL-2 were secreted at higher levels during 

culture of the second and third products (all p�0.001). The observed 

increases in CD54 upregulation, early T cell activation markers, and 

memory and activated mature B cells were maintained at booster treatment. 

Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune 

system activation that was consistent with boosting of an immune response 

primed with the first infusion. Immune activation was maintained at the 

booster infusion 3 months following initial sipuleucel-T treatment. 

157s 


Lymphoid and myeloid biomarkers for clinical outcome of combined 

immunotherapy with granulocyte-macrophage colony-stimulating factortranduced 

allogeneic prostate cancer cells (GVAX) and ipilimumab in 

castration-resistant prostate cancer patients. Presenting Author: Alfons 

J. M. van den Eertwegh, VU University Medical Center Department of 

Medical Oncology, Amsterdam, Netherlands 

Background: In a phase-I dose escalation trial in patients with castrationresistant 

prostate cancer we showed that GVAX and ipilimumab had an 

acceptable safety profile. Moreover, we observed tumor responses and 

prolonged survival as compared to the Halabi predicted overall survival 

(OS). However, ipilimumab can also lead to severe immune-related adverse 

events. To avoid unnecessary exposure to this risk, it is essential to identify 

biomarkers that correlate with clinical activity. Methods: Patients had 

castration-resistant prostate cancer and were chemotherapy-naïve. They 

received bi-weekly GVAX for a 24 week period combined with monthly 

intravenous administrations of ipilimumab. Each cohort of 3 patients 

received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In 

an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg 

ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets 

in blood were performed. Results: We observed a significantly prolonged OS 

for patients with high pre-treatment frequencies of CD4�CTLA-4�, 

CD4�PD-1�, or differentiated CD8� T cells, or low pre-treatment frequencies 

of differentiated CD4� T cells or CD4�CD25hiFoxP3� regulatory T 

cells. In contrast, increased frequencies of granulocytic Myeloid-Derived 

Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic 

CD14�HLA-DRlo/- MDSC were associated with reduced OS. Treatmentinduced 

CD4� T cell differentiation and CD4� and CD8� T cell activation 

was associated with clinical benefit. Moreover, treatment-induced activation 

of CD1c� conventional Dendritic Cells (cDC) and 6-sulfo LacNAc� 

inflammatory DC were associated with significantly prolonged OS. 

Conclusions: Together these data provide an immune profile to predict 

clinical outcome. Importantly, cluster analysis revealed pre-treatment, 

CRPC-associated expression of CTLA-4� by CD4� T cells to be a dominant 

predictor for OS after GVAX/ipilimumab. This potentially biomarker for 

patient selection should be validated in patients treated with ipilimumab. 


Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune 

cells within the prostate tumor microenvironment. Presenting Author: 

Lawrence Fong, University of California, San Francisco, San Francisco, CA 

Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy 

for patients with asymptomatic or minimally symptomatic metastatic 

castrate resistant prostate cancer (mCRPC). To date, studies of 

sipuleucel-T in patients with mCRPC have studied immune response in 

peripheral blood. The effects of sipuleucel-T on prostate tumors are 

unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label, 

phase 2 study of patients with localized prostate cancer who received 

sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic 

effects of treatment on prostate tissue. Patients received 3 infusions 

of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks 

prior to RP. The primary endpoint was the change in the frequency of 

lymphocytes between prostate biopsies (pre-treatment) and RP tissue 

(post-treatment), as assessed by immunohistochemistry (IHC). Results: The 

median age of the 42 enrolled patients was 61 years, and all had an ECOG 

performance status of 0. Thirty-eight patients received all 3 pre-RP 

sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 

32 patients. Treatment-related AEs were manageable and transient. 

Sipuleucel-T did not appear to impact surgery, as judged by operative 

complications, procedure time, and estimated blood loss. Frequent events 

that occurred �1 day after infusion (�10% of patients) were fatigue, 

headache, and myalgia. Significant increases (�3 fold) in CD3� and 

CD4� T cell populations were observed at the tumor interface (where 

benign and malignant glands interface), compared with the pre-treatment 

biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman- 

Keuls test: p�0.0001 for each comparison). FoxP3� CD4� T cells were 

also increased (p�0.0005) at the tumor interface, but represented a small 

fraction of the observed CD4� T cells. Conclusions: Neoadjuvant sipuleucel-T 

treatment is associated with an increased frequency of T cells in 

prostate cancer tissue at the interface of the benign and malignant glands. 

These data suggest that sipuleucel-T can modulate the presence of 

lymphocytes at the prostate tumor site. Work is ongoing to more fully 

characterize the immune response. 




IFN-� to improve immunotherapy for melanoma. Presenting Author: Marco 

Donia, Center for Cancer Immune Therapy, Department of Hematology, 

Copenhagen University Hospital Herlev, Herlev, Denmark 

Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes 

(TILs) holds the promise to change the long-term prognosis of 

patients with metastatic melanoma. In this study we have explored 

strategies to improve the efficacy of cell products for infusion through 

tumor immune-sensitization. Methods: We examined whether objective 

responses in our pilot ACT trial (NCT937625) were associated with the 

number of tumor-reactive T cells infused. Subsequently, we assessed the 

ability of immune-sensitizing agents to modulate the constitutive response 

of 12 clinical grade TIL products to matched autologous short-term 

cultured melanoma cell lines. Results: Our data showed that a high absolute 

number of infused tumor-reactive T cells is critical to achieve an objective 

response. In addition, a defective population of tumor-specific CD8� and 

CD4� T cells unable to exert antitumor effector functions ex vivo was 

detected in most TIL products. However, an antitumor specific response 

could be restored by pretreatment of the autologous tumor cells with low 

dose IFN-�. Of note, IFN-� treatment was invariably associated with 

increased cancer immunogenicity as demonstrated by up-regulation of 

MHC molecules. Conclusions: Combination strategies represent the next 

frontier of cancer immunotherapy. Although previous trials in melanoma 

showed that IFN-� does not mediate clinical benefit when used as 

monotherapy, our findings show that its ability to increase tumor cell 

immunogenicity may enhance the efficacy of current immune-based 

therapies such as ACT through improved activation of pre-existing but 

unresponsive tumor specific lymphocytes. Therefore, additional studies on 

the possibility of a sequential combination of low dose IFN-� and ACT are 

highly warranted. 


Human pharmacokinetic (PK) characterization of the novel dual-action 

anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/ 

recurrent epithelial tumors. Presenting Author: Manuel Hidalgo, START- 

Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain 

Background: MEHD is a novel dual-action human IgG1 antibody that blocks 

ligand binding to HER3 and EGFR, and elicits antibody-dependent 

cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity 

in a broad panel of tumor models, including models resistant to 

anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was 

to characterize the PK of MEHD associated with body weight (BW)-based 

dosing used in a phase I study in patients with epithelial tumors and to 

evaluate the potential for using fixed dosing in future studies. Methods: 

Preliminary non-compartmental and population PK analyses were performed 

using patient data from the dose-escalation stage [1, 4, 10, 15, 22, 

and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) 

of the phase I study. Patient demographic data and other relevant clinical 

covariates were evaluated in the population analysis. PK simulation of 

1000 subjects with a log-normal BW distribution was performed to 

compare the inter-individual variability of MEHD exposure following fixed 

or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. 

In the noncompartmenal analysis, the apparent clearance (CL) decreased 

in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 

mg/kg) and approached linearity at doses �10 mg/kg (q2w). In the 

population analysis, the PK profile of MEHD was well described by a two 

compartment model with linear and nonlinear clearance. The targetmediated 

clearance was consistent with that of anti-EGFR antibodies. The 

nonspecific CL and central volume of distribution (V1) values were 

approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a 

moderate effect on V1, but not on CL. PK simulations suggest that, 

compared with BW-based dosing, fixed dosing would result in less 

inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 

mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: 

The dual-action antibody MEHD demonstrated PK consistent with anti- 

EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule 

is supported. 


A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, 

combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced 

solid tumors. Presenting Author: Patricia LoRusso, Karmanos 

Cancer Institute, Detroit, MI 

Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are 

deregulated in many tumor types. Targeting both pathways may be more 

efficacious than targeting either pathway alone. In preclinical models, 

concurrent administration of GDC-0973, a potent, selective, MEK1/2 

inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved 

efficacy compared to either agent alone dosed continuously or intermittently. 

Methods: A phase Ib dose-escalation study with 3�3 design was 

initiated in patients (pts) with advanced solid tumors to evaluate the safety 

and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. 

Pts received: concurrent GDC-0973 � GDC-0941 once daily (qd) on a 21 

day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 

11, 15, 18 of a 28 day cycle � GDC-0941 qd on a 21/7 schedule (MEK 

int); or GDC-0973 � GDC-0941 qd on a 7 day on /7 day off schedule (7/7). 

Starting doses were 20 mg GDC-0973 � 80 mg GDC-0941 (21/7), 100 mg 

GDC-0973 � 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 � 130 mg 

GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were 

obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n�1), G4 

CPK elevation (n�1). Compared to the 21/7 MTD of 40 mg GDC-0973 � 

100 mg GDC-0941, higher doses of GDC-0973 � GDC-0941 were 

tolerated on the MEK int schedule. Overall, adverse events related to the 

study drug combination in � 20% pts were diarrhea, rash, nausea, fatigue, 

vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary 

analysis indicated PK of GDC-0973 and GDC-0941 are not altered when 

dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial 

metabolic response (� 20% decrease in mean SUVmax from baseline) at �1 

time points. Partial responses were observed in 3 pts (mBRAF melanoma, 

mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease 

� 5 months. Conclusions: Combination dosing of GDC-0973 and GDC- 

0941 is generally well tolerated, with toxicities similar to those observed in 

single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs 

of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules 

continues and updated data will be presented. 


A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR 

dual-action antibody, in patients (pts) with refractory/recurrent epithelial 

tumors: Expansion cohorts. Presenting Author: Andres Cervantes-Ruiperez, 

Department of Hematology and Medical Oncology, INCLIVA, University of 

Valencia, Valencia, Spain 

Background: Dysregulated human epidermal growth factor receptor tyrosine 

kinase (HER RTK) signaling is an important driver of tumor growth, 

metastasis, and survival. Extensive co-expression and heterodimerization 

suggest that simultaneous blockade of multiple HER RTKs may be more 

effective than blockade of a single RTK. MEHD is a novel dual-action 

human IgG1 antibody. Each antigen-binding fragment blocks ligand 

binding to HER3 or EGFR, and intended to inhibit signaling from all major 

ligand-dependent HER dimers. MEHD has single-agent activity in multiple 

tumor models including models resistant to anti-HER3 or anti-EGFR. 

Methods: This Phase I study evaluated safety, tolerability, pharmacokinetics 

(PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2 

weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET 

and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT 

assessments were performed q8w. No dose-limiting toxicity (DLT) was 

observed in six 3�3 cohorts from 1-30 mg/kg (n�30). We report results 

from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended 

Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC�12, NSCLC�9, 

SCCHN�10, pancreatic�5), median age 62.5 (35–87), all PS 0-1, 

median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of 

MEHD; 18 pts remain on study. PK data are consistent with human 

anti-EGFR antibodies. No related Grade (G) �3 adverse events (AEs) have 

been observed. Common related G1/2 AEs included rash/dermatitis (53%), 

diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and 

decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%). 

Related AEs � 24 h after first infusion included G1/2 headache (42%), 

fever (33%), and chills (17%), and decreased in intensity and frequency 

with later infusions. Early PD data indicate target inhibition in 8/36 pts 

(SCCHN�2, NSCLC�2, CRC�4), and best response by RECIST includes 2 

PR (both SCCHN), 6 pts with SD � 8 weeks (NSCLC�2, CRC�4), 7/8 

previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg 

q2w has an encouraging safety profile and evidence of anti-tumor activity. 

Phase II studies are planned. 




Patient-specific immunotherapy utilizing putative tumor stem cells in 

patients with metastatic melanoma: A pooled analysis comparing tumor 

cell and dendritic cell vaccines in two phase II trials and a randomized 

phase II trial. Presenting Author: Robert Owen Dillman, Hoag Institute for 

Research and Education and Hoag Family Cancer Institute, Newport 

Beach, CA 

Background: Metastatic melanoma is seldom cured, even in patients who 

achieve a complete remission, because new sites of disease emerge. Autologous, 

proliferating, self-renewing tumor cells (putative tumor stem cells and/or 

early progenitor cells), are critical to establishment of new depots of metastatic 

cancer, and may be excellent sources of antigen for vaccines. These trials 

addressed the impact on survival from immunizing with antigens from such 

cells. Methods: Data was pooled from 3 successive phase II trials, all of which 

included patients with documented metastatic melanoma, who were treated in 

protocols that utilized antigens from cell cultures of autologous tumor cells. 

S.C. injections were given weekly for 3 weeks, then monthly for 5 months. 

1992-2000: 74 patients were injected with irradiated tumor cells (TC). 

2000-2006: 54 patients were injected with autologous dendritic cells (DC) 

that had been co-cultured with irradiated autologous tumor cells (NCI-V01- 

1646). 2007-2011: in a randomized phase II trial, 24 patients were injected 

with TC, and 18 with DC (NCT00436930). Results: The table summarizes 

overall survival (OS) in each trial. In the pooled analysis there were 98 TC and 

72 DC patients. Characteristics were similar in terms of age (51, 52), male 

gender (62%, 62%), no evidence of disease at the time of treatment (46%, 

47%), and presence of M1c visceral disease at the time of treatment (13%, 

14%). OS was longer in patients treated with DC (median 63.1 vs 20.2 

months, 5-year OS 51% vs 26%, p�0.0002 Mantle-Cox log-rank test). The 

difference in OS in the randomized trial is also significant (p�0.007). 

Conclusions: Patient-specific DC vaccines primed with antigens from autologous 

proliferating, self-renewing tumor cells are associated with encouraging 

long-term survival rates, and are superior to patient-specific TC vaccines in 

populations of patients who have been diagnosed with metastatic melanoma. 

Vaccine # patients # deaths Median OS 2-yr OS 5-yr OS 

TC 74 60 20.3 mos 45% 28% 

DC 54 31 58.4 mos 72% 50% 

TC 24 16 15.9 mos 31% --- 

DC 18 5 Not reached 72% --- 


Correlation of interferon-g (IFN-�) response with survival in a phase II 

hyperacute (HAL) immunotherapy trial for non-small cell lung cancer 

(NSCLC). Presenting Author: John Charles Morris, University of Cincinnati, 

Cincinnati, OH 

Background: Lung cancer is the leading cause of cancer-related mortality. 

Patients progressing after initial systemic therapy have a poor prognosis. 

Thus, new therapies are needed. HAL immunotherapy exploits the hyperacute 

rejection of a xenotransplant as defense mechanism to initiate 

anti-tumor immune response by administering genetically modified allogeneic 

tumor cells expressing the �Gal moieties on their cell surface. HAL 

immunotherapy utilizes �Gal epitopes and natural human antibodies (Ab) 

against these targets as the proposed mechanism for anti-tumor immunity. 

Methods: We completed a phase II study of HAL immunotherapy in patients 

with metastatic or recurrent NSCLC, age �18, ECOG PS �2, �2 prior 

systemic therapies. Trial objectives were to determine response rate, safety 

and immunological responses. Patients received 300 x 106 HAL cells every 

2 weeks for 8 doses. Response was determined using RECIST and adverse 

events were assessed using CTCAE v3. Immune responses were assessed 

by changes in serum anti-�Gal titers and IFN-� response. Results: Twentyeight 

patients were treated. Eight (29%) demonstrated stable disease (SD) 

�16 wks including one patient that initially progressed and later regressed, 

surviving over 40 months. Median overall survival (OS) was 11.3 months 

(95% CI 3.8-21.9). Post vaccination, all patients responded by increasing 

anti-�Gal Ab levels (2-100 fold) and 61% (11/18) of tested patients 

showed increases in IFN-� levels (by ELISPOT). Interestingly, patients with 

increased IFN-� responses after vaccination (�10-500 fold-increase 

compared to baseline) had a median survival of 21.9 months compared to 

5.5 months in patients with lesser IFN-� responses after vaccination 

(p�0.001). In addition, patients with higher IFN-� responses showed 

reactivity to a NSCLC cell line that was not a component of HAL, suggesting 

cross-priming to shared tumor antigens. Conclusions: HAL immunotherapy 

is safe and feasible. The median survival compared favorably to that 

reported in patients receiving 2nd line chemotherapy for relapsed or 

advanced NSCLC. The correlation between IFN-� response and survival is 

highly encouraging. 


Effect of matrix metalloproteinase-2 on antitumor immunity. Presenting 

Author: Emmanuelle Godefroy, New York University, New York, NY 

Background: Cancer cells, including melanoma, can be highly resistant to 

traditional treatments such as chemotherapy and radiotherapy. As a result, 

a lot of effort has been put into developing immune therapies to treat 

cancer patients. The main barrier to design effective immunotherapies is 

the immunosuppression induced by the tumor. Matrix metalloproteinase-2 

(MMP-2) is over-expressed in most cancers including melanoma, and its 

expression is associated with increased dissemination and poorer survival/ 

prognosis. Here, we uncovered an immunosuppressive role of MMP-2 in 

inducing ineffective/detrimental TH2 immune responses and its underlying 

mechanisms. Methods: Human dendritic cells (DCs) were cultured in the 

presence of MMP-2 or various TLR agonists. DCs responses were monitored 

using immunostaining, ELISA or cytometric bead array methods. Autologous 

CD4� T cells were stimulated using these conditioned tumorassociated 

antigen (TAA)-pulsed DCs. TAA-specific CD4� T cells were 

cloned and characterized using the same techniques as for DCs. Results: 

Herewe showed that MMP-2-conditioned human DCs primed naïve CD4� T 

cells into an inflammatory TH2 phenotype, i.e. mainly secreting TNF�, IL-4 

and IL-13 and expressing GATA3. Accordingly, we detected MMP-2specific 

CD4� T cells displaying the same inflammatory TH2 profile in 

tumor-infiltrating lymphocytes from melanoma patients. We revealed the 

underlying mechanisms: on the one hand, MMP-2 was found to degrade the 

type-I IFN receptor IFNAR1, thereby preventing STAT1 phosphorylation, 

which is necessary for IL-12 production. On the other hand, MMP-2 

triggers the Toll-like receptor (TLR)-2 on DCs, which leads to NF-kB 

activation and OX40L expression. Both lack of IL-12 and over-expression of 

OX40L were found responsible for skewing T cell responses towards a 

detrimental TH2 phenotype. Conclusions: MMP-2, therefore, acts as an 

endogenous TH2 �conditioner� and may underlie the prevalence of detrimental 

TH2 responses in cancer. Our findings also described the responsible 

MMP-2-dependent mechanisms, which open the way to novel therapeutic 

strategies and/or targets to skew anti-tumor CD4� T cell responses towards 

a more efficient anti-tumor TH1 phenotype to treat cancer patients. 


Does the addition of molecular targeted therapy to standard treatments 

lead to better or worse outcomes overall? A systematic review of EGFRtargeted 

therapies used in combination with standard treatments. Presenting 

Author: Jennifer Rauw, University of Toronto, Toronto, ON, Canada 

Background: Combining novel targeted therapies with standard treatment is 

a common strategy in drug development. The primary aim of this systematic 

review was to provide a summary of the outcomes from studies combining 

EGFR targeted therapy (ETT) with standard treatments. Methods: A PubMed 

(1975-Jan, 2012) and ASCO (2005-2011) abstract database search was 

performed. Eligible studies were RCTs that compared standard therapies 

(chemotherapy, radiation therapy, or hormonal therapy) to standard therapy 

plus an ETT. Efficacy outcomes: overall survival (OS), progression free 

survival (PFS), objective response rate (ORR) time to progression (TTP), 

clinical benefit rate (CBR), and toxicity (total and grade 3�) were recorded. 

If any toxicity was significantly more frequent in one arm it was coded as 

such. Results: 128 studies (60 manuscripts, 68 abstracts) met criteria. 

Median study enrolment was 230 patients, with breast, lung, and colorectal 

cancer as the main tumor sites. ETT, cetuximab (41%), trastuzumab 

(19%), gefitinib (13%), erlotinib (13%), and lapatinib (16%), was combined 

with platinums, 5FU, taxanes, nucleoside analogs; hormonal therapy 

and/or radiation therapy. Refer to the table for efficacy results. Most 

frequent toxicities (common and grade 3�) in the combined arm were rash, 

diarrhea, hematological toxicity and fatigue. Conclusions: Despite enthusiasm 

for combining standard treatments with targeted therapies, we have 

demonstrated mixed efficacy results, with marginal benefit and worse 

toxicity. Quality of life (Q of L) was rarely reported. A similar analysis is 

underway for VEGFR, and mTor inhibitors, but raises the question of how 

best to approach the question of combination therapy. 

Outcome 

Not 

reported 

Significantly 

worse in 

combined arm 

No significant 

difference 

between arms 

159s 

Significantly 

better in the 

combined arm 

OS 60 (51%) 1 (0.8%) 39 (31%) 23 (18%) 

DFS 66 (52%) 1 (0.8%) 29 (23%) 32 (25%) 

TTP 106 (83%) 0 10 (8%) 12 (9%) 

CBR 108 (84%) 0 13 (10%) 7 (6%) 

ORR 73 (57%) 0 29 (23%) 26 (20%) 

Toxicity 58 (45%) 47 (36%) 22 (17%) 1 (0.8%) 

QofL 110 (86%) 0 12 (9%) 6 (5%) 



2573^ General Poster Session (Board #5F), Mon, 8:00 AM-12:00 PM 

Messenger RNA vaccination and B-cell responses in NSCLC patients. 

Presenting Author: Martin Sebastian, Medizinische Klinik II Hämatologie/ 

Onkologie, Rheumatologie, Infektiologie, HIV Klinikum der J.W. Goethe- 

Universität Frankfurt, Frankfurt am Main, Germany 

Background: Vaccination with mRNA is a novel technology in cancer 

immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules 

(RNActive) coding for five non small cell lung cancer (NSCLC)-associated 

tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report 

final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. 

Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease 

after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 

pts. were treated at three dose levels (400�g, 800�g and 1600�g 

CV9201) and observed for DLTs to select the highest tolerated dose for 

phase IIa. Primary endpoint was safety and tolerability; secondary endpoints 

were immune response, clinical efficacy and survival. Pts. received 

up to five vaccinations of CV9201 within 15 weeks. Antigen-specific 

immune responses against each of the 5 antigens were measured at 

baseline, and two weeks after the 3rd and 5th vaccination. Frequency of 

lymphocyte subsets and expression of activation and maturation markers 

were measured and retrospectively correlated with immunological and 

clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase 

IIa); No DLTs occurred, and the 1600 �g dose was investigated in phase 

IIa. The most frequent related adverse events were mild to moderate 

injection site reactions and flu-like symptoms. 3 patients (7%) had 

potentially related grade 3 AEs (fatigue, injection site granuloma, asthma 

attack) and no related SAEs were reported. There were no objective 

responses. Data on PFS and survival will be presented. Antigen specific 

immune responses against at least one antigen were induced in 65% of pts. 

(39% cellular and 49% humoral). Consistently, a significant �2 fold 

increase of pre germinal center B cells (pGCB) was observed in 61% of pts. 

This increase of pGCB correlated significantly (p�0.0028) with increase of 

total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase 

during treatment. Conclusions: Vaccination with CV9201 has a favorable 

safety profile and induces T and B cell responses against all included 

antigens. Vaccine-induced increase of pGCB is a new finding and might be 

used as a biomarker in cancer immunotherapy. 


Bispecific Fynomer-antibody fusion proteins targeting two epitopes on 

HER2. Presenting Author: Frederic Mourlane, Covagen AG, Zurich- 

Schlieren, Switzerland 

Background: Fynomers are small binding proteins (7 kDa) derived from the 

SH3 domain of Fyn kinase. They can be engineered to yield specific and 

high-affinity binding domains to target proteins of interest. In the past, we 

have isolated Fynomers with excellent physico-chemical properties binding 

to 16 different antigens. One important application of the Fynomer 

technology represents the genetic fusion of a Fynomer to an antibody to 

provide bispecific fusion proteins. Methods: Using phage display technology 

we have isolated Fynomers binding to tumor-associated antigens. After 

genetic fusion of these Fynomers to antibodies of interest the resulting 

bispecific proteins were evaluated in vitro and in vivo for their antitumoral 

activity. Results: The fusion of Fynomers to the antibodies of interest did not 

alter the favorable biophysical properties of the antibodies. First, the 

Fynomer-antibody fusion proteins could be purified with the same high 

yields from the supernatant of transiently transfected CHO cells as the 

unmodified antibodies (in the range of 100 mg/L). Second, the purified 

fusion proteins were monomeric and showed no signs of aggregation even 

after four months of storage at 4 °C or -20 °C in PBS as determined by size 

exclusion chromatography. Third, the Fc-mediated effector functions of 

antibodies were not altered by their fusion with Fynomers. Antibodydependent 

cellular cytotoxicity (ADCC) was maintained, and the affinity to 

the neonatal Fc-receptor (FcRn) was similar as observed for the unmodified 

antibody. In addition, the bispecific Fynomer-antibody fusion proteins 

demonstrated excellent growth inhibition of tumor cells in vitro and high 

efficacy in vivo in tumor xenograft mouse models. Conclusions: These 

encouraging preclinical results indicate that the bispecific Fynomerantibody 

fusions have highly promising properties with a great potential for 

further preclinical and clinical development. 


Adoptive cell therapy for melanoma patients using tumor-infiltrating 

lymphocytes, lymphodepleting chemotherapy, and low-dose interleukin-2. 

Presenting Author: Eva Ellebaek, Department of Oncology and Center for 

Cancer ImmuneTherapy, Department of Hematology, Copenhagen University 

Hospital Herlev, Herlev, Denmark 

Background: Adoptive T cell therapy is based on isolation of tumor 

infiltrating lymphocytes (TIL) from autologous tumor, in vitro activation and 

expansion, and the reinfusion of these cells into a lymphodepleted patient. 

Together with high-dose interleukin (IL)-2 this treatment has in a few other 

countries successively been given to patients with advanced malignant 

melanoma and an impressive 50% response rate has been observed. Here 

we report the experience from a Danish Translational Research Center 

using low-dose subcutaneous IL-2 injections. Methods: A pilot trial including 

patients with metastatic melanoma, PS �1, age �70, measurable and 

progressive disease, and no CNS involvement. Six patients were treated 

with lymphodepleting chemotherapy, TIL infusion, and 14 days of low-dose 

IL-2, 2 MIU/day. Results: Low-dose IL-2 considerably decreased the 

toxicity of the treatment with no grade 3-4 events related to this drug. Two 

of the 6 treated patients have an ongoing complete response (30� and 7� 

months), 2 patients had stable disease (4.5 and 5 months) and 2 patients 

progressed shortly after treatment. Five patients went through surgery but 

were not treated because of rapid disease progression (2), development of 

brain metastases (2) or the inability to grow cells (1). Tumor-reactivity of 

the infused cells and peripheral monocytes before and after therapy were 

analyzed. High tumor responses in the infusion products were correlated to 

clinical response and also an induction of tumor reactive T cells were seen 

in the peripheral blood for 1 patient in complete response. Conclusions: 

Complete and durable responses are induced after treatment with adoptive 

cell transfer in combination with low-dose IL-2 questioning the need for 

high and toxic doses of IL-2. 


A phase I study of the safety and pharmacodynamic effects of everolimus in 

combination with lenalidomide in patients with advanced solid malignancies. 

Presenting Author: Taofeek Kunle Owonikoko, Winship Cancer Institute, 

Emory University, Atlanta, GA 

Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are 

both potent anti cancer agents with immunomodulatory effects. Preclinical 

evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor 

and lenalidomide provided the rationale for this phase I study. Methods: 

Patients with advanced solid malignancies, ECOG performance status (PS) 

0-2 and adequate organ function were eligible. Using standard 3�3 dose 

escalation schema, patients were treated in cohorts of three with increasing 

doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day 

cycle. Treatment cycles were repeated until disease progression by RECIST 

criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment 

on circulating B and T lymphocytes subsets were assessed by multiparameter 

flow cytometry at baseline and after 2 cycles. Results: We enrolled 21 

patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5); 

median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient 

grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%) 

without dose limiting toxicities. The median number of completed cycles 

was3(1-�15) and best response in 14 of 18 evaluable patients was 

stable disease (range 2- �14 months); median PFS was 116 days (14- 

�498). The RP2D of E and L was defined as 10mg and 25mg once daily, 

respectively. PD endpoint analysis after 2 cycles of treatment showed a 

significant increase in activated cytotoxic T cell subset (CD8�ICOS1�) in 

patients with salivary or thyroid cancers compared to other tumor types 

(�2051.0 vs. �394 vs. -1687.4 respectively; p�0.0303) and a trend for 

an increase in patients with non-progressing tumors (�661.7 vs. -384.1; 

p�0.0988). Other significant correlations were: Changes in total B-cells 

(CD3-CD19�) with PFS; NK cells with age (p�0.0211) and activated T 

cells (CD3�CD69�; CD3�CD62L-; p�0.01) with gender. Conclusions: 

The combination of E and L is well tolerated at the recommended single 

agent doses and showed promising efficacy in neuroendocrine and salivary 

adenoidcystic carcinoma. Modulation of activated T cell subsets 

(CD8�ICOS1�) correlates with efficacy of these agents. 




Vaccine therapy with tumor-specific mutated ras peptides and IL-2, 

GM-CSF, or both in adult patients with solid tumors. Presenting Author: 

Osama E. Rahma, National Institutes of Health/National Cancer Institute, 

Bethesda, MD 

Background: We have shown in previous trials that vaccination with mutant 

ras peptides corresponding to the tumor mutation is feasible and can 

induce specific immune responses against the mutant proteins. Immune 

adjuvants are used to enhance the effect of antigen vaccines. Here, we 

tested the ras vaccine in combination with Interleukin-2 (IL-2), GM-CSF, or 

the combination of both in patients with advanced malignancies. Methods: 

We treated 53 patients with advanced cancers (38 CRC, 11 pancreatic, 3 

NSCLC and 1 cholangiocarcinoma) with 5000�g of the corresponding 

mutant ras peptide given SQ along with IL-2 (Arm A), GM-CSF (Arm B) or 

both (Arm C). IL-2 was given SQ at 6.0 million IU/m2/day starting day 5, 5 

days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 �g/day one 

day prior to each vaccination for 4 days. Vaccines were repeated every 4 

weeks for a maximum of 15 cycles or until disease progression. Results: The 

median PFS and OS for the full cohort was 3.6, and 16.9, respectively. 

Median PFS was 3.9, 3.2 and 3.6 months for arm A, B, C, respectively. 

Median OS was 17.3, 20.8 and 9.1 months, respectively. There was no 

difference in PFS or OS between the three arms (p� 0.74 and 0.99, 

respectively). In a subgroup analysis, patients with advanced CRC had a 

median PFS and OS of 3.5 and 14.2 months, respectively. Most adverse 

events were grade I-II toxicities and resolved spontaneously. Conclusions: 

Two important conclusions came out of this trial: 1) no difference was 

found in clinical response between the three arms; and 2) although patients 

with CRC in the subgroup analysis progressed earlier compared to historical 

control (3.5 vs. 7.3 months), the time from progression to death “post 

progression survival, PPS” was notably longer (10.3 vs. 5.6 months). This 

provides further evidence to the emerging understanding of the difference 

in clinical trial monitoring between immunotherapy and other types of 

therapy. Accordingly, removing patients with standard CTEP definition of 

progressive disease may adversely affect the clinical outcome of vaccine 

therapy. We believe that future clinical trial design strategies in cancer 

vaccine should be modified to allow patients to continue therapy despite of 

disease progression. 


Targeting hyaluronan (HA) in tumor stroma: A phase I study to evaluate the 

safety, pharmacokinetics (PK), and pharmacodynamics (PD) of pegylated 

hyaluronidase (PEGPH20) in patients with solid tumors. Presenting Author: 

Mitesh J. Borad, Mayo Clinic, Scottsdale, AZ 

Background: HA, a glycosaminoglycan, accumulates in ~25% of solid 

tumors and is associated with poor prognosis. Tumors that accumulate HA 

develop high interstitial fluid pressure (IFP) and become resistant to 

chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA 

and increased efficacy of chemotherapy. Methods: This ongoing phase 1 

study was designed to assess safety, tolerability, PK, PD, and the maximum 

tolerated dose (MTD) of PEGPH20 as a single agent in patients with 

treatment-refractory solid tumors. IV PEGPH20 was administered in a 

twice weekly or a once weekly dosing schedule with oral dexamethasone 

(dex) pre-and post dose. Biomarkers included tumor histochemistry to 

detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. 

Results: Fifteen patients have been enrolled into the study. Dose administration 

ranged from 0.5 �g/kg to 5 �g/kg. Musculoskeletal events (MSEs) were 

the most common and dose limiting toxicities. To date, up to 3 �g/kg twice 

weekly IV infusions of PEGPH20 were well tolerated with manageable 

Grade 1 MSEs in most patients. MTD has not been reached. Plasma 

concentrations of PEGPH20 showed dose proportional exposure with a 

terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected 

by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor 

biopsies from 2 colon patients demonstrated 23-60% reduction in tumor 

HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated 

increased tumor perfusion (Ktrans ) and decreased metabolic activity 8 and 

24hrs post-PEGPH20 in one patient each. Doses of �3 �g/kg were 

tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels � 3 

�g/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in 

dose-dependent systemic exposure and is tolerated with concomitant dex 

treatment. HA catabolites in plasma demonstrated the in vivo enzymatic 

activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI 

and FDG-PET images confirmed PD activity. Increased tumor perfusion by 

PEGPH20 may enhance drug delivery to tumor. Combination studies of 

PEGPH20 with cytotoxic chemotherapy are planned. 

161s 


An alternative clinical trial design for early cancer vaccine development to 

phase 3�3 design. Presenting Author: Emily Gammoh, National Institutes 

of Health, Bethesda, MD 

Background: Traditional phase I, “3�3 dose escalation” design, is conducted 

to identify the MTD and in some cases the optimal biologic dose. 

Given their unique mechanism of action and the profile of their clinical 

outcome, this design may not apply to cancer vaccines. The therapeutic 

cancer vaccine FDA guidance calls for an alternative early development 

design. Nevertheless, whether an alternative design should be based on 

“dose escalation” is still an opened question. Methods: We analyzed the 

toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine 

trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 

vaccine related systemic toxicities were reported in 4952 treated patients 

(1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used 

dose escalation reported vaccine related DLTs, both trials used bacterial 

vectors. Furthermore, correlation of immunological response with dose 

level showed no consistent trend. Conclusions: Our analysis suggests that in 

cancer vaccines neither toxicity nor cellular immune response correlates 

with dose levels. Accordingly, dose escalation is not suitable for most 

cancer vaccine studies. Here, we propose a two-step alternative design for 

early development of cancer vaccines. The first step is to determine and 

confirm the minimum Immune-Active Dose (IAD). If a vaccine class has 

been used in humans, IAD dose is chosen based on previous experience if 

the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation 

will be used. For a vaccine class that has not been tested or has 

undetermined toxicity we recommend “One Patient Escalation Design” 

(OPSD): one patient is treated per tested dose until an immune response is 

induced. To confirm this activity, an expanded cohort of 7 patients will be 

tested until demonstrating an additional response. This will then be used in 

phase II combination therapy trial. Alternatively, IAD can be directly tested 

in combination with an immune modulator in a phase II clinical trial using a 

two-stage design. The first stage of the phase 2 trial can be set at 4-5 

patients for a target response rate of over 50%. If no response is seen, then 

the immune modulator will be escalated in the second stage. 


Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of 

NGR-hTNF given at high doses in patients with refractory solid tumors. 

Presenting Author: Paolo Andrea Zucali, Department of Oncology, Humanitas 

Cancer Center, Rozzano, Italy 

Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) 

peptide for selectively targeting tumor necrosis factor (TNF) to a CD13 

overexpressed by tumor vasculature. Maximum tolerated dose (MTD) of 

NGR-hTNF was previously established at 45 �g/m2 , when given as 1-h 

infusion every 3 weeks (q3w), with dose limiting toxicities (DLT) being 

grade 3 infusion-related reactions (IRRs). We explored further dose 

escalation by prolonging infusion time (2-h) and using premedication 

(paracetamol). Methods: DLTs were defined as drug-related grade 3/4 

adverse events (AEs). PK and soluble TNF receptors (sR1-sR2) were tested 

in 46 pts. The volume transfer coefficient (Ktrans ) and initial area under 

gadolinium concentration (IAUGC) were assessed before and 2 hours after 

dosing by dynamic contrast-enhanced magnetic resonance imaging (DCE- 

MRI) in 37 pts. Results: 12 dose levels (DLs) from 60 to 325 �g/m² q3w 

were evaluated. 48 pts (PS 0/1: 21/27; M/F: 37/11; median age: 61 years) 

received a total of 117 cycles (range 1-6). Prior regimens ranged from 1 to 

7 (median 3). No DLT occurred and MTD was not reached. Study-emergent 

grade 3 and 4 AEs were reported in 12 (25%) and 5 (10%) pts, 

respectively. Grade 1/2 IRRs included chills (58%) and pyrexia (56%). 

Both Cmax (p�.0001) and AUC (p�.0001) increased with dose. Posttreatment 

peaks of sR2 were higher than sR1 (9.6 v 4.9 ng/mL; p�.0001). 

However, changes in sRs did not differ across DLs, with a plateau in 

shedding kinetics. By DCE-MRI assessment, median pre- and post-first 

cycle values declined from 0.15 to 0.09 min-1 for Ktrans (p�.02) and from 

10.2 to 7.2 mM/L/sec for IAUGC (p �.0005). Over treatment, 28 pts 

(76%) showed decreases in IAUGC (-47%, p�.0001) and Ktrans (-59%; 

p�.0001) that were inversely correlated with baseline Ktrans values 

(p�.0001) and NGR-hTNF Cmax (p�.03). Of 41 evaluable pts, 12 (29%) 

had stable disease for a median time of 2.9 months. Survival at 1 year was 

34%, with improved survival observed in pts with lower sTNF-R2 levels 

(p�.01) and greater Ktrans reductions (p�.05) after 1st cycle. Conclusions: 

NGR-hTNF can be safely escalated at doses higher than MTD and induces 

low shedding of receptors and early antivascular effects. 




A phase II, single arm clinical trial involving an alternative cancer treatment 

psorinum therapy in patients with unresectable metastatic colorectal 

carcinoma. Presenting Author: Aradeep Chatterjee, Critical Cancer Management 

Research Centre and Clinic, Kolkata, India 

Background: We prospectively studied the clinical efficacy of an alternative 

cancer treatment “psorinum therapy” in treating unresectable metastatic 

colorectal carcinoma (UMCRC). Methods: Our study was phase-II, open 

level, single arm and single stage. Participants eligibility criteria included 

(1) histopathology confirmation of the malignancy (2) metastatic and 

unresectable disease status (3) No prior conventional cancer treatments 

(4) Karnofsky performance status between 40 – 70%. The primary outcome 

measures of the study were (1) to assess the radiological tumor response 

rate (using CT scanning procedure and following the RECIST criteria); (2) to 

assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and 

finally, after 5 yrs of the study. The secondary outcome measure was to 

assess the side effects of the investigational anticancer drug (psorinum) if 

any. Psorinum (an alcoholic extract of scabies slough and pus cells) was 

administered orally at a dose of 0.02ml / kg body weight / day as a single 

dose on an empty stomach for a complete course duration of 2 yrs to all the 

participants along with allopathic and homeopathic supportive cares. 

Results: 105 participants included in the final analysis at the end of the 

study. According to the RECIST criteria, complete response occurred in 12 

(11.43%) cases and partial response occurred in 38 (36.19%) cases. 76 

(72.38%) of them survived at least 1 yr, 58 (55.24%) survived at least 2 

yrs, 51 (48.57%) survived at least 3 yrs, 43 (40.95%) survived at least 4 

yrs and 37 (35.24%) of them survived at least 5 yrs. These participants 

didn’t receive conventional or any other investigational cancer treatments. 

Conclusions: The results of the study show clinical efficacy of psorinum 

therapy in treating patients with UMCRC. The investigational drug psorinum 

is nontoxic. Randomized controlled clinical trial should be conducted 

for further investigation of this alternative cancer treatment in 

treating unresectable metastatic colorectal carcinoma to integrate it into 

the mainstream of oncology treatments. 


Phase I/II, two-part, open-label, multiple-dose, dose-escalation study of 

siltuximab in patients with solid tumors. Presenting Author: Eric Angevin, 

Institut de Cancérologie Gustave Roussy, Villejuif, France 

Background: Siltuximab (S) is a chimeric mAb with high affinity for soluble 

IL-6. This Ph 1/2 study evaluated safety, efficacy and PK of escalating, 

multiple IV doses of S from a new cell line in patients (pts) with advanced 

refractory solid tumors. Methods: In Ph 1, S was given to 20 pts with 

advanced solid tumors at escalating dose levels (2.8 or 5.5 mg/kg q2w or 

11 or 15 mg/kg q3w) and to 24 pts with taxane and platinum resistant 

ovarian cancer (OVC) or KRAS mutant (KRASmt) tumors at 15 mg/kg q3w. 

In Ph 2, 17 OVC pts and 23 KRASmt pts received the Ph 1 selected dose of 

15 mg/kg q3w. The Ph 2 primary efficacy endpoint was clinical benefit rate 

(CBR: CR � PR � SD of � 6 wk). Results: In Ph 1-2, 84 pts (35 colorectal, 

29 OVC, 9 pancreatic, 11 other) pretreated with a median of 4 prior tx 

regimens received a median of 3 (range 1, 45) cycles. 1 DLT occurred at 

5.5 mg/kg; MTD was not reached. 62% pts had AEs gr � 3 in Ph 1-2, most 

common were hepatic function abnormalities (15%), PS deterioration 

(12%), fatigue (11%). 10% pts had possibly S-related AEs gr � 3; only 

neutropenia (4%) was reported in �1 pt. 42% pts had SAEs, most were 

related to underlying disease, 2% were possibly S-related. 18 deaths 

occurred on study, 17 due to PD, 1 due to AE. No pt had antibodies to S. 

The PK profile was bi-exponential with a t1/2 ranging 15 � 20 d. PK profile 

of S from the new Chinese hamster ovary cell line appears similar to the 

previous murine Sp2/0 myeloma cell line. CBR in Ph 2 was 5%. ORR by 

RECIST was 26% SD in Ph 1, 9% SD in Ph 2. 1 OVC pt had CA 125 

response. In Ph 2 the median PFS was ~2moinboth cohorts; the median 

OS was 4.2 mo in KRAMSmt and 11 mo in OVC. Hb increased by a max of 

�10 g/L in 73% pts given 15 mg/kg in Ph 2, with 94% showing a median 

decrease of 68% at d 8 after dose 1 in hepcidin, a regulator of iron 

homeostasis. CRP was suppressed in all pts during tx, with median 

decrease 93% at 11 mg/kg and 88 � 93% at 15 mg/kg as early as d 8 after 

dose 1. Other biomarkers will be presented. Conclusions: S appears to be 

well tolerated; doses of 11 � 15 mg/kg q3-4w can be used in future 

studies. No CR/PR was observed, although some pts with advanced solid 

tumors had durable SD and CRP suppression. Improvement in Hb was 

observed in a large proportion of pts, indicating a role of IL-6 in anemia that 

needs to be further explored. 


Randomized phase II trial of multipeptide vaccination with or without a 

single pre-vaccine dose of denileukin diftitox in advanced melanoma. 

Presenting Author: Thomas Gajewski, The University of Chicago, Chicago, 

IL 

Background: The efficacy of immunotherapy approaches such as vaccines 

in melanoma appears limited, in part, due to immune suppressive mechanisms 

in the tumor microenvironment. One of these mechanisms is the 

presence of CD4�CD25�FoxP3� regulatory T cells (Tregs). It has been 

hypothesized that strategies to reduce Treg numbers should improve the 

efficacy of melanoma vaccines. Methods: The study design was to randomize 

24 HLA-A2� patients to receive vaccine alone or denileukin diftitox (18 

mcg/kg i.v.) as a single dose 4 days prior to the first vaccination. The 

vaccine formulation consisted of 4 melanoma antigen peptides (derived 

from MelanA, gp100, MAGE3, and NA17A) emulsified in Montanide and 

GM-CSF, administered i.d./s.c. every 2 weeks. The primary endpoints were 

assessment of depletion of Tregs from the peripheral blood, and measurement 

of antigen-specific CD8� T cell responses by ELISPOT. Secondary 

endpoints included clinical response and analyses of the tumor microenvironment 

for changes in Treg infiltration. Results: The treatment was well 

tolerated. Enrollment was halted at 16 patients when it was clear that 

immune response endpoints would not be reached. There was no significant 

decrease in Treg numbers, nor was there an increase in vaccineinduced 

T cell responses, when patients received denileukin diftitox prior 

to vaccination. In patients with biopsiable tumors, there was no decrease in 

Tregs in metastatic lesions post-versus-pre-treatment. Of the 9 patients 

who showed clinical benefit (1 PR, 8 SD), 4 of them received denileukin 

diftitox and 5 did not. Estimated time to progression was 146 days in the 

group that received denileukin diftitox and 131 days in the group that did 

not. Conclusions: Denileukin diftitox given as a single dose prior to 

vaccination was not sufficient to deplete Tregs or improve the potency of 

this melanoma vaccine. Alternative strategies to reduce Tregs, such as 

multiple doses of denileukin diftitox or anti-CD25 mAbs, should be 

considered. 


Association of humoral antitumor response with clinical benefit in catumaxomab-treated 

malignant ascites patients: Results from a phase IIIb study. 

Presenting Author: Peter Ruf, TRION Research GmbH, Martinsried, Germany 

Background: The bispecific antibody catumaxomab (anti-EpCAM x anti- 

CD3) which is approved for the treatment of malignant ascites (MA) 

patients (pts) in the EU elicits a humoral immune response against 

tumor-associated antigens. Here we present follow up data analyzing the 

influence of this antibody response on puncture free (PFS) and overall 

survival (OS). Methods: In the course of the phase IIIb study CASIMAS, MA 

pts with EpCAM positive tumors were treated with/without prednisolone 

premedication by 4 infusions of 10, 20, 50 and 150 �g of catumaxomab 

over 11 days (d). EpCAM and HER2-specific antibody responses in plasma 

samples of 23 pts were measured by ELISA. Additionally, samples of 5 pts 

receiving a second treatment cycle were analyzed. Pts with significant 

increase (� 2) or de novo development of anti-tumor antibodies within 38 d 

after treatment start were defined as responders (R). Non responders (NR) 

showed no humoral response by d 38 or died before. PFS and OS of R and 

NR were compared by Kaplan Meier analysis. Results: 11 of 23 pts (48%) 

showed an anti-EpCAM response and 14 of 23 pts (61%) developed 

HER2-specific antibodies. 6 pts (26%) reacted positive against both 

antigens, 4 pts (17%) had neither response. In contrast to the EpCAM R 

group where 73% of pts displayed detectable antibodies prior to therapy, 

antibodies against HER2 developed de novo. Of note, 4 of 5 individuals 

who received a second treatment cycle after recurring MA demonstrated an 

anti-HER2 Ig booster reaction which was stronger and faster in comparison 

to pts who received only one treatment cycle (median values at d 18: 65 vs. 

11 ng/ml). Most important, there was an almost 6 fold increase in median 

PFS between the HER2 R and NR group (68 vs 12 d, p � 0.044 (log-rank). 

There was also a trend towards improved OS for pts showing either 

anti-HER2 and/or anti-EpCAM responses (n�19) in comparison to pts with 

no response at all (n�4; 143 vs. 67 d, median, p � 0.054). Conclusions: 

The results indicate that active anti-tumor immunization triggered by 

catumaxomab treatment in MA pts is associated with improved clinical 

outcome. Further investigations of these vaccine-like effects with higher 

pts numbers are warranted. 




Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI 

responses in patients with advanced CEA-expressing malignancies in a 

phase I/II clinical trial. Presenting Author: Michael Morse, Duke University 

Medical Center, Durham, NC 

Background: Adenovirus (Ad) vectors are promising platforms for use as 

cancer vaccines because of their substantial immunogenicity; however, 

Ad-specific neutralizing antibodies, present due to natural infection, limit 

their use. We created a new vector containing additional deletions of the 

E2b gene and observed that this Ad5 [E1-, E2b-] vector, engineered to 

express carcinoembryonic antigen (CEA(6D)), could induce antitumor 

immune responses in mice despite pre-existing Ad5 immunity. The 

purpose of the current translational study was to evaluate the immunologic 

effect of increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice and then to 

extended these pre-clinical observations into a phase I/II study. Methods: 

Ad5 naïve female C57Bl/6 mice, 4-6 weeks old, were immunized subcutaneously 

3 times at 2 week intervals with doses of 1.4X107 viral particles 

(vp) up to1.4X109 vp of Ad5 [E1-, E2b-]-CEA(6D). Two weeks after the last 

immunization, splenocytes were harvested for immune determinations. 

Cohorts of patients (n�25 total) with advanced colorectal cancer, refractory 

to prior therapies, received escalating doses of Ad5 [E1-, E2B-]- 

CEA(6D) (109 to 1011 vp) subcutaneously every 3 weeks for 3 

immunizations.CEA-specific cell mediated immunity was measured by 

ELISPOT. Results: Increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice 

induced increasing CEA-specifc CMI responses. Similarly, patients who 

received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the 

highest levels of CEA-specific CMI responses. The induction of CEAspecific 

CMI responses increased over the course of the 3 injections despite 

the presence of pre-existing Ad5 immunity in the majority (75%) of 

patients. There were no drug related grade 3/4 toxicities.Two patients with 

stable disease remained so during the study. All other patients experienced 

progressive disease; however, 1-year survival was 54%. Conclusions: 

Multiple homologous doses of Ad5 [E1-, E2b-]-CEA(6D) could break 

tolerance and generate CEA-specific CMI responses in the setting of Ad 

specific immunity in colorectal cancer patients. 


Development of an assay based on SOMAmer affinity reagents that detects 

drug-unbound serum EGFR in the presence of cetuximab and panitumumab. 

Presenting Author: Noh Jin Park, Quest Diagnostics, San Juan 

Capistrano, CA 

Background: EGFR is an oncogene product whose extracellular domain 

(ECD) can be either up-regulated or down-regulated in serum of patients 

with various cancers. In colon cancer patients with positive tissue EGFR 

expression, 2 EGFR ECD-targeting monoclonal antibody drugs, cetuximab 

(Erbitux) and panitumumab (Vectibix), are widely used chemotherapeutic 

agents. Patient responses to these drugs vary, and the mechanism of this 

variability remains unelucidated. Methods: A Slow Off-Rate Modified 

Aptamer (SOMAmer) targeting the EGFR ECD was selected via Systematic 

Evolution of Ligands by Exponential Enrichment (SELEX). Using this 

SOMAmer as a capturing reagent and based on published studies ( Gold et 

al. PLoS ONE; Dec 7, 2010:10.1371/journal.pone.0015004), we developed 

a quantitative serum EGFR assay to reliably quantify EGFR in serum. 

Results: Recovery tests using various amounts of purified EGFR spiked into 

serum demonstrated a full level of EGFR. Intra and inter assay variability 

were tested and showed minimum variability. The detection range is 0.95 

ng/ml to 600 ng/ml. Interestingly, when serum samples from patients 

taking cetuximab or panitumumab at the time of blood collection were 

tested, we observed markedly lower levels of EGFR-captured SOMAmer. 

ELISA assays from 2 different vendors showed normal to high levels of 

EGFR in these samples. We further showed that pretreatment of normal 

serum with either cetuximab or panitumumab can dose-dependently 

reduce the EGFR SOMAmer signal. The data suggest that our EGFR 

SOMAmer assay detects serum EGFR molecules that are unbound by 

cetuximab or panitumumab. Some treated patient samples had more 

drastic reductions in circulating serum EGFR than others. Conclusions: 

Various assay development parameters such as accuracy, detection range, 

and intra and inter assay variability showed that a SOMAmer-based assay 

detecting serum EGFR can be used in a clinical setting. Our data suggest 

that this assay can accurately measure drug-unbound EGFR in patients, 

which may serve as a surrogate drug efficacy indicator, and this may help 

physicians to adjust the drug dosage. Further studies will be necessary to 

investigate this possibility. 

163s 


Effect of modulation of the hostile tumor microenvironment through 

adoptive transfer of IL-12 expressing MUC-16 targeted T cells on ovarian 

tumors in vivo. Presenting Author: Alena A. Chekmasova, Memorial 


Background: T cells may be genetically modified to recognize tumor 

associated antigens (TAAs) through the introduction of genes encoding 

artificial T cell receptors termed chimeric antigen receptors (CARs). 

MUC16 (CA125) is an antigen over-expressed on ovarian carcinomas and a 

serum marker for the diagnosis of ovarian cancer. We have previously 

demonstrated enhanced antitumor efficacy of CAR � T cells further modified 

to secrete IL-12. We therefore tested whether MUC-16 targeted T cells 

further modified to express IL-12 would exhibit an enhanced antitumor 

efficacy in a syngeneic immunocompetent tumor model of ovarian cancer. 

Methods: We have constructed SFG retroviral vectors encoding the second 

(4H11m28mz) generation CARs as well as IL-12 modified CAR 

(4H11m28mz/mIL12) targeted to the retained extra-cellular domain of 

MUC16, termed MUC-CD. We demonstrated an antitumor efficacy of these 

T cells in a syngeneic tumor model using the C57BL6 (B6) mice 

intraperitoneally (i.p.) injected with ID8(MUC-CD) tumor cells. Results: In 

our studies treatment of mice bearing established ID8(MUC-CD) ovarian 

tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T 

cells targeted to MUC-CD alone, fully eradicate highly advanced intraperitoneal 

ovarian tumors. Significantly, we found that mice treated with 

4H11m28mz/mIL12 T cells had increased number of modified T cells in 

the peritoneum at day 4 and 7 with increased recruitment of endogenous T 

cells to the site of the tumor when compared to controls and mice treated 

with 4H11m28mz T cells. The observed antitumor effect did not required 

prior lymphodepletion and was well tolerated in treated mice. Conclusions: 

CAR modified T cells targeted to the MUC-16 antigen efficiently eradicate 

orthotopic ovarian cancer in syngeneic immunocompetent mice with 

markedly enhanced antitumor efficacy seen in those mice treated with 

CAR � T cells further modified to secrete IL-12. These data support future 

clinical trials utilizing adoptive T cell therapy in patients with relapsed 

ovarian cancer. 


Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on 

multifunctional T-cell responses in ovarian, breast, and prostate cancer 

patients. Presenting Author: Neil Lorne Berinstein, Odette Cancer Centre, 


Background: To increase the efficacy of peptide cancer vaccines, we 

developed a novel vaccine platform called DepoVax, an adjuvanted waterfree 

depot formulation with the ability to generate enhanced immune 

responses. Naturally processed HLA-A2 restricted peptides that are selectively 

presented by breast, ovarian and prostate cancer cell lines, but not by 

normal HLA-A2� cells, were used as antigens with a proprietary adjuvant 

and a T helper peptide epitope to create a therapeutic cancer vaccine, 

DPX-0907. Methods: A phase I clinical study was designed to examine the 

safety and immune activating potential of DPX-0907 in advanced stage 

breast, ovarian and prostate cancer patients. A total of 23 late stage cancer 

patients were recruited and were divided into two dose volume cohorts in a 

three immunization clinical protocol. Results: DPX-0907 proved to be safe 

with no serious adverse effects related to the vaccine reported. Of those 

evaluable for immunogenicity, all breast cancer patients (3/3), most of 

ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated 

immune response to one or more of seven antigenic peptides, resulting in a 

61% response rate. Immune responses correlated with achievement of CR, 

PR or SD to last treatment. No difference in immune response rate or 

magnitude was seen between the two dose groups. DPX-0907 displayed 

strong immune induction potential, with 73% of immune responders 

showing responses with just one dose of vaccine. In 83% of responders, 

immune responses were detected at �2 time points post vaccination and 

64% had a persistent immune response at one month post last vaccination. 

Immune monitoring showed peptide-specific CD8 T cells, and these T cells 

were able to secrete multiple Th1 cytokines indicating their multifunctionality, 

a feature attributable to cells that mediate protective responses. 

Conclusions: These data support the ability of DPX-0907 to elicit Th1 

dominated, specific immunity and support the rationale for further testing 

in immunologically competent cancer patients. The novel DepoVax formulation 

may promote multifunctional memory responses with peptides from 

other tumor associated antigens. 




Phase I/II study of resiquimod as an immunologic adjuvant for NY-ESO-1 

protein vaccination in patients with melanoma. Presenting Author: Rachel 

Lubong Sabado, New York University Cancer Institute, New York, NY 

Background: The TLR 7/8 agonist, Resiquimod has been shown to induce 

local activation of immune cells, production of cytokines, and antigenpresentation 

by dendritic cells, features desirable for cancer vaccine 

adjuvants. In this study, we evaluated the safety and immunogenicity of 

vaccination with NY-ESO-1 protein emulsified in Montanide ISA-51 VG 

when given with or without Resiquimod in patients with surgically resected 

stage IIB-IV melanoma patients. Methods: This is a two-part study design. 

Part I represents an open-label dose-escalation with Resiquimod using 2 

cohorts treated with 100ug NY-ESO-1 protein emulsified in 1.25mL 

Montanide (day1) followed by topical application of 1000mg of the 0.2% 

Resiquimod gel on days 1 and 3 for cohort-1 (N�3) or days 1, 3, and 5 for 

cohort-2 (N�3). The cycles were repeated every 3 weeks, total of 4 cycles. 

Part II of the study is blinded. Patients were randomized to receive 100ug 

NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by 

topical application of placebo gel (Arm-A; N�8) or 1000mg of 0.2% 

Resiquimod gel (Arm-B; N�12) using the dosing regimen established in 

Part I. Blood samples were collected at baseline, one week after each cycle 

of vaccination, and at follow-up visit for the assessment of NY-ESO-1specific 

humoral and cellular immune responses. Results: Enrollment has 

been completed. 25/26 patients received all 4 vaccinations. The treatment 

was generally well-tolerated, with no grade 4 adverse events or studyrelated 

deaths. The most common toxicities were mild to moderate and 

included local injection site reactions (granuloma, pruritus, induration) and 

systemic flu-like symptoms. One patient experienced a grade 3 syncopal 

episode that was deemed unrelated to the drug. Another patient experienced 

a grade 3 injection site necrosis that was possibly related to the study 

drug and was removed from the study prior to receiving the 4th vaccine. 

Conclusions: This study demonstrates the safety of Resiquimod as an 

adjuvant for NY-ESO-1 protein vaccination. The study will remain blinded 

until all immune monitoring assays have been completed. An updated 

abstract will be submitted once the study is unblinded. 


Cellular function of the mononuclear phagocyte system (MPS) as a 

phenotypic probe for pharmacokinetics (PK) and pharmacodynamics (PD) 

of PEGylated liposomal doxorubicin (PLD) in patients with recurrent 

ovarian cancer. Presenting Author: Whitney Paige Caron, University of 

North Carolina at Chapel Hill, Chapel Hill, NC 

Background: A phenotypic probe is a test that can be administered to a 

patient as a potential indicator of a drug’s PK/PD which can then be used to 

individualize therapy. Since nanoparticles are cleared via the MPS, 

including blood monocytes (MO), we hypothesize that circulating MO could 

potentially play a major role in, and be a surrogate marker of nanoparticle 

clearance (CL). Furthermore, we postulate that the ability to measure MO 

functional activity in blood samples can be used to predict CL and 

subsequently PD endpoints such as progression free survival (PFS) and 

hand-foot syndrome (HFS), in patients (pt). Methods: PLD 30/40 mg/m2 IV 

x 1 with or without carboplatin (AUC � 5 mg/mL/min) was administered to 

pts (n�10) with recurrent ovarian cancer. Serial PK samples were obtained 

at time 0 to day 28 post dose. Plasma was processed to measure 

encapsulated and released doxorubicin using solid phase separation and 

HPLC. Data was analyzed with WinNonlin to obtain PK parameters. MO and 

granulocyte phagocytic function (uptake of FITC-labeled opsonized E. Coli) 

and oxidative burst activity (intracellular oxidation of dihydrorhodamine 

123) were assessed via flow cytometry at 0, 48, 96 h, and on day 28. For 

both assays, changes in mean fluorescence intensity of the gated MO 

population, following incubation of whole blood with the appropriate 

substrate, served as an index of activity. Pts were followed from the first 

dose of PLD until time of disease progression. Results: There was a direct 

linear relationship between encapsulated doxorubicin CL and both phagocytosis 

(R2 � 0.87) and oxidative burst activity (R2 � 0.64) in blood MO. 

Similarly, phagocytosis (R2 � 0.77) and oxidative burst probes correlated 

with PFS (R2 � 0.67) in the 4 pts who progressed while on PLD. Oxidative 

burst also correlated with degree of HFS (R2 � 0.56). There was no 

relationship between phagocytosis and oxidative burst in granulocytes and 

PK/PD of PLD. Conclusions: These findings indicate that probes of MPS 

function predict PLD CL, HFS and PFS and thus may be useful for 

individualizing PLD therapy in ovarian cancer and other malignancies. 


A phase I study of lapatinib (LPT) and cetuximab (CTX) in patients with 

CTX-sensitive solid tumors. Presenting Author: John F. Deeken, Lombardi 

Comprehensive Cancer Center, Georgetown University, Washington, DC 

Background: Preclinical research has shown that one mechanism of 

acquired resistance to CTX is via EGFR-ErbB2 heterodimerization, which 

can reactivate oncogenic pathways. LPT is a dual EGFR and ErbB2 

intracellular tyrosine kinase inhibitor. A phase I translational clinical study 

was performed to determine the maximum tolerated dose (MTD), dose 

limiting toxicities (DLTs), and clinical activity of CTX and LPT in patients 

with EGFR-driven solid tumor malignancies that can be treated with CTX. 

Methods: Patients (Pts) were enrolled in a 3�3 dose escalation trial. Prior 

CTX therapy was allowed. CTX was given at 400mg/m2 on Cycle 1, Day 1 

(C1D1), then 250 mg/m2 weekly. LPT dose levels (DL) were (1) 750mg, (2) 

1000mg, and (3) 1250mg orally daily. Rash management included daily 

sunblock, steroid cream, and doxycycline. Cycle length was 21 days, and 

patients were assessed for toxicity through the end of C2, and for efficacy 

after every 2 cycles. Fresh tumor biopsies were obtained at baseline and at 

the end of C1 to compare EGFR and ErbB2 expression levels and EGFR 

related pathway activation. DNA from blood samples was analyzed for 

pharmacogenetic (PGx) variations and correlations with toxicity and pharmacokinetics 

(PK). Results: Between October, 2010 to January 2012, 13 

pts were enrolled, with colon (4), lung (3), head and neck (3), and anal 

cancers (3); 10 were evaluable for toxicity. Treatment-related toxicities of 

any grade included: rash (67%), diarrhea (42%), fatigue (33%), nausea/ 

vomiting (17%), and dehydration (8%). DLTs included G3 rash in 1 of 6 pts 

on DL1, and G3 diarrhea despite optimal therapy in 1 of 4 pts on DL2. 

Enrollment to DL2 continues. Of 7 pts evaluable for response, 1 had an 

uPR, 3 had SD, including 1 with SD of �4 cycles, and 3 had DP. Both 

patients with uPR and prolonged SD were treated on DL1. Tumor 

EGFR-ErbB2 and EGFR pathway phosphorylation analyses and PGx results 

will be presented. Conclusions: The combination of CTX and LPT is well 

tolerated with expected toxicities. Efficacy was seen even on DL 1. Phase II 

clinical studies in CTX-sensitive diseases such as colon and head and neck 

cancer are planned. 


Phase I study of docetaxel injection concentrate for nano-dispersion 

(DICN), a novel polysorbate 80-free formulation of docetaxel. Presenting 

Author: Minish Mahendra Jain, KEM Hospital and Research Center, Pune, 

India 

Background: A polysorbate 80-free formulation of docetaxel may preclude 

the need for dexamethasone pre-medication and may also reduce toxic 

effects associated with polysorbate 80. DICN is a novel polysorbate 80-free 

formulation of docetaxel stabilized with lipid and polymer using NanotectonTM 

technology. We studied safety, tolerability, and the pharmacokinetics 

(PK) of DICN in patients with advanced solid malignancies. Methods: Entry 

criteria included: age 18-65 years, histologically/cytologically confirmed 

advanced malignancy, performance status � ECOG 2, estimated survival � 

12 weeks, and adequate organ function. A standard phase I 3�3 dose 

escalation schema was employed with an increase of 12.5 to 50% over 

previous DICN dose level as per safety profile. The infusion was 60 min for 

1 cycle and major objectives were to determine maximum tolerated dose 

(MTD), and PK and safety profiles. Premedication to prevent hypersensitivity 

was not administered to patients receiving DICN. Three patients were 

treated with docetaxel 75 mg/m2 to gather PK data. Plasma was analyzed 

for docetaxel level using a validated assay. Results: Twenty-seven patients 

treated with DICN had a mean age of 48.8 yrs (range 29-65); 21 were 

females; and entered with metastatic breast cancer (MBC; n�14), nonsmall 

cell lung carcinoma (NSCLC; n�6), ovarian (n�2), and other (n�5). 

Doses (mg/m2 ) studied were 60 (n�7), 75 (n�5), 100 (n�3), 125 (n�3), 

150 (n�6), and 170 (n�3). Despite lack of dexamethasone premedication, 

no patient receiving DICN reported a hypersensitivity reaction. Two 

DLTs (febrile neutropenia) were reported at DICN 170 mg/m2 . DICN PK 

(AUC AUC 0-24, 0-�, and Cmax) increased in a dose proportionate manner from 

60 to 170 mg/m2 . Compared with docetaxel 75 mg/m2 ,Cmax and AUC0-24 of DICN 75 mg/m2 was 1.4 and 1.2 times higher, respectively, and 1.9 and 

1.8 times higher, respectively for DICN 150 mg/m2 . The median Tmax of 

DICN 75 mg/m2 and docetaxel 75 mg/m2 were 1.00 and 0.517 hours, 

respectively. Conclusions: In this study,DICN demonstrated acceptable 

tolerability and a favorable PK profile. A 150 mg/m2 is the recommended 

phase II dose for DICN. 




Phase I and pharmacokinetic (PK) study of pazopanib (P) in combination 

with two schedules of ifosfamide (I) in patients (pts) with advanced solid 

tumors (STs). Presenting Author: Paul Hamberg, Erasmus University 

Medical Center, Daniel den Hoed Cancer Center, Rotterdam, Netherlands 

Background: P is a tyrosine kinase inhibitor of PDGFR, VEGFR and KIT. This 

study aimed to determine the recommended phase II dose (RP2D) of P 

combined with I. To assess the impact of scheduling on tolerability, two I 

schedules were explored. Methods: Pts with progressive ST, no standard 

therapy available, PS 0-1 and good organ function were eligible. Pts 

received daily P with 3-weekly I, 9 g/m2 /cycle, either continuously (Iciv) or 

as 3 hrs boluses (Ibolus) for 3 days. P was escalated in serial cohorts of 3-9 

pts per I-schedule. If in 3-6 pts dose-limiting toxicity (DLT) of 33.3% 

within 1st cycle was seen 3 more pts at that dose level (DL) were enrolled. 

RP2D was exceeded if in � 1/3 pts, � 2/6 pts or � 3/9 pts DLT occurred. P 

was maximized at 1000 mg/day. At RP2D, an expansion cohort of 6-9 pts 

was studied to confirm safety. PK samples of P and I were collected in all 

pts. Sampling allowed intra-individual comparison of I-PK with or without P 

and vice versa. Results: 47 pts were studied. For Iciv (25 pts), RP2D was 

the maximum dose of P (1000 mg), higher than the single agent RP2D. At 

RP2D 2 DLTs in 15 pts occurred: 1 febrile neutropenia (FN); 1 encephalopathy. 

With Ibolus (22 pts), P 400 mg with or without GCSF was not tolerated 

(5 DLTs in 10 pts: 3*FN, 1 encephalopathy; 1 proteinuria). At RP2D (P 

200 mg � Ibolus � GCSF) 3 DLTs in 12 pts (FN; encephalopathy, renal 

insufficiency) were observed. Toxicity occurring in �30% of pts in Iciv (all 

grades/grade 3-4,%) were neutropenia (92/92) anemia (92/8); thrombocytopenia 

(35/12), elevated ASAT, ALAT, alkaline phosphatase (73/4; 73/0; 

62/2), nausea (58/0), vomiting (73/0), diarrhea (54/0) and hypertension 

(31/12). 4/25 pts in Iciv evaluable for response had PR (2 sarcoma, 2 

ovary) and 10 prolonged (�3 mths) SD. In Ibolus, 6/20 pts had PR (2 

urothelial, 1 sarcoma, 1 ovary, 1 CUP, 1 mesothelioma) and 3/20 

prolonged SD. Preliminary PK analysis showed no effect of P on I-exposure, 

neither of Ibolus or Iciv on P. Conclusions: P is tolerated at a higher dose 

combined with Iciv compared to Ibolus (1000 vs 200 mg). PK cannot 

explain this difference. This study underlines the impact of scheduling on 

the tolerability of VEGFR-TKI and cytotoxic drug combinations. 


Pharmacokinetic modeling and simulation (PK M&S) supported dose 

escalation of PF-03446962, a monoclonal antibody (mAb) against activin 

receptor like kinase 1, in patients with solid tumors. Presenting Author: 

Erjian Wang, Pfizer Inc., San Diego, CA 

Background: PF-03446962 is a first in class mAb. The PK of mAbs is 

complex, as their clearance (CL) can be linear or non-linear, besides 

extremely slow. Caution must be exercised when designing mAbs’ dose 

escalation schemes. Along with safety and activity evaluation, we used PK 

M&S in real time to ensure that subsequent recommended doses did not 

expose too many patients to subtherapeutic levels while preserving safety. 

Methods: The model incorporated both Michaelis-Menten approximation 

and linear components. A prespecified target exposure was defined by 

preclinically projected therapeutic and toxic concentrations. The PK M&S 

results were used to make dose escalation decisions. Results: Eight dose 

levels (0.5, 1, 2, 3, 4.5, 6.75, 10, and 15 mg/kg) were studied in 44 

patients. CL of PF-03446962 exhibited nonlinear characteristics at low 

doses and linear at high doses. CL was saturated at dose levels of 3 mg/kg 

and above. Mean half-life was 2.6 days for the first dose level and 12-15 

days after CL saturation. The dose ratio of 15 to 0.5 mg/kg was 30, while its 

corresponding Cmax and AUC ratios were 46 and 97, respectively. 

However, the PK M&S accurately predicted exposure following each dose. 

95% of the observed drug concentrations across all dose levels were within 

the predicted values. Concentrations at the 4.5 mg/kg dose exceeded the 

predicted efficacious level over the dosing period. None of 44 patients in 

the study were exposed to the toxic level derived from a study in monkeys. 

PK data also implied a biologically active dose at 2 mg/kg dose and above, 

confirmed by observing target toxicities (ie, telangiectasia) and clinical 

tumor responses. One patient with PR was at the 2 mg/kg dose and 2 

patients with PR were at the 10 mg/kg. The PK M&S well predicted the drug 

exposure following multiple doses in patients, indicating that patients did 

not develop antidrug immunogenicity. Conclusions: The PK M&S based 

approach ensured that the majority of patients were treated at or near the 

therapeutic dose. It can be readily implemented in the conduct of dose 

escalation trials of antitumor mAbs, while minimizing risk to patients and 

maximizing efficiency. 

165s 


Modeling the combined efficacy of rilotumumab (R; AMG 102) plus 

epirubicin/cisplatin/capecitabine (ECX) for the treatment of locally advanced 

or metastatic gastric or esophagogastric junction (G/EGJ) cancer. 

Presenting Author: Sameer Doshi, Amgen Inc., Thousand Oaks, CA 

Background: R is an investigational, fully human monoclonal antibody to 

hepatocyte growth factor/scatter factor (HGF/SF) that inhibits signaling 

though the MET receptor. In a double-blind, placebo-controlled, phase 2 

trial of 121 patients with G/EGJ cancer, R (7.5 or 15 mg/kg) � ECX showed 

trends for improved progression-free survival (PFS) and overall survival 

compared to ECX alone. The combined effects of R and ECX on tumor 

reduction and PFS were modeled using the phase 2 data. Methods: A 

population pharmacokinetic (PK) model was used to estimate R PK 

parameters and individual R concentrations (C) over time. A tumor dynamic 

model was developed to characterize the combined effects of R with ECX on 

tumor growth and cell death and to evaluate the impact of baseline patient 

characteristics and lab values on model parameters. A discrete timesurvival 

model was developed with PFS and C data to evaluate the effect of 

R, ECX, and the interaction between R and ECX on PFS within a given time 

interval. Results: R exhibited linear PKs with an estimated mean clearance 

of 0.216 L/d/70 kg. The tumor dynamic model suggested that R and ECX 

worked jointly to reduce tumor size from baseline via inhibition of the tumor 

growth rate constant (Kgrowth) and stimulation of the death rate of tumor 

cells (Kdeath). Assuming the maximal inhibition of Kgrowth is 100%, the 

estimated mean C that provided 50% maximal Kgrowth inhibition (EC50) was 

6.71 �g/mL. The mean (SD) estimated effect of 7.5 and 15 mg/kg R on 

K was 90.1% (3.8%) and 95.5% (1.9%) inhibition, respectively. None 

growth 

of the tested baseline factors appeared to significantly affect tumor 

reduction by R � ECX. In the discrete time-survival model, the R and ECX 

combination significantly improved PFS, and the model suggests that the 

magnitude of the effect of one treatment was dependent on the other. 

Conclusions: R and ECX appeared to work in combination to decrease tumor 

size and to improve PFS. 


Individual PK-guided sunitinib dosing: A feasibility study in patients with 

advanced solid tumors. Presenting Author: Nienke A.G. Lankheet, Slotervaart 

Hospital, Amsterdam, Netherlands 

Background: Sunitinib treatment shows a clear dose-efficacy relationship. 

However, due to large inter-individual variations in plasma exposure, target 

total trough levels (� 50 ng/mL) are frequently not reached with the current 

dosing schedule. Therefore, a prospective Phase I study was performed to 

determine the safety and feasibility of PK-guided dosing of sunitinib. 

Methods: Thirty patients with solid tumors with a potential benefit from 

sunitinib treatment were included. Patients were treated continuously with 

sunitinib 37.5 mg once daily. At day 15 and 29 of sunitinib treatment, 

plasma trough levels of sunitinib and its active metabolite (N-desethyl 

sunitinib) were measured. If the total trough level (TTL) was � 50 ng/mL 

and the patient did not show any � grade 3 toxicity (CTCAE 4.02), the daily 

sunitinib dose was increased by 12.5 mg. If the patient suffered from 

� grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg. After 8 

weeks a final TTL evaluation was performed. Results: All 30 patients started 

treatment and in 18 patients all 3 TTLs were measured at the time of this 

analysis. Given TTL � 50 ng/mL and � grade 3 toxicity, a first sunitinib 

dose increase could be applied in 10 patients and a second dose increase 

in 2 patients at day 15 and 29, respectively. At day 15, day 29 and 8 weeks 

of treatment, mean TTLs were 49.7 ng/mL (coefficient of variation (CV) 

27.7%), 62.4 ng/mL (CV 35.5%) and 56.7 ng/mL (CV 47.8%), respectively. 

At day 15, using the sunitinib standard dose of 37.5 mg, target TTLs 

were reached in 8 patients (44%). At 8 weeks, the mean sunitinib daily 

dose intensity was increased to 40.3 mg (standard deviation (SD) � 11.0). 

At the end of the 8 week study period, 5 out of 18 patients (28%) were still 

at an increased sunitinib dose level without additional side effects. In these 

patients the mean daily sunitinib dose was 55.0 mg (SD � 6.8) and their 

final TTLs were all � 50 ng/mL (mean: 70.8 ng/mL (CV 29.8%)). Using 

PK-guided sunitinib dosing, target TTLs were reached in 10 out of 18 

patients (56%) at the final TTL evaluation, compared to 44% at day 15 

before any dose adjustment. Conclusions: Individual PK guided dosing is 

feasible and enables a significant increase in sunitinib dose intensity 

without causing additional toxicity. 




Clinical pharmacologic considerations for the phase II/III dose/regimen of 

the investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): 

Pharmacokinetics (PK), pharmacodynamics (PD), and exposure-safety 

relationships. Presenting Author: Karthik Venkatakrishnan, Clinical Pharmacology, 

Millennium Pharmaceuticals, Inc., Cambridge, MA 

Background: MLN8237, an oral selective AAK inhibitor, is primarily 

metabolized by multiple glucuronidation enzymes including the polymorphic 

UGT1A1. Phase 1 studies included comprehensive PK and PD 

sampling. We report integrated PK, PD, and PK-safety analyses in support 

of dose/regimen selection for phase 2/3 studies. Methods: Phase 1 studies 

in adults with advanced cancers evaluated dosing on d 1-7 in 21-d cycles or 

d 1-21 in 35-d cycles. Data from 294 patients in 4 phase 1 and 2 phase 2 

studies contributed to population PK modeling. PD endpoints included 

mitotic index (MI) in skin and chromosome alignment and spindle 

bipolarity (CA/SB) in mitotic tumor cells. Logistic regression analyses 

evaluated relationships between MLN8237 PK parameters and DLTs 

(N�86) or CNS adverse events (AEs; n�134) in 2 phase 1 studies. Results: 

MLN8237 displayed dose-linear PK (5-200 mg/d), described by a 2-compartment 

model with first order absorption. Covariate analyses did not 

reveal significant effects of age, body size, sex, UGT1A1 genotype, or 

creatinine clearance (�30 mL/min). Exposure-related increases in skin MI 

and decreases in CA/SB in tumor mitotic cells confirmed AAK inhibition by 

MLN8237. At the MTD of 50 mg BID (d 1-7 dosing) geometric mean 

steady-state exposures (48,200 nM.hr) were comparable to those associated 

with �50% CA/SB reductions in mitotic tumor cells (57,300 nM.hr). 

Exposures at the 21-d MTD (QD dosing) were lower, favoring 50 mg BID (d 

1-7 dosing) for further development. At 50 mg BID (d 1-7 dosing) logistic 

regression relating MLN8237 AUC to DLT rate estimated a DLT probability 

of 8% (95% CI 3-20%). Similar analyses identified Cmax rather than AUC as 

the predictor of CNS AEs, supporting BID dosing in adults to reduce peak 

concentrations while preserving total systemic exposure. Conclusions: 

MLN8237 exhibits dose-linear PK independent of age, body size, mild or 

moderate renal impairment, or UGT1A1*28 polymorphism. Exposures 

achieved at or near 50 mg BID are expected to result in tumor AAK 

inhibition, supporting a pharmacologically active dose range for future 

clinical development. 


Effects of metformin and sulfonylureas on overall and colorectal cancerspecific 

mortality. Presenting Author: Susan Spillane, Trinity College 

Dublin, Dublin, Ireland 

Background: Preclinical studies have suggested a role for metformin in the 

treatment of colorectal cancer (CRC). Associations between metformin 

versus sulfonylurea exposure and mortality (all-cause and colorectal cancer 

specific) are assessed in this population-based study of patients with a 

diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland 

records were linked to prescription claims data and used to identify a cohort 

of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From 

this cohort, 2 patient groups were identified and compared for outcomes - 

those who received a prescription for metformin �/- a sulfonylurea (MET) or 

a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC 

diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) 

were estimated using Cox proportional hazards models adjusted for age, 

sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin 

or statin exposure. Analyses were repeated stratifying by stage and site. 

Results: 5,617 patients with stage I-IV CRC were identified, of whom 369 

received a prescription for metformin or a sulfonylurea in the 90 days pre 

diagnosis (median follow-up 1.6 years; MET: n�257; SUL: n�112). In 

adjusted analyses metformin exposure was associated with a 28% lower 

risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95% 

CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific 

mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in 

colon cancer, metformin exposure was associated with a significant 

one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95) 

and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI 

0.40-1.02). No mortality benefit was observed for rectal cancer. The 

association between metformin exposure and reduced mortality was strongest 

for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32- 

0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions: 

Pre-diagnosis metformin exposure in CRC patients was associated with a 

significant reduction in mortality relative to sulfonylurea exposure. This 

benefit was greatest in patients with colon cancer and early stage disease. 


Docetaxel pharmacogenetics: The influence of RXR� and HNF4� genetic 

variations on docetaxel disposition in Asian nasopharyngeal carcinoma 

patients. Presenting Author: Sin Chi Chew, Division of Medical Sciences, 

National Cancer Centre, Singapore 

Background: The transactivations of the metabolism enzymes (CYP3A4/5) 

and efflux transporters (ABCB1/ABCC2) involved in docetaxel disposition 

are regulated by the orphan nuclear receptors such as PXR, CAR, RXR� and 

HNF4�. This study aimed to explore the associations between the genetic 

variations present in the genes encoding the orphan nuclear receptors, 

RXR� and HNF4�, on docetaxel disposition. Methods: The DNAs from 

healthy Chinese, Malay and Indian subjects (n�56 each) were screened for 

RXR� and HNF4� SNPs in exons and intronic/exonic boundaries by direct 

sequencing. The high frequency SNPs (�1%) were profiled in a cohort of 

local nasopharyngeal cancer patients (n�54). Genotypic-phenotypic correlations 

were conducted using Mann-Whitney U-test and Kruskal-Wallis 

test. Results: Eighty-eight and sixty-nine SNPs were identified from the 

healthy screening of RXR� and HNF4�, respectively, across 3 populations. 

A total of 30 and 35 high frequency SNPs in RXR� and HNF4�, 

respectively, were profiled in the patients. Six RXR� SNPs [IVS2�33G�A 

(rs2234753), IVS7�70A�G (rs1536475),*846G�A (rs4240711), 

*�4458G�A (rs3132291), *�4768C�A (rs4842196) and *�4988A�G 

(rs4842198)] and 6 HNF4� SNPs [-728A�C (rs1800963), IVS2- 

278A�G (rs55934816), IVS6�141A�G (rs6103731), IVS7-88T�C 

(rs2273618), IVS9–145T�C (rs3746574) and IVS9-67C�G 

(rs3746575)] were significantly associated with higher clearance and 

lower AUC0-� and/or Cmax of docetaxel (P�0.05). Conversely, HNF4� SNP 

[IVS9�354G�T (rs3818247)] was associated with lower clearance and 

higher AUC0-� and Cmax of docetaxel (p�0.05). A high linkage pattern was 

observed among the abovementioned RXR� SNPs except for IVS2�33G�A 

(rs2234753) (D’�0.74). Similarly, HNF4� SNPs were found to be highly 

linked, except for -728A�C (rs1800963) (D’�0.62). Conclusions: The 

results highlight the contributions of RXR� and HNF4� pharmacogenetics 

in influencing the inter-individual variability in docetaxel disposition in 

Asian nasopharyngeal patients. 


Antibody-dependent cell-mediated cytotoxicity (ADCC) evolution under 

treatment by cetuximab and links with treatment outcome in colorectal 

cancer (CRC) patients. Presenting Author: Marco Carlo Merlano, St. Croce 

General Hospital, Cuneo, Italy 

Background: ADCC plays a role in antitumor activity of IgG1 mAb by 

inducing immune cell-mediated lysis of tumor cells. We evaluated ADCC 

ability before and under cetuximab-based treatment and examined its 

impact on treatment outcome. Methods: 29 patients (17 men, 12 women, 

median age 72, range 51-84) with metastatic wild-type KRAS CRC treated 

with chemotherapy (irinotecan or Folfiri) plus cetuximab were prospectively 

enrolled. ADCC ex-vivo was measured before starting treatment and every 2 

months during treatment (1 to 7 measurements/patient, 12 patients with 

�2 measurements). 400 000 purified Natural Killer cells (CD3- CD56�) 

from patients were incubated with 10 000 target cells (CAL166 cancer cell 

line expressing EGFR) and 10 �g/ml cetuximab (triplicates). Cytotoxicity 

was measured by the LDH-release assay. ADCC was expressed as the % of 

lyzed target cells. Gene polymorphisms of Fc� receptors FCGR2a 

(131Arg�His) and FCGR3a (158Phe�Val) were analyzed (Allelic Discrimination 

assay). Results: The feasibility rate of ADCC measurement was 88%. 

ADCC basal values ranged between 30% and 100% (mean 62%, median 

66%). Basal ADCC was not influenced by patient gender. A tendency for an 

increased ADCC basal value was observed in younger patients: median was 

76% in the 6 patients � 60 vs 56% in the 23 patients over 60 years-old (p 

� 0.031). FCGR2A and FCGR3A gene polymorphisms were not linked to 

basal ADCC. The evolution of individual ADCC ability before treatment and 

2 months later revealed a significant drop in ADCC following treatment 

initiation (intra-patient comparison, n�18, p�0.006), with an absolute 

median drop of 19%. This decrease was not sustained over time and 

intra-patient comparison between basal value and 4-month measurement 

was not significant. 25 patients were assessable for survival (11 deaths). 

Basal ADCC values were not related to survival. Conclusions: A new 

generation of mAb is currently being developed with the aim to amplify 

ADCC. Present data illustrate the feasibility of ADCC measurement in 

mAb-treated patients and reveal an initial drop in ADCC under treatment 

that may reflect the variable chemotherapy-induced impact on host 

immunity. 




Biomarkers of vincristine neuropathy in Kenyan children. Presenting 

Author: Jodi L. Skiles, Riley Hospital for Children, Indiana University 

School of Medicine, Indianapolis, IN 

Background: In a U.S. population, cytochrome P450 (CYP) 3A5 highexpressers 

metabolize vincristine (VCR) more efficiently than lowexpressers 

and vincristine-induced peripheral neuropathy (VIPN) is less 

common in African-Americans than Caucasians. We test the hypothesis 

that more children in Kenya are CYP3A5 high-expressers compared to U.S. 

children and as such experience less VIPN. Methods: This study was 

conducted in Kenyan children with cancer (n�78) being treated with VCR 

at Moi University AMPATH Oncology Institute in partnership with Indiana 

University. Saliva Oragene kits for DNA extraction and genotyping were 

obtained. Whole blood was collected via finger stick on Whatman protein 

saver dried blood spot cards for analysis of VCR concentrations. VIPN was 

assessed prospectively using two neuropathy assessment tools (Modified 

Total Neuropathy Score (TNS) and National Cancer Institute Common 

Terminology Criteria for Adverse Events (CTCAE), version 4.0). Results: 

Compared to 14% in the U.S. sample, 94% of Kenyan subjects are 

CYP3A5 high-expressers (p�2.2x10-16 ). Kenyan children have significantly 

lower VCR plasma concentrations (11.15ng/ml/mg � 1.051) compared 

to US (primarily Caucasian) children (13.26ng/ml/mg � 2.897) one 

hour following the administration of VCR (p�0.011). By TNS VIPN 

assessment, 71% of Kenyan children developed VIPN compared to 100% 

of U.S. children (p�8.8x10-7 ). CYP3A5 high-expresser genotype is associated 

with lower TNS VIPN severity scores than low-expresser genotypes 

(p�0.006). TNS VIPN assessments show that height is positively correlated 

with severity of VIPN (p�0.025). CTCAE VIPN assessments also 

showed a positive correlation with height (p�0.036), but did not show any 

association with CYP3A5 genotype. Conclusions: Kenyan children are more 

likely to be CYP3A5 high-expressers than U.S. children and as such may 

metabolize VCR more efficiently. Supporting these data is that Kenyan 

children experience significantly less VIPN than U.S. children. CYP3A5 

genotype and height are independent predictors of VIPN in Kenyan children 

with cancer. The CTCAE may lack sufficient sensitivity to detect VIPN for 

use in future studies aimed at optimizing VCR dosing strategies. 


Dovitinib (TKI258): Exploration of pharmacokinetics and pharmacodynamics 

(PK/PD) for dose and regimen consideration. Presenting Author: Samira 

M. Garonzik, Novartis Pharmaceuticals, East Habover, NJ 

Background: Dovitinib is a potent oral inhibitor of Receptor Tyrosine 

Kinases with activity against FGFR, VEGFR and PDGFR. The objectives of 

this analysis are to describe the PK/PD of dovitinib to characterize the 

differences between two different dosing regimens, 400 mg once daily (qd) 

or 500 mg 5 days on, 2 days off (int) in terms of exposure and biomarker 

response. Methods: PK/PD data from 127 patients receiving dovitinib, 

100-600 mg int and 50 – 600 mg qd were available. Duration of therapy 

was 15 to 859 days. Plasma concentration-time data � sparse biomarker 

(BM) data were available after the first dose and at steady state (SS). Data 

was analyzed using non-linear mixed effects modeling to characterize 

nonlinearities in PK as well as BM response. VEGF, sVEGFR2 and PDGF 

were described by indirect response models and FGF23 was described 

using a mechanism based model to characterize acute drop, rebound, 

tolerance and increase to a new SS over time. Results: Raw data revealed 

prolonged absorption, linear clearance after the first dose, but dose 

dependent 2 in clearance at SS (leading to over-proportional accumulation), 

and apparent linear clearance at doses below 400 mg qd. 2 exposure 

for doses up to 400 mg at SS compared to 1st dose implied auto-induction. 

The PK was well described by a 1-compartment (CMT) model with 3 transit 

CMTs to characterize absorption lag. Auto-induction and over-proportional 

accumulation at SS were modeled as depending on cumulative exposure 

through a time-dependent process with half-life of 18 h. In our study, 

median (10th –90th percentile) Clearance was 30 (17 – 80) L/h on Day 1, 

and 96 (51 – 185) L/h at SS. The model predicted 36%1in VEGF, 18% 2 

in sVEGFR2, 82% and 57% 1in PDGF and FGF23 respectively at SS, for 

median exposure at a dose of 400 mg qd. Simulations of PK and biomarker 

responses were performed for different dosing regiments to assess relative 

safety and target effects. Conclusions: The PK/PD model suggests 400 mg 

qd may lead to over-proportional accumulation of dovitinib in �5% of 

subjects while int dosing minimizes this. 500 mg int may be a more 

tolerable regimen while maintaining adequate PD response, and is being 

used in the pivotal phase III study for dovitinib in patients with mRCC. 

167s 


Is cigarette smoke associated with increased catabolism of gemcitabine in 

patients with advanced solid tumors? Presenting Author: Meaghan Working 

O’Malley, University of Michigan Comprehensive Cancer Center, Ann Arbor, 

MI 

Background: Cigarette smoking can accelerate chemotherapy metabolism 

and result in lower plasma concentrations of the chemotherapeutic agent. 

Reduced drug levels may lead to undertreatment in smokers and, conversely, 

increased treatment-related neutropenia in nonsmokers. Methods: 

An IRB-approved retrospective chart review was performed on 151 patients 

with solid tumor malignancies who received gemcitabine alone or in 

combination with oral chemotherapy agents from July 1, 2009 to June 30, 

2011 at the University of Michigan. Using logistic regression, we compared 

toxicity, including neutropenia, and smoking history measured in packyears 

in smokers vs. nonsmokers to ascertain whether cigarette smoking is 

an independent factor predictive of toxicity to gemcitabine. Results: Tumor 

types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or 

other/unknown primary (15.2%). Most patients had advanced disease 

(stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB; 

n�107), 77.6% patients had stage III-IV disease. Within the PB cohort, 

most patients were “ever” smokers as compared to “never” smokers 

(60.7% vs. 39.3%). Logistic regression of this cohort showed that current 

smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers 

(OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with 

higher pack-year history: smokers with �50 pack-years had even less 

neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065- 

1.699]). Further statistical analysis of subgroups was not performed due to 

small sample size. Conclusions: Smokers with pancreatobiliary malignancies 

receiving gemcitabine had less treatment-related neutropenia as 

compared to never smokers, a finding that was more pronounced as 

pack-years increased. Decreased toxicity, including neutropenia, may be 

due to increased metabolism and drug clearance as a result of smoking. 

This may lead to potential undertreatment of smokers and, conversely, 

increased treatment-related toxicity in never smokers. A prospective 

clinical trial is needed to further elucidate this correlation, and is currently 

being designed. 


A randomized, double-blind, placebo-controlled study to assess the efficacy 

and toxicity of subcutaneous ketamine in the management of cancer 

pain. Presenting Author: David C. Currow, Flinders University, Adelaide, 

Australia 

Background: The dissociative anaesthetic ketamine is widely used for 

cancer related pain. A Cochrane review concluded that insufficient evidence 

was available to support its use in this setting. Methods: This phase 

III, multisite, double-blind, dose escalation, placebo, randomised controlled 

study aimed to determine whether ketamine, delivered subcutaneously 

over three to five days is more effective than placebo, when used in 

conjunction with adjuvant therapy in the management of chronic uncontrolled 

cancer pain. Ketamine would be considered to be of net benefit if it 

provided a reduction in average pain scores by �2/10 points from baseline, 

with limited breakthrough analgesia and acceptable toxicity. Results: For 

the 185 participants, there was no significant difference between the 

proportion of positive outcomes (0.04 (-0.10, 0.18) p�0.55) in the 

placebo and intervention arms (response rates 27% (25/92) and 31% 

(29/93)). Pain type (nociceptive versus neuropathic) was not a predictor of 

response. There was almost twice the incidence of adverse events worse 

than baseline in the ketamine group after day 1 (IRR � 1.95 (1.46, 2.61), 

p�0.001) and throughout the study. Those receiving ketamine were more 

likely to experience a more severe grade of adverse event/day (OR�1.09 

(1.00, 1.18), p�0.039). The number needed to treat for one additional 

patient to get a positive outcome from ketamine was 25 (6, �). The number 

needed to harm, because of toxicity-related withdrawal was 6 (4, 13). 

Conclusions: Ketamine does not have net clinical benefit when used as an 

adjunct to opioids and standard co-analgesics in cancer pain. 




Vectorized gene therapy of liver tumors: Safety and proof of concept of 

TG4023 (MVA-FCU1)/5-FC combination. Presenting Author: Faress Husseini, 

Hôpitaux Civils de Colmar, Colmar, France 

Background: TG4023 is a non-integrative and non-propagative Modified 

Vaccinia virus Ankara (MVA) expressing a chimeric yeast transgene (FCU1) 

coding for cytosine deaminase and uracil phosphoribosyl transferase that 

transform the pro-drug 5-flucytosine (5-FC) respectively into 5-FU and 

5-FUMP in infected cells; these derivatives then diffuse and kill additional 

tumor cells (bystander effect). Methods: This phase I study determined 

safety and Maximal Tolerated Dose (MTD) of a single intra-tumor injection 

of TG4023 combined with a 2-week dosing period of 5-FC 200 mg/kg/day. 

Plasma and tumor 5-FC (PK) and 5-FU (PD) concentrations were measured. 

Other assessments were tumor response, changes in tumor markers 

and immune response. Patient requirements were � 1 injectable primary or 

metastatic unresectable liver tumor of 2-5 cm, no treatment option left, 

ECOG PS � 2. Consenting patients were allocated to cohorts according to a 

3�3 dose-escalating design driven by Dose-Limiting Toxicities (DLTs) and 

Data Safety Monitoring Board recommendations. Results: Among 16 

enrolled patients (13 colorectal, 1 pancreatic and 1 liver cancers, 1 cancer 

of unknown primary) 6 were injected in one tumor with 107 plaque forming 

units (pfu) TG4023, 3 with 108 pfu and 7 with 4.108 pfu, using a multiport 

needle and ultrasound imaging guidance. 5-FC was given IV the first days 

then orally. One DLT (grade 3 transient increase in AST/ALT) was recorded 

at 4.108 pfu; other severe adverse events, diarrhea, hypertension, alkaline 

phosphatase increase were related to 5-FC; most frequent AEs were 

transient fever, asthenia, site injection pain, nausea/vomiting. 5-FU concentrations 

in tumor biopsies at Day 8 were 56�30 ng/g and 1.9� 2.6 ng/mL 

in plasma. 11/16 injected, 12/23 non-injected target tumors were stable 

and 10/16 patients progressed at week 6. One patient had a 3-fold 

decrease in CEA and CA 19.9. Conclusions: This study showed that 

vectorized gene therapy of liver tumors with TG4023/5-FC combination is 

feasible and safe, as supported by a high therapeutic index; MTD for 

TG4023 was 4.108 pfu for one injected tumor. A proof of concept of the in 

vivo conversion of the pro-drug 5-FC into 5-FU was obtained. 


Impact of body surface area on efficacy of gefitinib in patients with 

non-small cell lung cancer harboring activating epidermal growth factor 

receptor mutation. Presenting Author: Eiki Ichihara, Department of Respiratory 

Medicine, Okayama University Hospital, Okayama, Japan 

Background: Gefitinib is an essential drug for the treatment of non-small 

cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) 

mutation. Its approved dosage is fixed at 250 mg/body/day without any 

adjustment by physical size. On the other hand, most cytotoxic agents are 

administered with body surface area (BSA) based dose-adjustment to 

reduce the pharmacokinetic inter-patient variability. However, the impact 

of BSA on efficacy of gefitinib has not been fully evaluated. We here tried to 

clarify this issue using our retrospective cohort. Methods: We reviewed the 

medical records of consecutive advanced NSCLC patients harboring EGFR 

mutation who underwent gefitinib monotherapy at Okayama University 

Hospital from October 2002, when gefitinib was approved in Japan, to 

October 2011. Results: A total of 101 patients with EGFR-mutant tumors 

who received gefitinib (250 mg/body/day) were included in this study. The 

median progression free survival (PFS) of patients with high BSA (�1.5 m2 : 

the median value in this cohort) was significantly worse than that of 

patients with low BSA (�1.5 m2 ) (10.4 vs. 18.0 months, p � 0.019 

log-rank test). The multivariate analysis also showed a significant impact of 

BSA on PFS; (hazard ratio of 2.34 with 95% confidence interval of 1.78 - 

2.89, p � 0.002). By contrast, such significant association between BSA 

and PFS was not observed in cytotoxic chemotherapy (5.4 months vs. 3.7 

months, p � 0.49, log lank test). Conclusions: BSA affected PFS in the 

gefitinib monotherapy, potentially suggesting the need for appraisal of 

BSA-based dose adjustment even in this molecular-target therapy. 


The role of phase I clinical trials in advanced malignant melanoma: 

Retrospective analysis of CTEP-sponsored trials 1995-2011. Presenting 

Author: Jason John Luke, Dana-Farber Cancer Institute, Boston, MA 

Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). 

Many physicians do not refer to phase I due to perceived limited clinical 

benefit (CB�CR�PR�SD) and increased toxicity. To understand the 

actual experience of melanoma patients (pts) in phase I trials, we analyzed 

the outcomes of melanoma pts treated on CTEP phase 1 trials (1995- 

2011) and compared them to DTIC. Methods: We queried the CTMS of 

CTEP for phase I trials in which advanced melanoma pts were treated. 

Trials were separated into targeted (T), chemo (C) and immunotherapy (I). 

Pt characteristics, response and toxicity data were collected. Chemotherapy 

included chemo with targeted or immunotherapy. Toxicity was drug 

related if attributed possibly, probably or definitely to drug. Fisher’s Exact 

Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 

modern phase III clinical trials (1999-2011). Results: 937 pts (M595: 

F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics 

included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 

(majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and 

toxicity data are shown in the Table. Targeted therapy was associated with 

lower RR (p�.01), immuno with lower CB rate (p�.001) and chemo with 

higher incidence of G4 toxicity (p�.001) relative to the other groups. 

Comparing phase 1 to DTIC, RR and CB were not clinically different (phase 

I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was 

significantly higher (54% vs. 28%) in phase I (p�.0001). Conclusions: 

Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had 

similar therapeutic benefit but more toxicity compared to DTIC naïve pts in 

modern clinical trials. 

All (937) Targeted (182) Chemo (186) Immuno (569) 

Response Total % 95% CI Total % 95% CI Total % 95% CI Total % 95% CI 

CR � PR 59 6.3 4.8-8.1 4 2.2 0.6-5.5 14 7.5 4.2-12.3 41 7.2 5.2-9.7 

SD 192 20.5 59 32.4 53 28.5 80 14.0 

CB 251 26.8 24.0-29.8 63 34.6 27.7-42.0 67 36.0 29.1-43.4 121 21.2 18.0-24.9 

Not evaluated 61 6.5 15 8.2 16 8.6 30 5.3 

PD 

Toxicity 

625 66.7 104 57.1 103 55.4 418 73.3 

G3 G4 G3 G4 G3 G4 G3 G4 

% 42.2 12.1 42.3 9.3 46.2 23.7 40.8 9.1 

95% CI 39.0-45.4 10.0-14.3 35.0-49.8 5.5-14.5 38.9-53.7 17.8-30.4 36.7-44.9 6.9-11.8 


Multivariate screening of prognostic factors to identify a novel, simple, and 

objective marker to optimize patient selection and predict survival benefit 

in early-phase trials. Presenting Author: Chara Stavraka, Imperial College 

London, London, United Kingdom 

Background: Several prognostic indices have been devised to optimize 

patient selection for phase I trials. However, there is no consensus as to the 

optimal score and none qualifies as a marker of response. We developed a 

simple score through a multivariate screening of individual variables and 

compared its performance with existing prognostic scores including the 

Royal Marsden, Nijmegen and Prince Margaret Hospital scores. Methods: 

We retrospectively analyzed characteristics and outcomes of 120 referrals 

to our phase I center (2007 - 2011). Independent predictors for overall 

survival (OS) were identified from univariate (Kaplan Meier) and multivariate 

(Cox regression) analyses and used to create the Hammersmith Hospital 

score (HS). This was compared with the other indices for predicting 

progression free survival (PFS), OS and 90 day mortality (90 DM). 

Multivariate logistic regression and ROC curves were used to estimate 90 

DM and c-index was used to estimate the prognostic ability of the different 

indices. Changes in HS following treatment (�HS) were calculated at 6 

weeks RECIST in a subset of patients receiving targeted therapies (n� 50). 

Results: Median age was 62 years (range: 28 – 80); median OS 4.3 months 

(range: 0.2 – 39); 34% male; 25% PS�1. Multivariate screening identified 

albumin �35 g/L, lactate dehydrogenase (LDH) �450 U/L and sodium 

�135mmol/L as the strongest independent predictors of OS (p�0.05). 

These were entered into a 3-point score (HS) that classifies patients as 

being at high risk (score 2-3) vs. low risk (score 0-1) of worse OS (HR� 5.8, 

p�0.001), PFS (HR� 2.7, p� 0.04) and 90 DM (OR� 5.9, p� 0.001). All 

scores predicted for OS on univariate analysis (p�0.05). On multivariate 

analysis HS performed best to predict OS (HR� 3.9, p�0.001 C-index 

score� 0.71), PFS (HR� 2.6 p� 0.04) and 90 DM with area under the 

ROC curve 0.71. �HS independently predicted for OS (p�0.001), with 

worsening of the score reflecting poorer OS. Prospective validation is 

ongoing. Conclusions: HS is a simple score that outperforms other prognostic 

indices. This can be used to select individuals for future studies as well 

as an additional marker of response. 



Should patients with extrapulmonary small cell carcinoma receive prophylactic 

cranial irradiation? An Irish experience. Presenting Author: Jarushka 

Naidoo, Waterford Regional Hospital, Waterford, Ireland 

Background: Extrapulmonary small cell carcinoma (EPSCC) is a rare 

disease. Management is based on small cell lung carcinoma, and experience 

of disease biology on single institution studies. Prophylactic cranial 

irradiation (PCI) is not routinely administered in EPSCC. This study 

investigates the role of PCI in EPSCC, by analyzing the incidence, 

treatment and survival of patients with brain metastases in a national 

cohort. Secondary aims were to investigate disease biology and epidemiology. 

Methods: An audit was undertaken of patients diagnosed with primary 

EPSCC from the National Cancer Registry of Ireland, between 1995-2007. 

The number of patients who developed brain metastases, received cranial 

radiotherapy, and their survival data, were documented. Patient and 

disease characteristics, treatment, and survival data stratified by stage and 

primary site, were tabulated. Results: 280 patients were found. 141 

(50.4%) patients were male, and 139 (49.6%) were female. 186 (66.4%) 

patients had extensive stage disease, 65 (23.2%) had limited stage 

disease, and in 29 (10.3%) patients the stage was not known. 17 patients 

(5.4%) developed brain metastases, 11 of which (64.7%) received cranial 

irradiation. These patients had a median progression-free survival (PFS) of 

5.2 months, and a median overall survival (OS) of 10.2 months. The 

commonest primary sites were the oesophagus (n�43, 15.4%), cervix uteri 

(n�17, 6.0%), bladder (n�13, 4.6%) and prostate (n�10, 3.6%). There 

were 315 events of distant metastasis, and 21 local recurrence events. The 

commonest metastatic sites were the liver, 110 (34.9%), lymph nodes 58 

(20.7%), lung 38 (12.1%), and bone 36 (12.8%). The median PFS and OS 

for limited stage EPSCC was 8.8 months and 14.9 months, and 1.5 months 

and 2.3 months for extensive stage EPSCC. Conclusions: Brain metastases 

were uncommon in this cohort (5.4%), and patients lived longer, suggesting 

a low rate of mortality from brain metastases. PCI is thus probably not 

warranted in EPSCC. Prospective data are necessary to support PCI in 

EPSCC. This is one of the largest datasets on EPSCC, providing insights 

into disease biology. 


Evaluation of utility of pharmacokinetic studies in phase I combination 

trials. Presenting Author: Kehua Wu, The University of Chicago, Chicago, IL 

Background: There are many phase I clinical combination trials including 

drug-drug interaction (DDI) studies, but very few of them report positive 

results. We hypothesized that the utility of DDI studies is low in the absence 

of a mechanistic hypothesis. Methods: We retrospectively reviewed 119 

phase I (2 drug) combination studies published in 2007-2011. Results: 

Only 23 (19%) studies had a positive rationale, either inhibition/induction 

of a drug metabolizing enzyme or transporter, co-substrates for the same 

enzyme or transporter, potential for end-organ toxicity, or protein- binding. 

Only 9 (8%) studies demonstrated a statistically significant effect DDI, 

based on AUC of parent drug or active metabolite. There was a strong 

association between lack of rationale and a lack of interaction, as only 2% 

of studies without a rationale demonstrated a DDI, compared to 30% of 

studies with a rationale (Fisher’s exact test, p�0.0004) (Table). Conclusions: 

DDI studies should not be routinely performed as part of phase I clinical 

trials. 

Preclinical 

rationale 



papers with (�) DDI 


papers with (�) DDI 

(�) 94 2 

(�) 16 7 

169s 


Phase I/II dose-finding study of crizotinib (CRIZ) in combination with 

erlotinib (E) in patients (pts) with advanced non-small cell lung cancer 

(NSCLC). Presenting Author: Sai-Hong Ignatius Ou, Chao Family Comprehensive 

Cancer Center, Orange, CA 

Background: c Met expression is common in NSCLC tumors and has been 

implicated in the development of resistance to EGFR inhibitors. CRIZ is an 

ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical 

studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor 

activity in NSCLC cell lines that were either sensitive or resistant to EGFR 

inhibition. The phase I portion of a phase I/II study (A8081002; 

NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in 

pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior 

chemotherapy regimens, and no previous MET-directed therapy. Endpoints 

included maximum tolerated dose (MTD) determination, safety, and 

pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined 

with E 100 mg QD (150/100 and 200/100, respectively). Results: 

Twenty-five pts have been treated to date. Median duration of combination 

therapy in 150/100 (n�18) was 6.6 weeks (0.1–25.3); for 200/100 (n�7) 

was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 

2 and unable to receive at least 80% of the planned dose or �G3), all of 

which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and 

dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) 

and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related 

adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were 

diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued 

therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash 

in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n�1 each; 200/100: G3 

dry eyes, G1 esophagitis, n�1 each). One partial response (200/100; 

duration 61 weeks) and 9 stable diseases (n�7 150/100, n�2 200/100; 

duration 7–54 weeks) were observed overall. Co-administration of both 

doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK 

parameters appeared to be unaffected. Plasma exposure to E 100 mg QD 

with CRIZ was comparable to that of 150 mg QD from historical data. 

Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected 

AEs, and showed signs of activity in a pre-treated population. E 100 mg QD 

plus CRIZ 150 mg BID was defined as MTD. 


Effect of baseline QTc interval prolongation on oncology clinical trial 

enrollment. Presenting Author: Carolina Moreno, H. Lee Moffitt Cancer 


Background: An increasing number of clinical trials in oncology require 

normal or near-normal intervals of electrocardiographic corrected QT (QTc) 

as an eligibility criterion. However the normal QTc reference range 

(conventionally defined as �450ms) has been developed in broad populations 

of patients, and it is unclear whether average QTc intervals are higher 

in adult cancer patients. Methods: All electrocardiograms (ECGs) performed 

for any indication at the Moffitt Cancer Center during a one-week period 

were reviewed. The QTc interval for each patient was calculated according 

to the Bazett and Fridericia formulas. Mean and median QTc intervals were 

calculated along with standard deviations. The percentage of QTc intervals 

above 450ms, 470ms, and 500ms were calculated and graded accordingly 

to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). 

The effects of gender on the QTc interval were also evaluated. Results: 257 

patients underwent ECGs over a one-week period. A total of 90 patients 

(35%) had abnormally prolonged QTc. 50 patients (20%) had QTc 

prolongation �450 (� grade 1), 32 (12%) had QTc prolongation � 470 

(�grade 2) and 8 patients (3%) had QTc prolongation �500ms (�grade 3) 

using the Bazett formula. The corresponding numbers according to the 

Fridericia formula were 23 (9%), 13 (5%) and 2 (1%) . The median QTc 

interval was 441 (Bazett) and 422 (Fridericia) with a standard deviation of 

30 and 28 respectively. Women had a mean QTc of 438 (Bazett) versus 

443 for men. Conclusions: A very large percentage of patients seen at a 

comprehensive cancer center have QTc intervals above the normal reference 

range on routine ECGs. The growth in number of trials requiring a 

normal QTc interval as an eligibility criteria suggests that an ever-larger 

number of patients are excluded from trial participation. Regulatory 

agencies may need to reconsider eligibility criteria that substantially 

restrict trial enrollment and that accrue patients who are not reflective of 

the general patient population. 



TPS2613 General Poster Session (Board #10F), Mon, 8:00 AM-12:00 PM 

An exploratory study to investigate the immunomodulatory activity of 

BMS-936558 in patients with metastatic clear-cell renal cell carcinoma. 

Presenting Author: Charles G. Drake, Sidney Kimmel Comprehensive 

Cancer Center at Johns Hopkins University, Baltimore, MD 

Background: With the enhanced understanding of the immune response to a 

tumor, new immunotherapeutic agents may expand treatment options for 

metastatic renal cell carcinoma (mRCC). The programmed death-1 (PD-1) 

receptor is upregulated by activated lymphocytes, and upon binding to its 

ligands, inhibits lymphocyte function. In a phase 1 study of the anti-PD-1 

monoclonal antibody BMS-936558, encouraging antitumor activity has 

been observed in patients with previously treated mRCC. Responses 

occurred in extensive mRCC and were durable in many patients. Here we 

describe an exploratory study to investigate the immune-regulatory activity 

of various doses of BMS-936558 in patients with metastatic clear-cell 

RCC. Methods: Eighty patients with metastatic clear-cell RCC will be 

enrolled in this open-label, parallel group, randomized study. Patients who 

have received prior treatment with �3 therapies, including �1 antiangiogenic 

therapy, will be enrolled in Arms 1-3 (~20 patients per arm); 20 

treatment-naïve patients will be enrolled in Arm 4. BMS-936558 will be 

administered every 3 weeks until disease progression or unacceptable 

toxicity at 0.3 mg/kg (Arm 1), 2 mg/kg (Arm 2), and 10 mg/kg (Arms 3 and 

4). Patients in the 0.3-mg/kg group may escalate to 2 mg/kg if not 

responding. Tumor assessments will occur every 6 weeks for the first 12 

months then every 12 weeks for the remainder of the study. The primary 

objective is to evaluate the effects of BMS-936558 on the frequency of 

circulating immune cell subsets, levels of soluble factors associated with 

immune responses, and tumor infiltrating lymphocyte populations (based 

on pre-treatment and week 5 paired biopsies). Secondary objectives are to 

assess the safety, tolerability, antitumor activity, and immunogenicity of 

BMS-936558. Exploratory objectives include the association of clinical 

activity and safety with selected biomarkers in peripheral blood and tumor 

microenvironment and the characterization of the pharmacokinetics of 

BMS-936558. As of February 1, 2012, 30 patients were enrolled. 

TPS2615 General Poster Session (Board #10H), Mon, 8:00 AM-12:00 PM 

A phase I study of BMS-936558 in combination with gemcitabine/ 

cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel in patients with 

treatment-naive, stage IIIB/IV non-small-cell lung cancer. Presenting 

Author: Scott N. Gettinger, Yale University School of Medicine, New Haven, 

CT 

Background: Lung cancer is the leading cause of cancer-related mortality 

worldwide and non-small-cell lung cancer (NSCLC) accounts for ~85% of 

all cases. Platinum-based chemotherapy alone or in combination with 

bevacizumab is considered first-line standard of care for advanced NSCLC. 

Despite such therapy, most patients (pts) will experience disease progression 

within 6 months and die from their disease within 1 year. Programmed 

death-1 (PD-1) is a coinhibitory receptor that negatively regulates T-cell 

activation; PD-1 expression by tumor infiltrating lymphocytes is associated 

with poor prognosis in NSCLC. BMS-936558 is a fully human anti-PD-1 

monoclonal antibody that blocks ligand interaction with PD-L1 and PD-L2. 

In a phase 1 trial, BMS-936558 had antitumor activity at doses of 1-10 

mg/kg in pts with advanced tumors, and impressive tumor responses in 

heavily pre-treated pts with NSCLC. Here we describe a phase 1 study 

planned to evaluate the safety and tolerability of BMS-936558 in combination 

with 3 standard, platinum-based doublet chemotherapy regimens in 

pts with NSCLC. Methods: Treatment-naïve pts with stage IIIB/IV NSCLC 

will be enrolled. Treatment arms will include: A) gemcitabine 1250 mg/M2 on day 1 (D1) and day 8 (D8)/cisplatin 75 mg/M2 D1/BMS-936558 D1; B) 

pemetrexed 500 mg/M2 D1/cisplatin 75 mg/M2 D1/BMS-936558 D1; and 

C) carboplatin AUC 6 D1/paclitaxel 200 mg/M2 D1/BMS-936558 D1. The 

starting dose of BMS-936558 will be 10 mg/kg for each treatment arm. A 

decision to de-escalate to a lower dose (2 or 0.3 mg/kg) will be guided by 

the number of dose-limiting toxicities reported per treatment arm. Chemotherapy 

will be given for 4 cycles (1 cycle � 3 weeks). BMS-936558 will be 

administered every 3 weeks until disease progression, intolerable toxicity, 

or withdrawal of consent. The primary objectives are to assess safety and 

tolerability by measuring the frequency of adverse events (AEs), serious 

AEs, and laboratory abnormalities; secondary objectives are to determine 

the overall response rate and disease control rates based on RECIST 1.1. As 

of February 1, 2012, 2 patients were enrolled. 

TPS2614 General Poster Session (Board #10G), Mon, 8:00 AM-12:00 PM 

A phase I study of BMS-936558 plus sunitinib or pazopanib in patients 

with metastatic renal cell carcinoma. Presenting Author: Hans J. Hammers, 

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 

Baltimore, MD 

Background: Standard treatments for metastatic renal cell carcinoma 

(mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib, 

pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus, 

everolimus). However, most patients (pts) develop resistance and complete 

responses are rare. Upregulation of programmed death-1 (PD-1) in tumor 

infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with 

more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1 

interaction is a novel immunotherapeutic approach for mRCC. In preliminary 

results of a phase I trial, the anti-PD-1 monoclonal antibody BMS- 

936558 had antitumor activity in pts with advanced tumors, including 

objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a 

phase I study planned to evaluate the safety, tolerability, and maximum 

tolerated dose (MTD) of BMS-936558, when combined with sunitinib or 

pazopanib in pts with mRCC. Methods: This open-label study will have two 

parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558 

plus pazopanib) conducted in two parts (dose escalation and dose expansion). 

Pts must have received �1 prior systemic therapy to be eligible for 

dose escalation. Only treatment-naïve pts will be eligible for dose expansion. 

Up to 36 pts (18 per arm) will be treated in the dose-escalation phase. 

After determining the MTD of BMS-936558, treatment-naïve pts will be 

enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of 

each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed 

on Days 1 and 22 and sunitinib or pazopanib given according to product 

label. Adverse events will be graded according to NCI CTCAE v4.0. Disease 

will be assessed every 6 weeks for the first four assessments and then every 

12 weeks until disease progression. Pts will be treated until unacceptable 

toxicity, disease progression, or withdrawal of consent. The safety profile in 

pts treated at the MTD will be used to determine the recommended phase II 

study dose of BMS-936558 in each combination arm. Secondary objectives 

will include OR rate and duration of response based on RECIST 1.1. 

Exploratory analyses will investigate predictive biomarkers of BMS- 

936558. 

TPS2616 General Poster Session (Board #11A), Mon, 8:00 AM-12:00 PM 

A phase Ib/II study testing the safety and efficacy of combined inhibition of 

the AKT/PI3K and AR signaling pathways in castration-resistant prostate 

cancer: GDC-0068 or GDC-0980 with abiraterone acetate versus abiraterone 

acetate. Presenting Author: Roel Peter Funke, Genentech, South 


Background: Loss of PTEN, leading to activation of the AKT/PI3K pathway is 

frequent and associated with poor prognosis in prostate cancer. In addition, 

AR and AKT/PI3K cross-regulate by reciprocal feedback and combined 

inhibition of both pathways resulted in improved preclinical efficacy. This 

study is designed to evaluate the effect of combined inhibition of AR 

pathway (with abiraterone) and AKT/PI3K pathway (with either GDC-0068 

or GDC-0980). GDC-0068 is a potent, selective ATP-competitive inhibitor 

of AKT1, 2, and 3. Preclinical studies showed that cell and tumor models 

with PTEN loss are more likely to be sensitive to GDC-0068. GDC-0068 

was generally well tolerated in phase I and a MTD of 600 mg daily was 

identified. GDC-0980 is a potent pan-inhibitor of Class I PI3K and inhibits 

wild-type and mutated p110� isoforms, as well as mTOR kinase. The 

recommended phase II dose (RP2D) for single-agent GDC-0980 is 40 mg 

daily. Methods: This study will enroll CRPC patients previously treated with 

docetaxel. In phase Ib, the RP2D will be determined separately for 

GDC-0068 and GDC-0980 in combination with abiraterone 1000 mg qd 

and prednisone 5mg bid. In phase II, patients will be randomized 1:1:1 to 

receive GDC-0068 � abiraterone, GDC-0980 � abiraterone, or placebo � 

abiraterone. The primary endpoint of phase II is PFS measured by PCWG2 

in all patients and in patients with PTEN loss. Secondary endpoints include 

OS, PSA response rate, ORR, safety, Pharmacokinetics and biomarker 

analyses. The effect of each treatment on the number of circulating tumor 

cells will be assessed. Primary and secondary analyses will include all 

randomized patients and will be conducted according to assigned treatment 

arm. Kaplan-Meier methodology will be used to estimate median PFS 

for each arm. Up to 24 patients are planned to be enrolled in phase Ib; 240 

patients (80 per arm) are planned for phase II. This study is open for 

accrual; to date 2 patients have been enrolled in phase Ib. 



TPS2617 General Poster Session (Board #11B), Mon, 8:00 AM-12:00 PM 

First-in-human phase I trial of NHS-IL12 in advanced solid tumors. 

Presenting Author: Joseph W. Kim, Laboratory of Tumor Immunology and 

Biology, Medical Oncology Branch, National Cancer Institute, National 


Background: NHS-IL12 is an antibody-cytokine conjugate consisting of two 

heterodimers of interleukin (IL)-12, fused to a human monoclonal antibody 

specific for DNA-histone H1 complex exposed in tumor necrosis. IL12 is a 

proinflammatory cytokine, produced by activated phagocytes and dendritic 

cells, that plays a critical role in regulating the transition from innate to 

adaptive immunity. Early clinical trials of IL12 reported clinical responses 

in metastatic renal cell carcinoma, Kaposi sarcoma (50–71% response 

rate), T-cell lymphoma (56%), and non-Hodgkin’s lymphoma (21%). 

However, systemic toxicity limited further clinical development. NHS-IL12 

is designed to reduce toxicity associated with systemic administration of 

IL12 by selectively targeting delivery to necrotic areas of tumors. A 

fluorescence imaging study of NHS-murine (mu)-IL12 in mice with 

syngeneic lung carcinoma demonstrated effective targeting by NHSmuIL12. 

Immunohistochemistry studies further confirmed effective targeting 

of tumors by NHS-muIL12. In another study in canines with 

spontaneously occurring solid tumors, 2 of 11 subjects achieved a partial 

response with a single dose. Methods: This is a phase I dose-escalation 

study designed to determine the maximum tolerated dose of NHS-IL12 and 

to define the biologically optimal dose and schedule based on immunologic 

(pharmacodynamic) analysis of cytokines such as interferon-g, and IL-10, 

at multiple times points from 4 hours up to 2 weeks following the 

administration of NHS-IL12. Eligible patients (pts) include those with 

evaluable or measurable solid tumors who have progressive disease on at 

least one prior line of therapy. Pts with a condition associated with 

significant necrosis of non-tumor bearing tissue, (e.g., ulcerative colitis), 

are excluded. Modified immune-related response criteria are used to assess 

response, the major features of these criteria being (a) imaging confirmation 

of both progression and response at least 4 weeks after initial imaging, 

and (b) no consideration of new lesions unless the total measurable tumor 

burden meets the criteria for progressive disease. This trial opened to 

accrual in Nov. 2011 and may enroll up to 78 pts. 

TPS2619 General Poster Session (Board #11D), Mon, 8:00 AM-12:00 PM 

A phase I clinical trial of autologous, anti-CD19 gene targeted T cells for 

adults with B cell acute lymphoblastic leukemia (B-ALL). Presenting 

Author: Marco L. Davila, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: Complete remission (CR) rates for B-ALL in adults is high 

(�80%), but overall survival remains low (approximately 30%). Patients 

with relapsed disease have a very poor prognosis with a median survival 

measured in months. Therefore, there is a dire need for novel therapies for 

adults with relapsed or minimal residual B-ALL. To this end we have 

developed a novel T cell therapy for B cell malignancies using patient 

derived T cells genetically modified to express the 19-28z chimeric antigen 

receptor (CAR), an artificial T cell receptor specific to the CD19 antigen 

expressed on most B cell tumors. Human T cells retrovirally modified to 

express the 19-28z CAR successfully targets and eradicates B cell tumors 

in vitro and systemic human B cell cancers in mice. We have recently 

published the results of our initial Phase I clinical trial experience 

(Brentjens, Rivière et al., Blood 2011) utilizing this technology in adults 

with chronic lymphocytic leukemia. These results suggest clinical activity 

and demonstrate a persistence of 19-28z� T cells that is inversely 

associated with tumor burden. These studies suggest that 19-28z� T cells 

may be particularly effective in relapsed B-ALL because these tumors 

retain a degree of chemotherapy sensitivity, which will allow the infusion of 

T cells after salvage chemotherapy when patients have low tumor burdens. 

To our knowledge, this is the first clinical trial using autologous CD19 

targeted T cells in adults with B-ALL. Methods: We are enrolling patients to 

a Phase I T cell dose escalation trial (NCT01044069). Adults with CD19� 

B-ALL classified as a CR, relapsed, or refractory are eligible for enrollment. 

After patients are enrolled they are leukapheresed to obtain peripheral 

blood T cells, which are then retrovirally transduced to express the 19-28z 

CAR and expanded in our GMP gene transfer facility. Enrolled patients with 

relapsed or refractory B-ALL undergo a cycle of re-induction chemotherapy 

and conditioning cyclophosphamide followed by infusion of autologous 

19-28z� T cells. To date, 11 patients have been enrolled and 2 patients 

have been infused with 19-28z� T cells. 

171s 

TPS2618 General Poster Session (Board #11C), Mon, 8:00 AM-12:00 PM 

Safety, pharmacokinetics, and antitumor activity of MEDI-573, an investigational 

monoclonal antibody that targets IGF-I and IGF-II, in adult 

patients with advanced solid tumors. Presenting Author: Paul Haluska, 


Background: MEDI-573 is an investigational dual-targeting human antibody 

that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin 

receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid 

receptors, MEDI-573 may achieve antitumor activity without perturbing 

glucose homeostasis. Objectives of this phase 1 dose-escalation and 

expansion study are to evaluate safety and determine the maximum 

tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics, 

pharmacodynamics, and immunogenicity of MEDI-573 in adult patients 

with solid tumors. Methods: Patients with advanced solid tumors, 

Karnofsky status �60, and adequate organ function were treated with 

escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3 

weeks (30 or 45 mg/kg q3w) using a 3�3 design. Three patients per dose 

level were evaluated for safety. A biomarker-rich dose-expansion arm tested 

weekly 5 or 15 mg/kg MEDI-573 in patients with advanced bladder cancer. 

Results: Preliminary data are presented for 43 patients (25 M, 18 F), 

median age 64 years. No dose-limiting toxicities or serious toxicity patterns 

occurred at any dose level. Drug-related adverse events occurring in �10% 

of patients were fatigue (28%), decreased appetite (23%), nausea (16%), 

diarrhea (14%), and anemia (12%); the majority were � grade 2. 

Perturbations in insulin and growth hormone were not observed. Clinically 

significant changes in serum glucose were rare. The MTD was not reached 

after completely enrolling patients through the highest dose, 45 mg/kg IV 

q3w. Serum exposure of MEDI-573 increased with increasing dose. Full 

suppression of IGF-I/-II was achieved with weekly and q3w dosing. No 

neutralizing antibodies against MEDI-573 were detected. Of 43 patients, 8 

(19%) had stable disease �12 weeks. The longest exposure was 21 months 

in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 

demonstrated an acceptable safety profile at all doses tested. No doselimiting 

toxicity or serious toxicities, including those related to glucose 

homeostasis, were detected. These preliminary results support further 

clinical development. 

TPS2620 General Poster Session (Board #11E), Mon, 8:00 AM-12:00 PM 

A phase I study of 1-methyl-D-tryptophan in combination with docetaxel in 

metastatic solid tumors. Presenting Author: Erica Jackson, University of 

South Florida Morsani College of Medicine, Tampa, FL 

Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create 

immune suppression and unresponsiveness to tumor antigens in tumorbearing 

hosts. 1-methyl-D-tryptophan (1-MT), an oral inhibitor of the IDO 

pathway, showed favorable toxicity profile and biologic activity in prior 

studies. Remarkably, in prior animal models (MMTV-neu mice), 1-MT in 

combination with chemotherapy produced 30% greater tumor regressions. 

Based on this data, a phase I trial was initiated to study the synergism of 

1-MT with docetaxel. The primary goal of this trial is to determine the MTD 

and toxicity for the combination of docetaxel and oral 1-MT. A secondary 

endpoint will be to determine the PK data and the overall response rate. 

Methods: This phase I study utilizes a 3�3 design comprised of five dose 

levels. Dose levels 1-4 will evaluate docetaxel 60mg/m2 IV d1 q3wks plus 

1-MT at 300mg, 600mg, 1000mg, and 2000mg PO BID d1-21 respectively. 

Dose level 5 is docetaxel 75mg/m2 IV d1 q3wks � 1-MT 2000mg 

PO BID d1-21. Eligibility for this study includes patients with measurable 

metastatic solid malignancy, no prior docetaxel for metastatic disease, age 

�18, life expectancy �4 months, and adequate organ/marrow function. 

Patients will be excluded if they meet any of the following criteria: 

chemotherapy within the past 3 weeks, untreated brain metastases, active 

autoimmune disease, or GI disease causing malabsorption. In addition, any 

patients who have received prior immunotherapy such as ipilimumab are 

excluded. Treatment will continue until disease progression, unacceptable 

toxicity, or patient/physician discretion. Accrual to dose level 3 is complete 

and dose level 4 accrual is underway. The PK of 1-MT and docetaxel will 

also be characterized, using an HPLC assay. PK measurements for 1-MT 

are drawn on C1D1 after a single dose of 1-MT is given and then on C1D8 

after the morning dose of 1-MT is given. (Drawn at 0,1,2,4,8,12,24, and 

48 hours) Because IDO is hypothesized to cause regulatory T cell 

expansion, circulating Tregs will be quantified utilizing flow cytometry for 

CD4�CD25� FoxP3� cells. (NCT01191216) 




Safety, pharmacokinetics, and antitumor activity of MEDI3617, a selective 

angiopoietin inhibitor, in adult patients with advanced solid tumors. 

Presenting Author: Ronald B. Natale, Cedars-Sinai Outpatient Cancer 

Center, Los Angeles, CA 

Background: MEDI3617 is an investigational monoclonal antibody that 

inhibits angiogenesis by preventing the interaction of angiopoietin-1 and 

angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: This is an 

ongoing phase 1 dose-escalation and dose-expansion study in patients with 

advanced solid tumors, Karnofsky performance status �70, and adequate 

organ function. Patients were treated with escalating IV doses of MEDI3617 

on day 1 of each 21 day cycle in cohorts of 3-6 patients. The objectives are 

to evaluate the safety profile and determine the maximum tolerated dose, 

dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and 

clinical activity of MEDI3617. Results: Preliminary data are presented for 

21 patients (14M/7F), median age 65 yrs, evaluable for DLT. One DLT 

occurred: grade 4 neutropenia lasting more than 7 days. The most 

frequently reported drug-related adverse events (% of patients) were 

fatigue (24%), diarrhea (19%), nausea (19%), dysgeusia (14%), and 

headache (14%), all of which were � grade 2. All monotherapy dose levels 

have completely enrolled patients without exceeding the maximum tolerated 

dose. The exposure of MEDI3617 after the first dose showed a more 

than dose-proportional increase. Suppression of free Ang2 was dosedependent. 

Maximum accumulation of total Ang2 was observed at the 

lowest administered dose. No anti-MEDI3617 neutralizing antibodies were 

detected. Of the 21 patients, 4 continue on treatment (maximum of 6� 

months in a patient with carcinoid tumor of the jejunum) as of the data 

cut-off date. Of the 17 patients for whom response data are available, 5 had 

stabilization of disease of 12 weeks or greater. Conclusions: Preliminary 

safety and activity signals warrant continued evaluation of MEDI3617. This 

study was funded by MedImmune, LLC. 


Clinical pharmacokinetics (PK) of BMS-936558, a fully human anti-PD-1 

monoclonal antibody. Presenting Author: Shruti Agrawal, Bristol-Myers 

Squibb, Princeton, NJ 

Background: BMS-936558 is a fully human IgG4 monoclonal antibody 

targeted against human Programed Death-1 (PD1) receptor on activated T 

and B lymphocytes. Blocking of PD-1 prevents these activated cells from 

becoming anergic, thereby maintaining anti-tumor immunologic activity. 

Methods: The PK of BMS-936558 was characterized with data from a 

single ascending dose (SAD) and a multiple ascending dose (MAD) study in 

subjects with advanced solid malignancies. Subjects received a single IV 

infusion of 0.3 to 10 mg/kg BMS-936558 in the SAD study (MDX-1106-01 

Study) and 0.1 to 10 mg/kg BMS-936558 every two weeks in the MAD 

study (MDX-1106-03/CA209003 Study). The PK of BMS-936558 was 

characterized by non-compartmental analysis of intensively sampled PK 

data from a SAD study, as well as by population PK analysis of available 

intensive and sparse PK data from the SAD and MAD studies, respectively. 

Results: The PK of BMS-936558 is linear in the studied dose range with 

dose-proportional increase in Cmax and AUC with low to moderate 

(20-44%) inter-subject variability. Geometric mean clearance ranged from 

0.13 - 0.19 mL/h/kg, whereas mean volume of distribution ranged from 83 

-113 mL/kg. The range of mean terminal elimination half-life of BMS- 

936558 is 17 to 25 days which is consistent with half-life of endogenous 

IgG4. BMS-936558 PK was adequately described by a linear twocompartment 

model, and there was no evidence of a contribution of target 

mediated drug disposition to drug elimination within tested dose range. 

Body weight and gender are potentially clinically significant covariate for 

both clearance and volume of distribution (� 20% effect); and baseline 

CRP, LDH, and albumin are potentially clinically significant covariates for 

CL. The body weight normalized dosing employed produces trough concentrations 

that are approximately constant over a wide range of body weights. 

Conclusions: The pharmacokinetics of BMS-936558 is dose-proportional 

and body weight normalized dosing is appropriate to ensure consistent 

exposure over a wide range of body weights. 


3000 Oral Abstract Session, Sun, 9:45 AM-12:45 PM 

Phase I clinical and pharmacologic study of the focal adhesion kinase 

(FAK) inhibitor GSK2256098 in pts with advanced solid tumors. Presenting 

Author: Jean-Charles Soria, Institut Gustave Roussy, INSERM U981, 


Background: FAK has an important role in cancer invasion and metastasis. 

FAK and phospho-FAK (pFAK) are increased in advanced cancer and are 

correlated with poor prognosis. GSK2256098 is a potent and specific small 

molecule inhibitor of FAK. Methods: This is a first-time in cancer pts, dose 

escalation study (NCT01138033) to identify the maximum tolerated dose 

(MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and 

clinical activity. Part 1 used a modified accelerated titration procedure 

switching to standard 3�3 design based on toxicity during the first 21 days 

of treatment. Pts were treated with GSK2256098 orally twice daily (BID) 

with food. Safety was established in cohorts of 1-6 pts. After MTD 

determination, Parts 2 and 3 were opened to further evaluate safety, PK 

and PD. Serial PK samples were obtained over 24 h on Days 1 and 15. Preand 

post-dose skin, hair and tumor tissue biopsies were analyzed for pFAK. 

Results: 57 pts with advanced solid tumors have been treated at escalating 

doses ranging from 80 mg to 1500 mg BID: median age�58.8 (range 

21-84). The most common tumor types include: mesothelioma (23), ovary 

(7), colon (3), kidney (3), and pancreas (3). MTD was determined to be 

1000 mg BID. DLTs were Gr 2 proteinuria (1000 mg), Gr 2 nausea, 

vomiting, fatigue (1250 mg) and Gr 3 asthenia (1500 mg). Most frequent 

toxicities were nausea (32 pts, 56%), diarrhea (31 pts, 54%), vomiting (25 

pts, 44%), decreased appetite (18 pts 32%) and asthenia (11 pts, 19%). 

The majority of toxicities were Gr 1-2; Gr 3 drug-related events included 

hypertriglyceridemia (n�2), hyperlipasemia (2), asthenia (1), increased 

amylase (1), and loss of consciousness (1). Few dose reductions and 

interruptions have occurred. Minor responses/stable disease (SD) were 

observed in pts with mesothelioma (-12%, 27 wks), melanoma (-26%, 54 

wks), and naso/pharyngeal cancer (-31% target lesion, 30 wks) and SD in 

renal cell (48� wks). In preliminary analysis of single-dose PK, exposure 

generally increased in a dose-proportional manner, and the geometric mean 

t½ was 4.2 h. Accumulation was not observed with repeat dosing. 

Conclusions: GSK2256098 is well tolerated with evidence of clinical 

activity. PK supports BID dosing. 


Phase I study of OPB51602, a small molecule inhibitor of STAT3 

phosphorylation, in patients with refractory solid malignancies. Presenting 

Author: Boon C. Goh, Cancer Science Institute of Singapore, Singapore 

Background: STAT3 is constitutively activated by growth signaling pathways 

in many malignancies; in many cell lines inhibition of STAT3 leads to cell 

death. OPB51602 is a small molecule inhibitor of STAT3 phosphorylation 

(Tyr705) and activation. Methods: A phase I study of OPB51602 administered 

for 2 weeks every 3 weeks was initiated to determine the maximum 

tolerable dose (MTD), evaluate pharmacokinetics (PK), and assess pharmacodynamics 

effects on STAT3 in peripheral blood mononuclear cells 

(PBMCs). The starting dose was 2mg/day, and dose escalations to 5mg/d, 

10mg/d, 20mg/d, were planned. Single dose PK was done on the first day of 

administration for 4 days. Dose escalation was based on the “3�3” design, 

MTD was defined as the dose with at least 2/6 dose limiting toxicities 

(DLTs) in the first cycle and toxicities were graded by NCICTCv4.0. Results: 

32 patients (pt) were treated at doses of 2mg/d (n�7), 4mg/d (n�18), 

5mg/d (n�7). The main toxicities observed included nausea/vomiting, 

diarrhea, peripheral neuropathy and fatigue. 5 mg/d was the MTD, where 

cycle 1 DLTs of grade 3 diarrhea/dehydration and hyponatremia occurred in 

1 patient respectively. One pt developed grade 3 peripheral neuropathy at 

4mg/d cohort. PK showed maximal drug levels 2-3 hours after administration, 

bi-exponential decay, with mean oral clearance of 316.5 �/- 638.9 

L/h and long terminal mean half-life of 61.8 �/- 15.9 h on day 17. STAT3 

phosphorylation in PBMCs assessed in 6 pts receiving 4mg/d was reduced 

from 67.4 �/- 17.4% at baseline to 53.0 �/- 18.1% (p�0.001) after 

administration on day 1. Interestingly, reduction in tumor metabolism by 

PET CT on day 15 was observed in 4/8 pts receiving 4mg/d. A pt with 

heavily pretreated adenocarcinoma of lung at 5mg/d dose had partial 

response; another pt with metastatic endometrial cancer at 4mg/d dose 

experienced stable disease for 6 cycles. Conclusions: OPB51602 has an 

MTD of 5mg/d on this schedule, demonstrates inhibition of STAT3 

phosphorylation, and evidence of clinical activity. Further proof of concept 

studies of OPB51602 are warranted. 


173s 


A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 

dimesylate in patients with advanced cancer. Presenting Author: Matthew 

P. Goetz, Mayo Clinic , Rochester, MN 

Background: p38 MAPK regulates production of cytokines by the tumor 

microenvironment and its activation enables cancer cells to survive in the 

presence of oncogenic stress, radiation, chemotherapy, and targeted 

therapies. LY2228820 is a selective small-molecule inhibitor of p38 

MAPK and preclinical studies demonstrate antitumor activity as a single 

agent and in combination with standard agents. We performed a phase I 

study to determine the maximum tolerated dose (MTD) and dose-limiting 

toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and 

pharmacodynamics. Methods: Dose escalation was performed in a 3�3 

design. LY2228820 was taken orally every 12 hours on days 1-14 of a 

28-day cycle. Results: 54 patients received either capsules at 8 dose levels 

(10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels 

(160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC 

increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK 

induced phosphorylation of MAPKAP-K2 in peripheral blood with dosedependent 

maximum inhibition from 10 to 70% across the dose range 

10-200mg. The most common drug-related adverse events included 

fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient 

(200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) 

had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the 

MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, 

dizziness, and tremor) and observation of clinical activity at lower dose 

levels led to a recommended dose of 300mg (mean AUC0-24 � 11.7ughr/ml 

at steady state). Early clinical activity has been observed in ovary, 

breast, and kidney cancers. One patient with metastatic clear cell carcinoma 

of the kidney refractory to sorafenib, sunitinib, and temsirolimus had 

confirmed near partial response (29% decrease) after 8 cycles and remains 

on therapy. 15 patients (28%) achieved best overall response of stable 

disease, which in 12 patients (22%) was prolonged (�4 cycles). Conclusions: 

LY2228820 demonstrates acceptable pharmacokinetics, safety, and early 

clinical activity as a single agent in advanced cancer. A phase II study for 

patients with ovary cancer is planned. 


A phase lb, open-label, multicenter, dose-escalation study of the oral 

pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor 

GSK1120212 in patients (pts) with selected advanced solid tumors. 

Presenting Author: Philippe Bedard, Division of Medical Oncology & 

Hematology, Princess Margaret Hospital, Department of Medicine, University 

of Toronto, Toronto, ON, Canada 

Background: MAPK and PI3K/AKT signaling pathways regulate proliferation, 

differentiation and cell death in human cancers. Known interaction 

between the 2 pathways provides the rationale for combining both 

inhibitors in a phase I study. Methods: The objective is to determine the 

maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) 

for oral, daily administered, BKM120 � GSK1120212, mainly in pts with 

tumors with RAS/RAF mutations (mt). A Bayesian logistic regression model 

with overdose control guides the dose escalation of the treatment. Secondary 

objectives include safety, tolerability, PK and efficacy. Results: As of 

22.09.11, 49 pts were treated with BKM120 � GSK1120212 as follows: 

30mg � 0.5mg, 60mg � 0.5mg, 60mg � 1.0mg, 60mg � 1.5mg, 60mg 

� 2.0mg, 70mg � 1.5mg, 80mg � 1.0mg, 80mg � 1.5mg. 6 pts had 

dose-limiting toxicities (DLTs); all were reversible. Grade 3 DLTs were: 3 x 

stomatitis, 1 x dysphagia, 1 x LVEF decrease, 1xCKincrease, 1 x nausea, 

1 x anorexia, 1 x decreased oral intake. MTD and/or RP2D for the 

combination have not been reached. Most common adverse events (AEs) 

(�25%), all grades and causality, were dermatitis acneiform, diarrhea 

(51% each); nausea (41%); vomiting (37%); rash (33%); asthenia (31%); 

CK increase, decreased appetite, pyrexia or stomatitis (29% each) and 

hyperglycemia (27%). There were 4 on-treatment deaths unrelated to 

treatment. AEs led to treatment discontinuation, 17 pts (35%) and 

interruptions/dose reductions, 25 pts (51%). Apparent steady-states of 

BKM120 and GSK1120212 were reached by day 28. Plasma concentrations 

of BKM120 in combination with GSK1120212 were lower than for 

monotherapy. Exposure to GSK1120212 with BKM120 was similar to that 

observed in monotherapy studies. 3 confirmed partial responses have been 

observed in pts with KRAS mt ovarian cancer; 2 lasting �9 months. 2 

patients with BRAF mt melanoma, who had previously progressed on BRAF 

inhibitors, had stable disease, for 1 of whom treatment is still ongoing in 

cycle 6. Conclusions: BKM120 and GSK1120212 can be safely combined. 

Signs of clinical activity have been seen in pts with RAS/RAF mt tumors. 


174s Developmental Therapeutics—Experimental Therapeutics 


First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor 

AZD2014 in solid tumors. Presenting Author: Udai Banerji, Drug Development 

Unit, The Institute of Cancer Research/The Royal Marsden Hospital, 


Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with 

clear activity in in vivo and in vitro experimental models. Methods: This 

2-part study consisted of �rolling six� dose escalation (Part A) and 

expansion (Part B) phases. Part A: 3–6 pts per cohort received an oral 

solution of AZD2014 BD starting at 50 mg. A further 6 pts were treated in 

Part A below the MTD to study changes in pharmacodynamic (PD) 

biomarkers. Part B: additional pts were dosed at the MTD, including a 

group of ER�/PR� or HER2� patients with breast cancer. Primary 

endpoint: safety and tolerability; secondary endpoints: pharmacokinetics 

(PK), PD and efficacy. Biomarkers assessed: mTORC1: pS6 (S235/236) 

and p4EBP1 (T37/46); mTORC2: pAKT (S473). Results: 50 pts have been 

enroled in this ongoing study and interim data are reported: Part A, n�23 

(25 mg, n�6; 50 mg, n�8; 70 mg, n�5; 100 mg, n�4; all BD); Part B, 

n�27. The MTD was 50 mg BD. DLTs were seen at both 100 mg (Gr 2 and 

3 lethargy/fatigue, n�4/4) and 70 mg (Gr 3 mucositis, Gr 2 lethargy, 

n�2/4); no DLTs were seen at 25 mg or 50 mg. The most common AEs in 

order of incidence were fatigue, stomatitis, decreased appetite, nausea and 

diarrhea. Seven SAEs (nausea, vomiting, lethargy, abdominal pain, mucositis) 

reported by 3 pts were considered ‘possibly related’ to the study drug by 

investigators. AZD2014 is rapidly absorbed following single and BD 

multiple doses with a short t1/2 of ~3 h. At 50 mg (n�32), preliminary data 

show geometric mean AUCss�7.4 �g.h/ml and Cmax ss�1.7 �g/ml. One pt 

with acinar pancreatic cancer had a RECIST partial response. pAKT and 

p4EBP1 reductions were observed between 2–8 h in platelet-rich plasma 

and peripheral blood mononuclear cells respectively. Target modulation in 

paired tumor biopsies was seen at the MTD. Reduction in the phosphorylation 

of S6 and 4EBP1 was evident in 8/10 and 3/9 paired biopsies 

respectively. pAKT was reduced in 3/6 evaluable paired biopsies. As 

opposed to rapalogs, pAKT was not upregulated in any of the evaluable 

post-treatment biopsies. Conclusions: The MTD for AZD2014 is 50 mg BD. 

Further clinical evaluation of AZD2014 is now warranted based on the 

safety, PK and proof-of-mechanism PD data, as well as its preliminary 

clinical activity. Updated results will be presented. 

3006^ Oral Abstract Session, Sun, 9:45 AM-12:45 PM 

Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid 

and hematologic cancers. Presenting Author: Kent C. Shih, Sarah Cannon 

Research Institute, Nashville, TN 

Background: The mammalian target of rapamycin (mTOR) signaling pathway 

is frequently activated in cancer. The mTOR kinase exists in two 

multi-protein complexes, TORC1 and TORC2, which drive key cellular 

metabolic and proliferative functions. TORC1-selective inhibitors can 

induce feedback upregulation of TORC2 and treatment resistance. CC-223 

is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and 

TORC2, selected to address this escape mechanism. Methods: Subjects 

with advanced solid and hematologic cancers were enrolled using an 

accelerated (1�5) dose escalation design. CC-223 was administered 

orally once daily (QD) in 28 day cycles until disease progression. Safety, 

pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. 

Results: 28 subjects were treated across 5 dose levels: 7.5 (n�1), 15 

(n�2), 30 (n�9), 45 (n�7) and 60 mg (n�8). The most common 

(� 20%) related adverse events (all grades) were fatigue (64%), nausea 

(50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia 

and vomiting (32% each) and rash (29%). Dose-limiting toxicity (all 

grade 3) occurred in 4 subjects: hyperglycemia (30 mg), rash (45 mg), 

fatigue (60mg), and mucositis (60 mg). The maximum tolerated dose 

(MTD) was 45 mg QD. Dose proportional exposure was observed with a 

terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg). Inhibition of TORC1 (pS6, p4EBP1) and 

TORC2 (pAKT) biomarkers in blood cells was characterized to be exposuredependent 

and described by an Emax model. Near maximal inhibition of 

both TORC1 and TORC2 biomarkers was achieved at the peak concentrations 

of 30 or 45mg QD. Target inhibition was predicted to last 8 to 20 

hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 

months (ER� breast) and 7 subjects with stable disease (SD) lasting 8� 

weeks (range 8 to 23.3). Conclusions: CC-223 was well tolerated with 

toxicities comparable to other drugs in this class. Evidence of TORC1/ 

TORC2 pathway inhibition was observed as well as preliminary signals of 

anti-tumor activity, including one durable PR. Expansion cohorts in 

selected hematologic and solid tumors will evaluate CC-223 at the MTD of 

45 mg QD. 


First-in-human phase I study of LY2780301, an oral P70S6K/AKT 

inhibitor, in patients with refractory solid tumors. Presenting Author: 

Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal, 

Madrid, Spain 

Background: LY2780301is an oral potent, highly selective ATP competitive 

inhibitor against p70S6 kinase and AKT. We report on safety, pharmacokinetics 

(PK), pharmacodynamics (PD), and anti-tumor activity from the 

first-in-men study of LY2780301 in solid tumors. Methods: Eligible pts 

(ECOG�1) had relapsed solid tumors, adequate hematologic, renal, and 

hepatic functions. Using a predictive pre-clinical PK/PD model and 

non-clinical toxicology data, a total daily dose of 100-1000 mg, was 

selected. LY2780301 was given either once or twice daily for 28-day cycle 

until disease progression. Dose escalation (3�3 design) was based on 

CTCAE V4 toxicities. The primary objective was to define the recommended 

phase 2 dose of LY2780301. Secondary objectives were PK, PD (pS6 in 

skin), and preliminary antitumor activity. Results: 32 patients were treated 

at dose levels from 100mg – 500mg total daily dose. LY2780301 was well 

tolerated at all dose levels No dose-limiting toxicities were observed in 

cycle 1. Common toxicities potentially related to study therapy included: 

constipation (7pts), fatigue (5pts), nausea (4pts), diarrhea (3pts), and 

vomiting (3pts). Grade 3/4 toxicities potentially related to study therapy 

were: anemia (3pts), increased ALT/AST (1pt), and increased GGT (1pt). 

Average number of cycles received across all dose levels was 2. There were 

no partial or complete responses; best response observed was prolonged 

stable disease for 6.5 cycles. Plasma exposures of LY278030 exceeded 

predicted efficacious dose in all pts (AUC 0-24H �25000 ng*hr/mL). 

Increase in exposure with dose was observed (QD or BID) with significant 

inter-pt variability. The exposure increase was less than linear with dose. 

Preliminary PK parameters are CL/F 4.5L/h and t1/2 of 24 hours. pS6 

assessment in skin showed inhibition in � 50% of pts receiving 400-500 

mg per day. Positive correlation with the exposure of the didesmethyl 

metabolite was observed. Conclusions: LY2780301displayed favorable 

safety profile, and high PK exposures in the range of efficacious dose. The 

recommended dose will be defined in the range between 300 and 500 mg. 

Further exploration of PK/PD effect in mesothelioma is ongoing. 


First-in-human phase I study of the ALK inhibitor LDK378 in advanced 

solid tumors. Presenting Author: Ranee Mehra, Fox Chase Cancer Center, 

Philadelphia, PA 

Background: LDK378 is a novel, potent and selective small molecule 

anaplastic lymphoma kinase (ALK) inhibitor (IC50 0.00015 �M), that does 

not inhibit c-MET (IC50 3.2 �M). Tumor regression has been observed in 

ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being 

conducted to determine the MTD and safety profile in patients (pts) with 

tumors with ALK rearrangement, amplification or mutation. Other objectives 

were safety, PK and antitumor activity in pts with ALK-driven NSCLC, 

both naïve to ALK inhibitors and relapsed following previous ALK inhibitor 

treatment, and other ALK-positive cancers. Methods: Adult pts with 

advanced malignancies harboring a genetic alteration in ALK who progressed 

on standard therapy or for whom there was no effective therapy, 

were given once daily oral LDK378 on a continuous 21-day schedule. Dose 

escalation, starting at 50 mg/day, was guided by a Bayesian logistic 

regression model (BLRM) to determine the MTD. Results: At a January 5th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; 

median age 52 years; 87% ECOG PS 0/1) were enrolled and received 

LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade 

(Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia 

(1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed 

dose escalation, and there were no DLTs in 4 pts at 500 mg. Median 

duration of treatment with LDK378 was 7 weeks (range �1–22�). At the 

cutoff date, 13 (42%) pts discontinued treatment: 1 (3%) due to adverse 

events (AEs), and 12 (39%) due to disease progression; 18 (58%) pts were 

still on treatment. The most frequent AEs (all Gr) were nausea (45%), 

vomiting (36%), and diarrhea (29%). The most frequent Gr 3/4 AEs were 

diarrhea and dyspnea (2 pts [7%] each). At doses �400 mg steady state 

exposures exceeded efficacious exposures in xenograft models. Of 16 pts 

with available response data (RECIST, per investigator) there were 4/6 

responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZ-naïve 

pts, of whom 7 were treated below 400 mg. All responses were in NSCLC. 

Conclusions: Daily oral LDK378 is well tolerated up to 500 mg/day, and 

escalation continues at 750 mg/day. Preliminary responses have been seen 

in both CRZ-naïve and CRZ-relapsed pts. 



A first-in-human phase I study of the oral Notch inhibitor LY900009 in 

patients with advanced cancer. Presenting Author: Shubham Pant, Sarah 

Cannon Research Institute/University of Oklahoma Health Sciences Center, 

Oklahoma City, OK 

Background: Notch signaling plays a critical role during stem cell selfrenewal 

and is deregulated in multiple human cancers. The Notch pathway 

may be activated inappropriately by receptor mutation and overexpression 

as well as aberrant signals from the tumor microenvironment. LY900009 is 

a selective small-molecule inhibitor of gamma secretase, the enzyme that 

cleaves and thereby activates Notch receptors. Methods: Dose escalation 

was performed in cohorts of 3 patients (pts) using a modified continual 

reassessment method. LY900009 was taken orally thrice weekly (every 

MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, 

and clinical endpoints were evaluated. Results: 22 patients received 

LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts), 

15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment 

emergent adverse events possibly related to LY900009 across all grades 

included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%), 

anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting 

toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients, 

respectively, treated at 60mg. The maximum tolerated dose (MTD) was 

tentatively identified at 30mg. After a single dose, mean Cmax increased 

from 4 to 158 ng/ml and mean AUC0-t(last) increased from 14 to 1160 

ng-hr/ml. Both Cmax and AUC0-t(last) increased in a dose-dependent 

manner. Elimination half-life of LY900009 was approximately 2-3 hrs. 

LY900009 inhibited plasma levels of amyloid-� peptide (a downstream 

product of gamma secretase) in a dose-dependent manner with 80-90% 

inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one 

patient had colonic biopsy that showed markedly increased glandular 

mucin consistent with pharmacologic inhibition of the Notch pathway. Two 

patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles 

of therapy. Conclusions: LY900009 demonstrates acceptable safety and 

pharmacokinetics in patients with advanced cancer. Pharmacodynamic 

endpoints show pathway inhibition at tolerable doses. One more cohort at 

45mg is ongoing to refine the MTD and will be followed by an expansion 

cohort for patients with ovarian cancer. 


4:45 PM-5:45 PM 

Phase I/II study of the investigational aurora A kinase (AAK) inhibitor 

MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer 

(NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck 

cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary 

phase II results. Presenting Author: Peter Lee, Tower Cancer Research 

Foundation, Beverly Hills, CA 

Background: AAK is a key mitotic regulator that is amplified or overexpressed 

in multiple tumor types. MLN8237 is an investigational oral, 

selective AAK inhibitor being studied in both hematologic (phase III) and 

nonhematologic malignancies. In the phase 1 part of this study, MLN8237 

was generally well tolerated in pts with solid tumors. The maximum 

tolerated dose was 50 mg BID for 7d � 2 wks rest in 21-d cycles; this dose 

was recommended for phase II evaluation. Here we report preliminary data 

from the 5-arm phase 2 part (NCT01045421). Methods: 20 pts each with 

one of 5 tumor types in the relapsed/refractory setting were enrolled in 

phase II for efficacy evaluation: NSCLC (inc. 8–10 pts with mainly 

squamous-cell histology), SCLC (inc. 8–12 chemotherapy refractory pts), 

BrC (inc. 8–10 pts with a basal-like intrinsic subtype, and 8–10 HER2� 

pts), H&N (inc. 8–12 pts with tonsillar or base-of-tongue disease), or GE 

adenocarcinoma. Pts were aged �18 y, and had ECOG PS 0–1, measurable 

disease by RECIST, and �2 prior cytotoxic chemotherapy regimens 

(�4 in BrC). Oral MLN8237 was administered as an enteric-coated tablet 

at 50 mg BID for 7d � 2 wks rest in 21-d cycles. The primary endpoint was 

overall response rate. Response was determined by RECIST v1.1. Each arm 

with �2 partial responses (PR) is being expanded with 25 additional pts. 

Results: In 100 efficacy-evaluable pts, median age was 59 y (range 33–88) 

and 89% were caucasian. Pts received a median of 3 cycles (range 1–9). 

PRs were observed in 11 pts: H&N, SCLC (each n�3), BrC, GE adenocarcinoma 

(each n�2), and NSCLC (n�1). 45 pts had a best response of stable 

disease. In the safety population (n�196), most frequent grade �3 

drug-related AEs were neutropenia (37%), leukopenia (12%), fatigue, 

anemia, stomatitis, and thrombocytopenia (each 6%). Updated data will be 

presented. Conclusions: Preliminary phase II data suggest that oral 

MLN8237 is tolerable and has antineoplastic activity in a range of solid 

tumors studied. This study is currently ongoing to further evaluate 

MLN8237 in the expansion cohorts. 


175s 


4:45 PM-5:45 PM 

First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in 

adult patients (pts) with advanced solid tumors. Presenting Author: 

Michael Anthony Carducci, The Johns Hopkins University School of 

Medicine and Sidney Kimmel Comprehensive Cancer, Baltimore, MD 

Background: Aurora kinases A, B, and, C play essential roles in regulating 

cell division. Overexpression of aurora A and B in human tumors is 

associated with high proliferation rates and poor prognosis. AMG 900 is an 

investigational, orally administered, highly selective inhibitor of aurora A, 

B, and C that demonstrated activity in drug-resistant cell lines and human 

tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics 

(PK), and pharmacodynamics of AMG 900. Methods: Key eligibility 

criteria: � 18 years old, advanced solid tumors, measurable disease, ECOG 

� 2, and adequate organ function. AMG 900 was administered orally daily 

for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation 

phase, the starting dose was 1 mg and was escalated by 100% in 

subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade 

2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation 

continued in a standard 3�3 design at � 25% if DLT occurred or � 50% if 

G2 related toxicity occurred. The maximum tolerated dose (MTD) was 

determined without prophylactic G-CSF support. Results: As of OCT 2011, 

19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30 

mg) had received � 1 dose of AMG 900. Demographics were 58% women, 

median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4 

DLTs: G4 neutropenia � 7 days at 24 mg (n�1) and 30 mg (n�1); G4 

neutropenia � 7 days � G4 thrombocytopenia at 30 mg (n�1); and febrile 

neutropenia (FN) at 30 mg (n�1). MTD without G-CSF support was 24 mg. 

89% of pts had treatment-related adverse events (AEs). G�3 treatmentrelated 

AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2 

(11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed 

no obvious departures from dose-proportionality with a half-life of ~16 h. 

Tumor-response data were available for 17 pts: stable disease, 13 pts 

(range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort) 

with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease 

in CA-125 (SD � 6 months). Conclusions: AMG 900 administered at 24 mg 

daily for 4D Q2W is the recommended dose for phase 2 trials. Dose 

escalation is now ongoing to determine the MTD with prophylactic G-CSF. 


4:45 PM-5:45 PM 

A phase I study of selective cyclin dependent kinase inhibitor P1446A-05 

administered on an intermittent schedule in patients with advanced 

refractory tumors. Presenting Author: Sudeep Gupta, Tata Memorial 

Centre, Mumbai, India 

Background: Cyclin-dependent kinases (Cdks) have emerged as important 

targets in anticancer drug development. P1446A-05 is a potent and 

specific inhibitor of Cdk4-D1 (IC50-0.09�M), Cdk1-B (IC50-0.025�M), and Cdk9-T (IC50-0.022�M). This study was designed to determine the 

maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety profile, 

pharmacokinetics, and antitumor activity of orally administered P1446A-05 

in patients with advanced refractory tumors. Methods: This study was 

conducted at 5 centers in India. P1446A-05 was administered in escalating 

doses across 5 cohorts of eligible pts starting with a dose of 75 mg once 

a day (OD) for 14 days in a 21 day cycle utilizing a modified Fibonacci 

scheme for dose escalation. 10 pts positive for cyclin D1 expression in the 

tumor were enrolled at MTD. Treatment was continued until unacceptable 

toxicity or disease progression. For pharmacokinetic analysis, blood samples 

were collected on days 1 and 13/14 of cycle 1 at multiple time points. In 

consenting pts, skin and tumor tissue biopsies were collected on days 1 

(pre-dose), 8 and 15 of cycle 1. Results: A total of 29 patients were dosed. 

Two DLTs (abdominal pain and acute renal failure) were reported at 850 

mg/d. The MTD was 600 mg/d and diarrhea was reported as 1 DLT at this 

dose level. Six SAEs including one death related to study drug were 

reported. Pharmacokinetic analysis demonstrated a median half-life of 16 

to 26 h and linear increase in exposure at steady state across tested doses. 

Plasma concentration at 300 mg/d dose level crossed efficacy exposure of 

100mg/kg of five day dosing in SCID mice. The recommended phase II dose 

is 600 mg OD on this schedule. Stable disease for 4 to 6 cycles was 

reported in 5 pts. Of them, one patient each with breast cancer, spindle cell 

sarcoma in neck, and nasopharyngeal carcinoma had cyclin D1 over 

expression. No objective responses were observed in this group of heavily 

pretreated patients. Conclusions: The safety profile of P1446A-05 is 

considered acceptable. On this dosing schedule, the MTD is determined as 

600 mg/day. Further testing of P1446A-05 in phase II studies is planned. 




4:45 PM-5:45 PM 

A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in 

patients with advanced solid tumors: Dose escalation with an intermittent 3 

days on/4 days off schedule. Presenting Author: Rastislav Bahleda, Institut 


Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting 

CDKs 1,2,4, 7 and 9 in the low nanomolar range. A phase I dose escalation 

study was initiated to determine the maximum tolerated dose (MTD), 

pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with 

advanced solid tumors. Methods: BAY was administered twice daily in a 3 

days on / 4 days off schedule (cycle length 21 days, 3�3 design). PK was 

evaluated on cycle 1 day 1 and day 10. Response rate was assessed 

according to RECIST 1.1. PD markers included CK18 fragments in plasma. 

Results: As of Jan 08 2011, 34 pts were treated at doses of 0.6 (3 pts), 1.2 

(4), 2.4 (3), 4.8 (3), 9.6 (3), 19.2 (6) mg per day as oral solution and at 

doses of 10 (4), 15 (6) and 20 (2) mg per day as tablet. Tumor types 

included 10 colorectal, 4 mesothelioma and 20 others. Cohort 9 (20 mg 

tablet) is ongoing. Frequent CTCAEv4 grade 1/2 drug related AEs occurring 

in more than 25% of patients up to cohort 8 were asthenia, diarrhea, 

nausea, vomiting and anorexia. DLTs (grade 3, 1 pt each) were hyponatremia, 

aphtous stomatitis at 19.2 mg solution and arterial thrombosis at 15 

mg tablet. Aphthous stomatitis (20%) has not been observed with the 

tablet formulation. Other grade 3 related AEs were asthenia in 2 and 

nausea and vomiting in one pt each. Nausea and vomiting on treatment 

days were observed despite antiemetic treatment (aprepitant �/- setron). 

PK was dose proportional up to 9.6 mg, T1/2 was 10 hours, and relative 

bioavailability of tablet formulation was excellent; major metabolite levels 

were low (�10%). Levels of CK18 fragments did not correlate with dose or 

tumor response. Stable disease (SD) lasting for 2-4 months was observed in 

9 patients, among others in 4 of 4 mesothelioma and 2 of 2 ovarian pts. 

One additional pt with cholangiocarcinoma has ongoing SD lasting for 5 

months. One of the ovarian pts had a significant decline of CA125 lasting 

for 3 months. Conclusions: The tablet formulation of BAY 1000394 was 

better tolerated than oral solution. So far, doses up to a 15 mg per day with 

concomitant antiemetic treatment showed an acceptable tolerability. SD 

was observed in 10 of 25 heavily pretreated pts across cohorts3–8. 


4:45 PM-5:45 PM 

Molecular profiling of patients (pts) with colorectal cancer (CRC) and 

matched targeted therapy (MTA) in phase I clinical trials. Presenting 

Author: Rodrigo Dienstmann, Molecular Therapeutics Research Unit, Vall 

d’Hebron University Hospital, Barcelona, Spain 

Background: Molecular prescreening and biomarker enrichment strategies 

in Phase 1 trials with targeted therapies are anticipated to improve the 

outcomes of affected pts. Methods: As part of our personalized oncology 

program, tumors from pts with advanced chemorefractory CRC were 

analyzed for specific molecular aberrations (KRAS/ BRAF/ PIK3CA mutations 

[mut], PTEN and pMET expression) at the Vall d’Hebron Molecular 

Pathology and Genomics Labs. Those whose tumors were found to have a 

dysregulation were offered a Phase 1 trial with MTA. Results: During 2010 

and 2011, tumor molecular analysis was performed in 254 pts: KRAS mut 

(80/254, 31.5%), BRAF mut (24/196, 12.2%), PIK3CA mut (15/114, 

13.2%), KRAS�PIK3CA mut (9/114, 7.9%), PTEN low (97/183, 53.0% - 

HSCORE�50; 45/183, 24.6% - PTEN null), KRAS mut � PTEN low 

(38/138, 20.8%), pMET high (38/64, 59.4% with HSCORE�30). In total, 

68 pts (median, age 63 yrs; prior therapies 3), received 82 different 

matched therapies. Type of MTA: PI3K pathway inh (if PIK3CA mut, n�10; 

or PTEN low, n�32), MEK�PI3K pathway inh (if KRAS mut, n�10; or 

BRAF mut, n�1), second-generation anti-EGFR mAbs (if KRAS wild-type, 

n�11), anti-HGF mAb (if pMET high, n�10), mTOR inh � anti-IGFR-1R 

mAb (if PTEN low, n�5) and BRAF inh (if BRAF mut, n�3). Median time to 

treatment failure (TTF) with MTA was 7.9 weeks (CI95%:7.6-8.1) vs. 16.3 

weeks (CI95%:13.9-18.7) for their prior systemic antitumor therapy 

(p�0.001). If prior therapy non-standard (according to NCCN guidelines, 

n�39), TTF with MTA 7.9 weeks (CI95%:6.8-8.9) vs. TTF with prior 

therapy 8.7 weeks (CI95%:7.3-10.1). If an approved standard regimen 

(n�43), TTF with MTA 7.9 weeks (CI95%:7.6-8.1) vs. TTF with prior 

therapy 21.9 weeks (CI95%:15.0-28.7). Partial response was seen in one 

pt (1.2%, PI3K inh with PIK3CA mut) and stable disease � 16 weeks in 10 

cases (12.2%). Clinical benefit, defined as a TTF ratio � 1.3 (TTF on MTA/ 

TTF on prior therapy), was seen with 15.9% of the therapies (13/82). 

Conclusions: Preliminary results suggest that matching chemorefractory 

CRC patients with targeted agents in early clinical trials based on the 

current molecular profile does not result in longer TTF compared to their 

prior therapy. 


4:45 PM-5:45 PM 

A phase I and pharmacokinetic (PK) study of continuous daily administration 

of P1446A-05, a potent and specific oral Cdk4 inhibitor. Presenting 

Author: Desiree Hao, Tom Baker Cancer Centre, Calgary, AB, Canada 

Background: P1446A-05 is a novel oral inhibitor of Cdk4-D1, Cdk1-B, and 

Cdk9-T, and has been shown to inhibit tumor growth both in vitro and in vivo. 

Pharmacodynamic studies demonstrate that activation of Cdk1 reappears 

within 48 hours after P1446A-05 is withdrawn, suggesting the need for 

prolonged administration hence, we sought to evaluate the feasibility, safety 

and tolerability of a continuous daily schedule of P1446A-05 in patients (pts) 

with advanced malignancies. Methods: P1446A-05 was given at escalating 

doses of 75, 150, 250, 350 and 500mg. Samples were collected for PK at 

multiple time points over 24 hours on cycle 1 day 1 and 15, as well as at single 

time points on cycle 1 day 8, 22 and cycle 2 day 1. Results: Thirty-nine pts 

(median age�63 years, 51% male, 51% ECOG PS�1) collectively received 

more than 100 cycles of P1446A-05. The majority of drug-related toxicities 

were �Grade 2, the most common of which were diarrhea (n�54), nausea/ 

vomiting (n�27/17), fatigue (n�22) and anorexia (n�16). Two pts developed 

study-drug related diarrhea with hypokalemia/elevated creatinine and died 

during cycle 1. Dose-limiting toxicities (DLT) at 500mg (Table) led to 

subsequent de-escalation and expansion of the 350mg cohort. A total of 24 

pts were treated at 350mg; only one patient experienced dose-limiting 

diarrhea. PK data are summarized below. Accumulation ratios across dose 

levels suggest moderate accumulation with continuous dosing. Nine pts 

achieved stable disease (SD) for at least 2 cycles. One pt with alveolar soft 

tissue sarcoma, whose disease was progressing at enrollment, remains on 

treatment with SD after 11 cycles. Conclusions: The recommend phase II dose 

of P1446A-05 is 350mg. Further phase II studies at this dose will be 

conducted with potential enrichment strategies. 

DLTs and PK data. 

Dose 

level 

(mg) 

No. of 

pts in 

cohort 

No. of 

pts with 

DLT 

DLT event 

description 

Tmax (h) Cmax (ng/mL) AUC0-inf (ng.h/mL) 

Accumulation 

Day 1 Day 15 Day 1 Day 15 Day 1 Day 15 ratio 

75 3 0 4 2 107 195 3,033 24,893 2.22 

150 3 0 6 6 255 748 14,753 164,073 3.45 

250 3 0 4 4 446 1,027 15,208 54,503 3.07 

350 3�9�12 1 Diarrhea 4 4 512 992 16,700 38,099 2.30 

500 6 3 Elevated INR 

Sudden death 

Diarrhea 

6 2 1,040 2,239 38,125 76,779 2.43 


4:45 PM-5:45 PM 

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of 

a novel treatment with promising activity. Presenting Author: Andrew 

Eugene Hendifar, Sarcoma Oncology Center, Santa Monica, CA 

Background: BPM 31510 is a novel small molecule that targets the 

metabolic machinery of the cancer microenvironment to reverse the aerobic 

glycolytic phenotype of cancer cells. Effector downstream signaling results 

in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor 

vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR 

Meeting Abstracts 2011). Methods: A standard 3�3 phase I, doseescalation 

study design was used in patients with advanced solid tumors 

refractory to standard treatment. Primary objectives were establishment of 

the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) 

correlates. Secondary objectives included exploratory pharmacodynamics 

(PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential 

cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with 

advanced cancer who had failed multiple chemotherapeutic regimens had 

been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). 

Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 

elevation in PT/INR, otherwise there have been no grade 3/4 treatment 

related toxicities to date. The pharmacokinetics of BPM 31510 are linear 

and there were no sex differences in the parameters normalized by dose and 

body surface area. Tmax and Cmax are associated with the end of the 

infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no 

dependence of t1/2 on dose. Objective tumor responses have been noted at 

the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 

minor response (pleomorphic sarcoma). Six patients (19%) have had 

disease stabilization (� 4 months). Conclusions: Interim data from this 

phase I study indicate that BPM 31510 is well tolerated with no dose 

limiting toxicities to date. A partial response and minor response were 

observed and correlates with dose escalation. Taken together, there is 

strong rationale for further clinical development of this compound as an 

anti-cancer agent. 



4:45 PM-5:45 PM 

A first-in-human phase I study of MORAb-004 (M4), a humanized 

monoclonal antibody recognizing endosialin (TEM-1), in patients with solid 

tumors. Presenting Author: Luis A. Diaz, Sidney Kimmel Comprehensive 

Cancer Center at Johns Hopkins University, Baltimore, MD 

Background: Endosialin (TEM-1) is a membrane glycoprotein on the cell 

surface of activated mesenchymal cells (e.g. pericytes, fibroblasts and 

mesenchymal tumor cells) and on a subset of human cancers. It is involved 

in the development of tumor vasculature, stromal/tumor organization and 

PDGFRb signaling. M4 is a humanized IgG monoclonal antibody which 

targets TEM-1. Preclinical studies suggest that M4 may have single agent 

activity via inhibition of the tumor microenvironment and by direct effects 

on tumors expressing this target. Methods: A phase I dose escalation study 

in patients (pts) with advanced solid tumors was conducted to evaluate the 

safety, pharmacokinetic profile and preliminary efficacy of M4 administered 

intravenously on a weekly schedule; final results are presented. 

Results: 36 pts refractory to therapy were treated at 10 dose levels (0.0625 

to 16 mg/kg administered i.v. on a weekly schedule). Drug-related adverse 

events (AE) observed were primarily infusion toxicity (grade 1 and 2 fever, 

chills, headache, myalgia). The MTD was determined to be 12 mg/kg. DLT 

of grade 3 vomiting was observed at 16 mg/kg. Preliminary pharmacokinetic 

(PK) analyses demonstrate M4 accumulation beginning at 4 mg/kg, 

and that elimination mechanisms are saturable beginning at 0.25 mg/kg. 

Exposure (AUC) increases in a greater than dose-proportional manner, with 

the apparent t1/2 increasing proportionally with dose. Tumor shrinkage 

(Minor/mixed tumor responses, mR) were seen in four pts (soft tissue 

sarcoma (2), hepatocellular carcinoma, pancreatic neuroendocrine tumor). 

Each mR was associated with prolonged disease stabilization in these pts 

(6-14 months). A cohort (n�4) of pts with refractory colorectal carcinoma 

demonstrated disease stabilization (15-24 weeks). Analysis of archival 

tumor revealed TEM-1 stromal staining in all cases with tumor cell 

expression noted on a subset of tumors of mesenchymal origin. Conclusions: 

In this phase I study, M4 was tolerated up to 12 mg/kg (MTD) and early 

signs of potential activity were observed. Expanded cohorts of 1-12 mg/kg 

are ongoing to further define an optimal dose. 


4:45 PM-5:45 PM 

Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined 

with cisplatin or carboplatin in patients with advanced solid tumors. Presenting 

Author: Herlinde Dumez, Department of General Medical Oncology, University 

Hospitals Leuven, Leuven, Belgium 

Background: Volasertib (V) is a first in class, selective and potent cell cycle kinase 

inhibitor that induces mitotic arrest and apoptosis by targeting Plk. This phase I 

study evaluates dose-limiting toxicities (DLT), maximum tolerated dose (MTD), 

safety and pharmacokinetics (PK) of V combined with cisplatin (Cis) or 

carboplatin (Ca). Methods: Sequential cohorts of patients (pts) received a single 

2h infusion of V with Cis (arm A) or Ca (arm B) every 3 wks. Cis and Ca were given 

for up to 6 cycles (Cy); V was continued until progression or intolerance. MTD was 

the highest dose at which �1/6 pts experienced a DLT in Cy 1. MTD cohorts were 

expanded to 12 DLT-evaluable pts to further characterize safety. Results: As of 

January 11 2012, 61 pts (arm A: 30; arm B: 31) were treated. Pt characteristics 

were (arm A/B): median age 55/58 yrs, male 16/18 pts, ECOG PS 0: 13/14 pts, 

PS 1: 17/17 pts. Tumors included (pts): non-small cell lung cancer (15); 

sarcoma (8); colorectal cancer (6); melanoma (4); urothelial cancer (4); other 

(24). Pts received V � Cis for a median [range] of 3.5 Cy [1-6], V � Ca for 2 Cy 

[1-6] and V for 3.5 Cy [1-20] in arm A and 2 Cy [1-14] in B. PK analyses are 

ongoing. MTD was reached at V 300 mg � Cis 100 mg/m2 and V 300 mg � Ca 

AUC 6. Five partial responses (PR) were seen. 15/30 pts in arm A and 12/31 in B 

achieved stable disease (SD) or PR. PR or SD for �6 Cy was observed in 6/30 pts 

and 5/31 pts in arms A and B, respectively. Conclusions: In this phase I study, V 

in combination with Cis or Ca at full single-agent doses was well tolerated. 

Furthermore, several objective responses and cases of sustained SD were 

observed in heavily pretreated pts with advanced solid tumors. 

Dose levels N of pts DLTs in Cy 1 (n of pts) 

Arm A: 

V (mg)/Cis 

(mg/m 2 ) 

Arm B: 

V (mg)/Ca 

(AUC) 

*MTD 


A1: 100/60 3 - 

A2: 100/75 3 - 

A3: 200/75 3 - 

A4: 300/75 3 - 

A5: 300/100* 6�6 Increased serum creatinine (1) � 

fatigue (1), neutropenia (1) 

A6: 350/75 6 Increased alanine transaminase (1), 

neutropenia (1) 

B1: 100/4 3 - 

B2: 100/5 3 - 

B3: 200/5 3 - 

B4: 300/5 6 Thrombocytopenia with neutropenia (1) 

B5: 300/6* 6�7 Thrombocytopenia (1) � (1) 

B6: 350/5 3 Thrombocytopenia (1), 

neutropenia with thrombocytopenia, 

febrile neutropenia, fatigue, 

nausea and anorexia (1) 

177s 


4:45 PM-5:45 PM 

Phase I study of oral rigosertib in patients with advanced solid tumors. 

Presenting Author: Daniel W. Bowles, Division of Medical Oncology, 

University of Colorado Denver, Aurora, CO 

Background: Rigosertib (ON 01910.Na) is a new multi-targeted inhibitor of 

several kinases, including polo-like kinase 1 and PI-3 kinase, and is in 

advanced trials for myelodysplastic syndrome and pancreatic cancer as an 

IV agent. An oral formulation with good oral bioavailability has entered 

phase 1 in patients (pts) with advanced solid tumors to determine the dose 

limiting toxicities (DLT), recommended phase II dose, pharmacokinetic 

(PK) profiles, and to document any antitumor activity of this compound. 

Methods: Pts with histologically confirmed solid tumors refractory to 

standard therapy were given escalating doses of rigosertib (70, 140, 280, 

560, 700 mg) twice daily continuously. Doses were escalated until 

intolerable grade 2 or grade 3/4 toxicities, at which point the previous dose 

level was expanded to define the MTD. All pts were assessed for safety, PK, 

PD and response. Urinary PK assessments were also performed at the MTD. 

Results: 25 pts (median age� 59; median ECOG PS� 1) received a median 

of 6 weeks of therapy at 5 dose levels: (70 mg n�3; 140 mg n�2 ; 280 mg 

n�3; 560 mg n�10; 700 mg n�7). The DLT was dysuria at 700 mg and 

led to expansion at 560 mg bid. There were no DLTs in the expansion 

cohort. Grade 2/3 toxicities related to rigosertib included dysuria (5/1), 

cystitis (4/0), urinary frequency (3/0), hematuria (2/1), abdominal pain 

(2/0), pelvic pain (1/1), nausea (1/0), distention/bloating (1/0) and 

hyponatremia (0/1). Improvements in dysuria were seen with oral hydration 

and sodium bicarbonate. A confirmed PR occurred in 1 pt (HN squamous 

cell ca, 42� weeks), and SD was observed in 2 pts with ovarian cancer (56 

weeks, 28 weeks), and 1 pt each with pancreatic neuroendocrine (40 

weeks), carcinoid (32 weeks), nasopharyngeal (24 weeks) and renal cell 

(32� weeks) tumors. Preliminary PK data reveal plasma rigosertib levels 

above the predicted pharmacodynamically active levels. Conclusions: The 

MTD of oral rigosertib administered twice daily continuously is 560mg. 

Dysuria is the dose limiting and most common toxicity and can be managed 

with oral hydration and sodium bicarbonate. Antitumor activity has been 

observed. Final safety and efficacy results, plasma and urinary PK relationships, 

and mutational analyses from archival tissue will be presented. 


4:45 PM-5:45 PM 

Phase I study of intravenous PI3K inhibitor BAY 80-6946: Activity in 

patients (pts) with advanced solid tumors and non-Hodgkin lymphoma 

treated in MTD expansion cohorts. Presenting Author: Michael T. Lotze, 

Hillman Cancer Center G27A, Pittsburgh , PA 

Background: BAY 80-6946 (BAY) is a potent and highly selective reversible 

pan-Class I PI3K inhibitor, previously reported to be tolerated as a 1-hr 

infusion at a dose of 0.8 mg/kg on days 1, 8 and 15 every 28 days (MTD). 

Additional pts were treated in MTD expansion cohorts to assess safety, PK, 

biomarkers and clinical benefit in selected tumor types, as well as safety in 

Type 2 diabetics. Methods: To date, 23 nondiabetic pts with solid tumors 

and 5 with follicular lymphoma (FL) received BAY at the MTD, until disease 

progression or unacceptable toxicity. Tumor types were selected for high 

frequency of PIK3CA mutation, including breast cancer (BC; 16), endometrial 

(3), gastric (2), GU transitional cell (1) and ovarian clear cell (1). 

Partial enrichment for PIK3CA mutation was achieved by analysis of 

plasma DNA. 3 diabetic pts have been enrolled, at starting dose of 0.4 

mg/kg. PK was done after the 1st and 3rd doses. FDG-PET/CT scans were 

done at baseline and 48 hrs after the 1st dose for pharmacodynamic 

assessment. Results: Safety and tolerability assessments confirmed MTD. 

There were no 1st cycle DLTs. Almost all nondiabetic pts had acute Grade 

2/3 hyperglycemia (HG) following each dose; at least 10 of them received 

insulin for 1-3 days post dose. Hypertension (HTN) lasting � 24 hrs was 

common in pts with preexisting HTN, and manageable. 2 FL pts developed 

interstitial pneumonitis (IP) after cycles 2 and 3, both responsive to 

steroids. Diabetic pts tolerated 0.4 mg/kg. Tumor SUVmax consistently fell 

at 48 hrs. 3 of 4 FL pts had partial response (PR) after 2 cycles, with 2 

confirmed PR pts on BAY for 10� and 8� mos. 2 BC pts showed PR , 1 

confirmed. PIK3CA mutation (n�7) does not appear to correlate with 

response. Average T1/2 was 36 hrs. Observation of high Cmax in very obese 

pts led to recommended maximum dose of 65 mg. Conclusions: BAY 

induced PRs in pts with BC and FL. The acute toxicities of HG in most pts 

and HTN in some are manageable, and IP has been limited to 2 lymphoma 

pts and is responsive to steroids. The observed clinical activity of BAY, 

along with its acceptable safety profile, provide a rationale for the ongoing 

development of BAY in combination with cytotoxic and targeted agents. 




4:45 PM-5:45 PM 

A phase I, single-institution, open-label, dose escalation trial with an 

expansion cohort evaluating the safety and tolerability of AZD6244 and 

IMC-A12 in subjects with advanced solid malignancies. Presenting Author: 

Shabina Roohi Ahmed, The Johns Hopkins University School of Medicine, 

Baltimore, MD 

Background: Significant crosstalk exists between the PI3K and Raf/MEK/ 

ERK pathways and treatment of select cell lines with a MEK inhibitor and 

an IGF1-R inhibitor has been shown to cause greater inhibition of growth 

than either agent alone. IMC-A12 (I) is a recombinant human monoclonal 

antibody directed IGFI-R; it blocks interaction between IGF-1R and its 

ligands, IGF-I and -II. AZD6244 (A) is a highly selective, non-competitive 

MEK ½ inhibitor. Methods: The study is a phase I, dose-escalation with a 

standard 3�3 design. Eligible patients had advanced solid tumor, good 

end organ function and performance status with exclusion for poorly 

controlled diabetes or growth hormone abnormalities. Part 1: open label, 

dose escalation. Pts were treated with A at 50 mg BID, then 75 mg BID; I at 

12mg/kg q2wk held constant. DLTs were defined as grade (G) 3 or 4 

toxicities during cycle 1. Part 2: expansion cohort of 15 pts for correlative 

endpoints and PK studies; serial tumor biopsies will be evaluated for 

changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS. 

Mutational analysis of RAS and RAF will be done to correlate with PD 

endpoints and disease response. Results: Part 1: 16 patients accrued with 

6 treated at DL1 and 10 treated at DL2. Multiple tumor types were 

represented, including 4 colon, 2 thyroid, 2 pancreatic, and 1 breast. At 75 

mg of A, there was 1 DLT of visual changes. G3 AEs included nausea/ 

vomiting (n�2, 12%), visual changes/retinopathy (n�2, 12%), MRSA skin 

infection (n�1, 6%), (n�1, 6%), hyperglycemia (n�1, 6%), and stroke 

(n�1, 6%). Other common AEs included acneform rash (n�10, 63%), 

nausea/vomiting (n�6, 37%), anorexia (n�4, 25%), and diarrhea (n�3, 

19%). Of 10 evaluable patients in Part 1, 1 had a partial response and 4 

patients had stable disease (40%). Sustained responses of 10 and 14 

months were seen in the DTC patients. 3 patients are currently enrolled in 

the expansion cohort. The RP2D is 50 mg of A, due to the visual changes 

seen with 75 mg, and 12mg/kg of I. Conclusions: A at 50 mg QD combines 

safely with I 12mg/kg. An expansion cohort is underway to determine if this 

combination warrants further investigation. 


4:45 PM-5:45 PM 

A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human 

study of the oral class I PI3K inhibitor CH5132799, in patients with 

advanced solid tumors. Presenting Author: Aurelius Gabriel Omlin, Section 

of Medicine, The Institute of Cancer Research, Sutton, United Kingdom, 

and Drug Development Unit, The Royal Marsden NHS Foundation Trust, 


Background: The phosphatidylinositol 3-kinase (PI3K) pathway is a promising 

target in cancer. CH5132799 is a novel PI3K inhibitor, selectively 

inhibiting class I PI3Ks (�, �, � and �) with no inhibition of class II and III 

or mTOR, and with potent antitumor activity in preclinical studies (Tanaka 

et al, Clin Cancer Res; 17; 3272-81, 2011). First-in-human study 

objectives were determination of maximum tolerated dose (MTD), safety/ 

tolerability, PK/PD and clinical activity (RECIST). Methods: A3�3 dose 

escalation design was used. The initial dosing schedule of 

CH5132799(schedule A) was once a day (QD). Due to a relatively short 

half-life, a twice a day (BID) schedule (schedule B) was introduced. PK 

profiles were studied over 72 hours. PD analyses included quantification of 

various phosphoproteins in platelet rich plasma (PRP). Tumor assessments 

were performed at baseline and cycle 3 day 1 (C3D1) and FDG-PET scans 

at baseline, C1D8 and C3D1. Results: 29 patients (pts) with a variety of 

solid tumors have been treated (A 23 pts, B 6 pts, the most common tumors 

were breast, oesophageal, colorectal and ovarian). The starting doses were 

2 mg (A) and 48 mg (B). The current doses being explored are 96 mg (A) 

and 72 mg (B). The most frequently reported drug-related AEs were Grade 

1/2 diarrhea, nausea, fatigue, anorexia and anemia. 1 DLT (Grade 3 

elevated LFT) was observed in a hepatocellular carcinoma pt at 48 mg BID. 

MTD has not yet been determined. The preliminary mean �SD Cmax and 

AUC at 96 mg QD were 202�129 ng/ml and 1407�935 ng·hr/ml 

respectively, which is consistent with an efficacious exposure based on 

preclinical models. Some patients achieved the expected exposure at over 

32 mg. From single dose of 48mg there was a reduction of phosphorylation 

of AKT in PRP after treatment, consistent with pathway modulation. A 

patient with clear cell ovarian cancer and a PIK3CA mutation treated at 48 

mg BID showed �50% decrease in SUV on a PET scan at C1D8 and a 75% 

decrease in CA-125 at C2D1. 5 pts exhibited SD (�8 weeks). Conclusions: 

CH5132799 is well tolerated either QD �96 mg or BID �48 mg. 

Dose-escalation continues and updated safety/efficacy/PK/PD data will be 

presented. 


4:45 PM-5:45 PM 

A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or 

mFOLFOX-6 (F) in patients (pts) with advanced solid tumors. Presenting 

Author: Cristina Saura, Medical Oncology Department, Vall d’Hebron 


Background: Activation of the Akt pathway is observed in multiple tumors 

and may contribute to chemoresistance. GDC-0068 is an ATP-competitive 

small molecule inhibitor of all three isoforms of Akt; in a phase Ia study, it 

was well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 

days on/7days off) and pharmacodynamic down-regulation of Akt signaling 

in tumors at doses �100 mg. In vitro, GDC-0068 shows synergism with 

cytotoxic agents. This phase Ib study defines the dose limiting toxicities 

(DLT), MTD, safety and pharmacokinetics (PK) of GDC0068 in combination 

with D and F. Methods: Using a 3�3 designeligible patients (pt) with 

advanced/metastatic solid tumors were treated with either D, 75 mg/m2 day 

1 and GDC-0068 daily on days 2-15 of a 21 day cycle (Arm A); or F, bolus 

5FU 400mg/m2 , leucovorin 400 mg/m2 , oxaliplatin 85 mg/m2 all day 1, 

and infusional 5FU 2400mg/m2 for 46 hours and GDC-0068 daily on days 

1-7 of a 14 day cycle (Arm B). PK sampling was performed in Cycles 1 and 

2. Results: 23 pts have enrolled; Arm A (GDC-0068, mg): 100 (n�3), 200 

(n�4), and 400 (n�5); Arm B:100 (n�6) and 200 (n�5). Median prior 

therapies � 3. GDC-0068-related adverse events in � 10% of pts were 

diarrhea, nausea, vomiting, fatigue, and decreased appetite. All GDC-0068related 

AEs were grade 1 or 2, except one grade 4 neutropenia in Arm A. No 

DLTs have been reported to date. Preliminary data show no alteration in the 

PK of GDC-0068, D or F compared to phase Ia or historical data. Two 

heavily pretreated pts with cervical and PTEN-loss colon cancers treated in 

Arm B demonstrated both RECIST partial response and tumor marker 

decrease by first CT evaluation. Conclusions: The combination of GDC- 

0068 with D or F is well-tolerated and shows early signs of anti-tumor 

activity. Dose-escalations continue. 


4:45 PM-5:45 PM 

A five-arm, open-label, phase I/lb study to assess safety and tolerability of 

the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination 

with chemotherapy or erlotinib in patients with advanced solid tumors. 

Presenting Author: Carlos Becerra, Internal Medicine, Sammons Cancer 

Center, Dallas, TX 

Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated 

single-agent clinical activity. In vitro studies of trametinib plus docetaxel 

(doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth 

inhibition of lung cancer cell lines with and without RAS/RAF mutations. 

Trametinib�doc significantly increased apoptosis compared with either 

agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label 

study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, 

pem�carboplatin (pem�carbo), or nab-paclitaxel (nab-pac) 

(NCT01192165). Part I is dose escalation in patients (pts) with advanced 

solid tumors; part II is dose expansion in pts with lung and pancreatic 

cancers. A 3�3 dose-escalation design was used to determine the 

maximum tolerated dose (MTD) and the recommended phase II regimen 

(RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined 

during the first treatment cycle (21 days). Trametinib was started at 

0.5 mg/day; chemotherapy was given at full recommended doses. Erl was 

escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected 

pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts 

have been enrolled across all arms except trametinib�nab-pac. Preliminary 

exposure results of trametinib�doc, erl, or pem suggest no PK 

drug-drug interaction. The predominant DLT for trametinib�doc without 

growth factors (MTD � 0.5 mg�60 mg/m2 ) was neutropenia. When 

administered with growth factors, trametinib�doc has been given up to 1.5 

mg�75 mg/m2 with no DLTs. The predominant DLTs for trametinib�erl 

(MTD � 1 mg�100 mg) were diarrhea and mucositis and for 

trametinib�pem (MTD � 1.5 mg�500 mg/m2 ) were mucositis and febrile 

neutropenia. The MTD for trametinib�pem�carbo has not yet been 

determined. To date there are 5 PRs in the trametinib�doc group and 2 

PRs in the trametinib�pem group. An NSCLC expansion cohort for 

trametinib�pem is enrolling. Conclusions: Trametinib�doc and 

trametinib�pem have shown acceptable tolerability and initial evidence of 

clinical activity. 



4:45 PM-5:45 PM 

PX-866 and docetaxel in patients with advanced solid tumors. Presenting 

Author: Antonio Jimeno, Division of Medical Oncology, University of 

Colorado Denver, Aurora, CO 

Background: PX-866, an irreversible pan-isoform inhibitor of Class 1 PI-3K 

has additive to synergistic effects when combined with docetaxel in 

xenograft models of NSCLC and SCCHN. A phase I/II study of PX-866 and 

docetaxel was initiated to further evaluate this combination. Enrollment in 

phase I is complete, and the randomized, controlled phase II portion is now 

enrolling patients with either NSCLC or SCCHN. Phase I safety and 

pharmacokinetics were previously described; the recommended phase II 

dose of PX-866 was 8 mg daily, the same as the single agent MTD (Jimeno 

A, et al. AACR-NCI-EORTC, 2011). Updated phase I antitumor and 

biomarker results are presented here. Methods: Phase 1 consisted of dose 

escalation of PX-866 at 4, 6, or 8 mg po qd in combination with docetaxel 

75 mg/m2 IV once every 21 days (d). Patients had advanced solid tumors 

for which docetaxel was compendia listed. Tumor restaging was performed 

every 2 cycles. Archived tumor biopsies were collected for assessment of 

potential biomarkers of response, including PIK3CA and KRAS mutations 

and PTEN expression. Results: 43 pts were enrolled: NSCLC (n�6), 

prostate (n�5), ovarian (n�5), SCCHN (n�3), and pancreatic (n�3) were 

the most common tumor types. Median time on study (TOS) was 81 d 

(5-361), with 9 pts still on study. 16 pts received � 6 cycles (6-17), 

including 3 pts with NSCLC, and 4 pts with ovarian cancer. Biomarker data 

are available for 20 evaluable pts. Median days on study by mutational 

status was: PIK3CA/KRAS WT (n�13): 91 d (28-286); PIK3CA-MUT 

(n�5): 183 d (64-342); KRAS-MUT (n�3): 141 d (125-361); and 

PIK3CA/KRAS-MUT (n�2): 96 d (86-105). A trend toward longer TOS was 

observed in pts with PIK3CA-MUT vs PIK3CA/KRAS-WT (p�0.14). Assessment 

of PTEN is ongoing. Best response in 32 evaluable pts was 2 PR 

(6%), 22 SD (69%), and 8 PD (25%). The PRs were in NSCLC and ovarian 

cancer (both PIK3CA/KRAS WT). 8 other pts had �15% tumor shrinkage, 

including NSCLC (n�2). Conclusions: PX-866 with docetaxel was associated 

with a disease control rate of 75%, with 50% of evaluable pts 

demonstrating SD or better for � 6 cycles. Based on available data, a trend 

for a longer TOS was seen with PIK3CA-MUT pts. This relationship will be 

further evaluated in phase II. 


4:45 PM-5:45 PM 

A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid 

tumors. Presenting Author: Nicolas Isambert, Centre Georges François Leclerc, 

Dijon, France 

Background: Debio 0932 is an oral second-generation heat shock protein 90 

(HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier 

penetration, and promising anti-tumor activity both as monotherapy and combination 

against a broad range of tumors in pre-clinical models. Here we report the 

results of the dose escalation part of a phase I study in patients with advanced 

solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, 

non-randomized, 3 � 3 dose-escalation study to determine the maximum 

tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 

days of treatment in patients with advanced solid tumours or lymphoma resistant 

to standard therapy. The starting dose in both treatment groups was 50mg. 

Doses were increased according to an algorithm based on observed toxicity and 

dose limiting toxicities (DLT). Tumor assessments were performed every 8 

weeks. Results: Patient characteristics and results are summarized below. DLTs 

occurred at 1600mg in both dose groups. Adverse events (AE) were mostly 

CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac 

toxicity was observed. The main reason for treatment withdrawal was progressive 

disease. Investigator-reported cases of SD and PR were observed. Conclusions: 

Debio 0932 mono-therapy was generally well tolerated and showed promising 

signs of efficacy in patients with advanced solid tumors. The recommended 

phase II dose, established at 1000mg QD, will be tested in an additional 30 

patients in an ongoing expansion study. A phase I-II study of Debio 0932 in 

combination with standard of care in the first- and second-line treatment of 

NSCLC is planned. 

Q2D dosing 

N � 23 

QD dosing 

N � 28 

Mean age (range) (yrs) 58 (39-72) 55 (27-74) 

Gender M / F % 48/52 68/32 

Predominant cancer types % Colorectal 26 

Colorectal 29 

Lung 17 

Pancreas 13 

Lung 18 

>3 previous treatment regimens % 83 86 

Days on treatment (range) 69 (1 – 223) 66 (6 – 252) 

DLTs / dose Febrile neutropnia / 1600mg Diarrhea / 1600mg 

Asthenia / 1600mg 

Most frequent AEs % 

. 

. 

Constipation 

44 

36 

Diarrhea 

26 

61 

Nausea 

39 

46 

Vomiting 

39 

43 

Asthenia 

61 

71 

Decreased appetite 

35 

50 

Best overall tumor response 

. 

. 

PR % 

4 

0 

SD % 

17 

29 

PD % 

57 

61 

Not evaluable % 

13 

3 

Not assessed % 

9 

7 


179s 


4:45 PM-5:45 PM 

A first-in-human phase I study to evaluate the fully human monoclonal 

antibody OMP-59R5 (anti-Notch2/3) administered intravenously to patients 

with advanced solid tumors. Presenting Author: Anthony W. Tolcher, 

South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX 

Background: The Notch pathway plays a central role in embryonic development, 

the regulation of stem and progenitor cells, and is implicated 

centrally in many human cancers. OMP-59R5 is a fully human IgG2 

originally identified by binding to Notch2. It inhibits the signaling of both 

Notch2 and Notch3 receptors. Mouse xenograft studies using minimallypassaged, 

patient-derived xenografts show that OMP-59R5 impedes tumor 

growth and eliminates cancer stem cells (CSCs) in many tumor types. 

OMP-59R5 modulates the expression of stromal genes and genes associated 

with the function of tumor vascular pericytes. As such, OMP-59R5 is a 

novel anti-cancer agent that inhibits tumor growth through direct actions on 

tumor cells, including CSCs, and effects the stroma and vasculature. 

Methods: A phase I dose escalation study (3�3 design) was initiated in 

solid tumor patients. OMP-59R5 was administered to study safety, pharmacokinetics 

(PK), pharmacodynamics (PD), preliminary efficacy, and to 

determine the maximum tolerated dose (MTD). Results: Twenty-four patients 

have been enrolled in 5 dose-escalation cohorts at doses of 0.5, 1, 

2.5, and 5mg/kg administered weekly (QW) and 5mg/kg administered every 

other week (QOW). The most frequently reported drug-related adverse 

events were: mild to moderate diarrhea, fatigue, nausea, vomiting, decreased 

appetite, and constipation. Diarrhea was dose related and occurred 

at doses �2.5mg/kg weekly and appears less pronounced with every other 

week dosing. Two dose-limiting toxicities (grade 3 diarrhea and grade 3 

hypokalemia) occurred at 5mg/kg QW and 2.5mg/kg was established as an 

MTD for QW dosing. A QOW dosing schedule is currently under investigation. 

The PK of OMP-59R5 was characterized by fast and dose-dependent 

clearance. Two patients (Kaposi’s sarcoma at 5mg/kg and adenoid cystic 

carcinoma at 2.5mg/kg) had prolonged stable disease for �110 days. PD 

analyses for Notch pathway modulation are ongoing. Conclusions: OMP- 

59R5 is generally well tolerated. An MTD of 2.5mg/kg QW has been 

established and a QOW schedule is currently under study. Updated results 

will be presented. 


4:45 PM-5:45 PM 

Rational molecularly targeted combinations: A parallel-arm phase I trial of 

the humanized anti-IGF-1R antibody dalotuzumab (D) in combination with 

the allosteric AKT inhibitor MK-2206 or the gamma secretase inhibitor 

MK-0752, in patients with advanced solid tumors. Presenting Author: 

Irene Brana, Princess Margaret Hospital, Toronto, ON, Canada 

Background: Two rational strategies to interrogate the IGF-1R pathway were 

investigated in this parallel-arm phase I trial: 1) vertical inhibition with D 

and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk 

inhibition with D and MK-0752 to exert effects against cellular proliferation, 

angiogenesis and stem cell propagation. Methods: Patients (pts) with 

advanced solid tumors and no prior exposure to agents of the same targets 

were eligible. Dose escalation was based on a modified toxicity probability 

interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10 

mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO 

weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly 

plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle � 4 

weeks in both arms. Primary objectives were to determine DLT and RP2D of 

these combinations. Results: 30 patients were enrolled in the dose 

escalation phase (18 in Arm A and 12 in Arm B) with: median age � 56 

(range 36-74); M:F � 13:17; ECOG 0:1 � 12:18; primary diagnosis � 

colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens � 

3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg 

(G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 

leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events 

(AEs) were observed. RP2D of Arm A � D 10mg/m2 IV weekly and 

MK-2206 150 mg PO weekly. Other common AEs in Arm A included: 

fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10 

mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B � D 10mg/m2 IV 

weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other 

common AEs in Arm B included: anorexia, nausea and fatigue. No PR was 

observed and SD � 4 months occurred in 4 pts (all in Arm A). PK analyses 

are ongoing. Conclusions: Targeted combinations of D with MK-2206 or 

with MK-0752 were both tolerable. Expansion cohorts based on biomarker 

selection are underway, specifically ovarian cancer with high IGF1 expression/low 

RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low 

IGF2 expression for Arm B. 




4:45 PM-5:45 PM 

First-in-human phase I study: Results of a second-generation nonansamycin 

heat shock protein 90 (HSP90) inhibitor AT13387 in refractory 

solid tumors. Presenting Author: Daruka Mahadevan, Arizona Cancer 

Center, Tucson, AZ 

Background: AT13387 is a second-generation potent, novel non-ansamycin 

HSP90 inhibitor (IC50 0.71 nM). AT13387 has good tissue distribution, 

long tumor t1/2 resulting in extended knockdown of client proteins in cells 

and animal models of gastric, prostate and melanoma. Methods: AT13387 

was administered as a 1-hr IV infusion twice weekly on Days 1, 4, 8, 11, 15 

and 18 (Part A) and then subsequently, weekly on Days 1, 8 and 15 (Part B) 

of a 28-day cycle in a standard 3�3 dose-escalation design. The primary 

endpoint was to determine the MTD; secondary endpoints included PK, PD, 

safety and tolerability. Results: As of 1 Dec 2011, 53 patients received 

1–12 cycles of AT13387 (median 2). In Part A, AT13387 was evaluated at 

5 doses (10, 20, 40, 80, 120 mg/m2 ). In Part B, 4 additional doses (150, 

220, 260 and 310 mg/m2 ) were explored. Common treatment related 

toxicities (� 10%) included transient and reversible GI disturbance 

(vomiting, nausea, dry mouth, diarrhea, abdominal pain), fatigue, local 

infusion site irritation and systemic infusion-related symptoms including 

chills, rash, itch, cardiovascular (tachycardia, bradycardia, hypertension, 

hypotension), and visual changes (diplopia, transient flashes, delayed 

light/dark accommodation, blurred vision). Severity of infusion-related 

symptoms, GI toxicities, and fatigue at 310 mg/m2 prevented further dose 

escalation. A dose of 260 mg/m2 has been identified as the once weekly 

MTD and the study is currently accruing at this dose. Biological evidence of 

HSP90 inhibition, demonstrated by an increase in HSP70 in PBMCs, was 

detected at all doses and exhibited evidence of dose dependence. PK 

demonstrated dose proportionality, without significant accumulation. One 

durable RECIST PR (8 months) in an imatinib relapsed metastatic GIST 

patient with c-kit mutations in exons 11 and 17 was observed. Three SD � 

6 months (follicular cell thyroid carcinoma, metastatic uveal melanoma, 

GIST) were also observed. Conclusions: The MTD of AT13387, administered 

as a once weekly IV, is 260 mg/m2 . All drug-related toxicities were 

generally reversible. Single-agent activity was observed. Dose expansion at 

MTD and phase II studies are ongoing. 


4:45 PM-5:45 PM 

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor 

targeted multi-kinase inhibitor, administered orally QD to patients with 

advanced solid tumors. Presenting Author: Gennaro Daniele, Royal Marsden 

Hospital and Institute of Cancer Research, Sutton, United Kingdom 

Background: Golvatinib is a highly potent, small molecule ATP-competitive 

inhibitor of the c-Met receptor tyrosine kinase and multiple members of the 

Eph receptor family as well as c-Kit and Ron, based on isolated kinase 

assays. Golvatinib showed preclinical evidence of anti-tumor activity. This 

phase 1 study was performed to determine the MTD, safety, PK, PD and 

preliminary activity of golvatinib. Methods: Patients (pts) with advanced 

solid tumors, ECOG PS 0-1, � 18 years (yrs) and adequate organ function 

were eligible. Golvatinib was administered orally, once daily (QD), continuously. 

Blood samples for PK and PD analysis were collected at multiple 

time-points. Mandatory tumor biopsies for PD analysis were taken pre and 

post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13; 

median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100, 

200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n�15), 

lung (n�4), renal (n�4), esophageal (n�2), melanoma (n�2) and others 

(n�7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase 

(n�1; 200mg) and repeated Gr2 (n�1) and Gr3 (n�1) fatigue, both at 

450mg. The MTD was determined to be 400 mg QD. Frequently occurring 

adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea: 

65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%), 

ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed. 

Best response was stable disease in 6 pts lasting �84 days. PK showed 

high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed 

an increase in soluble c-Met and Ang 2 levels after golvatinib treatment. 

Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated 

MET gene copy number, with c-Met overexpression and post treatment 

decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in 

p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt. 

Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity. 

Preliminary PD analysis demonstrated evidence of c-Met target modulation. 

Further evaluation will continue in phase 2 combination studies. 


4:45 PM-5:45 PM 

Clinical pharmacokinetics of the Smac-mimetic birinapant (TL32711) as a 

single agent and in combination with multiple chemotherapy regimens. 

Presenting Author: Gerald J. Fetterly, Roswell Park Cancer Institute, 

Buffalo, NY 

Background: Birinapant is a novel small molecule Smac-mimetic that 

targets members of the inhibitor of apoptosis proteins (cIAP1, cIAP2 and 

XIAP) involved in the blockade of apoptosis. A population PK model was 

developed to characterize the interpatient variability in birinapant PK and 

to evaluate the effect of multiple combination regimens on birinapant 

disposition and safety. Methods: Birinapant was administered alone or in 

combination to 114 patients (55M/59F; 89% Caucasian) with advanced 

malignancies. Birinapant was administrated by a 30 min IV infusion QW 

alone (30 pats), or approx. 30 min. after chemotherapy with irinotecan (19 

pats), docetaxel (20 pats), gemcitabine (17 pats), liposomal doxorubicin 

(13 pats), or paclitaxel/carboplatin (15 pats). Birinapant dose levels ranged 

from 0.18 to 35 mg/m2 . Population PK modeling was performed to 

investigate the effect of the following patient covariates: [BW (38.5-127.5 

kg), age (27.5-86.0 yrs), CrCL (36.4-219.2 ml/min), ALT (6-121 IU/L), 

and TBIL (0.1-1.7 mg/dL)]. Results: A 3-compartment PK model described 

the time course of birinapant disposition with predicted values for T1/2, 

CL, and Vd of 40 h, 21 L/h and 10.2 L, respectively. Birinapant displayed 

linear PK across the dose range with no significant accumulation in plasma 

following weekly dosing. Goodness of fit plots supported the model fit, with 

residual variability of 23%. The PK of birinapant remained unchanged 

when combined with irinotecan, docetaxel, gemcitabine and liposomal 

doxorubicin. Concomitant administration with paclitaxel/carboplatin resulted 

in a 2-fold increase in birinapant AUC possibly due to reduced 

OATP1B3 mediated tissue uptake. Conclusions: These data show that 

birinapant possesses an excellent PK profile with dose proportional 

kinetics, a long terminal half-life for target coverage, low/moderate interpatient 

variability in CL and no significant accumulation following weekly 

dosing. Importantly, the PK of birinapant remained unchanged when 

combined with multiple chemotherapy regimens and the increased exposure 

with paclitaxel/carboplatin was not associated with any change in 

birinapant tolerability. 


4:45 PM-5:45 PM 

Proof of mechanism (POM) in the first-in-human trial of two novel 

indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors. 

Presenting Author: James H. Doroshow, Division of Cancer Treatment and 

Diagnosis, National Cancer Institute, Bethesda, MD 

Background: Indenoisoquinolines LMP 400 and LMP 776 form stable 

DNA-top1 cleavage complexes, have a preference for unique DNA cleavage 

sites, and are not substrates for ABC transporters compared to camptothecins. 

We conducted a randomized phase I trial of LMP 400 and LMP 776 

in patients (pts) with refractory tumors to establish safety and MTD of LMP 

400 and LMP 776 administered IV daily x5d,q28d; determine PK; 

evaluate TOP1 and �H2AX levels in tumor biopsies (bx); and compare 

pharmacodynamic responses of LMP400 and LMP776. Methods: Pts had 

refractory malignancies; � 18 yrs old; KPS � 70%; adequate organ 

function. DLT: drug-related gr � 3 non-hem or gr 4 hem toxicities during 

C1. Pts assigned to receive either LMP 400 or LMP 776. Dose level (DL) in 

mg/m2 /day for LMP 776: 1, 2, 3, 4.5 mg; LMP 400: 2.5, 5, 10, 20, 40, 

80. Accelerated titration design with one pt per dose level (DL), 100% dose 

escalation until one DLT or 2 gr 2 toxicities, then 3�3 design. Tumor bx 

and circulating tumor cells (CTCs) were obtained at baseline and C1D3. 

Results: Twenty pts accrued to date [LMP 400 (11 pts); LMP 776 (9 pts)]; 

M/F 7/13; median age 59 (range 32-71 yrs); diagnosis (# of pts): colorectal 

(10), vaginal adenocarcinoma (1), head and neck (2), bladder (1), 

melanoma (1), pancreas (1), thyroid (1), small cell lung (1), sarcoma (1), 

lymphoma (1). DLTs: LMP 400- gr 4 myelosuppression, gr 3 fatigue at DL 

6; DL 5 expanded to establish MTD; LMP 776 (DL2)- gr 4 hypercalcemia, 

no other DLTs, dose escalation continuing. One pt with irinotecanrefractory 

colon cancer had shrinkage of lung nodules post one cycle of 

LMP 400. Relative to baseline, 5 of 6 tumor bx demonstrated 20-50% 

reduction in TOP1 levels (LMP 776); an increase in �H2AX foci in tumor 

was observed in 2/6 LMP 776 and 1/1 LMP 400 pts. An increase in �H2AX 

was also observed in hair bulbs (3/3 pts) and CTCs (9/20 pts). PK for LMP 

400 and LMP 776: mean T1/2 48 and 36 h; Cl 1.5 and 2.0 L/h/m2 ;Vc30 

and 31 L/m2 , respectively. Conclusions: POM, as assessed by reduction in 

TOP 1 levels and increase in �H2AX in tumor and CTCs, and preliminary 

evidence of activity, has been demonstrated in this first-in-human trial of 

indenoisoquinoline-class of TOP1 inhibitors. Accrual is ongoing. 



4:45 PM-5:45 PM 

Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal 

CovX body inhibiting angiopoietin 2 (Ang-2), with sunitinib. Presenting 

Author: Lee S. Rosen, UCLA School of Medicine, Santa Monica, CA 

Background: CVX-060 (CVX) is a humanized monoclonal antibody fused to 

two Ang2 binding peptides. The recommended phase 2 dose (RP2D) is15 

mg/kg/wk by intravenous (IV) infusion. Sunitinib (Sun), a kinase with many 

targets including VEGFR1-3, is dosed 50 mg/day orally x 4/6 wks. Methods: 

Patients (pts) with solid tumors were to receive CVX at doses of 6, 12, or 15 

mg/kg/wk with Sun 50 mg/day x 4/6 wks in successive cohorts. Standard 

definitions of dose limiting toxicities (DLTs) were used. Serum PK was 

assessed by ELISA. Results: Thirty-four pts were treated at 5 dose levels 

(DL) –see table. The median age was 62 years (29-76), ECOG performance 

status 0-1. The safety of CVX plus lower Sun dose was established in DL 1.1 

due to DLTs at the initial cohort. The safety of full dose Sun was further 

established in 1.2 before further escalating the CVX dose. Overall, DLTs 

related to CVX and Sun included hemorrhage (DL 1.0), asymptomatic 

proteinuria (DL 1.2), ischemic colitis/lower GI bleed/recurrent lower GI 

bleed (DL 3.0) and abdominal pain/microperforation on CT (DL 3.0). The 

most common adverse events (AEs) related to either agent were fatigue 

(68%), diarrhea (50%), nausea (47%), hypertension (35%), and dysgeusia 

(32%). The majority of AEs were Gr 1 to 2. There were no PK interactions 

between CVX and Sun. Total serum Ang2 (bound plus free) increased with 

CVX treatment. Of the 34 patients, 24 (71%) remained on study � 8 weeks 

and 2 patients continue on treatment � 9 months. Anti-drug antibodies 

were seen in 16 patients at low titers without effects on PK or safety. 

Conclusions: In pts with advanced disease, CVX is able to be combined at 

the RP2D with Sun at its labeled dose without exacerbation of Sunassociated 

toxicities. Combination trials of CVX and other VEGF inhibitors 

are planned. 

Dose levels evaluated. 

Dose level CVX-060 mg/kg/wk Sunitinib mg/d x 4/6 wks Pts 

1.0 6.0 50.0 6 

1.1 6.0 37.5 3 

1.2 6.0 50.0 6 

2.0 12.0 50.0 3 

3.0 15.0 50.0 16 


A phase Ib dose-escalation study of TRC105 in combination with bevacizumab 

for advanced solid tumors. Presenting Author: David S. Mendelson, 

Pinnacle Oncology Hematology, Scottsdale, AZ 

Background: CD105 (endoglin) is an endothelial cell membrane receptor 

highly expressed on angiogenic tumor vessels that is essential for angiogenesis 

and upregulated by hypoxia and VEGF inhibition. TRC105 is a 

human/mouse chimeric anti-CD105 monoclonal antibody that completed 

phase I testing and is being studied in multiple phase II trials. Methods: Pts 

with advanced solid tumors (non-CNS), ECOG PS 0-1, and normal organ 

function were treated with escalating doses of intravenously administered 

TRC105 plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk and 

assessed for safety, PK, and response. Results: Twelve pts were treated (3 

with TRC105 at 3 mg/kg q1wk � BEV at 15 mg/kg q3wk, 5 with TRC105 at 

6 mg/kg q1wk � BEV at 15 mg/kg q3wk, and 4 with TRC105 at 6 mg/kg 

q1wk � BEV at 10 mg/kg q2wk), and 10 have completed the DLT 

evaluation period. TRC105 at 6 mg/kg q1wk � BEV at 15 mg/kg q3wk 

resulted in grade 1-3 headaches with sinus congestion following the cycle 1 

day 1 (C1D1) dose in 5 of 5 pts that improved with continued dosing. 

Treatment with BEV 10 mg/kg q2wk and sequential dosing with Bev 

starting on C1D1 and TRC105 on C1D8 resulted in decreased frequency 

and severity of headaches, allowing dose escalation to continue. TRC105 

serum concentrations that saturate CD105 binding sites (�200 ng/mL) 

were achieved continuously at 6 mg/kg q1wk. At 3 mg/kg q1wk TRC105 � 

15 mg/kg q3wk BEV, one pt with BEV-resistant ovarian cancer had stable 

disease for 6 cycles and one pt with refractory hepatocellular cancer who 

failed sorafenib and sunitinib had an AFP decrease from 1578 at baseline 

to 179 at the end of cycle 3. Two of three evaluable pts at 6 mg/kg q1wk 

TRC105 � 15 mg/kg q3wk BEV with VEGF-refractory tumors (HCC and 

CRC) are ongoing in C4 with stable disease. Dose escalation continues and 

TRC105 dose levels of 8 and 10 mg/kg are planned. Conclusions: The 

combination of TRC105 and BEV was tolerated with early evidence of 

activity in VEGF-refractory pts by sequential administration during initial 

dosing in C1. 


181s 


4:45 PM-5:45 PM 

NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 

targeted agent. Presenting Author: Dana Shelton Thompson, Sarah Cannon 

Research Institute/Tennessee Oncology, PLLC, Nashville, TN 

Background: NKP-1339 is a first-in-class small molecule anti-cancer 

compound that down-regulates GRP78, a key regulator of misfolded 

protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation 

occurs in many tumors, and is associated with intrinsic and chemotherapyinduced 

resistance. Preclinically, single agent NKP-1339 demonstrates 

activity against multiple tumor types, including chemoresistant lines. This 

phase I trial evaluates the safety, tolerability, maximum tolerated dose 

(MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339. 

Methods: Patients (pts) with advanced solid tumors, adequate organ 

function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15 

of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then 

adjusted to standard 3�3 design. Doses from 20-780 mg/m2 are evaluated. 

PD samples for plasma GRP78 are collected. At MTD, an expanded 

cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation: 

30 evaluable for dose determination; 4 replaced due to tumor progression 

in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79). 

Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8); 

neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8). 

Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt, 

occurred at 780 mg/m2 ; MTD is 625 mg/m2 . Gr 1 fever/chills is observed 

above 420 mg/m2 , but is prevented by steroid premedication. The most 

common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2 

fatigue. No lab abnormalities were noted except reversible creatinine 

elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial 

response was in 1 pt (NET); stable disease in 7 pts, including NET (2), 

NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy 

duration 14�-88� weeks. Soluble GRP78 is detected in the plasma of 

patients at baseline. Conclusions: NKP-1339is well tolerated with manageable 

side effects. Single agent activity is noted in multiple tumors including 

NET. Results from the expanded cohort and pre/post-therapy PD will be 

presented. Phase II single agent NKP-1339 and phase I NKP-1339 

combination trials are planned. 


The effect of bevacizumab on targeting of anti-epidermal growth factor 

receptor and anti-insulin-like growth factor 1 receptor antibodies. Presenting 

Author: Sandra Heskamp, Department of Medical Oncology, Radboud 

University Nijmegen Medical Centre, Nijmegen, Netherlands 

Background: Bevacizumab and cetuximab are approved antibodies for 

treatment of patients with metastasized colorectal cancer. However, the 

combination of bevacizumab and cetuximab does not improve progression 

free survival (Tol et al. NEJM 2009). This may be explained by the 

disruption of tumor vascularity by bevacizumab, thereby reducing targeting 

of other antibodies to the tumor. The aim of this study was to determine the 

effect of bevacizumab on the targeting of anti-EGFR and IGF-1R antibodies 

in tumors with SPECT/CT imaging. Methods: Mice with subcutaneous EGFR 

and IGF-1R-expressing SUM149 xenografts were injected intraperitoneally 

with a single dose of bevacizumab (10 mg/kg). After four days, mice 

received an intravenous injection of 17 MBq 111In-labeled cetuximab, an 

anti-EGFR antibody, or R1507, an anti-IGF-1R antibody. A control group 

was injected with labeled hLL2 anti-CD22, an irrelevant IgG . Three days 

after injection, SPECT/CT images were acquired and mice were dissected 

for ex vivo biodistribution. Tumors were analyzed immunohistochemically 

to determine vascular density (CD34), EGFR and IGF-1R expression. 

Results: SPECT imaging revealed that bevacizumab treatment reduced 

targeting of anti-EGFR and anti-IGF-1R antibodies by 42% and 35%, 

respectively. Ex vivo biodistribution showed that uptake of 111In-cetuximab in untreated tumors was 35.2 � 1.6 %ID/g, compared with 19.7 � 5.3 

%ID/g for bevacizumab treated tumors (p � 0.009). A similar effect was 

observed for 111In-R1507 (control: 26.7 � 2.8 %ID/g, bevacizumab:18.9 

� 2.8 %ID/g, p �0.009). No significant differences in tumor uptake were 

observed in mice that received the irrelevant IgG. Immunohistochemical 

analysis showed that vascular density decreased with 40%, while EGFR 

and IGF-1R expression was unaltered. Conclusions: Bevacizumab treatment 

can significantly reduce targeting of other antibodies to tumors. This 

underlines the importance of timing and sequencing of bevacizumab 

therapy in combination with other antibodies. 




Response of nonenhancing regions in glioblastoma to VEGF-signaling 

inhibitor cediranib correlates with tumor infiltration. Presenting Author: 

Summer A. Fakhro, Martinos Center for Biomedical Imaging, Massachusetts 

General Hopital, Charlestown, MA 

Background: Antiangiogenic therapy has limited direct antitumor effect in 

glioblastoma (GBM). Mainly its benefits may derive from anti-permeability 

and anti edema effects. In GBMs treated with cediranib we found that 

regions on MRI that are suggestive of being vasogenic edema, according to 

Diffusion Tensor Imaging (DTI) data, experience a greater decrease in 

volume than non-enhancing regions suggestive of being tumor infiltrated. 

Methods: Thirty-four newly diagnosed GBM patients were scanned on 

3Tesla Siemens at two pre-therapy time points (2 days apart). Patients were 

treated with cediranib, standard radiation and temozolomide. Due to 

technical difficulties, 4 patients were left out of the analysis. Diffusion 

images were acquired with TR�7500ms, TE�84ms and b-values 0 and 

700s/mm2 in 42 directions. A board certified radiologist determined the 

extent of abnormality on FLAIR and T1-weighted post contrast images. 

Non-enhancing regions (NER) were determined by subtracting the T1 

enhancing area and any necrosis from the FLAIR abnormality. Volume of 

NERs was observed at baseline and day 47 of treatment. Mean Apparent 

Diffusion Coefficient (ADC) and mean Fractional Anisotropy (FA) of the 

NER were used to represent extent of tumor burden. Tumor Infiltration 

Index (TII), a measure based on comparing DTI metrics in metastatic 

tumors to GBM, was also derived. Twelve patients with metastatic cancer to 

the brain who underwent the same imaging and analysis pretreatment were 

used. High FA and low ADC and TII represent areas with more tumor 

burden. Results: There was a significant correlation between mean FA in the 

NERs at baseline and the percent volume reduction of the NER at day 47 

(rho�0.45, p�0.02). Similarly, ADC and TII were correlated with percent 

volume reduction in the NER. Conclusions: DTI metrics have been used in 

GBMs to measure tumor infiltration. We found volume reduction of NERs to 

be inversely correlated to tumor burden. Thus, glioma patients with greater 

vasogenic edema may benefit from a different treatment paradigm than 

patients with lower vasogenic edema. 

% Volume reduction of NER at day 47 vs 

ADC mean FA mean TII mean 

Spearman correlation (rho) -0.33 0.45 -0.44 

p-value 0.083 0.015 0.017 


Phase I study of safety and pharmacokinetics of fruquintinib, a selective 

inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with 

advanced solid tumors. Presenting Author: Jin Li, Fudan University 

Shanghai Cancer Center, Shanghai, China 

Background: Fruquintinib is a novel oral small molecule compound discovered 

and developed by Hutchison MediPharma that selectively inhibits 

vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has 

demonstrated potent inhibitory effects on multiple human tumor xenografts. 

This first-in-human study is conducted to assess the maximum 

tolerated dose (MTD) and dose-limiting toxicity (DLT), safety and tolerability, 

pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib. 

Methods: This phase I study used the 3�3 design for dose-escalation 

of fruquintinib given once daily (QD) in 28-day cycles in patients with solid 

tumors who had failed standard therapies. Endpoints included safety, PK, 

and preliminary efficacy measurements. Results: To date 16 patients were 

enrolled in 5 dose cohorts of 1-6 mg QD, with age 42-69 yr, 44% male, 

ECOG 0-1 and all heavily pretreated. Tumor types included 9 colorectal, 3 

lung, 3 breast, and 2 gastric (one patient with bi-primary carcinoma of 

breast and colon). The most common adverse events included hypertension 

(50%), proteinuria (43.8%), hand-foot syndrome (HFS 43.8%), diarrhea 

(31.2%), and hoarseness (25%). Grade 3/4 AEs were diarrhea (25%), HFS 

(12.5%), thrombocytopenia (6.2%), and hyperbilirubinemia (6.2%). Three 

DLTs were observed: 2 grade 3 HFS both at 6mg and 1 grade 3 

hyperbilirubinemia at 4mg. PK analysis showed good and rapid absorption 

followed by slow terminal elimination with a half-life of approximately 37 

hours which was consistent across all dose groups. Both Cmax and AUC 

exhibited good dose proportionality over the studied dose range with low 

inter-patient variability following single and multiple doses. Among 8 

evaluable patients, 2 (1 colorectal and 1 gastric) had confirmed partial 

response for more than 4 months; 5 had stable disease, including 3 SDs of 

3-8 months. Conclusions: Fruquintinib was well tolerated at doses up to 4 

mg QD to date and demonstrated excellent pharmacokinetic properties. 

Encouraging clinical activity was observed. Further clinical studies are 

warranted and under planning. 


Phase I study of vandetinib in combination with gemcitabine and oxaliplatin 

in advanced solid malignancies. Presenting Author: Peng Wang, 


Background: Vandentinib (VAN) is a tyrosine kinase inhibitor with activity 

against vascular endothelial growth factor receptor-2 (VEGFR-2) and 3 

(VEGFR-3) as well as epidermal growth factor receptor (EGFR) and RET 

(‘rearranged during transfection’). Combinations of VEGFR kinase inhibitors 

and cytotoxic agents have been studied with interest, but have been 

associated with increased toxicity. This phase I trial evaluated the safety, 

tolerability and maximum tolerated dose of VAN in combination with 

gemcitabine (GEM) and oxaliplatin (OX). Methods: Subjects with advanced 

solid malignancy, � 2 prior regimens with adequate hematologic, hepatic 

and renal function were eligible. GEM and OX were administered intravenously 

at 1000 mg/m2 and 85 mg/m2 respectively every 14 days. VAN was 

administered orally at two dose levels: level 1 (200 mg) and level 2 (300 

mg) once daily continuously. After a maximum of 6 cycles of GEMOX, 

non-progressing patients were allowed to continue VAN until progression or 

intolerance. A dose level was determined to be tolerable if �2 DLTs out of 6 

evaluable subjects were observed. Response was assessed by restaging 

scan after every 2 cycles. Results: A total of 20 subjects were enrolled in the 

study; 15 male, 5 female. Median age 62 years (47-68). Nine subjects 

were enrolled on dose level 1 and 11 subjects on dose level 2. One subject 

in dose level 1 experienced a deep venous thrombosis in cycle 1 deemed a 

DLT. Thrombocytopenia (worst-grade 3) as well as diarrhea and rash 

(worst-grade 2) were observed in several patients, without dose-limiting 

toxicity in cycle 1. Reversible posterior leukoencephalopathy was observed 

in 1 subject following abrupt self-discontinuation of an antihypertensive 

mediation. The recommended phase 2 dose was established as GEM 

(1000mg/m2 ) OX (85mg/m2 ) and VAN (300mg). One subject with refractory 

small cell lung cancer had a confirmed partial response, and 10 

subjects (pancreas-7, bladder-2 and biliary-1) achieved stable disease 

�12 weeks. Conclusions: VAN in combination with GEM/OX was well 

tolerated at full doses of each of the 3 agents. Preliminary anti-tumor 

activity seen in refractory solid tumors supports further evaluation of this 

regimen. 


MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met 

and VEGFR: Dose-escalation phase I study. Presenting Author: Christian K. 

Kollmannsberger, British Columbia Cancer Agency, Vancouver, BC, Canada 

Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer 

greater anti-tumor activity than inhibiting either target alone. MGCD265 

has broad anti-tumor effects in preclinical models. Methods: Patients (pts) 

with advanced malignancies were enrolled in this Phase I, open-label, dose 

escalating study using the classic 3�3 study design. MGCD265 was 

administered every day over a 21-day cycle. The aim of this study is to 

determine the safety profile including the maximum tolerated dose and the 

dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), 

pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 

were also evaluated. Results: As of January 10, 2012, 56 patients were 

enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). 

MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a 

favorable safety profile. The DLTs (n�1 for each event) captured were: 

grade 2 hypertension (per protocol’s definition), grade 3 lipase elevation, 

grade 3 fatigue and grade 3 pituitary hemorrhage, all occurring at daily 

doses � 250 mg/m2 . Additional � grade 3 drug-related adverse events 

(observed beyond Cycle 1) were diarrhea, fatigue, elevated lipase and 

elevated alkaline phosphatase (n�1 for each event). Two schedules of 

MGCD265 were tested sequentially: once (QD) and twice daily (BID), 

respectively. Increasing the dose frequency to BID increased the exposure 

of MGCD265 by ~ 2 fold at steady state. To date, the exposure (Cmax) attained at steady state with the BID schedule was ~20 fold higher than the 

IC50 for Met and VEGFR inhibition and was also above the plasma 

exposures associated with efficacy in the Met-sensitive xenograft model 

(MKN45). Six patients achieved SD for 6 cycles or more (up to 12 cycles). 

Conclusions: The safety profile of MGCD265 continues to be favorable in 

this Phase I dose escalating study. While no evidence of objective 

responses have been noted to date, several pts have had prolonged SD. 

Dose escalation is ongoing. 



First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor 

sulfatinib in patients with advanced solid tumors. Presenting Author: 

Jian-Ming Xu, Cancer Center, 307 Hospital, Academy of Military Medical 

Science, Beijing, China 

Background: Sulfatinib is a highly selective oral small molecule tyrosine 

dual inhibitor of vascular endothelial growth factor receptors (VEGFR) and 

fibroblast growth factor receptors (FGFR). It demonstrated potent in vivo 

inhibitory effects on a variety of human tumor xenografts. Methods: This 

phase I dose-escalation study were to determine the maximum tolerated 

dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, 

and preliminary antitumor activity, and to assess potential pharmacodynamics 

(PD) markers of sulfantinib when given orally in continuous cycles of 28 

days, until disease progression or unacceptable toxicity. Results: Forty one 

patients (pts) have been enrolled and treated with doses of 50-300mg once 

or twice daily. Pts had a median age of 50 (36-70) yrs, with 63% male and 

93% gastrointestinal tumors. Common adverse events (AEs) included 

fatigue, hypertension, vomiting, nausea, diarrhea, electrolyte disorder and 

elevated AST/ALT, mostly grade (G) 1/2. Three DLTs including a G3 

coagulation disorders, upper gastrointestinal bleeding and impaired liver 

function were observed in the 50 and 265mg qd and 150mg bid cohorts, 

respectively. MTD has not been reached and the dose escalation is ongoing. 

Among 28 evaluable pts, 10 (36%) had stable disease (SD) for 8 weeks or 

longer, including liver and neuroendocrine cancer, GIST and solidpseudopapillary 

tumor of pancreas. A patient with GIST had SD of 9 

months at 265mg qd. There was a significant decrease in soluble VEGFR2 

level and increase in FGF23 level after 4-week treatment comparing to the 

baseline at 265 mg or higher daily doses, indicating inhibition of both 

VEGFR2 and FGFR. PK analyses showed that sulfatinib was rapidly 

absorbed with Tmax 1.3~2.8h and half-life of 15.3~19.1h. Both Cmax and 

AUC displayed dose-proportional increases and no obvious accumulation 

occurred at day 28. Conclusions: Sulfatinib was well tolerated at doses up to 

300 mg per day and demonstrated preliminary anti-tumor activity, especially 

in liver cancer and GIST. PD marker analysis indicates dual inhibition 

of VEGFR and FGFR. PK data suggests good dose proportionality in 

exposure without marked drug accumulation. 

3042^ General Poster Session (Board #12H), Mon, 8:00 AM-12:00 PM 

Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced 

solid tumor patients. Presenting Author: Shawn D. Spencer, SAIC- 

Frederick, National Cancer Institute at Frederick, Bethesda, MD 

Background: CD105 is an endothelial cell membrane receptor highly 

expressed on angiogenic tumor vessels. TRC105 is an anti-CD105 monoclonal 

antibody that inhibits angiogenesis and tumor growth by endothelial 

cell growth inhibition, ADCC and apoptosis. Methods: Patients with advanced 

solid tumors and normal organ function were treated with escalating 

doses of intravenously administered TRC105 and assessed for safety and 

pharmacokinetics (PK). PK parameters for determining dose-linearity were 

estimated following single doses on in 16 patients at 3, 10 and 15 mg/kg 

and correlated with safety. Results: TRC105 was tolerated at 10 mg/kg 

weekly and 15 mg/kg every 2 weeks, but hyproliferative anemia was 

dose-limiting at 15 mg/kg weekly and was associated with TRC105 

accumulation in serum from target saturation. Preliminary evidence of 

activity was observed with 21 of 45 evaluable patients progression-free at 2 

months, including two ongoing responders. The AUC-single dose relationship 

of TRC105 revealed supra-proportionality in serum exposure at 15 

mg/kg compared to 3 and 10 mg/kg. Dose proportionality using a power 

model revealed a nonlinear pharmacokinetic process (log[AUC] � 

0.125*Dose�2.67, r2 � 0.92, ANOVA p�0.0035). The steady state 

volume of distribution was low (� 5.40 L/70kg) indicating TRC105 was 

confined to the vasculature with a low capacity target (i.e., low relative 

abundance) making it susceptible to saturation. The post-infusion Cmax 

however was linearly related to dose (r � 0.85) which suggested the 

nonlinearity in clearance was attributed to target-mediated disposition. The 

nonlinear disposition in the presence of low distribution indicated TRC105 

bound avidly to endothelial cells. Concentrations expected to saturate 

CD105 binding were achieved continuously at 15 mg/kg dosed every 2 

weeks and 10 mg/kg/wk. TRC105 accumulated at 15 mg/kg/wk as the 

accumulation factor at 56 days was 1.77-fold over single doses on C1D1. 

Conclusions: TRC105 clearance decreased above the MTD resulting in drug 

accumulation and hypoproliferative anemia with weekly dosing. The 

nonlinearity in clearance was attributed to saturating target-mediated 

disposition, consistent with binding to proliferating endothelial cells. 


183s 


Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI) 

x-82 in patients (pts) with advanced solid tumors. Presenting Author: 

Kathleen N. Moore, Sarah Cannon Research Institute/University of Oklahoma 

Health Sciences Center, Oklahoma City, OK 

Background: VEGFR TKIs have shown benefit in the treatment of various 

tumor types. Side effects of the TKIs have affected the duration of therapy 

pts can tolerate, as well as the combinability with chemotherapy. X-82 is a 

highly potent VEGFR/PDGFR TKI with a smaller volume of distribution and 

limited tissue accumulation designed to minimize side effects while 

maintaining target effect. Methods: Pts with advanced solid tumors were 

enrolled using an accelerated titration scheme followed by 3�3 dose 

escalation design. X-82 was administered orally once daily (QD) or twice 

daily (BID) every 28 days. Safety, pharmacokinetic, clinical endpoints and 

blood-based biomarkers were evaluated. Results: 16 pts were treated across 

8 dose levels: 20 (n�1), 40 (n�1), 80 (n�1), 160 (n�1), 300 (n�2), 400 

mg QD (n�3), 140 mg BID (n�3) and 200 mg BID (n�4). The most 

common related adverse events (AEs) by pt were fatigue (4 G1, 1 G2), 

nausea (3 G1, 1 G2), diarrhea (3 G1), anorexia (1 G1, 1 G2), and vomiting 

(2 G1). G2 hypertension, resolved with treatment, was experienced by 1 

patient. No � G3 related AEs have been reported. Dose proportional 

exposure was observed with doses up to 160 mg QD, and BID dosing 

cohorts were added. At 160 mg QD X-82 has plasma concentrations �100 

ng/mL for at least 12 hours, the desired exposure predicted preclinically. 

Preliminary blood biomarker data (n�8) shows �25% decrease in VEGFR1 

in 62% of pts and in VEGFR2 in 25% of pts, including pts at 40 and 80 mg 

cohorts. Efficacy has also been noted, including 1 confirmed complete 

response lasting 24� weeks (pancreatic adenocarcinoma), and 6 pts with 

stable disease lasting 8� weeks (range 12.1�, 38.3� weeks), including 

the pt at 20 mg with SCLC (25.1 weeks). Conclusions: X-82 is a 

well-tolerated VEGFR/PDFGR TKI designed to minimize side effects while 

inhibiting target receptors. No MTD has yet been defined, though preliminary 

biomarker data are encouraging and clinical efficacy has been noted. 


A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic 

castration resistant prostate cancer (mCRPC). Presenting Author: Fatima 

H. Karzai, Medical Oncology Branch, National Cancer Institute, National 


Background: Pre�clinical and clinical evidence demonstrates an important 

role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane 

protein expressed on the surface of proliferating vascular endothelial 

cells. The expression of CD105 is required for the formation of new blood 

vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal 

antibody that binds to human CD105 (endoglin). It inhibits angiogenesis 

and tumor growth through inhibition of endothelial cell proliferation, 

antibody-dependent cellular cytotoxicity, and induction of apoptosis. The 

primary objective is to evaluate safety and identify the maximum tolerable 

dose (MTD) of TRC105. Secondary objectives include the assessment of 

TRC105 pharmacokinetics, PSA response rate, evaluation of progression 

free survival (PFS), overall response rate (ORR) and overall survival (OS). 

Methods: Patients with an ECOG performance status (PS) � 2, progressive 

mCRPC and either chemotherapy-naïve or post-docetaxel treatment were 

eligible. Six cohorts of patients, on escalating dose levels, receive TRC105 

intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks 

(cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week 

cycle. Response is assessed with imaging studies every 2 months for the 

first four months and then every 3 months thereafter. Results: Sixteen 

patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), 

median ECOG PS is 1 (range 0�2), median Gleason score is 8 (range 

6�10), median on�study PSA is 147.5 (range 0.1-3373), and median 

number of prior (non-hormonal) therapies is 3 (range 0�6). Median time on 

study is 16 weeks (range 8-28 weeks). One patient experienced a dose 

limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were 

seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 

patients with measurable soft tissue disease achieved stable disease for at 

least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two 

weeks with early evidence of clinical activity in mCRPC. An additional 

cohort (6), with dosage of 20 mg/kg, is currently under investigation. 

Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of 

this study. 




SORAVE: Phase I study for the treatment of relapsed solid tumors with the 

combination of sorafenib and everolimus. Presenting Author: Lucia Nogova, 

Lung Cancer Group Cologne, Center for Integrated Oncology, University 

Hospital Cologne, Cologne, Germany 

Background: Dual inhibition of signaling pathways interfering with angiogenesis 

and cell proliferation may increase anti-tumor efficacy. We evaluated 

the combination of the VEGFR inhibitor sorafenib (S) and the mTOR 

inhibitor everolimus (E) and used FDG-PET to assess pharmacodynamic 

(PD) activity of E. Methods: Patients with relapsed solid tumors were treated 

with escalating doses of E 2.5-10.0mg/d p.o. in a 14 days monotherapy run 

in phase followed by combination therapy with a fixed dose of S 400mg bid 

from day 15. The primary aim was to define a safe and feasible combination 

treatment regimen for a subsequent phase II trial. DLT was defined as any 

drug related toxicity of CTC IV° or toxicity requiring hospitalization or 

interruption of therapy for more than 2 weeks within the first 29 days of 

treatment. Pharmacokinetic (PK) analyses were performed on day 5, 14 

and 29 combined with explorative PD assessment of E by FDG-PET on days 

1, 5 and 14 of treatment. Results: Nineteen patients were treated with the 

combination of E and S. The DLT was not reached according to protocol 

definition. However, at a dose level of E 10mg/d p.o. the following adverse 

events (AE) occurred in the non-DLT interval: Pneumonia III°, treatment 

delay due to leucopoenia/thrombopenia III° and sudden cardiac death 

probably due to arrhythmia. Based on these observations, the dose level of 

7.5mg/day E p.o. in combination with 400mg S bid was defined as the 

MTD. The steady state of E alone was reached after 5 days of treatment and 

did not change until day 14. However, on day 29 everolimus plasma 

concentrations (AUC and Cmax) showed a significant 30 % reduction when 

co-administered with S. A metabolic response of the hottest lesion in PET 

on day 5 defined as � 80% of baseline was seen in 4 of 15 evaluable 

patients. Median PFS and OS were 4.2 and 5.4 months, respectively. A 

patient with neuroendocrine carcinoma reached the longest PFS of 16.6 

months. Conclusions: Treatment of patients with relapsed solid tumors with 

a combination of E 7.5mg/day and 400mg S bid is safe and feasible. The 

extension phase for confirmation of safety data, further PK and PD 

modeling and preliminary exploration of efficacy in KRAS mutant cancer 

patients will be performed at this dose level. 


A dose-escalation phase I study of oral pan-CDK inhibitor BAY 1000394 in 

patients with advanced solid tumors: Dose escalation with an intermittent 

28 days on/14 days off schedule. Presenting Author: Juneko E. Grilley- 

Olson, University of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting 

CDKs 1, 2, 4, 7, and 9 in the low nanomolar range. A phase I dose 

escalation multicenter study was initiated to determine the maximum 

tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics 

(PD) in patients (pts) with advanced solid tumors. Methods: BAY was 

administered twice daily as an oral solution on a 28 days on / 14 days off 

schedule (cycle length 42 days, 3�3 design). PK was evaluated on cycle 1 

day 1, 2, and 15. Response rate was assessed according to RECIST 1.1. 

Results: Ten pts were treated at doses of 0.6 (4 pts) and 1.0 (6 pts) mg per 

day. Tumor types included 3 non-small cell lung, 2 colorectal, 2 melanoma 

and 3 others. CTCAEv4 grade 1/2 drug related adverse events (AEs) 

occurring in more than 3 patients were nausea (5 pts), hot flashes (4), 

vomiting, diarrhea, dyspepsia, and fatigue (3). The median interval 

between start of treatment and occurrence of hot flashes was 23 days. 

Drug-related grade 3 AEs were hyponatremia (2 pts) and edema, lymphopenia, 

myalgia, fatigue, and hypokalemia in 1 pt each. Hyponatremia in one 

and hypokalemia in another patient were dose limiting toxicities in cohort 

2. Enrollment has been stopped. BAY PK was dose proportional and T1/2 was 13 hours; major metabolite levels were low. One pt with metastatic 

malignant melanoma pretreated with interferon, talimogene laherparepvec, 

and ipilimumab (best prior response: progressive disease) achieved stable 

disease (SD) lasting for 5 months. Three pts had SD lasting for 2.5 - 3 

months (thyroid, colorectal, squamous esophageal). Conclusions: BAY 

administered for 28 days on / 14 days off demonstrated a limited 

tolerability. This is in contrast to the ongoing 3 days on / 4 days off trial 

which is currently at a dose level of 20 mg per day. Hot flashes were an 

infrequent AE in the other dosing schedule but occurred in 4 of the 10 pts 

presented here. The long interval between start of treatment and occurrence 

of hot flashes suggests that the 28 days of continuous treatment 

contributed to the lower tolerability observed in this trial. The 3 days on / 4 

days off schedule will be used in the further clinical development of BAY. 


Phase I dose-escalation study of AZD7762 alone and in combination with 

gemcitabine in Japanese patients with advanced solid tumors. Presenting 

Author: Takashi Seto, National Kyushu Cancer Center, Fukuoka, Japan 

Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to 

enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff 

SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label 

dose-escalation study evaluated the safety, pharmacokinetics (PK), and 

preliminary efficacy (RECIST) of AZD7762 alone and in combination with 

gemcitabine in Japanese patients (pts) with advanced solid tumors 

(NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 

14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 

mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 

dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at 

doses of 6 (n�3), 9 (3), 21 (6), and 30 mg (8). The most common primary 

tumor site was lung (n�14). All pts had received �1 prior chemotherapy 

and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in 

two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) 

elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, 

thrombocytopenia, and elevated AST and ALT (Cycle 1; combination 

therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs 

resolved following treatment discontinuation. The most frequently reported 

adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia 

(50%), hypertension (25%) and fatigue (15%). Overall, the most common 

AEs were bradycardia (55%), neutropenia (45%), and hypertension, 

fatigue, and rash (30% each). AEs grade �3 were reported in 11 pts, the 

most common being neutropenia (45%) and leukopenia (25%). No pt died 

due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately 

linear manner. Gemcitabine did not appear to affect AZD7762 PK. 

Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose 

groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the 

monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in 

combination with gemcitabine. There were no objective responses; five pts 

(all lung cancer) had stable disease. Conclusions: The maximum tolerated 

dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was 

determined as 21 mg in Japanese pts. 


Clinical and correlative science results in a phase II study of UCN-01 in 

combination with irinotecan in recurrent triple-negative breast cancer 

(TNBC). Presenting Author: Cynthia X. Ma, Washington University School 

of Medicine, St. Louis, MO 

Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing 

“mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan 

(I) combined with UCN-01, a nonselective Chk1 inhibitor, showed 

promising activity in TNBC in our phase I study. The primary objective of 

the phase II trial was to determine the efficacy and toxicity. Correlatives 

included assessing tumor molecular subtype, TP53, PTEN and pathways 

targeted by UCN-01. Methods: Pts with measurable, metastatic (met) 

TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV on d2 and 35 mg/m2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial 

peripheral blood mononuclear cells (PBMC) and optional tumor biopsies 

were collected. Results: Twenty five pts were enrolled. All had prior A and T. 

The median no. of prior regimens for met disease was 3 (range 1-4). 

Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia. 

Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a 

clinical benefit rate (CR�PR�SD�6 mos) of 3/25 (12%), 95% CI (3, 

31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6 

was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC 

24h post UCN-01, but close to baseline by d8. Immunostain of cleaved 

caspase 3 (CC3), pHistone H3 (pHH3), �H2AX, and pS6 were done on 

serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6 

was reduced 24h post UCN-01. Results for other markers were variable. 

One case with TP53 deletion showed an induction of CC3, with an increase 

in pHH3 and �H2AX, suggesting abrogation of cell cycle arrest and 

enhanced DNA damage. Among 15 with sufficient specimen for analysis, 

most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2) 

by PAM50, low in PTEN level (11) and carried mutations in TP53 (8). 

Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95% 

CI: 2.9, - ) mos in wild type populations (p�0.004). Conclusions: This 

regimen had limited activity in TNBC. Despite the long half-life, drug 

activity is not detectable by d8 based on PBMC analysis. Our data indicates 

that future trials in TNBC should consider p53 status. 



Safety and efficacy results from two randomized expansions of a phase I 

study of a tablet formulation of the PARP inhibitor, olaparib, in ovarian and 

breast cancer patients with BRCA1/2 mutations. Presenting Author: L 

Rhoda Molife, Royal Marsden Hospital and Institute of Cancer Research, 

Surrey, United Kingdom 

Background: We previously reported the comparative bioavailability of the 

capsule (CAP) formulation of olaparib and the more convenient new tablet 

(TAB) formulation (Molife et al ASCO 2010). We subsequently performed 

two separate dose expansions (DE1 and DE2) to explore comparative safety 

and efficacy of the TAB (NCT00777582). Methods: Patients with breast or 

ovarian cancer and BRCA1/2 mutations, ECOG PS 0–2 and adequate organ 

function were randomized to receive: DE1: 200 TAB or 400 CAP; DE2: 300 

TAB, 400 TAB or 400 CAP (all mg BID). Endpoints included safety, 

pharmacokinetics and exploratory analysis of efficacy (change in tumor size 

at 8 weeks by RECIST 1.0). Groups were compared using analysis of 

covariance, including baseline tumor size and treatment as covariates; 

results are presented using least square (LS) means. Results: 24 patients 

(ovarian n�15, breast n�9) entered DE1 and 53 patients (ovarian n�38, 

breast n�15) entered DE2. Baseline characteristics including age, BRCA 

mutation status and tumor histology were balanced. The table shows key 

toxicity-related information and change in tumor size at 8 weeks by cohort. 

Conclusions: These data suggest a dose-response effect for tolerability and, 

possibly, efficacy with the new TAB between 200 and 400 mg BID. Further 

studies will require dosing according to patient tolerability within this dose 

range. 

DE1 DE2 

200 TAB 400 CAP 300 TAB 400 TAB 400 CAP 

(n�13) (n�11) (n�18) (n�16) (n�18) 

G3/4 AEs, n (%) 

Nausea 0 0 0 2 (13%) 0 

Fatigue 0 0 3 (17%) 1 (6%) 0 

Diarrhea 0 0 2 (11%) 0 0 

Anemia (Hb changes) 

Other, n (%) 

0 0 4 (22%) 4 (25%) 1 (6%) 

Blood transfusions 

Dose modifications, n (%) 

0 0 5 (28%) 7 (44%) 2 (11%) 

Dose reductions 2 (15%) 1 (9%) 4 (22%) 10 (63%) 3 (17%) 

Drug discontinuations due to AEs 

Change in tumor size, 8 weeks 

0 0 0 0 0 

LS, mean (%) 4.5 -12.8 -6.8 -28.6 -27.8 

Difference 17.3 21.0 -0.8 

95% CI -11.8, 46.3 1.3, 40.7 -20.8, 19.3 


Developing rational drug combination strategies for PARP inhibitors. 

Presenting Author: Farah Rehman, The Institute of Cancer Research, 

London, United Kingdom 

Background: The recent clinical development of Poly (ADP-ribose) polymerase 

(PARP) inhibitors has provided formal proof-of-concept that synthetic 

lethal approaches can be used to treat cancer. The promise of PARP 

inhibitors in BRCA mutant tumours is apparent but questions regarding 

their wider clinical use remain. To date, a number of clinical trials have 

been designed using PARP inhibitors as single agents as well as in 

combination with current standards of care. However, there is a paucity of 

pre-clinical information about PARP inhibitor/drug combinations and 

empirical clinical trials of standard of care plus PARP inhibitors may not 

represent the most effective approach to dissect this. We aim to identify 

effective drug combination strategies that could be used clinically in 

selected patient groups. Methods: Using a combination of high and medium 

throughput techniques and established methodologies for determining 

synergy, additivity and antagonism, we have characterised the effects of 

combining PARP inhibitors with a diverse panel of over 3,000 compounds 

in a range of tumour cell models including isogenic matched cell line pairs 

to determine the impact of genetic background on drug combination 

efficacy. We have integrated this data with functional profiling data to 

identify genetic backgrounds where these combinations may be most 

effective. Results: Results to date suggest promising combinations of PARP 

inhibitors with temozolomide, CHK1 inhibitors, ATM inhibitors and other 

agents. Some of these combinations show specificity for genetic backgrounds 

such as PTEN mutations. Conclusions: Screening of drug libraries 

has identified promising PARP inhibitor drug combinations and demonstrates 

how some drug combinations show specificity in particular genetic 

backgrounds. This raises the possibility of widening the therapeutic index 

in patients with these genetic backgrounds and treating a wider group of 

patients with PARP inhibitors. 


185s 


A phase I study of veliparib (ABT-888) in combination with carboplatin and 

paclitaxel in advanced solid malignancies. Presenting Author: Leonard 

Joseph Appleman, University of Pittsburgh Cancer Institute, Pittsburgh, PA 

Background: Veliparib (ABT-888, NSC 737664) is an orally available 

inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2: enzymes that 

recruit base excision repair machinery to single-stranded DNA breaks. 

Expression of PARP-1 may be increased in cancer cells and confer 

resistance to DNA-damaging agents. The objectives of this phase I study 

included determination of the recommended phase 2 dose (RP2D), 

maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics 

(PK) of veliparib in combination with paclitaxel (P) and carboplatin 

(C). Methods: Eligibility criteria included advanced solid tumors, � 3 prior 

chemotherapy regimens for advanced disease, ECOG performance status 

0-2. Veliparib was given PO BID on days 1-7 of each 21 day cycle, and P 

and C were administered on day 3. In dose levels 1-7, veliparib was not 

given during cycle 1 to serve as intra-patient control for toxicity and PK 

assessment, and DLT was evaluated during cycle 2. A standard “3�3” 

dose escalation was utilized starting at veliparib 20 mg BID, P 150 mg/m2, 

C AUC 5. Plasma concentrations of veliparib, P and C were determined by 

LC-MS/MS and AAS during cycle 1 and 2. Results: To date, 68 patients 

have been enrolled. Tumor types included lung (15), breast (14), melanoma 

(10), squamous cell of head/neck (7), and urothelial (5). Toxicities 

observed were expected with C plus P chemotherapy, including neutropenia, 

thrombocytopenia, peripheral neuropathy. DLTs were seen in 2 out of 7 

evaluable patients at the maximum administered dose: veliparib 120 mg 

BID, P 200 mg/m2 , C AUC 6, (febrile neutropenia, hyponatremia). 

Veliparib 80 mg, P 200 mg/m2 , C AUC 6 was well tolerated with 1 out of 9 

DLT (febrile neutropenia). Median number of cycles was 5 (1-17). Partial 

response was seen in 11 (Lung-2, breast-2, melanoma-2, urothelial-2, 

head and neck, gastric, unknown primary) and complete response in 1 

patient with breast cancer and 1 patient with urothelial cancer. Stable 

disease was observed in 35 patients. Veliparib did not affect the PK 

disposition of P or C. Conclusions: Veliparib in combination with P and C 

was well-tolerated with a safety profile similar to P and C alone. Promising 

anti-tumor activity was observed in several tumor types. 


Phase I study to determine the bioavailability and tolerability of a tablet 

formulation of the PARP inhibitor olaparib in patients with advanced solid 

tumors: Dose-escalation phase. Presenting Author: Avinash Gupta, Oxford 

University Hospitals NHS Trust, Oxford, United Kingdom 

Background: We previously reported the comparative bioavailability of the 

olaparib tablet (TAB) up to 200 mg BID, with the initial capsule formulation; 

gmean AUC0–Tfollowing 200 mg BID TAB was ~20% lower than 400 

mg BID capsule (CAP; Molife et al ASCO 2010). Olaparib 200 mg BID TAB 

had an acceptable tolerability profile suggesting further dose escalation 

might be justified. Methods: Study NCT00777582 was amended to include 

a dose-escalation phase, to define the maximum tolerated dose (MTD) and 

safety profile of the TAB, and 2 expansion phases to compare safety and 

efficacy of TAB doses vs 400 mg BID CAP. Expansion phase data are 

reported separately. Here, we report preliminary data from the doseescalation 

phase where patients (pts) with advanced solid tumors, ECOG 

PS 0–2 and adequate organ function were assigned to treatment with 

increasing olaparib BID TAB doses in 28-day continuous dosing cycles. 

Pharmacokinetic (PK) sampling was performed on days 1, 8, 15, 29, 57. 

Results: 30 pts (M:F, 3:27; median age 54 yrs [range 19–70]) were 

enrolled in the dose-escalation phase and received treatment at 5 dose 

levels: 250, 300, 350, 400 and 450 mg (each dose level, n�6). Overall, 

the most common AEs were nausea (80%), fatigue (73%) and diarrhea 

(36%). The majority of AEs were mild to moderate (CTC grade [G] 1/2). 

Hematologic toxicity in terms of, mostly mild, anemia, neutropenia and 

thrombocytopenia, appeared to increase at doses of 300 mg BID or higher. 

Two pts had dose-limiting toxicities at 450 mg (G3 thrombocytopenia and 

G3 anemia); the TAB MTD was 400 mg BID. Exposure increased proportionally 

with increasing dose: mean exposure after 400 mg BID was double that 

following the previously reported 200 mg BID dose. Following 300 and 400 

mg doses, gmean Cmax ss, AUC0–Tand Cmin ss matched or exceeded the 400 

mg BID CAP dose. Conclusions: The MTD of olaparib TAB was 400 mg BID. 

Based on PK analysis, the 300 and 400 mg BID doses were selected for 

evaluation in the MTD expansion phase to further define safety and 

preliminary efficacy. 




Phase I dose-escalation study to evaluate the safety, pharmacokinetics, 

and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as singleagent 

and in combination with temozolomide in patients with advanced 

solid tumors (NCT00920595). Presenting Author: Mario Campone, Institut 

de Cancérologie de l’Ouest - René Gauducheau, Centre de Recherche en 

Cancérologie, Saint Herblain-Nantes, France 

Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in 

cellular processing of DNA damage via the base excision repair pathway. 

CEP-9722, an orally available PARP1-2 inhibitor, demonstrated singleagent 

antitumor activity and synergy with temozolomide (TMZ) in xenograft 

models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, 

and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy 

and combination with TMZ. Methods: Adult patients with advanced 

solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day 

cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 

(days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 

150 mg/day in the first cohort and was escalated depending on the 

occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The 

safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral 

blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 

26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 

3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of 

CEP-9722 in combination with TMZ (150 mg/m2 ) was reached at 1000 

mg/day. The recommended dose was 750 mg/day. A total of 9 patients were 

treated at the recommended dose. DLTs were observed in 2 patients during 

cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 

mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day 

and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this 

study, 4 grade 3 treatment-related adverse events were observed. The 

pharmacokinetics showed high intra- and inter-patient variability at all 

doses. The pharmacodynamic analysis demonstrated PARP inhibition at all 

doses, but the high inter- and intra-patient variability prevented any 

conclusion regarding a dose / PARP inhibition relationship. Conclusions: 

TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 

and the combination CEP-9722/TMZ was well tolerated. In addition, a 

clear signal of PARP inhibition was demonstrated. 


A phase I study of chronically dosed, single-agent veliparib (ABT-888) in 

patients (pts) with either BRCA 1/2-mutated cancer (BRCA�), platinumrefractory 

ovarian cancer, or basal-like breast cancer (BRCA-wt). Presenting 

Author: Shannon Leigh Huggins-Puhalla, University of Pittsburgh 

Cancer Institute, Magee-Womens Hospital, Pittsburgh, PA 

Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2. 

Preclinically, PARP inhibitors have activity in tumors with defective 

homologous recombination (HR), particularly those that are BRCA�. 

Reduced levels of BRCA expression have been observed in ovarian cancer 

and basal-like breast cancer, which share genotypic and phenotypic 

similarities with BRCA� cancers. We postulated that these tumors types 

may be similarly sensitive to single-agent PARP inhibition. This study 

sought to establish the maximum tolerated dose (MTD), dose limiting 

toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and 

preliminary efficacy of chronically-dosed veliparib. Methods: A3�3 dose 

escalation phase I trial was performed. Nine dose levels (DL) were planned, 

and dose escalation started at 50 mg BID to a maximum of 500 mg BID. 

Veliparib was administered orally continuously on a 28 day cycle. Results: 

63 pts have been enrolled to date. Thirty-eight were BRCA� (20 ovary, 12 

breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube, 

endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the 

following dose levels: BRCA�: gr. 2 thrombocytopenia at 50 mg BID; 

BRCA�: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at 

400 mg BID. The MTD has not been determined and 500 mg BID is 

presently enrolling. Notable toxicities have included low-grade fatigue and 

nausea. PK was linear and non-saturable with t½of5h.Thenumber of 

cycles administered ranged from 1- 15, median 2. In BRCA� pts, there 

were 2 partial responses (breast, ovarian) and 10 pts had evidence of 

prolonged SD � 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7 

pts with SD� 4 months. Correlative studies, including assessment of PAR 

inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib 

is tolerable on a continuous oral dosing schedule with evidence of 

anti-tumor activity seen in BRCA� and BRCA-wt tumors. A mandatory 

biopsy expansion cohort is planned at the recommended phase II dose, 

which will allow further insights regarding efficacy and mechanisms of 

resistance to PARP inhibition. 


Phase I study of sequential sapacitabine and seliciclib in patients with 

advanced solid tumors. Presenting Author: Geoffrey Shapiro, Dana-Farber 

Cancer Institute, Boston, MA 

Background: Sapacitabine is an orally administered nucleoside analogue; 

the active metabolite CNDAC generates ss DNA breaks that are converted to 

ds DNA breaks (DSB) during subsequent replication, resulting in cell death 

if unrepaired. CNDAC-induced DSB repair is dependent on homologous 

recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of 

CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via 

compromise of HR protein activation and transcriptional inhibition of HR 

components. This phase I study evaluates sequential sapacitabine and 

seliciclib. Methods: Dose escalation was conducted in patients with 

incurable solid tumors and adequate organ function with sapacitabine 

b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days 

(d8-10) followed by 11 days of rest. At least 3 patients were evaluated per 

dose level. MTD was the highest dose level at which less than one-third of at 

least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to 

assess DNA damage following sapacitabine (d8 vs pre-treatment) and 

further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 

27 patients were treated. The MTD and RP2D is sapacitabine 50 mg 

b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations 

and neutropenia. The most frequent adverse events (all cycles, 

regardless of causality) included anorexia, fatigue, abdominal pain, dizziness, 

nausea, anemia, neutropenia, creatinine elevation, hyperglycemia, 

hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia, 

the majority mild to moderate in intensity. Skin biopsies showed a 

2.3-fold increase in H2AX staining post-sapacitabine (n�16; p�0.007) 

and a further 0.58-fold increase post-seliciclib (n�12; p�0.069). Two 

confirmed PRs occurred in patients with pancreatic and breast cancer, both 

BRCA mutation carriers. SD as best response �/� 12 weeks was observed 

in 6 additional patients, including one BRCA mutation carrier with ovarian 

cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and 

seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier 

status may be a potential biomarker for response across multiple tumor 

types. 


Using proton MRSI to predict response to vorinostat treatment in recurrent 

GBM. Presenting Author: Hyunsuk Shim, Emory University, Atlanta, GA 

Background: A major impediment to the development of new therapies for 

glioblastoma (GBM) is a lack of biomarkers indicating response. Epigenetic 

modifications are now recognized as a frequent occurrence in the early 

phases of tumorigenesis, playing a central role in tumor development. 

Epigenetic alterations differ significantly from genetic modifications in that 

they may be reversed by ‘‘epigenetic drugs’’ such as histone deacetylase 

inhibitors (HDACis). As a promising new modality for cancer therapy, the 

first generation of HDACi is currently being tested in phase I/II clinical 

trials. Methods: GBM alterations from therapy with HDACis, such as 

vorinostat (SAHA), include tumor redifferentiation/cytostasis rather than 

tumor size reduction limits the utility of traditional imaging methods such 

as MRI. Magnetic resonance spectroscopic imaging (MRSI) quantitates 

various metabolite levels in tumor and normal brain, allowing characterization 

of metabolic processes in live tissue. Results: In our preclinical model, 

MRS detected metabolic response to SAHA after only 3 days of treatment: 

reduced alanine and lactate and elevated myo-inositol, N-acetyl aspartate 

and creatine; each returning toward normal brain levels. This led to our 

clinical study of MRSI to evaluate the metabolic response of recurrent 

GBMs to SAHA � temozolomide. After only 7 days of SAHA treatment, 

MRSI can distinguish metabolic responders (normalization/restoration of 

tumor metabolites towards normal brain-like metabolism) from nonresponders 

(no significant change in tumor metabolites). Our initial cohort 

(n�6) consists of 3 responders and 3 non-responders with highly significant 

differences in their change in metabolite levels (p � 0.001). 

Conclusions: Our results provide exciting insights into the mechanisms by 

which HDACi exerts its effect on GBMs. Tumor cells have increased 

biosynthetic needs requiring reprogramming of cellular metabolism. This 

creates increased energy demands, making tumor cells even more vulnerable 

to interventions targeting their metabolism. HDACi may induce 

redifferentiation in tumors by targeting tumor metabolism. Thus, MRSI 

provides a novel modality to predict response to HDACi-containing combination 

therapy in GBM. 



A phase I/II study to evaluate the ability of decitabine and panobinostat to 

improve temozolomide chemosensitivity in metastatic melanoma. Presenting 

Author: Chang Xia, Hematology, Oncology, and Blood & Marrow 

Transplantation, UIHC, Iowa City, IA 

Background: Epigenetic gene regulation is likely a contributing mechanism 

of cancer initiation and progression. Emerging evidence indicates that 

epigenetics may also play a key role in the development of chemoresistance 

in melanoma. We proposed combining the histone deacetylase inhibitor 

panobinostat (PT) and the demethylator decitabine (D) to overcome the 

development of epigenetic mediated temozolomide (TMZ) resistance in 

metastatic melanoma. Methods: Eligible patients must be �18, stage IV 

melanoma, and naïve or previously treated, with good performance status 

(ECOG � 2) and normal organ functions. Patients with previous exposure to 

TMZ were allowed on study. The study includes the dose escalation of D 

and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on 

days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting 

day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle. 

TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. 

Primary endpoints of phase I study are to determine the toxicity, safety 

and maximum tolerated dose (MTD) of the D, PT and TMZ combination. 

Results: To date, the phase I portion of this trial is completed. We report on 

the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median 

age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least 

one cycle (n�14). Median number of cycles given: 2 (0-6). To date, no 

DLTs have occurred. The MTD was not reached. The only grade (G) 4 

adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved 

within 3 days. G3 AEs included lymphopenia (n�4, 23%), anemia (n�2, 

12%), leukopenia (n�2, 12%) and fatigue (n�2, 12%). Common G2 

toxicities were leukopenia (n�5, 30%), neutropenia (n�4, 23%), nausea 

(n�4, 23%) and lymphopenia (n�3, 18%). Conclusions: The combination 

of D, PT, and TMZ appears to be safe and well-tolerated. The recommended 

dose for the phase II study remains to be determined. 


A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) 

and epirubicin in patients with solid tumor malignancies. Presenting 

Author: Amy Patricia Moore, UCSF, San Francisco, CA 

Background: Preclinical and clinical data suggest pre-exposure of cancer 

cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase 

inhibitors. HDACi-induced histone acetylation and chromatin modulation 

facilitates DNA access and target recruitment for topo II inhibitors. In vitro 

data further suggest effective inhibition of HDAC2 is necessary for 

enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores 

the safety, tolerability, and maximum tolerated dose (MTD) of 

escalating doses of panobinostat given orally on days 1, 3, and 5 followed 

by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day 

cycles. Histone acetylation and HDAC2 expression are evaluated in preand 

post-treatment peripheral blood mononuclear cells (PBMCs) in all 

patients and in tumor cells of 16 patients treated at the MTD. Results: 36 

patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 

panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include 

melanoma (n�6), breast (n�6), sarcoma (n�16), ovarian (n�2), lung 

(n�2), and one each of neuroblastoma, pancreatic, testicular, and colon 

cancer. Prior to enrollment, patients received a median of 3 (0-8) prior 

chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities 

(DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia 

at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation 

at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting 

grade 3/4 hematological toxicities include neutropenia (n�19, 53%), 

febrile neutropenia (n�6, 17%), thrombocytopenia (n�6, 17%), and 

anemia (n�4, 11%). Of 34 evaluable patients, 5 had partial responses and 

14 had stable disease in anthracycline-refractory sarcomas (4) and 

Her2neu positive breast cancer (2), and small cell lung cancer. Correlative 

studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 

suggesting sufficient histone deacetylase inhibition. Conclusions: Sequencespecific 

combination of panobinostat and epirubicin shows early activity 

without potentiating epirubicin toxicity. Dose expansion in anthracyclinepretreated 

sarcoma patients is ongoing. 


187s 


Testing targeted demethylation to overcome resistance to epidermal growth 

factor receptor (EGFR) blocking agents in wild-type (wt) KRAS metastatic 

colorectal cancer patients (mCRC). Presenting Author: Ignacio Garrido- 

Laguna, Division of Oncology and Center for Investigational Therapeutics at 

Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT 

Background: Panitumumab, a monoclonal antibody against EGFR, led to 

improved progression-free survival (PFS) in patients with (wt)KRAS mCRC. 

However, the benefit of panitumumab is limited to a not yet identified small 

subset of (wt)KRAS patients. The CpG island methylator phenotype 

(CIMP-high) is present in 15-20% of CRC patients. Epigenetic silencing 

through methylation of PTEN and/or genes in the EGFR pathway might play 

a role in resistance to therapy. We assessed whether decitabine (a 

hypomethylating agent) reverted resistance to anti-EGFR therapies. Methods: 

Patients (n�19) with (wt)KRAS mCRC previously treated with anti-EGFR 

therapies were enrolled. Patients were treated with decitabine 45mg/kg IV 

on day (d)1 and d15 and panitumumab 6mg/kg IV on d8 and d22 q28days. 

Peripheral blood, skin biopsies and buccal smear samples were collected 

on d1, d8, d15 and d22 to assess methylation changes in PTEN, RASSF1A 

and SOCS-1 in response to therapy. Tumors were analyzed for PIK3CA 

mutations using PCR-based DNA sequencing of exon 9 and 20 by PCR as 

well as for PTEN by immunohistochemistry. Results: Median age was 53 

(range 31-72). Eleven (58%) patients were female; 15 (79%) had ECOG 

PS 1; 3 (16%) had ECOG PS 2; and 1 had ECOG PS 0. Median number of 

previous therapies was 4. The most common toxicities were rash (68%), 

hypomagnesemia (26%) and neutropenia (10%) (all grade 1-2). The most 

common grade 3-4 toxicities were neutropenic fever (5%) and hypomagnesemia 

(5%). Of 19 (wt)KRAS mCRC patients previously treated with 

anti-EGFR therapies, 2 (11%) had a partial response (PR) (-50% and 

-30%, respectively) and 3 (16%) had stable disease (SD) �4 months (7.8, 

5.9 and 4.2 months). Both responders were (wt)PIK3CA and (wt)PTEN. 

Clinical benefit rate (PR�SD) was 27%. Median PFS was 60 days (95% CI 

45.4-74.5), similar to median PFS after last anti-EGFR therapy, 61d (95% 

CI 50.6-71.3). Conclusions: Panitumumab � decitabine is an active 

combination in a subset of patients with mCRC previously treated with 

anti-EGFR therapies (2 PRs in this population). Efficacy assessment in an 

anti-EGFR therapy naïve population is warranted. Methylation studies are 

ongoing. 


Phase Ib study of CNTO 888 (anti-CCL 2) in combination with chemotherapies 

for treatment of patients with solid tumors. Presenting Author: Antonio 

Calles, START-Madrid, Centro Integral Oncológico Clara Campal, Madrid, 

Spain 

Background: CC-chemokine ligand 2 (CCL2) is expressed in various malignancies, 

implicated in angiogenesis, proliferation and metastasis. CNTO888 

is a hIgG1� mAb with selective high CCL2 binding affinity and showed 

preclinical antitumor activity. Methods: Primary objectives were safety and 

a recommended dose of CNTO 888 in combination with chemotherapy: 

Arm1-15mg/kg CNTO 888 � docetaxel 75 mg/m2 Q3W; Arm 2-15 

mg/kg CNTO 888 � gemcitabine 1000 mg/m2 on D1 and 8 Q3W; Arm 3 - 

15 mg/kg CNTO 888 � paclitaxel 175 mg/m2 and carboplatin AUC6 Q3W; 

Arm4-10mg/kg CNTO 888 Q2W � pegylated doxorubicin 50 mg/m2 Q4W. Two (Arms 1, 2, 3) or 4 (Arm 4) prior chemotherapies for advanced 

disease were allowed. Pharmacokinetic (PK) profile of CNTO 888 and 

chemotherapies, free and total CCL2, CTC/CEC count, and uNTX were 

evaluated. Adverse events (AE) and dose limiting toxicities (DLT) were 

evaluated after 6 subjects completed 1 cycle. Results: 53 subjects 

(22F/31M) were treated: Arm 1 n�15, Arm 2 n�12, Arm 3 n�12, Arm 4 

n�14. Two DLTs occurred: a grade 4 febrile neutropenia (Arm 1) and a 

grade 3 neutropenia (Arm 2). All 4 combinations were found to be safe and 

tolerable and continued enrolment to a minimum of 12 subjects evaluable 

for safety and PK. Best overall response were partial response (PR) (1) and 

stable disease (18; 2 � 4 months). One subject with pancreatic adenocarcinoma 

achieved PR, allowing for surgical resection. Most frequently 

reported (� 20%) related serious AEs are: Arm 1: Neutropenia, Stomatitis, 

Fatigue, Febrile neutropenia, Alopecia. Arm 2: Anemia. Arm 3: Thrombocytopenia, 

Alopecia, Neutropenia, Asthenia, Fatigue, Anemia, Arthralgia, 

Nausea, Vomiting. Arm 4: Stomatitis, Rash, Fatigue, Nausea, Anemia, 

Neutropenia. CNTO 888 did not affect the chemotherapy PK profile; 

similarly, chemotherapy did not affect the CNTO 888 PK profile. No 

subjects (n�38) tested positive for antibodies to CNTO 888. Free CCL2 

declined 2 hrs post treatment and returned to baseline levels by 48 hrs and 

continued to increase with further administrations in all treatment arms. 

There were no consistent changes with other biomarkers. Conclusions: 

CNTO 888 in combination with standard chemotherapy was well tolerated 

but few objective responses were seen. 




A phase I study of EP-100, a luteinizing hormone releasing hormone 

(LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with 

advanced refractory LHRH- receptor (R)-expressing tumors. Presenting 

Author: Ramesh K. Ramanathan, Virginia G. Piper Cancer Center at 

Scottsdale Healthcare/TGen, Scottsdale, AZ 

Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated 

to an 18 aa cytolytic peptide. Selective targeting in LHRH-R 

expressing cells occurs via direct binding to the extracellular membrane 

receptor followed by disruption of the membrane by the cytolytic peptide 

portion. A first in human, phase I study was performed. Methods: Eligible 

pts had adequate organ function and LHRH-R tumor expression, as 

determined by IHC. EP-100 was given IV (30-60 min) weekly x3for 

cohorts 1- 6 (n�20 at 0.6 - 5.2 mg/m2 ) and then twice weekly x3for 

cohorts 7- 11 (n�18 at 7.8 - 40 mg/m2 ) with a week break. The 

pharmacokinetic profile of EP-100 and antibody production against EP- 

100 was determined by a validated HPLC/MS and ELISA respectively. 

Potential activity of EP-100 on the pituitary gonadotropes was determined 

by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue 

obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 

were enrolled (female 76%) and treated. The LHRH-R expression rate in 

breast was 81% (N�21) and in ovarian cancer 56% (n�18). Most pts had 

breast (n� 16, 42%) ovary (n�7,18%), colon (n�4, 11%) or uterine 

(n�3, 8%) cancer. Pts were treated in a 3 � 3 standard dose escalation 

scheme. Doses were escalated 100% in the absence of a grade 2 drug 

related toxicity. MTD was not reached at the highest dose level of 40 

mg/m2 . Only one DLT occurred, a grade 2 increase in ALT/AST. The only 

other drug-related toxicity was a self limited infusion-related skin reaction 

(grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean 

half life ranged from 7.1 � 3.8 min to 15.9 � 3.6 min. Best response was 

stable disease for �12 weeks in 5 pts. In 3 pts rapid, sustained decreases 

in LH/FSH levels were noted. Antibody production against EP-100 was 

absent in all pts. Conclusions: The study has completed accrual, the phase 

II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well 

tolerated and not antigenic/immunogenic. Preclinical studies indicated 

synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus 

paclitaxel in ovarian cancer is planned. 


Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer 

patients responding to therapy. Presenting Author: Maria Alsina, Molecular 

Therapeutics Research Unit, Vall d’Hebron University Hospital, Barcelona, 

Spain 

Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised 

of lipid nanoparticle-formulated small interfering RNAs targeting 

vascular endothelial growth factor (VEGF)-A and kinesin spindle protein 

(KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks 

was well-tolerated and showed evidence of anti-VEGF pharmacology and 

antitumor activity. Methods: Patients treated on the phase I trial with stable 

disease (SD) or better after 4 months (8 doses) were eligible to continue on 

an extension study until disease progression. Main objectives included 

continued evaluation of safety/tolerability and assessment of disease 

response. Results: Seven of 37 patients (18.9%) evaluable for response 

went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 

5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had 

progressed after one or more prior therapies. Tumor types included head 

and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, 

renal cell carcinoma (RCC, N�2), and pancreatic neuroendocrine tumor 

(PNET, N�2). At the time of enrollment, 6 had SD and one (endometrial 

cancer with multiple liver metastases) had an unconfirmed partial response 

(PR). The average length of time on treatment (including phase I and 

extension studies) was 9.5 months (range 5-19). As of January 2012, 3 

patients remain on study, including the endometrial cancer patient with an 

ongoing PR who has had �80% tumor regression after 19 months of 

treatment at 0.7 mg/kg and two patients with RCC and PNET with 

continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other 

patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 

5.5 months, respectively, for adverse events that included fatigue or 

elevated alkaline phosphatase. A decrease in spleen volume, likely an 

on-target effect and not associated with any adverse events, occurred to a 

greater degree on the extension study than on the phase I trial and was most 

pronounced in patients receiving � 12 doses. Conclusions: ALN-VSP02 has 

preliminary activity against endometrial cancer, RCC and PNET and a 

favorable safety profile that permits chronic dosing. Phase II trials are 

warranted in these and other VEGF-overexpressing tumors. 


Improved sorafenib activity on hepatocellular carcinoma in Notch3 silenced 

in vivo and in vitro models. Presenting Author: Michele Baglioni, 

Department of Clinical Medicine, University of Bologna, and Center for 

Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, Bologna, 

Italy 

Background: Sorafenib is the only approved drug for the treatment of the 

advanced stage of HCC. Although its efficacy has been proven with 

randomized clinical trials, the clinical benefit seen in overall survival for 

advanced HCC patients treated with sorafenib could be improved. New 

molecules or combination of novel targeted agents to improve sorafenib 

efficacy for advanced stage HCC patients are needed. Notch genes are a 

family of receptors involved in many cell fate regulations, their expression 

has been found altered in many tumors, including HCC. The aim of this 

study was to study the combination of sorafenib and Notch3 signaling 

inhibition to improve sorafenib’s therapeutic effect. Methods: HepG2 and 

Huh7 cellular models were used for Notch3 stable silencing by retroviral 

introduction of specific interfering RNAs Xenograft models in both Notch3 

stable shRNA cell lines have been developed using NOD/SCID mice. 

Animals bearing tumors were treated with 60 mg/kg of sorafenib for 21 

consecutive days. Notch3, p21 and pGSK3�Ser9 protein expression were 

also analyzed in 20 human HCCs. Results: Notch3 silencing (shN3) in 

HuH7 and HepG2 cell lines treated with sorafenib showed an increase in 

cell death (3.8 to 5 fold increase) when shN3 cell lines were compared with 

their relative controls (GL2). A difference in tumor growth was observed 

between GL2 negative control vs shN3 xenografts in both HepG2 and Huh7 

after 21 days of sorafenib treatment. Two tailed student’s t test (shN3 vs 

GL2) P�0,04 and P�0,01 for Huh7 and HepG2 respectively. Molecular 

investigations have shown the involvement of p21 and GSK3� in the 

enhanced response to sorafenib in Notch 3 silenced models. A significant 

inverse correlation between Notch3 and pGSK3�Ser9 proteins accumulation 

(Spearman �� -0.666) (p � 0.01) and a direct correlation between 

Notch3 and p21 proteins expression (Spearman �� 0.681) (p � 0.01) was 

found in HCC samples obtained from patients. Conclusion: Our preclincal 

findings outline the effect of combined Notch3 inhibition and sorafenib. 

The molecular mechanisms responsible for sorafenib induced cell death 

associated with Notch3 silencing relays on inhibition of p21/CDKN1A and 

GSK3�Ser9 . This study is supported by a grant from Bayer Healthcare, Italy. 


Evaluation of toxicities of target therapy phase I and II trials on glioblastoma 

multiforme patients treated by curative radiotherapy: A metaanalysis. 

Presenting Author: Marcos Antonio Santos, Institut Gustave 

Roussy, Villejuif, France 

Background: An important limitation of the combination of target therapies 

(TT) to radiation (RT) is its potentially high level of toxicity. The objective of 

this study was to describe and quantify the drug related acute adverse 

events presented by patients taking part in phase I and/or phase II trials on 

TT combined to curative RT for the treatment of glioblastoma multiforme 

(GBM). Methods: A meta-analysis of summary data including all phase I, I/II 

and II trials published between 2000 and 2011 on newly diagnosed GBM 

patients treated by TT with RT was performed. Pooled incidence rates (IR) 

of all and specific toxicities were estimated using a generalized linear 

mixed model with fixed and random study effects. The pooled median of 

progression-free (PFS) and overall survivals (OS) were also considered. 

These results were compared to those obtained by patients receiving 

standard treatment (ST). Results: Twenty-one trials (8 phases I, 3 phases 

I/II and 10 phases II), testing 9 different drugs, have been selected, 

including 915 patients. The median follow-up varied from 1.4 to 34.0 

months. The estimated pooled IR of all toxicities was 68.6 [53.5-88.0] per 

1000 person-months of follow-up, compared to 20.7 [17.6-24.1] on ST 

(p�0.001). The pooled IRs of thrombocytopenia, neutropenia or leucopenia, 

fatigue, gastrointestinal events and treatment-related deaths are 11.2 

[7.5-16.9], 9.0 [6.1-13.4], 6.4 [4.1-10.0], 5.5 [2.9-10.2] and 3.2 

[1.6-6.4], compared to 4.1 [2.8-5.8], 4.9 [3.5-6.6], 4.6 [3.2-6.4], 0.8 

[0.3-1.6] and 0.1 [0.0-0.6], respectively, on ST. Median survival times are 

7.7 [6.1-9.8] and 13.8 months [11.9-16.1] on TT studies, and 6.9 

[5.8-8.2] and 14.6 [13.2-16.8], on ST, for PFS and OS, respectively, 

without statistically significant difference (p�0.39 and 0.55). The heterogeneity 

among specific toxicities and survival endpoints may be partially 

explained by the study design and/or the intake or not of temozolomide. 

Conclusions: The use of TT combined to RT represented a significative 

increase in severe adverse events in patients with GBM compared to ST, 

whereas no significant difference was observed in survival endpoints. 

Grants from French Cancer League. 



Microarray genomic expression (MAGE)-based therapy for heavily pretreated 

patients with metastatic solid tumors. Presenting Author: Joseba 

Rebollo, Plataforma de Oncología, USP-Hospital San Jaime, Torrevieja, 

Spain 

Background: Oligonucleotide-MAGE assay to identify tumor targets and 

potential active drugs based on molecular profiling in chemotherapy 

resistant/refractory (R/R) patients with metastatic solid tumors. A potential 

clinical benefit has been observed by Von Hoff et al (JCO 2010;20:4877- 

83). Methods: Patients (pts) with R/R metastatic solid tumors were 

included in the study. Pathology confirmed fresh-frozen biopsies were 

obtained and molecular profiling oligonucleotide-MAGE (Agilent Whole 

Human Genome 4x44K) results, confirmed whenever possible by IHC, were 

used to identify potential therapy targets. Results were discussed and 

offered to pts and the response evaluated using RECIST criteria. OS and 

PFS were measured from the beginning of therapy. All pts signed informed 

consent. Results: From August 2010 we performed 70 procedures in 69 

pts. No complications derived from the biopsy were observed. Thirty pts did 

not follow therapeutic recommendations and 9 pts are too early to evaluate. 

Thirty procedures from 29 pts are clinically evaluable. Ten pts were male 

and 19 female, with a median (M) age of 57 years (range 41-70). Seven pts 

had breast cancer, 5 NSCLC, 5 pancreas, 4 CRC, 2 ovary and one each of 

gastric, parotid gland, biliary tree, head and neck, esophagus and gallbladder 

cancers, respectively. The M previous treatments were 3 (range 1 to 

�6). Oligonucleotide-MAGE assay confirmed resistance in 82% of drugs 

previously used. AMof3conventional (range 0-5) and 2 experimental 

(range 0-4) potentially active drugs were identified. Partial response was 

observed in 7 (26.9%), stable disease �2 months in 12 (46.1%) and 

progression in 7 (26.9%) pts. Four pts were not evaluable. MPFS was 4 

months (95%CI: 1.815-6.185), MOS was 6 months (95%CI: 3.4-8.6) and 

1-year projected OS was 21%. Conclusions: We confirmed that it is possible 

to identify new potentially active drugs in heavily pretreated solid tumor pts 

with oligonucleotide-MAGE assay. Therapy based on these drugs showed to 

be active in one fourth of treated pts. These assays might be also integrated 

in early tumor stages to aid in the selection of chemotherapy drugs, and for 

this reason deserve further studies. Updated results will be presented. 


Feasibility to obtain a chemogram in circulating tumorigenic cells to guide 

further treatments in refractory solid tumors. Presenting Author: Antonio 

Cubillo, START-Madrid, Centro Integral Oncológico Clara Campal, Madrid, 

Spain 

Background: Circulating tumorigenic cells (CTCs) may be responsible for 

tumor progression, represent a new source of information of tumor biology, 

avoiding unnecessary biopsies. Gene-expression analysis (GEA) of CTCs 

could guide anti-cancer therapies in patients with refractory solid tumors. 

Methods: Pts �18y ECOG PS 0-2 with advanced refractory solid tumors 

were recruited. Twelve ml blood samples were collected from each pt and 

processed for isolation of CTCs using a novel cell adhesion assay (Vita-Cap, 

Vitatex Inc., Stony Brook, NY) following the manufacturer protocol. Total 

RNA was extracted with RNeasy Mini Kit (Qiagen Inc.) and GEA was 

performed with Affymetrix GeneChip Human Genome U133 Plus 2.0 array. 

The CEL file obtained for each pt sample was used in a gene-set expression 

analysis (GSEA) to determine the enrichment profile of the pt sample to a 

pre-determined set of 12 PGx-modeled drugs created from the GI50 data of 

the NCI-60 cell lines. The drug with the highest Normalized Enrichment 

Score (NES) obtained from the GSEA was selected as the most sensitive. 

The NES for each drug was standardized and rank-ordered according to 

Sensitive/Intermediate/Resistant categories to generate a nominal chemosensitivity 

profile for the pt. This generates a comprehensible report called 

chemogram (ChG). We assessed preliminary efficacy in pts treated based 

on ChG. Results: ChG was obtained in 74/75 pts (57% male/43% female, 

median age 57y [20-81]) Tumor’s type was GI 67% (CRC n�18; 

pancreatic n�18; gastric n�6; cholangiocarcinoma n�7), NSCLC 14%, 

breast 8%, sarcoma 8%, others 3%. Median of 2 previous lines of therapy 

[range 1-12]. ECOG PS was 1 in 56%. Average RNA/pt 2.4 ng/�l (95% CI 

1.5-3.4) Median time to obtain the report from blood extraction was 4 wks 

[range 2-7] Pts treated after the ChG were 37 (49%), of them 25 (69%) 

based on ChG recommended drug. In patients treated with ChG sensitive 

drugs, PFSratio � 1.3 (PFS on therapy after ChG/PFS on prior therapy) was 

24%, and 3 partial responses (12%) were observed. Conclusions: It is 

feasible to generate a sensitivity drug profiling on CTCs which shows 

preliminary activity and merits further studies. 


189s 


High concordance for MammaPrint 70 genes by RNA next generation 

sequencing. Presenting Author: Lorenza Mittempergher, Netherlands Cancer 

Institute (NKI-AVL), Amsterdam, Netherlands 

Background: The development of new biomarkers often requires fresh 

frozen (FF) samples. Recently we showed that microarray gene expression 

data generated from FFPE material are comparable to data extracted from 

the FF counterpart, including known signatures such as the 70-gene 

prognosis signature (Mittempergher L et al., 2011). As described by Luo et 

al (2010) RNA profiling using next generation sequencing (RNA-Seq) is 

now applicable to archival FFPE specimens. Methods: Technical performance 

and the comparison between the RNA-Seq 70-gene read-out and 

the MammaPrint test (Glas et al., 2006) is evaluated in a series of 15 

patients (11/15 with matched FFPE/FF material). RNA-Seq was carried out 

using minor adjustments of the Illumina TruSeq RNA preparation method. 

RNA sequencing libraries were prepared starting from 100ng of total RNA. 

Next, the DSN (Duplex-Specific Nuclease) normalization process was used 

to remove ribosomal RNA and other abundant transcripts (Luo et al, 2010). 

The libraries were paired-end sequenced on the Illumina HiSeq 2000 

instrument with multiplexing of 4 libraries per lane. The resulting sequences 

were mapped to the human reference genome (build 37) using 

TopHat 1.3.1(Trapnell et al., 2009). The HTSeq-count tool was used to 

generate the total number of uniquely mapped reads for each gene. Results: 

Between 14% and 45% of the total number of reads were assigned to 

protein-coding genes. The minimum coverage per 1000bp of CDS was 38 

reads. The 70 MammaPrint genes were successfully mapped to the 

RNA-Seq transcripts. We calculated the Pearson correlation coefficient 

between the centroids of the original good prognosis template (van’t Veer et 

al., 2002) and the 70-gene read count determined by RNA-Seq of each 

sample. Predictions based on the 70-gene RNA-Seq data showed a high 

agreement with the actual MammaPrint test predictions (�90%), irrespective 

of whether the RNA-seq was performed on FF or FFPE tissue. 

Conclusions: New generation RNA-sequencing is a feasible technology to 

assess diagnostic signatures. 


ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results 

from a first-in-human phase I study. Presenting Author: Carla D. Kurkjian, 

University of Oklahoma Health Sciences Center, Oklahoma City, OK 

Background: ME-143, a second generation isoflavone-derived compound, 

specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting 

in prompt apoptosis via pleotrophic caspase activation. A first generation 

compound, phenoxodiol (PXD), showed promising phase II activity 

with cisplatin in ovarian cancer. ME-143 is broadly active against human 

cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than 

PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/ 

kg) showed no STD level. The only significant findings were dose dependent 

hypospermia and testicular atrophy in rats. We report clinical and PK 

results from the first-in-human phase I study. Methods: A 3�3 dose 

escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg 

IV over 30 minutes weekly times 3, followed by a 1 week break, and then 

continuous weekly dosing in patients with advanced solid tumors. Dense 

PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 

300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first 

treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each 

of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). 

Five patients have discontinued protocol therapy, all due to PD. No DLT’s 

have been observed. Related AE’s include grade 1: myalgia (1), anorexia 

(1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: 

fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table 

below. Conclusions: ME-143 appears to be well tolerated when administered 

IV. Preliminary PK data suggest that drug levels achieve target 

concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/ 

mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, 

including the final pharmacokinetic analysis and planned phase II dose, 


Day 1 Day 15 

Dose 

2.5mg/kg 5.0mg/kg 2.5mg/kg 5.0mg/kg 

Cmax (mg/mL) 

T1/2 (hr) 

AUC0-t (mg*hr/mL) 

CL (L/hr) 

2.18 

4.12 

2.93 

69.73 

8.65 

6.95 

9.92 

37.30 

3.55 

4.36 

3.53 

56.18 

5.31 

5.55 

7.29 

41.52 




Integrated next-generation sequencing and patient-derived xenografts to 

personalized cancer treatment. Presenting Author: Elena Garralda, Clinical 

Research Programme. Spanish National Cancer Research Center (CNIO), 

Madrid, Spain 

Background: The knowledge of actionable somatic genomic alterations 

present in each tumor is making possible the era of personalized cancer 

treatment. Methods: Using massively parallel sequencing we performed 

whole exome sequencing analysis of tumor and matched normal blood 

samples of 8 patients (2 pancreatic adenocarcinoma, 1 neuroendocrine 

tumor, 1 glioblastoma, 1 uveal melanoma, 1 colon cancer) to identify 

putatively actionable tumor specific genomic alterations. We used 2 in 

silico methods (Polyphen and SIFT) to estimate the functional significance 

of a given confirmed mutation. Primary xenografts (PDX), generated by 

direct engraftment of tumor samples from the patients into immunocompromised 

mice, were used as an in vivo platform that provided the opportunity 

to test proposed personalized medicine strategies. Results: At this time 

exome sequencing analyses have been performed for 5 patients (1 patient 

died prematurely, 1 tumor sample was insufficient, 1 result is pending). 

More than 30 million bases of target DNA were analyzed in the tumor and 

normal samples in every case, with at least 70 distinct reads at each base. 

Tumor specific mutations (Muts) and copy number variations (CNVs) were 

identified: 5 Muts in the neuroendocrine tumor; 62Muts/6CNVs and 

38Muts/10CNVs in the pancreatic tumors; 63Muts/23CNVs in the glioblastoma; 

5 Muts in the melanoma. All samples profiled contained actionable 

alterations with the most relevant mutations affecting NF1, PTPN11, 

EPHA3, CDKN2A, FAS (glioblastoma); PI3KCA, ARID1A, ARID1B, DDR2, 

SMAD4, TP53, KRAS, PTCHD3 (pancreatic); CREB3L3, ITPR2 (neuroendocrine); 

GNA11, TAOK3 (melanoma). PDX from the pancreatic cancer 

patient was treated with a PI3K inhibitor and dasatinib, reported to be 

effective in discodin domain receptor 2 (DDR2) mutant cancer with no 

effect. Accordingly treatment of that patient with dasatinib was not 

effective and the level of this mutation in the tumor was observed to be low. 

Conclusions: Detection of actionable tumor-specific genomic alterations in 

the clinical setting is feasible. In silico methods and primary xenografts can 

help in the challenge of linking confirmed mutations to protein function 

and ultimately to clinical utility. 


OM-RCA-01, an FGFR1 specific humanized antibody for the treatment of 

renal cell carcinoma (RCC). Presenting Author: Ilya Tsimafeyeu, Kidney 

Cancer Research Bureau, Moscow, Russia 

Background: Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a 

potential therapeutic target for the treatment of metastatic RCC. We 

investigated the preclinical activity of OM-RCA-01, a novel therapeutic 

humanized anti-FGFR1 antibody with high affinity (Kd of 1.59 nM), in 

RCC. Methods: To assess the effect of anti-FGFR1 antibody on FGFmediated 

signaling, the human renal carcinoma Caki-1 FGFR1-expressing 

cells were dosed with OM-RCA-01 at 100, 10, and 1 mcg/ml. Control wells 

were left untreated. Three hours after dosing, bFGF was added at a 

concentration of 50 ng/ml. Additional control wells were treated with 

OM-RCA-01 without FGF-stimulation. Cell growth inhibition was determined 

using Promega’s Cell Titer-Glo assay. CR female NCr nu/nu mice 

were set up with 1 mm3 Caki-1 tumor fragments sc in flank. Tumor sizes 

were measured in a blind fashion twice a week with a vernier caliper. Mice 

with established tumors were randomly divided into vehicle, non-specific 

IgG or OM-RCA-01 groups per 10 animals in group. Endpoint was 

significant differences in tumor growth delay. Results: In vitro study showed 

that bFGF increased proliferation of the human FGFR1-expressing renal 

carcinoma cells (p�0.011). OM-RCA-01 antibody significantly inhibits 

FGF-triggered cell proliferation in comparison with control. In vivo, the 

tumors in untreated mice or mice treated with non-specific IgG continued 

their aggressive growth to reach the size of 2000 cm3, at which point the 

mice were killed. In contrast, treatment with OM-RCA-01 not only significant 

arrested further growth of the tumors (p�0.006) but also demonstrated 

differences in tumor volume compared with vehicle already on Day 

13. A similar anti-tumor activity of OM-RCA-01 was observed when the 

antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (p�0.917). 

Administration of 10 mg/kg antibody for up to 35 days resulted in minimal 

body weight loss and no observations of gross toxicity were made. 

Conclusions: Targeting FGFR1 blocks FGF/FGFR1 pathway in RCC. Monoclonal 

antibody OM-RCA-01 has significant early anti-tumor efficacy in 

Caki-1 xenograft model. Isolated blocking of FGFR1 by low-dose antibody 

could be safe and effective. 


CD30 expression in nonlymphomatous malignancies. Presenting Author: 

Jeff Porter Sharman, Willamette Valley Cancer Institute and Research 

Center, Eugene, OR 

Background: CD30 is commonly expressed in Hodgkin lymphoma (HL), 

anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma. 

Expression of CD30 in other solid tumors and non-lymphomatous 

malignancies has been reported but not investigated systematically. CD30 

is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate 

(ADC) that is approved for the treatment of patients with relapsed HL and 

systemic ALCL after failure of other therapies. A study was initiated to 

determine the incidence of CD30 expression in non-lymphomatous malignancies 

and to identify patients who may be candidates for treatment with 

brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies 

were eligible for screening if they were relapsed or refractory to 

previous therapy or had no effective treatment options available. Archived 

tissue from solid tumors was tested for CD30 expression by immunohistochemistry 

(IHC); fresh bone marrow or blood samples from multiple 

myeloma or leukemia patients were tested by flow cytometry. Patients were 

considered CD30 positive and eligible for a companion treatment protocol 

with brentuximab vedotin if �10% of malignant cells stained positive by 

IHC or �20% by flow cytometry. Results: At this interim analysis, a total of 

875 patients have been tested for CD30 expression: 95% had solid tumors, 

3% had leukemia, and 2% had multiple myeloma. Twenty-two patients 

(2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer 

(7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of 

4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative 

breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with 

small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid 

carcinoma (33%). One patient was identified with CD30-positive mast cell 

leukemia. In positive patients, the percent of CD30-positive malignant 

cells varied between 10 and 80%. Conclusions: CD30 expression was 

observed in multiple types of non-lymphomatous malignancies, thereby 

identifying additional populations who may be candidates for treatment 

with a CD30-targeted ADC, such as brentuximab vedotin. A companion 

clinical trial with brentuximab vedotin is currently ongoing. 


Clinical significance of PRL-3 genomic amplification/expression profiles 

and preclinical study of PRL-3 inhibitor in human gastrointestinal cancers. 

Presenting Author: Keishi Yamashita, Kitasato University School of Medicine, 

Sagamihara, Japan 

Background: PRL (phosphatase of regenerating liver) is a tyrosine phosphatase 

that dephosphorylates molecules involved in cancer invasion and 

metastasis and subsequently activates either PI3 kinase or Src pathway. 

PRL-3 was initially identified as a gene that is amplified in metastasis of 

colorectal cancer. We are thinking much of clinical potential of PRL-3 

inhibitor as a molecular targeted therapy in GI cancer. Methods: Immunohistochemistry 

and genomic status were assessed for PRL-3 in esophageal 

squamous cell carcinoma (ESCC)(n�88), gastric adenocarcinoma (n�173), 

and colorectal adenocarcinoma (n�107).RNA interference was used to 

determine its specific functional roles in GI cancers. Preclinical study using 

PRL-3 inhibitors (1-4-bromo-2-benzylidene rhodanine) was performed in 4 

ESCC and 4 gastric cancer cell lines that were intensely expressed for 

PRL-3, or TE5 which showed basal level expression. Results: (1) PRL-3 

expression is associated with lymph node metastasis in primary ESCC 

(p�0.0012), gastric adenocarcinoma (p�0.0001), and colorectal carcinoma 

(p�0.0001). In the primary tumors with lymph node metastasis, its 

expression was recognized in 96, 80, 86%, respectively. (2) If restricted to 

patients with PRL-3 expression, genomic amplification was found exclusively 

in stage IV ESCC (30%), and stage III/IV gastric cancer (40%). In 

colorectal cancer, PRL-3 genomic amplification is found in 35% of stage 

III/IV, but only in 10% of stage II (p�0.002). (3) PRL-3 RNA interference 

robustly suppressed metastatic cancer phenotypes. (4) PRL-3 inhibitor 

suppressed phenotypes as well in a dose dependent manner (0, 1, 10, and 

50 mM). Interestingly, 10 mM of the inhibitor could not suppress muscle 

cell (C2C12) that endogenously express PRL-3, but 50 mM suppressed it. 

Conclusions: PRL-3 inhibitor has a great clinical potential to suppress 

tumors with metastatic ability, that was represented by lymph node 

metastasis or recurrent disease of GI cancers. 



Effect of MDV3100, a novel androgen receptor signaling inhibitor, on cell 

proliferation and tumor size in an apocrine breast cancer xenograft model. 

Presenting Author: Sebastián Bernales, Medivation, Inc., San Francisco, 

CA 

Background: MDV3100, a new androgen receptor (AR) signaling inhibitor, 

has demonstrated therapeutic effects in men with post-docetaxel prostate 

cancer (AFFIRM). AR is also expressed in the majority of breast cancers. 

Molecular profiling of estrogen receptor negative (ER-) breast cancer 

classifies this disease into basal and molecular apocrine subtypes. Apocrine 

breast cancer represents ~50% of ER- tumors and is characterized by 

a steroid response gene signature that includes AR expression. Here we 

report the effects of MDV3100 on the growth of the ER-/AR� breast cancer 

cell line MDA-MB-453 in tissue culture and in an in vivo xenograft mouse 

model. Methods: MDA-MB-453 cells were maintained in 5% complete or 

5% charcoal-stripped serum supplemented with dihydrotestosterone (CSS- 

DHT). The DHT induced nuclear translocation of AR was determined by 

subcellular fractionation followed by western blot. AR target gene expression 

was measured by qPCR. To generate a mouse xenograft model, 5-6 wk 

old female NOD-SCID-IL2Rgc–/– mice were injected ortotopically with 

6x106 MDA-MB-453 cells into the fourth inguinal gland and were administered 

exogenous DHT (12.5 mg in a 60 day release pellet) or control pellets. 

When tumor size reached 100 mm3 , mice were treated with 10 mg/kg/day 

MDV3100 or vehicle (0.5% methocel solution) by oral gavage for 33 days. 

Results: Viability of MDA-MB-453 cells treated with 10 uM MDV3100 was 

reduced by 10% after 3 days and 27% after 6 days. Treatment with 25 uM 

MDV3100 reduced cell viability by 27% after 3 days and 36% after 6 days. 

Similar results were obtained when cells maintained in CSS-DHT were 

treated with MDV3100. Treatment with MDV3100 blocked DHT-induced 

nuclear translocation and concordantly reduced the expression of ARtargets 

fatty acid synthase, prolactin receptor, and gross cystic disease 

protein-15. In the xenograft model, MDV3100 inhibited tumor growth by 

78% as compared to tumors treated with vehicle. Conclusions: MDV3100 

reduced cell proliferation in apocrine cell lines. MDV3100 also suppressed 

exogenous DHT-induced growth of ER-/AR� tumors in vivo. These results 

support the evaluation of MDV3100 as a treatment for apocrine tumors. 


Targeted therapies for the treatment of non-small cell lung cancer: Bull’s 

eye or missed target? Presenting Author: Shakun M. Malik, U.S. Food and 

Drug Administration, Silver Spring, MD 

Background: Targeted drugs approved for advanced non-small cell lung 

cancer (NSCLC) include bevacizumab [(monoclonal antibody directed 

against vascular endothelial growth factor-A (VEGF-A)], erlotinib [(an 

epidermal growth factor receptor kinase (EGFR) inhibitor)] and crizotinib 

[(an anaplastic lymphoma kinase (ALK) inhibitor)]. The development 

programs for erlotinib and bevacizumab did not prospectively employ in 

vitro diagnostic tests to select patients (pts). Post-hoc exploratory analyses 

for bevacizumab based on VEGF-A levels have not identified subgroups with 

differential treatment effects: however for erlotinib, pts with activating 

EGFR mutations had greater improvement in overall response rates (ORR) 

and progression-free survival. Crizotinib is the first targeted therapy for 

NSCLC in which pts were selected using an analytically validated investigational 

test for ALK translocations. Crizotinib received accelerated approval 

on August 26, 2011 for the treatment of pts with locally advanced or 

metastatic ALK-positive NSCLC as detected by an FDA-approved test (Vysis 

ALK Break Apart FISH Probe Kit) that was approved by FDA on the same 

day. Methods: NDA file for crizotinib was examined. Results: Two single arm 

trials assessing efficacy of crizotinib monotherapy in ALK positive pts 

showed ORR of 61% and 50%. At FDA’s request, a cohort of 23 pts that 

tested negative for the ALK translocation evaluated showed ORR of 26%. 

Two additional pts had a single assessment and, if confirmed, the response 

rate would be 37% in this “marker negative” subgroup. Further exploration 

of this subgroup is a postmarketing commitment. Conclusions: Evaluation 

of target status (positive or negative) in all pts provides optimal information 

to guide clinical practice. As observed with crizotinib, responses may be 

observed in the “marker negative” subgroup. This unexpected finding may 

reflect the drug’s activity via alternate pathways, selection of a suboptimal 

biomarker for assessing ALK activation, or selection of a suboptimal 

cut-point for positive/negative. Accurate diagnostic tests will facilitate drug 

development with possible greater observed treatment effect and potentially 

smaller clinical trials. 



Inhibition of autophagy: Phase I safety, tolerability, and pharmacokinetics 

(PK) of hydroxychloroquine (H) in combination with vorinostat (V) in 

patients with advanced solid tumors. Presenting Author: Devalingam 

Mahalingam, Institute for Drug Development, Cancer Therapy and Research 

Center, University of Texas Health Science Center at San Antonio, 

San Antonio, TX 

Background: The histone deacetylase (HDAC) inhibitor V has pleiotropic 

effects, and induces both apoptosis and autophagy. As autophagy can 

promote cancer cell survival, we hypothesized that inhibiting autophagy 

would enhance the anti-cancer activity of V. Our pre-clinical studies 

showed that inhibition of autophagy using H significantly increased the 

pro-apoptotic effects of V. The primary objective of this NCI-funded study 

was to determine the maximum tolerated dose (MTD) of H in combination 

with V in patients (pts) with advanced solid tumors. Methods: Pts with ECOG 

PS 0-2 and adequate organ function received PO V 300-400 mg QD and H 

400-1000 mg QD in 21d cycles. 3�3 dose escalation. Dose limiting 

toxicities (DLTs) � non-hem toxicity � grade (Gr) 3 or hem toxicity � Gr 4 

in the first 2 cycles. PBMCs were analyzed for autophagic changes at 

baseline, week 1 � 6. PKs done on cycle 1.Tumor biopsies were performed 

at baseline and post-cycle 2 on 3 pts at MTD. Results: 31 pts enrolled, 27 

evaluable for DLT. No DLT was observed in cohort 1 (300 mg V/400 mg H) 

or cohort 2 (400 mg V/400 mg H). In cohort 3 (400 mg V/600 mg H) 1/6 

pts experienced a DLT of Gr 3 fatigue. Cohort 4 (400 mg V/800 mg H) 3/6 

pts had DLT of Gr 3 fatigue, and 1 had a Gr 2 seizure. Expansion of cohort 3 

resulted in no further DLTs. 10 pts got the MTD. Treatment-related 

toxicities were mostly Gr 1- 2: nausea/vomiting (10 pts), diarrhea (7), 

fatigue (5), anorexia (4), weight loss (3), anemia (4), elevated creatinine 

(4) and thrombocytopenia (2). Gr 3 toxicities were fatigue (4), anemia, 

thrombocytopenia and neutropenia (1 each). No drug-related deaths or Gr 

4 toxicities were noted. One pt (RCC) had a confirmed PR (cohort 2 active 

on cycle 32) and 2 pts with CRC had prolonged SD (�4 cycles). PK analysis 

indicated dose-proportional exposure for H. Changes from baseline in 

biomarkers of autophagy and HDAC inhibition were observed in PBMC and 

primary tumors with therapy. Conclusions: Recommended dose is V 400 

and H 600 mg QD. Dose-dependent fatigue was observed with the 

combination, but well tolerated at the MTD without any further increase in 

toxicities compared to V alone. Analyses of PK-PD interactions are 

underway. 


Translational assessment of the efficacy of CPI-613 against pancreatic 

cancer in animal models versus patients with stage IV disease. Presenting 

Author: Avi S. Retter, Eastchester Center for Cancer Care, Bronx, NY 

Background: CPI-613 is a novel agent that selectively targets the altered 

mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and 

autophagia. Results assessing clinical efficacy of CPI-613 translated from 

animal tumor xenograft models to patients with stage IV pancreatic cancer 

are presented. Methods: Efficacy of CPI-613 was tested in mice with 

pancreatic tumor xenografts generated by inoculation of BxPC-3 human 

pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320 

mg/m2 ), when used in combination with gemcitabine (1,000 mg/m2 ), was 

assessed in patients with stage IV pancreatic cancer. Results: In the animal 

pancreatic tumor xenograft model (n�10/grp), CPI-613 (25 mg/kg, IV, 1x 

weekly for 4 weeks) suppressed tumor growth by ~100%, when compared 

to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4 

weeks), suppressed tumor growth by only ~50%. Median overall survival in 

tumor-bearing mice treated with CPI-613 was ~240 days, which was 

significantly longer than those with gemcitabine or vehicle treatments (~65 

and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer 

(Table), the CPI-613�gemcitabine combination was well-tolerated. In 

those without prior chemotherapy before participating in the clinical trial 

(first three patients in the table), the CPI-613�gemcitabine combination 

prolonged survival that correlated with the dose of CPI-613. Conclusions: 

CPI-613 exhibits efficacy against pancreatic cancer in animal models, 

which is translational to patients with stage IV disease. 

Patients with stage IV pancreatic cancer. 

ID# Sex Age Race/ethnicity 

Chemotherapy prior to 

study participation 

CPI-613 dose a 

(mg/m 2 ) 

191s 

Survival b 

(months) 

1-106 M 52 Hispanic None 70 4.1 

1-110 F 65 Caucasian None 150 7.5 

1-113 F 77 African American None 190 �22 (still alive) 

1-107 M 63 Caucasian Gemcitabine 105 9.8 

1-111 F 76 African American 5-FU; gemcitabine; 

FOLFOX � transferrinlaced 

oxaliplatin 

150 11.3 

2-107 M 65 Caucasian Gemcitabine � erlotinib; 

Xenoda � oxaliplatin 

320 �10 

Abbreviations: f � female; ID � identification; M � male; mo � month. a CPI-613 was given in 

combination with gemcitabine (1,000 mg/m 2 ). b Survival was measured since the start of first 

chemotherapy the patient received. 




A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) 

with advanced solid tumors. Presenting Author: Tae Min Kim, Department 

of Internal Medicine, Seoul National University Hospital, Seoul, South 

Korea 

Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which 

showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR 

L858R/T790M double mutant cells. A phase I study was conducted to 

determine the MTD, pharmacokinetics, and antitumor activity. Methods: 

Eligible pts had advanced malignancies refractory to standard therapies. 

Standard 3�3 scheme was used in the dose escalation part, and additional 

12 pts were enrolled in the expansion cohort of molecular enrichment. 

Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), 

M:F�25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) 

were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 

mg, and two at 32 mg. The MTD was determined as 24mg. The most 

common drug-related adverse events were diarrhea, stomatitis, rash, 

pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 

unconfirmed, duration of response: 11.9 mo, 7.07 mo�, 4.5 mo�), and 

19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The 

median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) 

months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics 

proportional to dose-escalation, relatively short half-life, and little 

accumulation. Additional 12 pts in the expansion cohort are under 

treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive 

gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). 

Conclusions: HM781-36B was safe and well tolerable in advanced solid 

tumors. Preliminary evidence of anticancer activity has been observed. 

Updated data will be presented at the meeting. 


Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients 

with advanced malignancies and varying levels of liver dysfunction: S0711, 

a SWOG early therapeutics committee study. Presenting Author: John 

Sarantopoulos, Institute for Drug Development, Cancer Therapy and 

Research Center, University of Texas Health Science Center San Antonio, 

San Antonio, TX 

Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits 

BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, 

Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use 

in imatinib resistant CML. It is a small molecule targeted therapy 

hepatically metabolized primarily by CYP3A4. We conducted a phase I 

study to determine maximum tolerated dose (MTD) and pharmacokinetics 

(PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with 

advanced solid tumors or lymphoma, Zubrod �2, no baseline ascites or 

pleural effusions, adequate renal and bone marrow function, received PO D 

daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, 

moderate, severe, using Child-Pugh classification (CPC). Data also collected 

for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was 

escalated in sequential cohorts of pts within each LD category. Blood 

analysis for D concentrations were determined during cycle 1 using a 

validated LC-MC/MS assay. Study objectives included characterizing safety, 

tolerability, PK, identifying the MTD and obtaining preliminary evidence of 

efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses 

starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%, 

Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13, 

severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia 

27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural 

effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history 

of similar episode with previous sorafenib. Previous linear PK disposition, 

and no accumulation. No apparent PK differences between normal and 

mild groups. Cycle 1 Day 1 D 140 mg Normal Group: Cmax 129 ng/mL. Mild 

Group 140mg: Cmax 157 ng/mL. Prolonged disease stabilization (�4 

cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6). 

Conclusions: Recommended dose for Dasatinib given PO QD for pts with 

mild, moderate, or severe LD using clinical criteria with CPC and no 

baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose 

adjustment not necessary in pts with mild LD. 


Tumor drug distribution and target engagement of MLN9708, an investigational 

proteasome inhibitor, in patients with advanced solid tumors. 

Presenting Author: Alessandra Di Bacco, Translational Medicine, Millennium 

Pharmaceuticals, Inc., Cambridge, MA 

Background: MLN9708 is a potent investigational proteasome inhibitor, 

which upon intravenous (IV) administration immediately hydrolyzes to the 

active form MLN2238. MLN9708 is currently being evaluated in a phase 1 

trial in solid tumors (NCT00830869). This trial has a dose-escalation arm 

and five expansion cohorts: non-small cell lung cancer (NSCLC), soft tissue 

sarcoma, head and neck cancer, prostate cancer, and a tumor biopsy cohort 

of mixed histology. The purpose of the tumor biopsy cohort was to obtain 

pre- and post-dose biopsies to determine drug distribution and target 

engagement in post-dose tumor samples. The latter was measured by the 

increase in levels of ATF-3, a marker of unfolded protein response/ 

endoplasmic reticulum stress, which is upregulated in response to proteasome 

inhibition. Methods: The tumor biopsy cohort included 20 patients 

dosed at the maximum tolerated dose who consented to core needle 

biopsies during screening and after either the first or second dose of 

MLN9708 (IV 1.76 mg/m2 ; 4–20 hours post-dose). Tumor biopsies were 

individually weighed, homogenized, and analyzed for the presence of 

MLN2238 using a quantified LC/MS/MS methodology. ATF-3 levels in 

tumors were determined by an immunohistochemical assay (IHC) on six 

sections for each tumor biopsy. Tumor area was identified using Aperio 

Genie, a machine learning program for pattern recognition, and the 

percentage of ATF-3 positive area in the tumor was measured. Results: 

Biopsies from 20 patients were collected for assessment of drug distribution 

and target engagement. Ten patients with paired pre- and post-dose 

biopsies of sufficient size were considered evaluable for PK analysis; 

MLN2238 was present in all 10 (100%) post-dose biopsies analyzed. 

Tumor pairs from 7 patients passed quality control by H&E staining for 

tumor content and were evaluable for ATF-3 IHC. Six of 7 paired samples 

(86%) showed a statistically significant (p�0.05) increase in post-dose 

ATF-3 levels. Conclusions: Overall, emerging data from MLN9708 phase 1 

solid tumor analysis show that MLN2238 is present in tumors and 

demonstrates target engagement upon inhibition of the proteasome in 

tumor tissue biopsies. 


Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor 

targeted multi-kinase inhibitor, administered orally BID to patients with 

advanced solid tumors. Presenting Author: Toshihiko Doi, National Cancer 

Center Hospital East, Kashiwa, Japan 

Background: Golvatinib is a highly potent, small molecule ATP-competitive 

inhibitor of the c-Met receptor tyrosine kinase and multiple members of the 

Eph receptor family as well as c-Kit and Ron, based on isolated kinase 

assays. Golvatinib showed antiproliferative activity in human cancer 

xenograft models, warranting further investigation in the clinical setting. 

Methods: Japanese patients (pts) with advanced solid tumors that had 

progressed after approved therapy received oral golvatinib at escalating 

doses of 50 to 100, 200 and 300 mg administered twice daily (BID) in 

conventional 3 pt cohorts. The primary objective was to determine the MTD 

of golvatinib when administered continually BID. The secondary objectives 

were to evaluate the safety, PK, PD biomarkers, and efficacy. Results: 16pts 

were enrolled (8 M, 8 F; med age 59 years; ECOG 0-1). Tumor types were 

colorectal (5), gastric (4) and others (7). One DLT (Gr 3 ALT increase) and 1 

equivalent DLT (Gr 2 vomiting, nausea and anorexia) appeared in 2 pts in 

the 300 mg BID cohort and the dose escalation was terminated. The MTD 

was determined to be 200 mg BID. Frequently observed adverse drug 

reactions were proteinuria [50.0% (8/16)], ALT increased [43.8% (7/16)], 

AST increased, nausea, vomiting [37.5% (6/16)], and blood alkaline 

phosphatase increased, decreased appetite, diarrhea, leukopenia [31.3% 

(5/16)], which were all mild to moderate in severity with � Gr 2. No related 

severe adverse event was observed. Responses included 4 stable diseases 

(84-113 days) in 3 pts with gastric cancer and 1 patient with NSCLC, 11 

progressive diseases, and 1 non evaluable. The golvatinib plasma concentration 

after first-dose reached Cmax at a median time of 2 to 4 hours, and 

declined bi-exponentially with a t½ of approximately 40 hours. Cmax and 

AUC0-inf increased with dose. Analysis of blood PD biomarker showed a 

significant increase in soluble c-Met levels after golvatinib treatment. 

Conclusions: The MTD of golvatinib was achieved at 200 mg BID. Golvatinib 

was well tolerated with manageable toxicities at dose levels up to and 

including the MTD. 4 of 16 pts showed stable disease after golvatinib 

treatment. 



A phase I study of ombrabulin (O) combined with bevacizumab (B) in 

patients with advanced solid tumors (NCT01193595). Presenting Author: 

Gianluca Del Conte, Fondazione IRCCS Istituto Nazionale dei Tumori, 

Milan, Italy 

Background: O is a vascular-disrupting agent derived from combretastatin 

A4-phosphate that induces rapid but transient tumor vascular shutdown. In 

experimental models, the combination of O with VEGF-blockade induced 

more regressions than O alone. This phase I study was performed to 

determine the maximum tolerated dose (MTD), and assess the overall 

safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary 

antitumor activity of O plus B. Trial is funded by sanofi. Methods: Patients 

(pt) with advanced solid tumors, ECOG PS �1, and adequate organ 

function were eligible. Increasing doses of O (mg/m²) was administered 

intravenously (IV) on day (d) 1; B (5 or 10mg/kg) was administered IV on 

d2, in 21d cycles (C). A Bayesian design was applied to determine dose 

escalation steps and MTD. PK sampling was performed in C1 and C2. PD 

sampling for circulating endothelial cells (CEC) and progenitors (CEP) were 

performed throughout. Dynamic contrast-enhanced ultrasound (DCE-US) 

to assess tumor perfusion was performed before and after C1 and C2 

dosing. Results: 25 pts (M:F 6:19; median age 49 years [range 27-75]) 

have been treated at 8 dose levels of O/B: 8/5 (3), 11.5/5 (4), 11.5/10 (3), 

15.5/10 (3), 20/10 (3), 25/10 (3); 35/10 (3) and 42/10 (3). Ovarian 

cancer was the most frequent tumor type (n�11). Median Cs received was 

3 (1 to 14). No DLTs were observed during C1. Drug-related grade (g) 3-4 

adverse events (AE) included hypertension in 2 pts (8/5; 11.5/5) and ileal 

perforation in 1 pt with peritoneal carcinomatosis at laparotomy (11.5/10). 

A case of duodenal perforation was unlikely related (25/10). Two pts with 

ovarian cancer (11.5/5; 20/10) had confirmed partial responses (4.4 

months (mo) and 7� mo). 13/23 (57%) pts with � 1 tumor assessment 

had stable disease (n�8; median 4.3 mo [1.8-9.5]; 5 ongoing). Data from 

cohorts 1 and 2 demonstrated no evidence of a PK interaction.17/25 

patients demonstrated a peak in CEC, and 7/9 patients a peak in CEP. 4/7 

DCE-US evaluable pts had �50% drop in tumor perfusion (AUC) at Day 8 

of C1. Conclusions: O combined with B is well tolerated with early evidence 

of clinical activity. The MTD has not been reached (current dose level 

50/10); cohorts of O combined with B at 15 mg/kg will be tested. 


A phase I study of R04929097, an oral gamma secretase inhibitor, in 

combination with gemcitabine in patients with advanced solid tumors 

(PHL-078/CTEP 8575). Presenting Author: Suzanne Richter, Princess 


Background: RO4929097 (RO) is an oral inhibitor of �-secretase that 

disrupts Notch signaling. Gemcitabine (GEM) is active against many solid 

tumors with a favorable toxicity profile suited to combination. The primary 

objective of this trial is to establish the recommended phase II dose (RP2D) 

of RO in combination with GEM; secondary objectives include the evaluation 

of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch 

signaling and preliminary anti-tumor activity. Methods: Patients (pts) with 

advanced solid tumors were enrolled in escalating RO dose levels (DL) as 

follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3�3 

design. Treatment with RO was administered once daily on days (d) 1-3, 

8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles 

(c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 

grade (g) 3 non-hematological or g4 hematological toxicities, failure to start 

c2 within �14 days, or failure to receive �75% doses of RO or d8 GEM in 

c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: 

As of January 2012, 15 pts (median age 55) have been treated. DLTs were: 

DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to 

receive ³75% doses); all were reversible. One death (perforated viscus) 

related to disease progression was observed. Most common g1/2 toxicities 

were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis 

(3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia 

(1) was observed beyond C1. RO PKs demonstrated comparable 

exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was 

stable disease � 4 months in 3 pts (pancreas, tracheal, breast CA). 

Conclusions: RO and GEM can be safely combined. RO levels achieved 

exceeded the AUC0-24 for efficacy in preclinical models using daily dosing. 

The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 

45mg RO is ongoing to confirm the RP2D. 

DL n 

Cmax ng/ml 

(SD) D1 

Cmax ng/ml 

(SD) D10 

AUC 0-24 

(ng*hr/mlx10 4 ) 

(SD) D1 

AUC 0-24 

(ng*hr/mlx10 4 ) 

(SD) D10 

1 3 552 (100) 615 (382) 6.8 (1.0) 9.9 (7.2) 

2 7 833 (352) 1221 (315) 12.6 (4.8) 19.2 (5.9) 

3 3 986 (153) 1315 (332) 12.8 (1.2) 16.5 (8.2) 



A phase I study to assess oral bioavailability of a novel oral soft gelatin 

capsule formulation of rigosertib (ON 01910.Na) under fasted and fed 

conditions in patients with myelodysplastic syndromes. Presenting Author: 

Azra Raza, Columbia Presbyterian Medical Center, New York, NY 

Background: Rigosertib (ON 01910.Na) is a novel multikinase inhibitor, 

with selective cytotoxic effects on tumor cells without impact on normal 

cells. Rigosertib, administered as a 3-day continuous infusion, is now 

undergoing phase 3 evaluation in higher risk MDS patients refractory to 

hypomethylating agents. Here, we report the results of the effect of food on 

the absolute bioavailability of a novel rigosertib oral formulation (soft 

gelatin capsule) in MDS patients. Methods: This was a single-dose, 

three-treatment, three-period sequential design for studying the effects of 

food on the bioavailability of an immediate-release soft gelatin capsule 

formulation. The following dosing groups were tested in 12 patients: IV 

Dose 800 mg/m2 over 24 hours and oral dose 560 mg (2 x 280 mg 

capsules) under fasting and fed conditions. The oral dose was the 

recommended phase 2 dose, as reported previously (R.S. Komrokji et al., 

Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic 

Syndrome (MDS) – Phase I Study Results. Blood 2011, 118: 

Abstract #3797). Plasma samples were collected pre-dose, and over 32 

hours (IV dose) or 8 hours (oral dose) after dose initiation. Rigosertib 

plasma levels were analyzed by a validated LC/MS/MS method. Pharmacokinetic 

parameters were estimated by noncompartmental analysis (WinNonlinÒ). 

Results: Rigosertib pharmacokinetic parameters are presented in the 

table below. The results of the present study demonstrate good oral 

bioavailability under fasting condition.Oral administration of rigosertib 

after a meal decreased Cmax and AUC by 77% and 61%, respectively, 

compared to fasting conditions. Conclusions: The results of this study 

support the potential for oral delivery of rigosertib, which could become a 

preferred therapy over a 3-day continuous intravenous infusion. 

Parameter 

800 mg/m 2 IV 

(24-hr infusion) 

Dosing group 

560 mg oral 

(fasting) 

193s 

560 mg oral 

(fed) 

C max (�g/ml) 3.14 � 1.13 2.42 � 1.26 0.56 � 0.31 

AUC (�g-hr/ml) 52.7 � 19.2 6.89 � 3.98 2.71 � 1.51 

T max (hr) 2.91 � 1.30 1.00 � 0.45 2.82 � 1.15 

t 1/2 (hr) 3.25 � 0.97 2.79 � 1.23 2.61 � 0.93 

Bioavailability (%) N/A 34.9 � 17.6 13.8 � 6.04 


A phase I dose-escalation study of the HSP90 inhibitor AUY922 and 

erlotinib for patients with EGFR-mutant lung cancer with acquired resistance 

(AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). Presenting 

Author: Melissa Lynne Johnson, Feinberg School of Medicine, Northwestern 

University, The Robert H. Lurie Comprehensive Cancer Center, Chicago, 

IL 

Background: AUY922 is a highly potent, non-geldanamycin analog, HSP90 

inhibitor that degrades mutated EGFR and MET. Preclinical studies 

demonstrate that HSP90 inhibitors have anti-tumor activity in EGFR 

mutant, EGFR TKI-sensitive and TKI-resistant lung cancer xenograft 

models. To prevent disease flare after stopping EGFR TKIs in patients (pts) 

with EGFR mutated lung cancer, erlotinib (E) is often continued with 

subsequent lines of treatment for AR. This phase I study will determine the 

maximally tolerated dose (MTD) of AUY922 and E for pts with mutated 

EGFR and RECIST progression on EGFR TKIs. Methods: All pts have EGFR 

mutant lung cancer, with development of AR (per Jackman, JCO 2010) 

after treatment with an EGFR TKI. Pts underwent repeat tumor biopsies 

after development of AR and prior to study entry. Pts receive AUY922 IV 

weekly and E oral daily in 28-day cycles, with dose escalation using 

standard 3�3 design. Pharmacokinetics, serial ophthalmology evaluations 

and weekly assessment for toxicity are required. Tumor tissue from 

re-biopsy at study entry is analyzed for EGFR T790M and MET. Results: 

Since April 2011, 11 pts have been enrolled, in 4 of 5 planned cohorts 

(AUY922 25 mg/m2 � E 75 mg; AUY922 25 mg/m2� E 150 mg; AUY922 

37.5 mg/m2� E 150 mg; AUY922 55 mg/m2�E 150 mg). Prior to 

developing AR, pts were treated with EGFR TKIs for a median of 9 months 

(range 8-32). Of 9 pts with tissue analyzed thus far, 6 had EGFR T790M. 

Pts have received a median of two cycles (range 1-7), and 5 remain on 

study. There have been no dose-limiting toxicities. Adverse events reported 

in � 20% of pts were diarrhea, nausea, vomiting, fatigue, and rash, all 

graded 1 or 2. No cardiovascular, renal or hepatic toxicities have been 

observed. Three pts have reported “flashing lights” and 2 pts transient 

night blindness, all grade 1. Dose escalation continues. No partial 

responses have been seen in 6 evaluable pts, 4 patients have confirmed 

stable disease at 8 wks. Conclusions: AUY922 and E is a well-tolerated 

combination at dose levels up to AUY922 55 mg/m2� E 150 mg. Further 

dose-escalation, MTD, and correlation with markers of AR will be reported. 

Supported by Novartis, Inc. 




Phase I and pharmacokinetic study of farletuzumab in solid tumors. 

Presenting Author: Yasutsuna Sasaki, Saitama Medical University International 

Medical Center, Saitama, Japan 

Background: Farletuzumab (F) is a humanized monoclonal antibody against 

folate receptor � (FRA). Expression of FRA is reported to be 90% and 40% 

in ovarian cancer (OC) and gastric cancer (GC), respectively. The purpose of 

the study is to assess tolerability, pharmacokinetic profile and preliminary 

antitumor effect in solid tumors. Methods: Patients with OC or FRA 

expressing solid tumor who are resistant to standard treatments are eligible 

in the study. After pharmacokinetic (PK) run-in, F was administered by IV 

injection repeating every week until disease progression. PK profile was 

analyzed on day1 to day 10 in PK run-in and on day 22 to 29 in cycle 1. 

Dose limiting toxicities (DLTs) were defined as G4 hematological and G3/4 

non-hematological toxicities by NCI-CTCAE. Dose escalation was planed in 

4 cohorts (50, 100, 200 and 400mg/m2 ). Results: Sixteen patients (14 OC 

and 2GC) received F infusion. Neither DLTs nor G3/4 toxicities were 

reported in all cohorts. As adverse events, G1/2 infusion reaction (44%), 

headache (44%), cytokine release syndrome (38%), nausea (31%) and 

appetite loss (31%) were observed and medically managed. AUC and 

Cmax.were increased dose-dependently and linear PK profiles were identified 

with median clearance between 6.02 and 10.54 mL/hr/m2 in each 

cohort. No tumor shrinkage was recorded, but long-term disease stabilization 

for 22� mos. and 10� mos. were observed in one patient with clear 

cell OC (100mg/m2 ) and one patient with GC (400 mg/m2 ), respectively. 

No cumulative toxicities were observed in these 2 patients. Conclusions: 

The toxicities of F in Japanese patients were manageable with similar PK 

profile as compared with the US population (Konner et al. Clin Cancer Res 

2010: 16; 5288-95). Long term disease stabilization is observed in 

subpopulation of clear cell OC and GC. 


Associating retinal drug exposure and retention with the ocular toxicity 

profiles of Hsp90 inhibitors. Presenting Author: Dan Zhou, Synta Pharmaceuticals 

Corporation, Lexington, MA 

Background: In clinical trials certain Hsp90 inhibitors, including AUY922, 

SNX-5422, and 17-DMAG have caused visual symptoms suggesting retinal 

dysfunction; others, including ganetespib and 17-AAG, have not. Previous 

animal toxicology experiments have suggested that retinal changes may be 

linked to photoreceptor degeneration or cell death. Here histopathologic 

changes and/or exposure profiles of Hsp90 inhibitors with or without 

clinical reports of ocular toxicity were evaluated to understand the observed 

differences in toxicity profile between agents in this class. Methods: We 

reviewed visual symptoms among subjects administered ganetespib, a 

potent Hsp90 inhibitor currently in phase II trials; evaluated retinal 

morphology in rats and cyno monkeys given ganetespib; and compared 

TUNEL-positive photoreceptors and drug exposure profiles in the retina of 

rats treated with AUY922, 17-DMAG, and 17-AAG. Studies of ganetespib’s 

retinal pharmacokinetics and photoreceptor toxicity in rats are ongoing. 

Results: AUY922 and 17-DMAG induce visual disorders in the clinic. Both 

drugs induced marked photoreceptor cell death (increased TUNEL-positive 

cells) in rats with a high retina/plasma (R/P) exposure ratio, and a slow 

elimination rate (at 6 h post-dose, over 54% of AUY922 present at 30 min 

remained in the retina). In contrast, and consistent with an absence of 

clinical visual changes, 17-AAG at the maximum tolerated dose did not 

elicit photoreceptor injury. Further, retinal elimination was rapid (at 6 h 

post-dose, 94% of 17-AAG had been eliminated from the retina, resulting 

in a low R/P ratio). Ganetespib given by 1-hour IV infusion on days 1 and 15 

of four 21-day cycles did not cause histopathological changes in the retina 

of rats or cynos. This finding is consistent with very low rate (~3%) of 

drug-related visual symptoms observed among over 300 subjects to date 

that received ganetespib in the clinic. Conclusions: Unlike AUY922 and 

17-DMAG, ganetespib is not associated with ocular toxicity in humans, 

primates, or rodents. The findings suggest that Hsp90 inhibitors may elicit 

visual disorders when associated with high retina/plasma exposure ratio 

and lower retinal elimination rate. 


Phase IB study of an all-oral chemotherapy regimen, tesetaxel plus 

capecitabine, in patients with advanced solid tumors. Presenting Author: 

Michael Gary Martin, The West Clinic, Memphis, TN 

Background: Tesetaxel is a novel oral taxane that is not a substrate for 

P-glycoprotein, does not cause hypersensitivity, and may cause less 

neurotoxicity. The anticancer activity of tesetaxel exceeds other taxanes in 

various cell lines and xenografts. Phase II studies showed overall response 

rates [ORRs] of 50% and 38% in patients (pts) treated for 1st- and 2nd-line breast cancer, respectively, and 20% in pts with 2nd-line gastric cancer. 

Neutropenia was dose-limiting, and the maximally tolerated dose (MTD) 

was 27 mg/m2 once every 3 weeks. Capecitabine, an oral fluoropyrimidine, 

is commonly used for treatment of breast and gastric cancer. While the 

approved capecitabine dose is 2500 mg/m2 /day x 14 days, most pts are 

unable to sustain treatment at this dose due to hand-foot syndrome (HFS). 

A prior PK study suggested that short courses of tesetaxel could be 

combined with capecitabine at the recommended MTDs of both drugs with 

non-overlapping adverse events (AEs) (Cancer Chemother Pharmacol. 

68:1565, 2011). We conducted a phase IB study of the tesetaxel/ 

capecitabine regimen in pts using lower doses of capecitabine to confirm a 

tolerable combination dose for extended treatment. Methods: Eligibility 

included: solid tumor treated with � 1 line of chemotherapy; no prior 

taxane exposure; adequate organ function; ECOG PS � 1. Pts received 

tesetaxel 27 mg/m2 on Day 1 and capecitabine 1500-2000 mg/m2 /day (in 

divided doses on Days 1-14) every 3 weeks. Results: To date, 10 pts have 

been treated. AEs were largely Grade 1-2 (83%) and consistent with those 

for each drug as a single agent. Grade 3-4 neutropenia occurred in 3 pts 

(30%) and HFS in 4 (40%). Tesetaxel dose reduction was required in 1 pt 

for neutropenia; capecitabine dose reduction was required in 3 pts (30%) 

(2 for hand-foot syndrome, 1 for diarrhea). Comprehensive toxicity data will 

be presented. Conclusions: This combination of all-oral chemotherapy is 

generally well-tolerated, although lower than maximally approved doses of 

capecitabine are required, similar to other regimens that employ this agent. 

AEs are largely non-overlapping, which suggests this combination may be 

clinically useful in pts with advanced breast and gastric cancer. 


Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of 

the HSP90 inhibitor, AT13387, in patients with advanced solid tumors. 

Presenting Author: Khanh Do, National Cancer Institute, Bethesda, MD 

Background: AT13387, a synthetic, non-ansamycin, small molecule inhibitor 

of HSP90 (Kd 0.71 nM), binds to the N-terminal ATP-binding site 

resulting in down-regulation of key oncoproteins (HER2 and ERK). In 

xenograft models AT13387 produced tumor growth inhibition on a QD x 2 

dosing schedule. Objectives: To determine toxicity, MTD, PK, and pharmacodynamic 

(PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4. 

Methods: Adult patients (pts) with advanced cancers progressing following 

standard therapy; ECOG � 2; adequate organ function. One pt cohorts for 

first three dose levels (DLs, 20, 40, 80 mg/m2 ), planned 3�3 design at DL 

4 (120 mg/m2 ). PK evaluations on C1D1 and C1D15. Mandatory tumor 

biopsies in expansion cohort at MTD for HER2� tumors (baseline, C1D17) 

to evaluate HSP70 and HSP27 mRNA by RT-PCR; and client protein by 

IHC and immunoassay. HSP70 in PBMCs as a PD marker (pre-dose, D2, 

D15, D16) assessed by Western blot; serum markers of cell death, M30 

and M65 (baseline and pre-dose C1D16), assessed by ELISA. Results: 12 

pts treated up to DL 5 (160 mg/m2). Median age, 59; median # prior 

therapies, 3; diagnosis (# pts): colorectal (7); esophageal (2), liposarcoma 

(1); head and neck (1); synovial sarcoma (1). Drug-related toxicities (gr � 

2; # pts) in 9 evaluable pts: fatigue (5), rash (2), nausea (5), diarrhea (7), 

QTc prolongation (2), thrombocytopenia (5), AST (3) and ALT (2). Vision 

disorder (2 pts): gr 1, reversible, no objective findings on eye exams. DLT (1 

pt, with liver metastases): DL 5, gr 3 AST/ALT. PK was dose proportional; 

T1/2 8 hrs. In one paired tumor biopsy (DL 3) an increase in HSP70 (� 1.5 

fold) and HSP27 (2 fold) mRNA and a decrease in pERK was observed. 

M30 and M65 increased in 5/6 pts (p-value n.s.). Induction of HSP70 

(1.48 - 5.01 fold) in PBMCs was noted at all time points following first dose 

(� DL 2). 3/9 pts had SD after 2 cycles. Conclusions: Preliminary data 

indicate that AT13387 QD x2iswell tolerated and produces a sustained 

induction of HSP70 in PBMCs. Accrual is ongoing to establish the MTD and 

obtain further tumor biopsies for assessment of drug effect. Optional 

Indium-labeled trastuzumab scan will be used to evaluate drug effect on 

HER2 levels in pts with HER2 expressing tumors. 



A phase I study of dovitinib (TKI258) in Japanese patients with advanced 

solid tumors. Presenting Author: Hiroya Takiuchi, Osaka Medical College, 

Osaka, Japan 

Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated 

inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on 

responses observed in renal cell carcinoma, breast cancer, AML, melanoma, 

and multiple myeloma in clinical studies in the West, we investigated 

dovitinib in Japanese patients (pts). Methods: This multicenter phase 

I study determined the maximum tolerated dose (MTD) of dovitinib based 

on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with 

advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in 

period, dovitinib was administered orally once daily on a 5-days-on/2-daysoff 

schedule in 28-day cycles until disease progression or withdrawal. The 

planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic 

regression model based on the principle of escalation with overdose control 

was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 

100 mg (n � 3), 200 mg (n � 3), 300 mg (n � 7), 400 mg (n � 9), and 

500 mg (n � 6). The median age was 58.5 years (range, 30-76); 16 of 28 

pts (57%) were male. All pts had stage IV disease, with an ECOG 

performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is 

currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, 

cycle 19), 23 discontinued due to disease progression, and 4 discontinued 

due to adverse events (AEs). All DLTs were grade 3: anorexia (n � 1; 300 

mg), nausea/vomiting (n � 1; 400 mg), liver function disorder (n � 1; 400 

mg), and increased alanine transaminase (n � 1; 500 mg). The most 

common grade 3/4 AEs (occurring in �10% of pts) suspected to be related 

to study drug were lymphopenia (18%), neutropenia (14%), abnormal 

hepatic function (14%), decreased white blood cell count (14%), decreased 

appetite (14%), and hypertension (14%). Best responses were 

confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 

400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 

10 pts (36%). No treatment-related deaths have been reported. Safety and 

PK parameters were comparable to those of non-Japanese pts in the global 

study. Conclusions: The study has completed enrollment. Dovitinib was 

found to be tolerable at doses up to 500 mg, which was declared as the 

MTD in Japanese pts. 


Preclinical activity of the Hsp90 inhibitor, ganetespib, in ALK- and 

ROS1-driven cancers. Presenting Author: David A. Proia, Synta Pharmaceuticals 

Corporation, Lexington, MA 

Background: Ganetespib is a potent inhibitor of heat shock protein 90 

(Hsp90) currently being studied in a broad range of clinical trials. Phase II 

results with ganetespib demonstrated an encouraging objective response 

rate of 50% in non-small cell lung carcinoma (NSCLC) patients whose 

tumors contained ALK translocations and had progressed on previous 

treatments. To further understand the clinical potential of ganetespib in 

ALK-driven cancers, we evaluated its activity in (1) crizotinib-sensitive and 

-resistant cancer cells harboring ALK fusions; (2) cells expressing amplified 

ALK or ROS1 translocations (a kinase structurally similar to ALK); and (3) 

in combination with crizotinib. Methods: H3122 NSCLC cells, which 

express EML4-ALK, were treated with ganetespib, crizotinib or the combination, 

and cell viability and signaling cascades were assessed. Similar 

experiments were done in cells with amplified, constitutively active ALK 

(NB-39-nu) or ROS1 kinase fusions (HCC-78, U118MG). To generate a 

model of crizotinib resistance, NPM-ALK-expressing BaF3 cells were 

exposed to various crizotinib concentrations. Fifteen different ALK kinase 

domain substitutions were identified; clonal NPM-ALK/BaF3 cells were 

made for each resistance mutation and assayed for sensitivity to ganetespib. 

Results: Ganetespib was 50-fold more potent than crizotinib in killing 

H3122 cells, and when combined together at sub-lethal doses, displayed 

strong synergistic anticancer activity. Ganetespib showed similar potency 

in other cells driven by constitutively active ALK or ROS1 kinase fusions, 

due to abrogation of their oncogenic kinase activity. All 15 of the 

crizotinib-resistant NPM-ALK/BaF3 mutant clones were highly sensitive to 

ganetespib (IC50 values ranging from 14-23 nM), including the 7 

mutations reported to date in patients with ALK-driven tumors. Conclusions: 

Ganetespib effectively inhibits the activity of ALK and ROS1, kinases 

associated with several tumor types, resulting in marked single agent 

anticancer activity in cells driven by them. Importantly, ganetespib retains 

its potency irrespective of the mutational status of ALK. The strong synergy 

observed between ganetespib and crizotinib warrants further study. 


195s 

3089^ General Poster Session (Board #18G), Mon, 8:00 AM-12:00 PM 

Endoxifen for breast cancer: Multiple-dose, dose-escalation study characterizing 

pharmacokinetics and safety in metastatic breast cancer patients. 

Presenting Author: Ateeq Ahmad, Jina Pharmaceuticals, Inc., Libertyville, 

IL 

Background: Endoxifen is an active metabolite of tamoxifen, a drug used in 

the treatment of breast cancer. To be clinically effective, tamoxifen must 

be converted to endoxifen by CYP2D6. Direct administration of endoxifen 

would not be subject to pharmacogenetic variations or drug-drug interactions. 

Our preclinical studies (Breast Cancer Treat 122, 579-584, 2010) 

have validated the concept of using endoxifen for the treatment of breast 

cancer. In human (Clin. Pharmacol. Ther. 88, 814-817, 2010), the single 

oral doses tested up to 4 mg of endoxifen were safe, well tolerated and 

bioavailable. Methods: A multiple-dose escalating study was conducted in 3 

cohorts and each cohort had 6 patients (18 metastatic breast cancer 

patients). Endoxifen at 3 dose levels (2, 4, or 8 mg) was given once daily for 

28 days. Routine laboratory tests, vital signs and electrocardiograms were 

measured throughout the study. Blood samples for PK analysis were 

collected after 28 days post dose. Endoxifen in plasma samples was 

determined using LC-MS/MS. Results: Endoxifen was found to be safe up to 

8.0 mg. At steady state, it displays dose-proportional PK with respect to 

Cmax and AUC ( see Table below). Conclusions: Multiple daily endoxifen 

doses of 4.0-8.0 mg resulted in endoxifen exposures that would be 

sufficient for effective therapy. The favorable safety and multiple-dose PK 

profile of endoxifen warrants further evaluation of safety and efficacy of 

endoxifen in breast cancer patients. 

Pharmacokinetics parameters of endoxifen in metastatic breast cancer 

patients (n�5) after multiple-dose of 2, 4 or 8 mg of endoxifen tablets. 

Parameters (units) 2mg 

Mean � SD 

4mg 8mg 

Tmax (h)* 

Cmin ss (ng/mL) 

Cmax ss (ng/mL) 

AUCtau (ng.h/mL) 

PTF (%) 

5 (3.0-12.0) 

15.7�6.4 

24.5 �7.3 

445.3 �146.2 

50.8�19.0 

5 (4.0-6.0) 

44.0�11.6 

75.9 �18.5 

1363.3�396.3 

56.5 �17.9 

5 (4.0-6.0) 

80.4�26.7 

134.1�32.1 

2322.6�619.8 

57.6 �14.6 

Cav ss (ng/mL) 18.6 �6.1 56.8 �16.5 96.8�25.8 

*Data presented as median (range) 


Therapy of human solid tumor xenografts with CD74-targeted milatuzumab- 

SN-38 immunoconjugates. Presenting Author: David M. Goldenberg, 

Center for Molecular Medicine and Immunology, Morris Plains, NJ 

Background: CD74 is commonly considered to be an antigen present in 

hematopoietic cancers, but it is also expressed in a number of solid tumors. 

The humanized anti-CD74 antibody, milatuzumab (hLL1), was previously 

shown to have exquisite internalization properties, making it an attractive 

carrier for drug delivery. In this study, we evaluated hLL1 conjugates of a 

potent topo I inhibitor, SN-38, for treating solid tumors. Methods: Two 

hLL1-SN-38 conjugates, possessing either a pH-sensitive linker (‘CL2A’ 

form) or a cathepsin-B-cleavable linker (�CL2E� form), were examined. In 

vitro analyses were carried out in the A-375 human melanoma cell line, and 

therapy experiments were performed in female athymic nude mice bearing 

established s.c. A-375 or s.c. human pancreatic adenocarcinoma (Capan-1) 

xenografts using specified doses (i.p.) at a twice weekly � 4 wks 

schedule; animals were sacrificed when tumor volumes (TVs) reached 1 

cm3 . Results: Both A-375 and Capan-1 cell lines tested positive for CD74 

expression by IHC. In vitro, both SN-38 derivatives liberated free drug at 

the same rate when exposed to cathepsin-B at pH 5, while serum stabilities 

for CL2A and CL2E forms of the conjugates were ~1dand�10 d, 

respectively. In the A-375 melanoma cell line, IC50 for the hLL1-SN-38 

conjugates of CL2A and CL2E forms were 5 nM and 34 nM, respectively. In 

the aggressive A-375 s.c. model of melanoma, in nude mice (n �8; TV: 

0.23 � 0.06 cm3 ) treated with 12.5 mg/kg protein dose (total 1.7 mg/kg 

SN-38 eq.) of specific or non-specific SN-38 conjugates of CL2A and CL2E 

forms, only hLL1-CL2A-SN-38 conjugate was efficacious (Log-rank: 

P�0.009 vs. all controls), with a median survival time of 28 d vs. 10.5 d for 

untreated. Likewise, in mice bearing Capan-1 xenografts (n � 8-10; 

TV�0.27 � 0.05 cm3 ), two low doses of hLL1-CL2A-SN-38 (12.5 or 5 

mg/kg) significantly improved survival in comparison to saline control mice 

(p�0.035), whereas the CL2E form and a non-specific control demonstrated 

no efficacy. Conclusions: These results indicate the therapeutic 

potential of hLL1-CL2A-SN-38 conjugate and the importance of linker 

chemistry, and encourage additional testing in other CD74-positive solid 

cancers. 




BI 836845, a fully human IGF ligand neutralizing antibody, to improve the 

efficacy of rapamycin by blocking rapamycin-induced AKT activation. 

Presenting Author: Paul J. Adam, Boehringer Ingelheim RCV GmbH & Co. 

KG, Vienna, Austria 

Background: Analogs of rapamycin (rapalogs) targeting mammalian target 

of rapamycin complex 1 (mTORC1) have shown clinical activity in several 

cancers. Nonetheless, preclinical and clinical data suggest that there may 

be intrinsic resistance to rapalogs through a feedback loop which activates 

upstream signaling when mTORC1 is blocked. BI 836845 is a fully human 

antibody, currently in phase I clinical trials, which potently neutralizes both 

IGF-1 and IGF-2. We tested whether BI 836845 is able to improve the 

efficacy of rapamycin by inhibiting upstream signaling in preclinical 

models. Methods: Cancer cell lines were profiled in vitro and in vivo for 

sensitivity to BI 836845 and rapamycin, alone or in combination. Mitogenic 

signaling was examined by measuring levels of phosphorylated AKT 

(pAKT) using Western blot analysis. IGF bioactivity was determined using a 

cellular IGF-1R phosphorylation ELISA. Results: The combination of BI 

836845 and rapamycin was more effective than either agent alone at 

inhibiting the proliferation of Ewing’s sarcoma cells cultured in vitro as well 

as in a nude mouse xenograft model in vivo. Analysis of cell signaling 

upstream of mTOR demonstrated that treatment with rapamycin alone 

resulted in elevated pAKT, indicating feedback loop activation. BI 836845 

treatment alone or in combination with rapamycin inhibited AKT phosphorylation, 

demonstrating that the rapamycin-induced increase in pAKT was 

due to elevated IGF bioactivity. Consistent with this we demonstrated that 

rapamycin increased IGF bioactivity in mice and that this could be 

inhibited by BI 836845. We extended these studies to include other cancer 

cell lines and profiled the correlation between improved efficacy of the 

combination with BI 836845 inhibition of rapamycin-induced feedback. A 

correlation has been observed for cancer cells derived from several 

indications. Conclusions: Rapamycin treatment increases AKT activation 

via elevated IGF ligand bioactivity. This effect can be inhibited by BI 

836845, thus explaining the improved pre-clinical efficacy seen when both 

agents are combined. These data provide a rationale for the clinical 

combination of rapalogs and BI 836845. 


A phase I and pharmacokinetic study of multiple schedules of ganetespib 

(STA-9090), a heat shock protein 90 inhibitor, in combination with 

docetaxel for subjects with advanced solid tumor malignancies. Presenting 

Author: John S. Kauh, Winship Cancer Institute, Emory University, Atlanta, 

GA 

Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to 

the first-generation ansamycin class of Hsp90 inhibitors and has superior 

activity to these agents in preclinical studies. Ganetespib is well tolerated 

with promising antitumor activity. Based on synergy between ganetespib 

(G) and docetaxel (D), a phase I study evaluating preclinical dosing models 

was performed. Methods: Patients (pts) with advanced solid tumor malignancies 

and ECOG performance status (PS) 0-2 were eligible. Sequential 

cohorts of pts were treated (3�3 design) with increasing doses of D (day 1) 

and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and 

exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) 

were completed. PK sampling was performed during schedule A. The 

primary endpoint was determination of optimal doses and schedule of the 

two agents for combination therapy. Results: Twenty-seven patients were 

enrolled in schedules A (n�12), B (n�8), and C (n�7). Median age-64 

(44-75); 11-M, 16-F; ECOG PS: 0 (n�5),1(n�21), 2 (n�1). Most pts had 

NSCLC (n�9), others were head/neck (n�4), and SCLC (n�3). The defined 

MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 

(D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 

neutropenia of � 7 days), requiring expansion of level 2. The median 

number of cycles received is 2 (1-11), with 3 pts in schedule C still on 

study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 

had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 

weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, 

nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was 

not used at any time. PK data indicates similar G exposure alone compared 

to G administered prior to D. No accumulation was observed following 

once-weekly dosing, consistent with studies of G alone. Conclusions: The 

combination is well tolerated at the recommended doses of D 75 mg/m2 

and G 150 mg/m2. Promising anti-cancer activity was noted, and a 

randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is 

ongoing in advanced NSCLC (NCT01348126). 


Phase I dose-finding and pharmacokinetic study of a combination of 

elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid 

tumors. Presenting Author: Sanjay Goel, Montefiore Einstein Cancer 

Center, Bronx, NY 

Background: E is a new marine compound that has shown synergism with T 

in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines. 

Based on these findings, a phase I clinical trial was undertaken to identify 

the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h 

iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary 

objectives were evaluation of safety and feasibility, PK and preliminary 

efficacy results. Methods: Patients (pts) with advanced solid tumors with no 

standard therapeutic option were recruited. Cohorts of 3-6 pts were 

included at each dose level (DL), with escalating doses of E in increments 

of 25-50% according to toxicities, and 2 different T doses (100 and 150 

mg/day). Results: Thirty pts (median age, 57 years; 19 females) were 

evaluable. Main tumor types included NSCLC, colorectal, melanoma, and 

ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg � T 

100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin 

increase) was observed at DL3 (E 0.75 mg � T 150 mg). Another DLT (dose 

omissions due to ALT increase) was found at DL6 (E 2.25 mg � T 100 mg). 

Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%), 

rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis 

(17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and 

pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4 

pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological 

abnormalities were observed. Most toxicities were related to T; therefore, T 

dose was reduced to 100 mg/day. No PK interaction between E and T was 

observed. No objective responses were reported. Six pts attained stable 

disease �3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1 

invasive thymoma). Conclusions: E � T was a manageable combination; 

however, the difficulty of combining E with the standard dose of T (150mg) 

and the lack of activity made this combination unattractive for further 

development in the current schedule. Possibly, other schedules may 

demonstrate more efficacy. 


A phase I trial of the mTOR inhibitor temsirolimus (TEM) in combination 

with capecitabine (CAP) in patients with advanced malignancies. Presenting 

Author: Michael J. Pishvaian, Lombardi Comprehensive Cancer Center, 

Georgetown University, Washington, DC 


is critical for cell growth and proliferation. mTOR antagonists, such as 

TEM, have proven anti-cancer efficacy. Pre-clinical models and early phase 

clinical trials have demonstrated increased efficacy when an mTOR 

antagonist is combined with cytotoxic chemotherapy. Methods: Patients 

(pts) with advanced malignancies and adequate hepatic and renal function 

were eligible for enrollment. An alternating dose escalation of TEM and CAP 

was employed in separate q2week and q3week arms. Planned dose levels 

were: TEM 15 and 25mg IV weekly; and CAP 500, 750, 1000, and 1250 

mg/m2 orally twice daily (BID). Restaging occurred every 4 cycles for the 

q2week arm, and every 3 cycles for the q3week arm. PK samples assessed 

serum levels of sirolimus at Day 0, 8, and 15 of the q2week arm. Archived 

tumor specimens were assayed by immunohistochemistry (IHC) for expression 

of phospho-AKT, phospo-4EBP1, phoshpo-p70S6, and PTEN. Results: 

Thirty-two pts were enrolled, 30 of whom were evaluable for toxicity, of 

which 18 were male, age range 30-72 years, 25 with colorectal cancer. Pts 

had received an average of 4 prior lines of therapy. The most common 

adverse events (AEs) were mucositis and fatigue. The most common grade 

3/4 AEs were fatigue (n�4), diarrhea (n�2), and hypophosphatemia 

(n�2). In 16/30 pts, the dose of CAP was reduced. There were two DLTs, 

both hypophosphatemia in the q3week arm (TEM�25mg and 

CAP�1000mg/m2 ). For the q2week arm, the recommended phase II dose 

(RP2D) was TEM 25 mg � CAP 1000mg/m2 . For the q3week arm, the 

RP2D was TEM 25mg � CAP 750mg/m2 . Twenty-five pts were evaluable 

for response (18 for OS). There were no PRs or CRs, but 14/25 pts (56%) 

had SD, with 4/24 (16%) having prolonged SD of �6 months. Median TTP 

and OS were 3 and 7 months, respectively. Five pts are still on study. PK 

assessment of serum sirolimus levels, and the results of the IHC on 

archived tumor samples will be presented. Conclusions: The combination of 

TEM and CAP is safe on both a q2week and a q3week schedule. The 

combination demonstrated promising evidence of disease control in this 

highly refractory population and should be tested in disease-specific phase 

II trials. 



Phase I study of sirolimus plus gemcitabine in patients with advanced solid 

tumors: A Spanish Group for Research on Sarcomas (GEIS) study. Presenting 

Author: Juan Martin Liberal, Instituto Catalan Oncologia, Barcelona, 

Spain 

Background: In preclinical studies, combination of sirolimus with gemcitabine 

enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. 

Methods: Patients with advanced solid tumors, age 18-70 years, no prior 

mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, 

renal and hepatic function, were enrolled in this phase I study to assess 

safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting 

toxicity (DLT), maximum tolerated dose (MTD) and recommended dose 

(RD) of the combination of sirolimus and gemcitabine. A 3�3 dose 

escalation design with cohorts of 3-6 patients was used. Sirolimus was 

given po continuously. Gemcitabine was given iv 10mg/m2 /minute on days 

1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 

2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively. 

After observing DLTs at higher dose level and poorer mTOR signaling 

inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus 

gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment 

were performed to assess the inhibition of mTOR pathway. Results: 19 

patients were enrolled: median age 51 years (36-70); gender 12M, 7F. 

Median number of cycles was 4. Patients were treated at 4 dose levels, the 

MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and 

gemcitabine 800mg/m2 . 3 DLTs were observed, 1 at dose level 2 and 2 at 

dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and 

thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, 

neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients 

achieved partial response (1 uterine cervix cancer and 1 colon cancer). 

Immunohistochemistry of pS6 in skin biopsies showed significative inhibition 

of mTOR pathway at RD. PK parameters estimated were in agreement 

with those previously reported in the literature. No influence of sirolimus 

administration on gemcitabine clearance was found. Conclusions: Combination 

of sirolimus and gemcitabine is feasible and safe, allowing administration 

of active doses of both agents and achieving mTOR signaling 

inhibition. A phase II study to assess the activity of this combination in 

sarcomas is ongoing. 


A phase Ib proof-of-concept study of LBH589 (LBH) and everolimus (EVE) 

in advanced solid tumors enriched for Epstein-Barr virus (EBV)-related 

cancers. Presenting Author: Daniel Shao-Weng Tan, National Cancer 

Centre, Singapore, Singapore 

Background: Histone deacetylase and mTOR inhibition circumvent critical 

EBV-oncogenic pathways with preclinical studies demonstrating lytic 

induction in EBV infected cells, as well as immunomodulatory and 

antiangiogenic effects. Methods: Patients (Pt) with advanced solid tumors 

enriched for EBV–related cancers were enrolled to determine safety, 

tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics 

and preliminary antitumor activity. LBH was instituted 

7-days prior to combination treatment. NPC pt received antiviral prophylaxis 

of either acyclovir (Ac) or valaciclovir (Vc). Serum EBV DNA levels 

(EBNA-1) were measured weekly and plasma cytokines profiled using a 

31-plex Luminex panel. Results: 15 pt have been treated (M:F 13:2, 

median age 50, R: 38-63) 10 NPC, 5 non-NPC (colon, RCC, breast, 

gastric, sarcoma) at 3 dose levels – LBH (3x/wk)-EVE (daily):10-2.5, 10-5, 

15-5. Two dose limiting toxicities of G4 (grade) thrombocytopenia were 

observed at LBH15-RAD5. Significant adverse events (AE) (G�3) were 

dysphagia (1) and thrombocytopenia (3). Common AEs (G1/2) included 

fatigue (80%), anorexia (60%), mucositis (53%), xerostomia (26%), 

dysphagia (26%). Two minor responses were seen (1 NPC, 1 breast) and 2 

pt (1 NPC, 1 RCC) had prolonged stable disease (�16 weeks). Modulation 

of EBV DNA titres was seen only in NPC pt, with median fold-change from 

baseline of 10.9 (0.05-174). Pt on Ac prophylaxis (n�5) had significant 

increases in DNA titres (9-174 fold), while those on Vc (n�4) were less 

pronounced (0.05-11 fold, p�0.03), with one pt (with minor response) 

having persistent decline in EBV titres. In a limited pt subset (n�9, 30 

timepoints), plasma cytokine profiles were consistent with a T-cell response, 

specifically, elevated levels of FLT3L, IFN-gamma, IL-13 and 

IL-17. PK and PBMC target modulation studies are being analysed. 

Conclusions: LBH-EVE results in induction of EBV DNA titres with an 

associated host T cell response. MTD is LBH10-EVE5 in Asian pt, majority 

of whom had NPC. A pre-planned expansion cohort that incorporates 

multi-parametric functional imaging exploring two schedules of LBH in 

combination with EVE5 is ongoing. 


197s 


The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of 

patients (pts) with advanced solid tumors. Presenting Author: Hendrik- 

Tobias Arkenau, Sarah Cannon Research Institute, London, United Kingdom 

Background: The PI3 kinase (PI3K) pathway is the most deregulated 

pathway in cancers and is an attractive target for antitumor therapy. 

BEZ235 is an oral highly specific and selective inhibitor of the PI3K and 

TORC1/2. The MTD (1200 mg) and toxicity profile of BEZ235 once daily 

dosing has been established. This study was designed to evaluate twice 

daily dosing of BEZ235 and its effect on treatment tolerability, PK, PD, and 

preliminary efficacy. Methods: Pts with advanced disease were enrolled in a 

3�3 dose escalation schedule starting at 200 mg PO BID in 28 day cycles. 

For intrapatient PK comparison the first week pts received the total dose in 

a QD schedule. DLT assessment was in Cycle 1. Efficacy evaluations were 

every 2 cycles, and PK and PD were assessed. Results: 12 pts were enrolled 

at the following dose levels: 200 mg (n�3), 400 mg (n�3), 600 mg (n�3), 

and 600 mg (BID only, no QD lead-in) (n�3). No G4 AEs were reported. G3 

related AEs were mucositis (n�2), AST/ALT elevation (n�2), anorexia 

(n�1) and diarrhea (n�1). The most common related G1/2 adverse events 

(AEs) were anorexia (n�6), diarrhea (n�3), fatigue (n�2), and headache 

(n�2). DLTs of G3 mucositis were observed in 2 patients at the 600 mg 

BID dose level with 1 week 1200 mg QD lead-in, which were attributed to 

the QD lead-in dosing during the first week. 3 pts then enrolled at 600 mg 

BID without lead in and had no further DLT. PK shows consistent increase 

in PK parameters with dose level. Of 10 evaluable, 3 pts had stable disease 

(13� to 21� weeks, 2 colorectal, 1 endometrial). Of 9 evaluable, 4 pts at 

various dose levels had decreased PET SUV uptake by greater than 25%. 

Conclusions: BEZ235 is tolerable at a dose of 600 mg BID, with less toxicity 

than has been seen with equivalent QD dosing. Preliminary signs of clinical 

and PD activity are noted. 


Meta-analysis on the relationship between everolimus exposure and safety 

and efficacy. Presenting Author: Dalila B. Sellami, Oncology Clinical 

Development, Novartis Pharmaceuticals Corporation, Florham Park, NJ 

Background: Data on everolimus exposure–safety and response relationships 

are available from individual studies. We performed a meta-analysis 

to assess these relationships using everolimus predose minimum blood 

concentration (Cmin). Methods: Individual patient data from 5 phase 2 or 3 

oncology studies in which steady-state predose pharmacokinetic samples 

were taken from patients administered everolimus monotherapy 10 mg/day 

were pooled. In a Cox regression, the times to first grade �3 select adverse 

events (AEs) associated with everolimus and first progression-free survival 

(PFS) event were related to log-transformed instant or time-averaged Cmin as time-varying covariates stratified by study. Probability of tumor size 

reduction according to RECIST (yes vs no) was assessed using a generalized 

linear mixed model fitted with GEE method with log-transformed instant or 

time-averaged Cmin as covariates and treatment arm as fixed effect. Results: 

945 patients were evaluable for efficacy, 938 for safety. Patient characteristics 

were relatively well balanced across studies. Regardless of whether 

instant or time-averaged Cmin was used, a 2-fold increase in everolimus 

exposure increased the risk of grade �3 pulmonary, metabolic, and 

stomatitis events (Table); no increased risk of other grade �3 AEs was 

observed. A 2-fold increase in everolimus exposure increased the likelihood 

of tumor size reduction; there was a trend of reduced risk of a PFS event 

(Table). Conclusions: A 2-fold increase in everolimus exposure is associated 

with a higher probability of tumor size reduction and increased risk of 

high-grade pulmonary, metabolic, and stomatitis AEs associated with 

everolimus. 

Risk and odds ratios associated with 2-fold everolimus exposure increase. 

Tumor size 

Grade >3 AEs, risk ratio (95% CI) 

PFS event, 

risk ratio 

reduction, 

odds ratio 

Cmin Pulmonary Metabolic Stomatitis (95% CI) (95% CI) 

Time-averaged 1.93 1.30 1.49 0.90 1.40 

(1.12-3.34) (1.02-1.65) (1.05-2.10) (0.69-1.18) (1.23-1.60) 

Instant 2.15 1.37 1.44 0.88 1.43 

(1.17-3.92) (1.06-1.77) (1.01-2.05) (0.68-1.14) (1.25-1.63) 




A phase I study of S-222611 an oral reversible dual inhibitor of EGFR and 

HER2, in patients with solid tumors. Presenting Author: Richard D. Baird, 

University of Cambridge, Department of Oncology, Cambridge, United 

Kingdom 

Background: S-222611 is a novel oral, potent, reversible tyrosine kinase 

inhibitor with antiproliferative activity in human tumor cell lines expressing 

EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted 

the first study in patients (pts) with solid tumors expressing EGFR or HER2. 

Methods: Daily oral doses of S-222611 were escalated in successive 

cohorts from 100 mg to a maximum 1600 mg, using a 3 � 3 design. Full 

plasma pharmacokinetic (PK) profiles were obtained in all pts for 7 days 

after a single dose on Day 1 and for 24 h following 21 days of once daily 

dosing (Cycle 1). Trough PK samples were drawn weekly during the first 3 

weeks of daily dosing. A CT scan was performed at baseline and every 8 

weeks post-dose to assess response (RECIST). Results: Of 23 treated pts 

(16 male) aged 24-77y, 19 completed Cycle 1. One dose-limiting toxicity 

(DLT) has been seen to date, a rash at 1200 mg, which resolved on 

interruption and dose reduction. Other adverse events related to drug, 

diarrhea, rash, and nausea, were mild (grade 1 or 2) but more frequent at 

higher doses. Tumor responses have been seen over a wide range of doses. 

One complete clinical response was observed at 1200 mg in a pt with 

HER2 positive breast carcinoma previously treated with lapatinib and 

trastuzumab. Two pts showed confirmed partial responses (one with EGFR 

positive renal cell carcinoma at 200 mg daily and one with EGFR and HER2 

positive esophageal carcinoma at 400 mg daily); 2 pts showed unconfirmed 

partial responses and 3 pts (with vaginal, gastric and pancreatic adenoCa) 

showed stable disease for �6 months (mo); 2 pts have been treated for 

�12 mo. Plasma Cmax, AUC and steady state concentrations increased with 

dose up to 1200 mg, exceeding those eliciting maximal responses in mice. 

The plasma t½ is �24 h. Conclusions: S-222611 was generally tolerated 

well in doses up to 1200 mg, with only one DLT; rash, diarrhea and nausea 

have been readily manageable. PK data support once daily dosing to 

achieve highly effective concentrations. A substantial proportion of patients 

with HER2 or EGFR expressing tumors have shown partial responses 

or stable disease (�6 mo) and one patient has shown a complete clinical 

response. 


A phase I study of selumetinib (AZD6244/ARRY-142866) in combination 

with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal 

cancer (CRC). Presenting Author: Dustin A. Deming, University of Wisconsin 

Carbone Cancer Center, Madison, WI 

Background: KRAS mutations have been recognized as clinically important 

predictors of resistance to EGFR-directed therapies in CRC. Oncogenic 

activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation 

independent of growth factor receptor signaling. We hypothesized that 

targeting MEK with selumetinib could overcome resistance to cet in KRAS 

mutant CRC. A phase I study (NCT01287130) was undertaken to determine 

the tolerability, and pharmacokinetic profiles of the combination of 

selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the 

MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose 

escalation portion, patients (pts) with advanced solid tumors received fixed 

dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the 

expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD 

level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were 

treated at 3 dose levels in the dose escalation cohort and 14 pts were 

treated in the expansion cohort. Pts had the following tumor types: CRC 

73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8) 

prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. 

ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for 

tolerability and response. One DLT for grade 4 hypomagnesemia occurred, 

and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities 

included; rash, hyponatremia, and headache. The most common cycle 1 

grade 1 and 2 adverse events included acneiform rash (100%), fatigue 

(54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever 

(23%), and hypomagnesemia (15%). Most pts (60%) required no dose 

modifications. The MTD was established at selumetinib 75 mg PO BID and 

cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included 

2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 

CRC). Conclusions: The combination of selumetinib and cet is well 

tolerated, and preliminary anti-tumor activity was observed in multiple pts. 

Results of the KRAS mutant CRC expansion cohort will be presented. 


A phase I study of the gamma-secretase inhibitor RO4929097 and 

capecitabine in refractory solid tumors. Presenting Author: Noelle K. 

LoConte, University of Wisconsin Carbone Cancer Center, Madison, WI 

Background: RO4929097 is a oral inhibitor of gamma-secretase, which 

results in Notch signaling inhibition. Prior work has demonstrated that 

Notch-signaling inhibition enhances chemosensitivity of colon cancer 

cells. This study sought to combine RO4929097 with capecitabine (cape) 

and determine maximum tolerated dose (MTD), toxicities and efficacy. 

Preclinical and prior phase I work demonstrated possible autoinduction of 

RO4929097, so pharmacokinetic (PK) evaluation of RO4929097 and 

cape was planned. Methods: Adult patients with refractory solid tumors 

were eligible and received RO4929097 and cape at a fixed dose of 1000 

mg/m2 BID with escalating doses of RO4929097 on a 21-day cycle 

according to a 3�3 design. Cape was administered for 14 days and the 

RO49029097 once daily, 3 days per week. RO4929097 plasma concentrations 

were evaluated by LC/MS/MS on days 3 and 10 of cycle 1, and PK 

parameters analyzed with WinNonLin version 5.2. Results: 4 dose levels 

have been completed (20, 30, 45 and 68 mg); 18 of 19 patients are 

evaluable for toxicity and PK data is available for 11 patients. One DLT has 

been observed (intolerable grade 2 fatigue) at 68 mg. There have been 2 

confirmed partial responses: fluoropyrimide-refractory colon cancer (for 12 

cycles) and cervical cancer (for 6 cycles). The half-life, Cmax and AUC of 

RO4929097 all significantly decreased on day 10 compared to day 3, with 

an increase in clearance for all doses. The half-life was significantly shorter 

in dose level 3 (p�0.0012) and dose level 4 (p�0.0126) compared to 

dose level 1. Conclusions: RO4929097 plus cape was well tolerated. 

Activity was seen in cervical and colon cancer. Autoinduction of RO4929097 

was seen both with increasing cycle number and increasing dose. However, 

all plasma concentrations of RO4929097 were above those needed for 

Notch inhibition (1.9 ng/mL based on prior studies). Dose level 1 (cape 

1000 mg/m2 BID and RO4929097 20 mg daily) is the recommended 

phase II dose. 

N�11 

Ratio day 10/day 3 

Mean (95% CI) P value 

Half-life (hr) 0.62 (0.44 – 0.80) � 0.001 

Cmax/dose 0.63 (0.44 – 0.82) � 0.001 

AUC/dose 0.50 (0.12 – 2.57) 0.016 

Vd (mL) 1.88 (1.19 – 2.57) � 0.001 

Cl (mL/hr) 3.69 (2.13 – 5.25) � 0.001 


Phase I trial to assess the safety and pharmacokinetics of afatinib and 

weekly vinorelbine in patients with advanced solid tumors. Presenting 

Author: Antoine Hollebecque, Institut Gustave Roussy, Villejuif, France 

Background: Afatinib (A) is an oral, irreversible ErbB Family Blocker with 

activity in a wide range of tumor cell lines dependent on ErbB signaling. 

Vinorelbine (VNR) interferes with tubulin polymerization and spindle 

formation during metaphase. Additive or supra-additive activity of A or 

EGFR TKI with VNR has been demonstrated in preclinical models. Methods: 

This dose-escalation Phase I study established the safety profile, MTD and 

PK of A with i.v. and p.o. VNR using a modified 3�3 design. Eligible 

patients (pts) were �18 years with refractory advanced or metastatic 

tumors, an ECOG PS 0–1, and adequate organ and bone marrow function. 

VNR i.v. (25 mg/m2 )/oral (60 mg/m2 with escalation to 80 mg/m2 after 3 

weeks) was administered weekly on Days 1, 8, 15 and 22 with escalating 

oral daily doses of A 20 mg, 40 mg and 50 mg in 28-day treatment courses. 

Results: The study treated 55 pts: 30 pts for MTD determination and 25 pts 

in the PK expansion cohort (24 M/31 F), median age 54 years (range 

34–72). 28/27 pts were included in the VNR i.v./p.o. cohorts, respectively. 

Patients had NSCLC, breast, pancreatic (n�13/5/3), head and neck, 

stomach or colorectal cancer (n�2 each group); 28 pts had other cancers. 

At 20 mg A, no DLTs occurred in the VNR i.v./p.o. cohorts; whereas, at 50 

mg A, 4/6 pts and 3/5 pts experienced DLTs. At 40 mg A and VNR i.v./p.o., 

1/6 pts included for MTD determination experienced DLT, as did 7/13 pts 

and 2/12 pts in the VNR i.v./p.o. PK expansion cohorts, respectively. Main 

DLTs were diarrhea and febrile neutropenia. Median treatment duration 

(snapshot date 9 Dec 2011) across all dose groups was 80 days (range 

10–687), with 98 and 58 days in the MTD cohorts of VNR i.v./p.o., 

respectively. Related AEs observed in most patients were diarrhea, asthenia, 

nausea, vomiting, neutropenia, decreased appetite, mucositis and 

rash. Five pts had a PR, confirmed in 2 pts. Preliminary PK analyses 

suggest no drug–drug interaction between A and i.v. VNR. Conclusions: 

Afatinib in combination with weekly i.v./p.o. VNR is tolerated, with 

manageable, reversible, target-related side effects and promising signs of 

clinical activity in heavily pretreated patients. The MTD for A for both 

combinations is 40 mg daily. 



A phase Ib trial of FOLFIRINOX plus saridegib, an oral hedgehog (Hh) 

inhibitor, in pts with advanced pancreatic cancer (PDAC). Presenting 

Author: Andrew H. Ko, University of California, San Francisco Comprehensive 

Cancer Center, San Francisco, CA 

Background: FOLFIRINOX has emerged as the optimal 1st-line treatment 

option for pts with advanced PDAC and good performance status; whether it 

can serve as the backbone upon which to add targeted agents in clinical 

trial design remains uncertain. The goal of this multicenter phase Ib study 

is to evaluate FOLFIRINOX in combination with saridegib, a novel oral 

agent that inhibits the Hh signaling pathway. In preclinical models of 

PDAC, saridegib increases chemotherapy delivery by depleting peritumoral 

stroma and increasing vascularity. Methods: Pts with previously untreated 

metastatic or locally advanced PDAC and ECOG PS 0-1 were eligible. 

Treatment consists of once-daily saridegib with concurrent administration 

of biweekly FOLFIRINOX (omitting the 5-FU bolus). A 3�3 dose escalation 

design was used (see dose levels below). Prophylactic WBC growth factor 

support is mandated. DLT definitions include ALT/AST �10x ULN, grade 4 

plts or ANC �5 d, or grade 3-4 nonheme toxicity. CT scans are obtained 

every 4 cycles. Limited PK analyses are performed. Results: Seven pts have 

been enrolled at the first 2 dose levels. Grade 1-2 AEs include GI (N/V/D), 

dehydration, fatigue, and LFT abnormalities. There was one DLT (grade 3 

ALT elevation) at DL2. Other serious toxicities seen include grade 3 nausea 

(DL1) and grade 3 diarrhea (DL2). Tumor shrinkage has been observed in 

all 4 pts at DL1, ranging from 17-54%, with 2 unconfirmed PRs. Final MTD 

determination and updated safety and efficacy data will be presented at the 

meeting. Conclusions: A modified FOLFIRINOX regimen can be safely 

administered in combination with novel agents in clinical trials of PDAC. 

While saridegib was not beneficial when added to gemcitabine in a separate 

randomized phase II study, early evidence of significant responses on the 

current trial suggests that a more intensive chemotherapy platform may 

represent a preferable strategy in PDAC trial design. 

Dose level 

5-FU bolus 

(mg/m2) 

5-FU infusion 

(mg/m2 x 46 hrs) 

LV 

(mg/m2) Oxaliplatin Irinotecan 

(mg/m2) (mg/m2) 

IPI-926 

(mg/day) 

-1 -- 1600 400 50 120 130 

1* -- 1920 400 65 150 130 

2 -- 2400 400 85 180 130 

3 -- 2400 400 85 180 160 

*Starting dose level. 

3107^ General Poster Session (Board #21A), Mon, 8:00 AM-12:00 PM 

First-in-human phase I dose-escalation study of the oral selective C-met 

inhibitor EMD 1204831 in patients with advanced solid tumors. Presenting 

Author: Hesham M. Amin, Department of Hematopathology, University 


Background: The cell surface receptor tyrosine kinase c-Met and its ligand, 

the hepatocyte growth factor, are implicated in tumor cell migration, 

invasion, survival, and proliferation. EMD 1204831 is a novel potent and 

highly selective reversible, ATP-competitive small molecule c-Met inhibitor. 

Methods: This is a phase I, first-in-human clinical trial with escalating 

doses of EMD 1204831 (NCT01110083). The primary objective was to 

determine the maximum tolerated dose (MTD). Secondary objectives 

included evaluation of safety, pharmacokinetics (PK), pharmacodynamics 

(Pd), and preliminary anti-tumor activity. Eligible patients had advanced 

solid tumors not amenable to standard therapies. Following a classical 3�3 

dose-escalation scheme, successive cohorts of patients were treated with 

twice daily (BID) oral EMD 1204831 in 21-day cycles. Pd markers were 

evaluated in paired tumor biopsies (phospho-c-Met). Results: Until 31 

December 2011, 30 patients were enrolled and treated. The dose was 

escalated in successive cohorts starting from 50 mg BID up to 1400 mg 

BID. After first (single) administration, median Cmax and AUC0–12 values 

increased with dose. At higher doses, a decrease in exposure of EMD 

1204831 was noted after multiple dosing, potentially caused by autoinduction 

of the compound’s metabolism. Further dose escalation was discontinued, 

and no further patients were enrolled. One dose-limiting toxicity (DLT) 

of grade (G) 3 pancreatitis, considered as a serious adverse event (AE), was 

observed at 400 mg BID. No other DLTs or treatment-related serious AEs 

were observed. The remaining treatment-related AEs of G2 or higher 

included G3 and G2 lipase elevation (n�1 for each grade), G2 upper 

abdominal pain (n�2), G2 gastroesophageal reflux disease (n�2), and G2 

constipation (n�1). Twenty-five patients (83%) had no drug-related 

toxicity greater than G1. Of 29 patients evaluable for anti-tumor activity, 3 

had stable disease lasting for at least 4 months. Conclusions: Due to 

potential autoinduction of the compound’s metabolism, dose escalation 

was discontinued before an MTD was reached. Final safety, PK, and clinical 

tumor response results will be presented. 


199s 


NRAS mutations in patients with advanced cancers treated with targetbased 

therapies in early-phase clinical trials. Presenting Author: Vinu 

Madhusudanannair, Department of Investigational Cancer Therapeutics 

(Phase I Program), University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: NRAS mutations in cancers increase MAPK signaling. It is 

plausible that NRAS mutations may be associated with sensitivity to drugs 

targeting the MAPK pathway. Methods: Tumors from 689 patients with 

advanced cancers referred to the Clinical Center for Targeted Therapy 

(phase I program) were screened in a CLIA-certified laboratory for NRAS 

mutations and if feasible, for PIK3CA, KRAS, BRAF mutations and PTEN 

aberrations. Whenever possible, patients with NRAS mutations were 

treated with agents targeting the RAF-MEK pathway. Results: Of the 689 

patients, 58 (8%) had NRAS mutations. NRAS mutations were most 

prevalent in melanoma (26/170, 25%), thyroid (5/26, 19%), endometrial 

(2/27, 7%), non-small cell lung (1/31, 3%), ovarian (1/60, 2%) and 

colorectal cancers (1/74, 1%). NRAS mutations were not seen in any of the 

tested head and neck squamous cell cancers (n � 44); sarcomas (n � 41) 

and breast cancers (n � 25). None (0/62, 0%) of the patients tested for 

KRAS had simultaneous NRAS and KRAS mutations, and only 2/42 (5%) 

tested for BRAF had simultaneous NRAS and BRAF mutations. Of 58 

patients with NRAS mutations, 14 (24%) were enrolled in trials that 

included MEK axis inhibitors. Of these 14 patients, 13 had melanoma and 

1 had ovarian cancer and 4/14 (29%) demonstrated tumor shrinkage 

�10% from baseline. In comparison, only 22/187 (12%) patients with 

wild-type/unknown NRAS, KRAS and BRAF treated on the same trials 

demonstrated tumor shrinkage �10% (p�0.086). Conclusions: NRAS 

mutations are diagnosed in variety of advanced cancers. Patients with 

NRAS mutations demonstrated a trend to better antitumor activity with 

MEK axis inhibitors compared to patients without NRAS, KRAS or BRAF 

mutations. Further studies are warranted to delineate the role of NRAS 

mutations in patients treated with MEK axis inhibitors. 


Phase I trials of PS-341 (bortezomib, B) in combination with topotecan (T) 

in advanced solid tumors: A potential pharmacokinetic (PK) interaction. 

Presenting Author: Robert Morgan, City of Hope, Duarte, CA 

Background: Preclinical data has demonstrated that B when combined with 

camptothecins enhances apoptotic effects which may be independent of 

NF-�B status and dependent on the sequence of exposure to the proteasome 

inhibitor. Other data suggests PK interactions of B with some 

chemotherapeutic agents. It is hypothesized that B will act synergistically 

with T and enhance the apoptotic effects of T. Conflicting data exists 

regarding schedule dependent synergistic cytotoxicity of the combination. 

This study examined both sequences of administration and determined the 

PK of each sequence. Methods: A standard 3 � 3 schedule was used in both 

sequences (S). The dose of B was fixed with escalating doses of T. S1: B 1.3 

mg/m2 on days 1, 4, 8, and 11.T2to3.5mg/m2 on days 1 and 8 was given 

6 h before B. S2: B 1.3 mg/m2 on days 1, 4, 8, 11 followed by T2to3 

mg/m2 given 6 h after B. Cycle length was q28 days. PK sampling for both 

sequences was performed. Results: 54 pts (S1: 27, S2: 27) received a 

median of 2 cycles (range 1-7) of therapy. Pts were heavily pre-treated. For 

S1, the maximum tolerated dose (MTD) of B and T were 1.3 and 3 mg/m2 respectively. For S2, the MTD of B and T were 1.3 and 2.5 mg/m2 respectively. Dose-limiting toxicities (2 pt in each sequence) were gr 3 

thrombocytopenia in S1, and gr 4 thrombocytopenia in S2. Stable disease 

was seen in 6/27 pts in S1, and 6/27 in S2. PK results for S2 show no 

significant difference between the day 1 and day 8 PKs. However, the mean 

AUC (454�150 mg/Lxhr) and Cmax (123�51 mg/L) at the MTD of 2.5 

mg/m2 reached on this trial is similar to those reported with single agent 

doses of 4 mg/m2 given over 30 minutes weekly x 3. As a result, the 

estimated topotecan clearance (11.3�5 L/hr) when given following bortezomib 

is approximately one half of the reported clearance for the single 

agent. (Curtis et al, J Clin Pharmacol, 50:268, 2010). Conclusions: The 

tolerability and toxicity of both sequences was similar. MTD differs with S2 

having a lower tolerated dose of T. PK results suggest a possible drug-drug 

interaction with decreased clearance of T with S2. PK results for S1 are 

pending. Supported by CCSG CA62505. 




Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic 

breast cancer: A phase II clinical trial with ER imaging correlates. 

Presenting Author: Hannah M. Linden, University of Washington, Seattle, 

WA 

Background: Endocrine refractory,Indolent, soft tissue, and bone dominant 

metastatic breast cancer is a clinical problem, for which alternatives to 

chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have 

shown pre-clinical promise in estrogen receptor-modulation and restoring 

sensitivity to endocrine manipulation, suggesting potential clinical benefit. 

HDACi restore ER expression in ER-negative cells which are then sensitive 

to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive 

cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL, 

and could have a beneficial role in restoring ER-signaling in endocrineresistant 

tumors. We hypothesized that HDACi therapy could restore 

sensitivity to aromatase inhibitor (AI) therapy, in patients with prior 

progression on AI, and allow continued endocrine therapy. Recent data 

suggest clinical benefit of Tamoxifen and vorinostat given continuously 

(Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior 

work has shown the feasibility of monitoring regional ER expression and 

ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging 

(Linden 2011) providing a biomarker to interrogate the molecular target. 

Methods: Patients with metastatic breast cancer with prior clinical benefit 

from endocrine manipulation who progressed on AI therapy are eligible. 

Patients must be off ER blocking therapies, and functionally postmenopausal. 

Baseline FES and FDG PET are performed and patients receive 

investigational vorinostat treatment at 400 mg po BID for 2 weeks followed 

by serial FES and FDG PET to assess the impact of vorinostat on ER 

expression and tumor metabolism. Patients are retreated on their prior AI as 

a single agent for 6 weeks, followed by paired FES and FDG and clinical 

assessment. Patients with clinical benefit may continue on treatment: 2 

weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until 

progressive disease or toxicity. We have enrolled 4 of a planned 20 patients. 


A phase I and pharmacologic study of MM-111, a bispecific HER2/HER3 

antibody fusion protein, in combination with multiple treatment regimens 

in patients with advanced HER2-positive solid tumors. Presenting Author: 

Donald A. Richards, Texas Oncology-Tyler, Tyler, TX 

Background: The HER2/HER3 oncogenic heterodimer is a potent HER 

receptor pairing with respect to strength of interaction, receptor tyrosine 

phosphorylation, and downstream signaling through mitogen activated 

protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel 

bispecific antibody fusion protein that inhibits ligand activated HER3 

signaling through abrogation of ligand binding specifically in HER2 

overexpressing tumors. In preclinical models of HER2� solid tumors, 

MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression, 

and tumor growth. HER2 is a well-established target of anticancer 

agents such as trastuzumab and lapatinib, specifically in breast and gastric 

tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor 

activity of both trastuzumab and lapatinib and this phase I study seeks 

to determine if MM-111 can be safely used in combination with various 

standard of care HER2 targeting regimens, namely; (1) trastuzumab, 

cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3) 

trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open 

label, multicenter, dose-escalation study of MM-111 in an add-on design 

that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of 

MM-111 in combination. Each arm is designed to run as a separate phase I 

study to address safety and tolerability of each combination. For eligibility, 

patients are required to have documented advanced HER2-positive cancer, 

with adequate bone marrow, hepato-renal and cardiac function. The dose 

escalation for each arm utilizes a standard “3 � 3” design with MM-111 

dosed initially at a moderate dose of 10 mg/kg and escalated up to 20 

mg/kg to identify a phase II dose in combination with each regimen. Once 

the maximum tolerated dose or phase II dose is identified, expansion 

cohorts will accrue to further evaluate these combinations. The flexibility of 

the design allows additional combinations arms to be added. Key exploratory 

analyses will include an evaluation of safety, PK, and efficacy as 

evidenced by best overall response and duration of response. 


Design of a phase I clinical trial with PNT2258, a novel DNA interference 

oligonucleotide (DNAi), in patients with advanced solid tumors. Presenting 

Author: Drew Warren Rasco, South Texas Accelerated Research Therapeutics, 

LLC, San Antonio, TX 

Background: With the knowledge that Bcl-2 facilitates drug resistance and 

cell survival, a DNA interference (DNAi) strategy was applied to silence 

Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic 

mRNA targeting (antisense, RNAi, and miRNA targets) as it targets 

genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a 

novel single-stranded 24-base unmodified DNA designed to bind to an 

upstream region of the Bcl-2 promoter. The drug product (PNT2258) is 

PNT100 encapsulated in a specialized pH tunable liposome and is being 

assessed for safety and tolerability in a phase I trial. PNT2258 avoids the 

toxicities associated with modified oligonucleotides and double-stranded 

RNAs; since the liposome formulation is anionic and contains no surface 

spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated 

marked single agent activity in a diffuse large cell lymphoma, and 

therapy potentiation when combined with either rituximab in Daudi- 

Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An openlabel, 

single-arm, first-in-man phase I dose-escalation study of PNT2258 

in patients with advanced solid tumors was designed to evaluate safety, 

tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics 

of PNT2258 to recommend a dose for phase II studies. In this 

phase I study, pharmacodynamic effects of PNT2258 will be evaluated 

through analyses of soluble serum and plasma markers and peripheral 

blood mononuclear cells. Patients will receive PNT2258 as an intravenous 

infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 

21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with 

PNT2258 administered to one patient per cohort and dose-escalation will 

proceed by dose-doubling in each successive cohort until a dose level of 64 

mg/m2 is attained, provided no dose-limiting toxicities are observed in 

cycle 1. Thereafter, dose escalations shall proceed at 33% increments of 

the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions 

of up to six patients per cohort as needed. The ten planned dose cohorts 

have been completed with all patients enrolled. 


A phase I trial of riluzole and sorafenib in patients with advanced solid 

tumors and melanoma. Presenting Author: Janice M. Mehnert, Cancer 

Institute of New Jersey, New Brunswick, NJ 

Background: Metabotropic glutamate receptor 1 (GRM1) has been identified 

as a potential therapeutic target in melanoma. Over 60% of human 

melanomas express this cell surface glutamate receptor and excitation of 

GRM1 results in the activation of MAPK and PI3K/AKT pathways. Riluzole, 

an oral GRM1 blocking agent, results in growth arrest of melanoma cells in 

vitro and in vivo. We previously reported that administration of riluzole to 

melanoma patients suppressed activity of the PI3K/AKT and MAPK 

pathways in paired tumor samples (Yip Clin Cancer Res 2009). In 

preclinical studies, the efficacy of riluzole was attenuated in melanoma 

cells harboring BRAFV600E mutations, but sorafenib, a RAF kinase 

inhibitor, enhanced the effect of riluzole on these cells. The combination of 

riluzole and sorafenib was additive or synergistic in both BRAF mutant and 

BRAF wildtype melanoma cells in vitro and in BRAF wildtype cells in a 

xenograft model (Lee HJ Clin Cancer Res 2011). We thus designed a phase 

I trial to test the combination of riluzole with sorafenib in patients with solid 

tumors and advanced melanoma. Methods: The primary objective of this 

trial is identification of the maximum tolerated dose (MTD). An expansion 

cohort at the MTD is planned for patients with advanced melanoma to 

examine the correlation of clinical or radiographic response with signaling 

through the MAPK and PI3K/AKT pathways and with GRM1 receptor status 

of individual tumors. Eligible patients must have advanced solid tumors 

(phase I) or stage III unresectable/stage IV melanoma with biopsiable tumor 

(expansion cohort) and ECOG PS � 2. Riluzole will be administered at 100 

mg twice daily combined with sorafenib beginning at 200 mg daily and 

escalating in subsequent cohorts at 200 mg increments. Correlative 

studies: Tumors will be assessed for BRAF and NRAS mutational status. 

Pretreatment tumor blocks will be examined for GRM1 receptor status by 

immunohistochemistry. Pre and post treatment levels of pERK and pAKT 

will be measured in paired tumor samples to assess effects of treatment on 

MAPK and PI3K signaling. Limited sampling pharmacokinetic studies will 

be performed. Progress: Accrual to three cohorts is complete without DLT. 

Accrual to the final planned cohort is in progress. 



First-in-human phase I clinical trial of QBI-139, a human ribonuclease 

variant, in solid tumors. Presenting Author: Laura E. Strong, Quintessence 

Biosciences, Inc., Madison, WI 

Background: RNA has been recognized as a drug target for cancer therapy, 

as evidenced by the ongoing clinical trials of RNAi and antisense therapies. 

An alternative approach that circumvents the delivery and stability issues of 

RNAi and antisense is to harness the activity of naturally occurring enzymes 

that degrade RNA. Variants of human ribonucleases (RNase) have been 

generated with diminished binding to their natural inhibitor inside cells, 

which allows the new proteins to kill cancer cells. QBI-139, a variant that 

retains 95% sequence identity to a naturally occurring RNase, has 

demonstrated efficacy as both a single agent and in combination against 

multiple tumor types in in vivo models of human cancer. A first in human 

phase I trial was designed and initiated for QBI-139. Methods: Since 

QBI-139 showed efficacy against multiple cancers in model systems, a first 

in human phase I trial was designed for patients with advanced solid 

tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion 

once weekly for a cycle of three weeks. In the absence of disease 

progression or unacceptable toxicity, treatment can continue on the twenty 

one day cycle. The trial is a standard 3�3 design with cohorts of three to six 

patients receiving escalating doses of QBI-139 until the maximum tolerated 

dose (MTD) and/or recommended phase II dose is determined. The 

inclusion/exclusion criteria are typical for the patient population. Forty 

three patients have been treated to date (January 2012) without identification 

of dose limiting toxicity. The starting dose in the clinical trial was 3 

mg/m2 while the most recently completed cohort was treated with a dose of 

50.4 mg/m2 . Dose escalation is ongoing. The primary outcome is to 

evaluate the toxicity and tolerability of QBI-139 in patients with advanced 

refractory solid tumors. This information will allow for identification of the 

maximum tolerated dose. Clinical exposure levels are being monitored by 

measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139 

will be measured using RECIST criteria. Since QBI-139 demonstrated 

broad efficacy in model systems, another outcome of the phase I trial may 

be identification of the indications for the next stage of clinical development. 


BARIS: A phase I trial to evaluate the safety and tolerability of combined 

BIBF 1120 and RAD001 in solid tumors and to determine the maximum 

tolerated dose (MTD) of the combination. Presenting Author: Matthias 

Scheffler, Lung Cancer Group Cologne, Center for Integrated Oncology, 

University Hospital Cologne, Cologne, Germany 

Background: Simultaneious inhibition of several signallingpathways involved 

in angiogenesis as well as in tumor cell growth regulation by kinase 

inhibitor combination therapy may increase therapeutic efficacy. Here we 

evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and 

the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120in a phase I 

trial in advanced solid tumors.In addition we use DCE-MRI for early 

identification of patients with benefit from BIBF 1120. Methods: This is an 

open-label, monocentric phase I trial with three dosage arms in a classical 

�3�3� design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg 

BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be 

administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF 

1120 will be given. There is no interindividual dose escalation, and the 

enrollment of the patients will be performed sequentially. Eligible are all 

patients with relapsed or refractory advanced/metastatic solid tumors 

(UICC stage IV) and an ECOG performance state of 0-1 for whom no further 

standard therapies are available and who have predefined adequate organ 

functions. All patients will start with a 2-week run-in phase of 2 x 200 mg 

BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging 

(DCE-MRI) scans will be performed at baseline staging, on day 3 and day 

14. On day 14, there will also be 12 hours-pharmacokinetic (PK) 

assessment. Combination therapy within the forementioned dosage arms 

starts on day 15. After two weeks of combination therapy, on day 29, a 

DCE-MRI scan and 12-hours PK will be performed. Restaging for the 

evaluation of the efficacy will be performed on day 57. The safety of this 

combination will be assessed throughout the complete therapy phase using 

CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed 

until day 42. Patients who experience clinical benefit (i.e., response 

or stable disease) on day 57 with adequate tolerability of the combination 

will further receive the medication, as long as the benefit lasts. The trial is 

registered under NCT01349296 (clinicaltrials.gov). Recruitment in arm A 

has started in February 2012. 


201s 


Phase Ia/b study of combination carboplatin, paclitaxel, and ridaforolimus 

in patients with solid, endometrial, and ovarian cancers. Presenting Author: 

Hye Sook Chon, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 

FL 

Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is 

a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and 

oral formulations. PI3K/AKT/mTOR signalling is associated with resistance 

to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts 

AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin 

(PC) have broad activity including endometrial, ovarian, and many 

cancers. mTOR inhibition with PC has synergistic and additive effects in 

solid tumors. A common defect in endometrioid ca is mutation of PTEN, 

causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS 

over hormonal therapy of metastatic endometrial cancer in a randomized 

phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]). 

In 35 patients in a phase II study of RIDA, there were 7.7% partial response 

(PR) and 58% with stable disease with median duration 6.6 months 

(Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca 

ultimately develops a phenotype resistant to taxanes that may be overcome 

with mTOR inhibition. RIDA may therefore potentiate the response of 

endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts) 

with advanced solid ca and measureable disease and up to 3 prior therapies 

received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of 

each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered 

orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA 

cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics 

(PD) are collected. More than 1 anticipated DLT of thrombocytopenia or 

neutropenia in the latter part of the cycle shifts the escalation of RIDA to an 

alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design 

until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1 

endometrial, 1 urethral ca. The second cohort of an alternate schedule has 

been filled and evaluation continues. Further characterization of tolerability, 

efficacy, and PD are planned at the MTD in the phase IB expansion 

cohorts of 15 ovarian/15 endometrial cancers. 


A dose escalation, single arm, phase Ib/II combination study of BEZ235 

with everolimus to determine the safety, pharmacodynamics, and pharmacokinetics 

in subjects with advanced solid malignancies including glioblastoma 

multiforme. Presenting Author: Mohamad Adham Salkeni, University 

of Cincinnati Cancer Institute, Cincinnati, OH 

Background: Downregulation of a number of signaling pathways, including 

the mammalian target of rapamycin (mTOR) pathway, has been demonstrated 

to be efficacious in a large range of solid tumors such as breast, 

colon, endometrial, glial and hepatocellular carcinoma (HCC). However, we 

find that rapamycins lead to suppression of a negative feedback loop from 

S6 Kinase 1 (S6K1) to Protein Kinase B (PKB), leading to hyperactivation 

of PKB. In pre-clinical studies using a mouse model of carcinogen-induced 

HCC, we have demonstrated that combining BEZ235 (a potent and highly 

selective reversible ATP site competitive inhibitor of PI3K and mTOR) with 

everolimus (an allosteric inhibitor of mTOR) synergizes to inhibit tumor 

growth. BEZ235, an orally administered agent, has demonstrated preliminary 

antitumor activity in a first-in-human phase I study. The current study 

will evaluate this combination in patients with a variety of solid malignancies 

that includes glioblastoma multiforme (GBM). Methods: This study is 

divided into a phase 1b portion designed to determine safety of increasing 

doses of the combination, with extensive pharmacokinetics, pharmacodynamics 

and pharmacogenomics analysis; and a phase 2 portion that 

includes both solid tumors and GBM based on predominance of the mTOR 

and PI3K deregulation in these tumors, to determine preliminary antitumor 

activity and the recommended dose for phase 2 studies. We will also 

integrate biomarker assessment for gene expression products of the mTOR 

downstream pathway such as eukaryotic initiation factor 4E binding protein 

(4EBP1) and S6 kinase (S6K). The phase 1b portion has started accruing. 




A phase I study determining the safety and tolerability of combination 

therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, 

a MEK inhibitor, in advanced solid tumors enriched with patients with 

advanced differentiated thyroid cancer. Presenting Author: Shabina Roohi 

Ahmed, The Johns Hopkins University School of Medicine, Baltimore, MD 

Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, 

especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the 

development of many different types of cancers, including breast, colorectal, 

melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is 

the most common endocrine malignancy, but there is currently no approved 

therapy for advanced radioiodine-resistant disease. In DTC xenograft 

models, vertical inhibition of this pathway, achieved by targeting the 

vascular endothelial growth factor receptor (VEGFR) and MEK, has shown 

greater clinical efficacy than with either agent alone. Pazopanib (P) is a 

small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, 

PDGFR-�, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC 

from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months 

in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly 

selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al. 

reported an ORR of 81% in BRAF mutant melanoma patients when G was 

combined with a RAF inhibitor. Methods: A phase I, open label, dose 

escalation trial with P�G is currently accruing pts with advanced malignancies. 

The study is a standard 3�3 design with an expansion cohort of 25 pts 

with advanced DTC for correlative endpoints and PK studies. Pts will be 

treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held 

constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD. 

Eligibility includes advanced solid tumor, good end organ function and 

performance status, and PD within 6 months in the expansion cohort. The 

primary objective is to determine the safety and tolerability of the 

combination and determine the MTD. Secondary objectives include assessing 

preliminary efficacy as defined by RECIST criteria and PFS, and 

exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for 

changes in signaling through p-ERK. RAS and RAF mutation sites will be 

sequenced in order to correlate with PD endpoints and disease response. 

Currently, DL1 has accrued with no DLTs. 


Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), 

and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced 

or metastatic solid tumors. Presenting Author: Jeffrey R. Infante, 

Sarah Cannon Research Institute, Nashville, TN 

Background: The PI3K/mTOR and MAPK signaling pathways are frequently 

aberrantly activated in tumors and interact to promote growth and resistance 

to treatment. Simultaneous inhibition of both pathways may enhance 

antitumor activity. This trial investigates the combination of pimasertib, a 

highly selective MEK1/2 inhibitor, and SAR245409, a dual PI3K/mTOR 

inhibitor (ClinicalTrials.gov NCT01390818). Maximum tolerated dose 

(MTD) when administered once daily (qd) as a single agent to solid tumor 

patients (pts) is 90 mg for both compounds. Methods: Pts with advanced 

solid tumors characterized by frequent alterations of the MAPK or PI3K/ 

mTOR pathways (pancreatic, thyroid, colorectal, non-small cell lung, 

endometrial, renal, breast, ovarian and melanoma) and/or with identified 

alterations in genes activating these pathways, adequate performance 

status and organ function, and no retinal disease are eligible for entry. The 

primary objective of the trial is to determine the MTD of the combination 

therapy. Secondary objectives include: safety, pharmacokinetics (PK), 

pharmacodynamics (PD), biomarker identification and antitumor efficacy 

(response rate via RECIST v1.1). Both compounds are dosed together qd 

continuously in 21 day cycles. The study uses a classical 3 � 3 design, with 

modified Fibonacci (decreasing increments) dose escalation based on 

occurrence of dose-limiting toxicities (DLTs). In parallel with dose escalation, 

more pts may be enrolled in already tested lower dose level (DL) 

cohorts to further evaluate PK, PD, safety and antitumor activity. After MTD 

confirmation, additional pts may be enrolled in up to 4 disease-specific 

cohorts based on scientific rationale, and observed preclinical and clinical 

activity signals. As of January 25th 2012, 20 pts have been treated. No 

DLTs have been reported. 


LBA3500^ Oral Abstract Session, Sun, 9:45 AM-12:45 PM 

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, 

following induction first-line chemotherapy plus Bev, in patients with 

metastatic colorectal cancer (mCRC): Efficacy and safety results of the 

international GERCOR DREAM phase III trial. Presenting Author: Christophe 

Tournigand, Hôpital Saint-Antoine, Paris, France 








Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). 

Presenting Author: Eric Van Cutsem, Digestive Oncology Unit, Leuven Cancer 

Institute, University Hospital Gasthuisberg, Leuven, Belgium 

Background: Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT 

trial was conducted to evaluate REG in patients (pts) with mCRC who had 

progressed after all approved standard therapies. Methods: Enrollment criteria 

included documented mCRC and progression during or �3 months after last 

standard therapy. Pts were randomized 2:1 to receive best supportive care plus 

either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary 

endpoint was overall survival (OS). Secondary endpoints included progressionfree 

survival (PFS), overall response rate, disease control rate, safety and quality 

of life (QoL). Efficacy analyses across prespecified subgroups were evaluated 

using univariate Cox regression. Results: 760 pts were randomized (REG: 505; 

PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS 

and PFS were significantly improved in REG arm compared to PL arm: hazard 

ratio (HR) for OS 0.77 (95% CI 0.64-0.94, 1-sided p�0.0052), median OS 6.4 

vs 5.0 mos; HR for PFS 0.49 (95% CI 0.42-0.58, 1-sided p�0.000001), 

median PFS 1.9 vs 1.7 mos. Comparable OS and PFS benefits were observed in 

exploratory subgroup analyses by region, age, time from diagnosis of mCRC to 

randomization, prior lines of treatment, and KRAS status (shown in table). The 

most common grade 3� AEs related to REG were hand-foot skin reaction 

(16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea (7.2%) and rash/ 

desquamation (5.8%). QoL data will be presented. Conclusions: REG demonstrated 

statistically significant improvement in OS and PFS over PL, as well as 

comparable efficacy benefits across pt subgroups analyzed. 

OS PFS 

Subgroups N HR 95% CI HR 95% CI 

Region* 

North America, Western EU, 632 0.77 0.62-0.95 0.50 0.42-0.60 

Israel and Australia 

Asia 104 0.79 0.43-1.46 0.43 0.28-0.68 

Age 

< 65 yrs 475 0.72 0.56-0.91 0.42 0.34-0.51 

> 65 yrs 285 0.86 0.61-1.19 0.65 0.50-0.86 

Time from Dx of mCRC to randomization 

< 18 mo 140 0.82 0.53-1.25 0.58 0.41-0.84 

> 18 mo 620 0.76 0.61-0.95 0.48 0.40-0.58 

No. of prior treatment lines on or after metastatic disease 

< 3 395 0.79 0.60-1.04 0.53 0.43-0.67 

> 3 365 0.75 0.56-0.99 0.47 0.37-0.59 

KRAS ^ 

WT 299 0.65 0.48-0.90 0.48 0.36-0.62 

MUT 430 0.87 0.67-1.12 0.53 0.43-0.65 

* 24 pts from other regions not shown. ^ Historical record. 


203s 

LBA3501 Oral Abstract Session, Sun, 9:45 AM-12:45 PM 

Results of the X-PECT study: A phase III randomized double-blind 

placebo-controlled study of perifosine plus capecitabine (P-CAP) versus 

placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic 

colorectal cancer (mCRC). Presenting Author: Johanna C. Bendell, SCRI/ 

Tennessee Oncology, Nashville, TN 







CRA3503 Oral Abstract Session, Sun, 9:45 AM-12:45 PM 

Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression 

in patients with metastatic colorectal cancer (mCRC) previously 

treated with BEV plus CT: Results of a randomized phase III intergroup 

study (TML study). Presenting Author: Dirk Arnold, Hubertus Wald Tumor 

Center, University Cancer Center Hamburg (UCCH), Hamburg, Germany 








204s Gastrointestinal (Colorectal) Cancer 


Final analysis of the phase III randomized trial of cetuximab (CET) plus 

either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy 

refractory, K-RAS wild-type (WT), metastatic colorectal carcinoma 

(mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial. Presenting 

Author: Lillian L. Siu, Princess Margaret Hospital and University of Toronto, 


Background: The anti-EGFR monoclonal antibody CET has improved survival 

in pts with chemotherapy refractory, K-RAS WT mCRC. BRIV is a 

potent inhibitor of multiple receptor tyrosine kinases including both VEGFR 

and FGFR. The combination of CET and BRIV targets tumor growth and 

angiogenesis and demonstrated encouraging activity in an early phase 

clinical trial. Methods: Pts with mCRC previously treated with combination 

chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading 

dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800 

mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior 

anti-VEGF, but no prior anti-EGFR therapy. Primary endpoint was overall 

survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized 

(376 in Arm A and 374 in Arm B). Demographics: median age�64 

(range 27-88); male�64%; ECOG 0:1:2 (%)�32:58:10; �3 prior chemotherapy 

regimens�92%; prior anti-VEGF therapy�41%; K-RAS WT�97%. 

Primary analysis was conducted per protocol after 536 deaths were 

observed, with median OS of 8.8 months in Arm A and 8.1 months in Arm 

B, hazard ratio (HR)�0.88; 95% CI�0.74 to 1.03; p�0.12. Median 

progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in 

Arm B, HR�0.72; 95% CI�0.62 to 0.84; p�0.0001. Incidence of any 

�grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Time to 

deterioration of physical function was shorter and global quality of life 

scores were lower in Arm A vs Arm B. Planned subgroup analyses revealed 

no statistically difference in treatment effects on OS based on pre-specified 

factors of age, gender, ECOG and race. Likewise, no difference was 

detected based on exploratory subgroup analyses of LDH and prior 

anti-VEGF therapy. Conclusions: Despite positive effects on PFS, the 

combination of CET�BRIV did not significantly improve OS in pts with 

chemotherapy refractory, K-RAS WT mCRC. Final updated results based on 

20-25% additional events for a total of nearly 700 deaths, as well as 

further exploratory subgroup analyses, will be presented. 


FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) 

followed by FOLFIRI (6 cycles) in patients with initially resectable 

metastatic colorectal cancer: A GERCOR randomized phase III study 

(MIROX). Presenting Author: Mohamed Hebbar, Medical Oncology Unit - 

Hôpital Huriez, Lille, France 

Background: Perioperative FOLFOX4 is the standard chemotherapy (CT) in 

patients with resectable metastases from colorectal cancer (CRC) (Nordlinger 

et al, Lancet 2008). To increase curability and reduce the risk of 

severe neuropathy, we evaluated the sequential administration of a 

dose-dense oxaliplatin-based regimen followed by an irinotecan-based 

regimen. Methods: Patients with CRC and initially resectable or resected 

metastases were randomized between arm A (control): FOLFOX4 (12 

cycles; oxaliplatin 85 mg/m²) or arm B (investigational): FOLFOX7 (6 

cycles; oxaliplatin 130 mg/m²) followed by FOLFIRI (6 cycles; irinotecan 

180 mg/m²). CT was either perioperative or postoperative. Stratification 

criteria were: perioperative vs. postoperative CT, surgery alone vs. radiofrequency 

ablation �/- surgery, Blumgart’s prognostic score (0-1 vs. 2-3 vs. 

4-5). Only one metastatic site was allowed, but the number of metastases 

per organ was not limited. The primary endpoint was disease-free survival 

(DFS). Results: From May 2004 to June 2010, 284 patients were 

randomized (142 in each arm). Baseline patient characteristics were 

similar in both arms. Liver was the main metastatic site. There was only one 

metastasis in 70 (49.3%) patients in arm A and 69 (48.6%) patients in 

arm B. CT was administered perioperatively in 168 (59.1%) patients, and 

postoperatively in 116 (40.9%) patients. In case of perioperative CT, 

R0-R1 resection was achieved in 58/85 (68.2%) patients in arm A and 

67/83 (80.7%) patients in arm B. Grade 3 neuropathy occurred in 34 

(23.9%) and 28 (20.0%) patients in arm A and B, respectively. Grade 3/4 

thrombocytopenia and gastrointestinal toxicities (nausea, vomiting, diarrhea) 

were more frequent in arm B. Median follow-up was 50.4 months 

[95% CI: 45.6-54.4]. Median DFS were 22.4 months [95% CI: 17.9-36.2] 

in arm A and 23.0 months [95% CI: 19.7-35.6] in arm B (HR�0.97 [95% 

CI: 0.72-1.31]; p�.856). Conclusions: FOLFOX7 followed by FOLFIRI is 

not superior to the standard FOLFOX4 chemotherapy in patients with 

resectable metastatic colorectal cancer. 


Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: 

A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with 

metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen. 

Presenting Author: Carmen Joseph Allegra, University of Florida/Shands, 

Gainesville, FL 

Background: Aflibercept (Afl; also known as VEGF Trap) is a recombinant 

human fusion protein that acts as a decoy receptor and prevents the 

interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and 

placental growth factor (PlGF) with their receptors. In the phase III 

VELOUR study, Afl � FOLFIRI improved overall survival (OS) compared 

with FOLFIRI � placebo (pbo) in mCRC (ECCO 2011, abstract 6LBA). We 

report outcomes from a pre-specified subgroup analysis by prior B use. 

Methods: Pts with mCRC and progression during or after oxaliplatin were 

randomized 1:1 to receive either FOLFIRI � pbo or FOLFIRI � Afl 4 mg/kg 

IV Q2W with stratification by ECOG performance score (PS, 0v1v2)and 

prior B. OS and progression-free survival (PFS) in the prior B-treated pts are 

reported as median estimate and hazard ratios (HRs); 95.34% CI for OS 

and 95% CI for PFS. Results: Of the 1226 pts in the overall study, 187 in 

the pbo and 186 in the Afl group were stratified to prior B. The 2 arms were 

well balanced: median age 60 yrs; male 58%; PS 0-1 97%; and 55% �1 

metastatic organ. Although not powered for survival, Afl produced a 

consistent trend towards prolonged OS and PFS, regardless of prior B use, 

with no evidence of interaction (OS, P�0.7231; PFS, P�0.6954). The 

incidence of treatment-emergent adverse events in the Afl arm was similar 

in pts with prior B (100%) to those without (98.9%), with a similar 

incidence of grade 3/4 events (82.5% and 83.9%, respectively). 

Conclusions: Results of this pre-specified subgroup analysis indicate that 

adding Afl to FOLFIRI resulted in a consistent trend of increased OS and 

PFS, regardless of prior B use. Prior treatment with B did not appear to 

impact the safety profile of Afl. 

Pbo Afl HR 

Overall survival 

All pts 

12.1 

13.5 

0.817 

(N�1,226) (11.07-13.11) (12.52-14.95) (0.713-0.937) 

No prior B (N�853) 12.4 

13.9 

0.788 

mo 

(11.17-13.54) (12.72-15.64) (0.669-0.927) 

Prior B (N�373) 

11.7 

12.5 

0.862 

mo 

(9.82-13.77) (10.78-15.51) (0.673-1.104) 

Progression-free survival 

No prior B 

5.4 

6.9 

0.797 

mo 

(4.53-5.68) (6.37-7.20) (0.679-0.936) 

Prior B 

3.9 

6.7 

0.661 

mo 

(3.02-4.30) (5.75-8.21) (0.512-0.852) 


Impact on survival of primary tumor resection in patients with colorectal 

cancer and unresectable metastasis: Pooled analysis of individual patients’ 

data from four randomized trials. Presenting Author: Matthieu Faron, 

Institut Gustave Roussy, Villejuif, France 

Background: In patients with colorectal cancer (CRC) and unresectable 

metastasis, the prognostic impact of primary tumor resection still remains a 

matter of debates. The goal of this study was to estimate, after adjustment 

for prognostic factors, the effect of primary tumor resection on survival. 

Methods: Individual patients’ data of the 1155 patients with metastatic 

CRC included in 4 first-line chemotherapy trials (FFCD 9601, FFCD 

2000-05, ACCORD 13 and ML 16987) where retrieved. Patients were 

eligible for this study if they had synchronous metastasis judged unresectable. 

Primary endpoint was overall survival (OS), secondary endpoint was 

progression free survival (PFS). A Cox proportional hazard model stratified 

on the trial was used to estimate the impact on survival. Results: 810 

patients beginning first-line chemotherapy with either fluoropyrimidine 

alone, oxaliplatin, irinotecan and/or bevacizumab were eligible. Patients 

with a history of resection (n � 478 (59%)), as compared to those without 

(n � 332 (41%)), were more likely to have colonic primary (p � 0.0001), 

lower carcino embryonic antigen (CEA) (p � 0.0001) or alkaline phosphatase 

(ALP) level (p�0.04) and normal white blood cell count (WBC) (p � 

0.0001). In the univariate analysis, stratified on the trial, primary tumor 

resection was associated with a better OS (Hazard Ratio HR: 0.73 

[0.63-0.84]; p � 0.0001) and PFS (HR : 0.73 [0.63-0.84]; p � 0.0001). 

Multivariate analysis, adjusted for primary tumor location, CEA, ALP and 

WBC levels, OMS performance status and number of metastatic sites 

confirmed that primary tumor resection was an independent predictor of 

better OS (HR : 0.63 [0.53-0.75] ; p � 0.0001), and PFS (HR : 0.82 

[0.70-0.95] ; p � 0.0007). Significant interactions were found between 

resection and CEA level (p�0.02) and resection and primary tumor 

location (p�0.01) for OS (not for PFS) with a lower impact of resection with 

higher CEA levels or a colonic primary. Conclusions: This study confirmed 

the independent prognostic value on survival of primary tumor resection in 

patients with unresectable metastases of CRC. 



EORTC liver metastases intergroup randomized phase III study 40983: 

Long-term survival results. Presenting Author: Bernard Nordlinger, Hopital 

Ambroise Paré, Boulogne, France 

Background: This study evaluates the benefit of combining peri-operative 

chemotherapy and surgery for patients with liver only metastases from 

colorectal cancer (LM) deemed resectable on pre-operative imaging. The 

PFS results, the primary endpoint, were reported (ASCO 2007). We now 

report on the secondary endpoint overall survival (OS) results, after a 

median follow-up of 8.5 years. Methods: Between September 2000 and 

July 2004, 364 patients (pts) with up to 4 LM were randomized between 

peri-operative FOLFOX4 (oxaliplatin 85mg/m² and LV5FU2), 6 cycles 

before and 6 cycles after surgery, (CT arm), and surgery alone (S arm). OS 

was compared between arms using a 2-sided non-stratified log-rank test at 

the 0.05 level of significance (intent-to-treat analysis). Results: 182 pts 

were randomized in each arm (CT arm and S arm) of which 171 were 

eligible (CT and S) and 152 underwent resection (CT and S). In the CT arm, 

171 received preop CT and 115 received postop CT. At a median follow-up 

of 8.5 years, 221 deaths were reported (61 % of all randomized pts). 

Causes of death in CT arm were cancer relapse (85 pts), complication of 

surgery (2 pts), other causes (16 pts) and unknown cause (4 pts), and in S 

arm, cancer relapse (99 pts), complication of surgery (2 pts), other causes 

(11 pts) and unknown cause (2 pts). Observed median OS was higher in CT 

arm: 61 months (CT) vs. 54 months (S) in all randomized pts and 64 

months (CT) vs. 55 months (S) in eligible pts. The 5 year OS rate was 

51.2% (CT) vs. 47.8% (S) (all randomized) and 52.4% (CT) vs. 48.3% (S) 

(eligible pts). There was no significant difference in OS between arms 

(HR�0.88, 95% CI 0.68-1.14, p�0.34) (all randomized). After progression, 

second line treatment with chemotherapy was given in 59 % (CT) and 

77% (S) of the pts with cancer progression and repeat surgery in 46% (CT) 

and 40% (S), respectively. Conclusions: Peri-operative chemotherapy with 

FOLFOX4 improves PFS but does not significantly improve OS over surgery 

alone. A potential benefit may have been diluted by second treatment lines 

and by more deaths unrelated to cancer in the CT arm. 


4:30 PM-5:30 PM 

Validation of a genomic classifier (ColoPrint) for predicting outcome in the 

T3-MSS subgroup of stage II colon cancer patients. Presenting Author: 

Ramon Salazar, Institut Catala d’Oncologia, Barcelona, Spain 

Background: Adjuvant therapy for stage II patients is recommended for 

patients with high risk features, especially with T4 tumors. Adjuvant 

therapy is not indicated for patients with MSI-H status who are considered 

of being at low risk of disease relapse. However, this leaves the majority of 

patients with an undetermined risk. ColoPrint is an 18-gene expression 

classifier that identifies early-stage colon cancer patients at higher risk of 

disease relapse. Methods: ColoPrint was developed using whole genome 

expression data and was validated in public datasets (n�322) and 

independent patient cohorts from 5 European hospitals. Tissue specimen, 

clinical parameters, MSI-status and follow-up data (median follow-up 70 

months) for patients were available and the ColoPrint index was determined 

using validated diagnostic arrays. Uni-and multivariate analysis was performed 

on the pooled stage II patient set (n�320) and the subset of 

patients who were T3/ MSS (n�227). Results: In the analysis of all stage II 

patients, ColoPrint classified two-third of stage II patients as being at lower 

risk. The 3-year Relapse-Free-Survial (RFS) RFS was 91% for Low Risk and 

74% for patients at higher risk with a HR of 2.9 (p�0.001). Clinicopathological 

parameters from the ASCO recommendations (T4, perforation, �12 

LN assessed, and/ or high grade) or NCCN guidelines (ASCO factors plus 

angio-lymphatic invasion) did not predict a differential outcome for high 

risk patients (p� 0.20). In the subgroup of patients with T3 and MSS 

phenotype, ColoPrint classified 61% of patients at lower risk with a 3-year 

RFS of 91% (86-96%) and 39% of patients at higher risk with a 3-year RFS 

of 73% (63-83%) (p�0.002). No clinical parameter was significantly 

prognostic in this subgroup. Conclusions: ColoPrint combined with established 

clinicopathological factors and MSI, significantly improves prognostic 

accuracy, thereby facilitating the identification of patients at higher risk 

who might be considered for additional treatment. 



4:30 PM-5:30 PM 

Validation of two gene-expression risk scores in a large colon cancer cohort 

and contribution to an improved prognostic method. Presenting Author: 

Arnaud Roth, University Hospital Geneva, Geneva, Switzerland 

Background: Prognosis prediction for resected primary colon cancer is 

currently based on the tumor, nodes, metastasis (TNM) staging system. 

Gene expression based risk scores have been proposed, but need to be 

validated and integrated with clinical and TNM variables. We performed an 

independent assessment of the individual recurrence signatures developed 

for commercial use by Veridex and Genomic Health. Methods: The Veridex 

(aVDS) and Genomic Health (aGHS) risk scores were applied to existing 

gene expression data of 580 stage III and 108 stage II tumors from the 

PETACC-3 trial. Association of the scores with relapse-free (RFS) and 

overall survival (OS) of the patients was assessed singularly, and in a 

combination with TNM and other clinico-pathological variables, by univariate 

and multivariate Cox regression models and logrank methods. Results: 

Both risk scores were significantly associated with RFS in univariate and 

multivariate models (Table) for the stage III cohort. The scores contributed 

different and additive prognostic information, and reached highest effect 

sizes (approximate p-value 0.001 and HR per interquartile range 1.4 each) 

in a combined model (Table) that includes both scores as well as T-stage, 

N-stage and MSI status as significant factors. Analysis in the stage II cohort 

gave similar effect estimates. Conclusions: This study confirms in an 

independent colon cancer patient cohort that gene expression based risk 

scores improve current prognostic models. The best prognostic model was 

obtained by using clinico-pathological variables and both gene-expression 

risk-scores. 

aGHS aVDS 

RFS OS RFS OS 

Model HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value 

Univariate 1.32(1.10 - 1.58) 0.0023 1.35(1.10 - 1.65) 0.0043 1.25(1.05 - 1.50) 0.0130 1.22(0.99 - 1.50) 0.0571 

Multivariate 1.24(1.04 - 1.49) 0.0190 1.27(1.03 - 1.58) 0.0255 1.28(1.05 - 1.55) 0.0130 1.25(1.00 - 1.56) 0.0500 

Combined 

(aGHS 

� aVDS) 

1.36(1.13 - 1.65) 0.0014 1.40(1.11 - 1.75) 0.0037 1.41(1.15 - 1.73) 0.0011 1.38(1.09 - 1.75) 0.0074 

Hazard ratios for 1 interquartile range variation. 

205s 


4:30 PM-5:30 PM 

Identification and validation of gene expression subtypes in a large set of 

colorectal cancer samples. Presenting Author: Eva Budinska, Swiss Institute 

of Bioinformatics, Lausanne, Switzerland 

Background: From a clinical perspective colorectal cancer (CRC) is a 

heterogeneous disease whose biological background is insufficiently understood. 

In order to adapt targeted treatment to biologically different 

categories of CRC patients, in depth understanding of the molecular 

mechanisms involved in CRC heterogeneity is urgently needed. Methods: 

Consensus cluster analysis of 1113 stage II-III CRC gene expression 

profiles from PETACC3 and 4 public datasets defined a set of subtypes 

which were confirmed in an independent set of 720 samples. The similarity 

between tumors was based on a set of 54 meta-genes. This approach 

improves the robustness to measurement noise and gives equal chances to 

each biological process to be accounted for in the subtype definition. We 

tested the association of the subtypes with clinical variables, molecular 

markers and patient survival. Results: We identified and validated 5 major 

subtypes A-E, with different levels of expression in 6 main molecular 

processes: epithelial-mesenchymal transition (EMT), immune response, 

colon crypt differentiation, proliferation, Wnt signaling and chromosome 

20q. Significant differences in survival and an enrichment for markers such 

as MSI, BRAF mutation, site or p53 status were found between the 

subtypes. In addition, the new subtype classification uncovered heterogeneity 

within groups defined by these commonly used markers. Survival 

analysis showed significant prognostic value for meta-genes connected to 

EMT, proliferation and differentiation. Identical data processing and 

clustering applied to the validation set on the same meta-genes resulted in 

subtypes with almost identical expression patterns. Conclusions: We 

identified and validated robust molecular subtypes in the largest set of 

stage II-III CRC samples as a combination of multiple molecular processes, 

that complement current disease stratification based on clinico-pathological 

variables and molecular markers. The biological relevance of these 

subtypes was reflected in significant differences in survival. These insights 

open new perspectives for improving prognostic models and rationalize the 

prediction of tumor-specific drug sensitivity. 




4:30 PM-5:30 PM 

Validation of the 12-gene colon cancer recurrence score (RS) in NSABP 

C07 as a predictor of recurrence in stage II and III colon cancer patients 

treated with 5FU/LV (FU) and 5FU/LV�oxaliplatin (FU�Ox). Presenting 

Author: Michael O’Connell, National Surgical Adjuvant Breast and Bowel 

Project, Pittsburgh, PA 

Background: Standardized clinical tools which accurately quantify recurrence 

risk are needed for optimal adjuvant treatment of colon cancer. The 

12-gene RS has been validated in stage II colon cancer pts from QUASAR 

and CALGB 9581. We conducted a large prospectively-designed clinical 

validation study of RS, w/ pre-specified endpoints, methods, and analysis 

plan, in stage II and III colon cancer pts randomized to FU or FU�Ox in 

NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, 

stratified on stage (AJCC 6th ) and recurrence. Gene expression was 

quantitated by RT-PCR on 25 �m manually microdissected fixed colon 

tumor tissue. Data were analyzed by Cox regression controlling for stage and 

treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 

449 FU, 443 FU � Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary 

endpoint was met: RS predicted recurrence (HR/25 units�1.96, 95% CI 

1.50-2.55 p�.001). RS also predicted disease-free survival (p�.001) and 

overall survival (p�.001). RS predicted recurrence (p�.001) independent 

of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high 

RS group (26% of pts) had higher recurrence risk than low RS group (39% 

of pts): HR�2.11, p�.001. Cox model 5 yr recurrence risk (95%CI) in FU 

treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 

18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30- 

46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not 

have significant interaction w/ stage (p�0.90) or age (p�0.76). Relative 

benefit of Ox was similar across range of RS (interaction p�0.48); 

accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of 

Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in 

stage II and III colon cancer, capturing underlying biology and providing 

risk information beyond conventional factors. RS is not predictive of 

relative benefit of Ox added to adjuvant FU but enables better discrimination 

of absolute Ox benefit as a function of risk. Incorporating RS into the 

clinical context may better inform adjuvant therapy decisions for pts w/ 

stage III as well as stage II colon cancer. 


4:30 PM-5:30 PM 

Prognostic impact of BRAF and KRAS mutations and their relationship to 

DNA mismatch repair (MMR) status in 2,686 stage III colon cancer 

patients (pts) treated in a phase III study of adjuvant FOLFOX with or 

without cetuximab: NCCTG N0147. Presenting Author: Frank A. Sinicrope, 


Background: Activating mutations in the BRAF oncogene (mutBRAF) are 

associated with deficient MMR (dMMR) in sporadic colon cancers and are 

mutually exclusive with KRAS mutations (mutKRAS). We evaluated BRAF 

and KRAS in relation to MMR and disease-free survival (DFS) in stage III 

pts treated with adjuvant FOLFOX �/-cetuximab; study was amended 

mid-way to require prospective KRAS testing (Alberts SR, ASCO 2010). 

Methods: Extracted DNA from archival tumors was analyzed for BRAF exon 

15 (V600E) and KRAS exon 2 mutations by allele specific RT-PCR. Tumors 

with loss of any MMR protein (MLH1, MSH2, MSH6) were categorized as 

dMMR vs proficient (pMMR). DFS was censored at 4 yrs; median follow-up 

was 3.1 yrs. Results: Among 2,686 pts, 12% (314/2580) of tumors were 

dMMR; 28% (716/2579) had mutKRAS, and 14% (346/2515) had 

mutBRAF of which 43% (150/346) were dMMR. mutBRAF was associated 

with high grade, proximal site, T3-4, �4 LNs, and dMMR (all p�0.002); 

mutKRAS with low grade, proximal, �3 LNs, and pMMR (all p�0.02). 

Among dMMR tumors, mutKRAS was more frequent in distal vs proximal 

cancers (28% vs. 8%, p�0.0004). Both mutKRAS (HR�1.42, p�0.0001) 

and mutBRAF (HR�1.34, p�0.02) were associated with worse DFS and 

remained significant after adjustment for treatment, MMR, grade, site, T 

stage and LNs. mutBRAF (p�0.003) and mutKRAS (p�0.003) were each 

prognostic for DFS in pMMR, but not dMMR tumors (KRAS, p�0.79; 

BRAF, p�0.60). While MMR was not significant univariately, proximal 

dMMR tumors had favorable DFS [HR 0.8, 95% CI (0.6-1)] and distal 

dMMR tumors had poor DFS [HR 2 (1.1-3.4)] after adjusting for KRAS, 

BRAF, grade, T stage and LNs (pinteraction�0.02). pMMR/mutBRAF 

(p�0.027) and pMMR/mutKRAS (p�0.001) had worse DFS vs pMMR/ 

bothWT. Conclusions: mutBRAF and mutKRAS were significantly associated 

with worse DFS independent of treatment, covariates, and each other, 

with the DFS impact restricted to pMMR tumors. Prognostic impact of 

MMR was dependent upon tumor site after adjusting for covariates. 

Support: NIH Grant CA 25224, NCI K05CA 142885, Bristol-Myers 

Squibb, ImClone, Sanofi-Aventis, and Pfizer. 


4:30 PM-5:30 PM 

The prognostic importance of miRNA-21 in stage II colon cancer: A 

population-based study. Presenting Author: Sanne Kjaer-Frifeldt, Department 

of Oncology, Vejle Hospital, and Danish Colorectal Cancer Group 

South, Vejle, Denmark 

Background: Adjuvant chemotherapy for stage II colon cancer patients is 

still controversial and the debate on which patients should be considered as 

high risk patients is still ongoing. The decision is based on clinical and 

pathological markers of risk, which are inadequately informative in most of 

the patients, and better methods are highly needed. The aim of the present 

study was to investigate the possible prognostic importance of miRNA-21, 

quantified by in situ hybridization (ISH), in a unique, large populationbased 

cohort of patients treated for stage II colon cancer patients. Methods: 

The study included all patients diagnosed with stage II colon cancer in 

Denmark in the year 2003 (711 patients), representing a full population of 

five million people. Patients receiving adjuvant chemotherapy were excluded 

(N�15). One paraffin-embedded tissue block was obtained from 

each patient. A 6�m-thick section was processed for formazan-based 

chromogenic miR-21 ISH analysis and counter stained with nuclear red. 

The blue miR-21 ISH signal was assessed by image analysis to obtain two 

quantitative expression estimates: the total blue area (TB) and the ratio of 

TB with the nuclear density (TBR). Results: The miRNA-21 signal was 

predominantly observed in fibroblast-like cells located in the stromal 

compartment of the tumors. Patients expressing high levels of miRNA-21 

(high mean TBR) had significantly inferior cancer specific survival (CSS): 

HR � 1.26 (95% CI; 1.15-1.60), p �0.001. In the COX regression 

analysis (including; gender, T-category, malignancy grade, localization, 

tumor perforation, tumor fixation, number of lymph nodes and MSI status), 

mean TBR was found to be an independent predictive marker of poor CSS, 

HR � 1.41 (95%CI; 1.19-1.67, p� 0.001). The same applied to TB. 

Conclusions: The present study shows that increasing miRNA-21 expression 

level is significantly correlated to decreasing CSS. Analyses of 

miRNA-21 should be considered as a potential adjunct in the selection of 

high risk stage II patients. 


4:30 PM-5:30 PM 

BRAF, PIK3CA, and PTEN status and benefit from cetuximab (CET) in the 

treatment of advanced colorectal cancer (CRC): Results from NCIC CTG/AGITG 

CO.17. Presenting Author: Derek J. Jonker, The Ottawa Hospital Research 

Institute, Ottawa, ON, Canada 

Background: CET, a monoclonal antibody targeting the epidermal growth factor 

receptor, improves overall survival (OS) and progression free survival (PFS) in 

patients (pts) with KRAS wild-type (WT) chemotherapy refractory CRC. BRAF 

and PIK3CA mutation status, and PTEN expression levels may further predict 

benefit from CET therapy. Methods: Available colorectal tumour samples were 

analyzed from a phase III trial of CET plus best supportive care (BSC) vs BSC 

alone (NEJM 2007; 357(20)). BRAF and PIK3CA mutations (MUT) identified in 

tumour-derived DNA using a high resolution melting analysis to identify 

amplicons with mutations were confirmed by sequencing. PTEN expression by 

immunohistochemistry (IHC) was performed on tissue microarrays constructed 

from available tumour blocks. For each biomarker, prognostic (treatment 

independent) effects were assessed in patients on the BSC alone arm. Predictive 

effects (benefit from CET) on OS and PFS among all patients and those in the 

KRAS wild-type subset were examined using a Cox model with tests for 

treatment-biomarker interaction, adjusting for covariates. Results: Of 401 pts 

assessed for BRAF status (70% of CO17 population), 13(3%) had mutations. Of 

407 pts assessed for PIK3CA status (71% of CO17 population), 61(15%) had 

mutations. Of 205 pts assessed for PTEN (36% of CO17 population), 148(72%) 

were negative for IHC expression. No biomarker was prognostic for OS or PFS, 

and none were predictive of benefit from CET, either in the whole study 

population or the KRAS WT subset. Conclusions: In chemotherapy-refractory 

CRC, neither PIK3CA mutation status nor PTEN expression were predictive of 

benefit from CET therapy. BRAF mutations are uncommon in this setting. Larger 

sample sizes would be required to determine if BRAF status is predictive for CET 

benefit. 

Prognostic analysis in BSC patients 

adj HR (MUT vs WT), [for PTEN, negative vs present] 

Biomarker 

OS PFS 

BRAF 1.47, p�0.41 1.52, p�0.37 

PI3KCA 1.11, p�0.65 1.10, p�0.66 

PTEN 1.13, p�0.70 0.99, p�0.98 

Predictive analysis in KRAS WT subset 

adj HR (CET�BSC vs BSC), interaction p value 

OS PFS 

BRAF 1.39, p�0.69 1.18, p�0.84 

PI3KCA 0.79, p�0.63 0.73, p�0.50 

PTEN 0.75, p�0.61 2.47, p�0.08 



4:30 PM-5:30 PM 

Epiregulin (EREG) and amphiregulin (AREG) gene expression to predict 

response to cetuximab therapy in combination with oxaliplatin (Ox) and 

5FU in first-line treatment of advanced colorectal cancer (aCRC). Presenting 

Author: Richard A. Adams, School of Medicine, Cardiff University, 

Cardiff, United Kingdom 

Background: Previous data suggest the EGF ligands EREG/AREG may 

predict outcome of KRAS wt patients (pts) in the chemo-refractory setting 

but has not been previously reported from first line randomised trials. 

Methods: FFPE samples from primary tumors of pts in Arms A&B of the 

COIN trial of Ox fluoropyrimidine (Fp) �/- cet were analysed for EGFR IHC, 

KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. 

Ligand levels were assessed against baseline data, prognostic markers as 

uni/multivariate analyses and as predictive markers in wild type (wt) and 

mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) 

or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG 

continuous, using Flexible Parametric survival analysis. Optimal cutoffs for 

predictive effects were defined using point at which 95% CI first excluded 

zero. Results: 952/1630 (57%) of pts were evaluable for all parameters. 

EREG/AREG were highly correlated Pearson’s rho (�) � 0.74; p�0.0001. 

High EREG/AREG levels were associated with KRAS wt (p�0.005) and 

with primary tumor in left colon/rectum, presence of liver metastases and 

high CEA (p�0.05). In the control arm, high EREG/AREG conferred a 

better prognosis among KRAS wt pts in multivariate. EREG superseded 

AREG in a combined model. High EREG predicted for OS benefit in KRAS 

wt pts treated with FOLFOX �cet, with optimal cut-off 80th centile. OS HR 

for �cet �80th centile �0.33, 95% CI 0.14-0.78, p�0.011; �80% 

centile HR�0.99, 95% CI 0.67-1.47, p�0.96; interaction p�0.059; 

�50th centile HR�0.66, 95% CI 0.40-1.09, p�0.11; �50% centile 

HR�1.09, 95% CI 0.66-1.81, p�0.73; interaction p�0.17. Similar 

results were seen for PFS, with optimal cut-off 50th centile. There was no 

predictive effect for pts treated with CapOx. Conclusions: The data suggest a 

prognostic effect of EREG/AREG in aCRC. The original hypothesis, that 

KRAS wt patients with high EREG expression have improved outcome with 

cet, seems to be limited to patients treated with FOLFOX in the first-line 

setting. 


4:30 PM-5:30 PM 

Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in 

metastatic colorectal cancer (mCRC) patients (pts) treated with first-line 

FOLFIRI plus bevacizumab (BV). Presenting Author: Chiara Cremolini, 

U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto 

Toscano Tumori, Pisa, Italy 

Background: Despite several attempts, no predictors of benefit from BV 

have been so far identified. We reported the association of VEGF rs833061 

T/T to a worse outcome in mCRC pts treated with first-line FOLFIRI�BV, 

but not in a historical cohort treated with FOLFIRI. Recent post-hoc 

analyses on randomized trials suggested the potential prognostic and/or 

predictive role of other VEGF and VEGFR1/2 SNPs. Methods: Moving from 

our retrospective finding, we designed a prospective validation trial in 

mCRC pts treated with first-line FOLFIRI� BV to detect a HR for PFS of 1.7 

for VEGF rs833061 T/T compared to C- variants. With two-sided a�0.05 

and b�0.20, 199 events were required. Accrual was faster than expected 

and in the meanwhile promising results about other SNPs were reported 

and we therefore included a confirmatory analysis of VEGF rs699946 A/G, 

VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, 

rs12505758 C/T and rs2305948 C/T and EPAS rs4145836 A/G SNPs. 

Germ-line DNA was extracted from peripheral blood. SNPs were analyzed 

by PCR and sequencing. Results: Four-hundred-twenty-four pts were 

included. At a median follow up of 24 months, median PFS was 10.5 

months. At the univariate analysis, no differences in PFS according to 

VEGF rs833061 C/T variants were observed (p�0.38). Among analyzed 

SNPs, only VEGFR2 rs12505758 C- variants (n�118) were associated to 

shorter PFS compared to TT (n�306) (HR: 1.40 [95%CI: 1.07-1.84], 

p�0.015). In the multivariate model, this association retained significance 

(HR: 1.402 [95%CI:1.079-1.822], p�0.012), that was lost by applying 

multiple testing correction. Conclusions: This prospective experience failed 

to validate the hypothesized predictive impact of VEGF rs833061 variants. 

Also other previous retrospective findings on different candidate SNPs were 

not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic 

rather than predictive impact was previously reported, correlated with PFS. 

We suggest that future studies on biomarkers of benefit from BV should 

look at the complexity of tumoral angiogenesis at different levels and not 

only from the genetic perspective. 


207s 


4:30 PM-5:30 PM 

A novel interaction of genotype, gender, and adjuvant treatment in survival 

after resection of stage III colon cancer: Results of CALGB 89803. 

Presenting Author: Robert S. Warren, University of California, San Francisco, 


Background: The p53 tumor suppressor is frequently mutated in colon 

cancer, but the influence of such mutations on survival is remains 

undefined. We investigated whether domain-specific mutations in p53 are 

predictive of survival in stage III colon cancer. Methods: p53 was evaluated 

in an intergroup trial (CALGB 89803) of patients with stage III colon cancer 

who were randomized to receive adjuvant 5-fluorouracil/leucovorin (5FU/ 

LV) or 5FU/LV with irinotecan (IFL) Tissue was collected to allow correlation 

of molecular markers with outcomes. p53 was genotyped in 607 

patient tumors. Results: p53 mutations were identified in 274 tumors, 

divided ~ equally between zinc binding and non-zinc binding regions of the 

DNA binding domain. Overall, p53 status was not predictive of benefit from 

either adjuvant regimen. Unexpectedly, the 5 year overall survival (OS) of 

women with tumors harboring non-zinc binding mutations treated with 

5FU/LV was 97% compared to OS of 72% for women with p53 wild-type 

(wt) tumors (p �0.004). Adding irinotecan to 5FU/LV negated this survival 

benefit (5 year OS of 81% vs. 72%). Conversely, 5 year OS of women 

harboring tumors with zinc binding mutations who received 5FU/LV was 

50% compared to 72% for women with p53 wt tumors (p�0.04). Adding 

irinotecan to 5FU/LV reversed the poor survival of women with tumors 

harboring zinc binding mutations and improved 5 year OS (50% vs. 73%; 

p�0.1). No difference in OS was observed for men on either treatment arm 

or when genotype was considered. Conclusions: CALGB 89803 demonstrated 

a lack of survival benefit for stage III colon cancer patients when 

irinotecan was added to 5FU/LV (IFL). We now show that in the setting of a 

large clinical trial, refined stratification of women, based upon domainspecific 

mutations of p53 identifies subsets of patients likely to benefit 

from, or respond poorly to, adjuvant 5FU/LV. The interaction of p53 

genotype, gender, and adjuvant therapy regimen has the potential to be 

paradigm changing in the treatment of colon cancer, and possibly other 

malignancies. These data, if validated, suggest that evaluation of p53 

genotype and gender may guide clinicians to make rational choices of 

adjuvant therapy. 


4:30 PM-5:30 PM 

Ligand expression of the EGFR ligands amphiregulin, epiregulin, and 

amplification of the EGFR gene to predict for treatment efficacy in KRAS 

wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX: 

Analysis of the randomized AIO CRC-0104 trial. Presenting Author: 

Sebastian Stintzing, Department of Hematology and Oncology, Klinikum 

Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich, 

Germany 

Background: We investigated the expression of the EGFR ligands amphiregulin 

(AREG) and epiregulin (EREG) as well as the amplification of the 

EGFR-gene in tumor specimens of mCRC patients (pts) treated first-line 

with anti-EGFR targeted cetuximab together with CAPOX or CAPIRI. 

Expression levels were correlated with overall response rate (ORR), progression 

free survival (PFS) and overall survival (OS) to determine their 

relationship with effectiveness in this setting. Methods: A total of 185 

mCRC pts were randomized to cetuximab (400mg/m² day 1, followed by 

250mg/m² weekly) plus CAPIRI (irinotecan 200mg/m², day 1; capecitabine 

800mg/m² twice daily days 1-14, every 3 weeks; 20% dose reduction of 

both agents for pts older than 65 years) or plus CAPOX (oxaliplatin 

130mg/m² day 1; capecitabine 1000mg/m² twice daily days 1-14, every 

three weeks). The primary study endpoint was ORR. KRAS mutational 

status did not correlate with treatment outcome. The cut-offs for EGFRamplification 

using FISH, AREG and EREG levels determined by RT-qPCR 

were calculated using ROC analysis for ORR. Results: Within the subgroup 

of KRAS wildtype tumors, analysis of EREG- and AREG-expression was 

possible in 99 pts and of EGFR-amplification in 63 pts. Higher AREG levels 

correlated significantly with higher ORR (83% vs 46%, p�0.006, OR 

0.31), longer PFS (9.6mo vs 4.9, p�0.001, HR 0.35) and longer OS 

(39.9mo vs 17.2mo, p�0.001, HR 0.36). Higher EREG levels showed a 

significant correlation with ORR (74% vs 47%, p�0.036, OR 0.54), longer 

PFS (7.9mo vs 4.9mo, p�0.026, HR 0.57) and OS (33.0mo vs 20.2mo, 

p�0.041, HR 0.57). EGFR-amplification correlated significantly with 

higher ORR (71% vs 33%, p�0.004, OR 0.49), longer PFS (8.4mo vs 

4.6mo, p�0.004, HR 0.50) and longer OS (30.5mo vs 15.2mo, p�0.001, 

HR 0.44). Conclusions: In the treatment setting of cetuximab combined 

with CAIPIRI or CAPOX, AREG, EREG and EGFR-amplification predicted 

treatment efficacy. Within the subgroup of pts with KRAS wildtype tumors, 

EGFR-FISH and AREG expression have the strongest relationship with 

treatment efficacy. 




4:30 PM-5:30 PM 

Effect of low-frequency KRAS mutations on the response to anti-EGFR 

therapy in metastatic colorectal cancer. Presenting Author: David Tougeron, 

Department of Gastroenterology, Poitiers University Hospital, Poitiers, 

France 

Background: Monoclonal antibodies against the epidermal growth factor 

receptor (EGFR) are standard components of treatment algorithms in 

metastatic colorectal cancer (mCRC). It is already well established that 

only patients with wild-type KRAS tumors benefit from treatment with an 

anti-EGFR agent. Pyrosequencing is now used for a precise determination 

of KRAS mutation burden and a conservative cutoff of 10% was defined as 

the lower limit of quantification for the assignment of mutation status. Up 

to now, the impact of low-signal KRAS mutations below 10% on the 

response to anti-EGFR therapy in mCRC has not been evaluated. Methods: 

All consecutive patients treated by anti-EGFR for a mCRC between January 

2006 and June 2011 have been retrospectively analyzed by pyrosequencing 

using the therascreen KRAS Pyro Kit (Qiagen). All patients were defined 

wild-type (WT) for KRAS status using direct sequencing. The PFS data were 

plotted as Kaplan–Meier curve and compared by the log-rank test. Results: 

A total of 141 patients treated by anti-EGFR for a mCRC were included in 

the study. Mean age was 64.1 � 14.8 years and a majority of patients had 

synchronous metastases (68.6%). Patients benefited from anti-EGFR in 

first-line chemotherapy (30.7%), second-line (22.9%), third-line (35%) or 

later (11.4%). Majority of patients benefited from anti-EGFR combined 

with cytotoxic chemotherapy (91.4%), mostly irinotecan (78.6%). Using 

pyrosequencing, 117 tumors had a KRAS WT status and 24 tumors had 

low-signal mutation, between 2 and 10% (KRAS lowMT). Response rate 

according RECIST criteria were 13.6% versus 35.4% partial response, 

13.6% versus 37.2% stabilization and 72.7% versus 27.1% progression 

(p�0.01), for KRAS lowMT versus KRAS WT respectively. The PFS was 

respectively 2.6 � 0.2 months for KRAS lowMT versus 6.0 � 0.5 months 

for KRAS WT (p�0.024). Overall survival was not different between the two 

groups (27.4 months versus 33.0 months, p�0.4). Conclusions: Patients 

with tumors harboring KRAS lowMT benefit less of anti-EGFR therapy than 

patients with tumor harboring KRAS WT. While these results invite to 

consider low-signal tumors as positives, generalization awaits a large 

prospective trial. 


4:30 PM-5:30 PM 

Impact of age and medical comorbidity (MC) on adjuvant treatment 

outcomes for stage III colon cancer (CC): A pooled analysis of individual 

patient data from four randomized controlled trials. Presenting Author: 

Daniel G. Haller, Abramson Cancer Center at the University of Pennsylvania, 


Background: Studies show significantly improved disease-free and overall 

survival (DFS, OS) for oxaliplatin (Ox)-based vs. leucovorin/5-fluorouracil 

(LV/5-FU) adjuvant therapy in CC, with conflicting reports of Ox benefit in 

patients � 70 years old. The impact of MC on Ox benefit has not been 

assessed. We assessed the impact of age and MC on adjuvant treatment 

outcomes for stage III CC. Methods: N � 4,819 patients from NSABP C-08, 

XELOXA, X-ACT, and AVANT were analyzed by Ox therapy (XELOX/FOLFOX) 

vs. LV/5-FU, MC, and age; patients treated with bevacizumab were 

excluded. Endpoints were DFS (primary), OS, and safety. MC was assessed 

(except NSABP C-08) by adapted Charlson Comorbidity and NCI Combined 

Indices (CCI, NCI): Low (� 1) vs. high (� 1). Hazardratios (HR) were 

estimated by Cox regression analyses. Multivariate Cox regression analyses 

(MVA) tested for independent effects of age and MC on Ox benefit, 

controlling for gender, T, and N stage. Results: Patient demographics, MC, 

and disease characteristics (except lymph nodes examined) were well 

balanced across groups. Median follow-up was shorter in NSABP C-08 and 

AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). 

MVA-confirmed DFS/OS benefit was consistently shown for XELOX/FOLFOX 

vs. LV/5-FU, regardless of age or MC. Grade 3/4 serious adverse event (AE) 

rates were comparable across cohorts and CCI scores, and higher in 

patients aged � 70. Grade 3/4 AEs of interest, including peripheral sensory 

neuropathy, were comparable across ages and CCI scores, and higher with 

XELOX/FOLFOX. Conclusions: Ox benefit is modestly attenuated in patients 

aged � 70; however, significant benefit is observed regardless of age or MC 

in this analysis. Our results further support XELOX or FOLFOX as standard 

options for the adjuvant management of stage III CC in all age groups. 

Cox regression DFS HR OS HR 95% CI P 

CCI � 1 0.59 0.59 0.46–0.760.44–0.78 � .0001 .0003 

� 1 0.69 0.65 0.61–0.780.56–0.75 � .0001� .0001 

NCI � 1 0.58 0.46–0.730.42–0.74 � .0001� .0001 

0.56 

� 1 0.70 0.66 0.62–0.790.57–0.76 � .0001� .0001 

Age � 70 0.77 0.78 0.62–0.950.61–0.99 .014 .045 

� 70 0.68 0.62 0.61–0.760.54–0.72 � .0001� .0001 


4:30 PM-5:30 PM 

MicroRNA signature to predict sensitivity to anti-EGFR monoclonal antibodies 

in metastatic colorectal cancer (mCRC). Presenting Author: Federico 

Cappuzzo, Istituto Toscano Tumori-Ospedale-Civile-Livorno, Livorno, Italy 

Background: MicroRNAs (MiRNAs) are post-transcriptional regulators that 

bind to complementary sequences on target messenger RNA transcripts, 

usually resulting in gene silencing. Microarray technology is a powerful 

high-throughput tool capable of monitoring the expression of thousands of 

small noncoding RNAs at once. In the present study we aimed to 

investigate whether MiRNA signature was predictive for sensitivity to 

anti-EGFR monoclonal antibodies in mCRC. Methods: A total of 183 mCRC 

from two independent cohorts (cohort 1: 74 cases; validation cohort: 109 

cases) treated with cetuximab/panitumumab either alone (n�19) or in 

combination with chemotherapy (n�164) were included onto the study. 

MiRNA arrays were analysed using Agilent’s miRNA platform. Results: 

MiRNA array analyses identified the cluster miR-99a/Let7c/miR-125b 

located on 21p11.1 as associated with different outcome to anti-EGFR 

therapies. In the first cohort, individuals with high signature (n�25, 

33.8%) had a significantly longer progression free survival (PFS, 6.1 versus 

2.3 months, p�0.01, HR�0.42) and overall survival (OS, 29.8 versus 7.0 

months, p�0.04, HR�0.39) than patients with low signature (n�25, 

33.8%). Similar results were observed in the validation cohort. Patients 

with high signature (n�60, 32.8%) had a significantly longer PFS and 

longer OS than individuals with low signature (PFS 8.2 versus 4.2 months, 

p�0.04, HR�0.52; OS 12.8 versus 6.8 months, p�0.09, HR�0.65). To 

further assess the potential confounding effect of KRAS and BRAF 

mutations, we analyzed the outcome of patients with high and low signature 

in the 75 cases with KRAS or BRAF mutation and in 90 cases KRAS and 

BRAF wild-type. In the wild-type population, high signature patients 

(n�29, 32.2%) had a significantly longer PFS (8.8 versus 4 months, 

p�0.002, HR:0.46) and longer OS (17.7 versus 10 months, p�0.015, 

HR�0.62) than low signature individuals, with no difference in the KRAS 

or BRAF mutated patients. Conclusions: MiR-99a/Let7c/miR-125b signature 

is useful for improving selection of KRAS/BRAF wild-type mCRC 

patients candidate for anti-EGFR strategies. 


4:30 PM-5:30 PM 

Effect of oxaliplatin-based adjuvant therapy on post-relapse survival (PRS) 

in patients with stage III colon cancer: A pooled analysis of individual 

patient data from four randomized controlled trials. Presenting Author: 

Christopher Twelves, University of Leeds and St. James’s University 

Hospital, Leeds, United Kingdom 

Background: Oxaliplatin-based adjuvant therapy is the standard of care for 

stage III colon cancer; however, its impact on PRS in these patients is 

unclear. We therefore compared PRS in trials of patients with stage III 

colon cancer treated with oxaliplatin plus capecitabine (XELOX) or 5-flourouracil 

(5-FU; FOLFOX) vs. leucovorin/5-FU (LV/5-FU). Methods: Individual 

patientdata (N � 4,819) from NSABP C-08, XELOXA, X-ACT, and AVANT 

were pooled and analyzed by XELOX/FOLFOX vs. LV/5-FU; patients treated 

with bevacizumab were excluded. Hazard ratios (HR) were estimated by 

Cox regression analyses and multivariate Cox regression analyses controlled 

for age, gender, T, and N stage. Post-relapse treatment data were collected 

when available. Results: Patient demographics and disease characteristics 

(except lymph nodes examined) were well balanced across analytic groups. 

Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 

months) than in XELOXA and X-ACT (83 and 74 months). PRS was very 

similar for XELOX/FOLFOX and LV/5-FU (HR 0.94, 95% CI, 0.82–1.07; P 

� .33). Multivariate analyses supported these findings, but showed that 

PRS was associated with younger age and lower N stage at diagnosis after 

controlling for gender and T stage. PRS was also comparable for capecitabine 

or XELOX vs. LV/5-FU or FOLFOX (N � 5,819, HR 1.07, 95% CI, 

0.95–1.20; P � .26). Post-relapse therapies were comparable across the 

two cohorts. Conclusions: Adjuvant chemotherapy regimen did not impact 

on PRS in patients with stage III colon cancer; however, both N stage and 

age demonstrated independent effects on PRS. Studies have demonstrated 

significantly improved disease-free and overall survival for oxaliplatinbased 

therapy, and our data show that survival is not compromised by 

worsened PRS at subsequent relapse. 

Multivariate analysis PRS HR 95% CI P 

Randomized treatment: 

0.92 0.81–1.05 .23 

XELOX/FOLFOX vs. LV/5-FU 

Female vs. male 1.02 0.90–1.16 .71 

< 70 vs. > 70 0.70 0.60–0.81 � .0001 

T1–2 vs. T3–4 0.82 0.61–1.10 .19 

N1 vs. N2 0.73 0.64–0.83 � .0001 



4:30 PM-5:30 PM 

Randomized phase III study of adjuvant chemotherapy with oral uracil and 

tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in 

patients (pts) with stage III colon cancer (CC): Final results of Japan 

Clinical Oncology Group study (JCOG0205). Presenting Author: Yasuhiro 

Shimada, National Cancer Center Hospital, Tokyo, Japan 

Background: NSABP C-06 reported the non-inferiority of oral adjuvant 

uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and 

folinate (5-FU/LV) in disease-free survival (DFS) in stage II/III CC. Although 

adjuvant FOLFOX for stage III is standard care in US or EU, its toxicity and 

cost is major problem. This is the first report of JCOG0205, which 

compared UFT/LV to standard 5-FU/levofoloinate (l-LV) in stage III CC. 

Methods: Pts were randomized to 3 courses of 5-FU/l-LV (5-FU 500 mg/m2 , 

l-LV 250 mg/m2 , on days 1, 8, 15, 22, 29, 36, q8w), or 5 courses of 

UFT/LV (UFT 300 mg/m2 /day, LV 75 mg/day, on days 1–28, q5w). Primary 

endpoint was DFS. Sample size was 1,100, determined with one-sided 

alpha of 0.05, power of 0.78, and non-inferiority margin of hazard ratio 

(HR) of 1.27. Owing to interim analyses, the multiplicity-adjusted alpha 

and confidence coefficient of CI in the final analysis were 0.0433 and 

91.3%. Results: Between Feb 2003 and Nov 2006, 1,101 pts (1,092 

eligible) were randomized to 5-FU/l-LV (n�550) or UFT/LV (n�551). 

Median follow-up was 72.0 months, median age: 61, colon/rectum: 

67%/33%, number of positive nodes �3/4�: 73%/27%, stage IIIa/IIIb: 

75%/25%. The HR of DFS was 1.02 (91.3% CI, 0.84–1.23) and 

non-inferiority of UFT/LV was demonstrated (P�0.0236). Incidences of 

G3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% ALT 

elevation in UFT/LV. In the 2 arms (5-FU/l-LV, UFT/LV), diarrhea (9.6%, 

8.5%) and anorexia (4.0%, 3.7%) were similar. G3/4 diarrhea was 

one-third less and G3/4 ALT elevation was three times more common than 

those in C-06. No treatment-related death was reported. Conclusions: 

Adjuvant UFT/LV is demonstrated to be non-inferior to standard 5-FU/l-LV 

in DFS. Five-year OS (87.5%) is favorable to 69.6% in C-06, possibly due 

to D3 dissection and stage migration. UFT/LV should be an oral treatment 

option for stage III CC. 

5-FU/l-LV UFT/LV Overall 

N 546 546 1,092 

3Y DFS (%) 79.3 77.8 78.6 

5Y DFS (%) 74.3 73.6 73.9 

5Y OS (%) 88.4 87.5 87.9 

N 544 540 1,084 

G3/4 neutropenia (%) 8.4 1.5 5.0 

G3/4 ALT (%) 0.7 8.7 4.7 

G3/4 diarrhea (%) 9.6 8.5 9.0 


4:30 PM-5:30 PM 

Smoking status and prognosis in patients with stage III colon cancer: A 

correlative analysis of NCCTG phase III trial N0147. Presenting Author: 

Amanda I. Phipps, Fred Hutchinson Cancer Research Center, Seattle, WA 

Background: Prior observational studies have suggested that smoking is 

associated with poorer overall survival after colon cancer (CC) diagnosis. 

Using data from N0147, a phase III randomized adjuvant trial of patients 

with stage III CC, we assessed the relationship between smoking status and 

cancer outcomes (disease-free survival (DFS) and time to recurrence 

(TTR)), accounting for possible heterogeneity by patient and tumor characteristics. 

Methods: Patients completed a risk factor questionnaire at 

baseline prior to randomization to FOLFOX or FOLFOX�cetuximab 

(N�1968). Information was collected on smoking and other lifestyle 

factors, including alcohol consumption, body mass index (BMI), and 

physical activity. Multivariate Cox models assessed the association between 

smoking history and the primary trial outcome of DFS, as well TTR, 

adjusting for other lifestyle and clinical factors. The median follow-up was 

3.5 years. Results: Overall, 52% of patients were former or current smokers. 

Compared to never smokers, ever smokers experienced significantly shorter 

DFS [3-year DFS: 70% vs 74%, hazard ratio (HR)�1.21, 95% confidence 

interval (CI): 1.02-1.42]. This association persisted after adjusting for age, 

sex, tumor subsite, number of nodes involved, T-stage, mismatch repair 

deficiency, BRAF mutation status, performance score, physical activity, 

BMI, and alcohol consumption (HR�1.23, 95% CI: 1.02-1.49). There was 

significant interaction in this association by BRAF mutation status (p�0.02): 

smoking was associated with shorter DFS in BRAF wildtype CC patients 

(HR�1.25, 95% CI: 1.04-1.51) but not in BRAF mutant CC patients 

(HR�0.72, 95% CI: 0.47-1.10). Patterns of association with smoking, 

overall and by BRAF status, were identical in analyses of TTR. Conclusions: 

Overall, smoking was significantly associated with shorter DFS and TTR in 

CC patients. These adverse relationships were most evident in patients with 

BRAF wildtype CC. 



4:30 PM-5:30 PM 

Comparative evaluation of capecitabine or infusional leucovorin/5-fluorouracil 

(LV/5-FU) with or without oxaliplatin (Ox) for stage III colon cancer (CC): A 

pooled analysis of individual patient data from four randomized controlled trials. 

Presenting Author: Weijing Sun, Abramson Cancer Center at the University of 

Pennsylvania, Philadelphia, PA 

Background: A fluoropyrimidine � Ox is the standard of care for stage III CC but a 

fluoropyrimidine alone is recommended for selected patients in several practice 

guidelines. We assessed efficacy and safety of adjuvant capecitabine � Ox vs. 

LV/5-FU � Ox across a population of stage III CC patients enrolled in four trials. 

Methods: N � 5,819 patients from NSABP C-08, XELOXA, X-ACT, and AVANT 

were pooled and analyzed; bevacizumab-treated patients were excluded. Endpoints 

were disease-free survival (DFS, primary), relapse-free survival (RFS), 

overall survival (OS), and safety. Multivariate Cox regression analyses (MVA) 

controlled for age, gender, T, and N stage. Results: Patient demographics and 

disease characteristics (except lymph nodes examined) were well balanced 

across groups. The number of patients receiving capecitabine and LV/5-FU were 

1,942 and 3,877, respectively. Median follow-up was shorter in NSABP C-08 

and AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). 

Five-year DFS was 62.8% for capecitabine � Ox and LV/5-FU � Ox. The 

capecitabine by Ox interaction was significant for OS with a trend for DFS and 

RFS; likely due to improved outcomes with capecitabine alone and similar 

outcomes for capecitabine or LV/5-FU � Ox. Serious adverse event (AE) rates 

were similar for LV/5-FU- and capecitabine-based therapy (16% vs. 20%, 

respectively). Overall, treatment-related grade 3/4 AEs were more common with 

LV/5-FU (59% vs. 47%). Treatment-related grade 3/4 AEs of interest included 

peripheral sensory neuropathy (5% vs. � 1%), diarrhea (12% vs. 15%), febrile 

neutropenia (2% vs. � 1%), and hand–foot syndrome (� 1% vs. 12%). 

Conclusions: Adjuvant capecitabine � Ox and LV/5-FU � Ox show comparableefficacy 

benefits for the treatment of stage III CC; further supporting capecitabine 

or LV/5-FU-based regimens as standard options for the adjuvant therapy of stage 

III CC. 

Capecitabine � Ox vs. 

LV/5-FU � Ox 

Univariate MVA 

Cox regression HR 

95% CI P 

209s 

Ox interaction HR 

95% CI P 

DFS 1.01 .86 1.14 .17 

0.92–1.10 0.95–1.37 

RFS 1.01 .86 1.15 .15 

0.92–1.11 0.95–1.39 

OS 1.02 .65 1.33 .01 

0.92–1.14 1.06–1.67 


4:30 PM-5:30 PM 

Adjuvant chemotherapy (AC) use and outcomes in stage II colon cancer 

(CC) with and without poor prognostic features. Presenting Author: Aalok 

Kumar, British Columbia Cancer Agency, Vancouver, BC, Canada 

Background: AC is frequently considered inpatients (pts) with �high risk� 

stage II CC, defined by the presence of �/�1 poor prognostic features, such 

as obstruction or perforation, T4 stage, �12 lymph nodes retrieved, 

positive margins, and lymphovascular or perineural invasion. However, 

survival benefits associated with AC use in high risk pts remain largely 

unproven. Our aims were to 1) examine patterns of AC use in stage II CC 

and 2) explore the relationship between AC use and survival in high vs low 

risk pts. Methods: All pts diagnosed with stage II CC in British Columbia 

from 1999 to 2008 and evaluated at any 1 of 5 regional centers were 

reviewed. Kaplan-Meier and Cox regression methods were used to correlate 

a) high vs low risk status and b) receipt of AC with relapse-free (RFS), 

disease specific (DSS) and overall survival (OS). Results: We identified 

1,697 stage II CC pts: 1,236 (73%) high risk and 461 (27%) low risk 

among whom 363 (29%) and 61 (13%) received AC, respectively. 

Individuals with high risk features who received AC were younger (median 

62 vs 72 years, p�0.001) and had better performance status (ECOG 0/1 

47% vs 34%%, p�0.02). In the high risk group, AC was associated with 

improved 5-year OS, but not with RFS or DSS (Table). After adjusting for 

confounders, an OS advantage from AC persisted for high risk pts (HR 

0.67, 95CI 0.52-0.86, p�0.002), but no significant RFS or DSS benefits 

were seen (HR 0.76, 95CI 0.58-0.99, p�0.05 and HR 0.75, 95CI 

0.55-1.02, p�0.11, respectively). Subgroup analyses showed that individuals 

with T4 lesions had improved RFS (HR 0.63, 95CI 0.42-0.95, 

p�0.03), DSS (HR 0.59, 95CI 0.37-0.93, p�0.02), and OS (HR 0.50, 

95CI 0.33-0.77, p�0.002). Conclusions: In this population-based cohort 

of stage II CC, AC was associated with an OS advantage in high risk pts, 

likely due to pt selection. RFS and DSS benefits were mainly seen in T4 

lesions, suggesting a limited role for AC in pts deemed high risk based on 

clinical and pathological factors. Risk stratification based on molecular 

testing should be further explored. 

Survival in high vs low risk stage II CC. 

3-year RFS % p value 5-year DSS % p value 5-year OS % p value 

High risk 

AC 78 0.98 80 0.83 75 �0.01 

No AC 80 79 68 

Low risk 

AC 87 0.18 93 0.78 87 0.26 

No AC 93 93 85 




4:30 PM-5:30 PM 

BRAF V600 mutant colorectal cancer (CRC) expansion cohort from the 

phase I/II clinical trial of BRAF inhibitor dabrafenib (GSK2118436) plus 

MEK inhibitor trametinib (GSK1120212). Presenting Author: Ryan Bruce 

Corcoran, Massachusetts General Hospital Cancer Center, Boston, MA 

Background: BRAF V600 mutations occur in 10-15% of CRC and may 

predict lack of response to standard chemotherapy and anti-EGFR treatment. 

There have been no significant recent changes in the treatment of 

CRC. Novel therapeutic strategies for BRAF mutant CRC are critically 

needed. To collect preliminary efficacy data, an expansion cohort of 25 

BRAF mutant CRC patients (pts) was included in part 2 of a phase I/II study 

evaluating the combination of dabrafenib (BRAFi) and trametinib (MEKi). 

Methods: Eligible pts had BRAF V600 mutant CRC, measurable disease per 

RECIST 1.1, and previous treatment with anti-cancer therapies. Pts were 

treated with established dose of dabrafenib (150mg BID) and trametinib 

(2mg QD). Results: Data for 23 pts are available at data cut-off: median age 

54 years, 74% female, ECOG performance status 0 (48%) or 1 (52%). 

39% had received prior EGFR inhibitor treatment. 74% had received � 2 

prior chemotherapy regimens; 48% had � 1 biologic therapy. 48% had 

� 3 metastatic sites. Three of the 23 pts were non-evaluable at data cut-off 

as they had not reached the first restaging assessment. Among the 20 

evaluable pts, 1 (5%) achieved partial response and 10 (50%) stable 

disease. Minor responses (�10% to �30% tumor shrinkage) were observed 

in 4/10 patients (40%) with stable disease. The most frequent 

adverse events observed in all Part 2 patients who received the same dosing 

combination (n�75) included pyrexia (65%), fatigue (47%), nausea 

(44%), chills (41%), vomiting (31%), constipation (28%), diarrhea (24%) 

and rash (21%). Conclusions: Dabrafenib at 150 mg BID combines safely 

with trametinib 2 mg QD in this BRAF mutant CRC cohort. Based on the 

preliminary anti-tumor activity seen, further investigation is warranted in 

BRAF mutant CRC pts. Updated safety and efficacy data and an analysis of 

the relationship between efficacy and potential predictive biomarkers, 

including microsatellite status, PTEN loss, PIK3CA mutation, and total and 

phosphorylated EFGR levels, will be presented. 


4:30 PM-5:30 PM 

Overall survival (OS) of advanced colorectal cancer (aCRC) patients (pts) 

treated with the multipeptide vaccine IMA910: Results of a matched-pair 

analysis with arm C pts from COIN. Presenting Author: Tim S. Maughan, 

Gray Institute for Radiation Oncology and Biology, University of Oxford, 

Oxford, United Kingdom 

Background: IMA910 is a novel cancer vaccine consisting of 10 class I and 

3 class II tumor-associated peptides (TUMAPs), naturally presented on 

HLA molecules of CRC. Vaccine-induced immune responses are associated 

with prolonged OS of renal cell carcinoma pts treated with IMA901, a 

multi-peptide vaccine identified by the same antigen discovery platform. 

Methods: 92 HLA-A*02� aCRC pts with stable or responding disease after 

12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase 

I/II trial. After immunomodulation with cyclophosphamide (300 mg/m2 )to 

reduce regulatory T cells, pts were immunized intradermally (up to 16 

vaccinations) with IMA910 in combination with GM-CSF without (cohort 1; 

n�66) or with (cohort 2; n�26) topically applied imiquimod. Safety and 

PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of 

IMA910 pts was compared to matched pts from arm C (intermittent 

chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011]. 

Matching was performed in a prospectively defined, fully blinded fashion 

based on a propensity score involving all available prognostic factors. T-cell 

responses to individual IMA910 peptides were analyzed by HLA multimer 

and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs, 

OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1 

matched HLA-A*02� COIN pts (HR 0.675, 95% CI 0.458-0.995, 

p�0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP 

responders (�2 CD8� and �2 CD4� vaccine-induced T cells) had a 

significantly longer OS (HR 0.45, p�0.04) compared to matched COIN pts 

while non-multi-TUMAP responders showed similar OS compared to 

matched COIN pts (HR 0.76, p�0.22). Conclusions: OS of IMA910 pts was 

significantly longer in comparison to matched COIN pts with separation of 

survival curves at ~9 months and increasing OS difference over time. 

Multi-TUMAP immune responders had a significantly longer OS compared 

to non-multi-TUMAP responders and compared to matched COIN pts. 

These clinical and immune response data strongly suggest clinical activity 

of IMA910 in 1st line CRC pts and warrant further development. 


4:30 PM-5:30 PM 

Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with 

AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal 

carcinoma (CRC). Presenting Author: Giovanna Speranza, National Cancer 

Institute, Bethesda, MD 

Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly 

deregulated in CRC. Each can serve as a compensatory mechanism 

mediating resistance to single pathway blockade. Combined inhibition with 

MK-2206 and selumetinib (AZD6244) could enhance antitumor activity. 

Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004) 

are less than single agent MTDs. We conducted a biomarker driven trial of 

MK-2206 and selumetinib at the established combination doses to determine 

extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically 

validated immunoassays for pERK and pAKT. Methods: Patients (pts) with 

advanced CRC, refractory to standard therapy, ECOG � 2, adequate organ 

function, and disease amenable to bx were treated with oral MK-2206, 90 mg 

QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (� or WT). 

For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6 

hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a 

quantitative, chemiluminescence immunoassay (dilution linearity R2 � 0.985 

pERK, 0.995 pAKT; % CV at 0 � 6). 70% inhibition was considered biologically 

significant based on levels observed in preclinical models that demonstrated 

antitumor activity. Results: 11 pts enrolled to date (KRAS �, 6 pts; WT, 5 pts). 

2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal 

detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein 

inhibition data are available for 8 paired bx samples (Table). Conclusions: 

Although 4/8 pts demonstrated biologically significant inhibition in one marker, 

at the MTD for this combination no pt had � 70% inhibition of both targets. If 

repeated dosing does not produce the desired inhibition of pERK and pAKT, we 

will conclude that the dose reductions for each agent necessitated by the toxicity 

of the agents used in combination preclude the possibility of providing adequate 

dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS, 

BRAF, PIK3Ca, AKT) are planned. 

% Inhibition of phosphorylation 

pt pERK pAKT 

C1D1 

KRAS � 1 46 15 

2 �77 4 

3 61 23 

C1D1 

KRAS WT 4 53 19 

5 �70 34 

6 48 78 

C1D22 

KRAS � 7 77 20 

8 0 60 


4:30 PM-5:30 PM 

Molecular analysis of the randomized phase II/III study of the anti-IGF-1R 

antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and 

irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic 

colorectal cancer (mCRC). Presenting Author: David J. Watkins, The 

Royal Marsden Hospital, London and Surrey, United Kingdom 

Background: Previously reported results of this randomized study demonstrated 

that the addition of dalotuzumab (Dz) worsened the PFS and OS of 

chemofractory mCRC patients receiving Cx and Ir (Watkins et al; ASCO 

2011). Comprehensive molecular analysis has been undertaken retrospectively 

to identify possible predictors of Cx resistance and Dz response. 

Methods: Quantitative RT-PCR for IGF-1, IGF-2, immunohistochemistry for 

IGF-1R and microarray expression profiling was conducted on archival 

tumor tissue. All patients had received Cx and Ir with either placebo 

(n�107), weekly Dz (n�112), or 2 weekly Dz (n�110). Results: Data from 

292 and 206 patients was successfully obtained by RT-PCR or microarray 

respectively. Within the placebo arm, high IGF-1 expression was found to 

be associated with resistance to Cx (IGF-1-/IGF-1�; PFS 6.7/3.7 months, 

OS 15.5/9.6 months). High IGF-1 expression was associated with benefit 

from the addition of weekly Dz (placebo/weekly Dz; PFS 3.7/5.7 months, 

OS 9.6/18.2 months). By contrast the addition of Dz was not effective in 

tumors with high IGF-2 expression (placebo/weekly Dz; PFS 8.4/2.7 

months). Microarray analysis revealed distinct populations that differentially 

correlated with Cx and Dz response. An epithelial phenotype appeared 

more associated with Cx response, whereas a mesenchymal phenotype 

more associated with Dz response. Rectal cancers showed greater association 

with increased IGF-1 expression, EMT gene signature and Dz response. 

Conclusions: These data support IGF-1 and IGF-2 as potential biomarkers 

for response to Dz therapy and high IGF-1 as a marker of resistance to Cx 

therapy. Based on these data Dz is being further evaluated in a molecularly 

selected population of mCRC. 

Weekly Dz vs placebo arm 

Hazard ratio (95% CI) 

Difference 

in response rate% 

All patients 

n�191 

Colorectal 

high IGF-2 

n�25 

Colorectal 

high IGF-1 

n�48 

Rectal 

high IGF-1 

n�23 

- 7.4% - 13.3% � 14.6% � 24.6% 

PFS 1.30 (0.95, 1.78) 2.94 (1.09, 7.9) 0.59 (0.28, 1.24) 0.35 (0.10, 1.19) 

OS 1.37 (0.96, 1.95) 3.48 (0.97, 12.54) 0.67 (0.31, 1.45) 0.49 (0.15, 1.56) 



4:30 PM-5:30 PM 

Randomized phase II open-label study of mFOLFOX6 in combination with 

linifanib or bevacizumab for metastatic colorectal cancer. Presenting 

Author: Bert H. O’Neil, University of North Carolina at Chapel Hill, Chapel 

Hill, NC 

Background: Linifanib is a potent and selective inhibitor of VEGF/PDGF 

receptors. This trial assessed the efficacy and safety of mFOLFOX6 in 

combination with linifanib or bevacizumab as second-line treatment for 

metastatic colorectal cancer (mCRC). Methods: Patients (pts) with measurable 

mCRC refractory to 1 prior regimen and ECOG PS 0–1, stratified by 

prior bevacizumab treatment and radiotherapy, were randomized to receive 

mFOLFOX6 with bevacizumab 10 mg/kg on day (d) 1 of 14-d cycle (Arm A), 

mFOLFOX6 with daily linifanib 7.5 mg (Arm B), or mFOLFOX6 with daily 

linifanib 12.5 mg (Arm C). The primary endpoint was progression-free 

survival (PFS). Severity of adverse events (AEs) was graded using NCI- 

CTCAE v3.0. Results: 148 pts were randomized at 45 sites in 14 countries. 

32 pts (21.6%) had received prior bevacizumab. PFS and response data 

are shown below (Table). Median survival (OS) was not reached at median 

follow up 7.6 months. Palmar-plantar erythrodysesthesia (PPE) was the 

only Grade 3/4 AE significantly higher on linifanib (high dose, 16.3%) vs. 

bevacizumab (0%). Rate of any Grade 3� AE was significantly higher on 

linifanib vs. bevacizumab.Hypertension rates were 41.7% (Arm A), 40.0% 

(Arm B), and 36.7% (Arm C). AEs dose-related to linifanib were constipation, 

proctalgia, stomatitis, fatigue, weight decrease, decreased appetite, 

and PPE. Conclusions: The addition of linifanib to mFOLFOX6, compared to 

mFOLFOX6 � bevacizumab, did not provide a PFS advantage for mCRC. 

OS results will be updated for conference presentation. 

ArmAN�49 Arm B N�50 ArmCN�49 

Median PFS, m [95% CI] 9.0 [6.7, --] 6.6 [5.5, 9.2] 7.7 [6.3, 9.3] 

HR 1.45, P�0.186* HR 1.26, P�0.466* 

Confirmed response rate, % 34.7 24.0 22.4 

Best response rate, % 38.8 32.0 34.7 

Best % change in tumor size, median –23.1 –19.5 –22.2 

* Stratified log-rank test two-sided P-value compared with mFOLFOX6 � bevacizumab. 


Analysis of PTEN in patients with advanced colorectal cancer (CRC) 

receiving capecitabine alone or in combination with bevacizumab with or 

without mitomycin C in the phase III AGITG MAX trial. Presenting Author: 

Timothy Jay Price, The Queen Elizabeth Hospital, Adelaide, Australia 

Background: There is an urgent need for potential biomarkers for anti-VEGF 

therapies. The tumour suppressor gene PTEN is thought to have a potential 

role as a biomarker for anti-EGFR therapy in CRC, but there is also evidence 

that decreased levels of PTEN leads to increased expression of VEGF 

suggesting a potential relationship to outcome with anti-VEGF therapy*. 

The prognostic value of PTEN also remains controversial. Methods: Patients 

enrolled in the Phase III MAX trial of capecitabine (C) �/- bevacizumab (B) 

(�/- mitomycin C (M)) with available tissue were analysed for PTEN 

expression (loss v no loss) as assessed using a Taqman copy number assay 

to measure copy number variation at the PTEN locus. PTEN status was 

correlated with progression-free survival (PFS) and overall survival (OS) 

outcomes. The predictive value of PTEN status for bevacizumab efficacy 

was also examined. Results: Of the original 471 patients enrolled in the 

trial, tissue from 302 (64.1%) patients were analysed. Baseline characteristics 

of those with and without tissue were comparable. PTEN loss was 

observed in 38.7% of patients. There was no relationship between PTEN 

loss and KRAS or BRAF mutation. Patients with PTEN loss were more likely 

to have rectal primary (p�0.01) and less likely to have lung metastasis 

(p�0.03). By using the comparison of CvCB�CBM, PTEN status was not 

significantly predictive of the effectiveness of B for PFS or OS (Table). 

PTEN status is also not prognostic for PFS or OS in multivariate analyses 

adjusting for other baseline factors (Table). Conclusions: PTEN status did 

not significantly predict different benefit with anti-VEGF therapy. PTEN 

status was also not prognostic for survival in advanced colorectal cancer. 

P value 

CvsCB�CBM Loss No loss (for interaction) 

PFS HR 0.51 

HR 0.72 

P � .26 

0.33 - 0.79 0.52-0.98 

OS HR 0.75 

HR 1.00 

0.47-1.19 0.70-1.43 P � .35 

Prognosis Loss vs no loss P value 

PFS HR 0.90 

P�.42 

0.70 - 1.16 

OS HR 1.04 

P�.76 

0.79 - 1.38 



4:30 PM-5:30 PM 

Use of next-generation sequencing (NGS) to detect a novel ALK fusion and 

a high frequency of other actionable alterations in colorectal cancer (CRC). 

Presenting Author: Jeffrey S. Ross, Albany Medical College, Albany, NY 

Background: We hypothesized that NGS could identify genomic alterations 

that guide selection of targeted therapies and discover novel drug targets 

for primary and metastatic CRC. Methods: DNA was extracted and sequenced 

from 4 X 10 � FFPE sections from 40 (32 primary and 8 

metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean 

age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage 

unknown) using a targeted NGS assay in a CLIA laboratory (Foundation 

Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from 

14 genes often rearranged in cancer were fully sequenced for point 

mutations, insertions/deletions, copy number alterations (CNAs) and select 

gene fusions. Results: NGS revealed 125 genomic alterations in 39/40 

tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions 

(64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions 

(1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of 

CRCs respectively, with both mutated more frequently than reported in 

COSMIC. Alterations associated with potential sensitivity to targeted 

therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS 

(TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors); 

2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2 

GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2 

Mb tandem duplication generated a novel C2orf44-ALK gene fusion 

starting at the canonical exon 20 recombination site previously reported for 

the majority of ALK gene fusions. cDNA sequencing identified an 90-fold 

increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results 

in ALK kinase domain overexpression and contains the same intracellular 

domain as other ALK fusions including the ALK inhibitor sensitive 

EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from 

FFPE CRC samples uncovered an unexpectedly high frequency of genomic 

alterations, many of which may be clinically actionable by informing 

treatment decisions, including a novel ALK gene fusion. This previously 

unrecognized subset of CRC patients may be candidates for clinical trials of 

crizotinib or other ALK inhibitors. 


Final results of study 20050181: A randomized phase III study of FOLFIRI 

with our without panitumumab (pmab) for the second-line treatment (tx) of 

metastatic colorectal cancer (mCRC). Presenting Author: Alberto F. Sobrero, 

Ospedale San Martino, Medical Oncology, Genova, Italy 

Background: The primary analysis of study 20050181 showed that in 

patients (pts) with wild-type (WT) KRAS mCRC, pmab plus FOLFIRI given 

as second-line therapy significantly improved progression-free survival 

(PFS) vs FOLFIRI alone. Here, we report on a prespecified descriptive 

analysis planned for 30 months (mos) after the last pt was enrolled. 

Methods: Pts with mCRC, ECOG 0-2, who had one prior fluoropyrimidinebased 

chemotherapy regimen were randomized 1:1 to pmab 6.0 mg/kg 

Q2W�FOLFIRI (Arm 1) vs FOLFIRI (Arm 2). Co-primary endpoints were OS 

and PFS (central assessment). Secondary endpoints included objective 

response rate (ORR) and safety. Tumor KRAS status was determined by a 

blinded central lab. Results: 1186 pts were randomised and received tx: 

591 in Arm 1, 595 In Arm 2. 1083 pts (91%) had KRAS results. Adverse 

event rates were consistent with the primary analysis. Results are shown 

below. Conclusions: In pts with WT KRAS mCRC receiving pmab�FOLFIRI 

vs FOLFIRI, PFS and ORR were significantly improved, and there was a 

trend toward improved OS. Post-progression anti-EGFR tx may have 

attenuated any significant difference in OS between tx arms. In pts with MT 

KRAS mCRC, no difference in efficacy was observed between tx arms. 

KRAS testing is critical to select appropriate pts for tx with pmab. 

WT KRAS 

(n�597) 

PFS 

Median, mos 

(95%CI) 

Arm 1 

Pmab�FOLFIRI 

(n�303) 

Arm 2 

FOLFIRI 

(n�294) 

HR or OR 

(95%CI) p value 

6.7 (5.8–7.4) 4.9 (3.8–5.5) HR�0.82 

(0.69–0.97) 

HR�0.73a (0.60–0.88) 

14.5 (13.0–16.1) 12.5 (11.2–14.2) HR�0.92 

(0.78–1.10) 

OS 

Median, mos 

(95% CI) 

ORRb 36 (31–42) [107/297] 10 (7–14) [28/286] OR�5.50 

% (95%CI), [x/n] 

(3.32–8.87) 

MT KRAS 

(n�486) 

(n�238) (n�248) 

PFS 

Median, mos (95%CI) 

5.3 (4.2–5.7) 5.4 (4.0–5.6) HR�0.95 

(0.78–1.14) 

OS 

Median, mos (95% CI) 

ORR 

11.8 (10.4–13.3) 11.1 (10.3–12.4) HR�0.93 

(0.77–1.13) 

b 

13 (9–18) [31/232] 15 (11–20) [35/237] OR�0.93 

% (95%CI), [x/n] 

Pts receiving post-study 

anti-EGFR tx, n (%) 

(0.53–1.63) 

WT KRAS 38 (12.5) 101 (34.4) 

MT KRAS 21 (8.8) 79 (31.9) 

211s 

0.023 

0.001 a 

0.366 

�0.0001 

0.561 

0.482 

0.885 

aOn tx (including deaths occurring �60 days after last tumor assessment); bPts with baseline measurable 

disease (modified RECIST). 




Do we need adjuvant therapy in rectal cancer with complete pathologic 

response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal 

excision? Presenting Author: Verónica Pereira, Department of Medical 

Oncology, Hospital Clínic de Barcelona, Barcelona, Spain 

Background: Neoadjuvant chemo-radiotherapy (CRT) is the standard of care 

for patients (pts) with u�T3 by endoscopic ultrasound (EUS) rectal cancer. 

Although pts with complete pathological response (ypT0N0) fare well in 

multiple series, there is uncertainty of whether it’s due to the induction 

(CRT), due to the adjuvant chemotherapy (ACT) or due to the combination 

of both therapies. We have evaluated long-term outcomes in CRT-treated 

pts. Those with ypT0N0, were not treated with ACT. Methods: Pts with 

u�T3 rectal cancer, received neoadjuvant chemotherapy (225mg/m2/day 

5-fluorouracil (FU)) in continuous infusion (CI) per 5 weeks (wks) and 

concomitant radiotherapy (45 Gy). Laparoscopic surgery (LAP) was planned 

after an interval of 5-8 wks. Pts achieving ypT0N0 were no treated with 

ACT. Pts with ypT�1 or N1 were treated with 3 gr/m2 FU in 48 hour CI and 

LV 200 mg/m2 every 2 wks x 6 cycles. Results: From November 2000 to 

November 2008, a cohort of 173 pts were treated with induction CRT and 

167 pts underwent total mesorectal excision (LAP, n�158, open surgery 

n�9). Complete pathological response was achieved in 26/167 pts 

(15.5%). After a median follow-up of 58.3 months, pts with ypT0N0 have a 

5-year disease-free survival and overall survival rate of 96% (95% CI 76 to 

99%) and 100% (95% CI not estimable) respectively. Conclusions: Using 

these results, a clinical trial comparing observation versus adjuvant therapy 

in ypT0N0 after standard CRT, would need to enroll 3088 pts to show a HR 

of 0.75 in favor of ACT after 5 years of follow-up (alpha�.05, beta�.2). In 

case that the true DFS lied in the lower bound of the 95% CI, 636 patients 

would be needed under the same assumptions. These results do not 

support the administration of ACT to ypT0N0 patients. 


Maintenance therapy with biweekly cetuximab (C) in the first-line treatment 

of metastatic colorectal cancer (mCRC): The NORDIC 7.5 study 

(NCT00660582), by the Nordic Colorectal Cancer Biomodulation Group. 

Presenting Author: Per Pfeiffer, Department of Oncology, Odense University 

Hospital, Odense, Denmark 

Background: NORDIC 7.5 is a multi-center phase II trial of Nordic FLOX 

plus biweekly C followed by maintenance C in first-line treatment of mCRC, 

KRASwild-type (KRASwt). The aim was to complement the data of the 

NORDIC VII trial, arm C (Tveit et al, ASCO GI 2011). Specifically, the goal 

was to substantiate efficacy and safety of biweekly C as maintenance 

therapy and to assess time to failure of strategy (TFS) as an end-point in 

maintenance therapy studies. Methods: Patients had KRASwt, measurable, 

non-resectable mCRC; no prior chemotherapy for metastases; WHO PS 0-2 

and good organ function. Patients received 8 courses of FLOX (bolus 

5FU/folinic acid days 1 � 2 with oxaliplatin day 1 every 2 weeks) plus 

biweekly C (500 mg/m2 every 2 weeks) for 16 weeks followed by biweekly C 

as maintenance therapy until progression (PD). After at least 2 months of 

maintenance therapy, patients restarted FLOX plus biweekly C at the time 

of RECIST PD, and continued until a second RECIST PD. The primary 

endpoint was response rate (RR). Eighty-six patients were planned to 

confirm a response rate of 60%. While awaiting the results of Nordic VII, we 

amended the protocol to include 150 patients. Secondary endpoints 

included PFS, OS, resection rate, and safety. TFS was an explorative 

endpoint. Results: From July 2008 to September 2010, 152 KRASwt 

patients were included in 11 Nordic centers. Results were updated 

December 2011. Median age 64 years; 94% PS 0-1. RR 62%, median PFS 

8.0 months, median OS 23.2 months, median TFS 11.9 months. Ten 

patients (15%) had R0-resection of metastasis. FLOX � C was reintroduced 

in 47 of 85 patients (55%) who were candidates for retreatment 

and was started median 18 days after PD. Median duration of 

re-introduction was 5 months (1-29), 9 patients (20%) had response. 

Elevated baseline platelets and neutrofiles were associated with poor OS. 

The most common grade 3/4 non-hematologic AEs in were diarrea (9%), 

skin rash (9%), infection without neutropenia (7%), and fatigue (7%) 

Conclusions: Maintenance therapy with biweekly cetuximab is an encouraging 

strategy with efficacy and toxicity comparable to weekly cetuximab. 


Patterns of chemotherapy (CT) use in a U.S.-wide population-based cohort 

of patients (pts) with metastatic colorectal cancer (mCRC). Presenting 

Author: Thomas Adam Abrams, Dana-Farber Cancer Institute, Boston, MA 

Background: Few population studies have examined treatment regimens 

and duration in mCRC since the introduction of biologic therapies in 2004. 

Methods: We assessed 4,877 consecutive mCRC pts who received CT 

between Jan 2004 and Mar 2011 at academic, private, and community 

hospital-based practices participating in a US-wide CT order entry (COE) 

system that captures patient demographics, stage and treatment data. 

Multivariate analyses of prospectively recorded patient and provider characteristics 

identified significant predictors of specific therapeutic approaches. 

Results: Among all pts, median age was 64; 55% male; (ECOG 

PS 0/1/2�) (56%/33%/11%). In first-line CT, 17% of pts received 

fluoropyrimidine (FU) only, while 16% received FU and irinotecan and 

65% received FU and oxaliplatin. Older pts, those with poorer ECOG PS, 

and those treated in private practices were significantly more likely to 

receive FU only (all p �0.05). 53% of all pts received treatment in line 2, 

28% in line 3, and 13% in line 4. Mean duration of treatment was 170 days 

(line 1), 139 (line 2), 135 (line 3) and 126 (line 4). Bevacizumab (bev) was 

administered to 65% of pts at some point in their treatment. Among the 

51% who received bev in line 1, 33% continued bev beyond progression 

(BBP) in line 2. Pts treated at academic centers, pts who received longer 

duration of line 1 therapy, and pts whose providers had greater CRC pt 

volume were significantly more likely to continue BBP. Overall, 23% of pts 

received cetuximab (cet) (4% of all line 1 pts, 17% of line 2, 31% of line 3, 

and 29% of line 4). Mean duration of cet use was 168 days (line 1), 125 

(line 2), 133 (line 3) and 129 (line 4). Pts treated at academic centers, pts 

who received longer duration of line 1 therapy, and pts treated in the West 

US were significantly more likely to ever receive cet. Cet use decreased by 

18% following FDA label change restricting use to KRAS wt pts in Jun 

2009 (p �0.001). Of all pts, 6% received panitumumab at some point. Of 

those, 39% had previously received cet. Conclusions: This populationbased 

study provides insight into treatment patterns of mCRC in the US. 

Usage of biologic agents varies significantly according to patient, practice, 

and provider characteristics. 


Phase I study of EMD 525797 (DI17E6), an antibody targeting �� 

integrins, in combination with cetuximab and irinotecan, as a second-line 

treatment for patients with k-ras wild-type metastatic colorectal cancer. 

Presenting Author: Elena Elez, Vall d’Hebron University Hospital, Barcelona, 

Spain 

Background: EMD 525797 is a humanized monoclonal antibody that 

specifically targets all �� integrins, including ��1, ��3, ��5, ��6, 

and ��8. In colorectal cancer (CRC), ��3 is highly expressed on 

tumor-associated vessels, and ��5 is strongly expressed on tumor cells, 

vessels, and stromal cells. Overexpression of ��6 is associated with a 

significant reduction in median overall survival. Methods: Safety, tolerability, 

and anti-tumor activity of escalating doses of EMD525797 in combination 

with irinotecan and cetuximab were assessed in patients (pts) with 

metastatic CRC who had failed first-line fluoropyrimidine/oxaliplatincontaining 

chemotherapy. Pts received IV infusions over 1 hour of 250, 

500, 750, and 1,000 mg EMD 525797 every 2 weeks in combination with 

irinotecan at 180 mg/m2 IV every 2 weeks and cetuximab at 400 mg/m2 on 

Cycle 1, Day 1 and then 250 mg/m2 IV weekly. A standard 3�3 trial design 

was used. Three pts were enrolled at each dose level and if no dose limiting 

toxicities (DLTs) were observed, pts were enrolled at the next dose level. An 

additional 3 pts were added if 1 of the initial 3 pts in the cohort experienced 

a DLT. Results: A total of 16 pts received treatment.No DLTs were observed 

at any dose of EMD 525797 in combination with irinotecan and cetuximab. 

Serious adverse events related to EMD 525797 included Grade 3 hypokalemia 

and tachyarrhythmia. Dosing was well tolerated over treatment intervals 

as long as 18 months. Objective responses included 1 partial response 

(PR) at 250 mg; 1 complete response and 1 PR at 750 mg; and 2 PRs at 

1,000 mg. Two pts had prolonged stable disease lasting longer than 11 

weeks at 750 mg. Anti-tumor activity was observed in pts who had failed 

anti-VEGF therapy in combination with first-line chemotherapy. Conclusions: 

The combination of EMD 525797 with irinotecan and cetuximab was well 

tolerated and has anti-tumor activity. Further evaluation of this regimen is 

warranted and is underway in an open-label, randomized phase II study of 

two doses of EMD 525797 (500 and 1,000 mg) combined with irinotecan 

and cetuximab that are compared with standard irinotecan and cetuximab. 



Prospective study of EGFR intron 1 CA tandem repeats to predict factor 

benefit from cetuximab and irinotecan. Presenting Author: Carlotta Antoniotti, 

U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, 

Istituto Toscano Tumori, Pisa, Italy 

Background: Retrospective experiences have investigated the potential 

influence of EGFR intron 1 CA repeats on the efficacy of cetuximabcontaining 

treatments. Different series, adopting different criteria to define 

short (S) and long (L) variants, have provided contrasting results. Methods: 

We designed a prospective confirmatory study, to detect a HR for PFS of 

1.75 for L- compared to SS genotypes in a population of KRAS and BRAF 

wild-type irinotecan-resistant mCRC pts treated with cetuximab and 

irinotecan. Estimating a prevalence of 60% of the SS variant and setting a 

two-sided alfa�0.05 with a power of 80%, 104 events were required. We 

defined S and L allelic variants those presenting � and �20 CA repeats, 

respectively. EGFR (CA) n repeat polymorphism was assessed following a 

5’-end [�-33P] ATP-labeled PCR protocol. Results: One-hundred-fifteen pts 

were included. At a median follow up of 21.9 months, PFS and OS were 5.2 

and 13.4 months, respectively. Thirty-three (29%) out of 114 evaluable 

pts achieved response. EGFR (CA) n repeat genotype was L- and SS in 45 

(40%) and 68 (60%) out of 113 evaluable cases. No differences in PFS or 

OS were observed between L- and SS genotypes (median PFS: 4.4 vs. 5.3 

months, HR: 1.00 [95%CI: 0.67-1.51], p�0.991; median OS: 11.3 vs. 

14.2 months, HR: 1.30 [95%CI: 0.80-2.22], p�0.261). Ten (22%) out of 

45 L- pts achieved response compared to 22 (33%) out of 67 SS pts 

(Fisher’s Exact test: p�0.617). Other exploratory analyses adopting 

different cut-off values reported in literature led to similar results. 

Conclusions: This prospective study, including a clinically homogenous and 

molecularly selected population, does not confirm any predictive or 

prognostic effect for EGFR (CA) n repeat allelic variants with respect to the 

efficacy of cetuximab and irinotecan in advanced lines of treatment. The 

present experience strengthens the need of prospectively challenging 

retrospective findings, as an essential step on biomarkers’ way toward 

clinical practice. 


Utilization and outcomes of primary tumor surgery for stage IV colon cancer 

in the United States: A population-based study. Presenting Author: Yvonne 

Sada, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 

Background: Stage IV colon cancer treatment may include resection of the 

primary tumor. Current use of primary tumor surgery (PTS) in clinical 

practice is unknown. This study examined utilization and determinants of 

PTS and evaluated its effect on survival. Methods: Using national Surveillance, 

Epidemiology, and End Results registry data, stage IV colon cancer 

patients diagnosed from 1998-2008 were identified. Data on demographics, 

PTS, and tumor features were collected. Temporal changes in receipt of 

PTS were examined over 3 periods (1998-2000, 2001-2004, 2005- 

2008). Multiple logistic regression was used to identify significant determinants 

of PTS. 1- and 3-year cancer-specific survival was calculated in PTS 

and non-PTS patients. Cox proportional hazards models examined the 

effect of PTS on mortality risk. Results: 16,029 patients were identified. 

Median age was 69 (IQR: 57-78), and 50% were male. Approximately 67% 

of patients received PTS. Receipt of PTS significantly declined from 72% 

in 1998-2000 to 68% in 2001-2004, and 63% in 2005-2008 (p�0.01). 

Results from the logistic regression analysis showed that patients who were 

younger, white, married, had right sided cancer and higher tumor grade 

were more likely to receive PTS (all p�0.01). The 1- and 3-year survival 

was higher in patients who received PTS compared with those who did not 

(1-year: 55% (95% CI: 54-56) vs. 24% (95% CI: 23-26); 3-year: 19% 

(95% CI: 19-20) vs. 4% (95%CI: 3.4-4.9)). Adjusted for demographics 

and tumor features, risk of mortality was 54% (HR�0.46; 95% CI: 

0.44-0.48) lower in patients who received PTS than those without PTS. 

Recent year of diagnosis (HR�0.88; 95% CI: 0.75-0.80) and being 

married (HR�0.90, 95% CI: 0.86-0.95) were associated with lower 

mortality. Older age (HR�1.48; 95% CI: 1.39-1.56), black race (HR�1.09; 

95% CI: 1.03-1.15), right sided cancer (HR�1.21; 95% CI: 1.17-1.26), 

and poorly differentiated tumors (HR� 1.62; 95% CI: 1.46-1.80) were 

associated with increased mortality. Conclusions: PTS utilization for stage 

IV colon cancer has significantly declined, yet survival was higher in 

patients who received PTS. However, these findings are limited by the 

absence of co-morbidity and chemotherapy data. 


213s 


Capecitabine (cape)-associated hand-foot skin reaction (HFS) as a clinical 

predictor of improved survival in patients (pts) with colorectal cancer. 

Presenting Author: Ralf Hofheinz, Day Treatment Centre at the Interdisciplinary 

Tumour Centre Mannheim, Universitätsmedizin Mannheim, Mannheim, 

Germany 

Background: HFS is frequently observed during treatment with cape. Post 

hoc analyses of the X-ACT trial suggested that HFS may be associated with 

improved prognosis in cape recipients in stage III colon cancer. In the 

present analysis we evaluated the potential association of HFS and survival 

in pts with metastatic colorectal cancer and locally advanced rectal cancer. 

Methods: Pts receiving cape within AIO KRK-0104 and Mannheim rectal 

cancer trials were analyzed. HFS was graded according to NCI-CTC. Time to 

first occurrence of HFS was described per cycle and HFS developing during 

cycles 1 and 2 was defined as “early HFS”. Baseline characteristics in the 

groups of pts with or without HFS were compared using standard tests. 

Toxicities observed in both groups were compared with Fisher’s exact test. 

Progression-free (PFS) or disease-free (DFS) and overall survival (OS) data 

from both trials were pooled and the HFS group was compared to the 

non-HFS using Kaplan-Meier analysis. Results: A total of 374 pts are 

included, of whom 29.3% developed HFS. Of these, 70.9% had “early 

HFS”. Baseline characteristics were comparable between the HFS and the 

non-HFS groups concerning age, gender, ECOG status and UICC stage. On 

multivariate analysis none of these factors had influence on the occurrence 

of HFS. The percentage of all-grade hematological toxicities did not differ 

between both groups. Contrarily, patients in the HFS group had a 

significantly higher rate of all grade (but not grade 3-4) diarrhea, stomatitis/ 

mucositis and fatigue (p�0.01 resp.). Moreover, pts in the HFS group had 

improved PFS/DFS (29.0 vs. 11.4 months; p�0.015, HR 0.69) and OS 

(75.8 vs. 41.0 months; p�0.001, HR�0.56). Within the HFS group the 

PFS/DFS and OS were comparable between pts in the “early” and the “late 

HFS” groups. Conclusions: This analysis provides further evidence for the 

association of HFS and survival in patients with colorectal cancer. Baseline 

characteristics and the time of occurrence of HFS had no impact on 

survival. Patients developing HFS had a higher probability of developing 

any-grade gastrointestinal toxicity and fatigue while no correlation with 

hematological toxicity was noticed. 


Phase Ib study of dulanermin combined with FOLFIRI (with or without 

bevacizumab [BV]) in previously treated patients (Pts) with metastatic 

colorectal cancer (mCRC). Presenting Author: Saifuddin M. Kasubhai, 

Northwest Medical Specialties, Tacoma, WA 

Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNFrelated 

apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic 

pathways by binding to the pro-apoptotic death receptors DR4 and 5. This 

is the final update of the study assessing the safety of dulanermin 

combined with FOLFIRI (� BV) in previously treated mCRC pts. Methods: 

This was a multicenter, open-label, dose-escalation and cohort expansion 

study. Dulanermin was administered intravenously in 14-day cycles on 

Days 1, 2 and 3 at 9 mg/kg or 18 mg/kg, with FOLFIRI (� BV in pts not 

previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was 

assessed through 2 cycles (28 days). Adverse events (AE) were recorded 

through all cycles. Response was assessed with RECIST (v1.0). Results: A 

total of 27 pts received 1-48 cycles (median 10) of dulanermin with 

FOLFIRI (1 pt received BV). No DLTs were reported and no relationship 

between dulanermin dose level and AE incidence or severity was detected. 

The most frequent AEs reported as dulanermin-related were fatigue (37%), 

anemia (19%), diarrhea, nausea, stomatitis, and weight decreased (15% 

each). The most frequent Grade �3 AEs reported as dulanermin-related 

were fatigue (15%), anemia, febrile neutropenia and vomiting (7% each). 

Serious AEs reported as dulanermin-related included: vomiting, dehydration, 

and febrile neutropenia (1 pt each). Some of these events were 

reported as related to dulanermin and other study drugs. One pt died on 

study due to disease progression. Other reasons for discontinuation of study 

treatment included disease progression (21 pts, 78%), and physician’s 

decision and pt’s decision (2 pts each, 7%). One pt is still receiving 

treatment. Among the 27 pts, best responses included 6 (22%) partial 

responses (5 confirmed, 1 unconfirmed), 17 (63%) stable disease, 3 

(11%) progressive disease and 1 (4%) pt with no on-study tumor assessment. 

Conclusions: The addition of dulanermin to FOLFIRI (� BV) was well 

tolerated in previously treated mCRC pts. AEs were similar to those 

previously reported for the chemotherapy alone. Tumor responses were 

consistent with treatment response to FOLFIRI in this patient population. 




Effect of bevacizumab on rate of oxaliplatin-induced thrombocytopenia and 

splenomegaly. Presenting Author: Kanwal Pratap Singh Raghav, University 


Background: Oxaliplatin-based chemotherapy can cause hepatic sinusoidal 

injury (HSI) leading to portal hypertension. This results in splenic sequestration 

of platelets and thrombocytopenia. Evidence suggests that bevacizumab 

may protect against HSI, although the clinical impact of this has not 

been well examined. The purpose of our study was to evaluate rate of 

thrombocytopenia and splenomegaly as clinical end-points indicative of 

bevacizumab mediated modulation of oxaliplatin-induced hepatic toxicity. 

Methods: We performed a retrospective review of metastatic colorectal 

cancer patients treated at M D Anderson Cancer Center from 1/2003 to 

1/2010 with � 3 months of frontline fluoropyrimidine and oxaliplatin 

(FOLFOX) with or without bevacizumab. Patients with prior liver disease, 

liver surgery or absence of spleen were excluded. Splenic volumes pre, 

during and post FOLFOX therapy were determined with CT scans and 

correlated with platelet counts and treatment. Results: A total of 184 

patients [Bev cohort: FOLFOX/Bev (n �138); Non-Bev cohort: FOLFOX 

alone (n � 46)] were identified. Baseline characteristics (age, gender, 

spleen size and platelet counts) were similar in both groups. Median 

number of oxaliplatin cycles for each cohort was 9.00 (p � 0.9). The 

median total oxaliplatin dose did not differ between the two cohorts (p � 

0.9). Development of splenomegaly (volume increase � 30%) was more 

common in the Non-Bev cohort (48% vs. 32%; p � 0.013). The median 

time to develop splenomegaly was significantly longer in the Bev cohort 

(7.6 vs. 5.5 months; p � 0.023). Splenomegaly correlated with a higher 

rate of thrombocytopenia (defined as platelets � 150K) at 3 months (40% 

vs. 16%, p � 0.0005) and beyond (during 3 to 6 months of treatment, p � 

0.0001). Correspondingly, bevacizumab therapy was associated with lower 

rates of thrombocytopenia at 3 months (24% in Bev cohort vs. 43% in 

Non-Bev cohort, p � 0.006) and beyond (p � 0.003). Conclusions: In our 

cohort, addition of bevacizumab to oxaliplatin chemotherapy reduces the 

occurrence of splenic enlargement, which correlates with a decreased rate 

of thrombocytopenia. Further studies to understand the potential hepatoprotective 

mechanism of anti-VEGF therapy are needed. 


KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI 

and bevacizumab. Presenting Author: Marta Schirripa, U.O. Oncologia 

Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano 

Tumori, Pisa, Italy 

Background: Kinase suppressor of Ras (KSR) 1 is a scaffolding protein 

regulating the Raf/Mek/ERK cascade. Preclinical data showed that KSR1 

could increase estrogen receptor transcriptional activity after exposure to 

estrogens. Recent retrospective analyses suggested a possible role for 

KSR1 rs2241906 C/T polymorphism in predicting the outcome of patients 

with mCRC. Methods: MCRC patients receiving first-line 

FOLFIRI�bevacizumab prospectively enrolled in a translational research 

program were selected on the basis of KRAS and BRAF mutational status 

availability. KSR1 rs2241906 polymorphism was analyzed on DNA extracted 

from peripheral blood by means of PCR and direct sequencing. 

Taking into account the connection between estrogen pathway and KSR1, 

subgroup analyses according to gender were pre-planned. Results: 287 

patients were included. Main patients’ characteristics were the following: 

M/F�175/112; median age�62 (range 26-79); ECOG-PS 0/1-2�240/47; 

synchronous/metachronous disease�213/74; Köhne score (low/intermediate/high/data 

missing)�122/129/22/14; KRAS-BRAF mutational status 

(wt-wt/mut-wt/wt-mut)� 123/146/18. In the overall KRAS-BRAF wt population, 

KSR1 polymorphism did not affect the outcome. The analysis 

performed according to gender showed that in the KRAS-BRAF wt population 

females with KSR1 rs2241906 T/- achieved a significantly better PFS 

(median 15.9 mos) in comparison to C/C variant carriers (median 8.8 mos) 

(HR�0.44 [95%CI 0.21-0.91], p�0.010); meanwhile males with T/showed 

a worse PFS in comparison to those carrying the C/C variant 

(HR�1.92 [95%CI 1.05-3.53], p�0.021). These results were significant 

also in a multivariate model and a significant interaction of gender with PFS 

according to KSR1 allelic variants was demonstrated (p�0.004). 

Conclusions: This prospectively conceived pharmacogenetic study confims 

the role of KSR1 polymorphisms in affecting the outcome of mCRC 

KRAS-BRAF wt patients. In particular, these results indirectly indicate that 

estrogenic stimulation could affect the proliferation of KRAS-BRAF wt CRC 

cells through an interaction with KSR1. Preclinical investigations to further 

explore this preliminary hypothesis are ongoing. 


Comparative effectiveness of sphincter-sparing surgery (SSS) versus abdomino-perineal 

resection (APR) in rectal cancer: Patient-reported outcomes 

(PROs) from NSABP R-04. Presenting Author: Patricia A. Ganz, 

University of California, Los Angeles Jonsson Comprehensive Cancer 

Center, Los Angeles, CA 

Background: R-04 is a trial of pre-surgical RT and either capecitabine or 

5-FU with or without oxaliplatin in patients (Pts) with resectable rectal 

cancer. PROs were measured before treatment, post-RT, and 1 yr post-op. 

We compare PROs at 1 yr by type of surgery with hypothesis that APR Pts 

would have worse quality of life (QOL). Methods: Pts completed the FACT-C 

and EORTC-CR38 at all times. Baseline and 1 yr were compared within 

groups (SSS and APR) with paired t-test, and between groups at 1 yr, with 

adjustment for covariates of age, gender, clinical stage, baseline score, and 

surgery intent in a general linear model. These secondary/exploratory 

hypotheses were significant if p � 0.05. Results: 1,608Pts were randomized 

and 1405 completed baseline QOL form after consent, prior to 

treatment. 1,003 completed QOL form 1 yr post-op: 6 were ineligible, 10 

did not have surgery, leaving 987 Pts. 615 had SSS and 372 had APR. 

66.6% were male, 61.5% stage II, and almost all had post-surgical 

adjuvant chemotherapy. SSS Pts were significantly younger (60.3% vs. 

53.5% � 59 yr, p�0.04). FACT-C total and subscale scores were not 

significantly different by surgery type at 1 yr, with only minimal decline 

from baseline in both groups. For SSS Pts, EORTC-CR38 scores significantly 

worsened for body image, sexual function, sexual enjoyment (all p 

�0.0001), while future perspective improved (p�0.0001) at 1 yr from 

baseline. All symptom subscales except weight loss and micturition showed 

worsened symptoms (GI tract, chemo side effects, defecation problems, 

sexual problems) all p � 0.0001 at 1 yr from baseline. Compared to APR 

Pts, SSS had less severe functional problems and symptoms, especially in 

sexual enjoyment, weight loss, GI symptoms, and body image, all significant. 

Conclusions: Contrary to prediction, there were no significant differences 

in FACT-C scores for SSS vs. APR. Symptoms and functional 

problems were detected by the EORTC-CR38, reflecting expected differences. 

The largest differences between the surgical treatments were for GI 

symptoms and body image. Information from these PROs may be useful in 

counseling Pts anticipating surgery for rectal cancer. 


First European phase II trial of intravenous (iv) cetuximab (Cet) and hepatic 

artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin in patients 

with unresectable liver metastases from wt KRAS colorectal cancer (CRC) 

after systemic therapy failure (OPTILIV, NCT00852228). Presenting 

Author: Francis Levi, Medical Oncology Department, INSERM U776, Paul 

Brousse Hospital, Villejuif, France 

Background: HAI of chronomodulated (Chrono) irinotecan (I), 5-Fluorouracil 

(F) and oxaliplatin (O), or flat O combined with iv F-leucovorin allowed 

secondary metastases resections and prolonged survival in patients (pts) 

with CRC liver metastases despite prior chemotherapy failure (Bouchahda, 

Cancer 2009; Goere, Ann Surg 2010). Purpose: To prospectively evaluate 

safety and efficacy of combining iv Cet with HAI of IFO in pts with CRC liver 

metastases. Methods: This Phase II trial involved previously treated pts with 

unresectable CRC liver metastases. Pts received iv Cet (500 mg/m²) and 

Chrono or conventional HAI of I (180 mg/m²), F (2800 mg/m²), and O (85 

mg/m²) q2 weeks. Liver metastases were resected if adequately downstaged. 

Results: Planned accrual of 60 pts was reached on 01/24/2012. 3 

pts were not treated, 9 are ongoing. 48 consecutive treated pts (18F, 30 M; 

aged 32-76 years) are fully assessed and monitored. They had PS 0-1 

(98%), bilobar liver lesions (69%), a median of 8 metastases (1-50; largest 

diameter, 57 mm – 15-172). Prior chemotherapy involved one (43%), or 

two or three (57%) lines. A median of 5 protocol courses (1-13) was given. 

Main grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain 

(15%), fatigue (15%), nausea (15%), diarrhea (13%) and sensory neuropathy 

(4%). Objective response rate was 44% [30-58], with 6% radiological 

complete responses. Disease control rate was 85%. Secondary liver surgery 

was performed in 15 pts (31.3%).One pt with 25 metastases (1-6 cm) in all 

liver segments had pathologic complete response in 24 lesions removed 

through three-stage hepatectomy. She currently has an off treatment 

disease-free survival of 17� months.With a follow up of 4 to 47 months, 

median progression-free survival is 14.2 months [9.7-18.8], 1- and 2-year 

survival rates are 92.8% and 59.2% respectively. Conclusions: OPTILIV 

offers a safe and unusually effective treatment option for patients with CRC 

liver metastases after failure of systemic chemotherapy within a coordinated 

medico-surgical strategy. 



Plasma concentrations of YKL-40 in chemo-naive patients with metastatic 

colorectal cancer treated with FLOX with or without cetuximab: Results 

from the NORDIC VII study. Presenting Author: Line Schmidt Tarpgaard, 

Department of Oncology, Odense University Hospital, Odense, Denmark 

Background: KRAS status is presently the best biomarker to select patients 

with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition 

even though not confirmed in all phase III studies. In the NORDIC VII study 

a survival benefit of adding cetuximab to the Nordic FLOX regimen could 

not be confirmed. Identification of new predictive and prognostic biomarkers 

is essential. Plasma concentration of YKL-40 is emerging as a new 

biomarker in patients with cancer and inflammatory diseases. We tested 

the hypothesis that high plasma YKL-40 associates with short progression 

free survival (PFS) and short overall survival (OS) in patients included in the 

NORDIC VII Study. Methods: 566 patients with mCRC were randomized to: 

A) Nordic FLOX; B) FLOX � cetuximab; and C) FLOX for 16 weeks � 

cetuximab continuously. Plasma samples were available from 510 patients 

(90%). Pretreatment plasma YKL-40 was determined by ELISA (Quidel), 

and the plasma YKL-40 concentration was dichotomized according to the 

age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Plasma 

YKL-40 was elevated in 204 patients (40%) and the median plasma 

YKL-40 was higher in the study group compared to healthy subjects (120 

mg/l vs. 40 mg/l, p�0.001). Elevated plasma YKL-40 was associated with 

short PFS (HR�1.25, 95% CI 1.04-1.51, p�0.02). This relationship was 

demonstrated only in patients treated with FLOX chemotherapy alone 

(HR�1.42, 1.02-1.98, p�0.04). High plasma YKL-40 was associated 

with short OS in all patients (HR�1.55, 1.25-1.92, p�0.001) and in the 

different treatment groups (A: HR�1.54, 1.05-2.26, p�0.03; B: 

HR�1.40, 0.97-2.01, p�0.07; C: 1.79, 1.23-2.60, p�0.002). Multivariate 

analysis (YKL-40, performance status, number of metastatic sites) 

demonstrated that elevated plasma YKL-40 was an independent biomarker 

of short OS (HR�1.46, 1.17-1.81, p�0.001). Conclusions: Plasma 

YKL-40 may be a new prognostic biomarker in patients with mCRC treated 

with 1st line FLOX chemotherapy, with or without cetuximab. The predictive 

value of plasma YKL-40 is not yet clarified. 


Adjuvant chemotherapy (ACT) in stage II colon cancer (CC) in patients with 

Lynch syndrome. Presenting Author: Karsten Schulmann, Ruhr University 

Bochum, Knappschaftskrankenhaus Med. Dpt., Bochum, Germany 

Background: Previous studies showed conflicting results regarding the value 

of ACT in MSI-H CC. A recent study reported differential benefits from 

5-FU-based ACT comparing suspected sporadic vs suspected hereditary 

MSI-H CC. We sought to evaluate the prognostic impact of ACT in a large 

cohort of Lynch syndrome (LS) patients (pts) with stage II CC. Methods: To 

minimize selection bias diagnoses �2 years prior to registration in the 

database of the German HNPCC consortium were excluded. 278 patients 

(61% male, mean age 42.9y, 13% stage IIB, 51% with MMR gene 

mutation) were eligible. Overall Survival (OS), CC-specific Survival (CSS), 

and Disease Free Survival (DFS) were analyzed using Kaplan-Meier and Cox 

Regression analyses. Results: 5y OS, CSS and DFS were 95%, 95% and 

93% respectively. Right-sided CC was independently associated with lower 

DFS in stage II and IIA. Increasing age was associated with lower OS, CSS 

and DFS in stage IIA, however we observed only trends in the multivariate 

analysis. Surgery alone (without ACT) was associated with a slightly lower 

OS in stage IIA (univariate HR 3,659; 95% CI 0,81-16,5; P�0.092); but 

not with lower DFS and CSS. Prognosis was not different comparing 

FOLFOX vs. 5-FU-based ACT. Conclusions: Our data suggest that LS pts 

with stage II CC do not benefit from ACT. FOLFOX was not superior to 

5-FU-based ACT. If our results are confirmed, LS pts with stage IIA CC 

should not receive ACT. The group of stage IIB CC was too small to make 

definite conclusions. 

OS 

Univariate 

CSS DFS 

HR 95% CI HR 95% CI HR 95% CI 

Stage II 

(n�278) 

Age Per 10y 1,034 0,993-1,08 1,034 0,993-1,08 1,039 0,997-1,08 & 

Localization Right 

Left 1,58 0,64-3,90 1,58 0,64-3,890 2,78 1,10-6,98 * 

T-stage T3 

T4 2,12 0,69-6,51 2,12 0,69-6,51 2,66 0,85-8,37 && 

ACT No 

Yes 1,37 0,50-3,70 1,37 0,50-3,70 0,99 0,35-2,78 

ACT 5-FU 

FOLFOX 

0,04 0-887 0,04 0-887 1,82 0,33-9,93 

Stage IIA 

(n�242) 

Age Per 10y 1,049 1,000-1,100 ** 1,067 1,000-1,139 *** 1,052 1,003-1,104 § 

Localization Right 

Left 1,474 0,526-4,131 2,730 0,760-9,805 3,039 1,069-8,683 # 

ACT No 

Yes 3,659 0,808-16,562 ## 3,974 0,477-33,070 1,566 0,415-5,908 

ACT 5-FU 

FOLFOX 0,046 0.000-.... 0,045 0.000-.... 1,871 0,169-20,668 

*p�0.03; ** p�0.051; *** p� 0.052; § p�0.039; # p� 0.037; ## p�0.092; & p�0.07; && p�0.081. 


215s 


Primary side of origin affects the outcome of mCRC patients treated with 

first-line FOLFIRI plus bevacizumab independently of BRAF status and 

mucinous histology. Presenting Author: Fotios Loupakis, University of 

Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 

Background: Several studies tried to address the question of whether 

primary site of CRC could affect the outcome. Those analyses were limited 

by small sample size numbers and/or high degree of heterogeneity in stage 

and received treatments and/or limited information regarding molecular 

and pathologic features. Mucinous histology and BRAF mutations are more 

frequent in right-sided tumors and are both associated with worse outcome 

in the metastic setting. Methods: the analysis was conducted on a database 

of 455 mCRC prospectively enrolled in a pharmacogenetic translational 

study. Patients (pts) were treated with FOLFIRI/bevacizumab. Pts were 

excluded if data regarding mucinous histology and/or BRAF mutational 

status were lacking or if affected by synchronous right and left-sided 

tumors. Results: 200 pts were identified and included in the study. 

Mucinous histology, BRAF mutation and right-side primary were found in 

35 (17.5%), 14 (7%) and 56 (28%) patients respectively. Right-side 

tumors were more frequently BRAF mutated (p�0.001) and the association 

was still significant when adjusting for mucinous histology (p�0.001). 

There was a trend in the association between mucinous and side (p�0.082). 

At a multivariate analysis, pts with right-side primary were at higher risk of 

progression (HR�1.88 [95%CI: 1.25-2.84], p�0.0026) and death 

(HR�2.07 [95%CI: 1.23-3.49], p�0.006). At a prespecified analysis in 

the subgroup of non-mucinous and BRAF wild-type tumors, pts with 

right-side primary achieved median PFS and OS of 10.0 and 28.9 mos 

compared to 13.0 and 47.6 mos of left-side (PFS, right vs left: HR�1.87 

[95%CI: 1.19-2.91], p�0.003; OS: HR�1.91 [95%CI: 1.07-3.39], 

p�0.022). This was again confirmed in a multivariate model. Conclusions: 

These data underline a possible strong impact of side on the outcome of 

mCRC treated with first-line FOLFIRI plus bevacizumab. To give a biological 

explanation for these results, a GWAS on germinal DNA and geneexpression 

analyses on tumors are ongoing. In order to clarify the prognostic 

vs predictive role to antiangiogenic treatments of this feature analyses from 

2 phase III randomized trials have been planned. 


An 18-gene blood-based IVD test for colorectal cancer early detection with 

high sensitivity and specificity. Presenting Author: Ye Xu, Fudan University 

Cancer Hospital, Shanghai, China 

Background: Colorectal cancer (CRC) is often curable particularly diagnosed 

at early stages. Different screening strategies are in place in various 

counties. However, the compliance rate with current CRC screening 

recommendations remains poor. A simple blood-based IVD test would 

represent an interesting alternative. We previously reported a 100-gene 

signature for early detection of CRC using microarray technology. Based on 

this result, we have developed a new blood test with real-time PCR 

technology. Methods: 144 CRC cases and 153 Controls were enrolled. A 

total of 52 genes were selected as candidate markers to be transferred from 

microarray to real-time PCR. The gene expression profiles from 100 CRC 

cases and 100 Controls were used as a training set for signature discovery. 

Signature identification process was conducted by Minimum Redundancy 

Maximum Relevance (mRMR) feature selection method and Support Vector 

Machine (SVM) classification algorithm under the Leave-One-Out Cross 

Validation (LOOCV) framework. The optimal size of signature was determined 

by a stepwise inclusion selection procedure which started with one 

gene and repeatedly added genes one by one until all genes were included. 

The performance of each N-gene signature by the LOOCV was estimated 

and used to determine the best size of signature. Results: The gene 

expression profiles measured by microarray and real-time PCR technology 

were highly comparable and resulted in a significant correlation in term of 

fold change ratio between CRC cases and Controls (Pearson’s Correlation 

Coefficient � 0.95). An 18-gene signature was identified and validated in 

an independent validation set with 44 CRC cases and 53 Controls. The 

performance of 18-gene signature in the validation set reached 88.7% 

accuracy (95%CI: 0.80-0.94), 88.6% sensitivity (95%CI: 0.75-0.96), 

and 88.7% specificity (95%CI: 0.76-0.95). Conclusions: Our new results 

demonstrated the feasibility of technology transfer from microarray to 

real-time PCR. The blood test could be offered to individuals who are 

unwilling or unable to undergo colonoscopy to increase the CRC screening 

compliance rate. Meanwhile, its high specificity could also help to avoid 

unnecessary colonoscopies. 




Phase Ib study of dulanermin combined with first-line FOLFOX plus 

bevacizumab (BV) in patients (Pts) with metastatic colorectal cancer 

(mCRC). Presenting Author: Mark Kozloff, Ingalls Hospital and University 

of Chicago, Harvey, IL 

Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNFrelated 

apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic 

pathways by binding to the pro-apoptotic death receptors DR4 and 5. This 

study assessed the safety of dulanermin combined with FOLFOX�BV as 

first-line therapy in mCRC pts. Methods: This was a multicenter, open-label 

dose-escalation and cohort expansion study with treatment until disease 

progression or treatment intolerance. Dulanermin was administered intravenously 

in 14-day cycles on Days 1, 2 and 3 at 4.5 mg/kg or 9 mg/kg, with 

FOLFOX, and BV 5 mg/kg on Day 1. Dose-limiting toxicity (DLT) was 

assessed through 2 cycles (Days 1-28). Adverse events (AE) were recorded 

through all cycles. Response was assessed with RECIST (v1.0). Results: A 

total of 23 pts received 2-33 cycles (median 15) of dulanermin with 

FOLFOX�BV. No DLTs were reported. The most frequent AEs reported as 

dulanermin-related were fatigue (26%), neutropenia and nausea (22% 

each), and alanine aminotransferase increased and diarrhea (17% each). 

The most frequent Grade �3 AEs reported as dulanermin-related were 

neutropenia (13%) and infusion-related reaction (9%). Some of these 

events were reported as related to dulanermin and other study drugs. Three 

pts (13%) discontinued study treatment due to serious AEs: infusionrelated 

reaction (2 pts, 9%; both reported as dulanermin-related) and 

pulmonary embolism (1 pt, 4%). Other reasons for discontinuation included 

disease progression (13 pts, 57%), physician’s decision and pt’s 

decision (2 pts each, 9%), and non-compliance (1 pt, 4%). Two pts are still 

receiving treatment. Among the 23 patients, best responses included 13 

(57%) partial responses (9 confirmed and 4 unconfirmed), 7 (30%) stable 

disease and 3 (13%) progressive disease. Conclusions: Addition of dulanermin 

to first-line FOLFOX�BV was well tolerated overall in these mCRC pts. 

AEs were similar to those previously reported for FOLFOX�BV alone. Tumor 

responses suggest no adverse interactions between dulanermin and the 

standard first-line treatment evaluated in this study. 


Prognostic impact of miR-146 polymorphism in patients with resected 

colorectal cancer. Presenting Author: Jong Gwang Kim, Kyungpook National 

University Hospital, Daegu, South Korea 

Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory 

functions as tumor suppressors and oncogenes. The rs2910164 is a C 

to G polymorphism located within the sequence of miR-164a precursor, 

which leads to a change from a C:U pair to a G:U mismatch in its stem 

region. Recent evidence suggested that the rs2910164 SNP in miR-146a 

was associated with development of familial breast and ovarian cancers, 

and prostatic cancer. The aim of this study was to investigate the 

association between this genetic variant and prognosis of colorectal cancer 

(CRC) operated curatively. Methods: A total of 343 CRC patients underwent 

curative surgery were consecutively enrolled between 2004 and 2006. 

DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism 

was genotyped by polymerase chain reaction-restriction fragment 

length polymorphism (PCR-RFLP). Results: With a median follow up of 

42.3 months, the combined GG�CG genotype demonstrated a better 

survival outcome compared with the CC genotype in a Kaplan-Meier 

survival analysis. Multivariate analysis showed that the G allele of miR-146 

was associated with better progression-free and disease-specific survival as 

a dominant model adjusted to age, sex, histologic grade and stage 

[HR�0.54 and 0.49; p � 0.018 and 0.025, respectively]. Moreover, the 

tumors containing the G allele were histologically associated with more 

prominent lymphovascular invasion. Conclusions: Our results suggest that 

miR-146 polymorphism is possible prognostic marker in operated CRC 

patients in Korean. 


Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on 

outcome in patients with metastatic colorectal cancer (mCRC) treated with 

first-line chemotherapy. Presenting Author: Virginia Alonso-Espinaco, Hospital 

Clínic, Barcelona, Spain 

Background: Metastatic colorectal cancer (mCRC) patients (pts), with BRAF 

tumor mutation (V600E) present poor overall survival (OS). RAC1b, a RAC1 

spliced variant, is overexpressed in CRC, and impairs apoptosis by 

activation of nuclear-factor-KB. Because RAC1b and BRAF (V600E) are 

significantly associated in CRC (Matos et al, 2008), we evaluated if 

RAC1b/RAC1 mRNA expression ratio (RNA ER) was an independent 

prognostic factor in mCRC. Methods: We analyzed tumor samples from 186 

mCRC pts, treated in first-line therapy with FOLFOX or CAPOX in three 

Spanish hospitals. We examined BRAF (V600E) mutational status by 

allelic discrimination, RAC1b/RAC1 expression ratio by mRNA RT-PCR 

(quantitative real time polymerase chain reaction) and mismatch repair 

(MMR) deficiency by microsatellite instability (MSI) analysis. We assessed 

whether these biomarkers were independently predictive of response rate 

(RR), progression free survival (PFS) or OS. Results: 88% of samples were 

informative for BRAF, 75% for MMR status and 85% for RAC1b/RAC1 

(RNA ER). BRAF (V600E) was found in 7%, MSI-H in 5% and high 

�0.9-fold RAC1b/RAC1 (RNA ER) in 20% of pts. Five of 11 pts (46%) with 

BRAF mutation had high RAC1b/RAC1 (RNA ER) compared with 25/144 

(18%) without BRAF mutation (p�0.036). All pts with BRAF mutation 

were MMR and none of the MSI-H pts, showed high RAC1b/RAC1 (RNA 

ER). Patients with low RAC1b/RAC1 (RNA ER) and BRAF WT had higher 

response rate (68% vs 43%; p�0.035). Response rate were not different 

according BRAF mutation (64% WT vs 63% mutant) (p�NS). The 

multivariate regression analysis identified ECOG PS (HR: 4.2 (CI 1.4-12.7) 

as a significant variable for PFS and LDH levels (HR: 2.26 (CI 1.3-3.8), PS 

(HR: 3.85 (CI 1.5-9.8) and high RAC1b/RAC1 (RNA ER) (HR: 2.6 (CI 

1.1-5.9) for OS in WT BRAF pts. Conclusions: High RAC1b/RAC1 (RNA ER) 

constitutes a marker of poor OS and a potential marker of acquired 

chemo-resistance in WT BRAF mCRC pts treated with first-line oxaliplatinbased 

therapy. 


Phase II study of panitumumab (P) in combination with FOLFOXIRI as 

first-line treatment of metastatic colorectal cancer (mCRC): Activity in 

molecularly selected patients (pts). Presenting Author: Sara Lonardi, 

Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy 

Background: GONO-FOLFOXIRI demonstrated higher activity and efficacy 

compared to FOLFIRI. P with oxaliplatin- or irinotecan-based doublets is 

feasible and associated with improved activity in KRAS codon 12-13 

wild-type pts. BRAF and other RAS rare mutations have been suggested as 

additional potential biomarkers for anti-EGFR agents. Methods: Pts with 

untreated unresectable mCRC and wild-type BRAF-RAS genes were enrolled 

in this GONO multicenter phase II trial of biweekly P 6 mg/kg d1 with 

a modified FOLFOXIRI regimen (IRI 150 mg/m2 d1, OXA 85 mg/m2 d1, 

l-LV 200 mg/m2 d1 and 5FU 3000 mg/m2 48-h continuous infusion d1, 

reduced to 2400 mg/m2 due to grade 3-4 toxicity in 2 of first 3 pts 

enrolled). Primary end-point was response rate (RR, RECIST Criteria). 

Based on a two stage Simon’s Minimax design (p0�60%, p1�80%; 

a�0.05, � �0.2) at least 26 responses on 36 evaluable pts should be 

observed to satisfy the primary end-point. Results: 37 out of 87 screened 

pts were enrolled (M/F, 57/43%; median age 63 years, range 33-72; ECOG 

PS 0/1-2, 76/24%; primary colon/rectum, 70/30%; primary on site, 42%; 

sites of disease single/multiple, 54/46%; liver only mts, 35%). Among the 

first 3 pts treated with 5FU 3000 mg/m2 , 2 experienced SAEs (1 grade 4 

diarrhea and neutropenia; 1 grade 3 diarrhea). Grade 3-4 toxicities 

observed among the 34 pts treated at the amended dose were: neutropenia 

53% (2 febrile neutropenia); diarrhea 32%; stomatitis 15%; neurotoxicity 

(grade 2-3) 30%; cutaneous rash 24%. Delays or dose reductions were 

needed only in 9% and 10% of the total 310 cycles, respectively. One SAE 

(febrile neutropenia and sepsis) resulting in pt death occurred after 

amendment. 32 partial responses, 4 disease stabilizations and 1 progression 

were observed, with a RR of 86% (95% CI: 75-97%). 9 pts underwent 

local procedures on metastases, achieving an R0 resection in 8 and a 

pathologic complete response in 3 of them. At a median follow-up of 7.4 

months mPFS has not been reached. Conclusions: In molecularly selected 

unresectable pts adding P to FOLFOXIRI resulted in high activity and 

interesting resection rate. The regimen appears feasible. Further follow-up 

is needed to assess long-term outcome. 



Exploratory analysis of adjuvant chemotherapy benefits after preoperative 

chemoradiotherapy and radical resection for rectal cancer. Presenting 

Author: George J. Chang, University of Texas M. D. Anderson Cancer 


Background: Evidence regarding adjuvant chemotherapy (CTx) for patients 

with rectal cancer after preoperative chemoradiotherapy (CXRT) is limited. 

The aim of study was to explore the relationship between CXRT response 

and adjuvant CTx for patients with rectal cancer treated by CXRT and 

radical resection. Methods: We performed a retrospective consecutive 

cohort study of patients with locally advanced (cStage II-III by EUS, CT, or 

MRI) rectal carcinoma treated with preoperative CXRT and radical resection, 

1993 to 2008. To explore the late effects, we performed a landmark 

analysis of patients alive without recurrence at 24 months. The duration 

free from recurrence (FFR) was compared among patients with complete 

(CR, ypT0N0), intermediate (IR, ypT1-2N0), or poor (PR, ypT3-4 or N�) 

response according to adjuvant CTx use and type using multivariate Cox 

regression. Results: A total of 725 patients met criteria and were evaluated. 

Median follow-up was 69 months (IQR: 39-104 months). 611 patients 

received adjuvant CTx: 447 with fluoropyrimidine only (FP), and 139 also 

received oxaliplatin (Ox). Although receipt of adjuvant chemotherapy was 

not associated with 5-year FFR overall, (HR: 0.91, 95% CI: 0.58-1.43), 

adjuvant therapy did appear to suggest a benefit in the IR group (HR, 0.49; 

95%CI, 0.21-1.19). 2-year landmark analysis showed that adjuvant CTx 

was associated with a significant improvement in FFR among the IR 

patients only (HR, 0.28; 95% CI, 0.08-1.00, p�0.04). Among PR patients 

FP alone did not improve FFR (HR, 1.22; 95% CI, 0.7-2.12) but the 

addition of Ox was associated with a non-significant reversal in the 

direction of the effect (HR, 0.53; 95% CI, 0.16-1.79). Conclusions: In this 

exploratory analysis, the addition of adjuvant FP CTx appeared to favorably 

affect the duration FFR only for patients with rectal cancer and intermediate 

response to CXRT followed by radical resection. These data support the 

investigation of the role for adjuvant fluoropyrimidine therapy among 

patients with CR or IR and the addition of oxaliplatin for PR patients. 


Phase II study of combination therapy with S-1 and cetuximab in patients 

with KRAS wild-type unresectable colorectal cancer who had previously 

received irinotecan, oxaliplatin, and fluoropyrimidines (KSCC0901). Presenting 

Author: Kazuma Kobayashi, Department of Medical Oncology, 

Kochi Health Sciences Center, Kochi, Japan 

Background: Anti-epidermal growth factor receptor (anti-EGFR) antibodies 

alone or in combination with irinotecan (Iri) can be considered standard 

third-line therapy for KRAS wild-type (wKRAS) unresectable colorectal 

cancer (UNCRC). However, some UNCRC patients (pts) cannot tolerate 

Iri-containing therapy. S-1, an oral fluorouracil (FU) derivative, enhances 

the anti-tumor effect by inhibiting dihydropyrimidine dehydrogenase activity 

and reducing digestive toxicity. Combination therapy with cetuximab 

(C-mab) may restore 5-FU resistance in 5-FU–resistant CCs. Therefore, we 

examined the efficacy of S-1�C-mab therapy in wKRAS UNCRC pts, who 

had previously received Iri, oxaliplatin (OX), and FUs. Methods: The study 

design was multicenter, single-arm, open-label phase II study. The major 

inclusion criteria were written informed consent; histologically proven CRC 

and clinically proven UNCRC; presence of measurable lesions; previous 

therapy with Iri, OX, and 5-FU; documented progressive disease after 

5-FU–based chemotherapy; wKRAS tumors; age � 20 years; performance 

status (PS) 0–1; and adequate organ function. The treatment protocol was 

as follows: weekly durable intravenous (DIV) C-mab administration at 400 

mg/m2 (day 1) and 250 mg/m2 /week (except day 1) and oral administration 

of 80 mg/m2 /day S-1 on days 1–28 of each 42-day cycle. The primary 

endpoint was progression-free survival (PFS). A sample size of 39 was 

planned for a threshold PFS of 3.5 months and expected value of 6.0 

months, with one-sided alpha of 0.05 and beta of approximately 0.2. 

Results: One patient was ineligible; 38 pts (PS 0/1, 32/6; 1/2/�3 prior 

chemotherapy regimens, 4/23/11) were enrolled from 10/2009 to 12/ 

2010. The median PFS (central review) was 5.5 months (90% CI: 4.4 – 

5.7); median overall survival (OS), 13.1 months; and the best ORR, 

36.8%. The most common grade 3–4 adverse events were neutrophils, 

hypokalemia, rash, and dry skin. Conclusions: This study showed that 

S-1�C-mab may be a promising and well-tolerated treatment choice of 

wKRAS UNCRC, who had previously heavily treated by Iri, OX and FUs. 



Post-progression survival (PPS) according to treatment line, type, and time 

in phase III trials in advanced colorectal cancer (ACC). Presenting Author: 

Marc E. Buyse, International Drug Development Institute, Louvain-la- 

Neuve, Belgium 

Background: Since post-progression therapy influences overall survival 

(OS), PPS is of interest as a determinant of OS. We quantified the 

relationship between several median times to event in ACC: progressionfree 

survival (PFS), PPS and OS. We looked for factors with an impact on 

these times. Methods: We searched PubMed for phase III trials published 

between January 1998 and December 2010 in 12 leading journals. PPS is 

the difference between median OS and median PFS or time to tumor 

progression. The statistics of interest (median times [PFS, OS and PPS] 

and the ratio of PPS/OS) were compared using t-tests. Results: We retrieved 

70 trials that yielded 71 comparisons and 156 arms (one trial was factorial) 

involving 38,504 patients. Trials from the period 2005-10 enrolled more 

patients than trials from the period 1998-2004 (medians of 246 vs 174 

per arm; P�.026). PPS could be calculated for 60 trials and 135 arms 

(Table). Treatment type did not have an impact on any statistic. Treatment 

line had a significant impact on all times and on the ratio of PPS/OS, 

although the difference on the latter statistic was small. Treatment period 

had a significant impact on all times but not on the ratio of PPS/OS. 

Conclusions: None of the factors examined have a major impact on the ratio 

of PPS/OS. This suggests that in ACC, gains in PFS are translated into 

proportional gains in OS, one of the conditions required for PFS to be 

considered a surrogate for OS. 

PFS (months) PPS (months) OS (months) PPS / OS (%) 

Trial type N Average* p Average* p Average p Average* P 

Overall 135 6.3 - 9.0 - 15.3 - 59 - 

Chemotherapy only 

97 6.1 .30 9.0 .64 15.1 .43 59 .82 

At least one targeted agent 38 6.6 

9.3 

15.9 

59 

1st line only 

108 6.8 �.001 9.6 �.001 16.4 �.001 58 .004 

2nd / 3rd line 

27 4.0 

7.0 

11.0 

63 

Published 1998-2004 

59 5.2 �.001 7.8 �.001 13.0 �.001 60 .51 

Published 2005-2010 76 7.1 

10.0 

17.1 

58 

1st line, 1998-2004 

51 5.5 �.001 8.2 �.001 13.7 �.001 59 .16 

1st line, 2005-2010 57 8.0 

10.8 

18.8 

57 

2nd/3rd line, 1998-2004 8 3.1 .033 5.2 .016 8.3 .007 62 .74 

2nd / 3rd line, 2005-2010 19 4.4 

7.7 

12.1 

63 

N, Number of treatment arms; * Average of median values for treatment arms. 

217s 


Impact of body mass index (BMI) and weight changes on recurrence and survival 

in stage III colon cancer (CC). Presenting Author: Joanna Vergidis, British 

Columbia Cancer Agency, Vancouver, BC, Canada 

Background: Research suggests that physical activity can lower the risk of relapse 

and mortality from CC. It is unclear if such potential benefits are mediated 

through an effect on weight. Our aims were to 1) evaluate the impact of 

pre-treatment BMI on recurrence and survival in early stage CC, 2) examine how 

weight gains and losses from baseline may affect outcomes, and 3) explore if the 

effects of different body compositions are modified by adjuvant therapy (AT). 

Methods: Patients (pts) diagnosed with stage III CC from 2006 to 2008, 

evaluated at any 1 of 5 cancer centers in British Columbia, and who had their 

weights measured serially throughout their AT period were reviewed. Using Cox 

proportional hazards models, we compared outcomes among a) BMI�25 

[normal] vs. 25-30 [overweight] vs. �30 [obese] and b) weight increase or 

decrease of � vs. �/�5% and � vs. �/�10%, while controlling for confounders. 

Results: A total of 821 pts were included: median age was 65 years, 50% were 

men, and 83% were ECOG 0/1. At baseline, 43, 37, and 20% were normal, 

overweight, and obese, respectively. Compared to pts with normal BMI, those 

who were overweight or obese did not show an increased risk of recurrence (HR 

0.81, 95%CI 0.42-1.58 and HR 1.09, 95%CI 0.48-2.51, respectively, p 

trend�0.74) or death (HR 0.54, 95%CI 0.26-1.13 and HR 0.62, 95%CI 

0.22-1.74, respectively, p trend�0.24). A number of pts experienced weight 

gain or loss during their AT period, but none of these weight changes affected 

outcomes (Table). Receipt of AT did not modify the effects of BMI or weight 

change. In Cox models, advanced age and poor performance status were the 

main factors that consistently correlated with an increased risk of recurrence and 

death (p�0.05). Conclusions: Neither baseline BMI nor short-term weight 

changes during AT appear to affect outcomes in stage III CC. Physical activity 

likely exert its benefit on relapse and survival by influencing long-term weight 

changes or acting via other alternative mechanisms. 

Recurrence Death 

% of Cohort HR p value HR p value 

Weight gain 

/�5% 50.4 1.04 0.90 

/�10% 

Weight loss 

18.7 0.75 0.98 

/�5% 12.4 0.98 1.42 

/�10% 4.5 0.41 0.83 




Relationship of Src activity and prior oxaliplatin on outcomes after 

hepatectomy for metastatic colorectal cancer. Presenting Author: Van 

Karlyle Morris, University of Texas M. D. Anderson Cancer Center, Houston, 

TX 

Background: The nonreceptor tyrosine kinase Src regulates pathways 

critical to tumor proliferation, chemoresistance, and epithelial-tomesenchymal 

transition. In vitro, Src is activated after acute oxaliplatin 

exposure and in acquired oxaliplatin resistance, but not after 5-FU alone. 

Activation of Src and its substrate FAK in metastatic colorectal cancer 

treated with oxaliplatin has not been studied in human specimens. 

Methods: Samples from 170 hepatic resections from two cohorts of patients 

with metastatic colorectal cancer were examined by IHC for expression of 

activated Src (pSrc) and FAK (total and pFAK). In the first cohort (n�50), 

tissue was collected at consecutive hepatic resections before and after 

oxaliplatin. Patients in the second cohort (n�120) were compared based 

on whether or not oxaliplatin was administered after resection. IHC was 

graded semi-quantitatively, 0 to 4 based on intensity (first cohort), and by 

automated image analysis (second cohort). Results: In the first cohort, 

pFAK expression increased after oxaliplatin exposure (mean IHC score 

2.04 vs. 1.18, p�0.01). In the second cohort, Src activation was 

correlated with pFAK expression (p�0.01). Patients pretreated with 

oxaliplatin demonstrated increased expression of activated FAK (p�0.02) 

compared to 5-FU alone or irinotecan regimens. There was a weak 

association between total Src expression and the number of oxaliplatin 

cycles (p�0.06). Among patients in the second cohort, five-year relapsefree 

survival was inversely related to levels of pFAK (21.1%, 16.5%, and 

7.4% for low, medium, and high levels of pFAK, respectively; p�0.02) and 

of pSrc (19.6%, 13.6%, and 8.2% for low, medium, and high levels of 

pSrc, respectively; p� 0.01). Conclusions: Patients treated with neoadjuvant 

oxaliplatin demonstrated increased Src signaling in liver metastases, a 

finding associated with worse relapse-free survival. These results are 

consistent with prior in vitro studies correlating oxaliplatin exposure with 

Src pathway activation and support the idea that inhibition of Src, when 

used in combination with platinum chemotherapy, warrants further investigation 

in patients with metastatic colorectal cancer. 


Evaluation of FDG-PET in pretreatment staging in locally advanced rectal 

cancer: A prospective study. Presenting Author: Jose G. Guillem, Memorial 


Background: The utility of adding 18F-Fluorodeoxyglucose-Positron Emission 

Tomography (PET) to the pre-treatment staging of patients with locally 

advanced rectal cancer has not been well evaluated. Methods: Following 

completion of standard work-up, including physical examination, endorectal 

ultrasound, CT of the abdomen and pelvis, and chest CT or chest x-ray, 

150 patients with primary, resectable, biopsy-proven rectal adenocarcinoma 

requiring neoadjuvant chemoradiation were enrolled in a prospective, 

single-stage, phase II study evaluating the role of PET. All patients 

underwent a dedicated whole-body PET prior to initiation of neoadjuvant 

chemoradiation. The primary endpoint of this analysis was to determine the 

accuracy of PET in detecting extrapelvic metastatic disease in primary 

rectal cancer patients considered operable on the basis of currentlystandard 

work-up. Results: Among the 117 eligible patients found to be 

stage II or III by standard staging techniques, none (0%) were found by PET 

to have extrapelvic metastatic disease. PET yielded a false positive result in 

3 patients (2.6%). PET yielded a false-negative result in 3 patients who 

were subsequently diagnosed with metastatic disease: 2 pre-operatively 

(liver, lung) and 1 intra-operatively (obturator lymph node). In 1 patient, 

PET did identify a previously unappreciated obturator lymph node metastasis; 

left pelvic sidewall dissection at the time of rectal resection confirmed 

metastatic adenocarcinoma in one obturator lymph node. Conclusions: Of 

the 117 rectal cancer patients evaluated and found to have locoregional 

disease by standard examination and imaging techniques, none had 

extrapelvic metastatic disease accurately identified by PET. PET did not 

improve the accuracy of pre-treatment staging. As such, consistent with 

current NCCN guidelines, PET does not have a role in pre-treatment staging 

of locally advanced rectal cancer. 


Chemotherapy plus cetuximab in patients with liver-limited or non-liver-limited 

KRAS wild-type colorectal metastases: A pooled analysis of the CRYSTAL and 

OPUS studies. Presenting Author: Claus-Henning Kohne, Onkologie Klinikum 

Oldenburg, Oldenburg, Germany 

Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to 

first-line chemotherapy (CT) improved clinical benefit in patients (pts) with 

KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these 

trials the benefit of treatment according to whether pts had liver-limited disease 

(LLD) or non-LLD was analyzed. Methods: Cox‘s proportional hazards model for 

overall survival (OS) and progression-free survival (PFS) or logistic regression 

model for best overall response and R0 resection were used on individual pt data, 

stratified by study. Likelihood ratio tests were used to explore interactions. 

Results: Adding cet to CT significantly improved PFS and overall response rate 

(ORR) in LLD pts, and OS, PFS and ORR in non-LLD pts and increased R0 

resection rates (table). No treatment-by-study interactions were found. Treatment 

effects did not vary significantly by LLD status (PFS p�0.60, OS p�0.68, 

ORR p�0.0737, R0 resection p�0.71). However LLD vs non-LLD pts had 

improved outcome in each treatment arm: PFS, CT hazard ratio, HR�0.74, 

p�0.0910; CT � cet HR�0.66, p�0.0309; OS, CT HR�0.70, p�0.0091; CT 

� cet HR�0.74, p�0.0388; ORR, CT odds ratio�1.20, p�0.47, CT � cet odds 

ratio�2.32, p�0.0015; R0 resection, CT odds ratio�3.15, p�0.0496, CT � 

cet odds ratio�3.82, p�0.0018. Kaplan Meier survival plots will be shown. 

Conclusions: The OS benefit from adding cet to CT is more pronounced in 

non-LLD pts, thus strengthening the value of cet in palliative treatment.LLD 

status is associated with improved prognosis and may be predictive for response 

in pts receiving CT � cet, facilitating potentially curative resection. More pts 

(with R0 resection and longer follow-up) may be needed to confirm an OS benefit 

from CT � cet in LLD pts. 

CT 

(n�95) 

KRAS wt pts 

LLD Non-LLD 

CT� cet 

(n�93) 

CT 

(n�352) 

CT � cet 

(n�305) 

OS 

Median, mo 27.0 27.0 17.3 22.0 

HR 0.81 0.76 

p 

PFS 

0.25 0.0023 

Median, mo 9.2 11.9 7.4 9.4 

HR 0.53 0.68 

p 

Response 

0.0095 0.0004 

ORR% 43.2 72.0 37.2 52.8 

Odds ratio 3.51 1.88 

p 

R0 resection 

�0.0001 �0.0001 

Rate, % 5.3 11.8 1.7 3.3 

Odds ratio 2.38 1.97 

p 0.1121 0.1870 

Data (except for R0 resection) are adjusted for differences in baseline characteristics 


Association study of the let-7 microRNA-binding site polymorphism in 

3’-untranslated region (UTR) of the KRAS gene in stage III colon cancers 

from adjuvant trial NCCTG N0147. Presenting Author: Dan Sha, Mayo 

Clinic, Rochester, MN 

Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon 

cancer cell proliferation by inducing KRAS downregulation after binding to 

specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR 

polymorphism in the let-7 complimentary site (LCS6) that has been shown 

to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6 

G-allele showed worse survival in metastatic colorectal cancer from prior 

studies of limited sample size. In the current study, we evaluated the LCS6 

variant in 2,834 Stage III colon cancer patients and its association with 

disease-free survival (DFS), KRAS mutation status, and other clinicopathological 

features. Methods: In the NCCTG phase III trial (N0147), the LCS6 

variant was assayed in germline DNA extracted from whole blood using 

RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations. 

Chi-squared and two-sample t test were used to compare baseline factors 

and KRAS mutation status between patients defined by LCS6 variant 

status. Log-rank tests and multivariate Cox models assessed the unadjusted 

and adjusted associations between LCS6 status and DFS, respectively. 

Results: We identified 432 (15.2%) patients heterozygous or 

homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous 

for the LCS6 T-allele. G-allele carriers were significantly more frequent in 

Caucasians than other races (Chi-Squared Test, p�0.0001). No associations 

were found between the LCS6 genotype and T stage, positive lymph 

node number, tumor differentiation, or primary tumor location (all p�0.2). 

Moreover, the LCS6 genotype was not associated with DFS (hazard ratio � 

0.93, p�0.49) even after combining LCS6 genotype with KRAS mutation 

status. Conclusions: We report the largest association study investigating 

the LCS6 polymorphism and colon cancer outcome. There is no significant 

evidence that the germline LCS6 genotype was associated with DFS in 

stage III colon cancer patients. Additional studies are needed to determine 

if LCS6 genotype differs between tumor and germline DNA which may 

further clarify its prognostic value. 



Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial 

treatment with BEV plus XELOX in previously untreated patients (pts) with 

metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a 

phase III, randomized, multicenter study. Presenting Author: Suayib 

Yalcin, Hacettepe University Medicine Faculty, Ankara, Turkey 

Background: Colorectal cancer is one of the most frequent malignancies, 

second after breast cancer in women and third after lung cancer and 

prostate cancer in men. The aim of this study was to evaluate and compare 

the progression-free survival (PFS) between two arms: Arm A is a combination 

of BEV � XELOX; Arm B is a combination of BEV � XELOX for 6 cycles 

followed by maintenance BEV � capecitabine as first-line therapy in 

mCRC. Methods: BEV (7.5 mg/kg) � XELOX (capecitabine 1000 mg/m2 bid 

d1–14 � oxaliplatin 130 mg/m2 d1 q3w) were administered until progression 

(Arm A) or 6 cycles of BEV � XELOX followed by BEV � capecitabine 

were administered until progression (Arm B). PFS was the primary 

endpoint; secondary endpoints included overall survival (OS), objective 

response rate (ORR), and safety. A sample size of 118 pts was required to 

detect with 80% power an increase of 1.5 months in median PFS between 

two arms with a standard deviation of 3.9 months and significance level of 

0.05 (10% drop-out rate). Results: A total of 123 pts were randomized. 

Demographic characteristics were balanced between the arms. Median 

treatment period was 7.5 (range 0.5–13.9) and 8.1 (range 0.1–20.7) 

months in Arms A and B, respectively. There was a statistically significant 

difference in median PFS between arms, although there was no significant 

difference in ORR and OS (see table). Tolerability was acceptable in both 

arms with the following grade 3/4 adverse events (AEs): Arm A 48.4%; Arm 

B 34.4% (p�0.116). Grade 3/4 diarrhoea occurred in 9.7% vs. 3.3%, 

weakness in 8.1% vs. 8.2%, hand-foot syndrome in 3.2% vs. 1.6%, and 

neuropathy in 4.8% vs. 3.3% of pts in Arms A and B, respectively. 

Conclusions: These findings suggest that maintenance therapy with BEV � 

capecitabine following induction with 6 cycles of BEV � XELOX may be 

superior to continuous BEV � XELOX until progression inpts with previously 

untreated mCRC. 

Arm A 

(n�62) 

Arm B 

(n�61) p value 

Efficacy 

Median PFS, months 

8.3 

11.0 

0.002 

(95% CI) 

(7.1–9.5) (9.1–12.9) 

Median OS, months 20.2 23.8 0.1 

ORR, % 58.9 66.7 0.861 


Implications of generating genetic test results for colon cancer in the 

international, population-based colon cancer family registry. Presenting 

Author: Louise A. Keogh, The University of Melbourne, Melbourne, Australia 

Background: The ability to genotype large numbers of people rapidly and 

inexpensively for research purposes highlights the need to develop guidelines 

for providing medically-relevant research results - including unanticipated 

findings - to study participants. The Colon Cancer Family Registry 

(C-CFR) is the oldest and largest international colon cancer populationbased 

registry; its experience managing genetic research findings can offer 

guidance to clinicians and researchers. The C-CFR has enrolled 10,019 

cases with colon cancer and 24,708 family members in six registries in the 

US, Canada, Australia, and New Zealand. Deleterious (“high risk”) germline 

mutations have been identified in DNA mismatch repair (MMR) genes 

(MLH1, MSH2, MSH6, PMS2) and the MutYH gene. The aims of this 

presentation are to: (1) report the uptake of genetic test results by C-CFR 

participants; (2) systematically compare disclosure protocols and barriers 

to uptake by registry; (3) make recommendations to guide clinicians and 

researchers. Methods: Uptake of genetic test results was calculated from 

data collected by the C-CFR; key investigators (KIs) from each registry 

completed a survey about disclosure decision-making; KIs also took part in 

discussions to generate recommendations. Results: Registry-wide molecular 

testing has identified deleterious MMR germline mutations for at least 

one member of 424 families (4%) and 48 biallelic MutYH gene carriers. 

Uptake of test results ranged from 56-86% (n� 1542) across registries. 

Barriers to disclosure include: (1) lack of pre-existing notification protocols; 

(2) logistics of re-consent; (3) limited involvement of genetic 

counselors at some registries; (4) in the US, the requirement that genetic 

testing be performed in a CLIA approved laboratory; (5) IRBs declining 

approval; and (6) budget constraints. Conclusions: Based on our international 

registry’s findings we recommend that researchers generating genetic 

information establish plans for disclosure at the outset; obtain 

subject consent a priori; consider subject knowledge and disclosure 

preferences; provide guidance and budget for clinical follow-up; and 

involve genetic counselors. 


219s 


Prognostic significance of lymph node retrieval in localized rectal cancer 

(RC): A registry analysis of 8,964 patients (pts). Presenting Author: 

Amandeep Gill, University of California, Davis, Sacramento, CA 

Background: In contrast to colon cancer, the prognostic implications of 

reduced lymph node retrieval in RC are unclear. We investigated the 

association between the total number of lymph nodes examined in early 

stage RC and disease specific survival (DSS) in two cohorts: 1) pts who 

underwent surgery and adjuvant (ADJ) chemoradiation (chemoXRT), and 2) 

those who received neoadjuvant (NEO) chemoXRT. Methods: Using the 

California Cancer Registry, we identified 8,946 pts with stage I – III RC 

diagnosed from 2000 to 2007. Of these, 4,790 underwent tri-modality 

therapy: 2,946 patients (61.5%) had NEO chemoXRT and 1,844 patients 

(38.5%) had ADJ chemoXRT. Multivariate Cox proportional hazards models 

were constructed for DSS, adjusting for age, sex, race, socioeconomic 

status, T-stage and lymph node number. DSS was compared between NEO 

and ADJ cohorts within separate subgroups of pathologic node positive and 

node negative RC. Results: Although there was no difference in overall DSS 

between the NEO and ADJ cohorts, the median number of lymph nodes 

examined was reduced in patients who had undergone NEO chemoXRT (8 

vs. 11, p�0.0001). For all pts treated with tri-modality therapy, advancing 

age and higher T-stage were associated with significantly reduced DSS. 

Positive lymph nodes were associated with worse DSS regardless of the 

timing of therapy, although the effect was stronger for residual lymph nodes 

in the NEO cohort (HR 2.8 vs. 1.8 in ADJ cohort, p�0.001). For node 

negative pts in the ADJ cohort, increased lymph node retrieval was 

associated with improved DSS (HR per node 0.952, p�0.017); however, 

no association between lymph nodes examined and DSS was seen in the 

NEO cohort (p�0.282). Conclusions: Residual positive lymph nodes in pts 

treated with NEO chemoXRT are more strongly associated with poorer DSS 

than in pts treated with surgery and ADJ chemoXRT. NEO chemoXRT 

dissociates the connection between lymph node retrieval and survival in 

RC. This finding highlights a key difference between colon and RC and 

underscores the need for a different interpretation of the pathologic 

findings after NEO therapy. 


Association of microsatellite instability with prognosis in the pathologic N2 

colon cancer patients treated with adjuvant FOLFOX chemotherapy. Presenting 

Author: Jeong Eun Kim, Asan Medical Center, Seoul, South Korea 

Background: The impact of microsatellite instability (MSI) on survival has 

been rarely explored, with controversy, in stage III colon cancer treated with 

adjuvant 5-flurouracil-oxaliplatin combination (FOLFOX) chemotherapy. 

We evaluated association between MSI and survival in this population. 

Methods: We analyzed 312 patients (pts) with curatively resected stage III 

colon cancer treated with adjuvant FOLFOX chemotherapy. We determined 

MSI status using polymerase chain reaction amplification as high levels of 

MSI (MSI-H, � 2 unstable markers), low levels of MSI (MSI-L, 1 unstable 

marker), and microsatellite stable (MSS, no unstable marker). Results: Of 

312 pts, 8.3% showed MSI-H and they were younger (median age, 51.5 vs. 

58 years, p�0.018). MSI-H tumors were more commonly located ascending 

colon (46.2% vs. 23.1%, p�0.002) and had poorly differentiated 

features (30.8% vs. 5.2%, p�0.0001). After the median follow-up of 30.9 

months, 3-year relapse-free (RFS) and overall survival (OS) rates were 

76.1% and 91.7%, respectively. In univariate analysis, pathologic N2 

(pN2) was associated with reduced RFS (p�0.0001) and OS (p�0.002), 

while MSI status did not affect either RFS (p�0.254) or OS (p�0.961). In 

patients with pN2 tumors, however, MSI-H was associated with better 

survival compared with MSS/MSI-L; the RFS and OS in pts with pN2/MSI-H 

were comparable to those in pts with pN1 tumors (table). Conclusions: MSI 

status alone did not affect survival in our population. However, pts with 

pN2/MSI-H showed favorable survival outcomes comparable to those with 

pN1, and MSS/MSI-L/pN2 was associated with worst survival, implicating 

that MSI-H modifies the inherent worse prognosis of pN2 tumors. 

pN1 pN2 

MSS/MSI-L MSI-H MSS/MSI-L MSI-H p value 

3yr RFS (%) 86.4 88.0 58.9 85.7 �0.0001 




Short-term clinical outcomes from a randomized controlled trial to evaluate 

laparoscopic versus open complete mesocolic excision for stage II,III 

colorectal cancer (CRC): Japan Clinical Oncology Group study JCOG0404 

(NCT00147134). Presenting Author: Yusuke Nishizawa, National Cancer 


Background: The benefits of laparoscopic surgery (LAP) in comparison with 

open surgery (OP) have been suggested; however, the long-term survival of 

LAP for advanced CRC requiring complete mesocolic excision is still 

unclear. We conducted a study to confirm the non-inferiority of LAP to OP 

in terms of overall survival (OS)with less frequent post-operative morbidity. 

Short-term outcomes including post-operative complications are presented 

here. Methods: Only accredited surgeons from 30 Japanese institutions 

participated. Eligibility criteria included histologically proven CRC; tumor 

located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or 

deeper lesion without involvement of other organs; N0–2 and M0; tumor 

size ��8 cm; patient age 20-75 years. Patients were randomized 

preoperatively.Patients with pathological stage III received adjuvant chemotherapy 

with fluorouracil plus leucovorin. The primary endpoint is OS. and 

the planned sample size was 1050. Results: A total of 1057 patients were 

randomized (OP: 528, LAP: 529) between October 2004 and March 2009. 

Conversion to OP was needed for 29 (5.4%) patients in LAP arm (technical 

conversion; 2.3%, indicated conversion; 2.8%, complicated conversion; 

0.4%). Patients assigned to LAP had less blood loss compared with those 

assigned to OP (median 30 ml vs 85 ml, p�0.001), although LAP lasted 

52 minutes longer than did OP (p�0.001). Radicality of resection as 

assessed by number of resected lymph nodes did not differ between two 

groups. LAP was associated with earlier recovery of bowel function 

(p�0.001), and with a shorter hospital stay (p�0.001) compared with OP. 

Morbidity and mortality untill discharge did not differ between two groups, 

except for less wound-related complications in LAP (p�0.007). Conclusions: 

Laparoscopic complete mesocolic excision for stage II,III colorectal cancer 

can be performed safely and short-term clinical benefits was demonstrated. 

If the non-inferiority of LAP in OS is demonstrated in the primary analysis 

planned in 2014 , LAP will be the new standard procedure for CRC. 


A randomized phase II study of capecitabine-based chemoradiation with or 

without bevacizumab in resectable locally advanced rectal cancer. Presenting 

Author: Mercedes Martinez Villacampa, Instituto Catalán de Oncología, 

Hospital Durans i Reynals, Hospitalet de Llobregat, Spain 

Background: The addition of bevacizumab (BEV) to capecitabine (CAP)based 

chemoradiation (CRT) has shown encouraging efficacy in locally 

advanced rectal cancer (LARC), in nonrandomized studies. This randomized 

phase II study investigated the effect of adding BEV to preoperative 

CAP-based CRT in patients (pts), with LARC. Methods: The primary end 

point was pathologic complete response (pCR). A two-stage design was 

used. Assuming a minimum pCR rate of at least 15% in one of the arms, a 

difference between the two arms of 10%, and accepting a probability of 

correct selection of 87%, 41 pts per arm were needed. Patients with LARC 

(Stages II-III assessed by MRI) and ECOG PS �2 were randomized to 

concurrent radiotherapy 45Gy/25f/5 weeks � CAP (825mg/m²/bid) � BEV 

every 2 weeks (5 mg/kg for 3 doses) (arm A) or the same schedule without 

BEV (arm B). Surgery was scheduled 6-8 weeks after completing CRT. 

Results: 90 pts were randomized (arm A/B: 44/46). Patient’s characteristics 

were well balanced between both arms: male 61%, median age 62 

years, median distance from anal verge 7 cm, T3 79%, N� 87%. 40 

(91%)/43 (93%) of pts (arm A/B) finalized the planned CRT � surgery 

treatment. Overall grade 3-4 toxicity rates were 18 % and 13% (arm A/B, 

p�0.50); no grade 3-4 hematological toxicity was reported. Postoperative 

complications were 19(43%)/17(37%)(arm A/B). Efficacy data on patients 

who actually underwent surgery are reported in the table. Conclusions: The 

addition of BEV to CAP-based preoperative CRT has shown to be feasible 

and safe in the local control of LARC. No differences in pCR were observed 

and longer follow-up is needed to assess the impact on survival endpoints. 

Arm A: RT�CAP�BVZ Arm B: RT�CAP 

Surgery performed 43 (98%) 46 (100%) p:0.49 

pCR (ypT0N0) 7 (16%) 5 (11%) p: 0.54 

R0 resection rates 42 (95.45%) 44 (96%) p:1.0 

Downstaging (lower 

26 (59%) 18 (39%) p: 0.0429 

pT compared with 

the pretreatment cT) 

Sphincter saving surgery 27 (61%) 31 (67%) p: 0.66 


Phase II study of dacarbazine for metastatic colorectal cancer with 

determined MGMT status. Presenting Author: Alessio Amatu, Ospedale 

Niguarda Ca’ Granda, Milan, Italy 

Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA 

repair protein that removes mutagenic and cytotoxic adducts from O6- guanine in DNA. Roughly 40% of colorectal cancers (CRCs) display MGMT 

deficiency due to promoter hypermethylation leading to silencing of the 

gene. Alkylating agents exert their antitumor activity by DNA methylation at 

the O6 –guanine site, inducing base pair mismatch; therefore, activity of 

these compounds may be enhanced in CRCs lacking MGMT (Esteller, 

2004; Pegg, 1990). Despite anecdotal reports about activity of dacarbazine 

in CRC (Shacham-Shmueli, 2011) no clinical trials assessed monotherapy 

with dacarbazine for metastatic CRC. Methods: We conducted a 

phase II study of dacarbazine in CRCs who had failed standard therapies 

(oxaliplatin, irinotecan, fluoropyrimidines and cetuximab or panitumumab 

if KRAS WT), PS�0-1, with adequate organ function, and measurable 

disease as per RECIST criteria assessed by CT scans at baseline and every 8 

weeks. All patients had tumor tissue assessed for MGMT as promoter 

hypermethylation. Patients received dacarbazine 250 mg/m2 i.v. d1-4, 

q21 until PD or untolerable toxicity (with a maximum of 6 cycles in case of 

SD). We employed a Simon, two-stage design to determinate if the ORR of 

dacarbazine treatment would be � 10%. Secondary endpoints were 

association of response/resistance with loss of expression of MGMT, PFS 

and disease control rate. Results: In the first stage, from June 2011 to 

November 2011 we enrolled 40 pts (male 68%, median age 67 y [range 

29-81], PS�0 50%, KRAS mut 55%). Pts received a median of 3 cycles 

[range 1-11]. Toxicities included (All Grades/Grade 3-4 %): fatigue (58/5), 

constipation (38/0), nausea/vomiting (35/0), anemia (20/2.5), platelet 

count decrease (10/5). 36 pts were evaluable for objective response. 

Overall, 2 pts (5%) achieved PR and 5 pts (12.5%) had SD. All pts with PR 

had tumors with MGMT promoter hypermethylation. Conclusions: Having 

exceeded the boundaries of futility (at least 2 objective responses in the 

first stage), the trial proceeds to the second stage, enrolling 28 more 

patients. Analysis of MGMT promoter hypermethylation and association 

with sensitivity/resistance is performed at the end of the second stage. 


Analysis of plasma biomarkers potentially associated with antiangiogenic 

resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of 

cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in 

patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic 

colorectal carcinoma (mCRC). Presenting Author: Jeremy David 

Shapiro, Cabrini Hospital and Monash University, Melbourne, Australia 

Background: In the CO.20 trial, the addition of BRIV, a tyrosine kinase 

inhibitor targeting vascular endothelial and fibroblast growth factor receptors 

(VEGFR2,3 and FGFR 1,2,3), to CET, increased objective response 

rate and progression free survival, but did not significantly increase overall 

survival. Previous clinical studies demonstrated modulation of circulating 

angiogenic factors (CAF) in CRC which occur on therapy or upon progression 

(Kopetz JCO 2010). Methods: CO.20 pts were randomized 1:1 to CET 

plus either BRIV (Arm A) or placebo (ARM B) in a double-blind design. Pts 

may have had 1 prior anti-VEGF based therapy, but no prior anti-EGFR 

therapy. Primary endpoint was overall survival (OS). Baseline pre-treatment 

plasma samples were analyzed using commercial Multi-Analyte ELISAs to 

measure CAF, immunologic, and growth factors, with an initial discovery 

and subsequent validation data set. Results: 750 pts were randomized (376 

in Arm A and 374 in Arm B). Median OS in the intent-to-treat population 

was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio 

(HR)�0.88; 95%CI�0.74-1.03; p�0.12. In an exploratory subgroup 

analysis, there is a statistically non-significant trend favoring the effect of 

brivanib on OS among the 41% pts who received prior anti-VEGF therapy 

versus those who did not.Baseline plasma samples were collected from 

96% of pts, and analysis is ongoing. Results of the largest circulating 

biomarker analysis will be presented. CAF results will be compared with 

response and survival data to look for potential patient subgroups that may 

benefit more from the combination treatment. Conclusions: This large scale 

analysis will provide insights on the potential use of CAF or CAF profiles as 

predictive markers in CRC. 



The relationship between microRNA-126 and maintenance therapy with 

bevacizumab after bevacizumab plus chemotherapy as first-line treatment 

for patients with metastatic colorectal cancer: Results of the phase III 

Nordic ACT trial NCT00598156 translational study. Presenting Author: 

Torben Hansen, Danish Colorectal Cancer Group South, Vejle Hospital and 

University of Southern Denmark, Vejle, Denmark 

Background: Maintenance therapy during chemotherapy free intervals is a 

debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT 

trial patients benefitting from induction chemotherapy plus bevacizumab 

were randomized to bevacizumab with or without erlotinib. MicroRNA-126 

(miRNA-126) is believed to influence angiogenesis in several ways, and we 

investigated the relationship between miRNA-126 and progression free 

survival (PFS) under maintenance therapy. Methods: The miRNA-126 was 

analysed by polymerase chain reaction on both genomic DNA (by the 

pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin 

embedded primary tumors, (which were classified as low or high 

miRNA-126 expressing tumours using the median value as cut-off). 

Diagnostic biopsies were not processed due to limited tumour tissue. Of the 

159 randomized patients blood samples were available from 151 and 

primary tumours from 91. The PFS (from time of randomization) was 

compared using the Kaplan-Meier method and the log rank test. The Cox 

Regression analyses were used to test for independent contributions. 

Results: The A24G SNP was not related to PFS, but a significant association 

was seen between genotypes and miRNA-126 expression levels.Furthermore, 

the PFS was increased in patients with high tumor miRNA-126 

expression compared to patients with low expression, hazard ratio (HR) 

0.58 (95% confidence interval (CI) 0.38-0.90), p � 0.015. The median 

PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI 

2.6-4.5 months), respectively. Results did not differ between treatment 

arms, but the Cox Regression analysis confirmed an independent prognostic 

value of the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39- 

0.95), p � 0.030. Conclusions: The miRNA-126 may be a potential marker 

for bevacizumab containing maintenance therapy. A similar relationship 

with PFS has recently been demonstrated in patients with mCRC treated 

with chemotherapy only. The results call for validation. 


Molecular and clinicopathologic evidence of heterogeneity in KRASmutant 

colon cancers. Presenting Author: Vlad Calin Popovici, Swiss 

Institute of Bioinformatics, Lausanne, Switzerland 

Background: The activation of the MEK/ERK signaling cascade by KRAS or 

BRAF mutations has a high incidence in colorectal cancer (CRC). While 

these mutations are mutually exclusive, we have identified a highly 

conserved gene expression pattern, characteristic to BRAF mutants, that 

can also be observed in KRAS mutants (AACR 2011, JCO 2012), and 

which defines a distinct subpopulation. Its characterization is important as 

it may shed a light on the observed survival and treatment response 

variability of this group of CRCs. Methods: A set of 257 stage II and III 

KRAS mutant CRCs from the PETACC3 clinical trial and a subset of 150 

CRCs from TCGA project were used for this study. Gene expression data was 

available for all samples and, additionally, CNV and methylation data was 

available for some of the samples. Due to the limited number of MSI 

samples, the analyses were focused on MSS subpopulation. Results: The 

cluster analysis on the genes from the BRAF signature clearly indicated a 

major split of the KRAS mutants into two subgroups, that were further 

compared in terms of clinico-pathological and survival parameters. The 

BRAF-mutant-like (BML) subgroup was clearly enriched in MSI-H 

(p�0.001), right-sided (p�0.038) and mucinous histology (p�0.001) 

tumors. The enrichment in mucinous tumors remained significant also in 

stratified analysis by MSI status. In MSS, the BML subpopulation of KRAS 

mutants had the worst prognosis for overall survival (p�0.05, HR�1.6) 

and survival after relapse (p�0.004, HR�2.1). Analysis of differentially 

expressed genes between BML and the rest of KRAS mutants identified 

genes responsible for colon crypt differentiation, Wnt pathway activation 

and, more intriguingly, 50 other genes, all located on chromosome 20q, 

that had significantly different activation levels in BML tumors. Among 

these genes, there are a number of important tumor suppressors, like 

PLAGL2, TP53RK and POFUT1. No differences in type of KRAS mutation 

nor in PIK3CA mutations were found between BML and the rest of KRAS 

mutants. Conclusions: We identified a subgroup of KRAS mutants formed of 

more aggressive, poorly differentiated tumors. All these results prove that 

KRAS mutant CRCs form a heterogeneous group tumors. 


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Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA) 

and oxaliplatin in metastatic colorectal cancer (mCRC): A pooled analysis 

of COIN and OPUS study data. Presenting Author: Julien Taïeb, Georges 

Pompidou European Hospital, Paris, France 

Background: Infusional 5-FU/FA � oxaliplatin is a widely used schedule in 

the first-line treatment of mCRC. In the randomized phase II OPUS study, 

the addition of cetuximab to one such regimen (FOLFOX4) significantly 

improved response and progression-free survival (PFS) in patients (pts) 

with KRAS wild-type (wt) mCRC. However, in the randomized phase III 

COIN study, a benefit for the addition of cetuximab to first-line fluoropyrimidine 

(administered as either infusional 5-FU or capecitabine) � oxaliplatin 

was not confirmed in pts with KRAS wt tumors. Methods: A pooled 

study-based analysis of treatment outcome in pts with KRAS wt tumors 

from the OPUS study and COIN subgroup who received infusional 5-FU/FA 

� oxaliplatin (as the OxMdG regimen) was carried out using a random 

effects model. Outcome in the pooled analysis was considered in the 

context of other randomized studies investigating first-line chemotherapy 

regimens �/- cetuximab in pts with mCRC. Results: The pooled KRAS wt 

population included 179 pts from the OPUS study and 244 from the 

OxMdG subgroup of the COIN study. A benefit for the addition of cetuximab 

to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI 

1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but 

overall survival (OS) did not show a statistically significant improvement 

(HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to 

those of the KRAS wt population of the CRYSTAL study investigating 

infusional 5-FU/FA and irinotecan �/- cetuximab (response: odds ratio 

2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the 

improvement in OS was statistically significant in that study (HR 0.80, 

95% CI 0.67–0.95). Similar efficacy of FOLFOX � cetuximab and 

FOLFIRI � cetuximab in the first-line treatment of mCRC was also 

suggested by data from the randomized phase II CORE 1.2.001 and CELIM 

studies. Overall, the safety profile of infusional 5-FU/FA and oxaliplatin � 

cetuximab was found to be acceptable and manageable. Conclusions: The 

pooled analysis supports the use of cetuximab combined with infusional 

5-FU/FA and oxaliplatin in the first-line treatment of KRAS wt mCRC. 


Prognostic impact of preoperative plasma tissue inhibitor of metalloproteinase 

1 (pTIMP-1) in colorectal cancer (CRC) patients (Pts): A pooled 

analysis of 1,024 stage II/III pts. Presenting Author: Nils Brünner, Section 

for Pathobiology, Department of Veterinary Disease Biology, Faculty of Life 

Sciences, University of Copenhagen, Frederiksberg C, Denmark 

Background: Identification of a marker with strong prognostic impact on 

clinical outcomes would aid in the management of pts with primary, 

curatively resected CRC. We conducted a pooled individual pt data analysis 

to confirm the prognostic value of pTIMP-1 for overall survival (OS) in stage 

II and III CRC. Methods: pTIMP-1 was determined in plasma using 

immunoassays. Samples and clinical data were included from 5 studies 

with a total of 1,042 stage II/III pts resected between 1991 – 2006 

(Holten-Andersen (HA), 2000 [n�378], HA, 2004 [n�226], Waas, 2005 

[52], Birgisson, 2010 [225], Nielsen, 2011[n�161]). To provide comparable 

measures across studies, pTIMP-1 values were rescaled using 

fractional ranks (FR, based on ranks and sample size). Pts were grouped by 

the median of the pTIMP-1 FR score. Stratified log-rank tests and 

multivariate Cox models assessed the association between OS and pT- 

IMP-1 FR. Results: Overall, 59% were male; median age 69 years; 56% had 

stage II disease and 50% had colon cancer. The median follow-up was 5.5 

years with 457 deaths. Continuous pTIMP-1 FR as a linear effect was 

significantly associated with OS (p � .0001, HR�1.38 for a 0.3 unit 

increase in FR score, 95% CI 1.25 to 1.52).Pts with pTIMP-1 FR above vs 

below the median had significantly shorter OS (HR, 1.72; 95% confidence 

interval[CI], 1.42 to 2.08, p �0.0001), which remained significant after 

adjusting for age, gender, stage, disease location, and serological CEA (HR, 

1.31; 95%CI, 1.07 to 1.60; p � 0.009). Results by stage are shown in the 

table. No evidence of an interaction between pTIMP-1 and stage or disease 

location (colon vs. rectal) was observed (all p � 0.6). Conclusions: pTIMP-1 

is a strong prognostic marker for predicting OS independent of age, gender, 

CEA, stage and site of disease in curatively resected stage II and III CRC. 

Stage II Stage III 

pTIMP-1 FR < median pTIMP-1 FR > median pTIMP-1 FR < median pTIMP-1 FR > median 

N (%) 281 (48%) 302 (52%) 240 (52%) 218 (48%) 

# of events 71 125 116 145 

5-yr OS rate 

73.8% 

62.6% 

53.9% 

34.4% 

(95% CI) (68.2%-79.4%) (56.8%-68.4%) (47.1%-60.6%) (27.6%-41.2%) 

HR (95% CI) ref 1.73 (1.29 – 2.31) ref 1.71 (1.34 – 2.19) 

P 0.0002 �.0001 




Is conversion to resection possible with hepatic arterial infusion (HAI) and 

systemic (SYS) even in previously treated patients (pts) with unresectable 

colorectal liver metastases (UnCLM)? Presenting Author: Nancy E. Kemeny, 


Background: Previously, we showed thatHAI with FUDR � dexamethasone 

(Dex) plus SYS produced a 47 % resectability rate in a retrospective study 

of 49 pts with UnCLM. Methods: Prospectively evaluated UnCLM pts in a 

new protocol were combined with the above protocol (n�105 pts) and all 

were treated with HAI FUDR/Dex � Sys. Unresectability was defined as 

diffuse bilateral metastases, involvement of all hepatic/portal veins, and/or 

inability to preserve remaining liver with adequate perfusion. Factors 

associated with conversion were identified using a multivariate logistic 

regression model. Overall survival (OS) and progression free survival (PFS) 

were calculated from pump placement by the Kaplan-Meier method. 

Resectability was a time-dependent covariate in a Cox regression model. 

Results: 61 of the 105 pts had prior SYS (56 %with prior Oxali) and 45 

(74%) were progressing at the time of pump placement. In previously 

treated pts, 44% underwent resection, with a median OS of 45 mos. Of 44 

chemo-naïve pts, 57% underwent hepatectomy, with a median OS of 68 

mos. The following were significantly associated with resection conversion: 

lesion number [p�0.02], baseline CEA [p�0.04], females [p�0.03] and 

clinical risk score (CRS) [p�0.05]. In multivariate analysis, gender and 

CRS remained predictive of resectability. Surgery greatly reduced the 

hazard of death by 67% [HR: 0.33, 95%CI: 0.17-0.61, p�0.0004], after 

adjusting for several risk factors (Table). Median PFS was 12 mos for all 

pts. Conclusions: Even in previously treated pts,HAI � SYS is an approach 

to convert UnCLM to resection. Gender and CRS are associated with 

conversion to resectability. 

Multivariate Cox regression models. 

HR (95%CI) P value 

OS 

Surgery (yes vs no)* 0.33 (0.17-0.61) �0.001 

Gender (F vs M) 0.95 (0.51-1.77) 0.88 

CRS (>3vs3vs


Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with 

metastatic colorectal cancer (mCRC): Assessment as prognostic and 

predictive biomarkers of response to panitumumab (pmab). Presenting 

Author: Marc Peeters, Antwerp University Hospital, Edegem, Belgium 

Background: Pmab is a fully human monoclonal antibody against the 

epidermal growth factor receptor (EGFR). Significant improvement in 

progression-free survival (PFS) was demonstrated in pts with wild-type 

(WT) KRAS mCRC treated with pmab�FOLFOX4 (1st-line; study 

20050203), pmab�FOLFIRI (2nd-line; study 20050181), and pmab 

monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12 

and 13 are established biomarkers for lack of clinical benefit to anti-EGFR 

therapies. We retrospectively examined individual MT KRAS codon 12 and 

13 alleles as prognostic and predictive biomarkers of response in three 

phase 3 studies. Methods: Pts were randomized to receive FOLFOX4, 

FOLFIRI, or best supportive care �/- pmab 6.0 mg/kg Q2W in trials 

20050203, 20050181, and 20020408, respectively. The MT KRAS 

codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) 

were detected using the Therascreen K-RAS Mutation Kit (Qiagen). Results: 

MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096), 

45% (486/1083), and 43% (184/427) of pts in trials 20050203, 

20050181, and 20020408, respectively. MT KRAS allele distribution was 

conserved across studies and balanced between treatment arms. Baseline 

demographic and clinical features were comparable between all MT KRAS 

allele subgroups. There was no consistent evidence that any individual MT 

KRAS allele, compared to the remaining MT KRAS alleles or the entire MT 

KRAS group, differentially impacted PFS or overall survival (OS) in control 

arm-treated or pmab-treated pts. Only in the pmab�FOLFOX4 arm of study 

20050203 were G13D (unfavorably) and G12V (favorably) significantly 

associated with OS. Response rates were similar between MT KRAS allele 

groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses 

of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a 

significant negative predictive factor for OS. Conclusions: The lack of 

consistent results across three lines of therapy indicates pts whose tumors 

harbor MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab 

therapy. Currently, only pts with WT KRAS mCRC should be treated with 

EGFR antibodies. 


Is there any significant difference between tumor regression grade systems 

of rectal cancer? Presenting Author: Atthaphorn Trakarnsanga, 


Background: Tumor regression grade (TRG) is a measure of histopathologic 

response of rectal cancer to preoperative chemoradiation (CRT) and 

correlates with outcomes. Several TRG systems have been reported 

including Mandard (5, 3 tier), Dowrak/Rodel (5, 3 tier), Memorial Sloan 

Kettering Cancer Center (MSKCC), and American Joint Committee of 

Cancer (AJCC). The purpose of this study is to compare the different TRG 

systems and determine which one(s) best predict recurrence and survival. 

Methods: Review of prospective maintained database from 1998 to 2007 

identified 563 patients with locally advanced rectal cancer (T3/4 and/or 

N1) and treated with long-course CRT followed by total mesorectal 

excision. TRG was determined by measuring proportion of tumor mass 

replaced by fibrosis. Patients were then classified into the various TRG 

schemes which were compared by analyzing association with recurrence 

and survival using concordance index (CI) and reclassification index. CI is a 

measure that summarizes the predictive strength of a marker. Computing 

and contrasting CI across several markers is a way of selecting the best 

prognostic marker. Results: 75% of patients were noted to have clinical 

stage III disease by endorectal ultrasound or rectal MRI. Following 

resection with median follow-up of 39.3 months, 2% developed local 

recurrence and 17% developed distant metastasis. The median interval 

time between completion of CRT and surgery is 48 days. 20% demonstarted 

complete pathological response. CI of the 3 tier Mandard, 3 tier 

Dowrak/Rodel, MSKCC and AJCC are 0.665, 0.653, 0.683, and 0.694, 

respectively (higher number indicates better prediction). The AJCC was 

significantly more accurate in predicting recurrence than the 3- tier 

Mandard (p�0.002), and Dowrak/Rodel (p�0.006). AJCC had a higher CI 

than MSKCC although it did not reach significance (p�0.068). Comparing 

the 3 tier systems, MSKCC was most accurate and correctly reclassified 17 

% and 23 % of the patients Mandard and Dowrak/Rodel systems, 

respectively. Conclusions: TRG predicts recurrence and survival following 

combined modality therapy for rectal cancer. The TRG system that recently 

was proposed in the 7thAJCC staging is currently the most accurate 

predictor. 


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A phase II study of high-dose cetuximab plus irinotecan in colorectal 

cancer patients with KRAS-wild type tumors who progressed on prior 

standard dose cetuximab and irinotecan. Presenting Author: Ahmad Ali 

Fora, Roswell Park Cancer Institute, Buffalo, NY 

Background: Prior clinical data suggest a dose-related response to cetuximab 

(cmab) when combined with irinotecan in patients (pts) with KRAS 

WT tumors who do not develop grade � 2 rash with standard cmab dosing. 

However, the investigation of higher doses of cmab in the setting of 

acquired or innate resistance to standard dose cmab has not been 

previously investigated. We conducted a phase II clinical trial of high-dose 

cmab plus irinotecan in KRAS WT pts who progressed on standard-dose 

cmab plus irinotecan. Methods: Pts who progressed within 4 weeks from 

receiving a minimum of 6 weeks of standard dose cmab plus irinotecan 

were included in this study. Cmab was administered at 500 mg/m2 /week 

and irinotecan was administered at the same dose/schedule on which each 

individual patient previously progressed. All pts received doxycyline 100 

mg PO bid starting day 1 of treatment. 12-week PFS rate was the primary 

endpoint. The regimen was considered interesting if 7/36 patients had 

stable disease or response at 12 weeks. The study was closed early after 

meeting its primary endpoint. Results: 20 pts were treated on study: median 

age 65.5 yrs (44-84), 14 pts were males. 8 pts had grade � 2 

hypomagnesaemia (3 grade 3 and 2 grade 4), 6 pts had grade � 2 skin rash 

(1 grade 3, 0 grade 4), and 4 pts had grade � 2 diarrhea (1 grade 3, 0 grade 

4). 1 pt had a confirmed PR and 12 pts had a SD (at 6 weeks). In 9 pts, SD 

was confirmed at 12 weeks (3 pts� 24 weeks). Median PFS and OS were 

2.8 and 6.6 months, respectively. The 1-year survival was 25%. Conclusions: 

High-dose cmab plus irinotecan is well tolerated with an acceptable rate of 

diarrhea and skin toxicities but with an increased rate of grade 3-4 

hypomagnesemia. The prolonged disease stabilization and single response 

suggest that resistance to standard dose cmab plus irinotecan can be 

overcome by cmab dose escalation. The identification of predictive markers 

of response from dose escalation will be necessary to implement this 

strategy selectively in KRAS WT colorectal cancer patients. 


Association of genetic variants in obesity-related genes with tumor recurrence 

in stage II/III colon cancer. Presenting Author: Robert D. Ladner, 

University of Southern California Norris Comprehensive Cancer Center, Los 

Angeles, CA 

Background: High body mass index (BMI) is an established risk factor for 

colorectal cancer incidence and death. Recent studies found obesity before 

the diagnosis of colon cancer was associated with worse survival compared 

with normal weight. Single nucleotide polymorphisms (SNPs) of obesityrelated 

gene have been related with different cancer risk including 

colorectal cancer. Here we tested the hypothesis whether SNPs in obesityrelated 

genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA and 

DSCR1) may predict tumor recurrence in adjuvant colon cancer. Methods: 

Either blood or FFPE tissue specimens were obtained from 234 patients 

(107 females and 127 males; median age 59 years (range 22–78 years)) 

with stage II (105 patients) or III (129 patients) colon cancer at the 

University of Southern California/Norris Comprehensive Cancer Center. The 

median follow-up was 4.4 years. SNPs in obesity-related genes were 

determined by PCR-RFLP or PCR-based direct sequence. The primary 

endpoint of the study was time to tumor recurrence (TTR). Results: in 

univariable analysis, PPAR rs1801282 and DSCR1 rs6517239 were 

independently associated with time to tumor recurrence (TTR). Patients 

with PPAR CC genotype had longer median TTR 9.4 months (95% C.I: 5.6, 

12.4�) compared to those with CG genotype, had median TTR 3.4 months 

(95% C.I: 1.7, 16.8�)(p�0.04, log-rank test). Patients with DSCR1 AA 

genotype had shorter median TTR 6.6 months (95% C.I: 4.0, 16.8�) 

compared to those with AG and GG genotypes, which had longer median 

TTR 9.4 months (95% C.I: 5.7, 10.7�)(p�0.027, log-rank test). The 

multivariate analysis adjusting for stage and type of adjuvant therapy 

showed a trend in the association between PPAR rs1801282 and DSCR1 

rs6517239 and time to recurrence (Wald test p�0.08 and 0.058, 

respectively). Conclusions: Our preliminary results demonstrated polymorphisms 

in obesity-related gene might be potential molecular markers to 

predict TTR in adjuvant colon cancer. Further large and biomarker 

embedded trial needed to confirm our findings. 




FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutant 

metastatic colorectal cancer patients. Presenting Author: Lisa Salvatore, 

U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto 

Toscano Tumori, Pisa, Italy 

Background: BRAF V600E mutation plays a negative prognostic role in 

metastatic colorectal cancer (mCRC) patients, leading to a median PFS of 

4-6 months with first-line conventional treatments. Recently, results from a 

retrospective exploratory analysis suggested that an up-front intensive 

treatment with FOLFOXIRI plus bevacizumab could improve the outcome 

of BRAF mutant mCRC. Methods: Fifteen consecutive BRAF mutant mCRC 

patients treated with first-line FOLFOXIRI plus bevacizumab were included 

in a validation set. The primary endpoint was 6-months progression free 

rate (6m-PFR). Secondary endpoints were: overall survival, response rate 

and the pooled analysis of all main outcome parameters in both the 

exploratory and validation set. Results: In the validation set, 11 out 15 

patients included were progression-free at 6 months, for a 6m-PFR of 

73.3%. Primary endpoint was met. At a median follow-up of 21.6 months, 

median progression-free survival was 9.2 months while median OS has not 

yet been reached. In the pooled data analysis of the validation set and the 

initial retrospective cohort 24 out 25 total patients were evaluable for 

response: partial or complete response was obtained in 17 (68%) and in 1 

(4%) patient, respectively, for an overall response rate of 72%. At a median 

follow-up of 34.1 months, the pooled set of patients showed a median PFS 

of 11.8 months and a median OS of 23.8 months. Conclusions: These data 

suggest that FOLFOXIRI plus bevacizumab could be a reasonable option for 

the first-line treatment of BRAF mutant metastatic colorectal cancer 

patients. 


Activity of the anti-IGF-1R antibody dalotuzumab (MK-0646) in KRASmutant 

colorectal cancer: Preclinical and clinical data. Presenting Author: 

Sriram Sathyanarayanan, Merck Research Laboratories, Boston, MA 

Background: KRAS mutated metastatic colorectal cancer (mCRC) is inherently 

resistant to EGFR targeted therapy and carries an inferior prognosis to 

wild-type disease with a median survival of approximately 16 months. 

Methods: The activity of dalotuzumab (Dz) has been investigated in KRAS 

mutant pre-clinical colon cancer models. In addition efficacy data relating 

to a sub-set of KRAS mutant mCRC patients enrolled in a randomized 

phase II/III study (initiated prior to the introduction of KRAS genotyping) of 

Dz in combination with cetuximab (Cx) and irinotecan (Ir) are reported. All 

patients had received Cx and Ir with either placebo (n�20), weekly Dz 

(n�18), or 2 weekly Dz (n�31). Results: In pre-clinical models, Dz was 

found to be effective in inhibiting IGF-1 mediated cellular growth. 

Furthermore, in colorectal cancer xenograft models high IGF-1 was found 

to identify a sub-set of Dz responsive tumours. Combination studies 

demonstrated that Irinotecan exposure resulted in the activation of IGF-1R 

and PI3K signaling pathways, representing a possible cellular survival 

mechanism. In xenograft models the combination of Dz with irinotecan 

produced lasting tumor growth inhibition that persisted even after treatment 

withdrawal. Outcome data are reported for 69 patients with KRAS 

mutant mCRC enrolled in the randomized study. Efficacy data demonstrated 

differential activity between colon versus rectal tumours with 

evidence of activity in the rectal subgroup. Molecular analysis suggests that 

this observation may be mediated by differential IGF-1 expression. 

Conclusions: These data suggest that Dz in combination with irinotecan may 

have utility in the treatment of KRAS mutated colorectal cancer patients. 

Based on these data Dz is being further evaluated in a molecularly selected 

population of mCRC. 

Dz vs placebo arm 

Hazard ratio (95% CI) 

PFS OS 

Weekly Dz 2 weekly Dz Weekly Dz 2 weekly Dz 

Mean normalized IGF-1 

Cq values (rtPCR) 

All patients (n�69) 0.75 (0.35, 1.58) 1.14 (0.59, 2.20) 0.88 (0.42, 1.84) 0.96 (0.49, 1.90) 

Colon (n�37) 1.50 (0.60, 3.74) 1.63 (0.67, 3.94) 1.21 (0.47, 3.07) 1.31 (0.54, 3.19) 5.22 

Rectal (n�32) 0.17 (0.04, 0.79) 0.31 (0.08 1.22) 0.32 (0.09, 1.20) 0.37 (0.11, 1.18) 4.52 

p�0.043 


Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in 

intermediate-risk rectal cancer (RC) patients defined by magnetic resonance 

(MR): GEMCAD 0801 trial. Presenting Author: Carlos Fernandez- 

Martos, Medical Oncology Department, Fundacion Instituto Valenciano De 

Oncologia, Valencia, Spain 

Background: Retrospective data suggest that RT might not be needed in all 

patients with stage II/III RC. Modern systemic therapy might have local 

efficacy similar to chemoradiation (CRT). Methods: A multicenter phase II 

trial was undertaken to evaluate safety and efficacy of neoadjuvant 

CAPOX-B in patients with T3 middle third rectal adenocarcinoma. Eligible 

patients (pts) had measurable disease at the baseline and candidate for R0 

total mesorectal escision (TME) with intermediate-risk defined by pelvic 

MR a) T3 with distal border of tumor � 5 cm from the anal verge and below 

the sacral promontory. b) tumor �2 mm from the mesorectal fascia. Pts 

received 4 cycles of Cap 2000 mg/m2 (d1-14), Ox 130 mg/m2 (d1) and B 

7.5 mg/kg (d1) every 3 weeks (last cycle without B). Pts undergo re-staging 

with MR. One radiologist reviewed all pre- and post-treatment MR scans 

independently. Pts without progression proceed to TME 4-6 weeks from the 

last cycle. If progression, pts were to be referred for pre-op cap/RT followed 

by TME. 1º Endpoint: Tumor Response (RECIST). Design: Simon 2-stage; 

28 pts 1st stage and 46 pts 2nd stage. We report data on the planned 

analysis of pts included for 1st stage. Results: 28 eligible pts (10F/18M) 

were enrolled from 7/09-5/11. Tumor response, compliance and toxicity 

details are shown in table below. Two pN2 pts received postop Cap/RT. 

Conclusions: Neoadjuvant CAPOX-B is active and safe. Early parameters of 

efficacy are encouraging and seem similar to those observed with CRT. 

Efficacy 

MR response 

MR overall response 

MR complete response 

MR partial response 

MR stable disease 

p response 

pCR ( ypT0N0) 

pLN� 

TRG intermediate � total regression � 

Downstaging 

CRM free 

R0 resection 

Compliance 

4 cycles 

24* 

21 (87.5%) 95%; CI 68%-97% 

1 (4%) 

20 (83%) 

3 (13%) 

27v 

4 (15%) 

10 (37%) 

17 (63%) 

10 (37%) 

26 (96%) 

27 (100%) 

24 (86%) 

Toxicity G3� 14 (50%) 

Surgical complications G3� 3 (11%) 

Abbreviations: pCR, pathologic complete response; CRM, circumferential resection margin; 

TRG, tumor regression grade. � Dworak 2�3�4;*4MRnotdone. 1 died (diarrhea/renal 

failure), 1 perforation after 3th cycle, 2 withdrawal;v pts underwent surgery. 


Early tumor shrinkage in patients with metastatic colorectal cancer 

receiving first-line treatment with cetuximab combined with either CAPIRI 

or CAPOX: An analysis of the AIO KRK 0104 trial. Presenting Author: 

Dominik Paul Modest, Department of Hematology and Oncology, Klinikum 

Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich, 

Germany 

Background: This study investigated the impact of early tumor-shrinkage 

(ETS) on progression-free (PFS) and overall survival (OS) in patients with 

metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104trial. 

ETS was previously shown to be a predictor of treatment response to 

cetuximab. The present analysis, for the first time, evaluates the correlation 

of ETS with outcome parameters in patients undergoing capecitabinebased 

therapy. It also aims to correlate the predictive value of ETS and 

cetuximab-induced skin toxicity. Methods: The AIO KRK0104 trial was 

performed as a randomised study comparing capecitabine/oxaliplatin 

(CAPOX) plus cetuximab to capecitabine/irinotecan (CAPIRI) plus cetuximab 

in the first-line treatment of mCRC. 121 patients were available for 

evaluation of ETS at 6 weeks. ETS was defined as a relative change of 

�20% in the sum of the longest diameters of target lesions compared to 

baseline. Results: Tumors of 63 patients (71% KRAS wild-type (wt), 100% 

skin reactions) developed ETS, 58 tumors did not develop ETS (53% KRAS 

wt, 86% skin reactions). ETS was associated with prolonged PFS (8.9 vs. 

4.7 months, p�0.001, hazard ratio: 0.37) and OS (31.6 vs. 15.8 months, 

p�0.005, hazard ratio: 0.48) in patients with KRAS wt tumors but not in 

patients with KRAS mutant mCRC. ETS occurred more frequently with 

CAPOX- vs CAPIRI-based therapy (p�0.05). There was a highly significant 

correlation between the occurrence of ETS and cetuximab-related skin 

toxicity of any grade (I-III) (p�0.002). ETS was documented more 

frequently in patients with liver metastasis (p�0.09), metastatic involvement 

of �2 organs (p�0.09), KRAS wild-type tumors (p�0.06) and no 

previous adjuvant chemotherapy (p�0.06). Conclusions: In patients with 

KRAS wild-type mCRC receiving capecitabine- and cetuximab-based firstline 

therapy ETS correlates with prolonged PFS and OS. ETS also correlates 

with cetuximab-induced skin toxicity. Both parameters may therefore serve 

as post-randomisation surrogate markers of favourable outcome for cetuximab-based 

treatment. 



Examining the effects of metformin on survival outcome in stage II/III 

colorectal cancer patients with diabetes mellitus. Presenting Author: Guek 

Eng Lee, Department of Medical Oncology, National Cancer Centre, 

Singapore 

Background: Insulin resistance and deregulation of the insulin-like growth 

factor (IGF) axis is implicated in colonic carcinogenesis. Metformin inhibits 

hepatic gluconeogenesis and increases insulin sensitivity. It induces AMPK 

activation, thus inhibiting mTOR and downstream survival and proliferation 

pathways. We evaluated the effects of metformin on survival outcomes of 

patients with stage 2 and 3 colorectal cancer (CRC). Methods: Among 1455 

patients with stage II or III colorectal cancer, we identified 344 patients 

with both CRC and diabetes mellitus. 219 diabetic patients received 

metformin and 125 diabetic patients were not receiving metformin. 

Patient’s demographics, clinical and histopathologic characteristics, overall 

survival, time to recurrence and relapse-free survival were evaluated. 

Molecular analysis for AMPK, and mTOR pathway on archival tissue is 

ongoing. Results: After a median follow-up of 78 months (6.5 years), there 

was no difference in survival outcomes between diabetic and non-diabetic 

patients. Among diabetic patients, there were 99 relapses and 90 deaths. 

Metformin use was associated with improved overall survival (HR 0.23; 

95%CI: 0.15-0.35 p�0.01), time to recurrence (HR 0.63; 95%CI: 

0.41-0.96) and relapse-free survival (HR 0.47; 95%CI:0.33-0.67,p�0.01). 

In multivariate analysis, after adjustment for T stage, N stage and patients’ 

age, metformin use remained associated with improved overall survival (HR 

0.18, p�0.01); time to recurrence (HR 0.55; p�0.04) and relapse-free 

survival (HR 0.44, p�0.01). Results of molecular correlative studies 

performed on archival tissue will be presented at the meeting. Conclusions: 

Among patients with diabetes and colorectal cancer, use of metformin is 

associated with improved survival outcomes in both univariate and multivariate 

analysis lending support to the hypothesis that it may have anti-cancer 

activity. 


First-line chemotherapy plus cetuximab in patients grouped according to 

prognostic risk factors: Analysis of the CRYSTAL and OPUS studies. 

Presenting Author: Gunnar Folprecht, University Hospital Carl Gustav 

Carus, Dresden, Germany 

Background: Analysis of randomized trials has shown that mCRC patients 

(pts) can be divided into prognostic risk groups according to baseline 

clinical parameters including ECOG performance status, white blood cell 

count (WBC), alkaline phosphatase (ALP) and number of metastatic (met) 

sites (Köhne C, et al. Ann Oncol 2002;13:308-17). The effect of adding 

cetuximab to first-line chemotherapy (CT) on overall survival (OS) in these 

groups of KRAS wild-type mCRC pts was investigated in the CRYSTAL and 

OPUS studies. Methods: Pt risk groups were: low-risk (LRG� ECOG 0/1, 1 

met site) intermediate-risk (IRG� ECOG �1, �1 met site, ALP �300 U/L 

or, ECOG�1, low WBC, 1 met site) and high-risk (HRG� ECOG�1, �1 met 

site, ALP�300 U/L or ECOG�1, high WBC, or ECOG�1, low WBC and �2 

met sites). Exploratory analyses comprised estimates of effects using Cox‘s 

proportional hazards model for OS on individual pt data and comparison of 

treatment arms by log-rank test. Results: Data are shown in the table. In the 

pooled analyses, in both treatment arms OS was longest in LRG pts and 

shortest in HRG pts. Adding cetuximab to CT led to marked improvements 

in OS in the HRG (Hazard ratio [HR] 0.765, 95% CI 0.506–1.157, 

p�0.203) and IRG (HR 0.781, 95% CI 0.622–0.981, p�0.033), while 

improvements in LRG pts (HR 0.869, 95% CI 0.672–1.124, p�0.287) 

were observed only after prolonged follow up. Data were similar in the 

separate CRYSTAL and OPUS studies. Conclusions: The analysis confirms 

the concept of prognostic risk groups for OS according to baseline clinical 

parameters in pts with KRAS wt mCRC. Benefit from the addition of 

cetuximab to first-line CT in terms of OS appears to be more pronounced in 

the IRG and HRG. 

CT CT � cetuximab 

Study/risk group N Median OS, mo (95% CI) N Median OS, mo (95% CI) 

Pooled 

LRG 164 25.7 (21.9–28.7) 173 27.0 (24.8–29.5) 

IRG 213 16.4 (14.9–20.0) 166 22.2 (19.5–25.7) 

HRG 59 12.6 (9.2–14.4) 46 17.7 (13.1–19.3) 

CRYSTAL 

LRG 127 26.1 (21.2–29.9) 132 28.2 (24.9–31.5) 

IRG 172 16.6 (14.8–20.4) 141 23.5 (20.0–29.6) 

HRG 43 12.8 (9.2–14.6) 31 16.7 (8.3–19.0) 

OPUS 

LRG 37 23.9 (19.5–n.e.) 41 26.0 (22.9–n.e.) 

IRG 41 16.2 (12.0–21.6) 25 18.4 (11.0–19.8) 

HRG 16 11.8 (4.8–18.5) 15 19.9 (13.1–30.4) 

Abbreviation: n.e., not estimable. 


225s 


U.S. patients receiving resin 90Y microspheres for unresectable colorectal 

liver metastases: A multicenter study of 506 patients. Presenting Author: 

Andrew S. Kennedy, Cancer Centers of North Carolina, Cary, NC 

Background: Implantation of radioactive microspheres via the hepatic artery 

with Yttrium-90 ( 90Y) is termed “radioembolization, (RE)”. Resin microspheres 

were FDA cleared for use in colorectal liver metastases (mCRC) in 

2002. Rapid worldwide acceptance of this therapy has resulted in greater 

than 30,000 procedures conducted in the past 10 years. This investigatorinitiated 

study focuses on RE treatment outcomes in US-only patients since 

2002. Methods: A retrospective multi-institutional study was designed to 

analyze the outcome of consecutively treated mCRC patients undergoing 

RE by experienced treatment centers in the USA using resin 90Y microspheres. 

IRB approval was obtained by each center with independent data 

collection and analyses. Primary endpoints: CTC 3.0ae toxicity, RECIST 

response and survival; baseline treatment parameters, prior chemotherapy, 

and liver directed therapies. Results: 506 patients at 10 institutions (193 

M, 313 F) received 770 RE treatments; median age � 60.4 years (20.8 – 

91.9 years); median number of RE treatments per patient � 1.0 (1-5 

treatments). Active extrahepatic disease was present at first RE in 34.8% 

of patients. The majority (90%) of patients received prior chemotherapy, 

with 30.6% also having undergone prior hepatic surgery/ablative procedures. 

Median follow up after RE � 8.4 mo. (0.4 – 67.6 mo.) with median 

survival � 10.1 mo. (95% CI 9.1 – 12.0). For first RE treatment, median 

tumor volume was 146.0 mL (2.8 – 3228.0 mL). Median radiation activity 

delivered � 1.18 GBq (0.12 – 2.29 GBq), lung shunt median � 4.8 % (.02 

– 45%). Total grade 1-3 events were 32% GI, 44% fatigue and 1% liver 

failure. Only 2.4% of all treatments required an overnight stay postprocedure. 

Conclusions: The modern USA experience of 90Y therapy for 

unresectable, heavily pretreated mCRC liver metastases is encouraging 

with a median survival of 10.1 months after first RE procedure. Toxicity was 

mild and of short duration in most patients. RECIST response is being 

analyzed currently as are data of additional patients. 


A UGT1A1 *28 and *6 genotype-directed phase I study of irinotecan plus 

infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously 

untreated metastatic colorectal cancer (mCRC). Presenting Author: Yong Sang 

Hong, Department of Oncology, Asan Medical Center, University of Ulsan 

College of Medicine, Seoul, South Korea 

Background: We designed a phase I study to determine maximum tolerated dose 

(MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). 

Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 

groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 

(*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of 

irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. 

Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. 

Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA 

group. The MTD was estimated as 300 mg/m2 /2-week for the 1 DA group with 2 

DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT 

in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio 

of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, 

respectively (P�0.017). Of the 43 pts, five pts showed AUClast, SN38 that 

exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). 

The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete 

responses and 23 partial responses. Median progression-free and overall survival 

was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), 

respectively. Grade 3 or 4 toxicity during all treatment cycles included 

neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 

0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. 

Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 

DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are 

feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of 

irinotecan was 330, 270, 150 mg/m2 /2-week for pts with 0, 1, 2 DA based on 

pharmacokinetic analysis. 

Level and dose 

Number of patients 

Group of irinotecan Treated DLT occurred 

DLTs 

0DA 1 240 * 4 0 

2 270 3 0 

3 300 6 0 

4 330 6 1 Gr 4 neutropenia 

1DA 1 240 * 3 0 

2 270 14 0 

3 300 3 2 Gr 4 neutropenia, 

Gr 3 febrile neutropenia 

2DA -1 150 * 4 0 

0 180 - - 

* Starting dose of irinotecan for each dose level (mg/m2 ). 




Phase II trial of combined chemotherapy with irinotecan, S-1, and 

bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer: 

Update analysis—Hokkaido Gastrointestinal Cancer Study Group (HGCSG) 

trial. Presenting Author: Satoshi Yuki, Department of Gastroenterology, 

Hokkaido University Hospital, Sapporo, Japan 

Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853– 

860) previously demonstrated the non-inferiority of Irinotecan plus S-1(IRIS) 

to FOLFIRI for metastatic colorectal cancer(mCRC), with progression-free 

survival (PFS) as the primary endpoint. We previously reported that IRIS 

plus bevacizumab(IRIS/bev) is very effective as first-line treatment (Komatsu 

Y et al. ESMO 2010). We now report the updated results of this study. 

Methods: Eligible patients had to have mCRC with a confirmed diagnosis of 

adenocarcinoma, an age of �20 years, ECOG performance status (PS) of 

0-1, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. 

was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 

mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary 

endpoint was safety. The secondary endpoints included overall response 

(OR), progression-free survival (PFS), and overall survival (OS). Results: The 

target number of 53 patients was enrolled as of March 2009. The results 

are reported for 52 patients with evaluable lesions. The clinical characteristics 

of the patients were as follows. The median age was 63.5 years (range, 

48 to 82). The male:female ratio was 3:2. The performance status on the 

Eastern Cooperative Oncology Group scale was 0. In January 2012, on 

safety analysis, the incidence of grade 3 or 4 neutropenia was 27%. The 

incidences of other grade 3 or 4 adverse reactions were as follows: diarrhea, 

17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and gastrointestinal 

perforation, 0%. The overall response rate was 63.5%. Three patients 

had complete response. Thirty patients had partial response, 16 had stable 

disease, none had progressive disease, and 3 were not evaluable. Median 

progression-free survival was 17.0 months and median survival time was 

39.6 months. Conclusions: IRIS/Bev is a remarkably active and generally 

well-tolerated first-line treatment for patients with mCRC. Randomized 

control trial comparing this regimen with oxaliplatin containing regimen(X- 

ELOX or mFOLFOX6 plus bevacizumab) is being planned. 


Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and 

sorafenib (Sor) in patients with locally advanced, K-ras-mutated rectal 

cancer (LARC): A phase I/II trial (SAKK 41/08). Presenting Author: Roger 

Von Moos, Kantonsspital Graubünden, Chur, Switzerland 

Background: 40% of patients (pts) with LARC present with K-ras mutation. 

Sor is an inhibitor of ras/raf and of VEGFR. Furthermore Sor has radiosensitizing 

effects. These facts build a strong rationale to use Sor in combination 

with preoperative RT and Cape in pts with K-ras mutant tumors. Methods: 

Pts with K-ras mutated mrT3-4 and / or mrN�, M0 disease were recruited 

in cohorts of 7 pts per dose level (DL). Dose limiting toxicity (DLT) was 

defined as any G3 or higher non hematological toxicity (tox) or haematological 

tox during � 7 days, which are possibly, probably or definitely related to 

trial treatment occurring during and up to 4 weeks after last administration. 

If � 2 out of 7 pts experienced a DLT, then the next cohort was treated at a 

higher dose level. If � 2 out of 7 pts suffered from a DLT, this DL would be 

considered too toxic and a dose level below would be tested in the next 

cohort. The highest dose level with � 2 out of 7 pts experienced a DLT 

would be recommended for the phase II part. In all dose levels RT was given 

in 25 fractions at 1.8Gy (45Gy). Results: In 8 centers in Switzerland a total 

of 21 pts in 3 cohorts have been treated in the phase 1 study. After 

observing severe skin toxicity and diarrhea (2 pt with skin toxicity G3, one 

patient (pt) with diarrhea G3 plus hand-foot syndrome (HFS) (G3)) an 

amendment was implemented to reduce the Sor dose from 400mg BID to 

once daily. In DL 1 after the amendment, 2 pts experienced a DLT (enteritis 

G3, dermatitis G3). Two pts in DL 2 suffered from a DLT (cystitis G3 plus 

HFS G3, cardiac ischemia G3). Further non dose-limiting G3 toxicities 

after the amendment were lymphopenia (G3) (1pt, DL 2) and hypocalcaemia 

(G3) (1 pt, DL 2). No Grade 4 toxicity was seen. DL 2 is the 

recommended dose for phase II. Conclusions: After reducing the Sor dose to 

400mg once daily, neoadjuvant treatment with Sor in combination with full 

dose Cape and RT was tolerable and the toxicities manageable. 

Dose level 

(each with 7 pts) 

Capecitabine (mg/m 2 ) 

per day during 5 weeks 

Sorafenib (mg) 

per day during 5 weeks 

DL 1 before amendment 2 x 600 2 x 400 

DL 1 after amendment 2 x 600 1 x 400 

DL 2 after amendment 2 x 825 1 x 400 


Functional SNPs in vascular endothelial growth factor (VEGF-A) and overall 

survival (OS) in bevacizumab-treated patients with metastatic colorectal 

cancer (mCRC). Presenting Author: Janet E. Murphy, Massachusetts 

General Hospital Cancer Center, Boston, MA 

Background: Functional SNPs in VEGF-A are prognostic for OS in several 

malignancies, but not described definitively in mCRC. In bevacizumabtreated 

patients with advanced breast cancer, VEGF -2578AA and -1154A 

were predictive of OS—the latter SNP reported in a recent mCRC series as 

well. We examined the association between five functional VEGF-A SNPs 

and OS in a large cohort of bevacizumab-treated patients with mCRC. 

Methods: 403 patients with mCRC treated from 2004-2010 were included 

in a retrospective analysis. DNA extraction, genotyping, and SNP evaluation 

were performed according to standard protocols. Survival was calculated 

from the time of Stage IV diagnosis until death. Data were censored as 

of 12/31/2010. Results: There were 279 deaths in this group of 403 

patients (69%). Median age was 55.7 (24-86 y), and 54% of patients were 

male. Age, sex, race, tumor grade, chemotherapies, and curative surgery 

(metastatectomy to negative margins) were considered. Significant clinical 

predictors of OS in univariate Cox modeling were cetuximab treatment 

[HR�1.46; 95% CI 1.13-1.88; p�0.0014], irinotecan treatment 

[HR�2.10; 1.32-3.35; p�0.001], and curative surgery [HR�0.36; 0.25- 

0.75; p�0.001]. Significant negative interaction was found between both 

cetuximab and irinotecan and curative surgery, and in modeling that 

included this interaction, only surgery remained predictive. In multivariate 

analysis, no association was found between VEGF-A and OS (Table). 

Conclusions: There was no association between five functional VEGF-A 

SNPs and OS in this large bevacizumab-treated mCRC cohort. 

SNP Allelic pairs HR [95% CI] Allelic pairs HR [95% CI] 

VEGF-2578 C/A vs C/C 1.10 [0.82-1.46] A/A vs C/C 1.06 [0.77-1.46] 

VEGF-1154 A/G vs A/A 1.14 [0.89-1.47] G/G vs A/A 0.93 [0.63-1.37] 

VEGF-460 C/T vs T/T 1.02 [0.76-1.36] C/C vs T/T 0.95 [0.69-1.30] 

VEGF�405 C/G vs G/G 1.13 [0.87-1.47] C/C vs G/G 0.94 [0.67-1.32] 

VEGF�936 C/T vs C/C 1.14 [0.87-1.49] T/T vs C/C 0.90 [0.37-2.17] 


Treating patients with colorectal liver metastasis: A national decisionmaking 

analysis to understand choice of therapy. Presenting Author: 

Timothy M. Pawlik, Johns Hopkins Hospital, Baltimore, MD 

Background: Criteria for resectability of colon cancer liver metastases (CLM) 

are evolving, yet little is known about how physicians choose a therapeutic 

strategy for potentially resectable CLM. Methods: Physicians completed a 

national web-based survey that consisted of varied CLM case scenarios. 

Respondents choose among 3 treatment strategies: immediate liver resection(LR), 

preoperative chemotherapy followed by surgery(C¡LR), or palliative 

chemotherapy (PC). Data were analyzed using multinomial logistic 

regression, yielding relative risk ratios (RRR). Results: Of 219 respondents, 

79% practiced at academic centers and 63% were in practice �10 years. 

Median number of cases evaluated was 4/month. Surgical training varied: 

51% surgical oncology (SO), 44% hepatobiliary/transplant (HB/LT), 5% no 

fellowship. While each factor impacted choice of CLM therapy, the relative 

impact differed (p�0.01). Synchronous CLM presentation increased the 

choice of C¡LR (OR 4.27) and PC (OR 3.10) versus LR (p�0.001). For 

patients with more extensive intrahepatic disease (i.e., 5 tumors, both 

lobes) respondents strongly favored C¡LR (OR 5.12) and PC (OR 9.60) 

versus LR (p�0.001). The presence of hilar lymph-node disease was 

associated with a strong aversion to LR with surgeons more likely to choose 

C¡LR (OR 8.92) or PC (OR 49.9) (p�0.001). Interestingly, even the 

presence of a resectable solitary lung metastasis strongly deterred choice of 

LR with respondents favoring C¡LR (OR 4.43) or PC (OR 6.97) (p�0.001). 

While other factors such as patient age, tumor size, and extent of resection 

impacted choice of therapy, the relative size of these effects was modest. 

After controlling for clinical factors, surgeons with more years in practice 

were more likely to choose LR (RRR 1.4). SO-trained surgeons were more 

likely than HB/LT-trained surgeons to choose C¡LR (RRR 2.5) or PC (RRR 

4.15)(p�0.001). Conclusions: This is the first study to define the relative 

impact of key clinical factors on choice of therapy for CLM. While clinical 

factors influence choice of therapy, surgical subspeciality and physician 

experience are also important determinants of care. 



Genetic variants of kinases suppressors of ras in KRAS-BRAF wild-type 

metastatic colorectal cancer patients treated with cetuximab and irinotecan. 

Presenting Author: Leonor Benhaim, University of Southern California 

Norris Comprehensive Cancer Center, Los Angeles, CA 

Background: Scaffold proteins kinase suppressor of ras (KSRs) have 

emerged as critical modulators of the EGFR pathway that binds to RAS 

promoting ERK activation. KSR1 and KSR2 have been shown to be over 

expressed in various solid tumours including colon cancer. In-vitro, the 

down-regulation of KSR results in reduction of cells proliferation and 

tumour growth independently to KRAS status. Moving from this biological 

rational we investigated the correlation between functional polymorphisms 

in the KSR genes and clinical outcomes in patients with KRAS and BRAF 

wild-type mCRC treated with cetuximab and irinotecan. Methods: Germline 

DNA was obtained from peripheral blood of patients with mCRC KRAS and 

BRAF wild- type resistant to irinotecan treated with a combination of 

cetuximab and irinotecan. Seven functionally relevant SNP were selected 

on the basis of public literature resources and databases, 4 in the KSR1 

and 3 in the KSR2 genes and analyzed by PCR followed by direct 

sequencing. All candidate SNPs were evaluated for association with 

response rate, PFS and OS. Results: A total of 66 patients were included.After 

a median follow-up of 13.3 months, median PFS and OS were 

4.7 and 11.3 months respectively. Seventeen out of 66 patients (26%) 

achieved a RECIST response. In univariate analysis, KSR2 rs11068551 

any G(AG/GG) genotype was significantly associated with shorter PFS 

compared to that of A/A carriers (median 3.5 vs. 7.4 months, HR�1.74 

[95%CI: 1-3.04] p�0.049, log-rank test). This result remained significant 

in a multivariate model (HR�2.13 [95%CI: 1.15-3.95], p�0.017, logrank 

test). None of the other tested SNPs were significantly associated with 

outcomes. Conclusions: Beyond KRAS and BRAF, some proteins including 

KSR are involved in modulating the level of activation of the EGFR pathway. 

Our results show that the functionally relevant KSR2 rs11068551 could 

affect PFS in advanced mCRC patients treated with cetuximab and 

irinotecan. Preclinical studies to confirm and further explain these preliminary 

findings are ongoing. 


The effect of deprivation on uptake and outcomes in a population-based 

FOBt colorectal cancer screening program. Presenting Author: David 

Mansouri, Department of Surgery, University of Glasgow, Glasgow, United 

Kingdom 

Background: Population-based FOBt colorectal cancer screening has been 

shown to reduce cancer specific mortality and is used across the UK. 

Despite evidence that socioeconomic deprivation is associated with increased 

incidence of colorectal cancer, uptake of screening may be lower in 

those who are more deprived. The aim of this study was to assess the impact 

of deprivation on the screening process. Methods: A prospectively maintained 

database, encompassing the first screening round in a single 

geographical area, was analysed with deprivation categories calculated 

from the Scottish Index of Multiple Deprivation 2009. Results: Overall, 

395,698 individuals were invited to screening, 204,812(52%) participated 

and 6,094(3%) tested positive. 32% of screened individuals were in 

the most deprived quintile. Of the positive tests, 5,457(95%) agreed to be 

pre-assessed for colonoscopy. 839(16%) did not proceed to colonoscopy 

following pre-assessment. Of the 4,618 that attended for colonoscopy, 

cancer was detected in 7%. Colonoscopy results were not recorded in 

1,035(22%) cases. Lower uptake of screening was seen in males, those 

that were younger and those who were more deprived (p�0.001). Higher 

levels of deprivation were also associated with not proceeding to colonoscopy 

following pre-assessment (p�0.001). Higher positivity rates were 

seen in males, those that were older and more deprived (p�0.001). Despite 

higher positivity rates in the more deprived individuals (4% most deprived 

vs 2% least deprived, p�0.001), the positive predictive value of detecting 

cancer in those attending for colonoscopy was lower in those who were more 

deprived (6% most deprived vs 8% least deprived, p�0.040). Conclusions: 

Socioeconomic deprivation has a significant effect throughout the FOBt 

screening process. Individuals who are more deprived are less likely to 

participate in screening, less likely to complete the screening process and 

less likely to have cancer identified as a result of a positive test. This study 

adds further weight to existing evidence that individuals who are more 

deprived are less likely to engage in population-based FOBt colorectal 

cancer screening. Novel strategies to improve this are required. 


227s 


Correlation of specific cytokine profiles with high blood neutrophil-tolymphocyte 

ratio and outcome in metastatic colorectal cancer. Presenting 

Author: Zhi-Yu Chen, Fudan University Shanghai Cancer Center, Shanghai, 

China 

Background: High blood neutrophil-to-lymphocyte ratio (NLR) has been 

previously identified as a poor prognostic marker in patients with metastatic 

colorectal cancer (mCRC). However, the underlying pathophysiology associated 

with this marker is not well defined. We validated this biomarker and 

investigated the relationship between circulating cytokines and high NLR. 

Methods: NLRs were calculated retrospectively from the ratio of peripheral 

blood absolute neutrophil and lymphocyte counts, and segregated based on 

previously determined cutoff of �5 and �5. Four cohorts with a total of 

805 CRC pts were evaluated to confirm the prognostic clinical significance 

of NLR. Plasma cytokine levels were evaluated in exploratory (n�39) and 

validation cohorts (n�166) of previously untreated mCRC patients using 

multiplex-bead assays, and correlated with NLR. Results: High NLR is 

present in 20% of CRC patients and is associated with poor prognosis, 

independent of known prognostic factors (Table). Expression of 6 cytokines 

(IL-6, IL-8, IL-2Ra, HGF, M-CSF and VEGF) correlated with NLR�5 in both 

the exploratory and validation cohort. In the validation cohort, an additional 

14 cytokines correlated with NLR�5, including high EREG,AREG, and 

TGF-�, and low TRAIL. By hierarchial clustering, these 20 cytokines fall 

into 3 overlapping major clusters: angiogenic cytokines, inflammatory 

cytokines, and epidermal growth factor ligands. In the validation cohort, pts 

with a composite cytokine score below the median have longer survival than 

patients with high scores (40.0 mo vs 20.0 mo, HR � 2.24; 95% 

CI�1.47–3.41; P�0.001). Conclusions: High peripheral blood neutrophil/ 

lymphocyte ratio (NLR) is associated with poor outcomes independent of 

other known prognostic features. NLR correlates with discrete sets of 

cytokines which may reflect important biological features in poor prognosis 

mCRC. 

Median OS (months) 3-yr survival rate 

Cohort (number of pts) HR 95% CI P value NLR5 NLR5 

Untreated mCRC (166) 2.7 1.8-4.3 �0.001 34.2 15.3 

Phase � mCRC (167) 2.2 1.5-3.1 �0.001 9.0 3.7 

Hepatectomy mCRC (208) 1.8 1.1-2.9 0.01 13.3 (DFS) 9.5 (DFS) 38% 8% 

Stage II/ III CRC (274) 2.4 1.1-5.1 0.02 90% 75% 


HER2 status in locally advanced rectal cancer and metachronous metastases: 

Opportunity for a new therapeutic approach? Presenting Author: 

Lena-Christin Conradi, Department of General and Visceral Surgery, University 

Medical Center, Georg-August-University, Göttingen, Germany 

Background: Even though the implementation of multimodal treatment 

strategies including neoadjuvant radiochemotherapy (RCT) has led to 

improved survival distant metastases are still limiting the prognosis of 

rectal cancer patients. In this context, we investigated the HER-2 status in 

rectal cancer patients, UICC stages II and III. Our aim was to assess the 

HER-2 positivity rate in primary tumors and metachronous metastases. 

Methods: In this study 264 rectal cancer patients (192 male, 72 female; 

median age 64 years) from phase-II/-III-trials of the German Rectal Cancer 

Study Group (CAO/ARO/AIO-94 and 04) were included. HER-2 status was 

determined pretherapeutically in tumor biopsies as well as resection 

specimens and metachronous metastases (n�27) using immunohistochemistry 

(IHC0 to IHC3�) scoring and S-ISH-amplification detection. Tumors 

with IHC3� or S-ISH ratio ?2.0 were classified as HER-2 positive; results 

were correlated with clinicopathological parameters and long-term survival. 

Results: A positive HER-2 status was found in 12.4% of pre-treatment 

biopsies, in 29.3% of the resection specimens and 22.2% (n�6) of 

metastases. With a median follow-up of 46.5 months patients with 

HER-2-positivity showed better disease free survival (p�0.06) and cancerspecific 

survival (CSS, p�0.05). The 5-years survival rate was 96.4% 

(HER-2-positive) versus 79.5% (HER-2-negative). In multivariate analyses 

HER-2 status was as an independent (p�0.0053) predictor for CSS along 

with (y)pN-status (p�0.0001) and R-status (p�0.023). Conclusions: 

HER-2 amplification is detectable in a significant proportion (about 30%) 

of primary tumors of patients with advanced rectal cancer. Furthermore 

HER-2 amplification was detectable in 22% of resected metachronous 

metastases during follow-up. Therefore HER-2 represents a promising 

target and should be further assessed within prospective clinical trials. 




Cost-effectiveness analysis per life-year gained based on predictors of 

response for first-line metastatic colorectal cancer therapy in Spain. 

Presenting Author: Cristobal Belda-Iniesta, Centro Integral Oncológico 

Clara Campal (CIOCC), Madrid, Spain 

Background: Economic crisis, increasing prevalence and cost of mCRC 

management endanger availability of biological therapies for public health 

systems due to budget limitations. We performed a cost-effectiveness 

analysis based on markers of response/resistance including biological 

therapies available in Spain for mCRC. Methods: We aimed to calculate 

incremental cost-effectiveness ratio (ICER) per life-year gained (LYG) and 

progression-free year gained based on predictive markers for mCRC. 

Efficacy data include randomized trials (RT) that guided on-label uses of 

bevacizumab and cetuximab. Control arms from these trials were used as 

reference to calculate ICERs. Markers of clinical benefit (biological and 

radiological) were included in this model. Toxicity as predictor of efficacy 

was excluded for any therapy. Prices for drugs in Spain were assumed to 

represent the best-value for each drug including all possibilities to reduce 

pharmacy costs. For 1st line, median duration of therapy reported by RT 

was used to calculate the final budget. 70kg and 1.7 m were used as 

reference for patients dose calculations. If accessible, HR for PFS and OS 

were used instead of medians. Results: K-Ras status and early response 

measured by CT at 8 weeks were used as predictors of resistance and 

increased efficacy for cetuximab-based combinations. We have not identified 

any predictor marker for other drugs from RT. In this regard, 

FOLFIRI�cetuximab combination obtained an ICER below the widelyproposed 

Spanish threshold of 30,000 € per LYG if patients harbored wt 

K-Ras tumors and evidenced an objective response at 8 weeks. Other ICERs 

for different schedules were too distant from this limit, they will be 

presented at the meeting. Multivariate analysis confirmed the robustness of 

results. Conclusions: 1st line FOLFIRI�cetuximab therapy for wt K-Ras 

patients that get an objective response measured by CT at 8 weeks is the 

only cost-effective therapy option for mCRC below usual health-economic 

thresholds for Spain. Our results are critical to design cost-effectiveness 

based clinical guidelines for mCRC that will contribute to financial 

sustainability of public health system in Spain. 


Improved early prediction of individual prognosis for patients with mCRC: 

Joint modeling of tumor shrinkage with volume data for PFS and OS. 

Presenting Author: Ulrich Robert Mansmann, Institute of Medical Informatics, 

Biometry and Epidemiology, Klinikum Grosshadern, University of 

Munich, Munich, Germany 

Background: Piessevaux et al. (ESMO 2010) proposed a decrease in 

RECIST-based tumor size of 20% at week 8 following 1st-line therapy for 

mCRC as a predictor of clinical outcome (PFS and OS). We expanded upon 

this idea (ASCO GI 2012). A tumor volume algorithm was developed 

providing a better approximation to true tumor volume by using both the 

longest and the longest orthogonal diameters of a target lesion. In this study 

we compare the quality of early prediction-based individual patient 

prognosis based on tumor change according to either RECIST or the tumor 

volume algorithm. Methods: The prognostic method is combined with the 

volume algorithm and applied to the data from 2 studies (OPUS, n�337; 

CRYSTAL, n�1198) and 4 treatment regimens (FOLFOX4 �/- cetuximab 

and FOLFIRI �/- cetuximab), in patients with mCRC. The influence of the 

treatment regimen on early PFS and OS prognosis is studied by joint 

modeling. The quality of early prognosis depending on the tumor size 

assessment used is compared by the logarithmic scoring rule. Results: 

Individual volume shrinkage and baseline volume are considered prognostic 

factors. Individual predictions depend on the chemotherapy administered 

and whether cetuximab is added. Equivalent tumor baseline volumes 

and early volume changes, predict an up to 20% higher 1 year (y) PFS and 

2y OS rate for FOLFIRI than for FOLFOX. The addition of cetuximab to 

standard chemotherapy (CT) translates into a mean increase in shrinkage of 

10% resulting in an improvement in 1y PFS rates of 23% and in 2y OS 

rates of 18%. The quality of individual prediction over the 4 regimens is 

combined in one logarithmic (log) score. The log score for the RECISTbased 

prediction is 2.45 which is significantly higher than that for the 

volume-based prediction of 1.97 (p�0.0001). Lower scores correspond to 

a better prediction. Conclusions: The tumor volume algorithm enables a 

more precise prediction of individual patient PFS and OS than RECISTbased 

tumor assessments. Based on early tumor changes for CT, �/cetuximab, 

it is possible to calculate quantitative information on a patient’s 

prognosis. The model has high potential to guide individual clinical 

decision making for mCRC patients. 


Aflibercept versus placebo in combination with FOLFIRI in previously 

treated metastatic colorectal cancer (mCRC): Mean overall survival (OS) 

estimation from a phase III trial (VELOUR). Presenting Author: Florence 

Joulain, sanofi, Chilly Mazarin, France 

Background: VELOUR evaluated the efficacy and safety of the novel fusion 

protein aflibercept (VEGF Trap) in combination with FOLFIRI in mCRC 

patients previously treated with oxaliplatin. Median OS showed significant 

improvement with 12.06 months in placebo arm vs 13.50 months in 

aflibercept arm (p�0.0032; HR�0.82 [95.34% CI: 0.71 to 0.94]) [Van 

Cutsem, 2011]. Since survival data in oncology are usually right skewed, 

median survival is preferred for regulatory purposes. However, mean 

survival estimation can render a more meaningful estimate for long term 

benefit of interventions, and be effectively applied to clinical and economic 

decision support. Estimating mean OS also allows payers to derive an 

estimation of total costs and outcomes in the population. The purpose of 

this study was to estimate the mean OS for VELOUR trial. Methods: During 

the trial follow-up period, mean OS is not observable and can be estimated 

by extrapolating the trial Kaplan-Meier curve using a survival function. 

Several standard parametric distributions were tested: exponential, weibull, 

lognormal, loglogistic and gompertz. Akaike’s Information Criteria (AIC), 

Bayesian Information Criteria (BIC) and graphical method were used to 

evaluate the goodness of fit of the distributions. Models were run by 

treatment arm separately or combining the two arms and using treatment as 

covariate to control for variation. Results: Using AIC/BIC and graphical 

method, loglogistic function best fit the VELOUR data both with and 

without treatment as covariate. Weibull distribution is used for sensitivity 

analysis. Conclusions: Using loglogistic function, mean OS benefit for 

aflibercept in combination with FOLFIRI is at least 2.9 months (versus 1.4 

months difference in median survival). The results have important implications 

for clinical and economic decision support. Study NCT00561470 

was funded by sanofi, in partnership with Regeneron. 

Mean OS (months) 

Placebo* Aflibercept* Difference 

Loglogistic 

By treatment separately 18.9 25.5 6.6 

With treatment as covariate 20.3 23.2 2.9 

Weibull 

By treatment separately 14.9 17.9 3.0 

With treatment as covariate 15.0 17.7 2.7 

* � FOLFIRI 


Integrin genetic variants and stage-specific tumor recurrence in patients 

with stage II and III colon cancer. Presenting Author: Pierre Oliver Bohanes, 

University of Southern California Norris Comprehensive Cancer Center, Los 

Angeles, CA 

Background: Integrins are key elements in cancer biology regulating tumor 

growth, angiogenesis and lymphangiogenesis through interactions of the 

tumor cells with the microenvironment. Recent evidence showing that 

integrins are critical in cancer dormancy suggests that their differential 

expression or activity may be responsible for tumor recurrence. Moving 

from the hypothesis that integrins could have different effects in stage II 

and III colon cancer, we tested as a primary endpoint whether a comprehensive 

panel of germline single nucleotide polymorphisms (SNPs) in integrin 

genes could predict stage-specific time to tumor recurrence (TTR) in stage 

II and III colon cancer patients. Methods: A total of 234 patients, 105 

high-risk stage II and 129 stage III, treated with 5-fluorouracil-based 

chemotherapy at the University of Southern California were included in this 

study. The median follow-up time was 4.4 years. Whole blood samples were 

analyzed for 22 germline SNPs in integrin genes using PCR-RFLP or direct 

DNA-sequencing. Results: In the multivariate analysis,stage II colon cancer 

patients with at least one G allele for ITGB3 rs4642 had higher risk of 

recurrence (HR�4.027, 95%CI 1.556-10.421, p�0.004). This association 

was also significant in the combined stage II-III cohort (HR�1.975, 

HR 95%CI 1.194-3.269, p�0.008). The predominant role of ITGB3 

rs4642 in stage II diseases was confirmed using recursive partitioning, 

showing that ITGB3 rs4642 was the most important factor in stage II 

diseases. In contrast, in stage III diseases, both ITGB1 rs2298141 

(HR�1.909, 95%CI 1.054-3.459, p�0.033) and ITGA4 rs7562325 

(HR�0.227, 95%CI 0.064-0.804, p�0.022) were associated with TTR. 

The latter showed a significant interaction between stages (p�0.048). 

Conclusions: This study identifies germline polymorphisms in integrin 

genes as independent stage-specific prognostic markers for stage II and III 

colon cancer. These data strengthen the role of tumor dormancy in early 

colon cancer and may help to select subgroups of patients who may benefit 

from integrin-targeted treatments. 



Phase II study of preoperative radiation with concurrent capecitabine, 

oxaliplatin, and bevacizumab followed by surgery and postoperative 5-FU, 

leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally 

advanced rectal cancer: A trial of the Eastern Cooperative Oncology Group 

(E3204). Presenting Author: Steven J. Cohen, Fox Chase Cancer Center, 


Background: Oxaliplatin and bevacizumab potentiate the antitumor activity 

of fluoroyprimidines and radiotherapy in preclinical and clinical studies of 

colorectal cancer. This phase II trial evaluated the efficacy of the preoperative 

combination of capecitabine, oxaliplatin, and bevacizumab with 

radiotherapy in rectal cancer. Methods: Eligibility: resectable T3/T4 adenocarcinoma 

of the rectum � 12 cm. from anal verge. Preoperative treatment 

was capecitabine (825 mg/m² bid M-F), oxaliplatin (50 mg/m² weekly), 

bevacizumab (5 mg/kg D1,15,29), and pelvic external beam radiotherapy 

(50.4 Gy/28 fractions). Surgery was performed within 6-8 weeks. Within 

12 weeks of surgery, patients received 12 cycles of FOLFOX � bevacizumab 

(5 mg/kg) Q2 weeks. Pathologic complete response (path CR) was 

the primary endpoint. Secondary endpoints included resection rate and 

toxicity. Results: Fifty-seven patients (pts) enrolled from 7/06 to 5/10 and 

54 were eligible. Clinical staging: T3/4 (50/4), NX0/1/2 (2/16/31/5). Most 

common grade 3/4 non-hematologic toxicities during treatment were rectal 

pain (9), fatigue (8), and diarrhea (7). Two patients died of aspiration. Nine 

pts had early postsurgical complications (9 wound infections, 6 dehiscence, 

1 abscess) and 23 had late surgical complications (23 non-healing 

wounds, 12 dehiscence, 5 bowel obstruction/ileus, 2 abscess). Pathologic 

staging: T0/1/2/3 (11/3/15/19), N0/1/2 (32/10/7). Nine pts had path CRs 

(17%, 90% CI:[9%-27%]. Surgery was LAR (38) and APR (11). Twentytwo 

pts did not receive postoperative chemotherapy (39%), 16 due to 

adverse events. Five local recurrences have been reported. RFS and OS 

data are immature. Conclusions: The addition of oxaliplatin and bevacizumab 

to capecitabine and radiotherapy for locally advanced rectal cancer 

resulted in downstaging for the majority of pts but did not improve the 

pathologic complete response rate compared to historical controls. The 

combination resulted in significant early and late postsurgical complications. 


Six months versus twelve months of capecitabine as adjuvant chemotherapy 

for stage III (Dukes’ C) colon cancer: Initial safety report for the 

open-label randomized phase III study (JFMC37-0801). Presenting Author: 

Katsuyuki Kunieda, Gifu Prefectural General Medical Center, Gifu, 

Japan 

Background: The standard treatment duration of adjuvant chemotherapy 

(CT) in patients (pts) with stage III colon cancer is 6 months. On the other 

hand, no clinical trial showed the optimal treatment duration of oral 

chemotherapeutic agents in adjuvant setting for colon cancer. Sargent et al 

have reported that 83% of recurrences in stage II and III pts have occurred 

within the first 3 years after surgery and peak was observed around one year 

after surgery. Therefore, to clarify the benefit of 12 months administration 

of Capecitabine, we designed randomized phase III trial for a comparison of 

6 months treatment and 12 months treatment of capecitabine as adjuvant 

CT for stage III colon cancer. Methods: JFMC37 is a multicenter, randomized 

Phase III trial. Patients with fully resected Stage III colon or recto 

sigmoid cancer were eligible. Capecitabine was administered orally as 

tablets, 2,500 mg/m²/day for 14 days followed by a 7-days rest. Treatment 

is continued to 8 cycles (6 months) in arm A (A) or 16 cycles (12 months) in 

arm B (B). Patients were randomized 1:1 to A or B. Data size was estimated 

by disease free survival as primary endpoint. The statistical design is based 

on superiority hypothesis; 5-yrs DFS is 60% in arm A, 67% in arm B 

;unilateral ��0.05, 1-��0.8;and planed accrual is 1200 pts. Results: 

Between September 2008 to December 2009, 1304 patients were 

enrolled and then randomized. Both arms were well balanced for mean age: 

(A) 64.1, (B) 63.8; ECOG PS (%0/1): (A) 95.0/5.0, (B) 97.1/2.9; 

involvement of lymph nodes (%N0/N1/N2): (A) 77.1/19.9/3.1, (B) 76.6/ 

19.7/3.7. Treatment completion rate for A and B were 68.2% and 43.4%. 

Incidences of serious adverse events (SAEs) over 1% were neutropenia: (A) 

2.6%, (B) 3.8%, diarrhea: (A) 2.9%, (B) 2.1%, loss of appetite: (A) 1.3%, 

(B) 1.0%, fatigue: (A) 1.8%, (B) 1.2%, hand-hoot syndrome: (A) 16.4%, 

(B) 22.1%. Conclusions: There were no obvious differences in SAEs 

between arm A and arm B. Although twelve months of capecitabine showed 

a tendency to increase G3/4 hand-foot syndrome, we concluded that 

incidence of SAEs were acceptable and comparable to previously report. 


229s 


Prognostic significance of intermediate mucinous carcinoma in patients 

with microsatellite stable stage II or III colon cancer. Presenting Author: 

Gun Min Kim, Department of Internal Medicine, Yonsei University College 

of Medicine, Seoul, South Korea 

Background: Mucinous adenocarcinoma (MC) is a histological subtype of 

colorectal cancer with �50% of mucinous component of tumor volume. 

According to WHO classification, tumor less than 50% of the lesion 

composed of mucin was considered as non-mucinous carcinoma (NMC).Mucinous 

histology has been shown to be an independent adverse prognostic 

factor in some studies, but not in others. However, prognostic implication 

of intermediate mucinous carcinoma (IMC) which had focal mucinous 

component �50% of tumor volume has not been studied yet. The aim of 

this study is to explore prognostic impact of IMC in patients with resected 

stage II or III colon cancer. Methods: This study involved 917 patients who 

underwent curative resection for stage II or III colon cancer in Severance 

Hospital, from 2003 to 2009. The proportion of mucinous component was 

reviewed and re-classified correctly by pathologists. MC was defined tumor 

having �50% mucinous component. Tumor with mucinous component but 

less than 50% regarded as IMC and less than 10% mucin as NMC. Results: 

Among 917 patients, 63 (6.9%) and 60 (6.5%) were MC and IMC, 

respectively. Median follow-up duration was 50.2 months (0.9~109.7) and 

Stage 3 was 48.1% (441/917). The similarities between MC and IMC were 

found as right colon dominant (MC: IMC: NMC � 60%: 67%: 34%, 

p�.001) and higher incidence of MSI-high compared to NMC (MC: IMC: 

NMC � 27%: 30%: 11%, p�.001). In stage III, the disease-free survival 

(DFS) rate at 5 years was 44% for MC, 56% for IMC, and 74% for NMC 

(p�.001). Subgroup analysis according to MSI status showed that DFS had 

significant inverse correlation with proportions of mucinous components in 

MSI-low or MSS group, but patients with MSI-high tumor showed higher 

five-year DFS rate (�85%) regardless of mucinous component. For stage II 

colon cancer patients, both mucinous histology and MSI had little clinical 

significance. Conclusions: In patients with curative resection for stage II or 

III colon cancer, IMC had similar characteristics to MC, which were right 

colon dominant and high incidence of MSI-high tumor. The prognostic 

impact of IMC was intermediate risk between MC and NMC in stage III 

patients with MSI-low or MSS tumor, but not in MSI-high group. 


Effect of postoperative complications on adjuvant chemotherapy use in 

stage III colon cancer. Presenting Author: Ryan P. Merkow, Northwestern 

University, Feinberg School of Medicine, Chicago, IL 

Background: The National Quality Forum has endorsed the use of adjuvant 

chemotherapy in stage III colon cancer, yet a substantial treatment gap 

exists in the United States. Our objective was to evaluate the contribution 

of postoperative complications on the use of adjuvant therapy after 

colectomy for cancer. Methods: Patients from the National Surgical Quality 

Improvement Program and the National Cancer Data Base who underwent 

colon resection for cancer were linked (2006-2008). The association of 

complications on adjuvant chemotherapy use was assessed using multivariable 

regression models. Results: From 140 hospitals, 2368 patients 

underwent resection for stage III colon adenocarcinoma. Overall, 36.8% 

(871/2,368) patients were not treated with adjuvant therapy, of which 

47.8% (416/871) had documented severe comorbidities or advanced age 

(�80) as the reason for no adjuvant therapy receipt. Of the remaining 455 

patients, 21.3% (97/455) had �1 serious complication that could account 

for adjuvant therapy omission. The remaining 41.1% (358/871) patients 

did not have a documented reason for not recieving adjuvant therapy. 

Complications associated with adjuvant therapy omission were abscess/ 

anastomotic leak (OR 1.91, 95% CI 1.02-3.59), renal failure (OR 7.16, 

95% CI 1.92-26.79), prolonged ventilation (OR 7.92, 95% CI 2.97- 

21.13), re-intubation (OR 5.69, 95% CI 2.13-15.18), and pneumonia (OR 

4.05, 95% CI 2.07-7.90). Abscess/anastomotic leak was associated with a 

28-day delay in time to adjuvant chemotherapy (73 vs. 45 days, p�0.05). 

Superficial surgical site infection did not decrease adjuvant therapy receipt 

but delayed the time to its use (57 vs. 44 days, p�0.05). The occurrence of 

postoperative sepsis was associated with a 15-day delay to adjuvant 

chemotherapy (60 vs. 45 days, p�0.05). Conclusions: Serious postoperative 

complications explained nearly one quarter of the adjuvant chemotherapy 

treatment gap among stage III colon cancer patients. Postoperative 

complications affect treatment utilization and should be considered when 

calculating adherence with the Stage III adjuvant therapy for colon cancer 

measure. Judging provider performance using quality metrics is challenging 

without clinical data. 




Reappraisal of the risks and benefits of major liver resection in patients 

with initially unresectable colorectal liver metastases. Presenting Author: 

Francois Cauchy, HBP Surgery, Hôpital Beaujon, Clichy, France 

Background: Improvements in both surgical technique and efficacy of 

chemotherapy have increased the rate of resection for patients with initially 

unresectable colorectal liver metastases (IU-CRLM). We aimed to evaluate 

the short and long-term outcomes of major hepatectomy for such patients. 

Methods: From 2000 to 2011, 257 patients underwent major hepatectomy 

for CRLM. Seventy-eight (30%) of these patients were considered IU and 

required portal vein occlusion and/or �12 cycles or change in induction 

chemotherapy regimen to achieve resectability. Results: IU patients had 

respectively more lesions (5.6 vs.3.6, p�0.001), more frequently bilobar 

(70% vs.50% p�0.008) and synchronous (83.3% vs.70%, p�0.027) 

than initially resectable (IR) patients. Post-operative mortality (12.8% 

vs.1.7%, p�0.001) and major complications (46.2% vs.22.3%, 

p�0.0001) were higher in IU patients. An associated metabolic syndrome 

(HR 5.2, CI 1.2-21.9, p�0.025), high grade sinusoidal lesions (HR 2.4, CI 

1.1-5.8, p�0.044) and the need for vascular reconstruction (HR 6.3, CI 

1.2-34.4, p�0.032) were significant risk factors for major morbidity in IU 

patients. Significantly fewer IU patients received adjuvant chemotherapy in 

case of major postoperative complications compared to IR patients (47% 

vs. 83%, p�0.001). Overall 5-year survival was significantly lower in IU 

than in IR patients (26% vs.55%, p�0.032) and all IU patients had tumor 

recurrence within 3 years. The absence of adjuvant chemotherapy and 

tumor size �5 cm were the only factors associated with poor survival in 

multivariate analysis for IU patients. Conclusions: IU-CRLM patients 

requiring major liver resection displayed higher morbidity and mortality 

rates than IR ones, therefore compromising both short and long-term 

outcomes. Multimodal strategy should be reassessed in the presence of 

metabolic syndrome, sinusoidal lesions or major vascular involvement. 


Clinical utility of the preoperative Glasgow prognostic score in patients 

undergoing potentially curative resection for colorectal cancer. Presenting 

Author: Donald C. Mcmillan, Department of Surgery, University of Glasgow, 

Glasgow, United Kingdom 

Background: There is now good evidence that, in addition to TNM stage, the 

pre-operative combination of the standardised measurements of C-reactive 

protein and albumin, the Glasgow Prognostic Score (mGPS) provides 

valuable prognostic information. The aim of the present study was to 

examine the clinical application of the pre-operative mGPS in a large 

mature cohort of patients undergoing potentially curative resection for 

colorectal cancer. Methods: From a prospectively maintained database, 

consecutive patients (n� 797) with histologically proven colorectal cancer 

who were considered to have undergone potentially curative resection 

between January 1997 and December 2010 in a single surgical unit at the 

Royal Infirmary, Glasgow were included in the study. Results: Patients with 

an elevated mGPS were more likely to be older (p�0.001), female 

(p�0.05), have colonic tumours (�0.001), present as an emergency 

(p�0.001), had higher TNM stage (p�0.05) and more likely to die of their 

disease (p�0.01). The median follow-up was 66 months and using 3 year 

cancer-specific mortality as an endpoint, the area under the receiver 

operator curve was 0.652 (95% CI, 0.591–0.714; p�0.001) for the 

mGPS and 0.668 (95% CI, 0.610–0.727; p�0.001) for TNM stage. The 

cancer-specific survival, at 3 years, varied between 86% and 64% 

according to the mGPS and between 88% and 72% according to TNM 

stage. The cancer-specific survival, at 3 years, in patients with a mGPS 0 

was 91% and 81% for TNM stage II and III respectively. The cancerspecific 

survival, at 3 years, in patients with a mGPS 1 was 89% and 66% 

for TNM stage II and III respectively. The cancer-specific survival, at 3 

years, in patients with a mGPS 2 was 77% and 43% for TNM stage II and III 

respectively. Conclusions: The results of the present study show the clinical 

utility of the pre-operative mGPS in predicting cancer specific survival of 

potentially curative surgery for colorectal cancer. 


A population-based study of the effect of FDG PET/CT in the management 

of liver-limited colorectal adenocarcinoma (CRC) metastases. Presenting 

Author: Maria Yi Ho, Division of Medical Oncology, British Columbia Cancer 

Agency, Vancouver, BC, Canada 

Background: PET/CT scans are publically funded in British Columbia for 

staging in liver limited metastatic CRC. However, past studies have been 

equivocal about the utility of PET/CT as some report as high as a 20-30% 

change in management while others report �10% change in management. 

Our primary objective was to assess the effect of the addition of PET/CT to 

CT scanning for the management of liver limited colorectal cancer. 

Methods: Patients who underwent PET/CT scan for de novo liver limited 

metastatic disease from 2005-2011 in the province of British Columbia 

were identified using the PET/CT database. Patients recently completed or 

currently on chemotherapy were excluded. We determined the concordance 

rates between CT and PET/CT scans with respect to the extra-hepatic 

disease, the number of lesions in the liver and the location of liver lesions. 

Results: 349 patients were identified. The most common indications for 

PET/CT scans after an initial CT scan were: detection of extrahepatic 

disease (77%), confirmation of the malignant nature of the liver lesions 

(8%) and the extent of extrahepatic disease (15%). PET/CT and CT were 

discordant in 39% of cases for the extent of metastatic disease. PET/CT 

revealed extrahepatic disease in 27% of the cases for which CT only 

detected liver limited disease. In contrast, 13% of patients were downstaged 

when CT liver lesions were demonstrated not to be FDG avid. 

Concordance of PET/CT and CT scans on the number and location of liver 

lesions was 52% and 85%, respectively. PET/CT revealed additional 

number of liver lesions and multilobar disease in 26% and 12% of cases, 

respectively. Furthermore, the median time between PET/CT and CT were 

64.3 days and 64.1 days for concordant and discordant cases (p�0.88). 

Conclusions: PET/CT scans provided additional information compared to CT 

scans which could have implications for surgical management. Our study 

supports the utility and public funding of PET/CT in addition to CT in 

patients with potentially surgically curable metastatic CRC involving the 

liver. 


Does multiple mutational analysis of the EGFR pathway have a prognostic 

role in advanced colorectal cancer (CRC)? Presenting Author: Luisa Foltran, 

Azienda Ospedaliero-Universitaria, Udine, Italy 

Background: BRAF mutation is widely recognised as a strong negative 

prognostic factor in advanced CRC, while the prognostic value of KRAS 

mutations in codons 12-13 remains controversial. Exploring mutations in 

other downstream components of the EGFR pathway may have an impact 

on survival. Methods: A consecutive cohort of 201 metastatic CRC patients 

treated with systemic chemotherapy were analysed for KRAS (12-13-61- 

146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMark- 

TMQ96 ID instrument (Qiagen, Germany) with commercially available kits 

Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate 

microdissection guaranteed more than 70% of cancer cells for each 

sample. For the purpose of the survival analysis 4 categories were created: 

(1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of 

KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. 

Log-rank and Cox proportional tests were applied for statistical analysis. 

Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) 

were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples 

while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All 

mutations were mutually exclusive except for 24 (11.9%) patients with 

concomitant KRAS/PIK3CA mutations. Median survivals for different 

categories are shown. Patients harbouring BRAF mutation had the worst 

outcome (p�0.0006). Mutations of any codon of KRAS (12-13-61-146) 

also negatively impacted on survival (p�0.026), while the all wild-type 

(KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p�0.002). 

Conclusions: This study suggests the usefulness for early molecular profiling 

for advanced CRC patients. Mutational analysis of all EGFR pathway 

components may identify different prognostic subgroups. This information 

may drive treatment selection in clinical practice and stratification in 

clinical trials. 

Mutational status 


(months) 

HR for death 

(95% CI) 

BRAF mutation 5.1 4.5 (2.1-9.7) 

KRAS mutation 12-13 only 15.8 1.56 (1.1-2.3) 

Any of KRAS 61-146 /NRAS/ PIK3CA mutation 14.7 1.8 (1.1-3.3) 

All W-T (reference category) 22.2 1 



Neoadjuvant treatment of colorectal liver metastases (CRLM) with drug 

eluting beads trans-arterial chemoembolization (DEBIRI-TACE): A multiinstitute 

phase II study in resectable metastases. Presenting Author: 

Robert Peter Jones, University of Liverpool, Liverpool, United Kingdom 

Background: Perioperative chemotherapy confers 3-year progression free 

survival advantage following resection of CRLM and good pathologic 

response is associated with improved overall survival. However, systemic 

neoadjuvant chemotherapy can increase postoperative morbidity and 

mortality. TACE using preloaded Irinotecan eluting beads gives sustained 

delivery of drug directly to tumor, thereby maximising response and 

reducing systemic exposure. This study examined the feasibility and safety 

of neoadjuvant DEBIRI-TACE before CRLM resection. Methods: Patients 

with resectable CRLM received single DEBIRI-TACE (up to 200mg) 1 

month pre-hepatectomy. Primary end-point: tumor resectability, secondary 

end-points: safety, radiologic response (RECIST) and pathologic tumor 

response. Results: TACE attempted in 49 patients, successful in 40. 

Reasons for failed TACE included consent withdrawal (n�2), bilobar 

disease (n�2), tumour involving gallbladder wall (n�1), suspected hepatoma 

(n�1), arterial access difficulty (n�2), contrast medium allergy 

(n�1). Post-TACE complications: 1 acute pancreatitis (3%); 4 postembolization 

syndromes (10%). Imaging at 4 weeks post-TACE (30 

patients): complete response 0/40 (0%); partial response 1/40 (3%); 

stable disease 19/40 (48%); ‘progressive’ disease 10/40 (25%). 40 

patients proceeded to surgery, 38 underwent hepatectomy (2 peritoneal 

disease, resectability rate 95%). 30-day post-operative mortality 5% 

(n�2), neither death TACE related (1 intraoperative pneumomediastinum, 

1 aspiration pneumonia). 63 lesions (median 2 per patient) targeted with 

TACE. Histology: no residual disease 17%; 1-49% residual disease 59%; 

�50% residual disease 22%; no response 2%. Conclusions: Resection 

after neoadjuvant DEBIRI-TACE for CRLM is feasible and safe. Single 

treatment with DEBIRI-TACE resulted in tumor pathologic response similar 

to that seen after protracted systemic chemotherapy. 


Association of HER2 and IGF1 germline polymorphisms with outcome in 

metastatic colorectal cancer (mCRC) patients (pts) treated with secondline 

irinotecan (IR) with or without cetuximab (CB): The EPIC experience. 

Presenting Author: Dongyun Yang, University of Southern California Norris 

Comprehensive Cancer Center, Los Angeles, CA 

Background: EPIC, a multinational phase III clinical trial with IR � CB vs IR 

alone in mCRC pts in the second-line setting after failure of FOLFOX 

demonstrated a benefit for IR�CB in progression-free survival (PFS) and 

response rate (RR). We evaluated 6 functional germline polymorphisms 

involved in the IGF1 and HER2 for their potential role as molecular 

predictors of clinical outcome in pts treated in the EPIC study. Methods: 

DNA was extracted from all available formalin-fixed paraffin-embedded 

tumor samples from the EPIC trial. Genotyping was performed using 

PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. 

Univariate analysis (Fisher’s exact test for RR; log-rank test for PFS and OS) 

was performed to examine associations between polymorphisms and 

clinical outcome. Multivariate analysis (Logistic regression or Cox regression 

model) was conducted to control baseline patient characteristics and 

treatment. Results: 186 pts with available samples were treated either with 

IR/CB (arm A, 84 pts) or IR alone (arm B, 102 pts). Median age was 59 yrs 

(range 34-85yrs) for arm A and 61 yrs (range 25-90 yrs) for arm B. In arm 

A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or 

PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts 

(94%) had SD or PD. Median PFS for arm A was 3.0 months (95%CI 2.4- 

4.1 months) vs 2.7 months (95%CI 2.2-2.9 months) for arm B; median OS 

was 9.3 months (95%CI 7.1-21.1 months) for arm A vs 12.3 months 

(95%CI 10.4- 17.9 months) for arm B. KRAS mutation status was not 

significantly associated with outcome in our patient cohort. We found that 

HER2 rs 1136201 was significantly associated with response (RR: AA 

6.5%, AG 12.5%, and GG 27.3%, Fisher’s exact test p�0.045). IGF1 rs 

2946834 was significantly associated with PFS in both univariate and 

multivariate analyses (median PFS was 2.8 months in patients with CC or 

CT vs 1.8 months in patients with TT; log-rank p�0.009; Wald test 

p�0.008). Conclusions: Our study suggests the prognostic value of polymorphisms 

in the IGF1 and HER2-pathway in mCRC pts treated with IR� CB. 

Prospective validation of these findings in clinical trials is warranted. 


231s 


Efficacy and safety of bevacizumab in metastatic colorectal cancer (mCRC): 

Pooled analysis from randomized controlled trials (RCTs). Presenting 

Author: Niall Christopher Tebbutt, Austin Hospital, Heidelberg, Australia 

Background: Bevacizumab (BV) with chemotherapy (CT) is a standard 

treatment for mCRC. This analysis pooled individual patient data from the 

clinical databases of seven RCTs (phase II or III) of BV in 1st- or 2nd-line 

treatment to further define clinical outcomes, including within subgroups. 

Methods: Patient data were pooled from 1st-line (AVF2107, NO16966, 

ARTIST, AVF2192, AVF0780, AGITG MAX) and 2nd-line (ECOG E3200) 

trials. All analyses were based on the intent-to-treat population. Overall and 

progression-free survival estimates (OS, PFS) were calculated by Kaplan- 

Meier methods. To assess differences in time to response variables by 

treatment arm (CT vs BV � CT), stratified random (overall) and fixed 

(subgroup comparisons) models were used to estimate pooled hazard ratios 

(HRs) and 95% confidence intervals (CIs), with each study included as a 

stratum. Results: Of the 3,763 pooled patients (CT [n�1773]; BV � CT 

[n�1990]), 58.8% were male, 39.6% were �65 years, and 45.7% had an 

ECOG performance status �1. OS and PFS were statistically significantly 

increased in BV-treated patients vs control patients. Safety data in this 

pooled analysis were consistent with the profile of BV from the individual 

studies. Conclusions: The addition of bevacizumab to CT resulted in 

statistically significant improvements in survival outcomes for mCRC 

patients in the overall analysis, with PFS benefit extending across subgroups 

defined by CT intensity, CT regimen, and KRAS status. 

Overall: BV � CT vs CT 

HR (95% CI) P value 

OS 0.80 (0.71�0.90) .0003 

PFS 0.57 (0.46�0.71) �.0001 

Subgroup comparisons: BV � CT vs CT 

HR (95% CI) for OS HR (95% CI) for PFS 

Monotherapy (n�751) 0.86 (0.72–1.02) 0.56 (0.48–0.67) 

Doublets (n�3,012) 0.82 (0.76–0.89) 0.70 (0.64–0.76) 

Irinotecan regimen (n�1,027) 0.71 (0.61–0.83) 0.55 (0.47–0.64) 

Oxaliplatin regimen (n�1,985) 0.87 (0.79–0.96) 0.77 (0.70–0.85) 

KRAS wild-type patients (n�364) 0.70 (0.54–0.91) 0.57 (0.45–0.72) 

KRAS mutant patients (n�166) 0.85 (0.60–1.22) 0.54 (0.38–0.76) 


Incidence and prognostic impact of KRAS and BRAF mutations in patients 

undergoing liver surgery for colorectal metastases. Presenting Author: 

Georgios Karagkounis, The Johns Hopkins University School of Medicine, 

Baltimore, MD 

Background: Molecular biomarkers offer the potential for refining prognostic 

determinants in patients undergoing cancer surgery. Among patients with 

colorectal cancer metastases, KRAS and BRAF are important biomarkers, 

but their role in patients undergoing surgical therapy for liver metastases is 

unknown. In this study, the prevalence and prognostic significance of 

KRAS and BRAF mutations were determined in patients undergoing 

surgical therapy of colorectal liver metastases (CRLM). Methods: KRAS and 

BRAF analysis was performed on 202 patients undergoing curative intent 

surgical therapy of CRLM between 2003 and 2008. Tumor samples were 

analyzed for somatic mutations using sequencing analysis (KRAS: codon 

12/13, BRAF: V600E). The frequency of mutations was ascertained and 

their impact on outcome determined relative to other clinicopathologic 

factors. Results: KRAS gene mutations were detected in 58/202 patients 

(29%) undergoing surgery for CRLM, comparable to that reported in 

non-surgical patient series. In contrast, mutation in the BRAF gene was 

identified in very low frequency in this surgical cohort, found in only 4/202 

(2%) patients. KRAS mutations were associated with worse long-term 

survival (HR�2.13, CI�1.25-3.65), as well as risk of recurrence (HR�1.89, 

CI�1.12-3.19). ). In addition, KRAS mutation was also associated with 

risk of recurrence following surgical therapy (HR�1.89, CI�1.12- 

3.19).While other clinicopathologic features, including tumor number, 

CEA and primary stage were also associated with survival, KRAS status 

remained independently predictive of outcome. The low incidence of BRAF 

mutation limited the ability to determine its prognostic impact. Conclusions: 

While KRAS mutations were found in approximately one third of patients, 

BRAF mutations were found in only 2% of patients undergoing surgery for 

CRLM. KRAS status was an independent predictor of overall and diseasefree 

survival. Molecular biomarkers such as KRAS may help to refine our 

prognostic assessment of patients undergoing surgical therapy for CRLM. 




Relationship between genetic markers and quality of life (QOL) in stage III 

colon cancer (CC) patients (pts) prior to adjuvant treatment (N0147). 

Presenting Author: Jeff A. Sloan, Mayo Clinic, Rochester, MN 

Background: In metastatic colorectal cancer (CRC), previous studies suggested 

potential relationships between certain drug metabolizing (DM) 

genes (DPYD, ERCC2, GSTP1 and TYMS) and QOL prior to receipt of 

chemotherapy (Sloan, Plenary Session ASCO 2004). The current study is 

the first to examine relationships between similar DM genes and QOL in 

stage III CC pts. Methods: 1,583 CC pts on a randomized adjuvant stage III, 

phase III trial received FOLFOX, FOLFIRI, or either �/- Cetuximab. 

Genomic DNA and baseline QOL data via linear analogue self assessment 

(LASA) scales with 4 QOL variables were obtained. 53 DM SNPs were 

selected for known functional effect within potential regulatory sites. 

Two-sample t-tests assessed differences in QOL between pts with variants 

and wild-type status. Differences of at least 10 points on a 0-100 point 

QOL score were considered clinically significant. Results: 14 relationships 

between DM genes and QOL were detected at the nominal p � 0.05 level; 

six of these were related to DPYD, ERCC2, GSTP1 and TYMS. Relationships 

were also observed at the 0.05 level with polymorphisms of genes DPYS, 

ERCC1, MGMT, MTHFR, OPRT and UGT1A1 based on unadjusted and 

adjusted association tests. GSTP1 I105V and OPRT 5’UTR 28 A�G 

markers differed on fatigue scores (p�0.04, 0.005, respectively). Variants 

on MTHFR R594Q were associated with higher mental acuity scores 

(p�0.02). These relationships remained after adjusting for age, gender, 

race, T stage, PS, disease site, lymph nodes involved, and grade. The 

robustness of the observed associations varied with the multiple comparison 

adjustment method. Conclusions: Similar to the earlier study of stage IV 

CRC, we observed a possible relationship in pts with Stage III CC with 

regard to DM genes and QOL, although these relationships were more 

modest than observed in Stage IV pts. These DM genes may be in linkage 

disequilibrium with other genetic variants that more directly affect behavior 

and QOL. Further genome wide association studies are needed to clarify 

these relationships. 


Comparison of incidence and patterns of recurrence in colon cancer (Cca) 

treated by sentinel lymph node (SLN) mapping (M) versus conventional surgery. 

Presenting Author: Mohammed Saifullah Shaik, Hurley Medical Center/ 

Michigan State University, Flint, MI 

Background: Recurrence of Cca patients (pts) depends on the initial stage at 

diagnosis. SLNM upstages more pts than conventional surgery (Conv. Surg.) for 

nodal metastasis, this might have an impact on the incidence and pattern of 

recurrence. Hence comparative study was undertaken for recurrence in Cca pts 

undergoing SLNM Vs Conv.Surg. Methods: Group (Gp) A pts underwent SLNM 

with 1% Lymphazurin. The first 1-4 blue nodes were marked as SLNs followed by 

standard oncologic resection. Gp B pts underwent Conv. Surg. Data was 

collected for, TNM staging, Recurrence sites and follow up treatment. Minimum 

follow up of all pts was 12 month, with mean follow up period 44 months for both 

Gps. Results: There were 357 pts in GpA and 466 pts in GpB. For GpA pts, SLNM 

was successful in 99.6% of pts with average (Avg.) SLN was 2.8/pts. Avg. no. of 

LNs in GpA was 15.4/pts vs. 12.8/pt in GpB (p�0.001). For GpA pts, 46% was 

LN �ve vs 34% in GpB . Excluding T0, Tis and M1 pts at diagnosis, recurrence 

was calculated for 313 pts in GpA vs. 314 pts in GpB. An overall recurrence was 

7.9% in GpA vs 22.2% (p�0.001) in GpB with distant mets being most common 

in both Gps. Recurrence of LN �ve and LN –ve pts also were significantly lower 

in GpA vs GpB (Table). The pattern of recurrence between the two Gps is shown 

in the Table. Conclusions: SLNM upstages significantly more pts in Cca than 

conv. surg. Even though pattern of recurrence was similar in both Gps, better 

staging may have resulted in better treatment, reducing the recurrence in SLNM 

Gp. Hence SLNM may be beneficial for Cca surgery. 

Node �ve 

Node -ve 

Gp. A Gp. B 

Gp. A Gp. B 

(SLN) (Conv.) 

(SLN) (Conv.) 

T-Stage 

1A. Incidence of recurrence 

(# 112) (# 112) p°-value T-Stage (# 201) (# 202) p°-value 

T-1 0 1 T-1 0 8 

T-2 1 2 T-2 1 4 

T-3 16 30 T-3 4 14 

T-4 0 6 T-4 3 5 

Total * 17 39 0.008 Total * 8 31 0.0005 

(15%) (34.8%) 

(4%) (15.3%) 

1B. Patterns of recurrence. Gp. A Gp. B 

Local 1 (4%) 5 (7.1%) 

Regional (Reg) 4 (16%) 12 (17%) 

Distant 20 (80%) 53 (76%) 

Total number of recurrences Gp A Gp B 

Local 1 (3%) 5 (6%) 

Reg. lymph node and soft tissue 5 (15%) 16 (20%) 

Liver 13 (35%) 31 (37.3%) 

Lung 11 (30%) 10 (12%) 

Bone 1 (3%) 4 (4.8%) 

Peritoneum 0 (0%) 2 (2.4%) 

* Pts with Tis/T0/M1 disease were excluded (Gp A�41; Gp B� 61); ° Chi-square test. 


Pharmacogenetic profiling for oxaliplatin-based adjuvant chemotherapy 

(CT) benefit in stage II-III colon cancer (CC) patients: A GEMCAD study. 

Presenting Author: Jaime Feliu, Department of Medical Oncology, La Paz 

University Hospital, Madrid, Spain 

Background: Identifying molecular biomarkers for tumour recurrence is 

critical in successfully selecting early-stage CC patients who are more likely 

to benefit from adjuvant CT. We tested whether single nucleotide polymorphisms 

(SNP) within genes involved in biological pathways of interest for 

CC progression and treatment resistance would predict the risk of recurrence 

in stage II-III CC patients treated with oxaliplatin and fluoropyrimidines-based 

adjuvant CT. Methods: Genomic DNA was extracted from 

formalin-fixed paraffin-embedded samples from 202 surgically treated 

high-risk stage II (29.7%) and stage III (70.29%) CC patients receiving 

adjuvant CT (25.24% FOLFOX, 74.75% XELOX) from January 2004 to 

December 2008. Minimum follow-up was 36 months. Genotyping was 

performed for 62 SNPs in 31 genes using the MassARRAY (SEQUENOM) 

technology. Our results were validated in an independent cohort of 177 

stage II-III CC. Results: After a median follow-up of 51.4 months (7-96), 63 

patients (31.18%) had experienced a relapse and 31 (15.34%) had died. 

Three-year disease-free survival (DFS) and overall survival (OS) were 

72.2% (�/-0.032) and 89.1% (�/-0.022), respectively. Multivariate 

analysis showed that the risk of recurrence for patients with the E-selectine 

rs3917412 G�A G/G genotype was higher than for those with any A allele 

genotype [relative risk (RR): 2.02, 95% confidence interval (CI): 1.09- 

3.73, p�0.024]. In haplotype analysis, patients harboring the E-selectine 

rs3917412 G�A G/G and methylentetrahydrofolate reductase (MTHFR) 

rs1801133 C�T T/T haplotype had a higher risk of developing tumor 

recurrence compared to the E-selectine rs3917412 G�A any A and/or 

MTHFR rs1801133 C�T any C haplotype (RR: 3.39, 95% CI, 1.51-7.62, 

p�0.003). The ability to predict recurrence of this combined analysis was 

independently validated in the second cohort (RR: 3.75, 95% CI, 1.32- 

10.68, p�0.013). Conclusions: E-selectine and MTHFR SNPs were found 

to be independent prognostic markers for stage II-III CC patients, suggesting 

that this combined analysis provides additional prognostic information 

to that offered by clinicopathologic variables. 


Effect of perioperative complications on recurrence and survival after 

resection of hepatic colorectal metastases: Analysis of data from a 

randomized controlled trial. Presenting Author: Camilo Correa-Gallego, 


Background: Perioperative outcomes such as blood loss, transfusions and 

morbidity have been associated with cancer specific survival, but this is 

unsupported by prospective data. Methods: Patients were derived from a 

previously reported prospective randomized trial of acute normovolemic 

hemodilution (ANH) versus standard management during major hepatectomy. 

Patients with metastatic colorectal cancer (mCRC) were selected for 

analysis. Chemotherapy and survival data were obtained from the medical 

record. Disease extent was measured using a clinical risk scoring (CRS) 

system. Log-rank test and Cox proportional hazard model were used to 

evaluate recurrence free (RFS) and overall survival (OS). Results: This trial 

enrolled 130 patients, 90 of whom had mCRC. Median follow up was 54 m; 

median age was 53 yr; 56% were men. The CRS was �3 in 55% of 

patients, and 57% had additional extrahepatic procedures. Morbidity and 

mortality were 33% and 3%. Chemotherapy was split before and after 

surgery in 70%; 10% received only preoperative and 19% only postoperative 

treatment, which was initiated after a median time of 6 wks (IQR � 

4-7). RFS and OS were 29 and 59 m. On multivariate analysis, (�) 

resection margin, high CRS and perioperative complications predicted 

shorter RFS and OS. Delayed initiation of postoperative chemotherapy (� 8 

wks) while most common in patients with complications (37 vs 12%; p: 

0.01), was not a significant predictor of shorter RFS or OS. Randomization 

(ANH vs standard) was also not significant in this regard. (See Table.) 

Conclusions: In this prospective randomized cohort, perioperative morbidity 

was a highly significant independent predictor of cancer specific outcome, 

associated with but not entirely explained by delayed initiation of chemotherapy. 

Variables affecting overall (OS) and recurrence free (RFS) survival. 


Multivariate 

months Univariate P P-HR 

CRS (high vs low) 

OS 32 vs 74 0.02 �0.01 – 3 

RFS 21 vs 46 0.03 �0.01 –3 

Margin (� vs -) 

OS 34 vs 71 0.05 0.03 – 0.5 

RFS 29 vs 32 0.2 0.04 – 0.5 

Complications (Y vs N) 

OS 27 vs 75 �0.01 �0.01 – 3.4 

RFS 18 vs 60 �0.01 �0.01 – 3.5 

Delayed chemotherapy (Y vs N) 

OS 30 vs 75 0.06 0.06 – 3 

RFS 29 vs 59 0.1 0.3 



Colorectal cancer characteristics and outcomes in patients less than age 

50: A comparison of an urban university hospital with the NCI SEER 

database. Presenting Author: Edith P. Mitchell, Kimmel Cancer Center at 

Thomas Jefferson University, Philadelphia, PA 

Background: Cancer of the colon and rectum is the third most commonly 

occurring cancer, as well as the third leading cause of cancer deaths in 

American men and women. Colorectal cancer in younger patients is 

believed to have worse pathological features and prognosis than in older 

patients. The objective of this study was to assess pathological features and 

outcomes of CRC in patients less than age 50 using an institutional sample 

and comparing to the Surveillance, Epidemiology and End Results (SEER) 

database. Methods: Included in the study were a total of 4595 cases from 

the Tumor Registry at Thomas Jefferson University Hospital (TJUH) over a 

twenty year period from 1988 through 2007 and 290,338 cases from the 

Surveillance, Epidemiology and End Results (SEER) database from 1988 

through 2004. Patients less than age 50 were compared to those age 50 

and older. Results: Patients under age 50 with CRC presented with more 

advanced stage tumors in both data sets (�0.0001) , and had more poorly 

differentiated tumors than older patients (PTJUH�0.02754; PSEER�0.0001). Patients under 50 also had more mucinous/signet ring 

cell tumors with 12 percent to 8.1 percent in the TJUH data (p�0.002916) 

and 13.2 percent to 10.3 percent in the SEER data (p�0.0001), with 

younger males having the highest prevalence in both data sets. Younger 

patients had fewer proximal tumors than patients 50 and over, and a higher 

proportion of rectal tumors (p�0.001). Patients under age 50 were more 

likely to have positive nodes at all stages (PSEER �0.0001) relative to 50 

and over, as well as more likely to develop peritoneal metastases 

(PTJUH�0.3507),, but less likely to have lung metastases PTJUH�0.05249) than older pts. Despite their poor pathologic features, patients under age 

50 had better than or equal survival to those 50 and older. Conclusions: 

Colorectal cancer patients under age 50 presented with worse histological 

characteristics and metastasized much sooner, yet the younger patients 

had better than or equal survival to those ages 50 and older. Ongoing 

studies will assess differences in treatment and molecular features between 

younger and older colorectal cancer patients. 


Clinicopathologic and molecular associations of PIK3CA and PTEN mutation 

in colorectal cancer. Presenting Author: Fiona Lee Day, Ludwig 

Institute for Cancer Research, Parkville, Melbourne, Australia 

Background: The phosphatidylinositol 3-kinase (PI3K) signaling pathway 

has been implicated in the development of colorectal cancer (CRC), 

however a systematic analysis of pathway members and their association 

with clinical, pathological and other molecular features has been lacking. 

Methods: We determined the prevalence of PIK3CA (exons 9, 20) mutations 

in a large cohort (n�1092) of community-based patients (pts) with stage 

I-IV CRCs. A subset (n�744, 68%) were also tested for mutation in PTEN 

(exons 3,4,5,6,7,8), PTEN LOH and CIMP. All tumors were characterised 

for MSI, KRAS and BRAF mutations, and annotated for clinico-pathologic 

features and patient outcomes in a prospectively-recorded database. 

Detected novel PIK3CA exon-specific correlates were further explored in a 

combined analysis integrating the data of other published cohorts (total 

n�3677). Results: PIK3CA mutations occurred in 11.6% of primary 

tumors and were associated with older pt age (p�0.009), proximal site 

(p�0.001), lower lymphovascular invasion (p�0.018) and KRAS mutation 

(p�0.001), but not with gender, tumor stage or differentiation. Direct 

comparison of PIK3CA exon 9 and 20 mutations in the combined analysis 

(mixed effect logistic regression) finds both at increased frequency in 

KRAS-mutant tumors (p�0.098 for difference); however PIK3CA exon 20 

mutations uniquely correlated with BRAF mutation (p�0.002 for difference), 

MSI (p�0.001) and CIMP-high status (p�0.031). PTEN mutations 

were present in 5.8% of tumors and associated with proximal site 

(p�0.013), mucinous histology (p�0.013), MSI (p�0.001), CIMP-high 

(p�0.001), and BRAF mutation (p�0.001). There was a trend toward 

mutation of both PIK3CA and PTEN and strong selection for two hits to 

PTEN (mut/mut or mut/LOH, p�0.001). In our cohort neither PIK3CA or 

PTEN mutation were associated with pt survival outcomes. Conclusions: In 

CRC, common mutations in the PI3K signaling pathway are universally 

associated with proximal site, however display unique gene- and exonspecific 

associations with tumor histology, MSI, CIMP, KRAS and BRAF 

mutation. These need to be considered when exploring targeted therapeutic 

options for pts with CRC. 


233s 


Novel colon cancer tumor suppressor gene, �-defensin 1, to predict 

recurrence in patients with stage II and III colon cancer. Presenting Author: 

Melissa Janae Labonte, University of Southern California Norris Comprehensive 

Cancer Center, Los Angeles, CA 

Background: Human �-defensin 1 (hBD-1) encoded by the DEFB1 gene is 

an antimicrobial peptide involved in the innate immune response and is 

expressed in epithelial cells, including the colon. hBD-1 has been shown to 

have tumor suppressor functions in urothelial cancer models. We tested 

whether 4 germline single nucleotide polymorphisms (SNPs) in DEFB1 

could predict time to tumor recurrence (TTR) in stage II and III colon 

cancer (CC) patients. We then sought to demonstrate if hBD-1 has tumor 

suppressor functions in CC models. Methods: A total of 234 patients, 105 

stage II and 129 stage III, treated with 5-FU-based chemotherapy at the 

University of Southern California were included. The median follow-up time 

was 4.4 yrs. SNPs were analyzed from whole blood samples using direct 

DNA-sequencing. To gain insight into hBD-1’s function, hBD-1 expression 

in CC cell lines was determined by qRT-PCR and Western blotting. hBD-1 

expression was induced ectopically and CC cells and viability, membrane 

permeability, cell-cycle and apoptosis analyzed. Results: Stage III patients 

with rs1800972 DEFB1 -44G containing genotypes had longer TTR than 

patients with C/C genotype (11.3 mo vs 2.7 mo; p�.008). In contrast in 

stage II, patients with rs1799946 DEFB1 -52A containing genotypes, had 

significantly longer TTR than patients with G/G genotype (16.8 mo vs 5.9 

mo; p�.017). In the multivariate analysis, both DEFB1 -44C/G and DEFB1 

-52G/A SNPs remained significant, respectively in stage III (HR�.419; 

95%CI .201-.87; p�.020) and in stage II (HR�.360; 95%CI .152-.853; 

p�.020). Haplotype of all four SNPs was significantly associated with 

stage-specific TTR (to be presented at the meeting). In CC cell line models, 

there was a loss of hBD-1 expression, and induction of hBD-1 expression 

resulted in a loss of cell viability, membrane permeability and the induction 

of apoptosis. Conclusions: The results demonstrate for the first time 

evidence of hBD-1’s potential influence on the microenvironment and its 

role as a tumor suppressor in CC. Further studies need to be conducted to 

better understand the role of hBD-1 in CC development and progression 

and evaluate the potential utility of hBD-1 as a therapeutic strategy. 


Methylations of NEUROG1, p16, and MLH1 and recurrence following 

adjuvant FOLFOX in colorectal cancer. Presenting Author: Hyun-Jung Lee, 

Department of Internal Medicine, Seoul National University Hospital, 

Seoul, South Korea 

Background: CpG island methylator phenotype (CIMP) is characterized by 

concurrent methylation of multiple CpG islands in tumor DNA, which can 

inactivate tumor suppressor genes or promote carcinogenesis. The prognostic 

impact of CIMP on treatment outcome of colon cancer patients receiving 

adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We 

investigated CIMP markers in colorectal cancer patients treated with 

adjuvant FOLFOX. Methods: Sporadic colorectal cancer patients treated 

with curative resection followed by adjuvant FOLFOX were included. DNA 

was extracted from formalin-fixed paraffin-embedded surgical specimen. 8 

CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, P16, 

RUNX3 and SOCS1) were examined using MethyLight analysis. Diseasefree 

survival (DFS) was evaluated according to each methylation loci. 

Results: A total of 322 patients were included. Methylation at 1 or more loci 

was observed in 150 patients (46.6%) and 6 or more loci in 15 (4.7%). 

During a median follow-up duration of 39.7 months, 55 recurrences were 

observed. Three year DFS in the patient cohort was 84%. CRABP1 (23.9%) 

was the most frequently methylated loci, followed by p16 (22.7%) and 

NEUROG1 (20.8%). Patients having methylation at NEUROG1 (3 year 

DFS 78% in (�) vs. 86% in (-), p � 0.014) and p16 (3 year DFS 78% in 

(�) vs. 86% in (-), p � 0.12) had worse DFS, whereas methylation at MLH1 

had better DFS (3 year DFS 100% in (�) vs. 86% in (-), p � 0.19). In a 

combined analysis, patients with MLH1(-)/NEUROG1(�)/p16(�) had 

worst treatment outcome compared to MLH1(-)/NEUROG1(�) or p16(�), 

MLH1(-)/ NEUROG1(-) /p16(-), and MLH1(�) (3 year DFS 62%, 82%, 

87%, and 100%, respectively; p � 0.002). In multivariate analysis, 

NEUROG1(�)/p16(�) was associated with significantly higher recurrence 

compared with other patients (adjusted hazard ratio (HR) 2.15 (95% 

confidence interval (CI) 1.08 - 4.27, p � 0.029). Conclusions: Methylation 

status of NEUROG1, p16, and MLH1 is associated with recurrence 

following adjuvant FOLFOX in stage II/III colorectal cancer. Further 

validation and translational studies to improve treatment outcome in the 

subset of patients are warranted in the future. 




Impact of “poorly differentiated clusters” in primary lesion as a novel 

prognostic indicator in colorectal liver metastasis. Presenting Author: 

Tsuyoshi Konishi, Gastroenterology Center, Cancer Institute Hospital, 

Tokyo, Japan 

Background: Preoperative predictors for survival are needed in colorectal 

liver metastasis in order to select poor-risk group that truly requires 

perioperative chemotherapy. This study aimed to elucidate survival predictors 

in patients undergoing curative hepatectomy for colorectal liver 

metastasis, particularly focusing on the impact of poorly differentiated 

clusters (PDC); a novel histologic grading system in primary lesion. 

Methods: A total of 424 consecutive patients undergoing curative resection 

of both primary colorectal cancers and metastatic liver lesions at two 

referral centers were enrolled in the study. Determinants of overall survival 

(OS) and recurrence free survival (RFS) after hepatectomy were investigated 

by univariate and multivariate analysis, using detailed clinicopathological 

parameters in primary and metastatic lesions. Cancer clusters of �5 

cancer cells and lacking a gland-like structure were counted under a x20 

objective lens in a field containing the highest number of clusters at 

invasive front of primary lesions, and tumors with �5,5to9,and�10 

clusters were classified as PDC grade (G)1, G2 and G3, respectively (n�65, 

132, and 227 tumors, respectively). Results: OS and RFS at 3 years were 

59% and 27%, respectively, with average follow up period of 43 months. 

PDC grade in primary lesion was strongly associated with both 3-year-OS 

(83%, 62%, and 51%, respectively, p�0.0001) and 3-year-RFS (55%, 

30%, and 17%, respectively, p�0.0001). Multivariate analysis revealed 

that PDC grade in primary lesion was the most potent prognostic factor after 

hepatectomy independent of T and N of primary lesion and size of liver 

metastasis. Conclusions: PDC grade in primary lesion is a novel potent 

prognostic indicator in colorectal liver metastasis, which is independent of 

T and N. It is noteworthy that PDC grade can bias the survival in clinical 

studies targeting perioperative chemotherapy in colorectal liver metastasis. 


Effect of BSA dosing on 5-FU exposure among colorectal cancer patients 

depending on their gender and age. Presenting Author: Abebe Haregewoin, 

Myriad Genetics, Inc., Salt Lake City, UT 

Background: 5-fluorouracil (5-FU) remains the cornerstone of colorectal 

cancer (CRC) therapy and its dosing is based on body surface area (BSA). 

Although convenient, BSA dosing disregards factors that impact 5-FU PK 

such as genotype, age, gender, etc. Thus, patients receiving the same BSA 

based dose show a wide range of 5-FU plasma levels (measured as AUC in 

mg · h/L), resulting in ineffective or toxic doses affecting therapy outcome. 

An optimal therapeutic AUC target range of 20-30 mg · h/L has been 

proposed. Methods: Plasma samples from the initial treatment cycle of 927 

CRC patients who received 2,400 mg/m2 continuous infusion of 5-FU over 

44-48 hours, with or without bevacizumab, were tested for 5-FU exposure 

using an immune-based assay (OnDose). AUC results were analyzed to 

evaluate gender and age effects. Results: There are 391 (42.2%) female 

and 536 (57.8%) male patients with age ranging from 17-93 years 

(mean/SD: 58.5/11.8). See table. These analyses indicate that in comparison 

to the proposed optimal AUC target range of 20-30 mg · h/L, females 

receive supra-optimal doses compared to males (p�0.0083). Age also 

affects the 5-FU AUC (p�0.0002), with younger patients more likely to 

receive suboptimal doses than older patients. Conclusions: BSA dosing is 

an unreliable indicator of exposure and may lead to under dosing in males 

and younger patients, and overdosing in females and older patients, 

potentially resulting in corresponding diminished efficacy or increased 

toxicity. Data suggest that therapy could be optimizedby 5-FU dose 

adjustment in subsequent cycles based on PK monitoring so that AUC 

values will converge towards the target range irrespective of gender or age. 

A large clinical trial is in progress to validate these findings. 

Patient characteristic 

Below 

(8 - 19 mg · h/L) 

AUC target range 

Within 

(20 - 30 mg · h/L) 

Above 

(31 - 60 mg · h/L) 

Gender 

Female 169 (43.2%) 165 (42.2%) 57 (14.6%) 

Male 272 (50.7%) 210 (39.2%) 54 (10.1%) 

Age (years) 

< 45 68 (56.2%) 43 (35.5%) 10 (8.3%) 

46-50 60 (55.1%) 37 (33.9%) 12 (11%) 

51-55 79 (57.7%) 45 (32.8%) 13 (9.5%) 

56-60 66 (46.8%) 58 (41.1%) 17 (12.1%) 

61-65 74 (47.1%) 69 (44%) 14 (8.9%) 

66-70 41 (35.6%) 53 (46.1%) 21 (18.3%) 

> 70 53 (36.1%) 70 (47.6%) 24 (16.3%) 


Effect of the 12-gene colon cancer assay results on treatment recommendations 

in patients with stage II colon cancer. Presenting Author: Thomas H. 

Cartwright, Ocala Oncology, Ocala, FL 

Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has 

been clinically validated as an independent predictor of individual recurrence 

risk in stage II colon cancer patients following surgery. As a result, 

physicians have been ordering the Oncotype DX assay for stage II colon 

cancer patients since January 2010, yet no data exist on the assay’s impact 

on adjuvant treatment planning in clinical practice. We performed a survey 

to characterize the impact of the assay on adjuvant treatment recommendations 

in stage II colon cancer. Methods: U.S. medical oncologists (n�346) 

who ordered Oncotype DX for �3 patients with stage II colon cancer were 

contacted and asked to complete a web-based survey regarding the single 

most recent stage II colon cancer patient for whom the assay was ordered. 

The survey was developed through cognitive interviews with four medical 

oncologists, and the protocol was institutional review board approved. 

Results: We analyzed survey results from 116 eligible physicians. Physicians 

were more often in community (86%) than academic or other 

practices, and had a median of 14.5 years (range, 2-40) of practice 

experience. The median patient age was 62 years (range, 32–85). Most 

patients (81%) had T3 disease. Patients had �8, 9-11 and �12 nodes 

examined 3%, 13% and 84% of the time and 38% had comorbidities. Of 

the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and 

46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20 

(range, 1-77). Before obtaining the RS, chemotherapy was planned in 52 

(45%) patients, observation in 40 (34%), and there was no recommendation 

in 24 (21%). For the 92 patients with pre-assay recommendations, 

recommended treatment changed after obtaining the RS for 27 patients 

(29%). Treatment intensity decreased for 18 (67%) and increased for 9 

(33%) of 27 changed recommendations. A significant trend of decreasing 

treatment intensity with lower RS values was observed (p�.0035). 

Conclusions: These findings indicate that for stage II colon cancer patients, 

treatment recommendations were changed by RS results in 29% of 

patients. Use of the Oncotype DX assay may lead to reductions in treatment 

intensity, contributing to the assay’s cost effectiveness. 


Use of gene set analysis (GSA) for molecular classification of responders 

and nonresponders to FOLFOX therapy in colorectal cancer (CRC). Presenting 

Author: Stephen Yip, British Columbia Cancer Agency, Vancouver, BC, 

Canada 

Background: Folinic acid (FOL) fluorouracil (F) and oxaliplatin (OX) chemotherapy 

is a commonly used therapy for CRC. Lacking in current literature 

are clinically relevant classifiers for potential responders. GSA technique is 

statistical method that detects significance of sets of genes, instead of 

examining a gene-by-gene basis. The objective of this study was to identify 

differential functionally annotated gene expression profiles associated with 

response to FOLFOX therapy in CRC tumors using gene-by-gene and GSA 

approaches. Methods: Genome wide expression profile data were collected 

on pre-treatment tumor tissues from patients with unresectable CRC 

receiving FOLFOX therapy (n � 83, Affymetrix HG U133A, GSE28702, 

Tsuji et al. BJC 2012). Gene expression was compared between responders 

(n � 42) and Non-responders (n � 41). GSA was conducted on 3272 

curated gene sets from the Molecular Signatures Database (Subramanian, 

Tamayo et al. 2005, PNAS 102, 15545-15550) annotated by biological 

pathway, biochemical function and clinical behavior. Significant analysis 

of Microarray (SAM) and GSA (Tibshirani et al.) was done to identify gene 

sets associated with FOLFOX response. Results: Differential expressions of 

23 genes were significantly associated with response, based on a single 

gene approach (p-value � 0.05). 13 of these were located on Chromosome 

17 (p � 0.001). Among these, the top 5 ranked genes included NPEPPS, 

MBTD1, CEP44, LTA4H and CPNE4 which are involved in metal ion 

binding and aminopeptidase activity. GSA revealed only 44 out of 3272 

gene sets were significantly associated with response, with a false discovery 

rate less than 25%. Increased expression of B-lymphocyte differentiation 

and Ras-signalling-related gene sets was associated with responders while 

mTOR signaling and hematopoietic stem cell-related genes set were 

associated with non-responders. Conclusions: Our data showed that differential 

biological pathways could be identified to predict response to 

FOLFOX therapy for CRC patients. Analysis may be useful to help define 

clinically relevant biologic subtypes among patients with metastatic colorectal 

cancer. 



Phase II trial evaluating a 12-week regimen of interdigitating FOLFOX 

chemotherapy plus pelvic chemoradiation for the simultaneous treatment 

of primary and metastatic rectal cancer. Presenting Author: Michael 

Michael, Peter MacCallum Cancer Centre, Melbourne, Australia 

Background: Current chemotherapy regimens used during chemoradiation 

(CRT) are adequate for radiosensitization but suboptimal for systemic 

control. The aim of this study was to assess tolerability, and local/systemic 

benefits of new regimen delivering intensive chemotherapy and radical 

radiotherapy in an interdigitating manner. Methods: Phase II prospective 

study for patients (pts) with untreated simultaneous symptomatic primary 

and metastatic rectal cancer. The treatment regimen: 12 weeks long. 

FOLFOX chemotherapy (oxaliplatin 100mg/m2, leucovorin 200mg/m2, 

5-FU 400mg/m2 bolus, all day 1, and 5FU continuous infusion [CI] 2.4 

g/m2/46 hours) was given in weeks 1, 6, and 11. Pelvic CRT: 25.2 Gy in 3 

weeks, 1.8 Gy/fr, with concurrent oxaliplatin 85mg/m2 day 1 and 5-FU CI 

200mg/m2/day given in weeks 3-5, and 8-10. Pts received, in 12 weeks, 3 

courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin/ 

5-FU. All pt were staged with CT, MRI and FDG-PET before and posttreatment. 

Results: 26 pts treated. The mean age was 61 years, 69% male. 

Rectal primary MRI stage was T2 4%, T3 81% and T4 15%. Liver and lung 

metastases were present in 81%, and 35% of pts, respectively: 38% of 

patients had more than one site of metastatic disease. 24 pts (92%) 

completed the 12-week treatment regimen. All pts received the planned 

radiation dose. 65% of pts received the planned number of oxaliplatin 

courses with 88% of pts receiving at least 75% of the protocol oxaliplatin 

dose. In this 12-week period, grade 3 toxicities were neutropenia 23%, 

diarrhoea 15%, and radiation perineal skin reaction 12%. Only grade 4 

toxicity was neutropenia: 15%. PET metabolic response (CR�PR) rate for 

rectal primary was 96%. Overall PET metabolic response rate for metastatic 

disease was 60% (CR rate 16%). Conclusions: It is thus feasible to 

deliver intensive chemotherapy and radical radiotherapy in an interdigitating 

manner to treat both primary and metastatic rectal cancer simultaneously. 

High completion and response rates are encouraging. This regimen is 

the subject of a current phase II neoadjuvant trial for resectable rectal 

cancer (TROG 09.01). 


A phase I dose-escalation study of TAS-102 in patients (pts) with refractory 

metastatic colorectal cancer (mCRC). Presenting Author: Manish Patel, 

Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL 

Background: TAS-102 is an oral combination of a novel antimetabolite 

5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) 

that prevents degradation of FTD. In preclinical studies, TAS-102 is 

effective against human colorectal tumors with innate and acquired 

resistance to 5FU. A Japanese randomized phase 2 study demonstrated a 

significant survival improvement of TAS-102 over placebo in refractory 

mCRC (HR�0.56 p�0.0011, EMCC2011). The present study was conducted 

to determine the MTD of TAS-102 in Western pts with refractory 

mCRC. Methods: Pts with mCRC who had received at least 2 lines of 

chemotherapy including a fluoropyrimidine, irinotecan and oxaliplatin were 

enrolled at an initial dose level of 30 mg/m2 BID days 1- 5 and days 8-12 

every 4wks using a standard 3�3 design. A second dose level of 35 mg/m2 , 

which was the MTD for Japanese pts, was the maximal targeted dose in this 

study. Results: 12 pts received TAS-102 (30/35 mg/m2�3/9, M/F�7/5, 

Age 44-75, PS0/1�8/4). Pts received a median of 3 prior regimens for 

metastatic disease. No DLT was observed in the initial dose level (0/3) and 

one DLT (grade 3 febrile neutropenia) was observed at 35mg/m2 (1/9). 

Other drug-related � grade 3 toxicities observed in cycle 1 included 

neutropenia at 58% (7/12). To date, a median number of treatment cycles 

at the MTD has not been reached as 5 pts are still receiving therapy (range 

1-3� cycles). Conclusions: Western patients with refractory mCRC showed 

the same MTD as Japanese pts (35 mg/m2 BID, days 1- 5 and days 8-12 

every 4wks) and the safety profile was consistent between the populations. 

The trial has entered an expansion phase to assess further safety and 

preliminary efficacy. A phase 3 trial is being planned. 


235s 


Evaluation of the prognostic utility of miRNA and multiple genetic markers 

in stage IIA colon cancer. Presenting Author: Elizabeth Mambo, Asuragen 

Inc., Austin, TX 

Background: The variable prognoses of stage II colon cancer subjects have 

provoked a therapeutic dilemma of who should receive adjuvant therapy. 

Presently, prognosis is evaluated on often subjective histopathological 

features. Reliable, objective markers that can accurately predict recurrence 

risk are needed. Using retrospectively collected tumor samples with known 

clinical outcome, we evaluated the prognostic utility of miRNA together 

with clinicopathological features and molecular markers with suggestive 

prognostic value. Methods: We evaluated the expression of miRNA in 118 

stage IIA FFPE tumors (73 non-recurrent, NR; 45 recurrent, R) using the 

Affymetrix Gene Chip V1.0 microarray, and performed RT-qPCR to verify 

select miRNAs. We also sequenced KRAS codons 12/13, and BRAF codon 

600, and assessed MSI status using a fluorescent PCR-based assay. MMR 

protein expression was determined by IHC. An empirical approach was 

applied to screen miRNA using combinatorial criteria of microarray 2-way 

ANOVA analysis, Kaplan-Meier curve logrank, and single and multivariate 

Cox-regression. miRNA was the most significant predictor among all 

histopathological and molecular features (FDR�0.05). A miRNA classifier 

was built with nested two-layer cross-validation. Results: The top miRNA 

model was selected based on AUC estimates and Cox-regression p-value. 

This model included 30 miRNAs; 25 of these were common with the 

empirical approach, confirming the robustness of candidate selection. The 

miRNA classifier distinguished R from NR cases with an AUC of ~0.74. 

Among all histopathological and molecular features evaluated, grade was 

significantly associated with disease-free survival (logrank p�0.05). Both 

single variate and multivariate Cox analysis revealed that grade and PMS2 

status were strongly associated with recurrence (p�0.05). Lastly, lack of 

expression of PMS2 and MLH1, BRAF V600E and MSI was highly 

correlated (� coefficient � 0.6), and associated with non-recurrent 

disease. Conclusions: These data provide strong support for miRNAs as 

independent prognostic biomarkers for stage IIA colon cancer.Validation 

work is ongoing to demonstrate the potential utility of these miRNAs in 

patient stratification. 


Surgical resection and peri-operative chemotherapy for colorectal cancer 

(CRC) liver metastases in routine clinical practice: A population-based 

outcomes study. Presenting Author: Christopher M. Booth, Queen’s University 

Cancer Research Institute, Kingston, ON, Canada 

Background: Resection of liver metastases combined with peri-operative 

chemotherapy is an important treatment option for patients with advanced 

CRC. Most of the literature describes outcomes achieved in highly selected 

patients treated at a few high volume institutions. Here we report the 

results of a population-based study of the management and outcome of all 

patients who underwent resection of CRC liver metastases in Ontario, 

Canada. Methods: All cases of CRC in Ontario who underwent surgical 

resection of liver metastases in 1994-2009 were identified using the 

population-based Ontario Cancer Registry (OCR). The OCR captures 

diagnostic and demographic information on ~98% of all incident cancer 

cases in Ontario. We linked electronic records of treatment to the OCR to 

identify surgery, neoadjuvant (NACT) and adjuvant chemotherapy (ACT). 

We describe time trends in treatment and survival using 3 study periods: 

1994-1999, 2000-2004, 2005-2009. Results: During 1994-2009, 2717 

patients underwent resection of CRC liver metastases in Ontario; mean age 

was 65 years and 61% were male. From 1994-2009 there was a 103% 

increase in the number of patients undergoing resection of liver metastases 

(117/year to 237/year) while incident cases of CRC during this time 

increased by 31% (5285/year to 6956/year). Use of NACT increased over 

the study period: 94-99, 11% (78/700); 00-04, 15% (124/830); 05-09, 

36%; (424/1187), (p�0.001). Use of ACT also increased: 94-99, 38% 

(263/700); 00-04, 40% (335/830); 05-09, 45% (532/1187), (p�0.006). 

In 2005-2009 there was substantial variation across geographic regions in 

use of NACT (range 19% to 46%, p�0.029) and ACT (range 31% to 56%, 

p�0.015). Five year overall survival during the 3 study periods was 36% 

(95%CI 32-39%), 40% (95%CI 36-43%), and 47% (95%CI 43-51%) 

(p�0.001). Conclusions: Resection of CRC liver metastases in routine 

practice in the general population of Ontario is associated with survival 

outcomes that are comparable to those reported in case series from leading 

comprehensive cancer centres. Survival improved over the study period 

despite a greater proportion of patients with CRC undergoing liver resection. 




Triplet chemotherapy (TC) with FOLFIRINOX regimen in metastatic colorectal 

cancer (mCRC): Experience of the Val d’Aurelle Center. Presenting 

Author: Emmanuelle Samalin, Digestive Oncology CRLC Val d’Aurelle, 

Montpellier, France 

Background: TC is a treatment option for mCRC to improve the tumor 

response rate in selected patients (pts) and the conversion rate of initially 

non-resectable liver metastases. The aim of this study was to evaluate the 

impact and feasibility of FOLFIRINOX regimen in mCRC pts. Methods: All 

mCRC pts with non-resectable disease who have received FOLFIRINOX 

alone or combined with targeted therapies (bevacizumab or cetuximab) 

from October 2000 to December 2010 were selected for this analysis. 

Clinical data were collected in a mCRC specific data base and analyzed by 

the end of 2011. Results: Ninety two pts (52% of men), median age 59 yrs 

(range: 27-76) were treated with FOLFIRINOX (D1 oxaliplatin 85 mg/m² IV 

2H then irinotecan 180 mg/m² IV 90 min and elvorin 200 mg/m², then 5FU 

200 mg/m² and 2400 mg/m² by 46H infusion, D1�D15) alone (64%) or 

combined with cetuximab(30%) or bevacizumab (6%), as 1st-line in 82 pts 

(89%). Prophyllactic G-CSF was given in 58% of them. Primary tumor was 

located in colon (58%) or rectum (42%), and 64 (69%) of pts presented 

with synchronous metastases: liver 100%, lung 40%, peritoneum 17% and 

nodes 17%. Median number of cures was 8 (range: 1-12). There was 1 

toxic death. Grade 3-4 toxicities were: diarrhea 22%, neuropathy 21%, 

cutaneous 12%, neutropenia 28%, febrile neutropenia 0%, thrombopenia 

6%. Objective Response rate according to RECIST criteria was 72% 

[CI95% 61-81] including 10 pts with complete response (11%). The 

primary tumor was resected in 70 pts (76%) and 14% had KRAS mutated 

tumor. Among the pts with liver metastases, 63 (68%) pts were evaluated 

for secondary resectability by a multidisciplinary committee and 40 pts 

(43%) had resection achieved (70% R0). Median overall survival was 49 

months [CI95%28-62]. Conclusions: These results confirm the feasibility 

of FOLFIRINOX regimen with or without targeted therapies and its efficacy 

in terms of response rate and overall survival as 1rst-line treatment in 

selected mCRC pts. 

TPS3635^ General Poster Session (Board #38H), Mon, 8:00 AM-12:00 PM 

MAVERICC: A randomized phase II study of mFOLFOX6-bevacizumab (BV) 

versus FOLFIRI-BV with prospective biomarker stratification in previously 

untreated metastatic colorectal cancer (mCRC). Presenting Author: Sachdev 

P. Thomas, Illinois Cancer Care, Peoria, IL 

Background: The identification of prognostic and predictive biomarkers 

could significantly improve the risk-benefit ratio and cost-effectiveness of 

1st-line mCRC regimens. This is the first prospective study of tumoral 

ERCC1 (chemo-resistance marker to platinum compounds) and plasma 

VEGF-A as potential biomarkers for oxaliplatin- and BV-containing regimens, 

respectively, in an effort to further define the optimal chemotherapy 

backbone with biologic therapies, including BV, for mCRC. Methods: In this 

randomized, open-label, global, phase II study, patients (N�360) with 

histologically or cytologically confirmed CRC and �1 measurable metastatic 

lesion are stratified at screening by tumoral ERCC1 mRNA expression 

(high vs low, cutoff of 1.7 [ERCC1/�-actin mRNA]). Eligibility criteria 

include completion of adjuvant therapy �12 months before screening and 

an ECOG performance status �1. Blood samples are collected to quantify 

plasma VEGF-A levels. Patients within each ERCC1 stratification group are 

randomized 1:1 to mFOLFOX6-BV or FOLFIRI-BV administered in 2-week 

cycles. BV will be given at a dose of 5 mg/kg IV q2w. Patients will remain on 

study treatment until disease progression (PD) or unacceptable toxicity. If 

oxaliplatin or irinotecan need to be discontinued, BV and 5-fluorouracil or 

capecitabine are to be continued until PD. The primary objectives are: 1) to 

assess ERCC1 and VEGF-A as biomarkers of progression-free survival (PFS) 

for oxaliplatin- and BV-containing regimens in 1st-line mCRC, and 2) 

within ERCC1 high patients, to test whether FOLFIRI-BV is associated with 

a prolonged 1st-line PFS compared to mFOLFOX6-BV. Secondary objectives 

include assessing the impact of these markers on overall survival, 

objective response, hepatic metastases resection, and safety. Exploratory 

endpoints include correlative analyses with additional tumor tissue, blood, 

and SNP markers. The first patient was enrolled in August 2011. An 

interim biomarker distribution assessment of the first 100 patients is 

planned, and the evaluation of the primary endpoints is estimated for early 

2015. Clinicaltrials.gov: NCT01374425. 


A randomized, double-blind, phase (Ph) III study of the irinotecan-based 

chemotherapy FOLFIRI plus ramucirumab (RAM) or placebo (PL) in 

patients (pts) with metastatic colorectal carcinoma (mCRC) progressive 

during or following first-line therapy with bevacizumab (BEV), oxaliplatin 

(OXALI), and a fluoropyrimidine (FP) (RAISE) (NCT01183780). Presenting 

Author: Axel Grothey, Mayo Clinic College of Medicine, Rochester, MN 

Background: Vascular endothelial growth factor (VEGF) and the VEGF 

receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. 

RAM is a fully human IgG1 monoclonal antibody that inhibits binding of 

VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. 

In a preclinical study, antiangiogenic and antitumor effects were observed 

when DC101, an antibody that targets murine VEGFR-2, was administered 

to mice bearing human colon cancer xenografts. Antitumor activity for RAM 

has been demonstrated in a Ph I study in pts with solid tumors over a wide 

range of RAM dose levels and in a Ph II study with RAM � mFOLFOX-6 as 

1st-line therapy in pts with mCRC. Methods: This ongoing, randomized, 

double-blind, placebo-controlled Ph III study includes mCRC pts with 

measurable or nonmeasurable disease and ECOG performance status of 

0-1 who have experienced disease progression during or within 6 months 

following 1st-line therapy with BEV, OXALI, and any FP. Randomization is 

stratified by geographic region, KRAS status, and time to progression after 

initiation of 1st-line therapy. Pts are randomized 1:1 to either RAM 8 mg/kg 

or PL every 14 days. Pts in both arms receive FOLFIRI (irinotecan: 180 

mg/m2 , folinic acid: 400 mg/m2 , 5-fluorouracil: 400 mg/m2 bolus followed 

by 2400 mg/m2 continuous infusion over 46-48 hours). The primary 

endpoint is overall survival (OS). The sample-size estimate assumes 85% 

power to detect at least a 2.5-month median OS difference (HR � 0.8) 

between treatment arms with a 1-sided alpha of 0.025. Secondary 

endpoints include progression-free survival, tumor response, safety, pharmacokinetics, 

immunogenicity, and correlations between biomarkers and 

clinical outcome. CRC tissue and blood collection is mandatory for 

biomarker analyses. As of 05 January 2012, 238 of 1050 planned pts have 

been enrolled from 100 sites in North America, South America, Europe, 

Asia, and Australia. 


TRICC-c: BIBF 1120 versus placebo in patients receiving oxaliplatin plus 

fluorouracil and leucovorin (mFOLFOX6) for advanced, chemorefractory 

metastatic colorectal cancer (mCRC)—A multicenter, randomized phase II 

trial in progress. Presenting Author: Andreas Berger, Department of 

Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle, 

Germany 

Background: Colorectal cancer (CRC) is the second leading cause of 

cancer-related death in western countries. With advances in the treatment 

of metastatic CRC (mCRC) in the last decade using combination chemotherapy 

and bevacizumab, a monoclonal antibody against the vascular 

endothelial growth factor (VEGF), progression free survival (PFS) in first 

and second line setting was substantially improved. Tumour angiogenesis 

is also driven by other factors but VEGF including Platelet Derived Growth 

Factor (PDGF) and Fibroblast Growth Factor (FGF). BIBF1120 is a potent, 

orally available triple angiokinase inhibitor that blocks the receptor tyrosine 

kinase activity of human VEGFR1-3, FGFR1 and -3 and PDGFR� and -�. 

Thus, BIBF1120 could be an exciting addition to the treatment of patients 

with chemorefractory CRC. Methods: Randomized, double-blind, placebocontrolled, 

multicentre, phase II trial of BIBF1120 (orally, 200 mg, bid, 

d1-d14, Arm A) vs. placebo (Arm B) in patients receiving mFOLFOX6 

(oxaliplatin, 85 mg/m2 , fluorouracil, 400 mg/m2 bolus and 2400 mg/m2 over 46 h, leucovorin, 200 mg/m2 ) q14 d for patients (ECOG performance 

status 0-1) with chemorefractory mCRC who received one prior line of 

chemotherapy. Scheduled are 90 patients per treatment arm. Primary 

endpoint: PFS, Secondary endpoints: objective response, overall survival, 

duration of overall response, safety. Additionally there will be an explorative 

analysis of predictive biomarkers for BIBF1120. 4 of planned 180 patients 

have been enrolled. We expect the last patient out in June 2013. (Trial 

identifier: NCT01362361.) 



The GAIN-C study (BP25438): Randomized phase II trial of RG7160 

(GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI 

alone in second-line KRAS wild type (WT) or mutant metastatic colorectal 

cancer (mCRC). Presenting Author: Andres Cervantes-Ruiperez, Department 

of Hematology and Medical Oncology, INCLIVA, University of Valencia, 

Valencia, Spain 

Background: GA201 is a novel, dual-acting, humanized, glycoengineered 

IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent 

cellular cytotoxicity (ADCC) activity in combination with signal inhibition. 

GA201 demonstrates significantly enhanced in vitro/vivo activity compared 

to cetuximab (cet) both as a single agent and in combination with 

irinotecan, in both KRAS mutant and BRAF mutant models and promising 

clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) 

including KRAS mutant mCRC. A randomized ph II program was launched: 

one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is 

presented here. Methods: Main inclusion criteria are progression on 1L 

containing oxaliplatin, ECOG 0-1, and adequate hematological and liver 

function. Main exclusion criteria: prior anti-EGFR treatment. A total of 160 

patients in 2L mCRC (stratified for EGFR expression, disease progression 

before or after 6 months after starting 1L, prior treatment with bevacizumab 

Y vs N) will be randomized to receive either GA201 (day 1, 8 of cycle 

1 then q2W) or cet (qW) � FOLFIRI q2W (KRAS WT) or to receive GA201� 

FOLFIRI or FOLFIRI alone (KRAS mutant). Collection of archival tumor 

plus a mandatory fresh tumor biopsy at baseline were implemented 

because ph I data showed that EGFR expression is not concordant between 

the two specimen types and to optimize assessment of potential immune 

related biomarkers. The fresh tumor biopsy will be centrally analyzed for 

EGFR (immunohistochemistry) and KRAS status. Primary objective is 

progression free survival; secondary endpoints are to define objective 

response rates, the safety profile, pharmacokinetics and pharmacodynamics. 

A comprehensive biomarker program (blood and tumor), mainly 

immune-phenotyping, immunohistochemistry in tumor samples (Ventana) 

and immune functional tests (including adaptive responses) were set up to 

investigate potential predictive biomarkers and the mode of action of 

GA201. Study is ongoing worldwide in 9 countries with the safety run-in 

phase completed in Nov 2011. Recruitment is planned to be completed by 

end of April 2012. 


Sequential first-line treatment for metastatic colorectal cancer with capecitabine, 

irinotecan, and bevacizumab: Capecitabine plus bevacizumab 

(Cape-Bev) versus capecitabine, irinotecan plus bevacizumab (CAPIRI- 

Bev): The AIO KRK 0110/ML22011 randomized, phase III trial. Presenting 

Author: Clemens Albrecht Giessen, Department of Hematology and Oncology, 

Klinikum Grosshadern and Comprehensive Cancer Center, LMU 

Munich, Munich, Germany 

Background: Several randomized trials have indicated that combination 

chemotherapy applied in metastatic colorectal cancer (mCRC) does not 

significantly improve overall survival when compared to the sequential use 

of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present 

study investigates the question in bevacizumab-based first-line treatment 

including escalation- and de-escalation strategies. Methods: The AIO KRK 

0110/ML22011 trial (ClinicalTrials.gov NCT01249638) is a two-arm, 

multicenter, open-label randomized phase III trial comparing the efficacy 

and safety of Cape-Bev versus CAPIRI-Bev in the first-line treatment of 

metastatic colorectal cancer. Patients with unresectable metastatic colorectal 

cancer, ECOG PS 0-1, will be assigned in a 1:1 ratio to receive either 

capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5 

mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14), 

irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). 

Patients included into this trial are required to consent to the analysis of 

tumor tissue and blood for translational investigations. In Arm A, treatment 

escalation from Cape-Bev to CAPIRI-Bev is recommended in case of 

progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to 

Cape-Bev is possible after 6 months of treatment or in case of irinotecanassociated 

toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The 

primary endpoint is time to failure of strategy (TFS). Secondary endpoints 

are ORR, OS, PFS, safety and quality of life. Conclusion: The AIO KRK 

0110 trial is designed for patients with disseminated, but asymptomatic 

mCRC who are not potential candidates for surgical resection of metastasis. 

Two bevacizumab-based strategies are compared: one starting as singleagent 

chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and 

another starting with CAPIRI-Bev and allowing de-escalation to Cape-Bev 

and subsequent re-escalation if necessary. By January 2012, 79 of 

planned 516 patients have been enrolled. 


237s 


A pilot trial of a combination of therapeutic vaccines (GI-4000 and 

GI-6207) as adjunctive therapy with first-line therapy with bevacizumab 

plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed 

Ras-mutant positive or negative metastatic colorectal cancer. Presenting 

Author: John Marshall, Lombardi Comprehensive Cancer Center, Georgetown 

University, Washington, DC 

Background: A promising approach for the treatment of cancer is the 

development of vaccines that target specific tumor antigens. In the 

metastatic CRC patient population, targeted and active immunotherapy 

may inhibit cancer progression and improve survival. This trial is designed 

to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus 

standard therapy in patients with metastatic colorectal cancer. GI-4000 is 

a proprietary immunotherapy that uses whole, heat-killed recombinant 

Saccharomyces cerevisiae yeast (called Tarmogens � Targeted Molecular 

Immunogens). GI-4000 is designed to activate a cellular immune response 

to target cells with activating ras mutations. Tarmogens have been shown to 

elicit selective killing of target cells that express a number of cancer 

antigens, including mutated Ras, by activation of antigenspecific T cell 

mediated responses. Methods: The study population consists of subjects 

with metastatic colorectal cancer with an activating mutation in ras. Newly 

diagnosed subjects receive FOLFOX (or FOLFIRI) � bevacizumab (Bev) � 

GI- 4000; 3 weekly injections of GI-4000 are followed by 8 cycles of Bev � 

FOLFOX (or FOLFIRI); day 1 and 2 every 14 days. Doses of GI-4000 are 

administered on day 8 of each cycle. Upon completion of chemotherapy, 

GI-4000 continues along with Bev maintenance every 2 weeks for up to 5 

years or until subjects experience intolerance, disease recurrence, or death. 

If Bev is stopped, GI-4000 may continue on the same maintenance 

schedule alone. Subjects that have already completed standard chemotherapy 

(FOLFOX or FOLFIRI) may enter the study and receive Bev � 

GI-4000 every 2 weeks for up to 5 years. Enrollment is ongoing and will 

continue up to 52 subjects. 


A randomized, phase II, multicenter, double-blind, placebo-controlled 

study evaluating onartuzumab (MetMAb) in combination with mFOLFOX6 

plus bevacizumab in patients with metastatic colorectal cancer. Presenting 

Author: Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, 

TN 

Background: Dysregulation of the HGF/Met (Met) pathway has been linked 

with poor prognosis in colorectal cancer. Crosstalk between the Met and 

vascular endothelial growth factor (VEGF) pathways may be important 

during tumorigenesis. Aberrant activation of the HGF/Met pathway may 

promote angiogenesis via tumor cell secretion of angiogenic factors or 

directly activating endothelial cells. Onartuzumab (MetMAb) is a monovalent, 

monoclonal antibody that specifically binds to the Met receptor. The 

combination of onartuzumab and VEGF inhibition in preclinical models 

resulted in enhanced antitumor activity over either treatment alone. 

Preclinical efficacy data support the combination of onartuzumab with 

platinum agents. In phase I studies, onartuzumab has been generally well 

tolerated alone and in combination with bevacizumab. Adverse events most 

commonly associated with onartuzumab are peripheral edema and fatigue. 

Methods: This is a randomized, two-arm, phase II study in patients with 

previously untreated metastatic colorectal cancer. Patients (n�188) will 

be randomized (1:1) to either mFOLFOX6/bevacizumab/placebo or mFOL- 

FOX6/bevacizumab/onartuzumab. Oxaliplatin will be discontinued after 8 

cycles with remaining drugs continued until progression. The primary 

endpoint of this study is PFS in all patients. PFS by Met IHC diagnostic 

status (Met positive vs Met negative) will also be analyzed. Secondary 

endpoints include OS, ORR, safety, and biomarker analyses. Primary and 

secondary analyses will include all randomized patients and will be 

conducted according to assigned treatment arm. Kaplan–Meier methodology 

will be used to estimate median PFS for each treatment arm. An 

estimate of HR with 95% CI will be determined using a Cox regression 

model. Safety will be assessed in all patients receiving at least one dose of 

any treatment. This study is open for accrual; further details can be found 

on ClinicalTrials.gov (NCT01418222). 



TPS3641^ General Poster Session (Board #39F), Mon, 8:00 AM-12:00 PM 

A randomized, double-blind, placebo-controlled, multicenter, multinational, 

phase II trial of L-BLP25 in patients with colorectal carcinoma 

following R0/R1 hepatic metastasectomy. Presenting Author: Carl Christoph 

Schimanski, University of Mainz, Mainz, Germany 

Background: Approximately 15-20% of patients diagnosed with colorectal 

cancer (crc) develop metastatic disease. Surgical resection remains the 

only potentially curative treatment. 5-year survival following R0-resection 

of liver metastases lies ~28 -39%. Recurrence occurs in ~70% of pts. 

Adjuvant chemotherapy has not significantly improved clinical outcomes. 

The primary objective of the LICC trial (L-BLP25 in Colorectal Cancer) is to 

analyze whether L-BLP25, an active cancer immunotherapy, extends 

recurrence-free survival (RFS) time over placebo in colorectal cancer pts 

following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 

glycoprotein, which is highly expressed in hepatic metastases from crc. In a 

phase IIB trial, L-BLP25 showed acceptable tolerability and a trend toward 

longer survival in pts with stage IIIB NSCLC. Methods: This is a multinational, 

phase II, multicenter, randomized, double-blind, placebo-controlled 

trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must 

have stage IV cr adenocarcinoma limited to liver metastases. Following 

complete resection of the primary tumor and all syn-/metachronous 

metastases, eligible pts are randomized 2:1 to receive either L-BLP25 or 

placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary 

treatment with sc L-BLP25 930 �g once weekly for 8 weeks, followed by 

maintenance doses at 6-week (years 1 and 2) and 12-week (year 3) 

intervals until recurrence. In the control arm, CP is replaced by saline 

solution and L-BLP25 by placebo. Primary endpoint: RFS time. Secondary 

endpoints: OS time, safety status, tolerability, RFS/OS in MUC-1 positive 

cancers. Exploratory immune response analyses are planned. First recruitment 

was of Q3 2011. To date, 8 of 20 centers are initiated and 4 pts 

recruited. Completion of recruitment is scheduled for Q3 2013. Primary 

endpoint will be assessed in Q3 2016: Follow-up will end Q3 2017. No 

interim analysis is planned. Design and implementation of this vaccination 

study in colorectal cancer is feasible. No major issues identified during 

setup of the study. 


ATTACHE: A phase III, multicenter, randomized comparison of chemotherapy 

given prior to and post surgical resection versus chemotherapy 

given post surgical resection for hepatic metastases from colorectal cancer. 

Presenting Author: Jonathan Fawcett, Queensland Liver Transplant Service, 

Brisbane, Australia 

Background: No randomized studies have directly compared the role of 

peri-operative to adjuvant chemotherapy for resectable liver metastases. 

Benefit from post operative compared to peri-operative treatment has been 

suggested in a recent retrospective study of 499 patients with resected 

colorectal liver metastases which showed improved survival with entirely 

post-operative chemotherapy. Given this data and that of the small 

randomised trials demonstrating improved surgical outcomes with adjuvant 

chemotherapy, the role of entirely post-operative chemotherapy as a means 

of improving outcomes while reducing the negative effects of pre-operative 

treatment needs to be examined. Methods: 200 patients randomized 1:1 to 

6 months of treatment post-operatively or 3 months of treatment preoperatively 

and 3 months post-operatively. Site investigators will nominate 

chemotherapy schedule (mFOLFOX6, XELOX or FOLFIRI when adjuvant 

oxaliplatin received previously) prior to randomisation. Primary endpoint: 

proportion of patients in each arm with surgical complications within 30 

days. Secondary endpoints: proportion of patients completing planned 

chemotherapy, post operative mortality rate (in each group), tolerability 

and safety of treatment, response rate by RECIST V1.1 and CEA, time to 

progression, time to treatment failure, overall survival, QoL (EORTC 

QLQ-C30 and QLQ-LMC21). A planned prospective meta-analysis with 

MRC (UK) and NSABP C-11 trials will have sufficient power to examine the 

effect of schedule (peri- or post-operative) on progression free survival 

(PFS). Eligibility: Patients with histologically proven colorectal cancer with 

radiologically confirmed, resectable liver metastases without evidence of 

extra-hepatic disease are eligible. Patients with synchronous metastases 

who have undergone resection of the primary tumour are eligible but 

patients requiring combined resection of primary cancer and liver metastatic 

disease are excluded. Patients with involved hilar nodes or wound 

implant metastases will not be eligible. Trial Status: Study opened to 

accrual August 2011. 


FOLFIRI plus 5 mg/kg of bevacizumab versus 10 mg/kg as second-line 

therapy in patients with metastatic colorectal cancer who have failed 

first-line bevacizumab plus oxaliplatin-based therapy: A randomized phase 

III study (EAGLE Study). Presenting Author: Masato Nakamura, Aizawa 

Hospital, Matsumoto, Japan 

Background: There has been much controversy about continuation of 

bevacizumab (BV) with a second-line regimen after progression on a 

BV-containing first-line regimen. Recently, it was announced that a phase 

III study (AIO 0504 / ML 18147) met its primary endpoint of overall 

survival. It means BV-based regimen (5 mg/kg) extends survival when 

continued beyond initial treatment in patients with metastatic colorectal 

cancer(mCRC). The verified data from a randomized phase III study 

(E3200) indicates that BV at 10 mg/kg in the second-line setting followed 

by BV-naive treatment extends survival. The dose of BV 5 mg/kg could be 

lower than the recommended dose in the second-line CRC treatment. Thus 

we planned this second line phase III study (EAGLE study) to evaluate the 

appropriate dose of BV (5 or 10 mg/kg) with FOLFIRI in patients with mCRC 

who have failed BV plus oxaliplatin-based first line regimen. Methods: 

EAGLE is a multicenter randomized phase III study of FOLFIRI plus BV 5 

mg/kg versus 10 mg/kg in mCRC who have failed BV plus oxaliplatin-based 

first line regimen (UMIN000002557).The primary endpoint is PFS. The 

secondary endpoints are the toxicity, response rate, time to treatment 

failure, OS. Eligible patients were older than 20 years of age, had 

histologically proved CRC, ECOG performance status 0 or 1, adequate 

organ function, progression or difficult to continue after BV plus oxaliplatinbased 

first line regimen, more than four times administration of BV and 

oxaliplatin in the first-line. Patients were randomized 1:1 to FOLFIRI with 

BV 5mg/kg or 10 mg/kg.The planned sample size was 370 patients to 

detect 30% risk reduction (median PFS assumed to be 5.0 months in arm 

A, 7.0 months in arm B) with 90% power assuming a two-sided significance 

level of 0.05, an accrual time of 2.5 years and a follow-up time of 1 

year. Between September 2009 to January 2012, 387 patients were 

enrolled at 100 sites in Japan. This phase III study will answer the question 

of the appropriate dose of BV after progression on a BV-containing first-line 

regimen. 


LBA4000 Oral Abstract Session, Sat, 3:00 PM-6:00 PM 

A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine 

(EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). 

Presenting Author: Tom Samuel Waddell, Royal Marsden Hospital NHS 

Foundation Trust, London, United Kingdom 








Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel 

(wPTX) for advanced gastric cancer (AGC) refractory to combination 

chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 

trial. Presenting Author: Shinya Ueda, Kinki University School of Medicine, 

Osakasayama, Japan 

Background: A combination CT of FP has been regarded as the standard 

first-line treatment for AGC. Although two randomized trials showed a 

survival benefit of second-line CT (CPT-11 or docetaxel) compared with 

best supportive care, no standard regimen has been established. In Japan, 

wPTX has been used more frequently than docetaxel as the second-line CT. 

The objective of this study was to compare CPT-11 with wPTX in patients 

(pts) with AGC refractory to FP. Methods: Patients with AGC refractory to the 

first-line FP regimen were randomized 1:1 to either CPT-11 (150 mg/m2 , 

q2w) or wPTX (80 mg/m2 , days 1, 8, 15, q4w). The primary endpoint was 

overall survival (OS) and secondary endpoints were progression-free survival 

(PFS), overall response rate (ORR), adverse events and receiving rates 

of third-line CT. To demonstrate an increase in median OS from 5 months 

(wPTX) to 7.5 months (CPT-11) with 2-sided alpha 5% and 80% power, 

220 pts were required. Results: Between Aug 2007 and Aug 2010, 223 pts 

were enrolled; 112 pts were randomized to CPT-11 and 111 pts to wPTX. 

Baseline characteristics were well balanced between arms. Median OS was 

8.4 months for CPT-11 and 9.5 months for wPTX (HR 1.132; 95% CI, 

0.86-1.49; p�0.38). Median PFS was 2.3 months for CPT-11 and 3.6 

months for wPTX (HR 1.14; 95% CI, 0.88-1.49; p�0.33). The ORR was 

13.6% (12/88) for CPT-11 and 20.9% (19/91) for wPTX (p�0.20). The 

most common grade 3/4 adverse events were neutropenia (39.1% for 

CPT-11 vs. 28.7% for wPTX), anemia (30.0% vs. 21.3%), anorexia 

(17.3% vs. 7.4%) and fatigue (12.7% vs. 6.5%). Four (4%) CPT-11 and 

three (3%) wPTX recipients died within 30 days after the last administration. 

Subsequent CT was performed in 80 pts (71%) for CPT-11 and 97 pts 

(89%) for wPTX. Seventy-five pts (67%) in the CPT-11 group and 87 pts 

(80%) in the wPTX group received the crossover CT. Conclusions: The 

WJOG4007 trial, the first phase III study comparing second-line CT 

regimens for AGC, did not demonstrate the superiority of CPT-11 over 

wPTX. Thus, wPTX can be adopted as a control arm of future phase III trials 

of second-line CT for AGC. 


239s 


Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the 

Stomach (ITACA-S) trial: Comparison of a sequential treatment with 

irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by 

docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment 

for radically resected gastric cancer. Presenting Author: Emilio 

Bajetta, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 








Phase III randomized trial of definitive chemoradiotherapy (CRT) with 

FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final 

results of the PRODIGE 5/ACCORD 17 trial. Presenting Author: Thierry 

Conroy, Centre Alexis Vautrin, Vandoeuvre-lès-Nancy, France 








240s Gastrointestinal (Noncolorectal) Cancer 


Optimum time to assess complete clinical response (CR) following chemoradiation 

(CRT) using mitomycin (MMC) or cisplatin (CisP), with or without 

maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of 

ACT II. Presenting Author: Robert Glynne-Jones, Mount Vernon Centre for 

Cancer Treatment, Middlesex, United Kingdom 

Background: In the ACT I trial, relapse-free survival was improved with CRT 

compared to RT alone, but the CR rate at 6 weeks was similar (39% CRT, 

30% RT alone; p�0.08). Most studies assessed CR between 6 and 12 

weeks following completion of CRT. We investigated the association 

between observation of CR at 3 different time-points and progression-free 

and overall survival (PFS, OS), to determine the optimal time to assess this 

early endpoint. Methods: ACT II recruited 940 pts between 2001 and 

2008. It compared, in a factorial design, CisP versus MMC when combined 

with 5-FU CRT, and two cycles of maintenance chemotherapy versus no 

maintenance. CR (complete absence of tumour and node negative) was 

assessed by rectal exam or imaging at 11, 18 and mandated CT at 26 weeks 

after the start of CRT. Median follow-up was 5 years. Pts were excluded 

from analysis if assessment was not done/ missing at one or more time 

points (n�245). Data from 695 pts were analysed. Results: Pt characteristics 

(all 940) median age 58 years; tumour site – canal (84%), margin 

(14%); stage T1-T2 (52%), T3-T4 (46%); N� (32%), N0 (62%). CisP did 

not improve OS (HR: 0.96, p�0.89) or PFS (HR: 0.85, p�0.43) compared 

to MMC. This is consistent with the lack of an absolute difference at 18 and 

26 weeks, but not at 11 weeks (where a difference was found). CR patients 

(compared to not-CR) had a significantly lower risk of progression/death. 

The association between these outcomes and response was strongest at 26 

weeks. 202/695 (29%) pts not in CR at 11 weeks were CR at 26 weeks. 

Conclusions: 29% of pts not in CR at 11 weeks achieved CR at 26 weeks. 

Early surgical salvage would not have been appropriate for these pts. We 

recommend assessment at 26 weeks in future trials. 

Absolute risk 

HR (95% CI) 

difference (95% CI) 

(CR vs not-CR) 

Pts with CR CR rate % MMC CisP PFS OS 

Week 11 429 65.6 57.9 7.7% (0.52, 14.9) 0.74 (0.56, 0.97) 0.68 (0.48, 0.97) 

p�0.04 

p�0.03 

p�0.03 

Week 18 527 75.4 76.2 0.8% (-7.2, �5.6) 0.54 (0.40, 0.73) 0.44 (0.31, 0.64) 

p�0.81 

p�0.001 

p�0.001 

Week 26 582 83.5 84.0 0.5% (-5.9, �5.1) 0.26 (0.19, 0.35) 0.23 (0.16, 0.33) 

p�0.88 

p�0.001 

p�0.001 


Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular 

carcinoma (HCC) who failed one systemic therapy: Results of a randomized 

controlled phase II trial (RCT). Presenting Author: Lorenza Rimassa, 

Department of Oncology, Humanitas Cancer Center, Rozzano, Italy 

Background: Tivantinib (T) is a selective, oral inhibitor of c-Met, the tyrosine 

kinase receptor for hepatocyte growth factor involved in tumor cell 

migration, invasion, proliferation and angiogenesis. T has shown promising 

results in HCC in phase 1 studies as monotherapy and in combination with 

sorafenib. Methods: This multi-center RCT, enrolled pts with unresectable 

HCC, 1 failed systemic therapy, ECOG PS �2. Child-Pugh B-C were 

excluded. Pts were randomized 2:1 to oral T {360 mg bid (A), 240 mg bid 

(B)} or placebo (P), stratifying by PS and vascular invasion (VI). Treatment 

continued until disease progression (PD) or unacceptable toxicity. RECIST 

1.1 response was evaluated by CT / MRI every 6 weeks. Crossover to 

open-label T was allowed after PD. Primary endpoint was time to tumor 

progression (TTP) in the intent-to-treat (ITT) population by central radiology 

review. Other endpoints included disease control rate (DCR), PFS, OS, 

efficacy in Met� (Met � 2� in �50% of tumor at immunohistochemistry) 

pts, safety. Results: Characteristics of the 107 enrolled HCC pts (A� 38, 

B� 33, P� 36) in T/P: 58/28 male; median age 70/68; PS 0 41/21; VI 

22/13; Met� 22/15; Met- 27/13. Dose A was reduced to B in all pts due to 

G�3 neutropenia (NEUT) rate. Major TTP, DCR and PFS benefits were 

obtained in Met� pts, with preliminary OS trend favoring T (HR�0.47) and 

no detrimental effect in Met- pts. DCR (95% CI) in T/P was 44 (31-56) / 

31(16-48)% for ITT and 50 (28-72) / 20 (4-48)% in Met� pts. Most 

common AEs in T were asthenia (26.8%), NEUT (25.4%), low appetite 

(25.4%); most common drug-related AEs were NEUT (25.4%), anemia 

(15.5%). Most frequent drug-related serious AE was neutropenic sepsis 

(4.2%). Efficacy was similar inA/Bwith less frequent NEUT in B (21.1% / 

6.1%). Final OS, PK, biomarker data will be presented. Conclusions: 

Compared to P, T significantly benefited second-line HCC pts, especially if 

Met�, with manageable safety profile at 240 mg BID. 

Median: 

TTP (mos) 

T arm P arm HR CI* Log-rank p value 

ITT 1.6 1.4 0.64 0.43-0.94 0.04 

Met � 

PFS (mos) 

2.9 1.5 0.43 0.19-0.97 0.03 

ITT 1.7 1.5 0.67 0.44-1.04 0.06 

Met � 2.4 1.5 0.45 0.21-0.95 0.02 

*90%CI for primary TTP. 95%CI for other endpoints. 


Evaluation of MET pathway biomarkers in a phase II study of rilotumumab 

(R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, and 

capecitabine (ECX) in patients (pts) with locally advanced or metastatic 

gastric (G) or esophagogastric junction (EGJ) cancer. Presenting Author: 

Kelly S. Oliner, Amgen Inc., Thousand Oaks, CA 

Background: R is an investigational, fully human, monoclonal antibody to 

HGF/SF, the ligand of the MET receptor. A double-blind, P-controlled, 

phase 2 study randomized 121 G/EGJ cancer pts 1:1:1 to 15 mg/kg R � 

ECX (Arm A, n � 40), 7.5 mg/kg R � ECX (Arm B, n � 42), or P � ECX (Arm 

C, n � 39). OS and PFS improved with the addition of R to ECX (Iveson et 

al, European Multidisciplinary Cancer Congress 2011; abstr 6.504). High 

tumor MET levels have been associated with poor prognosis in G cancer 

(Nakajima et al, Cancer 1999;85:1894-1902). We explored MET pathway 

biomarkers to identify pts who may benefit from R. Methods: MET protein 

levels and gene copy numbers were measured in archival tumor samples by 

immunohistochemistry (IHC) and fluorescence in situ hybridization, respectively. 

High and low MET subgroups were defined by several predefined 

strategies. Total HGF and soluble MET (sMET) protein in plasma were 

measured by ELISA and MSD assays, respectively. Treatment and biomarker 

effects on OS and PFS were analyzed by Cox proportional hazard 

models and Kaplan-Meier estimates. Results: Tumor samples were evaluable 

for MET protein from 62 pts in Arms A � B and 28 pts in Arm C. Pts 

with METHigh tumors (� 50% tumor cells positive) in Arms A � B had 

improved median OS than those in Arm C (11.1 mo [80% CI: 9.2-13.3] vs 

5.7 mo [80% CI: 4.5-10.4]; HR � 0.29, 95% CI: 0.11-0.76, p � 0.012). 

Conversely, pts with METLow tumors (� 50% positive) in Arms A � B had a 

trend toward unfavorable OS compared with those in Arm C (HR � 1.84, 

95% CI: 0.78-4.34). In the chemotherapy only arm (Arm C), pts with 

METHigh tumors had poorer OS (HR � 3.22, 95% CI: 1.08-9.63) than pts 

with METLow tumors. Similar trends were seen with PFS. Predefined 

dichotomization schemes for tumor MET gene copy number and baseline 

plasma levels of total HGF or sMET did not correlate with OS or PFS. 

Conclusions: High MET expression by IHC may predict clinical benefit to R 

� ECX in G/EGJ cancer pts. High MET expression may also be associated 

with poor prognosis for ECX-treated pts. Further investigation is needed to 

confirm these findings. 


Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from 

a phase II randomized discontinuation trial (RDT). Presenting Author: Chris 

Verslype, Hepatology, University Hospitals Gasthuisberg, Leuven, Belgium 

Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and 

VEGFR2. MET over-expression has been observed in advanced hepatocellular 

carcinoma (HCC). Anti-VEGF pathway agents have shown clinical 

benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF 

signaling pathways with cabo may therefore be a promising treatment 

strategy. Methods: Eligible HCC patients (pts) were required to have 

measurable disease per RECIST, � 1 prior systemic regimen and Child- 

Pugh score of A. Pts received cabo at 100 mg qd over a 12 wk Lead-in 

stage. Tumor response (mRECIST) was assessed q6 wks. Treatment � wk 

12 was based on response: pts with PR continued open-label cabo, pts with 

SD were randomized to cabo vs placebo, and pts with PD discontinued. 

Primary endpoint in the randomized phase was progression free survival 

(PFS). The primary endpoint was overall response rate (RR) per mRECIST 

in the Lead-in stage. Results: Enrollment has been completed (n � 41); all 

pts are unblinded. Median age: 61 years (33 to 83). Males: 76%; Asian: 

37%. HCC etiology: Hep B 24%; Hep C 22%; alcohol abuse 20%; other 

38%. Extra-hepatic spread observed in 70%. Median number of prior 

systemic treatments was 1; prior sorafenib was 51%. Median baseline AFP 

was 368 ng/mL (3 – 259,298); 86% had elevated AFP at baseline. Median 

follow-up was 5.5 mos (0.8 -18.5). 29 pts (71%) completed the Lead-in 

stage. Median PFS from Study Day 1 was 4.2 mos. 2/36 pts evaluable for 

tumor assessment at 12 weeks achieved a confirmed PR (cPR) by original 

RECIST (RR 5%). One more pt randomized at Week 12 achieved a cPR at 

18 weeks. 28/36 pts (78%) with �1 post-baseline scan had tumor 

regression (with no apparent relationship to prior sorafenib therapy). The 

overall disease control rate (DCR � PR�SD) at Week 12: was 68% (Asian 

subgroup: 73%). AFP responses (defined as reduction from baseline of 

�50% in pts with elevated AFP at baseline) in 26 pts with �1 postbaseline 

result: 10/26 (38%). Most common Gr 3/4 AEs: diarrhea (17%), 

palmar-plantar erythrodyesthesia (15%), and thrombocytopenia (10%). 

Conclusions: Cabo treatment exhibits activity in HCC pts regardless of prior 

sorafenib treatment. The safety profile was comparable to that of other 

VEGFR TKIs. 



A randomized controlled phase II study of the prophylactic effect of 

urea-based cream on the hand-foot skin reaction associated with sorafenib 

in advanced hepatocellular carcinoma. Presenting Author: Zhenggang Ren, 

Zhongshan Hospital, Fudan University, Shanghai, China 

Background: Sorafenib (SOR) has become the standard treatment for 

advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) 

is one of the most common adverse events associated with SOR and its 

occurrence can impact patient quality of life and lead to dose modification 

or interruption, both of which may negatively impact clinical outcomes. 

This randomized controlled trial is the first large prospective study to 

investigate the prophylactic effect of urea-based creams on HFSR associated 

with SOR. Methods: Patients with advanced HCC treated with SOR 

were randomly assigned 1:1 to receive prophylactic urea-based cream (Arm 

A) or best supportive care (BSC) following development of HFSR (Arm B). 

SOR was administered 800 mg daily. Urea-based cream was given twice 

daily for up to 12 weeks starting on Day 1. BSC was at the physician’s 

discretion and excluded urea-based creams. The primary endpoint was the 

incidence of all-grade HFSR in the first12 weeks. Results: Eight hundred 

sixty eight patients were enrolled; 439 patients in Arm A and 432 patients 

in Arm B. There was no difference of baseline characteristics between two 

arms. Over the 12 week period of study, the incidence of all-grade HFSR 

was significantly lower in Arm A compared to Arm B; n�246 (56.0%) 

patients in Arm A versus n�318 (73.6%) patients in Arm B, p�0.0001. 

The incidence of grade �2 HFSR tended to be lower in Arm A compared to 

Arm B, but did not reach statistical significance; n�96 (21.9%) patients 

Arm A versus n�126 (29.2%) patients in Arm B, p�0.1638. The median 

time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm 

B; 84 days (95% CI 45-93 days) in Arm A and 34 days (95% CI 29-43 

days) in Arm B (p�0.001). Conclusions: This is the first large prospective, 

randomized control trial examining the prophylactic use of urea-based 

creams for treatment of HFSR associated with a multikinase inhibitor. 

Compared to BSC, prophylactic topical use of a urea-based cream appears 

to be effective in preventing and/or delaying the incidence of HFSR 

associated with SOR treatment in patients with advanced HCC. 


4:45 PM-5:45 PM 

Assessment of HER2 gene amplification in adenocarcinomas of the 

stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical 

trial. Presenting Author: Michael Alexander Gordon, Keck School of 

Medicine of the University of Southern California, Norris Comprehensive 


Background: Trastuzumab has been approved for treatment of patients with 

HER2-positive metastatic gastric carcinoma; however, relatively little is 

known about the role of HER2 in the natural history of this disease. 

Methods: Patients enrolled in the INT-0116/SWOG9008 phase III gastric 

cancer clinical trial (n�559) were retrospectively evaluated for HER2 gene 

amplification by fluorescence in situ hybridization (FISH)(n�258), overexpression 

by immunohistochemistry (IHC)(n�148) and HER2 amplification 

by silver-enhanced in situ hybridization (n�77) based on availability of 

tissue specimens. The purpose of the original clinical trial was to evaluate 

the benefit of post-operative 5-fluorouracil/leucovorin plus radiation therapy 

compared to surgery alone. Results: HER2 gene amplification rate by FISH 

was 10.9% in tumor tissue from 258 patients evaluated. HER2 status 

determined by FISH was 92% concordant with SISH. HER2 overexpression 

rate by IHC was 12.2% among 148 patients evaluated, with 90% 

agreement between FISH and IHC. There was a significant interaction 

between HER2 status by FISH and treatment with respect to both OS 

(p�0.034) and DFS (p�0.020). Among patients with HER2 non-amplified 

cancers, treated patients had a median OS of 44 months compared to 24 

months for patients in the surgery only arm (34 and 17 months respectively 

for DFS, p�0.003). Among 28 patients with HER2 amplified cancers, the 

medians for OS were 16 months in the treated arm, and 22 months in the 

surgery arm (p�0.55) (13 and 11 months respectively for DFS, p�0.87). 

We were unable to detect a statistically significant treatment benefit in this 

small subset of patients with HER2 amplification. HER2 amplification 

status was not an independent prognostic marker of OS among patients 

who received no postoperative chemotherapy or radiation therapy (p�0.76). 

Conclusions: Patients lacking HER2 amplification responded significantly 

to treatment as indicated by both OS and DFS. 


241s 


4:45 PM-5:45 PM 

Adverse prognostic impact of heterogeneous HER2 gene amplification in 

patients with esophageal adenocarcinoma (EAC). Presenting Author: Harry 

H. Yoon, Mayo Clinic, Rochester, MN 

Background: HER2 expression in upper digestive cancer is reported to be 

heterogeneous, which substantially affects interpretation of HER2 positivity 

in the clinic. Yet the frequency and prognostic impact of HER2 genetic 

heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods: 

HER2 amplification (fluorescence in situ hybridization) and protein expression 

were examined in untreated surgical EAC specimens (N � 661) at 

Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as 

amplification (HER2/CEP17 ratio � 2) in 5-50% of cancer cells; poly17 

refers to � 3 copies of chromosome 17. Most tumors were T3-4 (68%) or 

lymph node (LN)-positive (73%). Cox models were used to assess diseasespecific 

(DSS) and overall survival (OS). Results: HER2 amplification was 

detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2 

heterogeneity. HER2 heterogeneous tumors had a significantly higher 

frequency of poly17 and high tumor grade. HER2 heterogeneity by 

amplification vs expression were correlated. Since heterogeneity was 

limited to HER2-amplified tumors, survival analysis was stratified by 

amplification status. In multivariable analysis, only HER2 heterogeneity 

and metastatic LN number were prognostic (Table). Conclusions: Among 

HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated 

with increased poly17 and independently predicts 2-fold higher risk of 

cancer-specific death. Among HER2-nonamplified cases, poly17 is independently 

associated with worse survival. These novel findings demonstrate 

aggressive subgroups in HER2-amplified and -nonamplified EACs that have 

important implications for HER2 analysis and evaluation of benefit from 

HER2 targeted therapy. 

DSS 

Variable 

a OS a 

HR p HR p 

HER2-amplified N � 117 

Heterogeneity, yes vs no 2.0b 0.025 2.0c 0.026 

Grade, 4 v 1-3 1.1 0.7 1.1 0.8 

T stage, 3-4 v 1-2 

No. LN 

1.3 0.2 1.3 0.3 

d 1.1 �.001 1.4 �.001 

Poly17, yes v no 

HER2-nonamplified N � 544 

0.7 0.1 0.7 0.1 

Heterogeneity None 

Grade, 4 v 1-3 1.3 0.01 1.3 0.007 

T stage, 3-4 v 1-2 

No. LN 

2.0 �.001 1.9 �.001 

d 1.1 �.001 1.1 �.001 

Poly17, yes v no 1.4 0.012 1.3 0.023 

a Adjusted for all covariates; b 95% confidence interval (CI) 1.1 – 3.8; c 95% CI 1.1 – 3.7; d Per metastatic LN. 

HR, hazard ratio. 


4:45 PM-5:45 PM 

Profiling of activated receptor tyrosine kinases in advanced gastric cancers 

identifies patients with poor prognosis. Presenting Author: Phillip Sangwook 

Kim, Prometheus Laboratories Inc., San Diego, CA 

Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge 

due to its poor prognosis. Trastuzumab is the only known targeted 

therapy that has demonstrated a survival benefit in a small subset of 

metastatic GCAs. Addition of molecular diagnostics for predicting prognosis 

and therapeutic outcomes can significantly enhance the clinical 

management of GCAs. Herein, we identify activated receptor tyrosine 

kinases (RTKs) in distinct GCA subsets that correlate with disease-free 

survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from 

434 stage I to IV GCA patients were profiled for HER1, HER2, HER3, 

p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative 

Enzyme Enhanced Reactive (CEER) immunoassay. CEER is a highly 

sensitive and specific proximity assay that relies on the formation of a triple 

antibody complex surrounding the target protein. Results: p95HER2, a 

known trastuzumab resistance mechanism, was identified for the first time 

in 79% of IHC/FISH-based HER2(�) GCAs. Full-length HER2 expression 

was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2 

protein. 232/434 GCAs expressed at least one activated RTK analyzed in 

our study. Of these 232 patients, 121 patients that presented with stage II 

or III disease at the time of surgery; demonstrated a worse progression-free 

survival as compared to those where none of the analyzed RTKs were 

activated (32.6 months vs 76.5 months, p�0.0318). HER axis members 

were the most commonly activated RTKs with 64% of such GCAs. 

Approximately 71% of activated cMET tumors demonstrated a coactivation 

with a HER axis member with a preference for HER1 in ~61% of 

cMET-activated GCAs. Patients with p-MET(�):p-HER1(�) GCAs had a 

worse prognosis as compared to those with p-MET(�):p-HER1(-) GCAs 

(46.2 months vs 82.8 months, p�0.0184). Conclusions: CEER-based RTK 

characterization revealed concomitantly activated signaling pathways in 

GCAs which could predict disease recurrence. Comprehensive molecular 

profiles of GCA tumors can allow for the implementation of these companion 

biomarkers in GCA therapeutic clinical trials. 




4:45 PM-5:45 PM 

Impact of insulin-like growth factor 1 receptor (IGF1R) and amphiregulin 

(AREG) expressions on survival in patients with stage II/III gastric cancer 

enrolled in the ACTS-GC study. Presenting Author: Wataru Ichikawa, 

National Defense Medical College, Tokorozawa, Japan 

Background: Exploratory biomarker analysis was conducted to identify 

factors related to outcomes of patients enrolled in the ACTS-GC study, a 

randomized controlled trial comparing adjuvant S-1 administration with 

surgery alone in 1,059 patients with stage II/III gastric cancer. Methods: 

Formalin-fixed paraffin-embedded surgical specimens were retrospectively 

examined in 829 patients (78.3%), and 63 genes involved in pyrimidine 

metabolic pathway, growth factor signaling pathway, apoptosis, DNA 

repair, etc., were analyzed by quantitative real-time RT-PCR after TaqMan 

assay-based pre-amplification. Gene expression levels were normalized to 

the geometric mean expressions of GAPDH, ACTB, and RPLP0, used as 

reference genes. The expression of each gene was categorized into low and 

high values at those median. The impacts of gene expression on survival 

were analyzed using the 5-year survival data of the ACTS-GC. The 

Benjamini and Hochberg procedure was used to control the false discovery 

rate (FDR). Results: Among 63 screened genes, IGF1R and AREG most 

strongly correlated with overall survival (OS), with FDR of 0.0048 and 

0.018, respectively. OS was significantly worse in IGF1R high patients 

than in IGF1R low patients, but better in AREG high patients than in AREG 

low patients. The hazard ratio (HR) for death in the analysis of OS (S-1 vs. 

surgery alone) was lower in the high IGF1R group (HR, 0.55; 95%CI, 

0.40-0.76) than in the low IGF1R group (HR, 0.72; 95%CI, 0.49-1.06). 

Likewise, the HR for death in the analysis of OS (S-1 vs. surgery alone) was 

much smaller in the low AREG group (HR, 0.57; 95%CI, 0.41-0.79) than 

in the high AREG group (HR, 0.74; 95%CI, 0.51-1.08). Interactions were 

not statistically significant. Conclusions: IGFR1 gene expression was 

associated with poor outcomes after curative resection of stage II/III gastric 

cancer, whereas AREG gene expression was associated with good outcomes. 

No interaction for survival was evident between S-1 and these gene 

expressions. 


4:45 PM-5:45 PM 

Multivariate analysis including biomarkers in the phase III RADIANT-2 

study of octreotide LAR plus everolimus (E�O) or placebo (P�O) among 

patients with advanced neuroendocrine tumors (NET). Presenting Author: 

James C. Yao, University of Texas M. D. Anderson Cancer Center, Houston, 

TX 

Background: In this large phase III trial, median progression-free survival 

(PFS) improved by 5.1 mo with E�O compared to P�O in patients (pts) 

with NET associated with carcinoid syndrome. Baseline imbalances including 

WHO performance status (PS) and primary site favoring P�O confounded 

primary analysis. Chromogranin A (CgA) and 5-hydroxyindoleacetic 

acid (5-HIAA) are important biomarkers in NET. Analyses were performed 

to identify prognostic factors and adjust for baseline imbalances. Methods: 

Pts were randomized to E�O (n�216) or P�O (n�213). Potential 

prognostic factors including baseline CgA (�2�ULN vs �2�ULN), baseline 

5-HIAA (�median vs �median at baseline), age (�65 vs �65), 

gender, race, WHO PS (0 vs 1, 2), primary site (lung vs other), prior 

somatostatin analog use (yes vs no), duration from diagnosis (�6 mo, 6-24 

mo, 2-5 yr, �5 yr), and organs involved (liver, bone) were assessed in 

univariate analysis using the log rank test and stepwise regression using 

Cox proportional hazards model. Results: Median PFS (mo) was significantly 

longer for pts with nonelevated CgA (27 vs 11; p�.001) and nonelevated 

5-HIAA (17 vs 11; p�.001). Analyses also indicated age (14 vs 12; 

p�.01), WHO PS (17 vs 11; p�.004), liver involvement (14 vs not 

reached; p�.02), bone metastases (8 vs 15; p�.001), and lung as primary 

site (11 vs 14; p�.06) as potentially prognostic. Multivariate analysis 

indicated that significant prognostic factors for PFS included baseline CgA 

(HR, 0.47; CI, 0.34-0.65; p�.001), WHO PS (HR, 0.69; CI, 0.52-0.90; 

p�.006), bone involvement (HR, 1.52; CI, 1.06-2.18; p�.02), and lung 

as primary site (HR, 1.55; CI, 1.01-2.36; p�.04). Adjusted for covariates, 

a 38% reduction in risk of progression was observed for E�O (HR, 0.62; 

95% CI, 0.51-0.87; p�.003). Conclusions: In the phase III RADIANT-2 

trial, baseline CgA levels, WHO PS, lung as primary site, and bone 

involvement were important prognostic factors. Exploratory analysis adjusted 

for these prognostic factors indicated significant benefit of everolimus 

therapy. 


4:45 PM-5:45 PM 

Actionable targets in pancreatic cancer detected by immunohistochemistry 

(IHC), microarray (MA) fluorescent in situ hybridization (FISH), and 

mutational analysis. Presenting Author: Daniel D. Von Hoff, Virginia G. 

Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ 

Background: A great need exists for new therapeutic approaches for patients 

with pancreatic cancer. Methods: The study cohort included 1029 patients 

analyzedfor a.) up to 29 different immunohistochemical biomarkers – (e.g., 

COX-2, MGMT, PGP, RRM1, TOPOI, TOPOII, SPARC etc.)b.); in up to 450 

patients’ specimens a whole genome expression analysis was performed 

using HumanHT-12 v4 beadChips ( Illumina Inc.,San Diego, CA) c.) in up 

to 695 patients FISH for c-Myc, EGFR, HER2 and TOPO2A gene copy 

amplifications; and d.) in up to 783 patients sequencing for KRAS, EGFR, 

PI3CA and BRAF, was performed. Results: IHC identified actionable targets 

included; 74% high COX-2; 57% negative ERCC1; 8% negative MGMT; 

22% negative MRP1; 47% negative PGP; 77% low RRM1, 44% high 

SPARC; 30% high TOPO2A; 61% high TOPOI and 73% negative TS. Other 

biologically important findings by IHC for possible new therapeutics 

included 27% negative PTEN; and 20% high PDGFR. Microarray results 

presented multiple overexpressed targets for consideration including 36% 

of specimens with overexpressed adenosine deaminase; 28% asparagine 

synthase; 17% BCL2; 20% survivin; 23% carboxylesterase; 67% DNMT1; 

40% thymidine phosphatase; 49% EPHA2 (and others in the src family of 

kinases); 57% FOLR2; 41% HDAC1; 62% HiF1�; 23% IL2RA (CD25); 

46% NFkB1; 48% OGFR; 32% RARA; 26% VEGFR; and 43% vitamin D 

receptor. FISH yielded 2% amplified EGFR and 10% amplified Her2neu. 

Sequencing noted 73% mutated KRAS and 3% mutated PIK3CA. 

Conclusions: Examining actionable targets in patients’ pancreatic cancers 

(a)reiterates the commonality and importance of KRAS mutations in this 

disease (needs renewed targeting effort) (b)suggests that TOPO2 inhibitors 

(particularly if transport into tumor can be improved) should be examined 

in this disease (c)suggests other pathways to target including DNA repair, 

epigenetic, Src and inflammation (d) suggests protein turnover, amino acid 

targets and folate receptor2 as fresh areas to explore against the disease. 

Supported in part by a Stand Up To Cancer Dream Team Award. 


4:45 PM-5:45 PM 

Predictive and prognostic factors for treatment and survival in 305 patients 

with advanced gastrointestinal poorly differentiated neuroendocrine carcinoma: 

The NORDIC NEC study. Presenting Author: Halfdan Sorbye, 

Haukeland University Hospital, Bergen, Norway 

Background: Gastrointestinal poorly differentiated neuroendocrine carcinoma 

(GI-NEC) are aggressive tumors with Ki-67�20% and usually 

metastatic at diagnosis. Knowledge about GI-NEC is limited. We retrospectively 

reviewed clinical data to identify predictive and prognostic markers 

for advanced GI-NEC patients. Methods: Epidemiological, biochemical, 

histopathological, treatment and survival data were registered for advanced 

GI-NEC patients diagnosed during 2000-2009 at 12 Nordic university 

hospitals. Results: 305 patients were included. Palliative chemotherapy 

was given to 252 patients, median survival was 11 months. Response rate 

to 1st-line chemotherapy was 31%, 33% had stable disease. Ki-67�55% 

was by ROC analyses the best cut-off value concerning correlation to 

response rate. Response rate to platinum-based chemotherapy was lower in 

patients with Ki-67�55% (14% vs.44%, p�0.001). Response rate for 84 

patients given 2nd-line chemotherapy was 18%, whereas 33% achieved 

SD. The most important negative prognostic factors for survival were poor 

performance status, primary colorectal tumors, and elevated baseline 

platelets or lactate dehydrogenase (LDH) levels. Patients with Ki-67�55% 

had longer median survival (15 months) than patients with Ki-67�55% 

(10 months) (p�0.001). Survival and response rates did not differ between 

the different platinum chemotherapy schedules (cisplatin-based vs. carboplatin-based) 

or morphology subtypes. 53 patients received best supportive 

care only with a median survival of 1 month. Conclusions: This is, to our 

knowledge, the largest study reporting patient and tumor characteristics, 

treatment and survival in advanced GI-NEC. Performance status, location 

of primary tumor and blood levels of platelets and LDH were the strongest 

prognostic factors for survival. Patients with Ki-67�55% had significantly 

longer survival than patients with higher Ki-67, but were less responsive to 

platinum-based chemotherapy. Our data indicate that to consider all 

GI-NEC as one single disease entity may not be correct. 



4:45 PM-5:45 PM 

Maintenance sunitinib (MS) or observation (O) in metastatic pancreatic 

adenocarcinoma (MPA): Clinical and translational results of a phase II 

randomized trial (NCT00967603). Presenting Author: Michele Reni, San 

Raffaele Scientific Institute, Milan, Italy 

Background: Combination chemotherapy (CT) prolonged progression-free 

survival at 6 months (PFS6) of patients (pts) with MPA from �20% with 

gemcitabine (GEM) to �50%. To prolong CT over 6 months has unproven 

benefit and is hampered by cumulative toxicity. This open-label, randomised, 

multi-centre phase II trial explored the role of MS in pts with MPA 

without progressive disease (PD) after CT, using an O group as calibration 

arm. The role of circulating endothelial cells (CEC) as biomarker of MS 

activity was explored. Methods: Adult pts with pathologic diagnosis of MPA, 

performance status (PS) �50%, without radiological PD or CA19.9 raise 

�20% after 6 months of CT were stratified based on PS and previous CT 

and randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum 

of 6 months (arm B). Primary endpoint was PFS6. Sample size (H0 10%; 

H1 30%; a .10; b .10) was 26 pts per arm and MS had to be considered of 

interest with �5 pts PFS6. CEC were evaluated by flow cytofluorometry on a 

baseline peripheral blood sample. Results: 56 pts (29 arm A; 27 arm B) 

were enrolled. One arm B pt had kidney cancer and was excluded. Pts 

characteristics were (A/B): median age 64/61 years; median PS 90/100; 

median CA19.9 45/32; previous CT: GEM 3/3; combination CT 26/22. 

Main grade 3-4 toxicity in arm B was 15% neutropenia; 12% thrombocytopenia 

and hand-foot syndrome, 8% diarrhea. Second line CT was given to 

76% of pts in both arms. One arm A (3%) and 6 arm B pts (23%; p�.01) 

were PFS6; 2y overall survival (OS) was 4% and 25% (p�.09). Blood 

sample for CEC analysis was available for 46 of 55 pts (84%). In arm A, 

median PFS was longer for pts with CEC number �30 (lower terzile group) 

when compared to �30 (2.9 versus 1.9 months; p.08). MS significantly 

increased PFS in CEC �30 group (3.4 months; p�.01). No PFS difference 

between arms was observed in �30 group (2.3 months). Conclusions: This 

is the first randomized trial on maintenance therapy in MPA. In arm B, the 

primary endpoint was fulfilled and 2y OS was remarkably high, suggesting 

that MS may have a role in pts with MPA. The number of CEC may be useful 

to predict benefit from MS. 


4:45 PM-5:45 PM 

Dual blockade of epidermal growth factor receptor (EGFR) and insulin-like 

growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic 

cancer: Phase I/randomized phase II trial of gemcitabine, erlotinib, and 

cixutumumab versus gemcitabine plus erlotinib (SWOG-0727). Presenting 

Author: Philip Agop Philip, Karmanos Cancer Institute, Wayne State 

University, Detroit, MI 

Background: Targeting a single pathway in pancreatic adenocarcinoma 

(PAC) is unlikely to impact its natural history. EGFR targeting with erlotinib 

added to gemcitabine (G) marginally improved the outcome of patients with 

advanced disease. We tested the hypothesis that if the EGFR and IGF-1R 

pathways are simultaneously blocked then progression free survival (PFS) 

would be significantly improved by abrogating reciprocal signaling that 

leads to resistance to either drug. Methods: This was a phase I/randomized 

phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab 

combined with erlotinib and G in patients with metastatic PAC. The 

control arm was erlotinib plus G. The primary endpoint of the RP2 portion 

of the study was PFS. Eligibility included patients with untreated metastatic 

disease, performance status 0/1, fasting blood glucose less than 

institutional upper limit of normal, and willingness to provide tissue and 

blood specimens for correlative studies. Results: In phase I portion (n�10) 

safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and G 

1000 mg/m2 IV D 1, 8, and 15 of a 28-day cycle was established. In the 

RP2 portion (n�124) 114 eligible patients (median age 63) were included. 

On the cixutumumab arm, 59% of patients were female vs. 40% on 

control arm. Median PFS and overall survival were 3.7 and 6.7 months, 

respectively, in both arms of the study. Major grade 3 and 4 toxicities were 

(cixutumumab/control) elevation of transaminases (12%/6%), fatigue 

(16%/12%), gastrointestinal (35%/28%), neutropenia (21%/10%), and 

thrombocytopenia (16%/7%). Grade 3/4 hyperglycemia was seen in 16% 

of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both 

arms of the study (� 5%). Five treatment-related deaths were reported: 2 

cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R 

inhibitor cixutumumab did not improve the progression free or overall 

survival of patients with metastatic PAC treated with erlotinib and G in a 

molecularly unselected population. 


243s 


4:45 PM-5:45 PM 

FOLFIRI.3 (CPT-11 plus folinic acid plus 5-FU) alternating with gemcitabine 

or gemcitabine (G) alone in patients (pts) with previously untreated 

metastatic pancreatic adenocarcinoma (MPA): Results of the randomized 

multicenter AGEO phase II trial FIRGEM. Presenting Author: Isabelle 

Trouilloud, Hôpital Européen Georges Pompidou, Paris, France 

Background: CPT-11 showed modest activity and tolerability in MPA. We 

developed a new strategy to improve efficacy and tolerability of CPT-11 

based regimen in MPA pts. Methods: Chemotherapy-naive pts with histologically 

proven MPA, bilirubin levels � 1.5 ULN and performance status (PS) 

0-1 were randomized in a phase II trial to receive either FOLFIRI.3 (CPT-11 

90 mg/m2 as a 60-min infusion on day (D) 1, leucovorin 400 mg/m2 as a 

2-hr infusion on day 1, followed by 5-FU 2000 mg/m2 as a 46-hr infusion 

and CPT-11 90 mg/m2 , repeated on D3, at the end of the 5-FU infusion, 

every 2 weeks) for 2 months alternarting with G (1000 mg/m² at a fixed 

dose rate of 10 mg/m²/min on D1, D8, D15, D29, D36 and D43) for 2 

months (arm A) or G alone (arm B). Using Fleming design the primary end 

point was rate of progression free survival (PFS) at 6 months from (H0) 

25% over (H1) 45% needing to include 49 pts/arm. Results: Between 2007 

and 2011, 98 pts were enrolled (males: 59, median age: 62 years, PS 0: 

32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%) in 

arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25 

and febrile neutropenia 4/0. No toxic death occurred. Response rate were 

40 and 11% as disease control rate (CR�PR�SD) were 73 and 52% in arm 

A and B, respectively. The primary endpoint of the trial was met with rate of 

PFS at 6 months of 48% (95% CI: 33-63) in arm A while in arm B PFS was 

30% (95% CI: 17 - 44). One year PFS was 23% (95%CI: 11.5-36) and 

11% (95%CI: 4-21), respectively. Conclusions: FIRGEM strategy is feasible 

and efficient with a manageable toxicity profile in good condition pts 

with MPA. A phase III trial comparing this strategy with the FOLFIRINOX 

triplet therapy focusing on quality of life should now be performed. 


4:45 PM-5:45 PM 

Long-term survival in patients with pancreatic cancer: Relevant factors in 

CONKO-001. Presenting Author: Marianne Sinn, Medical Department, 

Division of Hematology, Oncology and Tumor Immunology Charité - 

Universitätsmedizin Berlin, Berlin, Germany 

Background: Long-term survival (LTS) in patients with pancreatic cancer is 

still rare, even in resectable and potentially curative stages. Few prospective 

data are available to identify predictive factors. The CONKO-001 study 

establishing adjuvant gemcitabine (GEM) may provide data to answer this 

question. Methods: CONKO-001 patients (pts) with an overall survival � 5 

years were included in this analysis and compared to those with � 5 years. 

Central re-evaluation of the primary histology was done to confirm the 

diagnosis of pancreatic adenocarcinoma. Univariate analysis with the 

x²-test identified qualifying factors (p�0.10). Logistic regression with a 

stepwise selection process was used to investigate the influence of these 

covariates on LTS. Results: Of the 354 pts included in the intention-to-treat 

analysis of CONKO-001, 53 (15%) pts with an overall survival of more than 

5 years could be identified, for 39 (74%) tumor specimens could be 

obtained. In 38 (97% of pts with LTS) the diagnosis of adenocarcinoma 

was confirmed, 1 showed a high-grade neuroendocrine tumor. Relevant 

factors for all 53 pts with LTS compared to remaining 301 non-LTS pts in 

univariate analysis were active treatment (GEM) (68% in LTS pts vs 48% in 

non-LTS pts; p�0.006), tumor grading (G1 17% vs 3%, G2 64% vs 55%, 

G3 17% vs 40%; p�0.000), tumor-size (T2 15% vs 9%, T3 74% vs 84%; 

p�0.004) and lymph nodes (N0 47% vs 25% N1 53% vs 74%; p�0.003. 

Significance could not be demonstrated for resection margin (R0 vs R1), 

sex, age, Karnofsky performance status (�80% vs 80% vs �80%) and CA 

19-9 (40-100 U/ml vs �40 U/ml) at study entry. In the multivariate 

analysis tumor grading (gr) (odds ratio gr 3 vs gr 1�0.07; gr 3 vs gr 2� 

0.38; p�0.017) and active treatment (odds ratio GEM vs observation�0.38; 

p�0.004) were the only independent prognostic factors. 

Conclusions: Long-term survival can be achieved in adenocarcinoma of the 

pancreas. In pts with completely resected pancreatic cancer, tumor grading 

and active treatment with GEM were the only predictive factor for LTS. 




4:45 PM-5:45 PM 

Phase I/II study of preoperative (pre-op) short course chemoradiation (CRT) 

with proton beam therapy (PBT) and capecitabine (cape) followed by early 

surgery for resectable pancreatic ductal adenocarcinoma (PDAC) of the 

head. Presenting Author: Theodore S. Hong, Massachusetts General 

Hospital, Boston, MA 

Background: Standard adjuvant 6 week CRT may delay and reduce 

tolerability of adjuvant gemcitabine-based chemotherapy. We explore the 

safety and efficacy of a one-week course of pre-op CRT with PBT and cape 

followed by early pancreaticoduodenectomy (PD). Methods: Patients with 

radiographically resectable, biopsy-proven PDAC of the head were enrolled 

from May 2007-December 2010 on this prospective, NCI-sponsored 

clinical trial. Eligibility included no CT involvement of SMA or celiac artery; 

No metastatic disease. Dose level 1 consisted of PBT delivered 3 Gy x 10. 

Pts in subsequent dose levels received 5 Gy x5inprogressively shortened 

schedules: level 2 (wk1MWF,wk2TTh), level 3 (wk1MTThF,wk2M), 

level 4 (wk 1 M-F). PBT was targeted at pancreatic mass with elective nodal 

coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. Surgery was 

performed 1-6 wks after completion of cape. Patients were recommended 

to receive 6 mo of gemcitabine after surgery. Genotyping of 15 genes 

(including KRAS, PIK3CA, BRAF, NRAS, TP53, IDH1) was performed. 

Results: 50 pts were enrolled on study. 48 patients are eligible for this 

analysis. 3 pts were treated at each of dose levels 1-3. 6 pts were at dose 

level 4, which was selected as MTD. No DLTs were observed. 35 patients 

were treated in the phase II portion at the MTD. Gr 3 toxicity was noted in 2 

pts (chest wall pain-1, colitis-1). 38 pts underwent PD. Reasons for no PD 

were: metastatic disease-9, unresectable tumor-1. Mean post-op length of 

stay was 7 days (range 5-47). 6/38 (16%) resected pts had positive 

margins. 28/38 (74%) had positive nodes. Median follow up is 21 months 

among the 19 patients still alive. 4/48 (8%) local failures in ALL patients. 

mOS and mPFS are 18 and 10 months respectively for ALL patients and 27 

and 14 months for RESECTED patients. Of 28 patients with genotype data 

available, 22 (79%) had KRAS mutations. 10/22 KRAS mt and 4/6 KRAS 

wt pts are alive. Conclusions: Pre-op CRT with 1 wk of PBT and capecitabine 

followed by early surgery is well tolerated and associated with favorable 

local control. Complete genotype and DPC4 data will be presented at the 

meeting. 


4:45 PM-5:45 PM 

Correlation of hand-foot skin reaction (HFS) with treatment efficacy in 

pancreatic cancer (PC) patients (pts) treated with gemcitabine/capecitabine 

plus erlotinib: A subgroup analysis from the AIO-PK0104 randomized, 

cross-over phase III trial in advanced PC. Presenting Author: Michael 

Haas, Department of Hematology and Oncology, Klinikum Grosshadern and 

Comprehensive Cancer Center, LMU Munich, Munich, Germany 

Background: AIO-PK 0104 investigated the efficacy and safety of gemcitabine/erlotinib 

(G/E) followed by capecitabine (C) vs. C/E followed by G. 

The present subgroup analysis evaluated the correlation between Cassociated 

skin toxicity and outcome parameters in PC. Methods: Within 

this multicenter phase III trial, pts with confirmed advanced PC were 

randomly assigned to 1st-line treatment with either C (2,000 mg/m2 /d, 

d1-14 q d21) plus E (150 mg/d, arm A) or G (1,000 mg/m2 over 30 min 

weekly x 7, then d1, 8, 15 q d28) plus E (150 mg/d, arm B). A cross-over to 

either G (arm A) or C (arm B) was performed after treatment failure (e. g. 

disease progression or unacceptable toxicity). Time to treatment failure 

after 1st- and 2nd -line therapy (TTF2) was the primary study endpoint. 

Treatment-related skin toxicity was evaluated separately for each treatment 

arm/each regimen based on NCI-CTCv2. Results: Of 279 eligible pts, 47 

had locally advanced, 232 had metastatic disease and 141 pts received 

second-line chemotherapy. For the present subgroup analysis data on skin 

toxicity were available from 255 pts. For the 73 pts (29%) with a HFS (any 

grade documented at any time during the treatment strategy), TTF2 and OS 

both were significantly prolonged compared to pts without HFS (7.4 vs 4.0 

months, p�0.001 and 9.7 vs 5.5 months, p�0.002, respectively). 

Considering HFS during 1st-line treatment in 123 pts within the CE arm, 

these results could be confirmed for the 47 pts (38%) with a documented 

HFS of any grade (TTF2: 7.6 vs. 3.2 months, p�0.001; OS: 10.2 vs. 4.4 

months, p�0.001). In pts receiving 1st-line treatment with G/E (n�132) 

no difference in outcome was observed for pts with (n�13) or without 

(n�119) HFS of any grade (TTF2: 5.7 vs. 4.2 months, p�0.375; OS: 8.4 

vs. 6.6 months, p�0.505). Conclusions: The current subgroup analysis of 

AIO-PK0104 supports the assumption of a correlation between HFS in PC 

pts treated with capecitabine or capecitabine/erlotinib and efficacy endpoints 

like TTF2 and OS. A capecitabin-associated HFS thus might be 

predictive for efficacy in patients with advanced PC. 


4:45 PM-5:45 PM 

A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) 

or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with 

metastatic pancreatic cancer (PC): Interim analysis of a University of 

Chicago phase II consortium study. Presenting Author: Daniel Virgil 

Thomas Catenacci, University of Chicago, Chicago, IL 

Background: Sonic Hh (SHh), the ligand for the Hh pathway, is overexpressed 

in �80% of PC. V, a small molecule antagonist of the Hh 

signaling pathway, has activity in preclinical PC models. Methods: We 

conducted a multi-center, placebo-controlled, phase IB/randomized phase 

II trial of GV or GP. Eligible pts, KPS 80-100, had previously untreated 

metastatic PC, or had completed adjuvant therapy � 6 months (mo) prior. 

Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh 

serum levels; serial contrast perfusion CT imaging. To allow for early 

stopping due to lack of efficacy, a planned interim analysis was performed 

after approximately 50% of the expected number of PFS events occurred. 

The protocol stipulated that the trial would be terminated if the probability 

of rejecting the null hypothesis were the trial to continue (conditional 

power) was �10%. All pts received G 1000mg/m2 over 30 minutes, days 

(D) 1, 8, 15, Q28D. Pts, stratified by KPS (80 v 90/100), and disease 

status (newly-diagnosed/recurrent), were randomized to V (150 mg PO 

daily) or P. For pts on P, cross-over was allowed at progression. Results: 70 

evaluable pts (V/P 35/35) enrolled at 12 sites 2/10-6/11. Pt characteristics: 

median age 63/63 (range 49-79/48-82); KPS 80: 8/8; 90: 12/14; 

100: 15/13. Grade 3/4 toxicity (%pts): neutropenia 20/26; hyponatremia 

3/11; fatigue 9/6; hyperglycemia 14/6; elevated alkaline phosphatase 

9/11. Response (%): complete 0/3, partial 0/11, stable disease 49/31. 

Median PFS: 3.7/2.4 mo (95% CI: 2.4-4.6/1.9-3.7; adjusted HR 0.92 

[0.52-1.64]). Upon progression/unblinding, 23 GP pts crossed over to GV. 

Median overall survival (OS): 6.3/5.4 mo (95% CI:4.9-7.8/4.2-8.0, adjusted 

HR 0.97, [0.47-2.01]). 1-year survival (%): 24/24. Laboratory and 

radiological correlatives will be presented. Conclusions: GV has an acceptable 

toxicity profile. This trial did not meet criteria for futility at this interim 

analysis. The study is expected to complete accrual of 112 pts in February 

2012. The final analysis will be reported after 90 events. Funded by NCI 

N01-CM-62201. 


4:45 PM-5:45 PM 

Ethnic gene profile of genes involved in angiogenesis to predict regional 

bevacizumab efficacy difference in gastric cancer. Presenting Author: 

Takeru Wakatsuki, University of Southern California Norris Comprehensive 


Background: AVAGAST showed regional bevacizumab (Bev) efficacy difference 

(RBED), namely, Asian (Asi) patients (pts) with gastric cancer (GC) 

had no benefit whereas European and Pan-American patients had more 

benefit from Bev. Recently, germline gene polymorphisms in angiogenesis 

have been recognized as predictive marker for Bev efficacy. Allele frequency 

(AF) in gene polymorphisms may vary depending on ethnicity. We 

tested the hypothesis whether angiogenic pathway gene polymorphisms 

may have different AF among Asi, Caucasian (Cau), and Hispanic (Hisp) in 

GC and this disparity may explain RBED. Methods: Three-hundred pts 

[Japanese (Jap), Cau, and Hisp, 100 from each race] with histopathologically 

confirmed GC were collected from Japan, USA, Austria, and Italy 

between 1991 and 2011. These pts were divided into 2 groups as training 

set (n�50) and validation set (n�50) in each race. Seven functional gene 

polymorphisms previously reported as predictive marker were selected. All 

samples were analyzed using PCR-based direct DNA- sequencing. Fisher’s 

exact test was used to compare the distribution of AF among races. Results: 

Significant disparate distributions in favorable AF for Bev were shown 

among races in Table. Jap GC pts had significant lower AF of 5 predictive 

gene polymorphisms in training set, and among these 5, three predictive 

gene polymorphisms were also validated. Conclusions: Our preliminary 

results showed significant disparate AF distributions in predictive gene 

polymorphisms for Bev, and these disparities may explain RBED in 

AVAGAST. Further investigation is warranted to elucidate RBED. 

The favorable allele frequencies for bevacizumab. 

Training set Validation set 

Cau (%) Hisp (%) Jap (%) P value Cau (%) Hisp (%) Jap (%) P value 

VEGFR2 rs12505758 T/C 84.0 85.0 68.8 0.009 87.0 83.3 64.3 0.004 

VEGFR1 rs9582036 C/A 79.0 86.0 82.7 0.660 75.0 80.0 83.0 0.740 

VEGF-A rs699946 A/G 78.0 60.2 49.0 0.001 78.0 76.0 58.0 0.021 

VEGFR2 rs11133360 C/T 55.1 43.8 70.8 0.002 60.0 35.9 68.0 �0.001 

VEGF-A rs833061 C/T 52.0 35.0 29.6 0.020 50.0 40.0 33.0 0.200 

VEGF-A rs699947 A/C 51.0 34.0 27.6 0.013 51.0 36.0 29.0 0.026 

VEGF-A rs1570366 A/G 39.0 17.0 14.6 0.001 37.0 22.0 20.4 0.130 



4:45 PM-5:45 PM 

Multicenter randomized phase II trial of cisplatin, irinotecan plus bevacizumab 

(PCA) versus docetaxel, cisplatin, irinotecan plus bevacizumab 

(TPCA) in patients (pts) with metastatic esophagogastric cancer (MEGCA). 

Presenting Author: Peter C. Enzinger, Dana-Farber Cancer Institute, 

Boston, MA 

Background: In MEGCA, PCA has a 65% response rate (RR) and 8.3 mos 

time to progression (Shah. JCO 2006); TPCA has a 66% RR and 8.9 mos 

progression-free survival (PFS) (Enzinger. ESMO 2008 updated). Methods: 

Chemo naive pts with MEGCA were stratified: ECOG (0/1 vs. 2) and disease 

site (Gastric or GEJ/esophageal) and randomized 1:1 to PCA or TPCA. PCA 

-- cisplatin 30mg/m2 and irinotecan 65mg/m2 on d1, 8, and bevacizumab 

10 mg/kg d1 docetaxel 30mg/m2, cisplatin 25mg/m2 and irinotecan 

50mg/m2 on d1, 8, and bevacizumab 10 mg/kg d1. Cycles were 3 weeks. 

Response assessment - q6wks (RECIST 1.1). Primary endpoint was PFS. 

Results: 85 patients: median age�61 (40-85); male/female� 70/15; 

ECOG: 0/1/2�(34/49/2); gastric/GE junction/esophageal�27/21/37; measurable/evaluable: 

78/7; sites of metastatic disease (# of pts): lymph nodes 

(34), liver (31), lung (11), bone (5), abdomen (4), peritoneum (4), other 

(11). There were two treatment-related deaths: esophageal hemorrhage, 

sudden death (both TPCA). Conclusions: Both regimens were efficacious 

and reasonably well tolerated. The addition of docetaxel to the attenuated 

PCA combination did not significantly improve efficacy. 

PCA (N�44) TPCA (N�41) P value 

Major response 56.8% (41.0, 71.7) 48.8% (32.9, 64.9) 0.518 

PFS median (N�85) 7.7mos (5.8, 10.1) 8.4mos (6.8, 9.8) 0.861 

OS 1-year (N�85) 52.6% (36.0, 66.8) 59.1% (42.2, 72.7) 0.866 

OS median (N�85) 

Grade III-IV toxicity % 

12.5mos (9.6, 15.5) 13.3mos (11.5, 15.4) 0.866 

Neutropenia 25.0 31.7 0.492 

Thrombocytopenia 4.5 4.9 1.000 

Diarrhea 22.7 31.7 0.465 

Fatigue 15.9 19.5 0.778 

Vomiting 9.1 12.2 0.733 

Infection 11.4 7.3 0.714 

Anorexia 2.3 9.8 0.192 

Thromboembolic 4.5 9.8 0.423 

HTN 4.5 4.9 1.000 


4:45 PM-5:45 PM 

The pattern and timing of disease recurrence in squamous cancer of the 

anus: Mature results from the NCRI ACT II trial. Presenting Author: David 

Sebag-Montefiore, St James Institute of Oncology, Leeds, United Kingdom 

Background: Concurrent chemoradiation (CRT) is standard treatment for 

patients with squamous cell carcinoma of the anus. Although the majority 

of patients achieve long term disease control, locoregional failure is either 

detected early (failure to enter complete remission) or at a later date as 

locoregional recurrence. We explore the pattern and timing of disease 

recurrence within a phase III trial (ACT II), which mandated standardised 

radiation fields and doses (50.4Gy in 28 daily fractions). Methods: The UK 

ACT II trial recruited a total of 940 patients (2000 -2008) and compared 

cisplatin with mitomycin when combined with 5flurouracil CRT and two 

cycles of maintenance chemotherapy versus no maintenance using a 

factorial 2x2 design. Patient characterstics: T1/2 52%, T3/4 46%; N� 

32% N0 62%. The loco-regional response to treatment was assessed by 

clinical examination at 11, 18 and 26 weeks after CRT. Clinical examination 

was performed every two months for year 1; 3-monthly for year 2; then 

6-monthly for years 3-5. CT scans of chest/abdomen/pelvis were performed 

at 6,12 24 months. Sites of failure were recorded on a case record form 

(primary site [PS], inguinal [ING], pelvic nodes [PEL], metastatic [METS]. 

Results: After a median follow up of 5 years, the crude pelvic failure (PF) 

rate is 18% (163/924). Of the 163 PF, 133 pts (82%) were pelvic only and 

30 (18%) had PF � metastasis. 93% of all pelvic recurrences were 

detected during the first three years (54% yr 1, 26% yr 2 and 13% yr 3). 

The pattern was similar for PF only and PF � mets (data not shown). Only 

46 (4%) of patients had [METS] as the first disease related event. 117/133 

(88%) patients with PF only are evaluable for analysis of the pattern of 

failure., 53% occurred at the primary site (PS) only, 23% were PS � nodal 

(5% [ING] 13% [PEL] and 5% [ING�PEL], and 25% nodal only (6% 

[ING],14% [PEL] and 5% [ING�PEL]). Conclusions: The ACT II trial results 

with mature follow-up demonstrate a low rate of pelvic failure. Intensive 

follow up to detect potentially salvageable pelvic failure should be 

restricted to a maximum of three years in future trials as only 7% of 

relapses occur beyond this time point. 


245s 


4:45 PM-5:45 PM 

A randomized phase II study of continuous versus intermittent S-1 plus 

oxaliplatin in first-line treatment of patients with metastatic gastric 

carcinoma. Presenting Author: Sook Ryun Park, Center for Gastric Cancer, 

National Cancer Center, Goyang, Gyeonggi, South Korea 

Background: We conducted a randomized phase II study to compare 

continuous vs. intermittent S-1 � oxaliplatin (SOX) after induction of 6 

cycles of SOX in patients (pts) with metastatic gastric cancer (MGC). 

Methods: Pts �18 yrs with chemo-naive MGC, normal organ function, 

ECOG PS 0-2, and measurable or evaluable lesion(s) were initially given an 

induction treatment of 6 cycles of SOX (S-1 40 mg/m2 bid on D1-14 � 

oxaliplatin 130 mg/m2 on D1 q 3 wks). Pts with CR/PR or SD were 

randomized to continue SOX (arm A) until progression/intolerable toxicity 

or discontinue until progression when SOX was re-administered (arm B). 

The primary endpoint was overall survival (OS), and secondary endpoints 

included progression-free survival (PFS), response rate, safety, quality of 

life, and biomarker correlative studies. Results: From July 2007 to Dec 

2010, a total of 250 pts entered into the study. Median age was 53 yrs 

(range, 24-69); PS 0/1/2�13/219/18; M/F�162/88. Three pts did not 

receive treatment and 126 (50.4%) discontinued treatment before or at 

the completion of 6 cycles of SOX due to progression (45.6%), pt refusal 

(2.8%), or adverse events (2.0%). A total of 121 pts were randomized: 59 

(48.8%) to arm A and 62 (51.2%) to arm B. Clinical characteristics were 

well balanced between arms. SOX continuation resulted in a significant 

reduction in the risk of progression (median PFS, 10.5 months for arm A vs. 

7.2 months for arm B; HR�0.57, 95% CI 0.39-0.84, p�0.005). With a 

median follow-up of 34.0 months (range, 10.5-53.3 months), there was no 

significant difference in OS (median OS, 22.6 months for arm A vs. 22.7 

months for arm B; HR, 0.79, 95% CI 0.51-1.25, p�0.31). Arm A had 

higher rates of grade 3/4 fatigue (28.8% vs. 8.1%, p�0.004) and 

neuropathy (25.4% vs. 8.1%, p�0.014) but other grade 3/4 hematologic 

(neutropenia, 35.6% vs. 32.3%; thrombocytopenia, 23.7% vs. 21.0%; 

anemia, 15.3% vs. 6.5%) or non-hematologic toxicity rates were not 

significantly different. Conclusions: Continuous chemotherapy with SOX 

after induction therapy improved PFS but not OS. Supported by NCC Grant 

1010180 (S-1 and oxaliplatin was provided by JEIL Pharm. Co., Ltd. and 

sanofi-aventis Korea Co., Ltd., respectively). 


4:45 PM-5:45 PM 

Phase II trials of cetuximab (CX) plus cisplatin (CDDP), 5-fluorouracil 

(5-FU) and radiation (RT) in immunocompetent (ECOG 3205) and HIVpositive 

(AMC045) patients with squamous cell carcinoma of the anal 

canal (SCAC): Safety and preliminary efficacy results. Presenting Author: 

Madhur Garg, Albert Einstein College of Medicine/Montefiore Medical 

Center, Bronx, NY 

Background: Epidermal growth factor receptor (EGFR) expression and HPV 

infection are common in SCAC. We therefore initiated 2 phase II studies to 

evaluate the safety and efficacy of the EGFR inhibitor CX given concurrently 

with CDDP/5-FU/RT in HIV-positive (AMC045) and immunocompetent 

(E3205) patients with SCAC. Methods: All patients received CX (400 

mg/m2 loading, then 250 mg/m2/wk IV x 6-8 wks) plus CDDP (75 mg/m2 

IV q28 days x 2) and 5-FU (1000 mg/m2/day IV infusion days 1-4 q 28 

days x 2) concurrently with RT (45-54 Gy) beginning with CX dose 2. 

Patients in E3205 also received 2 cycles of CDDP/5-FU alone prior to 

CX/CDDP/5-FU/RT; this was discontinued on recommendation of the NCI 

Anorectal Task Force after 28 patients. Both trials were powered to detect a 

reduction in 3-year local-regional failure (LRF) rate from 35% to 17.5% 

(alpha�0.10, beta�0.10), the primary end point. Other endpoints included 

progression free survival (PFS) and overall survival (OS). The results 

below include complete toxicity and preliminary efficacy data (including 

only the first 28 patients from E3205). Results: Expedited reporting was 

required for type I (any grade 5, grade 4 cardiac) or II (grade 4 RT skin, 

diarrhea) adverse events, with prespecified rates of �5% or �20%, 

respectively defined as unacceptable. Early stopping rules were not invoked 

for either trial. LRF rates data will be presented after more detailed case 

review is completed. Conclusions: CX plus CDDP/5-FU/RT is feasible in 

patients with SCAC, including patients with HIV infection. Preliminary 

safety and efficacy data appear encouraging, but accrual without neoadjuvant 

CDDP/5-FU continues in E3205, and additional followup of both 

study cohorts is required in order to determine whether pre-specified 

efficacy endpoints were met. 

AMC045 E3205 

No. 45 28 

Stage I/II/III 24%/42%/34% 11%/50%/39% 

Completed protocol therapy 37 (82%) 22 (79%) 

Type I/II adverse events 2 (4%)/0 1 (4%)/1 (4%) 

Colostomy rate 7% (1-18%) 14% (4-33%) 

2 year PFS rate (95% CI) 80% (61-90%) 92% (81-100%) 

2 year OS rate (95% CI) 89% (73-96%) 93% (83-100%) 




4:45 PM-5:45 PM 

Randomized phase II trial of gemcitabine plus S�1 combination therapy 

versus S�1 in advanced biliary tract cancer: Results of the Japan Clinical 

Oncology Group study (JCOG0805). Presenting Author: Makoto Ueno, 

Kanagawa Cancer Center Hospital, Yokohama, Japan 

Background: Gemcitabine plus cisplatin combination (GC) therapy is the 

standard therapy for advanced biliary tract cancer (BTC). In previous trials, 

gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had 

shown considerable efficacy in patients with BTC. The aim of this trial is to 

evaluate the efficacy and safety of the two regimens and to determine which 

is more promising as a test arm regimen for a subsequent phase III trial. 

Methods: Chemotherapy-naive patients with recurrent or unresectable BTC 

(gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary 

duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0-1,andadequate 

organ function were randomly assigned to receive GS (gemcitabine: 1,000 

mg/m2 , iv, days 1 and 8; S-1: 60 mg/m2 , p.o., days 1 - 14, every 3 weeks) or 

S-1 (80 mg/m2 , p.o., days 1 - 28, every 6 weeks). We assumed that 

%1-year survival of one regimen is 30% and that of the other regimen is 

more than 40%. To ensure at least 85% probability of correct selection, 98 

eligible pts are required. The decision rule was that the regimen with higher 

%1-year survival will be considered as more promising regimen. Results: 

From February 2009 to April 2010, 101 pts (GB, n�38; IHBD, n�35; 

EHBD, n�20; AV, n�8) were randomized (GS, n�51; S-1, n�50). For the 

GS arm and S-1 arm, %1-year survivals were 52.9% and 40.0%, the 

median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95%CI 

0.54-1.36]; p�0.52), and the median progression-free survival time were 

7.1 and 4.2 months (0.44 [0.29-0.67]; p�0.0001). Grade 3/4 hematological 

toxicities were more frequent in the GS arm than in the S-1 arm, 

(percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 

29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0; respectively. 

Although two treatment-related deaths occurred in the GS arm 

(pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological 

toxicities were infrequent and reversible in both arms. Conclusions: The 

GS arm was superior in %1-year survival to S-1. Here we consider GS to be 

more promising as the test arm for a subsequent phase III trial comparing 

with GC. 


4:45 PM-5:45 PM 

Observations of hepatocellular carcinoma (HCC) management patterns 

from the global HCC bridge study: First characterization of the full study 

population. Presenting Author: Joong-Won Park, National Cancer Center, 

Goyang, South Korea 

Background: HCC is a major health problem across the world. The global 

HCC BRIDGE study is the first global, large-scale, observational study to 

document the real-world experience of HCC patients from diagnosis to 

death. Methods: This longitudinal cohort study (started March 2009) 

includes HCC patients newly diagnosed between January 2005 and June 

2011 and treated at major medical centers, with data collected retrospectively 

and prospectively as recorded in patient charts. Full patient enrollment 

is expected at the end of January 2012. Results: At the time of the 

first interim analysis (July 2011), 12,442 treated HCC patients were 

enrolled at 42 sites in Asia (n�8909, 72% [China: n�6295, 71%; Japan: 

n�295, 3%]), Europe (n�2040, 16%) and North America 1493 (n�1493, 

12%). Mean age was 57 years; 82% were male. The predominant risk 

factor was HBV in Asia (76%) and HCV in Europe (48%), North America 

(45%) and Japan (69%). Most patients were diagnosed without surveillance 

(Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In 

Asia, Europe and North America, the predominant BCLC stage at diagnosis 

was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded 

treatments in Asia, Europe and North America were resection (31%, 15%, 

21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other 

locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 

8%). Treatments ever used (2005–2011) in Asia, Europe and North 

America were resection (33%, 17%, 24%), transplantation (2%, 6%, 

12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 

37%) and systemic therapy (9%, 20%, 21%). These results will be 

updated with data from the full study population (approx. 19,000 patients), 

and preliminary survival data will be presented. Conclusions: As the 

largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE 

study provides valuable insights into global HCC disease characteristics 

and patient management. Based on prior analyses, differences in risk 

factors among regions confirm well-known trends, while other observed 

differences (e.g., treatment variations) may be related to country- and 

site-specific practices and patient characteristics. 


4:45 PM-5:45 PM 

Gemcitabine and oxaliplatin (GEMOX) alone or in combination with 

cetuximab as first-line treatment for advanced biliary cancer: Final analysis 

of a randomized phase II trial (BINGO). Presenting Author: David Malka, 


Background: Gemcitabine-platinum chemotherapy (CTx) regimens are widely 

accepted as first-line standard of care for patients (pts) with advanced 

biliary cancers (ABC). EGFR overexpression has been observed in ABC, 

suggesting that the combination with anti-EGFR monoclonal antibodies 

may be appropriate. Methods: Patients with ABC, WHO performance status 

(PS) 0-1, and without prior palliative CTx were eligible for this international, 

open-label, two-stage, non-comparative, randomized phase II trial. 

Patients received GEMOX (gemcitabine, 1 g/m² [10 mg/m²/min] at day [D]1 

� oxaliplatin, 100 mg/m² at D2, arm A) or GEMOX � cetuximab (500 

mg/m² at D1 or 2, arm B), every 2 weeks. The primary endpoint was crude 

4-month progression-free survival (PFS) rate (H0, �40%; H1, �60%; 

planned sample size, 100 pts, increased to 150 pts by amendment to allow 

subgroup analyses). Secondary endpoints were objective response rate 

(ORR), disease control rate (DCR), PFS, overall survival (OS), and toxicity 

(NCI-CTC v3.0). Exploratory endpoints included early metabolic response 

as assessed by PET at 1 month, and tumor KRAS mutational analysis. 

Results: From Oct. 2007 to Dec. 2009, we enrolled 150 pts (median age, 

62 years; male, 57%; metastatic, 79%; cholangiocarcinoma, 84%; median 

follow-up, 30 months) (Table). Conclusions: GEMOX-cetuximab regimen 

was well tolerated and met its primary endpoint (4-month PFS 

�60%). However, median PFS and OS were similar in both arms. 

Exploratory analyses (e.g., KRAS tumor status) are underway to identify pt 

subgroups deriving benefit from the addition of cetuximab to CTx. 

Arm A Arm B 

Cycles (median) (n) 10 10 

Toxicity (%) 1 

Peripheral neuropathy 2 

46 49 

Neutropenia 16 22 

Fatigue 13 17 

Thrombocytopenia 19 11 

Gastrointestinal 15 13 

Allergy/hypersensitivity 1 8 

Rash 0 7 

Efficacy [95% CI] 

ORR (%) 3 

29 [18-40] 23 [13-33] 

DCR (%) 3 

77 [67-88] 87 [79-95] 

4-month PFS (%) 53 [41-64] 63 [52-74] 

PFS (median, months) 5.3 [3.7-6.6] 6.0 [5.0-7.4] 

OS (median, months) 12.4 [8.6-16.0] 11.0 [8.9-13.7] 

1 Grade 3-4, NCI-CTC v3.0. 

2 Grade 2-3, Modified Levi’s scale. 

3 In 131 evaluable pts. 


Final results of a phase I/II study in patients with pancreatic cancer, 

malignant melanoma, and colorectal carcinoma with trabedersen. Presenting 

Author: Helmut Oettle, Universitätsmedizin Berlin Charite, Campus 

Virchow-Klinikum, Berlin, Germany 

Background: TGF-�2 overexpression in solid tumors triggers key cancer 

pathomechanisms, i.e. suppression of antitumor immune responses system 

and metastasis. Trabedersen specifically inhibits TGF-�2 expression. 

In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics 

(PK), and efficacy of i.v. trabedersen in patients with advanced tumors. 

Methods: A total of 61 patients with pancreatic cancer (PancCa, n�37), 

malignant melanoma (MM, n�19), or colorectal carcinoma (n�5) were 

treated with i.v. trabedersen as 2nd to 4th-line therapy with escalating doses 

in 2 treatment schedules. (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 

10d off; up to 10 cycles). Within the 1st schedule, the MTD was established 

at 160 mg/m2 /d. In the 2nd schedule dose-escalation was stopped before 

reaching MTD. In the Phase II-part of the study further PancCa and MM 

patients were treated with 140 mg/m2 /d. For assessment of PK parameters, 

plasma time profiles were analyzed for trabedersen and its n-1 to n-5 

metabolites by non-compartimental analysis. Results: Trabedersen was safe 

and well-tolerated. The only expected adverse reaction identified is 

non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal 

hemorrhage und pyrexia) were considered as possibly related to study 

medication. Further clinical development will focus on PancCa patients 

receiving 140 mg/m2 /d trabedersen as 2nd-line treatment. Survival analysis 

of these patients revealed a mOS of 13.4 months (n�9; 95% CI: 2.2, 

39.7). One PanCa patient had a complete response of liver metastases and 

is still alive after 75 months. Promising efficacy data were also seen in MM 

patients enrolled into the last cohort (140 mg/m2 /day) with a current mOS 

of 9.3 months (n�14; 95% CI: 6.5, 12.2). PK analyses showed for both 

treatment schedules that exposure to trabedersen was in the expected 

range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as 

clearance (2.22-4.37 L/h*m2 ) were independent of dose. Conclusions: 

Trabedersen showed excellent safety and encouraging survival results in 

the Phase I/II clinical study. A randomized, active-controlled study in 2nd line stage IV PanCa patients is in preparation. 



Updated results of the GEST study: Randomized phase III study of 

gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in 

unresectable advanced pancreatic cancer in Japan and Taiwan. Presenting 

Author: Akira Fukutomi, Shizuoka Cancer Center, Sunto-gun, Japan 

Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) 

demonstrated the non-inferiority of S-1 to GEM with respect to the primary 

endpoint of overall survival (OS) in patients with pancreatic cancer (PC). 

We now report the updated results of this study. Methods: The GEST study 

was a randomized, 3-arm, phase III study. Chemotherapy-naive patients 

with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, 

and adequate organ functions were randomly assigned to receive GEM 

(1000 mg/m2 , iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on 

BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2 , iv, d1 and 8 plus S-1 

60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint 

was OS, used to assess the non-inferiority of S-1 and the superiority of GS 

to GEM. Patient information was updated in July 2011. Results: At the time 

of this follow-up analysis, median follow-up was 29.8 months with 795 OS 

events, compared with 18.4 months with 710 OS events out of 832 

patients at the previous analysis. Median OS was 8.8 months (95% CI: 

8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 

group (HR�0.96, 97.5% CI: 0.79-1.17, p�0.001 for non-inferiority), 

which is consistent with prior results (HR�0.96, 97.5% CI: 0.78-1.18, 

p�0.001). In the GS group, median OS was 9.9 months (95% CI: 

9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p�0.28 for superiority 

versus the GEM group). On subgroup analysis, GS was associated with a 

non-statistically significant trend toward better OS compared with GEM 

among patients with locally advanced disease and those with a PS of 1. 

Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 

15.9 months (95% CI: 13.0-19.7) in the GS group (HR�0.72, 95% CI: 

0.51-1.03) among patients with locally advanced disease, and 6.2 months 

(95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) 

in the GS group (HR�0.62, 95% CI: 0.46-0.83) among patients with a PS 

of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary 

endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one 

of the standard treatments for advanced PC. As for GS therapy, there is 

room for further investigation. 


Incidence and characterization of venous thromboembolic events (VTE) in 

patients with pancreatic cancer: Effect of timing of VTE on survival. 

Presenting Author: Maithili A. Shethia, University of Texas M. D. Anderson 


Background: Patients (pts) with pancreatic cancer are at high risk for VTE, 

and the occurrence of VTE can affect pts’ prognosis. The purpose of this 

study was to evaluate the incidence of VTE and the impact of timing of VTE 

(early vs. late) on survival. Methods: Medical record of 260 pts with 

pancreatic cancer, newly referred to UT MDACC during one year period 

from 1/1/2006 to 12/31/2006, were reviewed for the incidence of VTE 

during a 2-year follow-up period from the date of diagnosis. All VTE 

episodes were confirmed by radiologic studies. Survival analysis was 

conducted using Kaplan-Meier analysis and Cox proportional hazard 

models. Results: Of the 260 pts, 47 pts (18%) had 51 episodes of VTE 

during the 2-year follow-up. The median age of the pts with VTE was 61 

years (range: 28-86) and 53% were males. Of the 47 pts with VTE, 27 

(57%) had PE, 19 (40%) had DVT and 1 had concurrent PE/DVT. Three pts 

had recurrent VTE during the study period. Median follow-up time for OS 

was 192 days (range: 1-1652 days). Kaplan-Meier Survival analysis 

showed that those who developed VTE earlier (within 30 or 90 days) had 

shorter median overall survival (OS) compared with those who had VTE 

beyond these time points. The hazard ratios, 95% CI, and median OS at 1 

year are summarized in the table below. Conclusions: The incidence of VTE 

is high in pts with pancreatic cancer. The timing of VTE had a significant 

impact on OS; pts who had an early development of VTE had a shorter 

overall survival. 

Timing of VTE* 

1 year OS Median 1 year OS** 

Hazard ratio 


Early VTE 

vs. late VTE p value*** 

Within 30 days 3.52 (1.71-7.23) 0.0006 116 vs. 295 0.0003 

Within 90 days 5.33 (1.85-15.35) 0.0019 152 vs. NR 0.0006 

* From the date of diagnosis of pancreatic cancer to date of diagnosis of VTE; ** 

days; *** Log-rank; NR: not reached. 



Efficacy and safety of bevacizumab combined with chemotherapy in the 

treatment of patients with metastatic well-differentiated duodenopancreatic 

endocrine tumors (BETTER study). Presenting Author: Michel 

Ducreux, Institut Gustave Roussy, Villejuif, France 

Background: Gastrointestinal neuroendocrine tumors (NET) overexpress 

vascular endothelial growth factor (VEGF), thus we hypothesized that 

Bevacizumab (Bv), a monoclonal antibody targeting VEGF in combination 

with chemotherapy may show an activity in duodeno-pancreatic NET. 

Methods: This multicenter, open-label, non-randomized, two- group phase 

II trial assessed in one group the efficacy and safety of Bv (7.5 mg/kg IV on 

day 1, every 3 weeks), combined with 5-FU/streptozotocin (stz): 5-FU 400 

mg/m²/d; Stz 500 mg/m²/d IV, d1-5/ every 42 days, during a minimum of 6 

months in patients (pts) with progressive, metastatic, well-differentiated 

duodeno-pancreatic NET (WHO 2000), not previously treated with chemotherapy, 

ECOG PS �2 and Ki 67 index � 15%. Primary endpoint was 

progression-free survival (PFS). Secondary endpoints were overall survival 

(OS), response rate, safety and quality of life. Study duration was 24 

months. Results: In the ITT population, 34 pts were enrolled, 22 (64.7%) 

were men, median age 55.3 years (37.0-77.6), 33 (97.1%) pts had 

ECOG-PS 0/1. Most metastases were in the liver 33 (97.1%) pts or lymph 

nodes 14 (41.2%) pts. Ki-67 proliferative index was 0-2% in 8 (25%) pts, 

3-4% in 5 (15.6%), 5-9% in 6 (18.8%), 10-14% in 12 (37.5%) and 15% 

in 1(3.1%) pt. Median treatment duration was 14.0 months; median 

number of cycles was 10. At 24 months, median PFS was 23.7 months 

[95%CI: 14.5; not reached] based on 18 events. PFS rate at 18 months 

was 62%. Tumor control rate was 100% (n� 34) including partial response 

in 19 (55.9%) pts and stable disease in 15 (44.1%) pts. Survival rate at 24 

months was 88%. Median OS was not reached, 5 patients died. CTC grade 

3/4 Adverse Events (AEs) occurred in 23 (67.6%) of pts, mainly digestive 5 

(14.7%) pts. G3/4 Bv targeted AEs were hypertension in 7 (20.6%) pts and 

thromboembolism in 4 (11.8%). Conclusions: Efficacy data in this phase II 

trial assessing a novel approach with Bv and 5-FU/stz in duodenopancreatic 

NET is encouraging and the toxicity profile is acceptable. 

Results suggest that Bv may have a place in the treatment of pancreatic 

NET and warrant further investigation in a phase III trial. 


A pooled analysis of phase II trials of gemcitabine (GEM)-containing 

doublets plus bevacizumab (BEV): Should combination chemotherapy 

serve as the backbone in clinical trials of advanced pancreatic cancer 

(APC)? Presenting Author: Katherine Van Loon, University of California, 

San Francisco Comprehensive Cancer Center, San Francisco, CA 

Background: GEM has served as the chemotherapy platform for most phase 

III clinical trials in APC, inc. CALGB 80303 (GEM �/- BEV). However, 

GEM-based combination regimens may confer superior outcomes in select 

pts and represent a preferred backbone in clinical trial design testing 

targeted agents. Methods: Data was pooled from 5 phase II trials evaluating 

GEM-based cytotoxic doublets plus BEV in APC. 1 o endpoint was OS. 2o endpoints included ORR, CA19-9 response, and adverse events (AEs). 

Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional 

hazard model estimated univariate hazard ratios (HR) of death. 

Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, 

and 91.6% had metastatic disease. Median age � 60y. Pooled OS data (in 

mos), stratified for PS and stage, is shown in the table. ORR across all 

trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts 

who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% 

CI 0.23-0.54, p�0.001). 76.5% of pts had elevated baseline CA19-9; of 

these, 62% achieved �50% reduction (HR 0.50; 95% CI 0.34-0.73, 

p�0.001). BEV-related AEs �grade 3: HTN (10.6%), hemorrhage (9.5%), 

VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). 

Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those 

without (HR 0.77; 95% CI 0.48-1.24, p�0.29). Conclusions: Recognizing 

the limitations of single-arm phase II trial design and cross-study comparisons, 

these results compare favorably to those from CALGB 80303. The 

standard paradigm of GEM �/- drug X in clinical trial development for APC 

needs to be reconsidered. Based on our data as well as the recent phase III 

FOLFIRINOX study, building on more intensive combination chemo regimens 

in future trials may represent a better strategy, especially for pts with 

good PS. 

gem/ox � 

bev 

gem/cap � 

bev 

gem/cis � 

bev 

gem/doc � 

bev 

gem/ox � 

bev 

Phase II 

total 

247s 

CALGB 

80303 

N 50 

Median OS 11.7 

PS 

0 

1 

2 

Stage 

Locally advanced 

Metastatic 

50 

9.8 

52 

8.4 

27 

10.4 

79 

8.4 

179† 

9.9 

11.1 

9.1 

3.3 

14.2 

9.5 

602 

5.8 - 5.9 

7.9 

4.8 

2.4 

9.9 

5.7 

† Reflects 4 studies with available raw data. 




Baseline albumin (b-alb) as a potential predictive biomarker for the efficacy 

of bevacizumab (B) therapy (tx) in patients (pts) with advanced pancreas 

cancer (APCA): A comparative analysis. Presenting Author: Ludmila Katherine 

Martin, The Ohio State University Medical Center, Columbus, OH 

Background: Phase III studies of B in unselected pts with APCA have 

demonstrated no improvement in outcome. Recent data suggest certain 

subsets of APCA patients may benefit from B. Lower b- alb results in a 

15-20% increased rate of B clearance that may decrease exposure to B. 

The resulting clinical implications are not well understood. We evaluated 

the potential predictive and prognostic role of b-alb in pts with APCA 

receiving gemcitabine (G)-based tx with or without B. Methods: Relevant 

data were collected from 3 prospective phase II studies of G-based tx. Pts 

were grouped according to exposure to B (Gr 1) or no B (Gr 2) and by b-alb 

� 3.4 g/dL (� LLN) or � 3.4 g/dL (�LLN). Univariate and multivariate 

analyses of clinical outcome (OS, TTP) were conducted for each group and 

all pts. Results: 100 pts (46M, 54F) with median age 63 (range 28-82) 

were included. 94% had stage IV. Median b-alb was similar in both groups. 

Clinical outcomes by alb are outlined in the table. In Gr 1 but not Gr 2, 

b-alb � 3.4 g/dL was significantly associated with improved OS and TTP. 

For pts with b-alb �3.4 g/dL, maintenance of alb �3.4 g/dL throughout tx 

was significantly associated with improved survival in Gr 1 but not Gr 2. 

Multivariate analysis revealed significant association between alb � 3.4 

and OS regardless of B status (p�0.004) although this was strongly 

influenced by the survival differential in Gr 1. Conclusions: APCA pts with 

b-alb � 3.4 g/dL appear to derive significant benefit from B and this benefit 

is most pronounced in pts who maintain alb � 3.4 g/dL throughout B tx. 

This finding was not observed in pts treated without B. b-alb � 3.4 g/dL 

including maintenance of alb � 3.4 g/dL during B tx may predict for 

improved efficacy of B in APCA. These findings require further investigation 

in larger prospective trials. 

Clinical outcome according to alb. 

Group 1 (N�42) Group 2 (N�58) 

b-alb � 3.4 g/dL b-alb � 3.4 g/dL p b-alb � 3.4 g/dL b-alb � 3.4 g/dL p 

(N�28) 

(N�14) 

(N�43) 

(N�15) 

mOS (m) 10.7 3.1 0.00175 7.3 5.4 0.22 

mTTP (m) 7.7 2.7 0.009 3.9 2.8 0.76 

alb � 3.4 w/tx alb 2to � 3.4 w/tx p alb�3.4 w/tx alb 2to � 3.4 w/tx p 

(N�9) 

(N�19) 

(N�8) 

(N�29) 

mOS (m) 20.1 8.6 0.003 8.9 5.9 0.63 


Development of the SP120 rabbit monoclonal antibody for determining 

hENT1 status and predicting response to gemcitabine in pancreatic ductal 

adenocarcinoma. Presenting Author: Stefan Hubert Boeck, Department of 

Hematology and Oncology, Klinikum Grosshadern and Comprehensive 

Cancer Center, LMU Munich, Munich, Germany 

Background: Human equilibrative nucleoside transporter 1 (hENT1) is the 

primary membrane channel through which gemcitabine (Gem) enters 

pancreatic tumor cells. Patients whose tumors have low expression of 

hENT1 may derive little benefit from Gem therapy. Methods: We have 

developed and analytically validated a rabbit monoclonal antibody, SP120, 

immunohistochemistry (IHC) in vitro diagnostic (IVD) assay, used on the 

VENTANA BenchMark ULTRA automated slide staining platform, for 

assessing hENT1 expression in pancreatic adenocarcinoma. Results: SP120 

was shown to be sensitive and specific for membrane expression of hENT1 

with variable expression demonstrated across a panel of primary pancreatic 

adenocarcinoma samples. Using retrospectively collected primary tumor 

samples (n � 201) from a randomized controlled clinical adjuvant trial 

(RTOG 97-04), we developed and verified a hENT1 scoring algorithm and 

cut-off for identifying patients least likely to benefit from Gem (hENT1low). 

We confirmed the predictive value of the hENT1 assay by showing 

there was no association with clinical outcome in the 5FU-treated control 

group. The distribution of hENT1 expression was similar between these 

samples and an independent set of 130 pancreatic adenocarcinoma 

specimens from the AIO-PK0104 study (77 were confirmed metastatic 

biopsies). Importantly, 100% concordance in hENT1 status (high vs. low) 

was demonstrated between 16 primary tumors and paired, contemporaneous 

metastatic lesions. Overall, using this cut-off, approximately two thirds 

of pancreatic tumors displayed low-hENT1 expression across the different 

data sets (n � 363). Conclusions: The hENT1 IHC IVD has been developed 

and is being used in a pivotal trial of a novel lipid-conjugated Gem 

(CO-101, which enters tumor cells independently of hENT1), vs. Gem in 

hENT1-low pancreatic cancer patients (NCT01124786). This study is the 

first prospective test of the hypothesis that gemcitabine is not active in 

tumors with low hENT1 expression. 


Antitumor activity of nab-paclitaxel and gemcitabine in resectable pancreatic 

cancer. Presenting Author: Rafael Alvarez-Gallego, Centro Integral 

Oncológico Clara Campal, Madrid, Spain 

Background: Nab-paclitaxel in combination with gemcitabine has shown 

interesting clinical activity in patients with advanced pancreatic cancer 

(PDA) likely related to its ability to eliminate pancreas cancer stroma. In 

this study we explore clinical and pathological effects of the combination in 

patients with operable PDA. Methods: Patients with resectable o borderline 

resectable pancreatic cancer were treated with gemcitabine(1000mg/m2 

days 1, 8 and 15) and nab-paclitaxel(125mg/m2 days 1, 8 and 15) for two 

cycles prior to surgery. Response was assessed by FDG-PET, CA199 levels 

and elastography, an EUS-based non invasive assessment of tumor stroma. 

Results: 16 patients were included into the study. 2 patients (12.5%) 

showed a progression disease (both with hepatic metastases) and were not 

operated. Median value for PET SUVmax decreased from 7,1 pre-treatment 

to 4,6 post-treatment(p�0.004), including 7(50%) of patients with a 

partial metabolic response and the mean CA199 decreased from 2654 to 

52(p�0.02) with 43% patients having a more that 75 % decrement in 

tumor marker. The elastography ratio value diminished from 36 pretreatment 

to 18 post-treatment(p�0.003) and correlated with improvement 

in SUVmax(p�0.04) and CA199 response(p�0,07). Grade 3-4 

toxicities were neutropenia in 18% (none febrile neutropenia), thrombocytopenia 

in 12.5 and 6.2% transaminase elevation. So far 9 patients have 

been operated and in 8(89%) a complete resection (R0) was achieved. 1 

patient had a complete pathological response and 4 patients had near 

complete responses with only a few(� 5%) residual tumor. In-depth 

analysis of stromal composition after treatment showed, compared to a 

series of 10 cases untreated and treated with conventional chemoradiation, 

decreased myofibroblast content, increase vessel density and distorted 

collagen fibers. Conclusions: Neoadjuvant treatment with gemcitabine plus 

nab-paclitaxel is feasible and results in significant clinical activity. Noninvasive 

elastography appears and attractive method to monitor tumor 

response. The rate of pathological responses and R0 resections in substantial 

for this setting. Biological studies of resected specimens show unique 

effects in tumor stroma. 


A phase III trial of ganitumab (GAN, AMG 479) with gemcitabine (G) as 

first-line treatment (tx) in patients (pts) with metastatic pancreatic cancer 

(MPC): An analysis of safety from the GAMMA trial (GEM and AMG 479 in 

Metastatic Adenocarcinoma of the Pancreas). Presenting Author: Charles 

S. Fuchs, Dana-Farber Cancer Institute, Boston, MA 

Background: GAN is an investigational, fully human, monoclonal antibody 

inhibitor of IGF1R. GAMMA is assessing the safety and efficacy of GAN plus 

G as first-line tx in MPC pts (ClinicalTrials.gov ID: NCT01231347). 

Methods: This is an ongoing, global, phase III, double-blind study. Pts are 

randomized 2:2:1 to receive placebo, GAN 12 mg/kg, or GAN 20 mg/kg (IV; 

days 1 and 15 Q28D) with G 1000 mg/m2 (IV; days 1, 8, and 15 Q28D). 

The planned sample size is 825. Primary endpoint: overall survival. Key 

secondary endpoints: progression-free survival, 1-year survival rate, patientreported 

outcomes, and safety. This study includes multiple planned safety 

analyses conducted by an independent Data Monitoring Committee (DMC). 

The current predefined safety analyses occurred when 150pts received � 1 

cycle of tx. Results: As of Sep 16, 2011, 207 pts are included in this 

aggregate analysis: 50% male; median age, 63 yrs (range 36-83); ECOG 

PS 0/1, 50%/50%. Of the 207 pts, 204 pts received study tx, and 61 pts 

ended study tx. Most frequent adverse events (AE) are shown (table). Ten 

pts (5%) died during or within 30 days of the end of tx. Seven events were 

attributed to or associated with disease progression. One event of cardiac 

failure was reported to be possibly tx related. Pulmonary embolism was 

suspected but not confirmed. Conclusions: The GAMMA study continues 

per protocol. The only grade 3/4 AE occurring in more than 5% of patients 

to date is neutropenia. 

Any grade AE occurring in > 15% of pts or higher grade AE in > 3% of ptsa . 

Any grade-n(%) 

CTCAE v3.0 

Grade 3/4-n(%) 

CTCAE v3.0 

AE, MedDRA terms 

Thrombocytopenia b 

Neutropenia 

79 (39) 8 (4) 

c 

72 (35) 47 (23) 

Nausea 69 (34) 4 (2) 

Fatigue 56 (27) 9 (4) 

Decreased appetite 45 (22) 2 (1) 

Vomiting 38 (19) 4 (2) 

Pyrexia 36 (18) 0 (0) 

Diarrhea 35 (17) 1 (0) 

Leukopenia 34 (17) 7 (3) 

Alanine aminotransferase increased 28 (14) 9 (4) 

Hyperglycemia 27 (13) 9 (4) 

Aspartate aminotransferase increased 23 (11) 7 (3) 

Asthenia 21 (10) 6 (3) 

a Analysis includes all 3 tx arms and excludes 3 pts who did not receive any tx; b Includes 

platelets decreased; c Includes neutrophils decreased. 



Phase I/II study of 90Y-clivatuzumab tetraxetan ( 90Y-hPAM4) combined 

with gemcitabine (Gem) in advanced pancreatic cancer (APC): Final 

results. Presenting Author: Allyson J. Ocean, New York Presbyterian 

Hospital-Weill Cornell Medical College, New York, NY 

Background: A Phase I/II trial evaluated single and repeated cycles of 

fractionated radioimmunotherapy (RAIT) with 90Y-labeled humanized mAb 

( 90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: 

Cycles of Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4 were 

repeated until progression, withdrawal or unacceptable toxicity. In Part I, 

90 2 Y doses were escalated with Gem fixed at 200 mg/m . In Part II, Gem was 

increased up to 1000 mg/m2 , with 90Y fixed at 12 mCi/m2 for cycle 1 and 

lowered for retreatment. Results: Of 100 pts entered, 10 withdrew early, 

while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 

90 2 Y-hPAM4 weekly x3at6.5, 9, 12, or 15 mCi/m , with the same cycle 

repeated 1-3 times in 13 pts. By CT-RECIST criteria, 6 pts (16%) had PRs 

and 16 (42%) had stabilization as best response (58% disease control). 

After cycle 1, 52% (13/25) with PET-avid images had �25% SUV 

reduction, and 33% (9/27) with elevated CA19-9 levels decreased by 

�50%. The median OS was 7.7 mo., but 11.8 mo. for retreated pts [46% 

(6/13) survived �1 yr.], and with improved efficacy at higher 90Y doses. 

NCI-CTCv3 Grade 3-4 platelets or ANC developed in 20/38 (53%) after 

cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 

pts at 12 or 15 mCi/m2 ). In Part II, 52 pts received increased Gem without 

evidence of improved efficacy, while 13 pts were retreated with more 

acceptable toxicity at lower 90Y doses of 6.5 or 9 mCi/m2 . Treatment was 

well tolerated with no infusion reactions. Infections requiring IV antibiotics 

occurred at a low rate and responded to appropriate coverage (bacteremia/ 

sepsis, 7%; febrile neutropenia, 4%; ascending cholangitis, 3%; pneumonia, 

2%; others 1%). One case of bleeding occurred, due to rectal tumor 

invasion. Anecdotal reports of good performance and decreased pain 

medication requirements require further validation. Conclusions: Fractionated 

RAIT with 90Y-hPAM4 combined with low-dose 200 mg/m2 GEM 

appears promising as a treatment regimen for APC. Hematologic toxicity 

was dose limiting. A 90Y-hPAM4 dose of 12 mCi/m2 for cycle 1 and 6.5 

mCi/m2 for cycle 2 have been selected as suitable for further clinical 

development in the first-line setting. 


A phase II multi-institutional study to evaluate gemcitabine and fractionated 

stereotactic body radiotherapy for unresectable, locally advanced 

pancreatic adenocarcinoma. Presenting Author: Joseph M. Herman, Sidney 

Kimmel Comprehensive Cancer Center at Johns Hopkins University, 

Baltimore, MD 

Background: Phase I/II studies with single-fraction (25 Gy) stereotactic 

body radiotherapy (SBRT) for pancreatic ductal adenocarcinoma (PDA) 

have shown local progression free survival (LPFS) rates of �90%, but are 

limited by late GI toxicity and minimal tumor response. We performed a 

phase II multi-center trial of gemcitabine (GEM) and fractionated SBRT to 

determine if a high rate of LPFS with reduced toxicity could be achieved. 

Methods: After multidisciplinary review, 32 pts with locally advanced PDA 

received GEM in sequence with SBRT (6.6 Gy in 5 consecutive daily 

fractions, 33 Gy total). LPFS, metastasis free survival (MFS), and overall 

survival (OS) were measured from date of tissue diagnosis. Objective tumor 

response (OTR) was assessed by RECIST/PERCIST. EORTC QLQ-C30/ 

PAN26 questionnaires were used to measure QOL. Results: Median f-up 

was 12 mos (range, 2-23). Mean age was 69.9 yrs (SD, 9.8) and 62% were 

male. Pts received a mean of 2.2 (SD, 1.0) GEM doses prior to SBRT and 

8.3 (SD, 5.6) doses total. All pts completed SBRT. Median OS was 15.9 

months (95% CI, 12.7-18.8). Stratification by CA19-9 � or � 90 at 

diagnosis yielded a hazard ratio of 6.2 for � 90 (p�0.021). Median LPFS 

has not been reached and median MFS was 10.2 mos (95% CI, 2.9-17.5). 

LPFS rate at 1 year was 87%. OTR on CT was seen in 41%, while 41% had 

stable disease and 18% progressed. Tumor metabolic activity decreased in 

17/18 patients with pre/post-SBRT PET available. Mean peak SUV was 4.0 

pre-SBRT versus 2.4 post-SBRT (p�0.002). Median CA19-9 was reduced 

from 124.7 prior to SBRT to 43.9 afterwards. Acute toxicity included: 

grade 2 anorexia (37%), fatigue (28%), nausea (22%), abd pain (19%), 

weight loss (9%), diarrhea (3%); gr 3 nausea (9%); and gr 4 nausea (6%). 

Late gr �3 GI toxicity was seen in 9%. Mean QOL score 4 wks post-SBRT 

was similar to baseline (p�0.38). At 6 mos there was a trend towards 

improved QOL (p�0.07). Conclusions: Fractionated SBRT with GEM 

achieves high rates of LPFS and tumor response. Minimal grade �3 acute 

and late toxicity was observed. SBRT is more likely to benefit patients with 

Ca-19-9 �90. A combination of SBRT with more aggressive chemotherapy 

may further improve outcomes. 


249s 


Evaluation of predictive factors for thromboembolic events in patients with 

advanced pancreatic cancer: Evaluation of the CONKO-004 (PROSPECT) 

study cohort. Presenting Author: Uwe Pelzer, Universitätsmedizin Berlin, 

Charité Centrum für Tumormedizin, Berlin, Germany 

Background: Patients (pts) with advanced pancreatic cancer (APC) often 

suffer from symptomatic thromboembolic events (sVTE). The CONKO-004 

trial showed that the low molecular weight heparin (LMWH) enoxaparin 

reduces sVTE (p�0.05, number needed to treat: 12) without increasing the 

rate of major bleeding when prophylactically applied. Our goal was to 

identify predictive factors for sVTE in pts with APC undergoing first-line 

chemotherapy. Methods: We analyzed the 152 (out of 312) pts randomized 

in the observation group.SVTE incidence was 9.9%. To identify foremost 

risk factors we used clinical parameters like performance status, stage, 

grading, primary or recurrent, gender, age, body mass index, erythropoietin 

stimulating agents (darbepoetin), as well as baseline laboraty parameters 

such as creatinine, hemoglobin, WBC, platelets, INR, ptt, CEA, carboanhydrat 

19-9, AST, ALT, AP and GGT. The multivariate logistic regression 

model with forward stepwise selection process was used for this estimation. 

With reference to a previously proposed scoring system (Khorana et al; 

Blood 2008) we evaluated the score as well. Results: No single parameter 

could be isolated demonstrating significant influence on the incidence of 

sVTE in pts with APC. We verified the Kohrana scoring model with our 

152/312 pts. Applying the score to our pts we didn’t discriminate pts 

between the two high risks groups (Table). Conclusions: Predictive models 

may help to identify cancer pts at high risk for sVTE to consider preventive 

anticoagulation. Within a cancer entity at high risk for sVTE such as pts 

with APC we did not succeed in the identification of single predictive 

parameters.For pts with APC undergoing first line chemotherapy primary 

prevention with LMWH should therefore be considered for the whole group 

of pts for at least three months. 

0 1-2



Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in 

pancreatic neuroendocrine tumor (PNET): Results of a planned interim 

efficacy analysis. Presenting Author: Timothy J. Hobday, Mayo Clinic, 

Rochester, MN 

Background: PNET has long had few effective therapies other than chemotherapy. 

Recent placebo-controlled phase III trials of the mTOR inhibitor 

everolimus and the VEGF/ PDGF receptor inhibitor sunitinib noted improved 

progression-free survival (PFS). However, objective response rates 

(RR) with these agents are still �10%. Preclinical studies suggest 

enhanced anti-tumor effects with combined mTOR and VEGF targeted 

therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM 

(25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV 

q 2 weeks) in patients (pts) with well or moderately differentiated PNET 

and progressive disease by RECIST within 7 months of study entry. 

Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 

patients, with interim analysis for futility after the first 25 evaluable pts. Pts 

had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate 

hematologic and organ function. Continued octreotide was allowed, but not 

required. Prior interferon, embolization, and � 2 chemotherapy regimens 

were allowed. Results: Confirmed PR was documented in 13 of the first 25 

(52%) evaluable patients. 21 of 25 (84%) patients were progression-free 

at 6 months. Both endpoints exceeded the protocol-defined criteria to 

continue enrollment. For 36 evaluable patients, the most common grade 

3-4 adverse events attributed to therapy were hypertension (14%), leukopenia 

(11%), lymphopenia (11%), hyperglycemia (11%), mucositis (8%), 

hypokalemia (8%), and fatigue (8%). Conclusions: The combination of 

TEM/BEV has substantial activity in a multi-center phase II trial with RR of 

52%, well in excess of single targeted agents in PNET. 6-month PFS was a 

notable 84% in a population of patients with RECIST criteria progression 

within 7 months of study entry. Accrual is ongoing. 


Addition of algenpantucel-L immunotherapy to standard of care (SOC) 

adjuvant therapy for pancreatic cancer. Presenting Author: Jeffrey M 

Hardacre, University Hospitals Case Medical Center, Cleveland, OH 

Background: Resected pancreatic cancer carries a one year survival rate of 

~65%. Algenpantucel (HyperAcute-Pancreas, HAPa) exploits the hyperacute 

rejection mechanism of xenotransplantation by administering genetically 

modified, irradiated, allogeneic tumor cells expressing aGal moieties 

on their surface. We propose that addition of algenpantucel-L to SOC 

adjuvant therapy may improve survival for patients with resected pancreatic 

cancer. Methods: Open-label, dose-finding, Phase 2 study (16 sites) 

evaluating HAPa (100/300 M cells / dose) � SOC (RTOG-9704: Gemcitabine 

� 5-FU-XRT) for resected pancreatic cancer patients. Primary 

endpoint: 1-year disease-free survival (DFS). Secondary Endpoints: overall 

survival (OS), toxicity and immunologic analysis. Results: : 70 patients, 

median age 62 years, 47% female, 81% lymph node positive, median 

tumor size 3.2 cm, and 17% post-operative CA 19-9 � 180 received SOC 

� HAPa. 1-year DFS of 63% and OS of 86% compares favorably to 

historical controls (~45%% and 65%, respectively) for this high risk 

population. Subgroup analysis of patients receiving 300M cells /dose 

shows a higher 12-month DFS compared to 100M cells/dose, 81% vs. 52% 

(p � 0.02). Likewise, patients receiving 300M cells/dose tended to better 

1-year survival compared to a 100M cells/dose, 96% vs. 80% (p � 0.053). 

Forty-four (63%) developed strong (G1-G3) skin reactions at the injection 

sites including many long term survival patients with periodic skin flares at 

injection sites far beyond their last vaccination. In 13/45 (29%) tested 

patients, an increase of �30% in anti-mesothelin Ab titer was seen after 

immunization. Thirty-nine (56%) presented with eosinophilia (range: 5- 

45%), including one patient with persistent eosinophilia and stable lung 

metastasis for over 2 years. Conclusions: Addition of HAPa to standard 

adjuvant therapy for resected pancreatic cancer shows promising immunological 

activation and may improve survival. A multi-institutional, phase 3 

study is currently underway. 


A phase I study of nab-paclitaxel (A), gemcitabine (GEM), and capecitabine 

(X) in patients with metastatic pancreatic adenocarcinoma (MPA). Presenting 

Author: Thach-Giao Truong, University of California, San Francisco 

Comprehensive Cancer Center, San Francisco, CA 

Background: GEM-based doublets, such as GEM � capecitabine (X), may 

be beneficial in select pts with MPA. Given preclinical evidence of synergy 

when a taxane is added to GEM � X, as well as recent phase I/II study 

results showing substantial activity with GEM � nab-paclitaxel (A) (ORR of 

48%, median OS � 12 mos at MTD), we conducted a phase I study 

evaluating the 3-drug combination of A, GEM, and X (AGX) given biweekly 

in pts with MPA. Methods: Pts with previously untreated MPA and ECOG PS 

0-1 were eligible. A (100-150 mg/m2 ) and GEM (750-1000 mg/m2 at 10 

mg/m2 /min) were both administered on day 4, and X (500-1000 mg/m2 bid) on days 1-7, of each 14-day cycle. A 3�3 dose escalation design was 

used, with expanded cohort at MTD. Primary objective was to establish 

MTD of this regimen; secondary objectives include safety and preliminary 

assessment of efficacy. DLT definitions: gr 3-4 ANC or neutropenic fever; gr 

4 plts; gr 2-4 hand-foot syndrome (HFS), neuropathy or diarrhea; or other gr 

3-4 non-heme toxicity. Results: Fifteen patients were enrolled across two 

dose levels (age range, 45-74 y). Final MTD was established at dose level 0, 

consisting of A 100 mg/m2, GEM 750 mg/m2, and X 750 mg/m2 bid. At 

dose level 1, two of 4 pts experienced DLTs (gr 3 LFT elevation, gr 3 ANC). 

For the entire study cohort, 10 pts (67%) experienced at least one gr 3-4 

AE, including LFTs (20%), N/V (13%), and fatigue (7%). Gr 3-4 heme 

toxicity was uncommon. Other notable AEs (any grade): fatigue (87%), 

rash/HFS (67%), N/V (53%), diarrhea (40%), neuropathy (33%). Median # 

cycles received � 4 (range, 2-16). 73% of pts d/c’ed study treatment due 

to disease progression. Best response for the entire cohort (n�14 evaluable 

pts): 2 PR, 8 SD, 4 PD (disease control rate � 71%). Of 12 pts with 

elevated CA19-9 at baseline, 5 (42%) had �50% biomarker decline. 

Conclusions: Recognizing the limits of cross-study comparisons and small 

sample size, these results do not match those reported at MTD in the phase 

I/II trial of GEM (1000 mg/m2) � A (125 mg/m2 ). The modest activity seen 

with this AGX regimen may have resulted from suboptimal dosing, and 

suggests that dose intensity may be an important factor when trying to 

incorporate nab-paclitaxel into multidrug regimens. 


A phase I/II study of the MEK inhibitor BAY 86-9766 (BAY) in combination 

with gemcitabine (GEM) in patients with nonresectable, locally advanced or 

metastatic pancreatic cancer (PC): Phase I dose-escalation results. Presenting 

Author: Jean-Luc Van Laethem, Hôpital Universitaire Erasme, Brussels, 

Belgium 

Background: Targeting the RAS–RAF–MEK–ERK pathway may be useful in 

the treatment of PC, as 75–90% of PCs have KRAS mutation. BAY is an 

orally bioavailable, potent, allosteric MEK 1/2 inhibitor that showed 

single-agent activity, and synergistic activity with GEM, in ectopic, orthotopic, 

syngenic and patient-derived xenograft PC models. Methods: The 

phase I part aimed to determine the maximum tolerated dose (MTD) of BAY 

in combination with GEM, and the pharmacokinetics of BAY and GEM. 

3�3 study design was used. After informed consent, eligible patients with 

advanced PC received GEM 1000 mg/m2 (30-min, once-weekly IV infusion 

for 7 out of 8 weeks in cycle 1 [C1], and 3 out of 4 weeks in subsequent 

cycles) and oral BAY 30 mg BID (dose level 1 [DL1]) or 50 mg BID (DL2). 

No escalation beyond DL2 was planned. MTD was the highest dose at which 

maximum 1 out of 6 evaluable patients displayed dose-limiting toxicities 

(DLT) during C1. Results: As of 6 Jan 2012, 17 patients were enrolled and 

treated (10 at DL1, 7 at DL2). DL1 cohort has completed; DL2 evaluation 

is ongoing. At DL1, DLTs occurred in 1/6 evaluable patients: a patient with 

extensive liver metastasis developed chemotherapy-associated steatohepatitis 

(CASH) and died of hepatic failure. Rare CASH cases have been 

reported to be associated with GEM alone, but co-involvement of BAY 

currently cannot be ruled out. To date, 3 patients have completed C1 at 

DL2 without DLTs. DL2 completion is expected in March 2012. BAY�GEM 

showed a manageable tolerability profile. The most frequent treatmentrelated 

grade 3–4 adverse event (AE) at any DL was neutropenia (n�6). 

The most frequent clinically relevant BAY-related AE was acneiform rash 

(n�11), which was mostly grade 1–2 (one case grade 3) and manageable. 

BAY�GEM showed evidence of clinical efficacy: partial responses were 

seen in 4/10 patients at DL1 and 1/3 patients at DL2. No pharmacokinetic 

interaction between BAY and GEM was seen at DL1. Conclusions: In 

patients with advanced PC, BAY 30 mg BID in combination with GEM had a 

manageable safety profile, with acneiform rash as the clinically most 

relevant toxicity attributable to BAY. 



Updated survival analysis of preoperative gemcitabine (gem) plus bevacizumab 

(bev)-based chemoradiation for resectable pancreatic adenocarcinoma. 

Presenting Author: Rachna T. Shroff, University of Texas M. D. 


Background: Preop therapy for resectable pancreatic cancer (PC) maximizes 

access to multimodality therapy and increases the R0 resection rate. Based 

on our phase I chemoradiation (chemoRT) trial in PC patients, we 

hypothesized that the addition of bev to gem-based chemoRT in pts with 

resectable PC may allow more pts to undergo pancreaticoduodenectomy 

(PD), improve the rate of R0 resections, and prolong overall survival. 

Methods: Pts with biopsy proven, stage I/II adenocarcinoma of the pancreatic 

head or uncinate process received 6 weekly infusions of gem (400 

mg/m2 ) and 3 infusions of bev (10 mg/kg, every 2 wks) with concomitant 

RT, 50.4 Gy at 1.8 Gy/fr. Pts were restaged 4-6 wks after the last dose of 

radiation. Those without disease progression and with good PS underwent 

surgery. Pts with adequate recovery received bev (10 mg/kg) every 2 weeks 

for 3 mo starting ~ 6 wks after surgery. Results: This study enrolled 11 of a 

planned 31 pts but was terminated early due to unforeseen postop 

complications. Median age is 64 yrs; all pts had ECOG-PS 0-1. Median 

CA19-9 was 52. Median follow-up from surgery was 41 mths. All completed 

chemoRT; 10 underwent restaging and 1 pt died from cardiac arrest 

before restaging. 9 pts (90 %) went to surgery and underwent a successful 

R0 PD. Pathologic PR rate (�50 % tumor kill) was 56 %. As we have 

previously reported, preop grade 3-4 toxicities were infrequent and major 

postop complications occurred in 5 of the 9 pts (56%) who underwent PD. 

Median overall survival (OS) was 30.1 mths (range: 2.6 - 63.9) for the 

entire cohort. Of the 9 resected pts, median OS was 45.5 mths with 5 of 11 

pts (45%) achieving survival longer than best historical control (median 

58.2 mths). Conclusions: The addition of bev to our prior backbone of 

gem-based preoperative chemoRT led to a higher resection rate (90%) than 

our previous protocols. Updated survival results of this study are promising. 

Taken together, these results may prompt further investigation of this 

regimen with modifications in the timing of bev delivery. 


International experts’ panel for the development of guidelines for the 

definition of time to event endpoints in clinical trials (DATECAN project): 

Results for pancreatic cancer. Presenting Author: Franck Bonnetain, 

Biostatistics and Epidemiology Unit, Centre Georges François Leclerc, 

Dijon, France and EA4184, College of Medicine, Dijon, France 

Background: Variability in the definition of survival endpoints in oncology 

trials was identified (Mathoulin et al.JCO 2008). Lack of a formal 

consensus could cause this, which limits inter-trial comparisons. The 

DATECAN project aimed at obtaining a formal consensus recommendation 

for defining survival endpoints for randomized clinical trials (RCTs) in the 

following cancer sites: pancreas, sarcoma/GISTs, breast, colorectal, gastric/ 

œsophagus, head and neck, kidney-bladder. We report results for pancreatic 

cancer. Methods: Based on a literature review of RCTs (2006-2009), 

we identified survival endpoints and events currently used. A 2-round 

modified Delphi method using RAND scoring (range:1-9) was used to reach 

consensus. Academic research groups were contacted for participation in 

order to select clinicians and methodologists for Pilot and Scoring groups 

(�30 experts/localization). Results: The Pilot group identified 14 endpoints 

that needed definition through consensus, such as progression free survival 

(PFS), time-to-treatment failure, time to quality of life deterioration. 

Endpoint definitions were seeked by disease setting (detectable disease vs 

not). Amongst the 52 European experts contacted, 33 and 30 participated 

to the 1st and 2nd round respectively. The experts scored a total of 204 

events; a consensus was reached for 25 (12%) at the 1st round and 156 

(76%) at the 2nd round. As example PFS was defined as time interval 

between the date of randomization, and the day of first local, regional 

progression or occurrence of distant metastases (including liver or non liver 

metastases) or occurrence of 2nd pancreatic cancer or death (all causes), 

whichever occurs first. The consensus was finalized during a face-to-face 

meeting organized during the ESMO 2011 congress and general rules were 

proposed for final ratification. Conclusions: Based on this consensus, an 

European charter is being finalized and proposed for endorsement to all 

academic groups in order to harmonize results and to allow formal 

comparisons of pancreatic RCTs. The impact of these definitions on trial 

results will be also investigated in a further project. 


251s 


A phase IB study of erlotinib in combination with gemcitabine and 

nab-paclitaxel in patients with previously untreated advanced pancreatic 

cancer: An Academic GI Cancer Consortium (AGICC) study. Presenting 

Author: Lawrence P. Leichman, Comprehensive Cancer Center at Desert 

Regional Medical Center, Palm Springs, CA 

Background: The combination of gemcitabine (gem) and nab-paclitaxel 

(nab) has demonstrated promising activity in advanced pancreatic cancer. 

Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase 

IB study to evaluate the safety of the three drug combination and obtain 

preliminary evidence of efficacy. Methods: Patients (pts) with previously 

untreated locally advanced (la) or metastatic (met) pancreatic cancer with 

ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily 

erl days 1-28 Q28 days. Standard 3�3 design was used with dose levels 

(DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 

75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was 

defined as �grade (gr) 3 non-hematologic, febrile neutropenia, �gr 3 

thrombocytopenia, or missing �2 doses gem, nab or �5 doses erl within 

first cycle (C). Results: Nineteen pts were enrolled and completed a total of 

62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA 

(15/2/2), median age 63 (range 54-78), ECOG PS 1�11, met/la (12/7). In 

DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/ 

sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the 

next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 

other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 

DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 

pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). 

Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 

toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), 

and hypotension (2). Of 13 pts evaluable for response, 6 had partial 

response (46%), 5 stable disease (38%), and 2 progressive disease (15%) 

as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 

months respectively. Conclusions: The combination of erlotinib with gemcitabine 

and nab-paclitaxel is not tolerable at standard single agent dosing of 

all drugs. However, significant clinical activity was noted, even at DL -3. 

Further study of the combination will need to incorporate reduced dosing. 


Tumor IGF-1 expression as a predictive biomarker for IGF1R-directed 

therapy in advanced pancreatic cancer (APC). Presenting Author: Milind M. 

Javle, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: IGF-1 up-regulates PC proliferation and invasiveness through 

activation of PI3K/Akt signaling pathway and down-regulates PTEN. We 

investigated IGF-1 expression in tissue and blood as potential predictive 

markers in phase II study of IGF1R-directed monoclonal antibody, MK- 

0646 in APC. Prior phase I established the MTD of MK0646 at 5 mg/kg 

with gemcitabine (G) and erlotinib (E) and 10 mg/kg with G alone. Methods: 

Patients (pts) with stage IV, previously untreated APC, ECOG PS 0-1, 

adequate hematologic and organ function were enrolled. Arm A: G 1,000 

mg/m2 over 100 min, weekly x 3, MK-0646 weekly x 4; Arm B: G 1000 

mg/m2 and MK-0646 � E 100 mg daily. Arm C (control) was G 1,000 

mg/m2 � E 100 mg. Cycles were repeated every 4 weeks. Pts were equally 

randomized in the 3 arms. Primary study objective was progression-free 

survival (PFS). Pre-treatment peripheral blood samples were measured for 

IGF-1 level by ELISA; archival core biopsies were analyzed for IGF-1 mRNA 

expression. RNA extraction from FFPE samples used Roche Transcriptor 

First Strand cDNA Synthesis Kit. TaqMan PreAmp technique was used to 

amplify target cDNA prior to TaqMan RT-PCR analysis. Cox proportional 

hazards model for PFS analyzed the interaction between tissue IGF-1 

expression and treatment. Results: 50 pts were enrolled (A�15, 

B�16,C�16 pts, 3 ineligible). Median PFS of arms A, B and C were 5.5 

months (95% CI: 3.9 – NA), 3.0 months (95% CI:1.8 – 5.6) and 2.0 

months (95% CI: 1.8 – NA), respectively (log-rank test; p � 0.17). Median 

OS of A was 11.3 months (95% CI: 8.9 – NA), B 8.9 months (95% CI: 5.3 – 

NA) and C 5.7 months (95% CI: 2.0 – NA) (log-rank test; p � 0.44). 35 

archival core biopsies were analyzed, 21 had adequate tissue for analysis. 

Using a Multivariable Cox proportional hazards model for PFS, where IGF-1 

was dichotomized at the median, there was a 76% reduction in the risk of 

disease progression or death in arm A as compared with the control (arm C) 

at high IGF-1 level (p � 0.16). When IGF-1 was fitted as a continuous 

variable, this reduction was 96% (p � 0.08). There was no correlation 

between tissue and serum IGF-1. Conclusions: Tissue expression of IGF-1 

level may represent a promising predictive biomarker for IGF1R-directed 

therapy in APC. 




A randomized phase III multi-institutional study of TNFerade biologic with 

5-FU and radiotherapy for locally advanced pancreatic cancer: Final results 

Presenting Author: Aaron Tyler Wild, Department of Radiation Oncology 

and Molecular Radiation Sciences, Johns Hopkins University School of 

Medicine, Baltimore, MD 

Background: TNFerade biologic (TNF) is a novel means of selective delivery 

of TNF-� to tumor cells by gene transfer through intratumoral (IT) injection. 

TNF is a replication deficient adenovirus vector containing TNF-� cDNA 

ligated downstream from a radiation-inducible Egr-1 promoter, allowing 

spatiotemporal constraint of TNF-� production to the radiation field. Herein 

we report the final results of a multi-center, randomized, open-label, 

controlled phase III trial of TNF with chemoradiotherapy for locally 

advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with 

locally advanced PDA were randomized 1:2 to standard of care (SOC; 

5-FU/RT followed by GEM) versus TNF � SOC. RT dose was 50.4 Gy in 28 

fractions. Concurrent 5-FU (200 mg/m2 /day IV) started on day 1 of RT each 

wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or 

endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was 

given until progression or toxicity. Results: Of 277 pts, 187 were randomized 

to TNF and 90 to SOC. Demographic/baseline characteristics were 

similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs. 

7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for 

TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95% 

CI, 7.6-11.2) for SOC (p�0.6). TNF delivery method did not affect OS (9.4 

mos for PTA vs. 11.5 for EUS; p�0.7). Baseline CA19-9 � 1000 was 

found to impart independent risk to TNF pts (HR�1.7; p�0.02). Subgroup 

analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF 

compared to SOC (10.9 vs. 9.0 mos, respectively; p�0.04). TNF resulted 

in more grade 1-2 fever/chills (p�0.001) as well as grade 3 (p�0.001) and 

4(p�0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/ 

chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity 

rates. Conclusions: TNF � SOC did not prolong OS for locally advanced 

PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and 

CA19-9 � 1000. PTA and EUS injection achieved similar rates of efficacy 

and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-� 

(pyrexia/hypotension/chills) was common, but grade 3-4 was minimal. 


Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma 

(PC) at Memorial Sloan-Kettering Cancer Center (MSKCC). Presenting 

Author: Maeve A. Lowery, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: The PRODIGE/ACCORD trial recently established FFX as a 

treatment option for good performance status (PS) pts with stage IV PC 

(Conroy et al, NEJM 2011). We evaluated the activity and toxicity 

associated with FFX therapy in pts with advanced PC treated at MSKCC 

outside of a clinical trial. Methods: 80patients (pts) treated withFFX as 

1st-line therapyat MSKCC between 07/1/10 and 12/30/11, were identified 

from an institutional database (prior IRB approval). Records were reviewed 

for demographic, treatment, toxcity, and response data. Results: 61 and 19 

pts received FFX for stage IV and III PAC respectively. Demographics and 

outcomes are summarized in the table. Median starting dose of FFX was 

80% of that used in the PRODIGE/ACCORD trial. Median overall survival 

(OS) was 12.5 months (mo) (95% CI 9.5–15.5) in pts treated with 1st line 

FFX for stage IV PAC and 13.7 mo (95% CI 11.3–15.8) in pts with stage III 

PAC. 68% of pts with stage IV PAC who discontinued FFX for disease 

progression (PD) or toxicity received 2nd-line gemcitabine-based therapy. 

Conclusions: We observed activity and acceptable toxicity in carefully 

selected patients treated with FFX at 80% dose intensity and routine use of 

growth factor support. Treatment with FFX resulted in median OS of � 1 

year in pts with stage IV PAC and is an active front-line regimen. 

1st line: Stage IV 

N�61 

1st line: Stage III 

N�19 

Age (yrs) 

Sex 

Male 

64 (range 46-80) 

- 

33(54%) 

58 (range 37-69) 

- 

11(58%) 

Female 

Primary tumor 

28(46%) 

- 

8(42%) 

- 

Head 

23(38%) 

14(74%) 

Body 

21(34%) 

2(10%) 

Tail 

Prophylactic growth factor 

Median number of cycles 

Dose reduction/discontinutation for toxicity 

17(28%) 

51(84%) 

7 

32(52%) 

3(16%) 

15(79%) 

6 

9(47%) 

GI 

11(18%) 

4(21%) 

Myelosupression 

4(7%) 

1(5%) 

Neuropathy 

9(15%) 

1(5%) 

Drug reaction 

4(7%) 

1(5%) 

Other 

Subsequent surgery/RT 

Best response* 

4(7%) 

N/A 

- 

2(10%) 

1(5%)/10(53%) 

- 

PR 

21(40%) 

4(21%) 

SD 

23(45%) 

13(68%) 

PD 

8(15%) 

2(11%) 

* Evaluable pts N�52 (1 pt not yet staged, 3 pts� 2 cycles FFX due to toxicity/5 pts due to 

non-treatment-related death). 


M402, a heparan sulfate mimetic and novel candidate for the treatment of 

pancreatic cancer. Presenting Author: Birgit C. Schultes, Momenta Pharmaceuticals, 

Cambridge, MA 

Background: Recent advances in pancreatic cancer research implicate the 

involvement of several heparin-binding growth factors (such as HGF, 

HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. 

We have rationally designed a heparan sulfate mimetic, M402, which 

has been previously shown to affect tumor progression and metastasis 

through disruption of multiple pathways. We hypothesized that M402 

could modulate tumor-stroma interactions and enhance the efficacy of 

gemcitabine, and evaluated its efficacy in two preclinical models. Methods: 

A genetically engineered mouse model (GEMM; KrasLSLG12D p53LSLR172H ) 

featuring spontaneous pancreatic tumor formation and metastasis assessed 

M402’s effect on tumorigenesis and metastasis. The orthotopic 

Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, 

a fibrotic response that hinders effective delivery of chemotherapeutics, via 

inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate 

cells. In both models, M402 was studied as monotherapy and with 

gemcitabine. Results: In the GEMM, M402 significantly prolonged survival 

in combination with gemcitabine while each monotherapy showed modest 

efficacy. M402, alone and in combination, also reduced metastases and 

local invasion and inhibited epithelial-to-mesenchymal transition. In the 

Capan-2 model, gemcitabine was increasingly less effective as desmoplasia 

progressed over time. The addition of M402 to gemcitabine increased 

its efficacy with respect to primary tumor burden. Metastasis, invasion, and 

surrounding fibrotic lesions appeared particularly impacted by the combination 

treatment. M402 was also effective as monotherapy with dosedependency, 

which correlated with reduced SHH signaling. Conclusions: 

M402 can modulate tumor-stroma interactions involved in the metastatic 

and desmoplastic pathways in two pancreatic cancer models supporting 

the translation of these findings into a clinical study. A first-in-human study 

is planned that will evaluate the safety, pharmacokinetics, efficacy, and 

biomarker profiles of escalating M402 doses in combination with gemcitabine 

in patients with metastatic pancreatic cancer. 


Benefits of platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma 

(PC) associated with BRCA mutations: A translational case 

series. Presenting Author: Olusola O. Faluyi, Princess Margaret Hospital, 


Background: The prognosis of PC is poor with limited response to standard 

chemotherapy. Prior randomized studies of cisplatin and gemcitabine in PC 

demonstrated no additional benefit over gemcitabine alone. Preclinical 

data and case reports suggest that BRCA mutant PC may have increased 

sensitivity to Pt-chemo. Our case series characterizes the benefits of 

Pt-chemo in germline BRCA mutant PC. Methods: Patients with PC and 

germline BRCA mutations were identified using the Ontario Pancreatic 

Cancer Study and Pharmacy databases. Review of clinical records provided 

demographic, treatment and survival data. Radiology review assessed 

responses to chemotherapy. RNA was extracted from tumor samples for 

gene expression studies using a panel of DNA repair genes and Nanostring 

technology. BRCA loss of heterozygosity (LOH) was also investigated. 

Results: We identified 14 PC patients with BRCA mutations (8 BRCA2, 6 

BRCA1). 11 of these had metastatic disease of which 5 received Pt-chemo. 

Of the 5 treated with Pt-chemo, there were 3 partial responses (PR) and 2 

complete responses (CR) using Recist criteria. For the remaining 6 not 

treated with Pt-chemo, there was 1 PR with gemcitabine. Additionally, two 

patients with locally advanced disease at diagnosis became resectable 

following Pt-chemo. Overall survival was superior for patients receiving 

Pt-chemo (33.0�25.6 vs 7.3�4.5 months; p�0.04). Gene expression 

and LOH results will be presented. Conclusions: Responses and survival 

associated with Pt-chemo observed in our case series of BRCA mutant PC 

adds to existing data supporting the use of Pt-chemo in this subgroup. 

Despite the low (2 to 5%) prevalence of BRCA mutations in PC, the benefits 

gained from personalizing treatment using Pt-chemo supports BRCA 

testing in selected patients. 



Inequal benefits from regionalization of cancer care: The pancreatic cancer 

surgery paradigm. Presenting Author: Theodore P. McDade, Surgical 

Outcomes Analysis & Research, University of Massachusetts Medical 

School, Worcester, MA 

Background: Regionalization has been proposed for high-level care, including 

multidisciplinary cancer treatment and complex procedures. Pancreatic 

resections can serve as a marker for both. Using Massachusetts 

Division of Health Care Finance and Policy (DHCFP) data, we investigated 

regionalization of surgery for pancreatic cancer (PCa), its potential effect 

on perioperative outcomes, and disparities in access to high-volume PCa 

surgery centers. Methods: Using MA DHCFP Hospital Inpatient Discharge 

Data, 2005-2009, 10,524 discharges for PCa were identified, of which 

746 were associated with pancreatic resection. Discharges with missing or 

out-of-state residence were excluded (n�704). Using geodetic methods 

and ZIP codes, center-to-center distances were calculated between patient 

(pt) and treating hospital. Median ZIP income was estimated from 2009 

census data. High volume hospitals (4 of 25 performing pancreatic 

resections in MA) were defined using Leapfrog Criteria (� 11 per year (87th percentile for MA). Chi-square and logistic regression analyses were 

performed using SAS software. Results: Median age was 65. Pts were 

predominantly White (87.2%), with median ZIP income of $54,677. Pts 

travelled in-state up to 112 miles (median 15.4), with the majority 

resected at high volume hospitals (76%). Median length of stay (LOS) was 

8.0 days, with LOS�1 week associated with low volume hospitals 

(p�0.0002). Of 14 in-hospital deaths, 7 were at low volume hospitals 

(4.14% of 169 pts) compared to 7 at high volume hospitals (1.31% of 535 

pts) (p�0.0214). Predictors of shorter travel distance were: Black race (OR 

4.45 (95% CI 1.66-11.93)), operation at low volume hospital (OR 2.62 

(95% CI 1.81-3.77), and increased age (per year) (OR 1.02 (95% CI 

1.00-1.03), but not sex or median income. Conclusions: Using MA 

statewide discharge data, regionalization of pancreatic cancer surgery to 

high-volume, better-outcome centers is seen to be occurring. However, it is 

not uniform, and disparities exist between groups of cancer pts that do and 

do not travel for their care. In the current era of scrutiny on cost, quality, 

and access to cancer care, further study into predictors of pts receiving 

optimal care is warranted. 


Phase II trial of bevacizumab, irinotecan, cisplatin, and radiation as 

preoperative therapy in esophageal adenocarcinoma. Presenting Author: 

David Ilson, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Preop chemo and radiotherapy (RT) with weekly irinotecan (I), 

cisplatin (C) and 5040 cGy is tolerable and active [Cancer, in press]. 

Bevacizumab (B) � weekly I/C in advanced esophagogastric cancer 

increased response rate and PFS without an increase in toxicity [JCO 24: 

5201; 2006]. In a phase II trial in esophageal adenocarcinoma (EA) we 

combed B � I/C with RT as preop therapy. A toxicity analysis after 10 

patients (pts) undergoing surgery indicated no unexpected toxicity with B 

[JCO 27: Abstract 4573; 2009], and we completed a planned accrual of 33 

pts. Methods: Pts had resectable distal esophageal or Siewert’s I or II EA, 

T2-3 or N1 staged by EUS, PET, and CT scan. Induction chemo: I: 50-65 

mg/m2 � C: 30 mg/m2 weeks 1,2,4,5, B: 7.5 mg/kg weeks 1 and 4; 

Chemort: 180 cGy daily fractions to 5040 cGy, I/C weeks 7,8,10,11� B 

weeks 7,10. Esophagectomy was planned 6-8 weeks after RT. Postop: B: 

7.5 mg/kg every 3 weeks for 8 cycles. Results: 33 pts were enrolled. 26 

male: 7 female; distal esophagus 11 (33%), GEJ 22 (67%); 21 T3N1 

(64%); 10 T3N0 (30%); 2 T2N0-1 (6%). 25/33 pts went to surgery (76%), 

24 had R0 resection (73%). Pathologic CR 5 pts (15%). 8 pts did not going 

to surgery: 2 for adverse events (9%, 1 CVA due to patent foramen ovale, 1 

esophageal perforation due to endoscopic biopsy), 6 for progressive disease 

(18%). 21/24 pts (88%) received adjuvant B, 20 (95%) completed all 

cycles. Grade 3/4 toxicity in 30 evaluable pts during chemort: 24% 

neutropenia, 3% neutropenic fever, 23% esophagitis, 13% dehydration, 

13% thrombocytopenia, 7% pulmonary embolism, 3% nausea/vomiting. 

Surgical complications: 3 anastomotic leaks (12%), 4 respiratory failure 

(16%), 1 pulmonary embolism (4%), 2 post op deaths (8%). At a median 

follow up of 20 months, PFS was 14 months and OS was 30 months. 

Conclusions: The addition of B to preop chemoRT in EA was tolerable 

without increase in treatment toxicity or surgical complications. There was 

no suggestion of improved pathologic CR, PFS, or OS with the addition of B 

to I/C/RT. Evaluation of B in phase III trials of chemort does not appear 

warranted. Supported by a grant from Genentech. 


253s 


Choice of chemotherapy in the treatment of metastatic squamous cell 

carcinoma of the anal canal. Presenting Author: Cathy Eng, University of 


Background: Metastatic squamous cell carcinoma (SCCA) of the anal canal 

is an uncommon malignancy with no standard approach. The reported 

median overall survival (OS) is 9-12 months (M) following 5-FU � cisplatin 

(FC)-based therapy. The aim of this study is to evaluate first-line chemotherapy 

approaches in this patient (pt) population. Methods: A retrospective 

analysis was conducted of 428 pts with metastatic SCCA of the anal canal 

identified from the MDACC tumor registry between 1/1/2000 - 5/31/2011. 

Electronic medical records were reviewed for histology, date of diagnosis 

and/or recurrence, site of metastasis, type of therapy provided, response 

rate (RR), progression-free survival (PFS), OS, and lines of salvage therapy. 

All eligible pts were required to be treatment-naïve for metastatic disease 

and have radiographic imaging at MDACC. Waiver of informed consent was 

obtained. Results: 99 pts fulfilled all criteria; 10 were lost to follow-up; 12 

did not initiate chemotherapy. 77 pts were evaluable; M: F � 20:57; 

median age � 55 years (range: 37 - 82); HIV(�) � 5% (4/77); prior 

chemoXRT with curative intent: 70% (54/77), complete response (CR): 

87% (47/54), median time to development of metastatic disease �17M. 

29% (22/77) presented with metastatic disease. Sites of disease included 

distant lymph nodes (41%); liver (45 %); lung (25%); bone (15%); and 

brain (8%). The median follow up was 37M. 73% (56/77) of patients were 

treated with platinum-based therapy; 51% (n�39) received FC and 22% 

(n� 17) received carboplatin � paclitaxel (CP). The median PFS was 6M; 

FC trended better than CP for PFS (7M vs. 5M, p�0.067). The overall 

median OS � 29M. 40% (31/77) of pts received neoadjuvant first-line 

therapy followed by metastasectomy (68%), XRT (26%), or both (6%); 

resulting in a median OS � 35M. Conclusions: Metastatic SCCA of the anal 

canal is a malignancy in which 5-FU�cisplatin is a commonly used 

regimen. Our analysis suggests FC results in improved PFS over CP but is 

underpowered supporting further analysis. The short median PFS with 

front-line chemotherapy, and yet longer OS reflects the challenges in 

treating this patient population and the importance of multidisciplinary 

management in select cases. 


A phase II study of neoadjuvant therapy with cisplatin, docetaxel, panitumumab 

plus radiation therapy followed by surgery in patients with locally 

advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051). 

Presenting Author: Carolyn E. Reed, Medical University of South Carolina, 

Charleston, SC 

Background: Multiple clinical trials have incorporated preoperative chemotherapy 

and radiation (RT) in an attempt to improve local tumor control, 

distant disease failure and overall survival rates for locally advanced but 

resectable adenocarcinoma of the distal esophagus and gastroesophageal 

junction (GEJ). This multicenter, cooperative group study combined active 

chemotherapy agents cisplatin (C), docetaxel (D) and the targeted EGFR 

agent panitumumab (P) in the induction phase followed by concurrent 

chemotherapy (CDP) and radiation. Pathologic complete response (pCR), a 

surrogate for improved survival, was the primary endpoint. Methods: From 

01/15/09 to 07/22/11, 70 patients (pts) with Siewert I or II adenocarcinomas 

and clinical stages T3N0M0, T2-3N1M0 or T2-3N0-1M1a (celiac LN 

� 2 cm) were accrued. Patients received cisplatin (40 mg/m2 ), docetaxel 

(40 mg/m2 ) and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, 9 with RT 

(5040 cGy, 180 cGy/day x 28d) beginning week 5. The decision rule had a 

90% power with a 0.10 significance level to detect a pCR rate of at least 

35%. Secondary objectives included near-pathologic complete response 

(near-pCR), toxicity, and overall and disease-free survival rates. Results: 

Five pts were ineligible. Of the remaining 65 pts (59 M, 6 F; median age 

61), 12 pts did not undergo surgery (5 progressed, 4 refused, 3 other). Of 

the 58 evaluable pts, the pCR rate was 32.8% (90% CI: 22.6% -42.9%) 

and near-pCR 22.4% (90% CI: 13.4%-31.4%). Total doses of C, D, and P 

were achieved in 76%, 80%, and 73%, respectively (n � 70). 66 pts 

(94%) received the total RT dose. Sixteen pts (23%) had a grade 4� 

non-heme adverse event possibly related to treatment. Venous thrombosis 

(5 pts) was most common. Conclusions: The CDP regimen in the neoadjuvant 

setting in patients with esophageal adenocarcinomas is active (pCR � 

near-pCR � 55.2%) and feasible. The toxicity though tolerable is substantial. 




Bisphosphonates and esophageal cancer: A RADAR report. Presenting 

Author: Beatrice J. Edwards, Department of Medicine, Geriatrics Division, 

Northwestern University Feinberg School of Medicine, Chicago, IL 

Background: In 2009, the US Food and Drug Administration (FDA) reported 

on 23 patients who had developed distal esophageal cancer, with alendronate 

(ALN) within 2 years of initiation of therapy. Similarly, 31 cases of 

esophageal cancer were reported from Europe and Japan. Esophagitis has 

been associated with oral BPs. Erosive esophagitis and persistent mucosal 

abnormalities have been noted with crystalline material (similar to ground 

ALN). Our objective was to assess the FDA Adverse event reporting system 

(FDA AERS) for a safety signal. Methods: The FDA Adverse Event Reporting 

System (AERS) database was searched using terms related to esophageal 

cancer combined with all drug names for bisphosphonates (search period: 

1996-2010). Disproportionality ratios were calculated: Proportional reporting 

ratio (PRR) and Empiric Bayes Geometric Mean (EBGM) determining 

that the esophageal cancer cases were more common with bisphosphonates 

than with other drugs in the database. Results: We identified 128 

cases of bisphosphonate-associated esophageal cancer; 114 (89%) female 

and 14 male (11%), mean age 72 � 12 yrs; the drugs included alendronate 

(n�96, 75%), risedronate sodium (n�14, 11%), ibandronic acid (n�10, 

7.8%), zoledronic acid (n�7, 5.4%) and pamidronate (n�1, 1%). Barrett’s 

esophagus was listed in 3 cases of esophageal carcinoma. A 

significant safety signal was found only for alendronate with a PRR� 6.4 

(95% C.I. 5.29, 7.730; p�0.001), EBGM � 6.3 (95% C.I. 5.1, 7.6 

p�0.001). Conclusions: Our analysis of FDA AERS identifies a larger 

number of cases of esophageal cancer than previously described, and a 

significant safety signal with alendronate use. Avoidance of oral bisphosphonates 

in patients with Barrett’s esophagus, and persistent mucosal abnormalities 

is recommended. Increased awareness and vigilance is needed for 

patients receiving oral bisphosphonate therapy. 


Trastuzumab (TRA) in combination with different first-line chemotherapies 

for treatment of HER2-positive metastatic gastric or gastroesophageal 

junction cancer (MGC): Findings from the German noninterventional 

observational study HerMES. Presenting Author: Susanna Hegewisch- 

Becker, Internistische Praxisgemeinschaft Eppendorf, Hamburg, Germany 

Background: The international phase III study ToGA has recently shown that 

TRA is effective in prolonging survival in HER2-positive MGC. However, few 

data are available for TRA as part of routine clinical practice. Methods: This 

non-interventional observational study was conducted to evaluate the 

efficacy, safety and feasibility of TRA in previously untreated pts with 

HER2-positive MGC. Results: Between Apr 2010 and Jan 2012, data from 

110 pts were collected. All pts were evaluable for safety. Baseline pt 

characteristics were as follows: median age 63 yrs (range 29–88); gender 

(male 70%; female 29%); ECOG PS (0: 25%; 1: 50%; 2: 15%; 3: 5%); 

distant mets (91%); liver mets (54%), lymph node mets (35%); peritoneal 

carcinomatosis (23%). The median duration of TRA treatment was 4.4 

months (0–17.1). According to the schedule of chemotherapy TRA was 

administered every 2–3 wks in a median dose of 4–6 mg/kg BW. Only 28% 

of pts received TRA according to the label in combination with cisplatin and 

5-FU or capecitabine. The remainder received: cisplatin, 5-FU and 

leucovorin (17%); 5-FU, leucovorin, oxaliplatin and docetaxel (8%); 5-FU, 

leucovorin and oxaliplatin (7%); capecitabine (6%); other combinations 

(25%); TRA monotherapy (7%). Although most pts didn’t receive cisplatinbased 

therapy, preliminary median progression-free survival was 6.8 

months, thus comparable to the ToGA data. Most common adverse events 

(AEs, all grades) were diarrhoea (7%), vomiting (5%) and nausea (5%). 

Most common grade 3/4 AEs were vomiting (3%), nausea (2%) and fatigue 

(2%). Health-related quality of life as assessed by EORTC QLQ-C30 and 

QLQ-STO22 remained stable during observation time. An updated analysis 

of approx. 200 pts will be presented at the meeting. Conclusions: TRA 

combined with diverse chemotherapies is safe and effective in the routine 

treatment of MGC. Cisplatin-free less toxic regimens are feasible and 

equally effective. The results are in line with those from the ToGA trial and 

suggest that treatment with TRA should be regarded as standard of care for 

pts with HER2-positive MGC. 


Combined analysis of randomized controlled trial (RCT) and patientpreference 

trial (PPT) evaluating second-line chemotherapy (SLC) in 

advanced gastric cancer (AGC). Presenting Author: Soonil Lee, Dankook 

University Hospital, Cheonan, South Korea 

Background: While prolonged overall survival (OS) from SLC compared to 

best supportive care (BSC) has recently been demonstrated for AGC (Park 

et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We 

assessed whether patient preference, willing to participate onto RCT, or 

other parameters contributed to this OS improvement. Methods: In the 

phase III trial, pretreated AGC patients (n�372) were first offered RCT. If a 

patient agreed to participate, randomly assigned 2:1 to SLC or BSC 

(n�202). If refused RCT, but agreed to receive treatment of their 

preference, they were offered SLC or BSC (PPT; n�170). OS of RCT 

participants was compared to that of whole patient population according to 

prognostic subgroups. In addition, analyses of OS unadjusted for multiple 

comparisons were conducted across predefined subgroups. Results: Median 

OS was 6.3 months among 254 patients treated with SLC and 3.3 months 

among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 

0.637; one-sided p�0.001). Compared to the RCT patients, younger age 

group, those with an ECOG performance status (PS) of 0, and with one prior 

chemotherapy were under-represented in the PPT patients. OS was 

comparable between RCT (5.0 months) and PPT (4.4 months) patients 

even after controlling for major prognostic factors (log-rank p�0.322). The 

OS benefit for SLC was preserved when analyzed according to baseline 

parameters. Parameters that were associated significantly with a prolonged 

OS included a PS of 0, the chemotherapy-free interval �3 months, and one 

prior chemotherapy. When the analysis was adjusted for these three 

parameters, patients who received SLC still had improved OS (HR, 0.554; 

95% CI, 0.441 to 0.696; p�0.001). Conclusions: The 54% participation 

rate obtained in the current study represents the best achievable rate for 

this kind of phase III RCT involving BSC only arm. Even if we consider 

differences in the baseline characteristics between RCT and PPT patients, 

it is concluded that the RCT results can be generalized for the patient 

population and provided additional evidence supporting the use of SLC in 

patients with pretreated AGC. 


Does in-house availability of multidisciplinary teams increase survival in 

upper GI cancer? Presenting Author: Christian Kersten, Center for Cancer 

Treatment, Sørlandet Hospital Trust, Kristiansand, Norway 

Background: Treatment of esophageal, gastric and pancreatic cancers (UGI) 

is recommended to be discussed by a multidisciplinary team (MDT), 

despite lack of evidence that this approach leads to increased survival. In 

2001, a cancer centre with irradiation and chemotherapy facilities was 

established in the Norwegian county of West Agder (WA), providing the 

potential for local in-house MDT meetings. Our primary objective was to 

evaluate the effect of the establishment of in-house MDT availability 

(iMDTa) on survival in a cohort of UGI patients in WA. We compared 

survival figures for WA with those of other Norwegian counties with 

complete, less complete and without iMDTa. Methods: We defined “iMDTa” 

as a single administrative institution with all departments on one campus, 

serving the population of one county. We compared cause-specific survival 

rates for 2000-04 and 2005-08 for UGI patients living in counties with 

(MDT-Yes), without (MDT-No) and with a mix (MDT-mix) of iMDTa, with the 

county of WA which had a change in iMDTa (MDT-Change) during the study 

period. Crude survival was modelled with Kaplan-Meier method and Cox 

regression analysis was used to adjust for age and region (sex and stage 

distributions were similar in all counties). Results: We analyzed 12530 UGI 

patients living in five Norwegian regions. Median age was 74 (17-98) yrs 

and median follow-up was 5 (0-138) months. The regions with the highest 

level of iMDTa achieved the largest increases in survival, compared to the 

counties with limited or no iMDTa. Median overall survival for all UGI 

patients in WA/MDT-Change increased from 129 to 300 days from 2000-8, 

p�0.001. Compared to the county with MDT-Mix, the county with 

MDT-Change reached a statistically significant reduction in the risk of 

death (HR) for both esophageal (1.12- 0.60) and stomach cancers 

(0.87-0.63), but not for pancreatic cancers (1.04-1.01). Conclusions: In 

parallel with an increasing use of in-house MDT, we found a striking and 

more than two-fold increase in survival in the Norwegian county of 

WA/MDT-Change. This survival gain is partly explained by increased use of 

chemotherapy. During the same time period, no increase in survival was 

found in the MDT-No or MDT-Mix counties. 



Correlation between overall survival and other endpoints in clinical trials of 

second-line chemotherapy for patients with advanced gastric cancer. 

Presenting Author: Kohei Shitara, Aichi Cancer Center Hospital, Nagoya, 

Japan 

Background: The correlation between progression-free survival (PFS) or 

time to progression (TTP) and overall survival (OS) has been evaluated in 

patients with advanced gastric cancer (AGC) who received first-line 

chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and 

Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had 

been done in patients who underwent second-line chemotherapy for AGC. 

Methods: We evaluated the potential of PFS, TTP, response rate (RR), or 

disease control rate (DCR) to act as surrogates for OS in phase II and III 

trials of second-line chemotherapy for AGC by comprehensive literaturebased 

analysis. Correlations between each endpoint and OS were evaluated 

by Spearman rank correlation coefficient (�). Subgroup analyses by trial 

region or type of failure to previous chemotherapy were also conducted. 

Results: Fifty-six trials, including four randomized studies, were selected 

for analysis and covered a total of 61 treatment arms and 3,038 patients; 

34 studies were conducted in Asia, 20 studies in Non-Asian countries, and 

two studies in both regions. Median PFS were similar in Asian and 

Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be 

longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p�0.01). Median 

PFS/TTP and OS showed a moderate correlation with � of 0.51 (95% CI, 

0.31-0.73). Correlation tended to be higher in PFS (� � 0.62) than TTP (� 

� 0.29) and higher in non-Asian trials (� � 0.73) than Asian trials (� � 

0.32). Correlation between PFS/TTP and OS among the trials in which 

eligibility required failure to previous fluorouracil and cisplatin also showed 

low correlation (� � 0.48). The RR and DCR also did not show high 

correlation with OS (� � 0.30 for RR; 95% CI 0.04-0.56; � � 0.53 for 

DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each 

arms of the four randomized studies showed a low correlation with � of 

0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not 

correlate sufficiently with OS to be used as surrogate endpoints in patients 

with AGC who underwent second-line chemotherapy. Further research is 

needed based on individual patient data from ongoing randomized trials. 


Customization of treatment for patients with esophageal adenocarcinoma 

(EAC) who achieve clinical complete response (cCR) after chemoradiation 

using initial standardized uptake value (iSUV) of 18f-fluorodeoxyglucose PET. Presenting Author: Akihiro Suzuki, University of Texas M. D. Anderson 


Background: Patients with localized esophageal adenocarcinoma (EAC) 

receive preoperative chemoradiation followed by surgery (trimodality [TM] 

therapy) or definitive chemoradiotherapy (bimodality [BM] therapy) based 

on comorbidities and tumor geography. However, we cannot individualize 

recommendations beyond these parameters. We hypothesized that iSUV 

could customize therapy. Methods: Data source was our prospective 

database of fully staged EAC patients (2002-2010). All patients had a cCR 

(post-chemoradiation negative biopsy and post-chemoradiation physiologic 

uptake on PET). iSUV cut-point was derived by recursive partitioning. 

Results: For 323 cCR patients, the median follow-up was 40.8 months. 206 

(63.8%) patients had TM and 117 (36.2%) had BM therapy. Median OS of 

TM patients and BM patients were 94.8 months (95 % CI; NA-NA) and 

36.5 months (95% CI; 30.5-42.4; p�0.001), respectively. Similar differences 

were observed in RFS (p�0.001). The median iSUV was 9.4 (range, 

0-58.0). Intriguingly, TM patients with iSUV of �6 had a better OS (94.8 

months; 95% CI; 39.1-150.5) and RFS (94.8 months; 95% CI; 18.2- 

171.4) compared to BM patients with iSUV of �6 OS (31.4 months; 95% 

CI; 21.0-41.9; p��0.001) and RFS (17.2 months; 95% CI; 14.5-19.8; 

p�0.001). However, the prognosis of TM and BM cCR patients with iSUV 

�6 was similar (OS, p�0.62 and RFS, p�0.46). The pathological CR 

(pathCR) rate in TM patients was similar irrespective of iSUV of �6 

(27.1%) vs. iSUV �6 (28.6%; p�0.85). Conclusions: Our unique data 

provide an insight into the fate of cCR EAC patients by iSUV. Patient with 

iSUV �6 dramatically benefit from surgery and TM therapy is encouraged. 

iSUV and pathCR do not correlate. iSUV can customize therapy of localized 

EAC patients. 


255s 


Measuring transcripts of components of the BRCA1 DNA repair pathway, 

components of the hippo-YAP pathway, �-TrCP, HER2, AEG-1, EZH2 and 

other genes in advanced gastric cancer. Presenting Author: Jia Wei, 

Nanjing Drum Tower Hospital, Nanjing, China 

Background: The primary goal of this study was to classify gastric cancer in 

two different sub-groups. We speculated that HER2-positive gastric cancers 

could be regulated by �-TrCP, while tumors unaffected by �-TrCP 

activation could be more dependent on the Hippo-YAP signaling pathway, 

in which TAZ increases the expression of AXL. Gastric cancer can 

overexpress AEG-1 and EZH2. The relationship between EZH2 and the 

Hippo-YAP pathway was explored in this study. We also explored BRCA1 

complexes, including upstream components, such as 53BP1 and MMSET. 

Methods: Paraffin-embedded samples were collected from 132 advanced 

gastric cancer patients (p) treated with first-line FOLFOX, 58 of whom 

received second-line docetaxel-based treatment. Gene expression levels of 

HER2, �-TrCP, TAZ, AXL, EZH2, AEG-1, BRCA1, and genes involved in 

DNA repair pathways (RAP80, PIAS1, PIAS4, MDC1, 53BP1, MMSET, 

and UBC9) were quantified by real-time PCR. BIM, IDO, and SPINK1 were 

also examined. Results: A close correlation was found for the majority of the 

genes, for example, BRCA1-MMSET (rho�0.28; P�0.002) and AXL-TAZ 

(rho�0.58; P�0.001). Median overall survival (OS) was 12.5 months (m). 

Among the 58 p receiving second-line docetaxel, in p with high levels of 

BRCA1, OS was 24.9 m, while it was 19.1 m in p with intermediate levels 

and 9.5 m in p with low levels (P�0.009). OS was 28.6 in p with high 

levels of MMSET, 13.8 in p with intermediate levels and 12.3 in p with low 

levels (P�0.001). In the multivariate analysis, only BRCA1 was a significant 

marker for OS (Table). Conclusions: The study showed the predictive 

value of BRCA1, which could be useful for customizing chemotherapy with 

or without docetaxel. In addition, MMSET requires further study since it is 

involved in DNA repair upstream of BRCA1. 

HR 95% CI p 

�-TRCP 

1.22 1 Ref. 

ERBB2 

19.86 1 Ref. 

AEG-1 

1.12 1 Ref. 

BRCA1 

7.62 1 Ref. 


Investigatory study of biomarkers for gastric cancer based on a cDNA bank. 

Presenting Author: Takashi Oshima, Gastroenterological Center, Yokohama 

City University, Yokohama, Japan 

Background: We have constructed a cDNA bank using mRNA extracted from 

frozen specimens of gastric cancer tissue and adjacent normal gastric 

mucosa and studied biomarkers for the individualized therapy of gastric 

cancer and the identification of new treatment targets. We report currently 

available results. Methods: We studied 227 patients in whom at least 5 

years had elapsed since surgery for gastric cancer. The disease stage was IB 

in 29 patients, II in 66, III in 103, and IV in 29. Among the 139 patients 

who postoperatively received fluoropyrimidine anticancer agents, 82 with 

stage II or III disease were given adjuvant chemotherapy with S-1. A total 

116 genes were selected as candidate biomarkers on the basis of the 

results of comprehensive DNA microarray analysis, extraction from a serial 

analysis of gene expression (SAGE) database, and other studies. The 

relative expression levels of these 116 genes in gastric cancer tissue and 

adjacent normal mucosa were measured in each case by a quantitative 

polymerase chain reaction assay using the cDNA databank described 

above, and the relations between clinical histopathological factors and 

treatment outcomes were examined. Results: In patients who underwent 

gastrectomy, high expression levels of the secreted protein acidic and rich 

in cysteine (SPARC), sulfatase 1 (SULF1), and inhibin, beta A (INHBA) 

genes were significantly associated with poor outcomes. In patients with 

stage II or III disease who received adjuvant chemotherapy with S-1, high 

expression levels of the insulin-like growth factor receptor 1 (IGF-1R), 

KIAA1199, thymidylate synthase (TS), and regenerating IV (Reg IV) genes 

were significantly associated with poor survival. Conclusions: Investigatory 

studies using a cDNA bank of biomarkers for gastric cancer suggested that 

expression levels of the SPARC, SULFI, and INHBA genes are useful 

prognostic factors in patients who undergo gastrectomy for gastric cancer. 

Expression levels of the IGF-1R, KIAA1199, TS, Reg IV, and INHBA genes 

may be useful biomarkers in patients who receive adjuvant chemotherapy 

with S-1. 




Efficacy and safety of bevacizumab combined with capecitabine in progressive, 

metastatic well-differentiated digestive endocrine tumors (BETTER 

study). Presenting Author: Emmanuel Mitry, Institut Curie, St. Cloud, 

France 

Background: Neuroendocrine digestive tumors are highly vascularized 

neoplasms known to express the vascular endothelial growth factor (VEGF). 

We assessed the activity of bevacizumab (Bv), a monoclonal antibody 

directed against VEGF combined with capecitabine (CAP). Methods: In this 

multicenter, open-label, non-randomized, two-group phase II trial, one 

group assessed Bv (7.5 mg/m² on d1/3 weeks) combined with CAP (1,000 

mg/m2 twice daily, orally d1-14, resumed on day 22). Eligible patients (pts) 

had progressive, metastatic well-differentiateddigestive tract endocrine 

tumors (WHO 2000 classification), ECOG-PS �2, Ki 67 index � 15%, no 

prior systemic chemotherapy and acceptable organ functions. The primary 

endpoint was progression-free survival (PFS). Secondary endpoints were 

overall survival, response rate, safety and quality of life. Pts were treated for 

a minimum of 6 months and study duration was 24 months. Results: From 

Jun 2007 to Oct 2009, 49 pts were enrolled, 26 (53.1%) were men; 

median age 60.3 years (41.2-82.3); ECOG-PS was 0/1 in 46 (93.9%) pts. 

Primary tumor site was: small intestine 40 (81.6%) pts, caecum 3 (6.1%), 

rectum 4 (8.2%) and stomach 2 (4.1%). Ki-67 proliferative index was 

0-2% in 17 (35.4%) pts, 3-4% in 14 (29.2%), 5-9% in 13 (27.1%), 

10-14% in 4 (8.3%) Metastatic sites were liver: 46 (93.9%) pts, lymph 

nodes: 24 (49.0%), peritoneum 23 (46.9%). Median treatment duration 

was 13.8 months; median number of cycles was 19. At 24 months, median 

PFS was 23.4 months [95%CI: 13.2; not reached] based on 26 events. 

PFS rate at 18 months was 55%. Tumor control rate was 87.8% (n�43) 

including partial response in 9 (18.4%) pts and stable disease in 34 

(69.4%) pts. Survival rate at 24 months was 85%, median overall survival 

was not reached, 8 patients died. CTC grade 3/4 Adverse Events (AEs) 

occurred in 41 (83.7%) pts, mainly digestive 14 (28.6%) pts. Main G3/4 

Bv targeted AE was hypertension in 15 (30.6%) pts. Conclusions: In this 

chemotherapy resistant tumor, the combination of capecitabine and 

bevacizumab, assessed in a phase II study, shows such encouraging results 

that this combination may become a reference in the medical treatment of 

ileal NET. 


Cetuximab, paclitaxel, cisplatin and concurrent radiation in Chinese 

patients with locally advanced esophageal squamous cell carcinoma: An 

open-label, multicenter, phase II study. Presenting Author: Jinming Yu, 

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, 

Jinan, China 

Background: In China more than 90% of esophageal malignancies are of 

squamous cell carcinoma (SCC). We conducted this Chinese multicenter 

trial to determine the efficacy and safety of the addition of cetuximab with 

paclitaxel, cisplatin, and concurrent radiation for patients with esophageal 

SCC and to determine whether KRAS status predicts response. Methods: 

Patients with unresectable locally advanced cervical, upper or midesophageal 

SCC without distant metastasis were eligible for this open-label 

phase II trial. All patients received cetuximab (400 mg/m2 day 1 before 

chemoradiotherapy and 250 mg/m2 q1w � 7 weeks), paclitaxel (45 mg/m2 q1w � 7 weeks) and cisplatin (20 mg/m2 q1w � 7 weeks) with 59.4 Gy of 

radiation. The primary end point was response rate. Second end points 

included toxicity, overall survival (OS), progression-free survival (PFS), and 

KRAS mutation status. Results: Fifty-five patients were enrolled and 

evaluable to safety. Non-hematological adverse events were generally grade 

1 or 2, and were most often rash (94.5%), mucositis (58.2%), fatigue 

(45.5%), nausea (41.8%) and hepatic dyfunction (40%). Hematologic 

adverse events included grade 3 neutropenia (32.7%) and grade 3 anemia 

(1.82%). Ten patients did not complete the protocol therapy (6 for 

chemotherapy dose delays, 1 for paciltaxel hypersensitivity, 1 by the 

treating physicians for unstated reasons, 1 for concurrent unrelated 

infection, and 1 for tracheo-esophageal fistula). The response rate was 

97.7%. The 1-year OS and median OS was 87.3% and 16.8 months, the 

1-year PFS and median PFS was 30.4% and 13.9 months, respectively. No 

mutations were detected at KRAS codons 12 or 13 in the 52 available 

specimens. Conclusions: Cetuximab can be safely administered with 

chemoradiation for Chinese patients with esophageal cancer and may 

improve the clinical response rate. KRAS mutations were too rare to be 

analyzed as a predictor of response. 


NeoFLOT: Multicenter phase II study of perioperative chemotherapy in 

resectable adenocarcinoma of the gastroesophageal junction or gastric 

adenocarcinoma. Presenting Author: Christoph Schulz, Department of 

Hematology and Oncology, Klinikum Grosshadern and Comprehensive 

Cancer Center, LMU Munich, Munich, Germany 

Background: The rationale of the NeoFLOT-trial was the intensification of 

neoadjuvant chemotherapy (NACT) by prolongation of preoperative treatment. 

This strategy is based on the notion that while perioperative 

treatment is notably beneficial in locally advanced gastroesophageal cancer 

(GEC), postoperative chemotherapy can only be applied in a fraction of 

patients (pts). Methods: Pts with T3, T4 and/or N� adenocarcinoma (GEC) 

were eligible for this multicenter phase II trial. NACT consisted of 6 cycles 

of oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 , fluorouracil 2600 mg/m2 and docetaxel 50 mg/m2 (FLOT) applied q 2 wks. Staging was performed 

after 3 cycles to select pts with progressive disease (PD) for immediate 

surgery. Primary endpoint was the R0-resection rate. Secondary endpoints 

included the pathological complete response rate (pCR), histologic tumor 

regression grade (Becker 2003), safety, and progression-free survival 

(PFS). Results: From 10/2009 to 06/2011, 59 pts were enrolled of whom 

58 pts were assessable for safety. Median age was 61 years (range: 32-79), 

58.6% (34/58) had tumors of the gastroesophageal junction. 50 pts 

underwent surgery and were assessable for the primary endpoint. R0resection 

rate was 86.0% (43/50). pCR was achieved in 20.0% (10/50) of 

pts. During NACT, 6.9% (4/58) of pts developed progressive disease. Dose 

reduction was performed in 43.1% (25/58) of pts resulting in a median 

dose intensity of 89.2%. Grade 3/4 neutropenia was observed in 29.3% 

(17/58) of pts, febrile neutropenia grade 3/4 in 1.7% (1/58). Common 

grade 3/4 non-hematologic adverse events were diarrhea (13.8% (8/58)) 

and mucositis (6.9% (4/58)). Treatment related mortality was 3.4% (2/58) 

with 2 cases of sepsis. After a median follow-up of 9.1 months, median PFS 

and OS have not been reached. Conclusions: These data indicate that NACT 

with 6 cycles FLOT is well-tolerated and highly effective in resectable GEC. 


Oxaliplatin, irinotecan, bevacizumab followed by docetaxel, bevacizumab 

in inoperable gastric cancer: First efficacy results of a multicenter phase II 

trial (AGMT Gastric-3) of the Arbeitsgemeinschaft Medikamentöse Tumortherapie. 

Presenting Author: Ewald Woell, St. Vinzenz Krankenhaus Betriebs 

GmbH, Zams, Austria 

Background: In our previous phase II trials (AGMT-Gastric-1 and AGMT 

Gastric-2) efficacy of oxaliplatin and irinotecan as well as oxaliplatin, 

irinotecan and cetuximab was shown. Time to progression however was 

short suggesting acquired chemotherapy resistance. Therefore sequential 

chemotherapy combined with bevacizumab is investigated in the presented 

trial. Methods: Oxaliplatin 85 mg/m2 biweekly (q2w) and irinotecan 125 

mg/m2 q2w are administered for the first three months followed by 

docetaxel 50mg/m2 q2w for three months. Chemotherapy for 6 months is 

combined with bevacizumab 5 mg/kg q2w which is administered until 

progression. For this abstract 36 patients (pt.) with histologically proven 

unresectable and/or metastatic gastric adenocarcinoma have been evaluated 

in a first line setting. Median age: 62.5 years (range 26-80 years), PS 

0: 25 patients, PS 1: 10 patients, missing: 1 patient, single metastatic 

site: 24 patients, multiple metastases: 10 patients, missing: 2. Results: 

Frequently reported adverse events (more than 20% of pt.) were predominantly 

grade 1 or 2 and included diarrhea (25/36, 69%), polyneuropathy 

(17/36, 47%), nausea (17/36, 47%), fatigue (15/36, 42%), neutropenia 

(13/36, 36%), abdominal pain (11/36, 31%), hypokalemia (9/36, 25%). 

Grade 3 and 4 toxicities included neutropenia (6/36, 17%), diarrhea 

(3/36, 8%), hypokalemia (3/36, 8%), anemia in (2/36, 6%), leucopenia 

(2/36, 6%), thrombocytopenia (1/36, 3%), nausea in (1/36, 3%). Objective 

response rate after 3 cycles was available in 25 patients: CR 1/25 

(4%), PR 14/25 (56%), SD 8/25 (32%), PD 2/25 (8%). After 6 cycles 

there were 12 evaluable patients with CR 2/12 (16.7%), PR 5/12 (41.7%), 

SD 4/12 (33.3%) and PD 1/12 (8.3%). Conclusions: The combination of 

oxaliplatin and irinotecan with bevacizumab followed by docetaxel with 

bevacizumab is feasible and very active in advanced gastric cancer. 



Post-recurrence survival in patients with previously resected esophageal 

adenocarcinoma (EAC). Presenting Author: Mark Lewis, Mayo Clinic 

College of Medicine, Rochester, MN 

Background: EAC recurrence after surgery with curative intent is believed to 

carry a uniformly dismal prognosis that may discourage further therapy. To 

date, the post-recurrence survival of patients has not been examined in 

EAC. Our aim was to examine site of recurrence in relation to outcome in 

EAC patients after surgery. Methods: Among EAC patients (N � 796) 

rendered margin-free at surgery performed at Mayo Clinic, most were T3-4 

and lymph node (LN)-positive; none received neoadjuvant therapy. The 

patient subset who had documented disease recurrence (N � 401) formed 

the current study population. Cox models were used to examine overall 

survival (OS) post-recurrence. Results: Among patients with recurrence, 

median time to recurrence (TTR) was 11 months. Site of recurrence 

included loco-regional (regional LNs, esophagogastric, anastomosis), chest, 

abdomen, or distant sites in 97 (27%), 144 (40%), 181 (50%), and 88 

(24%) patients, respectively. Most recurrences (66%) were limited to one 

site. Chest-involved recurrence was significantly associated with improved 

OS (hazard ratio [HR] 0.78, P � .047), even after adjusting for TTR, 

number of recurrence sites, tumor pathology, and palliative chemotherapy. 

This result was confirmed when multivariate analysis was restricted to 

patients who had only 1 recurrence site (Table) or who had biopsy-proven 

recurrence (P � .080). In separate models, abdomen-involved (HR � 1.3, 

P � .016) or bone-involved (HR � 1.6, P� .008) recurrences were 

independently associated with worse OS. Conclusions: Chest-involved 

recurrence of EAC independently predicts for improved survival, whereas 

abdominal and bony sites of recurrence predict for worse outcome. Primary 

tumor grade and node number were durable prognosticators after recurrence. 

These novel data provide useful prognostic information and have the 

potential to influence clinical decision-making. 

Predictors for post-recurrence survival in a multivariate model. 

HRa p 

Chest-only, yes v no 0.69b .021 

Grade, 4 v 1-3 1.36 .027 

Malignant LN, per additionalnode 1.06 .003 

Palliative chemo, yes v no 0.57 �.0001 

TTR, > v < 11 mos 0.99 .265 

a Adjusted for all variables. b 95% confidence interval 0.50 - 0.95. 


Phase II trial of tesetaxel, an oral taxane, as second-line therapy for patients 

with advanced gastroesophageal cancer. Presenting Author: Mary Frances 

Mulcahy, Northwestern University, Chicago, IL 

Background: Tesetaxel is a novel, orally administered taxane. It is not a 

substrate for P-glycoprotein, and preclinical data suggest tesetaxel has 

potent antitumor activity that exceeds standard taxanes in human tumor 

xenografts while causing substantially less neuropathy. Tesetaxel is not 

associated with hypersensitivity, thus eliminating the need for premedication 

and extended observation. A prior study showed an overall major 

response rate (ORR) of 20% with tesetaxel used as 2nd-line therapy in 

patients (pts) with advanced gastric cancer. We previously showed that 

“flat” (i.e., non weight-based) dosing with tesetaxel was associated with 

excessive variability; therefore, we amended the final trial design to 

evaluate whether we could extend the prior observations in a confirmatory 

Phase 2 trial using the MTD. Methods: Eligibility included: adenocarcinoma 

of stomach/GE junction; 1 prior fluoropyrimidine-platinum regimen; ECOG 

PS 0-1; and adequate organ function. Tesetaxel was administered orally 

once every 3 weeks starting at 27 mg/m 2 escalated to 35 mg mg/m2 pending tolerance. ORR was the primary endpoint; estimated overall 

survival (OS) was secondary. Results: To date, 24 pts -- from a final target of 

27 – have been enrolled (10 men, 14 women; median age, 58 yrs [range, 

26-81]). Preliminary ORR in 15 evaluable cases to date are shown in the 

table below. At this time, only 4 pts have died and median survival is too 

early to estimate. Grade 3-4 adverse events have included neutropenia 

(27%), anemia, fatigue (13% each), and anorexia (7%). One pt (7%) 

experienced Grade 3 peripheral neuropathy. There have been no episodes 

of febrile neutropenia. Conclusions: Oral tesetaxel administered once every 

3 weeks is active against gastric cancer in the 2nd-line setting. The 

observed 20% ORR confirms earlier data and appears at least equivalent to 

docetaxel (ORR� 5%-19%), as reported in 4 prior studies in this 

population. Tesetaxel was well tolerated and was not been associated with 

hypersensitivity. We expect to present final ORR and estimated OS from 

this trial. 

Response N � 24 

Evaluable (n) 15 

Partial 3 (20%) 

Stable disease 3 

Progression 9 

Too early 10 

Response duration, mos 1.5�,3�,4� 


257s 


Prognostic impact of FHIT, APC, and HER2 status in resected gastric 

cancer: A clinical-biological risk stratification model. Presenting Author: 

Emilio Bria, Department of Pathology and Diagnostics, University of 

Verona, Verona, Italy 

Background: The dismal prognosis of gastric cancer prompts for the 

identification of factors predictive of survival/response to treatment. The 

potential prognostic value of 11 molecular markers was investigated in a 

retrospective series of 208 resected gastric cancers. Methods: Molecular/ 

clinicopathological data were correlated to cancer-specific/overall survival 

(CSS/OS) using a Cox model. Molecular data were: microsatellite instability, 

CDX2, APC, ß-catenin, E-Cadherin, FHIT, P53, p21, HER-2 (IHC/ 

FISH), TOPO2A amplification (FISH) e PIK3CA mutation (exons 9/20). 

ROC analysis provided optimal cut-offs and model validation. A logistic 

equation with regression analysis coefficients was constructed to estimate 

individual patients’ probability (IPP) of death. Internal cross-validation 

(100 simulations, 80% of the dataset) was accomplished. Multivariate 

model Ratios served to derive a prognostic continuous score to identify risk 

classes. Results: 208 patients were studied (median follow-up 16 months, 

range 1-155). Multivariate analysis selected 8 independent CSS predictors: 

sex (HR 1.53, p�0.04), stage (HR 5.40, p�0.0001), R (HR 2.69, 

p�0.0001), localization (HR 1.64, p�0.008), LN (HR 1.55, p�0.02), 

APC (HR 1.91, p�0.001), FHIT (HR 1.54, p�0.05) and HER-2 (HR 1.92, 

p�0.08). Independent OS predictors were: sex, age, stage, R, localization, 

LN, APC and HER-2. Cross-validation analysis confirmed APC, FHIT and 

HER-2 as the biological variables displaying significant correlation with 

CSS (replication: 98%, 51%, 31%). The multivariate model predicted a 

2-yr IPP of cancer-death/death with a prognostic accuracy of 0.87 (SE 

0.02)/0.91 (SE 0.02). A 2-class risk stratification model was developed 

with the ROC generated cut-off prognostic score (AUC 0.87, SE 0.03; 

Sensitivity 85.3%, Specificity 78.9%); see table below. This 2-class model 

has a prognostic performance for CSS/OS of 0.82 (SE 0.03)/0.81 (SE 

0.02). Conclusions: FHIT, APC and HER-2 represent powerful prognostic 

factors for resected GC and may complement clinical parameters to 

accurately predict individual patient risk. 

Low risk (score < 6) High risk (score > 6) p value 

CSS 82.5% 16.4% �0.0001 

OS 79.7% 15.6% �0.0001 


Outcome of 58 trimodality-eligible esophagogastric cancer (EC) patients 

who achieved clinical complete response (cCR) after preoperative chemoradiation 

but then declined surgery. Presenting Author: Takashi Taketa, 


Background: For patients with EC who can withstand surgery, the preferred 

therapy is trimodality. However, after achieving a cCR (defined as postchemoradiation 

negative endoscopic biopsy for cancer and post-chemoradiation 

physiologic FDG uptake by PET), some patients are tempted to 

decline surgery. Literature is sparse on the outcome of such patients. 

Methods: Between 2002 and 2011, we identified 621 trimodality-eligible 

EC patients in our prospective database. All patients had to be trimodalityelgible 

and must have received preoperative chemoradiation and completed 

preoperative staging that included a repeat endoscopic biopsy and 

PET-CT prior to surgery among other routine tests. Results: Of 621 

trimodality-eligible patients identified, 58 patients declined surgery after 

completing chemoradiation. All patients had a cCR. The median age was 

69 (range, 47-85). Male (84.5%) and Caucasian (91.4%) were dominant. 

Baseline stage was II (44.8%) or III (51.7%) and histology was adenocarcinoma 

(67.2%) or squamous cell carcinoma (29.3%). 40 patients remain 

alive at a median follow up of 50.4 months (95% CI, 38.6-62.1). 5-year OS 

and relapse-free survival were 56.7�9.0% and 32.9�7.7%. Of 12 

patients with local recurrence during surveillance, 11 had salvage resection. 

Conclusions: Although, the outcome of EC patients with cCR who 

declined surgery appears reasonable, in the absence of a validated 

prediction/prognosis model, only trimodality therapy must be encouraged 

for trimodality-eligible patients. Supported by UT M. D. Anderson Cancer 

Center grants and generous donors. 




Phase II study of oxaliplatin and sorafenib in advanced gastric cancer after 

failure of cisplatin-fluoropyrimidine-based (PF) treatment. Presenting Author: 

Rosa Gallego, Hospital Clinic, Barcelona, Spain 

Background: PF-based chemotherapy is the standard first line treatment in 

advanced GC. Although some drugs as taxanes or oxaliplatin (Ox) have 

shown efficacy in combination with P or F, no established second line 

exists. RAF/MEK/ERK pathway activation as well as VEGF expression have 

been related with more advanced GC. Sorafenib (S) is a potent Raf and 

VEGFR inhibitor and Ox has demonstrated non-cross resistance with P. 

Methods: A multicenter phase II to evaluate the efficacy of OX- S 

combination in gastric or GEJ adenocarcinoma (pts) with progressive 

disease after CF based first line chemotherapy, was planned. Other 

inclusion criteria: ECOG 0-2, measurable disease and adequate organ 

function. Treatment doses were Ox 130mg/m2 /3 weeks and S 800 

mg/bid/d until progression or toxicity. CT scan evaluation every 3 cycles. 

The study followed a A-Hern single-stage design (HR � 1.67, median 

expected PFS of 4.3m if treatment ineffective, sample size: 43). The study 

was closed with the inclusion of 40 pts, maintaining a power � 87%. Ten 

pts would have to be alive and free of progression at 12m to consider the 

study positive. Results: Forty pts were included and evaluable for PFS. 

Thirty-six pts were evaluable for response. Median age was 63 ( range 39 - 

76) years, ECOG 0/1/2 in 36/59/5 % of pts. PFS to 1st line was � 6m in 

59% of pts. One CR and, 47.2% of SD were observed. Gr ¾ toxicity (%) 

was: neutropenia (9.8), thrombocitopenia (7.3), neurotoxicity (4.9) and 

diarrhea (4.9). Median PFS was 3 (95 %CI: 2.3-4.1 )m and median OS was 

6.5 ( 95% CI: 5.2-9.6)m. PFS at 12 m was 0%. Median OS in pts with PFS 

to 1º line � 6m/ �6m was 9.7m and 5.6m respectively (p0.04). 

Conclusions: The combination of Oxaliplatin-Sorafenib in advanced GC 

patients previously treated with CF shows a safe profile but these results do 

not support the implementation of a phase III trial. Our results show that 

PFS under a CP-based first line therapy determine subgroups of GC 

patients with different clinical behaviors. 


Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric 

cancer (AGC) enrolled in the phase III GRANITE-1 study. Presenting 

Author: Kun-Huei Yeh, National Taiwan University Hospital, Taipei, Taiwan 

Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol 

2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the 

oral mammalian target of rapamycin inhibitor EVE showed that incidences 

of stomatitis, rash, infections, and pneumonitis were greater in Asian pts; 

however, the number of Asian pts enrolled was small. GRANITE-1 provides 

an opportunity to evaluate EVE safety in a broader Asian population. 

Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts 

aged �18 y with confirmed AGC and disease progression after 1 or 2 lines 

of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d � best 

supportive care (BSC) or placebo � BSC. Randomization was stratified by 

region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of 

world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was 

continued until disease progression or unacceptable toxicity. Adverse 

events (AEs) were collected throughout the study and for 28 d after final 

dose of study drug and assessed according to the Common Terminology 

Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival. 

Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363 

(55%) were enrolled in Asia and received EVE (n�243) or placebo 

(n�120). EVE did not significantly reduce the risk of death in the overall 

(HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or 

ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common 

any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased 

appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs 

35%). Among EVE-treated pts, rates of any-grade rash, infections, and 

pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs 

2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and 

pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and 

0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt 

(from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The 

safety profile of EVE in Asian pts with AGC was similar to that observed in 

ROW pts with AGC and with EVE in other cancers. No new safety signals 

were identified. Pneumonitis was relatively uncommon in Asian and ROW 

pts. 


Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, 

and oxaliplatin with or without docetaxel, in elderly patients with locally 

advanced esophagogastric cancer. Presenting Author: Sylvie Lorenzen, 

National Center for Tumor Diseases, University of Heidelberg, Heidelberg, 

Germany 

Background: The aim of this study was to determine feasibility and efficacy 

of perioperative chemotherapy in elderly, potentially operable esophagogastric 

cancer patients. Methods: Patients aged 65 or older with locally 

advanced esophagogastric adenocarcinoma were randomized to perioperative 

chemotherapy consisting of four preoperative and four postoperative 

cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) with or without 

docetaxel 50mg/m² (FLOT), every 2 weeks. Results: 44 patients with a 

median age of 70 years were randomized to either FLO (22) or FLOT (22) 

chemotherapy. In the FLO and FLOT group, 20 and 18 patients completed 

four cycles of preoperative chemotherapy and 17(77.3%) and 15(68.2%) 

patients proceeded to surgery, with 88.2% and 93.3% R0 resections, 

respectively. FLOT was associated with significantly more treatmentrelated 

NCI-CTC grade 3/4 adverse events, including neutropenia 

(p�.0001), leukopenia (p�.0001), stomatitis (p�0.02) and nausea 

(p�0.02) and a higher rate of patients experiencing a �10-points 

deterioration of EORTC QoL global health status scores (FLOT, 54%; FLO 

23.1%) at 8 weeks. No perioperative mortality was observed, however 

postoperative morbidity was nearly doubled with the FLOT regimen (60% 

versus 35.3% for FLO), mostly due to wound infections in the FLOT group 

(20%). 11 (64.7%) and 9 (60.0%) of patients in the FLO/FLOT group were 

able to undergo postoperative chemotherapy. Compared with the FLO 

group, the FLOT group had a better response rate (61.9% vs. 18.2%) and a 

trend towards an improved median disease free survival (21.1 vs. 12.0 

months; p�0.09). Conclusions: Age alone is not a contra-indication for the 

selection of patients for three-drug regimens in the multimodal treatment 

approach. FLOT seems to be more effective than FLO, but is associated 

with an increased toxicity and higher postoperative morbidity. Therefore, 

careful patient selection is warranted. 


A phase II study of tivantinib monotherapy in patients with previously 

treated advanced or recurrent gastric cancer. Presenting Author: Kei Muro, 

Aichi Cancer Center Hospital, Nagoya, Japan 

Background: Tivantinib is a selective, non-ATP competitive, small-molecule 

inhibitor of c-MET and is under development in several cancers such as 

NSCLC and HCC. Elevated expressions of c-MET and its ligand, hepatocyte 

growth factor, have been frequently found in gastric cancer, and are 

associated with a more aggressive phenotype. In this single-arm phase II 

study, we evaluated the efficacy of tivantinib monotherapy in Asian patients 

(pts) with previously treated metastatic gastric cancer (MGC). This is the 

first clinical trial evaluating the efficacy of a selective c-MET inhibitor for 

MGC. Methods: Eligibility criteria included MGC with at least 1 measurable 

lesion per RECIST; 1 or 2 prior chemotherapy regimens; ECOG PS 0 or 1; 

and normal CYP2C19 metabolism. Tivantinib was daily administered 360 

mg bid orally. The primary endpoint was disease control rate (DCR) defined 

as CR, PR or SD after 8 weeks administration. Pretreatment tumor tissue 

collection was required to evaluate the relationship between biomarkers 

and efficacy. Pharmacokinetic (PK) evaluation was also conducted. Results: 

Thirty patients received tivantinib and were eligible for analysis: median 

age 62.5 (41-70) years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14); 

12 pts (40%) with prior gastrectomy. No objective response was observed, 

and DCR was 36.7% (11/30 pts). Median progression-free survival was 43 

(95% CI: 29.0-92.0) days. Grade 3 or 4 adverse events (AEs) occurred in 

13 pts (43.3%), in which neutropenia (n � 4) and anemia (n � 4) were 

recognized as drug-related. Only 2 pts discontinued due to AEs. There is no 

treatment-related death and novel safety concern. c-MET gene amplification 

(� 5 copies/cell) was observed in 4 pts (13.3%). No obvious 

relationship of treatment outcome with biomarkers including c-MET gene 

amplification, c-MET, p-c-MET and HGF expression in tumor and serum 

HGF was identified. Gastrectomy and/or ethnicity (Korean or Japanese) did 

not affect PK parameters. Conclusions: Tivantinib as a monotherapy showed 

only a modest efficacy in previously treated MGC, and further trial testing in 

combination would be warranted in MGC. It would be an important finding 

that gastrectomy do not affect PK profile of tivantinib. 



Interim safety results from a phase II/III trial with 5-FU, oxaliplatin, and 

docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients 

with locally advanced, resectable gastric/oesophagogastric junction (OGJ) 

cancer: A study of the AIO. Presenting Author: Ulrike Koock, Krankenhaus 

Nordwest, UCT-University Cancer Center, Frankfurt, Germany 

Background: Perioperative ECF is a standard treatment for localized 

gastric/OGJ adenocarcinoma. However, 5-year survival rate remain below 

40%. The FLOT regime is an effective new combination with pathologic 

response rates in the 15% range. This phase II/III study compares both 

regimens in resectable stages. Methods: Pts are stratified by different 

baseline criteria and randomized to either 3 � 3 perioperative cycles of 

ECF (Epirubicin 50 mg/m2 , d1 Cisplatin 60 mg/m², d1 5-FU 200 mg/m², 

d1-d21, qd21) or 4 � 4 cycles of perioperative FLOT (Docetaxel 50mg/m2, 

d1 5-FU 2600 mg/m², d1 leucovorin 200 mg/m², d1 Oxaliplatin 85 mg/m², 

d1, qd14). 5-FU can be replaced by Capecitabine in the ECF-arm (ECX). 

This is a preplanned toxicity analysis after 200 pts in order to decide 

whether to continue to a phase III trial. Results: 202 pts have been 

randomized so far. Median age is 62 yrs; 79% of pts are male. The 

Primaries were Gastric in 43.4%, OGJ in 53.2% and not evaluable/ 

documented in 3.4% of pts. 190 pts were eligible for the safety analyses. 

Median no. of preoperative cycles was 3 and 4 with ECF/ECX and FLOT, 

respectively, and 68.7% vs. 66.0% of pts (ECF/ECX vs. FLOT) started 

postoperative chemotherapy (ct). Grade 3/4 side effects were observed in 

52.1% of ECF/ECX and 59.6% of FLOT pts with no significant differences 

between arms regarding individual grade 3/4 toxicities. Thromboembolic 

events occurred in 14.5% vs. 8.5% in pts with ECF/ECX vs. FLOT (p�.25). 

Serious adverse events occurred in 60.3% vs. 39.7% of pts with ECF/ECX 

vs. FLOT. Preoperative delay/interruptions of ct were observed in 74.0% vs. 

61.7% of pts with ECF/ECX vs. FLOT (p�.07). Dose modifications of 

preoperative ct were performed in 28.1% vs. 22.3% of treatment cycles 

with ECF/ECX vs. FLOT, respectively. 121 pts underwent surgery. Severe 

surgical morbidity was similar in both arms (ECF/ECX, 15.8%; FLOT, 

14.1%). Surgical mortality was observed in 2 and 1 pts with ECF/ECX and 

FLOT. Toxic deaths were observed in 1 pt each. Conclusions: Perioperative 

FLOT is feasible and safe. This supports the continuation of the trial as a 

phase III. 


Relief of bowel-related symptoms with telotristat etiprate in octreotide 

refractory carcinoid syndrome: Preliminary results of a double-blind, 

placebo-controlled multicenter study. Presenting Author: Thomas M. 

O’Dorisio, University of Iowa Hospitals and Clinics, Iowa City, IA 

Background: Diarrhea associated with carcinoid syndrome has been attributed 

to tumor production of serotonin. Telotristat etiprate, (LX1032, 

LX1606), is an oral inhibitor of peripheral serotonin synthesis. This study 

explored the safety, tolerability, and efficacy of telotristat etiprate in 

carcinoid patients with octreotide-refractory diarrhea. Methods: Carcinoid 

patients with �4 bowel movements (BMs)/day on octreotide were randomized 

3:1 to receive telotristat etiprate or placebo as double-blind treatment. 

Patients enrolled in sequential, escalating dose cohorts of 150, 250, 350, 

or 500 mg tid, followed by a 500 mg tid expansion cohort. Patients were 

followed for toxicity, 24-hr urinary 5-HIAA (u5-HIAA), BM frequency, and 

self-reported bowel-related symptoms. Subjects were asked “In the past 7 

days, have you had adequate relief of your carcinoid syndrome bowel 

complaints such as diarrhea, urgent need to have a bowel movement, 

abdominal pain or discomfort?” Responses (yes or no) were analyzed as 

categorical variables. Results: 16 patients enrolled in the 4 escalating dose 

cohorts and 7 in the expansion cohort; 18 on telotristat etiprate and 5 on 

placebo. Median age: 62 yrs; mean 6.3 BMs/day (range, 4-10). AEs 

included primarily mild-moderate diarrhea, nausea, and abdominal discomfort. 

In treated subjects, adequate relief was reported as: Week 1 - 6/18 

(33.3%), Week 2 - 5/16 (31.3%), Week 3 - 5/15 (33.3%), and Week 4 - 

6/13 (46.0%). No placebo subjects reported improvement at any timepoint. 

Biochemical response (�50%reduction in u5-HIAA) and BM response 

(�30% reduction in daily BMs for 2 weeks) were associated with 

reporting of adequate relief. For evaluable telotristat etiprate-treated 

patients, 9/16 (56%) experienced a biochemical response and 5/18 (28%) 

experienced a clinical (BM) response; no placebo subjects achieved either 

biochemical or clinical response. Conclusions: Treatment with telotristat 

etiprate was associated with decreases in u5-HIAA and BM frequency, and 

with self-reported relief of bowel related symptoms. Treatment in an 

extension phase with open-label telotristat etiprate is ongoing. 


259s 


Assessment of the 7th edition of the AJCC classification and a proposal of a 

new classification in patients with gastric cancer undergoing D2 gastrectomy. 

Presenting Author: Vincenzo Catalano, UOC Oncologia, A. O., Pesaro, 

Italy 

Background: Studies on Asian, US, and German patients have moved some 

criticisms on the validity of the 7th edition of the AJCC classification to 

discriminate outcome of gastric cancer stages. We investigated the effect 

of this AJCC classification in a high-quality surgical populations of patients 

receiving D2 lymphadenectomy. Methods: From the prospective database 

at San Salvatore Hospital, Pesaro, we identified 515 patientswith gastroesophageal 

junction (Siewert II and III) or stomach adenocarcinoma who 

underwent gastrectomy with curative intent from 1998 to 2010. Lymphadenectomy 

extended to the 3rd level 12p/b nodes (D2/D3) was performed in 

all patients. Overall survival (OS) probabilities, calculated from the date of 

surgery to the date of death, from any cause, were estimated using the 

Kaplan-Meier method and compared using the log-rank test. Results: 58% 

of patients were male,median age was 73 years (range 36-96). Median 

number of examined lymph nodes was 32 (range, 1-89), and only 8.9% of 

patients had less than 15 examined lymph nodes; 96 patients received 

adjuvant chemo- or chemoradiotherapy. As shown in the table, we proposed 

a revised staging system (Pesaro Staging System, PSS), which performs 

better than the 7th edition of AJCC classification in terms of survival 

differences between stages. Conclusions: This study confirms once again 

that the 7th edition of the AJCC classification does not discriminate 

adequately the outcome from stage to stage. In a European population of 

patients undergoing gastrectomy plus at least D2 lymphadenectomy, the 

revised staging system, PSS, better defines patient prognosis. 

7th edition AJCC Staging System Pesaro Staging System 

Stage Groupings n 5-yr OS (%) p* Stage Groupings n 5-yr OS (%) p* 

IA T1N0 106 86.6 I T1N0-2, T2N0 165 85.7 

IB T2N0, T1N1 55 83.3 .9926 II T3-4aN0, T2N1-2 84 68.4 .0018 

IIA T3N0, T2N1, T1N2 61 67.6 .0447 IIIA T3-4aN1-2 105 53.8 .044 

IIB T4aN0, T3N1, T2N2, T1N3 65 64.8 .7468 IIIB TxN3, T4bNx 117 28.1 .0023 

IIIA T4aN1, T3N2, T2N3 58 56.3 .3845 IV TxNxM1 44 4.6 �.0001 

IIIB T4bN0-1, T4aN2, T3N3 87 35.6 .0376 

IIIC T4bN2-3, T4aN3 39 8.0 .0016 

IV TxNxM1 44 4.6 .0741 

* Compared with row above. 


Association of clinical complete response (cCR) after preoperative chemoradiation 

and pathological complete response (pathCR) in patients with 

gastroesophageal cancer (GEC) and indispensability of trimodality therapy 

(TMT). Presenting Author: Naga K Sucharita Cheedella, University of Texas 


Background: TMT strategy has the highest level-1 evidence for treating 

localized GEC. High rates of cCR (defined as post-chemoradiation negative 

endoscopic biopsy and physiologic uptake on PET) are common and have 

questioned the benefit from surgery in patients with cCR after chemoradiation. 

We hypothesized that cCR would be associated with a high rate of 

pathCR than � cCR. Methods: The data were analyzed retrospectively in 

563 patients who had esophagectomy for GEC in between 2002 and 2010 

at UTMDACC. Among them, 284 had TMT and post-chemoradiation 

endoscopic biopsies and PET (before surgery). Multiple statistical methods 

were used. Results: Of these 284 TMT patients, 218 (77%) patients 

achieved a cCR. However, only 67 (31%) of 218 had a pathCR. The 

sensitivity of cCR for pathCR was 97.1 % (67/69) but the specificity was 

low, 29.8 % (64/215). Intriguingly, 66 patients who had � cCR, only 2 

patients (3%) had a pathCR. The difference in the rate of pathCR between 

the cCR and � cCR groups was significant (P � 0.001). Conclusions: Our 

data show that cCR is frequent after chemoradiation but the pathCR rate is 

not high and it is associated with specificity that is too low for clinical 

implementation. Therefore, all TMT-eligible patients, irrespective of the 

achievement of cCR or � cCR must be encouraged to undergo surgery. 

Therapies that overcome chemoradiation resistance and could increase the 

pathCR rate are needed for esophageal preservation in select GEC patients. 

Supported by UTMDACC and generous donors. 

Path CR 

cCR 

� - 

Total 

� 67 151 218 

- 2 64 66 

Total 69 215 284 




Tolerability and efficacy of a biweekly docetaxel, fluorouracil, leucovorin, 

oxaliplatin regimen (TFOX) in previously advanced metastatic gastric and 

oesogastric junction (AGC) adenocarcinoma. Presenting Author: Simon 

Pernot, Hôpital Européen Georges Pompidou, Paris, France 

Background: The DCF regimen is superior to 5-FU-Cisplatin in term of 

response rate (RR) and overall survival (OS) in advanced gastric cancer, but 

is also more toxic. Oxaliplatin is better tolerated and can effectively replace 

cisplatin in AGC patients (pts). We hypothesize that incorporating Docetaxel 

into a simplified FOLFOX regimen should be a tolerable and 

efficient option, and could facilitate the use of this drug in 1st line in AGC. 

Methods: TFOX regimen was given biweekly as follow: Docetaxel (50mg/ 

m2), oxaliplatin (85mg/m2), leucoverin (400mg/m2) and 5FU continuous 

infusion 48h (2400mg/m2). Main inclusion criteria were: pts with histollogically 

proven metastatic or locally advanced gastric or oesogastric junction 

adenocarcinoma, previously untreated, PS�2. Using Fleming design the 

primary end point was response rate, needing a sample size of 40 pts. 

Results: Between 02/2008 and 07/2011, 41 pts with AGC were enrolled 

(oesogastric junction: 17 pts, diffuse type: 22 pts, metastatic: 37 pts); 

mean age was 53.5 years (31-73), 26 pts were male. PS 0/1/2: 11/24/6 

pts, 14 pts had a relapse after a R0 resection. The total number of cycles 

administered was 310 (mean 7.6 cycles/pts) and 90% of pts received at 

least 4 cycles. No toxic death occurred. Grade 3-4 toxicities were observed 

in 20 pts (48%). Grade 3-4 toxicities were neutropenia (29%) febrile 

neutropenia (7%), neurotoxicity (10%), asthenia (10%). ORR was 63% 

(n�26) [IC95% 48-78], with 2 complete responses. Disease control rate 

(CR�PR�SD) was 78% (n�32) [IC95% 65-90]. Median progression free 

survival and overall survival were 6.5 months [IC95% 5.02-10.85] and 

12.1 months [IC95% 7.25-15.28], respectively. Conclusions: TFOX is 

effective with a manageable toxicity profile in first line treatment for AGC 

pts. Tolerability of this regimen compares favourably with DCF reported 

tolerability. TFOX may be an alternative option for intensive 1st line 

treatment and should now be evaluated in randomized trials. 


Assessment of HER2 status from an epidemiology study in tumor tissue 

samples of gastric and gastro-esophageal junction cancer: Spanish results 

of the HER-EAGLE study. Presenting Author: Lourdes Gomez, Hospital 

Virgen del Rocío, Sevilla, Spain 

Background: Overexpression of HER2 is an important biomarker in gastroesophageal 

junction (GEJ) and gastric cancer (GC) and a predictive factor 

for trastuzumab (T, Herceptin). The ToGA phase III trial showed the benefit 

in overall survival of adding trastuzumab to chemotherapy inHER2-positive 

advanced GEJ/GC patients, following validated scoring criteria by a central 

laboratory. This study examines the incidence of HER2 positivity (local 

laboratories) in GEJ/GC according to EMA Herceptin label. Methods: 

HER-EAGLE was an epidemiological, non–interventional, international 

study assessing HER2 status by IHC/ISH in tumor samples from any stage 

GEJ/GC patients. Neutral buffered 10% formalin embedded tissues (surgical 

excision specimens or minimum 6-8 biopsies) analyzed via validated 

Ventana and Dako methods and scoring criteria used in ToGA: HER2positive 

if IHC 3� or IHC 2� (FISH/SISH confirmed; HER2/CEP17 ratio � 

2.0); HER2-negative if IHC 0 or IHC 1�. Overall and subgroup estimates 

calculated with 95%CI. Data from the Spanish cohort are presented. 

Results: The Spanish cohort of HER-EAGLE included 1,954 participants 

(63.7% males) from 33 hospitals (Dec2010 to Aug2011), with 469 

biopsies (24.0%) and 1,479 excisions (75.7%). Samples were 13.7% GEJ 

and 86.3% GC, and the adenocarcinomas were 1,137 intestinal (58.2%), 

510 diffused (26.1%), 163 mixed (8.3%; Laureen classification), and 144 

not available (7.3%). Median time from sampling to HER2 analysis of 5.1 

years (range from days to 12 years). Total of 210 cases tested IHC 3� 

(10.7%), 215 IHC 2� (11.0%), 308 IHC 1� (15.8%), and 1,221 IHC 0 

(62.5%). Overall, HER2 positivity (IHC 3� or IHC2�/ISH�) was 14.1% 

(95%CI 12.61 – 15.75). HER2 positivity by histological type was higher in 

intestinal adenocarcinomas (19.5%) compared to diffused (4.5%) or in 

mixed (9.2%). Conclusions: HER-EAGLE confirmed the feasibility of 

community based HER2 testing in GC as the first study with a high number 

of samples analyzed by local laboratories. The incidence of HER2-positivity 

(EMA label definition) was similar to the ToGA screening population, and it 

was again higher in adenocarcinomas of intestinal type (19.5%). 


Prognostic value of lemur tyrosine kinase-3 (LMTK3) polymorphism in 

Japanese (J) patients (PTS) with localized gastric adenocarcinoma (GAC). 

Presenting Author: Afsaneh Barzi, Norris Comprehensive Cancer Center, 

University of Southern California, Los Angeles, CA 

Background: LMTK3 is an estrogen receptor � (ER�) regulator. Recent 

studies show that [rs808419(r8) and rs9989661(r9)] and LMTK3 expression 

are prognostic in breast and colon cancers. Our group demonstrated 

that r9AA is associated with shorter time to recurrence in Caucasian(C) and 

Hispanic(H) females(F) with GAC. We investigated the significance of 

LMTK3 polymorphism in J PTS with GAC. Methods: Blood or tissue samples 

of 169 J PTS who had surgery with/without adjuvant chemotherapy (ACT) 

were analyzed. Genomic DNA was extracted using the QIAmp kit; all 

samples were analyzed using PCR-based direct DNA-sequencing. The 

endpoints of the study were disease-free survival (DFS) and overall survival 

(OS). Kaplan-Meier curves and log-rank test were used for univariate 

analysis. Multivariate analysis was performed to test the interaction 

between polymorphism and gender adjusting for other variables. Results: 

60 F and 109 males were enrolled in this study, 17% stage(s) IB, 31% s II, 

36% s III, 17% s IV (AJCC-6). The median age was 67(31-88). 65% of PTS 

received S-1 based ACT. Median follow-up was 4 years(ys). Prognosis was 

worse in men with r9 AA than AG/GG, at 1 year 67% (95% CI 40-83%) with 

AA vs 99% (95% CI 91-99%) of AG/GG were alive (p� 0.039). Median 

survival was not reached in the AG/GG group; in the AA group median DFS 

and OS was 1yr (p� 0.03) and 2ys (p� 0.039) respectively. In the 

multivariate analysis adjusting for s, age, and ACT, males carrying AA had 

increased risk of disease recurrence (HR 3.84 95%CI 1.86-7.92, p� 

0.001) and dying (HR 3.47 95%CI 1.58-7.62 p�0.002) compared to 

those with AG/GG (HR�1, reference). Conclusions: r9 AA was associated 

with significantly worse DFS and OS in J male with GAC. These results 

confirm our previous findings that LMTK3 is an independent prognostic 

factor for localized GAC; interestingly the relationship between gender and 

prognostic significance is the opposite in J vs. C/H. The gender disparity 

can be due to the differences in the etiology (histological subtypes), 

management strategies, allele frequency, and degree of estrogen exposure 

in the two populations. Additional studies are warranted to identify the 

underlying biological mechanism. 


A prospective trial for defining a subset of patients with limited metastatic 

gastric cancer who may be candidates for bimodal treatment strategies: 

FLOT3. Presenting Author: Salah-Eddin Al-Batran, Krankenhaus Nordwest, 

UCT-University Cancer Center, Frankfurt, Germany 

Background: The utility of surgery for metastatic gastric cancer is debated. 

A prospective trial was performed to evaluate a prognostic model for 

selecting patients (pts) treated with systemic chemotherapy (ct) who may 

also be candidates for surgical intervention. Methods: Using a predefined 

algorithm pts with untreated gastric cancer were prospectively stratified 

into 3 groups: operable (OD), limited metastatic (LD), or extensive 

metastatic (ED) disease and treated with 5-FU, oxaliplatin, leucovorin and 

docetaxel (FLOT). LD was defined as: distant intra-abdominal lymph node 

metastases only or/and a maximum of 1 organ involved, normal serum 

alkaline phosphatase, � 5 liver lesions, no visible carcinomatosis (peritoneum 

or pleura), and ECOG � 1. All other metastatic pts were ED. Pts with 

OD received 4 preoperative ct cycles followed by surgery and 4 postoperative 

cycles. Pts with LD received 8 cycles with surgery allowed for complete 

macroscopic resection. Pts with ED received 8 cycles with surgery allowed 

for palliation only. The study had 80% power to detect a HR of 0.55 for 

overall survival in favor of the LD group (vs. ED group; 2-sided log-rank 

p�0.05). Results: 238 of 252 pts included were eligible (OD/LD/ED: 

51/60/127). LD pts had distant lymph nodes only (41%), liver (22%), lung 

(17%), localized peritoneal involvement (7%), or others (13%). A median 

of 8 ct cycles was applied to all groups. Median OS was 22.9 vs. 10.7 

months in pts with LD vs. ED, respectively (HR 0.37; 95% CI, 0.25 – 0.56; 

p �0.001). LD was the strongest predictor of OS in the multivariate 

analysis including all single determinants of LD status (p�.002). Surgical 

resection was conducted in 96%, 62%, and 12% in the OD, LD, and ED 

groups, of which R0 resection (primary) was achieved in 82%, 81% and 

33%, respectively. Within the LD arm, operated pts had better outcome 

than non-operated pts (median OS 31.3 vs. 15.9 months; p�.004) and pts 

with lymph node only involvement had best outcome. Conclusions: This 

clinical model identifies a subset of pts with (limited) metastatic gastric 

cancer who have a favorable outcome and who may be candidates for 

bi-modal treatment strategies. 



Neoadjuvant chemoradiotherapy with 5-fluorouracil-cisplatin combined 

with cetuximab in patients with resectable locally advanced esophageal 

carcinoma: A prospective phase I/II trial (FFCD-PRODIGE 3)—Preliminary 

phase II results. Presenting Author: Laetitia Dahan, APHM La Timone, 

Marseille, France 

Background: Chemoradiotherapy (CRT) for locally advanced esophageal 

cancer is based on 5FU combined with cisplatin. The anti-EGFR antibody 

cetuximab increases the efficacy of RT-based regimen for patients (pts) 

with cancer of the head and neck. This phase I/II trial was evaluating MTD, 

safety and pathologic complete response (pCR) rate of the combination of 

cetuximab with platinum-based CRT in esophageal cancer. Methods: 

Inclusion criteria: squamous cell carcinoma or adenocarcinoma of the 

esophagus, stage II-III, WHO PS 0-1. A radiotherapy of 45 grays (1.8 

Gy/25F) was given over 5 weeks. During phase I, four patients experienced 

limited toxicity to dose level 0, and treatment was desescalated to dose 

level -1: weekly cetuximab (400 mg/m2 one week before start of radiotherapy 

and 250 mg/m2 during radiotherapy), and 5 FU (500 mg/m2 per 

day D1-D4) combined with cisplatin (40 mg/m2 D1) on week 1 and 5. Nine 

pCR over 27 resections were needed to show a pCR rate�20% (��5%, 

power � 90% ). Thirty three patients were included in the phase II. Results: 

From 07-2007 to 01-2011, 33 pts were enrolled, 20 squamous cell 

carcinoma (60.6%), 13 adenocarcinoma (39.4%), 25 (75.8%) stage III 

and 8 (24.2%) stage II. Among 32 pts who received CRT, the main grade 

3-4 toxicities were esophagitis (4 pts), leucopenia (1 pt), anaphylaxis 

reaction (1 pt), rash (1 pt). Resection was achieved in 27 pts (25 R0)/31 

who underwent surgery. Complete or near complete pathologic response 

(TRG grades 1 and 2 to Mandard) was achieved respectively in 5 (18.5%) 

and 6 (22.2%) pts. There were 4 deaths at 30 days post surgery. Severe 

postoperative complications were pulmonary complications (8), anastomotic 

stricture (4), gastric necrosis (1) and infection (7). The median 

overall survival was 15.7 months [11.01-.], and the median relapse free 

survival was 13.7 months [5.47-.]. Conclusions: Adding cetuximab to 

preoperative chemoradiotherapy including 5FU and cisplatin did not 

increase pCR. The recommended dose level of chemotherapy determined 

during phase I could explain those disappointing results. We won’t initiate a 

phase III trial. 


Randomized phase II study of preoperative concurrent chemoradiotherapy 

with or without induction chemotherapy with S-1 and oxaliplatin in patients 

with resectable esophageal cancer. Presenting Author: Dok Hyun Yoon, 

Department of Oncology, Asan Medical Center, University of Ulsan College 

of Medicine, Seoul, South Korea 

Background: The value of adding induction chemotherapy (ICT) to preoperative 

chemoradiotherapy followed by surgery has not been delineated well. 

Methods: Patients with stage II, III or IVA (by AJCC 6th ed.) esophageal 

cancer were randomly allocated to either 2 cycles of ICT (oxaliplatin 130 

mg/m2 on day 1 and S-1 at 40 mg/m2 bid on days 1-14, every 3 weeks), 

followed by concurrent chemoradiotherapy (CCRT) (46 Gy, 2 Gy/day with 

oxaliplatin 130 mg/m2 on day 1 and 21 and S-1 30 mg/m2 bid, 5 days/week 

during radiotherapy) and surgery (arm A, n�48), or the same chemoradiotherapy 

followed by surgery without ICT (arm B, n�49). Primary outcome 

was to compare pathologic complete response (pCR). Results: Thirty six and 

35 patients underwent surgery with or without ICT, respectively. pCR rate 

among those who underwent surgery was significantly lower in arm A 

(30.6% vs. 54.3%, p�0.043). However, no difference in progression-free 

survival (PFS) and overall survival (OS) was observed with a median 

follow-up of 19.5 mo (95% CI, 19.1-22.4). Two-year PFS rate was 63.8% 

in arm A and 55.2% in arm B (p�0.626) and 2-year OS rate was 70.1% 

and 62.6%, respectively (p�0.515). While 47 (arm A) and 48 (arm B) 

patients received at least 44 Gy of radiotherapy, relative dose intensity 

(RDI) for oxaliplatin during CCRT was significantly lower in arm A vs. arm B 

(92.7% � 19.6% vs. 99.7 � 1.8%, p�0.017). RDI for S1 did not 

significantly differ (94.1% � 17.3% vs. 98.5% � 5.9%, p�0.095). G3/4 

thrombocytopenia was significantly common in arm A (37.5% vs. 4.1%, p 

�0.001), which contributed to lower RDI of oxaliplatin. Three patients in 

arm A, compared to none in arm B, failed to survive for 90 days after 

surgery. Conclusions: Adding this ICT to preoperative chemoradiotherapy 

seems to cause lower pCR rate and higher toxicity during CCRT. 


261s 


Positive association of gastric cancer surgery outcome with surgeon 

specialization in a Shanghai high-volume general hospital. Presenting 

Author: Zhenbin Shen, Department of General Surgery, Zhongshan Hospital, 

Fudan University, Shanghai, China 

Background: Numerous studies suggest positive relationship between 

hospital volume and cancer treatment outcomes, the surgeon’s experience 

and specialty training may also be important. This was examined in a high 

volume hospital in Shanghai among patients who underwent gastric cancer 

(GC) surgery. Methods: Data on consecutive patients (pts) undergoing R0 or 

R1 GC resection in Zhongshan hospital between January 2003 and June 

2010 were collected and analyzed. Follow-up on pts who were non- 

Shanghai residents were less complete therefore excluded. Post-operative 

mortality, pathologic results and survival outcome for pts treated by 

surgical training, i.e., sub-specialized vs., non-specialized, were obtained. 

Survival was calculated by the Kaplan-Meier method and Log-rank test was 

used to determine statistical significance. To determine whether subspecialty 

surgical training was an independent factor for overall survival 

(OS), univariate and multivariate analyses were performed using Cox 

proportional hazards regression. Results: Total 5,046 pts underwent R0 or 

R1 GC resection were identified.1594 pts had complete covariate data, 

survival information and were included in the study. Of them, the 

sub-specialized group included 217 cases treated by 3 surgeons, while the 

non-specialized group included 1377 cases treated by 52 surgeons. 5-year 

cumulative OS was higher in the sub-specialized group (62.9% vs. 54.6%, 

p�0.032). Multivariate analysis showed that tumor stage(p�0.001), 

location of tumor (p�0.003), vascular invasion (p�0.001) and surgeon 

(HR�1.54, p�0.001) were all associated with OS. The incidence of 

positive margin was higher in non-specialized group (2.0% vs. 2.7%, 

p�0.001) and the probability of retrieved lymph nodes less than 15 was 

more in non-specialized group (25.9% vs. 7.3%, p�0.001). Postoperative 

mortality was also higher in non-specialized group than in specialized 

group(1.5% vs. 0.9%, p�0.001). Conclusions: In high volume general 

hospital, sub-specialty training is desirable in gastric cancer surgery, the 

quality of gastric cancer surgery can be further improved by sub-specialty 

training leading to better treatment outcome. 


Multicenter phase II study combining panitumumab with chemoradiation 

followed by surgery for patients with operable esophageal cancer (PACTstudy). 

Presenting Author: Sil Kordes, Academic Medical Center, Amsterdam, 

Netherlands 

Background: A consistent finding in many studies in patients with operable 

esophageal and gastro-esophageal junction cancer is that response to 

preoperative therapy, particularly the absence of residual disease in the 

surgical specimen, is an indicator of better disease-free and overall 

survival. One of the potential strategies to improve these local effects of 

preoperative chemoradiation (CRT) is the concurrent inhibition of the 

epidermal growth factor receptor (EGFR). Therefore in our trial we evaluated 

the pathologic response of panitumumab in combination with neoadjuvant 

CRT as first line treatment of operable adenocarcinomas or squamous 

cell carcinomas of the esophagus. Methods: Patients with resectable 

cT1N1M0 or cT2-3N0-2M0 tumors received preoperative CRT consisting 

of 3 administrations of panitumumab (6mg/kg) in weeks 1-3-5, weekly 

administrations of carboplatin (AUC � 2) and paclitaxel (50 mg·m2 ) for 5 

weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per 

week) followed by surgery. The primary endpoint was the percentage of 

pathologic complete responses (pCR). Results: From January 2010 till 

December 2011, 91 patients were enrolled. 3 patients were not resected 

due to the development of metastatic disease during CRT. Results of all 

patients will be presented at ASCO. The majority of the 74 patients 

operated thus far had T3 (85%) and node positive (77%) tumors. 21.6% 

reached pCR and 13.5% had less than 10% viable tumor cells in the 

resected specimen. R0-resection was achieved in 98.6%. There were 58 

patients with adenocarcinoma and 11 patients with squamous cell carcinoma. 

The pCR of these patients were 15.5% and 45.5%, respectively. 

Main grade 3 toxicities were esophagitis, fatigue, rash and anorexia. 1 

postoperative death occurred due to ischemia of the esophageal reconstruction. 

Conclusions: The addition of panitumumab to chemoradiotherapy with 

carboplatin and paclitaxel was feasible without increasing postoperative 

mortality, but did not improve the rate of pathologic complete responses 

compared to historical data. 




Two-year follow-up of a phase II study on catumaxomab as part of a 

multimodal approach in primarily resectable gastric cancer. Presenting 

Author: Carsten Bokemeyer, Department of Oncology/Hematology, University 

Hospital Hamburg, Hamburg, Germany 

Background: Perioperative chemotherapy (CT) has demonstrated as survival 

benefit in locally advanced gastric cancer (GC) in randomized trials. 

However, the overall cure rate is 30-40% and a significant number of 

patients are not able to receive the postoperative part of their CT regimen. 

In Europe, the trifunctional antibody catumaxomab is approved for the 

treatment of malignant ascites based on a pivotal trial which also included 

GC patients. A new multimodal approach combining neoadjuvant CT, 

followed by gastrectomy and intraperitoneal (i.p.) immunotherapy with 

catumaxomab was assessed in a single-arm multicenter phase II study. We 

here report 2-year follow-up data. Methods: GC pts (T2/T3/T4, N�/–, M0) 

received 3 cycles of neoadjuvant fluoropyrimidin/platinum-based CT followed 

by ´en-bloc´ R0-gastrectomy. Catumaxomab was administered i.p. as 

intraoperative bolus (10 �g) followed by 4 consecutive 3-hour infusions of 

10-150 �g. Primary safety endpoint was the rate of predefined postoperative 

complications observed during 30 days after surgery. Key efficacy 

endpoints included disease-free (DFS) and overall survival (OS). Results: 

The original study data presented at the WCGC in 2011 (Schuhmacher et 

al.,Ann Oncol (2011) 22(suppl. 5)) showed that the primary endpoint was 

met and the described application regimen is safe. At time of surgery, 

27.8% of patients were stage I, 27,8% of patients were stage II, 22,3% of 

patients were stage III and 14,8% of patients were stage IV as assessed 

according to pTNM measures. At 24 months 39/54 (safety analysis set) 

patients were still alife,14/54 were dead, (one patient lost to follow-up), 

24/37 had no progression, only 13/37 patients relapsed (for 2 patients 

disease status was not recorded). At the 2 year cut off DFS was 56.4% 

(95% CI: 41–69%), OS was 75% (95% CI: 60–85%). Conclusions: 

Catumaxomab as part of a multimodal therapy in primarily resectable GC is 

a feasible option. The 2-year follow up efficacy results show promising data 

for DFS and OS in a cohort of locally advanced gastric cancer pts. 


Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid 

and 5-fluorouracil (TCF-dd) followed by oxaliplatin, folinic acid, 5-fluorouracil, 

and irinotecan (COFFI) in locally advanced or metastatic gastric 

cancer (MGC). Presenting Author: Gianluca Tomasello, Istituti Ospitalieri, 

Cremona, Italy 

Background: MGC is a chemosensitive tumour. According to the Norton- 

Simon hypothesis, a reduction of tumor burden could best be achieved by 

shortening the interval between the cycles, and the resistance might be 

overcome by switching from initial chemotherapy to a new, non crossresistant 

one. We previously reported on the high efficacy of a new strategy 

using 2 sequential, non cross-resistant chemotherapy regimens in MGC 

(Cancer Chemother Pharmacol 11 Jan; 67 (1): 41-8). Aim of this study is to 

evaluate this therapeutic approach in a larger case series. Methods: 43 

patients (pts) treated at our centre from November 04 to April 11 were 

included. All pts were chemo-naïve and received 4 cycles of TCF-dd (see 

reference above for doses) every 2 weeks. Subsequently and irrespective of 

their response, they received 4 cycles of COFFI (see reference above ) every 

2 weeks. In both regimens pegfilgrastim 6 mg sc on day 3 was included. 

Results: Median age: 63; 74% male. PS 0-1. After the first regimen 

(TCF-dd) 43 pts were evaluable for response.We registered 3 CR, 27 PR, 7 

SD, 5 PD and 1 not evaluable for an ORR at ITT of 70% (95% CI, 58-85). 

All pts proceeded to the second regimen (COFFI) and 40 pts were evaluable 

for response. The 3 CR observed after TCF-dd were maintained. Among the 

27 pts with PR after TCF-dd, 2 achieved CR, 14 improved the response, 6 

maintained PR, 3 progressed. Among the 7 pts with SD after TCF-dd, 1 

achieved CR, 3 achieved PR, 2 progressed and 1 is not valuable. Among the 

5 pts with PD after TCF-dd, 1 achieved CR, 4 achieved RP. After COFFI we 

observed 5 CR, 21 PR, 9 SD and 5 PD. The ORR in the 40 pts was 60% 

(95% CI, 50-80). Considering both regimen ORR was 93%. mTTP was 

12.1 months (95% CI, 8,1-16,2). mOS was 16.1 months (95% CI, 

12.7-21.6). At Dec ’11, 4 out of 8 pts who achieved CR are alive and 

disease free. Most frequent G3-4 toxicities were: astenia (32%), neutropenia 

(35%), anemia (14%), neurotoxicity (21%). Conclusions: The study 

confirms that a sequential dose-dense strategy using TCF-dd followed by 

COFFI is feasible and highly effective and deserves to be tested in a 

randomized study which is on going. 


A phase II study of capecitabine-oxaliplatin and cetuximab in patients 

(pts) with advanced/metastatic gastric cancer (G) or gastroesophageal 

junction (GEJ) adenocarcinoma. Presenting Author: Syma Iqbal, University 

of Southern California Norris Comprehensive Cancer Center, Los Angeles, 

CA 

Background: There have been limited advances in the treatment (tx) of pts 

with metastatic G or GEJ adenocarcinoma. The combination of fluroropyrimidines 

and platinums are standard regimens for this disease. The epidermal 

growth factor receptor pathway has been identified as a target and KRAS 

mutations are rare. Methods: The primary objective was to assess the 

proportion of pts with progression within 4 months. Secondary objectives 

include response (RR), progression free survival (PFS) overall survival (OS), 

toxicity and molecular correlates. A two-stage Simon phase II design was 

used to distinguish between a 30% vs. 50% 4 month PFS; with analysis 

planned at 27 and 53 pts. Eligible pts were chemonaive, metastatic/ 

unresectable with measurable disease. Pts received capecitabine 850 

mg/m2 BID D1-14, oxaliplatin 130 mg/m2 IV D1, cetuximab 400 mg/m2 

(load) then 250 mg/m2 IV D1, 8, 15, q21 days. Blood and tissue were 

analyzed for genes in the DNA repair and EGFR pathways. Results: 61 pts 

were accrued, 2 GEJ and 59 G; 42 male, 19 female; median age 56 years 

(28-86); 54 pts were evaluable. The 4 month PFS rate 61% (95%CI 

47-73%), PFS 5.4 months (95% CI 3.5-6.7); RR 50% (95%CI: 36-64%), 

1 (1.9%) complete, 26 (48.1%) partial, 22 (40.7%) stable disease; 2 

(3.7%) pts became resectable; median OS 14.9 months (95% CI 8.8- 

22.2) with median follow-up of 21.8 months. 65% (39/60) of pts had 

grade 3 (36 pts) or 4 (3 pts) toxicity; most common, anorexia (13.3%), 

diarrhea (13.3%), fatigue (13.3%), nausea (15%), vomiting (15%); grade 

3 hand/foot (5.3%), acneiform rash (3.3%). SNP’s in LRIG4, (regulator of 

EGF signaling) and PAI1 (tumor angiogenesis, cell proliferation, migration 

and adhesion) were significantly associated with RR (67% G/G vs 17% A/A 

,p�0.044) and PFS (5.8 months 5G/4G vs 3.4 months 5G/5G, p�0.017) 

respectively. Conclusions: XELOX and cetuximab has promising activity, 

comparable to existing regimens. Novel SNP’s were identified correlating 

with RR and PFS which may allow for optimization of pt selection. 


Lenalidomide for second-line treatment of advanced hepatocellular cancer 

(HCC): A Brown University Oncology Group phase II study. Presenting 

Author: Howard Safran, Brown University Oncology Group, Providence, RI 

Background: Lenalidomide inhibits fibroblast growth factor (FGF), vascular 

endothelial growth factor (VEGF) and multiple tumor growth pathways. 

There is no standard of care for patients who progress after sorafenib. 

Therefore, we performed a phase II study to determine the activity of 

lenalidomide in second-line HCC therapy. Methods: Patients with advanced 

HCC who progressed on or were intolerant to sorafenib were eligible. Prior 

chemoembolization, RFA, or surgery were allowed. Eligibility criteria also 

included bilirubin �4 mg/dL, AST and ALT �5 times upper limit of normal, 

ECOG performance status 0-2, platelet count �60,000/mm3 , absolute 

neutrophil count �1000/mm3 , and creatinine �2mg/dL. Patients were 

treated with lenalidomide 25mg orally days 1-21 of a 28 day cycle until 

disease progression or unacceptable toxicities. The planned original 

sample size was 25 patients but when early activity was demonstrated the 

study was expanded to 40 patients. Results: The study has completed 

accrual of 40 patients. The median age was 60.5 years (17-88 years). 

Nineteen patients were Child-Pugh A, 16 patients were B, and 5 patients 

were C. Twenty four patients had extrahepatic disease. Preliminary data is 

available on the first 37 patients. One patient had grade 4 neutropenia. 

Grade 3 toxicities included ANC (n�2), fatigue (n�4), rash (n�2), arthritis 

(n�1), diarrhea (n�1), dehydration (n�2). One patient developed variceal 

bleeding which precipitated encephalopathy and death. Of the 32 patients 

with elevated baseline AFP, nine (28%) had a �50% reduction including 

one patient with a reduction in AFP from 56,900ng/ml to 5 ng/ml. Six of 

the first 37 patients (16%) had a radiographic partial response. Two 

patients achieved a complete response and have not progressed at 36 and 

32 months. Conclusions: Lenalidomide can be administered to patients 

with advanced HCC and significant hepatic dysfunction. Promising, and in 

a small percentage of patients, dramatic and durable activity has been 

demonstrated. Investigations are underway to explore the mechanism of 

action of lenalidomide in HCC. 



A phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in patients 

with advanced hepatocellular carcinoma (HCC). Presenting Author: Jennifer 

J. Knox, Princess Margaret Hospital, Toronto, ON, Canada 

Background: There is strong rationale to combine an m-TOR inhibitor (TEM) 

with a VEGF inhibitor (BEV) as a potentially active and well tolerated 

treatment for HCC. Both agents have shown modest single agent activity in 

HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage 

Simon design planned 25 or 50 patients (pts) to test the null hypothesis 

that true tumor response rate is at most 10% andtrue 6-mo progressionfree 

survival rate (PFS) (by RECIST) is at most 65%, or no better than single 

agent BEV (6 mo PR �2 pts or PFS 6 mo �18 out of 25.) Toxicity, TTP, 

PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with 

disease unresectable or amenable to other localised therapies, Child Pugh 

A liver status and no prior systemic therapy involving the VEGF or m-TOR 

class of agents. TEM was administered at starting dose 25 mg IV 

d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle). 

Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were 

enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85% 

male, PS 0/1: 35/65, 58% metastatic, �85% BCLC stage C. With med 6 

cycles (range 1-14) delivered, most pts (88%) experienced a grade 3� 

adverse event (a/e.) Common grade 3 a/es related to treatment included 

thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue 

(8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4% 

each). There was one possible treatment related death. Per protocol dose 

reductions/discontinuation for TEM-related a/es were most common. There 

were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt 

developed a late PR at cycle 13. Median TTP on study was 6 mos, median 

PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive. 

Accrual closed at end of stage 1 as neither the number of responses nor the 

PFS at 6 mos passed the futility stopping rule set for this combination. 

Conclusions: This multicenter study is the first HCC trial evaluating the 

BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did 

not surpass assumptions based on single agent BEV in HCC. Further study 

of BEV/TEM combination in this advanced HCC population is not recommended. 


Serum folate, LINE-1 hypomethylation, and overall survival in a prospective 

cohort of hepatocellular carcinoma patients. Presenting Author: Abby 

B. Siegel, Columbia University, New York, NY 

Background: Folate plays a central role in DNA methylation reactions, but 

the relationship between folate and methylation status has not been 

studied in HCC patients. We hypothesized that low folate levels would 

correlate with global hypomethylation, and worsened survival in HCC 

patients. Methods: 72 newly-diagnosed HCC patients were enrolled in a 

prospective study, beginning 10/08, and followed until 9/11. We excluded 

those with previous malignancy, and uncompensated Child Pugh (CP) B or 

C disease. We used pyrosequencing to evaluate quartiles of LINE-1 

methylation in plasma as a surrogate for global tumor hypomethylation. We 

evaluated the relationship between folate deficiency (serum folate levels � 

6ng/mL), DNA hypomethylation (LINE-1 methylation � 25th percentile 

i.e., � 69.4%), and overall survival in our cohort. Results: Median age was 

60; 82% were men and 67% had hepatitis C. Mean serum folate levels 

were 12.1 ng/mL (SD � 5.3 ng/mL), while mean % LINE-1 methylation 

was 69.9 (SD � 4.6). In a univariate analysis, folate deficiency and LINE-1 

hypomethylation were significant predictors of poor overall survival (HR � 

3.77; 95% CI: 1.37, 10.41, and HR�3.50; 95% CI: 1.51, 8.13, 

respectively). These markers remained independent predictors of survival 

in a multivariate model including age, CP class, AJCC stage and AFP. HR 

for folate deficiency in this model was 3.52 (95% CI: 1.16, 10.70), and HR 

for LINE-1 hypomethylation was 2.74 (95% CI: 1.10, 6.85). We also found 

a significant association between folate deficiency and LINE-1 hypomethylation 

(p � 0.04). Conclusions: We provide novel data that folate deficiency 

is an independent predictor of worsened overall survival in patients with 

HCC in a multivariate model. Further, we show that global changes in DNA 

methylation assesed in plasma correlate with folate levels, supporting a 

possible mechanistic link between the two. Folate supplementation, and 

the use of other agents which modulate methylation, deserve further study 

in HCC. 


263s 

4100^ General Poster Session (Board #48C), Mon, 8:00 AM-12:00 PM 

A phase I/II study of AZD6244 in combination with sorafenib in advanced 

hepatocellular carcinoma. Presenting Author: Su Pin Choo, National 

Cancer Center Singapore, Singapore 

Background: Preclinical studies have shown that pharmacological inhibition 

of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect 

of sorafenib in both orthotopic and ectopic models of HCC. We conducted 

this study to determine tolerability, pharmacokinetics, and pharmacodynamics 

of AZD6244 when combined with sorafenib in advanced HCC. Methods: 

Patients with biopsy-proven unresectable BCLC B/C hepatocellular carcinoma 

were recruited. Only those with Childs-Pugh A or B (7) liver cirrhosis 

and without prior systemic therapy were included. Sorafenib at 400mg bd 

was given 1 week before initiation of AZD6244 which was escalated in 

subsequent cohorts from 75mg om based on 3�3 design. PK and PD 

studies and QOL assessments were performed. DCE-MRI imaging was 

performed to assess tumor vascularity in response to treatment. Results: 

Fourteen patients were recruited (including 2 replaced). 11 had evaluable 

disease. Characteristics: all male, all Chinese, 12 were BCLC C stage. Two 

DLTs were seen out of 6 patients at dose level 1 (AZD6244 at 50mg bd) 

which were grade 3 fatigue and grade 3 abdominal pain with elevated 

transaminases. When an additional dose level 1A was added (ADZ6244 at 

100mg om), 2 out of 3 patients had DLTs of grade 3 raised aspartate 

transaminase and grade 3 diarrhea. Thus, the MTD was determined to be 

AZD6244 at 75mg om when combined with sorafenib 400mg bd. Common 

toxicities were diarrhea (83%), rash (58%), fatigue (50%), hypertension 

(42%), anorexia/vomiting/thrombocytopenia (25%). Two patients had reversible 

LVEF dysfunction and there were no eye toxicities. PK of AZD6244 

showed oral clearance of 11.2 � 6.8 L/h and terminal half-life of 6.0 �2.0 

h.Objective responses were 3 PR, 6 SD and 2 PD.DCE-MRI measurements 

demonstrated significant reductions in permeability surface area product 

(PS, ml/100ml/min) and fractional intravascular blood volume (v1, ml/ 

100ml) seven days after starting sorafenib. No additional antivascular 

activity was observed when AZD6244 was added to sorafenib. Conclusions: 

The recommended phase II dose for AZD6244 is 75mg om when combined 

with sorafenib 400mg bd for advanced HCC patients. This combination is 

feasible, shows activity and warrants further investigation. 


Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced 

hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker 

correlates. Presenting Author: Robin Katie Kelley, Helen Diller Family 

Comprehensive Cancer Center, University of California, San Francisco, San 

Francisco, CA 

Background: Mammalian target of rapamycin inhibitors added to SOR 

augment antitumor effect in HCC models. We developed a phase 1 trial to 

determine maximum tolerated dose (MTD) and recommended phase 2 dose 

(RP2D) of TEM plus SOR in HCC patients (pts). The study was approved 

and funded by the National Comprehensive Cancer Network (NCCN) from 

general research support from Pfizer, Inc., and conducted at 2 NCCN 

centers. Methods: Eligibility: �1 measurable site. No prior systemic therapy 

(Tx). ECOG �2, Child Pugh �7, bilirubin �2 mg/dL, platelets (PLT) 

�75,000/mcL. Design: 3�3 escalation. Dose-limiting toxicity (DLT) window 

28 days. MTD expansion cohort of 9 pts for PK and biomarkers. 

Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: 

Tumor necrosis, alpha fetoprotein (AFP)-L3, des-�-carboxyprothrombin, 

and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts 

enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 

(43%), HBV 4 (19%), HBV�HCV 2 (10%), ETOH 2 (10%), unknown 4 

(19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions 

for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT 

Gr3 hand-foot syndrome (HFS). Most common related �Gr 3 AE: HypoPO4 

(52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% 

each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, 

Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best 

response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 

11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on 

study: Range �1 to 19�months; median 3� months for pts who 

completed �1 cycle (16/21). 16/21 (76%) had baseline elevated AFP 

�20; 8/16 (50%) had �50% decline. CTC were detected in 5/5 of tested 

samples. Decreased tumor enhancement on Tx was seen. Conclusions: 

DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; 

tolerability may be impacted by cirrhosis. Encouraging durable radiographic 

and AFP responses occurred. 

Dose level (DL) TEM (mg IV/week) SOR (mg PO) Accrual to date 

-2 10 200 QD 0 

-1 (RP2D) 10 200 BID 9 � 5 expansion 

1 (starting) 15 200 BID 7 

2 15 400 BID 0 




A phase II trial of MEK inhibitor BAY 86-9766 in combination with 

sorafenib as first-line systemic treatment for patients with unresectable 

hepatocellular carcinoma (HCC). Presenting Author: Ho Yeong Lim, Division 

of Hematology-Oncology, Department of Medicine, Samsung Medical 

Center, Sungkyunkwan University School of Medicine, Seoul, South Korea 

Background: Sorafenib (S) is the only approved systemic treatment for 

unresectable HCC. Nevertheless, there remains an unmet medical need for 

more effective treatment options for this disease. BAY 86-9766 (B) is an 

oral, allosteric inhibitor of MEK, a key component of the MAP kinase 

pathway. This study evaluated the efficacy and safety of a combination 

therapy with B plus S in patients (pts) with HCC. Methods: This is a single 

arm, open-label, phase 2 study. Eligible were pts with unresectable HCC, 

Child-Pugh Class A, performance status (PS) 0-1, and no prior systemic 

anticancer therapy for HCC. Pts started Cycle 1 (21 days) with B 50 mg bid 

orally plus S 600 mg daily (200 mg AM, 400 mg PM) orally. If there was no 

hand-foot skin reaction, fatigue, or gastrointestinal toxicity � grade 2, S 

was escalated to 400 mg bid from Cycle 2 on. Treatment continued until 

progression or withdrawal criteria were met. Tumor assessment was 

performed every 6 weeks during treatment. Safety was evaluated every 

week for the first 6 weeks and every 3 weeks thereafter. Results: Seventy pts 

from Asia started study treatment. Pts were predominantly male (86%); 

median age was 56 years; 54% had PS of 0 and 46% PS of 1. The vast 

majority had liver cirrhosis (83%) and infection with HBV (76%) or HCV 

(17%). Sixty-five were evaluable for efficacy per protocol. Three pts (5%) 

had confirmed partial response and 25 pts (38%) had prolonged stable 

disease (�10 weeks), with a disease control rate of 43%. Median 

time-to-progression was 4.1 months. Survival data are not mature, yet. The 

most frequent drug-related adverse events (AEs) were rash (60%), diarrhea 

(59%), AST elevation (43%), vomiting (30%), nausea (29%), ALT elevation 

(26%), and anorexia (26%). There were 4 Grade 5 related AEs (hepatic 

failure, sepsis/hepatic encephalopathy, tumor lysis syndrome, and unknown 

cause, respectively). Dose modifications due to AEs were necessary 

in almost all pts. The median daily dose was 64.2 mg for B and 443.3 mg 

for S, respectively. Conclusions: B in combination with S showed antitumor 

activity in pts with HCC. However, frequent dose modifications due to AEs 

might have limited the treatment effect of this combination. 


Randomized phase II study of the x-linked inhibitor of apoptosis (XIAP) 

antisense AEG35156 in combination with sorafenib in patients with 

advanced hepatocellular carcinoma (HCC). Presenting Author: Ann Sing 

Lee, Tuen Mun Hospital, Tuen Mun, Hong Kong 

Background: XIAP inhibits caspases which are proteases responsible for 

apoptotic cell death. It is highly expressed in HCC. AEG35156 is a second 

generation antisense oligonucleotide targeting XIAP mRNA, thus lowers the 

apoptotic threshold of cancer cells. It also accumulates in the liver. This 

study is designed to assess the added benefit of combining AEG35156 with 

sorafenib. Methods: Patients with histologically or clinically diagnosed 

(AASLD criteria) HCC who had failed or were unsuitable for resection or 

ablative therapies were randomized (2:1) to receive either weekly injection 

of AEG35156 300mg in combination with sorefanib 400mg BID or 

sorefanib alone. The primary end point was progression-free survival (PFS). 

Other endpoints were overall survival (OS), response rates and safety. 

Results: 51 patients were recruited. 48 patents were evaluable. There were 

31 patients in the combination arm and 17 in the control arm. The median 

age was 60. 88% of patients were male. 81% of patients were hepatitis B 

carrier. 90% of patients belong to Child-Pugh class A. The median 

follow-up was 16.2 months. The PFS for the combination arm was 4.0 

months (95% CI: 1.2-4.1) and 2.6 months for control arm. The OS for the 

combination arm was 6.5 months (95% CI: 3.9-11.5) and 5.4 months for 

the control arm. There were 3 partial responders (Choi’s criteria) in the 

combination arm (10%, 95% CI: 3-27%) and none (0%) in the control 

arm. Patients who had the study treatment interrupted (PFS 4.0, 95% CI: 

2.4-5.4) or had dose modification (PFS 4.45, 95% CI: 1.0-6.5) according 

to protocol did significantly better than those who had no dose reduction 

(PFS 1.2, 95% CI: 1.2-4.0) and those in the control arm (PFS 2.6, 95% CI: 

1.2-5.4). This also applies to OS. Regarding toxicities, there were one 

AEG35156 related serious adverse event (SAE) of hypersensitivity and two 

sorafenib related gastrointestinal SAE. Conclusions: AEG35156 in combination 

with Sorafenib was well tolerated in patients with advanced HCC. 

Dose reduced AEG35156 in combination with sorafenib have shown more 

activity than sorafenib alone and warrants further investigation. 


A prospective cohort study using a Japanese nationwide survey to evaluate 

the therapeutic effects of surgery and percutaneous ablation for hepatocellular 

carcinoma. Presenting Author: Kiyoshi Hasegawa, Hepato-Biliary- 

Pancreatic Surgery Division, Department of Surgery, Graduate School of 

Medicine, University of Tokyo, Tokyo, Japan 

Background: Which is the best treatment for less advanced hepatocellular 

carcinoma (HCC) with good liver function remains one of the most 

important and unsolved problems. To solve this problem, we conducted this 

study and evaluated the therapeutic impacts of surgical resection (SUR), 

percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) 

on long-term outcomes in patients with HCC. Methods: A large-scale 

database constructed by a Japanese nationwide survey was used for this 

study. Between 2000 and 2005, 28,510 patients with HCC were treated 

by SUR, PEI, or RFA, among whom we identify 12,968 patients with no 

more than 3 tumors (�3cm) and liver damage of class A or B. The patients 

were divided into SUR group (n�5,361), RFA group (n�5,548), and PEI 

group (n�2,059). Rates of overall and recurrence-free survival were 

compared among them. Results: Median follow-up was 2.16 years. Overall 

survival rates at 3 and 5 years were respectively 85.3%/71.1% in the SUR 

group, 81.0%/61.1% in the RFA, and 78.9%/56.3% in the PEI. Recurrence-free 

survival rates at 3 and 5 years were 56.7%/36.2%, 42.8%/ 

28.3%, and 35.7%/23.1%, respectively. On multivariate analysis, the 

hazard ratio for death was significantly lower in the SUR group than in the 

RFA (SUR vs. RFA:0.84, 95% confidence interval, 0.74-0.95; p�0.006) 

and the PEI (SUR vs. PEI:0.75, 0.64-0.86; p�0.0001). The hazard ratios 

for recurrence were also lower in the SUR group than in the RFA (SUR vs. 

RFA:0.74, 0.68-0.79; p�0.0001) and the PEI (SUR vs. PEI:0.59, 

0.54-0.65; p�0.0001). Conclusions: Surgical resection would provide 

longer overall and recurrence-free survival than either RFA or PEI in 

patients with HCC. 


Blood signatures for early liver cancer detection in patients with chronic 

hepatitis B. Presenting Author: Choong-Chin Liew, GeneNews Ltd, Richmond 

Hill, ON, Canada 

Background: Some 20-30% of patients with chronic hepatitis B (CHB) 

eventually develop hepatocellular carcinoma (HCC), a disease with poor 

prognosis and high mortality unless detected early. Ultrasound and/or 

alpha-fetoprotein (AFP) are widely used for HCC surveillance. However 

these technologies are operator-dependent, have low sensitivity and are 

considered inadequate for screening. This study describes a blood-based 

gene-expression signature prognostic for HCC in CHB patients. Methods: 

PaxGene was used to extract RNA from whole blood samples taken from 

more than 1,000 Malaysian patients (matched HCC, CHB, healthy controls). 

Complementary DNA was generated from isolated RNA via reverse 

transcription and analyzed using Affymetrix U133Plus 2.0 with MAS 5.0 

normalization. To minimize bias we developed a novel algorithm based on 

SentinelPair regression analysis to identify biomarker panels. A Monte 

Carlo search identified pair combinations that could differentiate between 

cancer and controls. Twelve genes were selected for qRT-PCR Cohort 1 

verification (n�139). Six genes were then short-listed for qRT-PCR Cohort 

2 verification using independent samples (n�150). Results: Multivariate 

quantitative microarray analysis of 147 samples (HCC�47; CHB�50; 

controls�50) identified 12 probe sets differentially expressed between 

HCC patients and controls and CHB (ROC AUC�0.90). These genes were 

evaluated using qRT-PCR on the same cohort (ROC AUC�0.86). Six genes 

were subsequently short listed for qRT-PCR Cohort 2 verification. The AUC 

of the 6-gene-combination of Cohort 2 (HCC�50; CHB�50; controls�50) 

was 0.80. Importantly, of the thirteen HCC with low AFP (�15ng/ml), 9 

were predicted as “positive.” Conclusions: Blood RNA biomarkers identified 

in this study may form the basis of a test that can be used in patients with 

CHB for detection of early HCC, potentially improving prognosis for this 

cancer. This blood-based test would represent a significant clinical 

alternative to ultrasound and/or AFP. 



Treatment of advanced or metastatic hepatocellular cancer (HCC): Final 

clinical results of a single-arm phase II study of bevacizumab and 

everolimus. Presenting Author: Gerhard Treiber, Department of Internal 

Medicine, Zollernalb Clinic, Balingen, Germany 

Background: mTOR inhibitors are emerging drugs for treatment (Tx) of 

advanced hepatocellular cancer (HCC), their therapeutic effects may be 

potentiated by combination with anti-VEGF partners (Treiber G, Expert Rev 

Anticancer Ther 2009). Methods: Pts with histologically confirmed advanced 

HCC were included. Tx consisted of RAD001 in a daily start dose of 

5 mg orally and bevacizumab 5mg/kg iv every 2 weeks, up to 24 weeks. 

Primary endpoint was TTP, secondary endpoints were OS, RR, changes in 

biomarkers, and safety and tolerability besides PK analysis. Pts with either 

a CPT Score � 9, a CLIP score � 3, or a Performance Status of ECOG � 2 

were not eligible. Radiological TTP was centrally evaluated by both, 

conventional(c)-, and modified(m)-RECIST criteria on a PP basis. Additionally, 

we included a combined endpoint (TTPcomb: time to either clinical or 

radiological progression leading to termination of treatment) as assessed by 

the local centers in all recruited patients. Results: 33 pts (ITT) were 

recruited (26 with Child A, 7 with Child B; median CLIP score was 2, mean 

age 67 y, and mean BMI 28). 17/33 pts. had previous Tx (including 

sorafenib � 3 months). Drop out other than PD was due to consent 

withdrawl, lost to FU, and AE (n�5), therefore 28 patients had received 

study medication �2 wks (PP). There were 65 CTC-AE grade 3/4 events 

occuring in 22 pts. Median Tx duration was 69 days on RAD001, and a 

median of 5 cycles of bevacizumab were applied. Dose adjustements for 

RAD001 were performed in 20 pts, mean cumulative individual RAD dose 

was 334 mg, there was no association between Cmin of RAD and TTP or 

OS. On ITT, median TTPcomb was 2.0 mo and median OS was 9.0 mo. On 

PP, median TTP approached 3.8 mo (conventional RECIST) and median 

OS 9.7 mo. Using (m)RECIST, 5 pts. achieved PR within the first 8 wks, 

and this was accompanied by a significant VEGF plasma decrease (median 

of -65%), on (c)RECIST best response seen was SD. Conclusions: Combination 

Tx of RAD001 and bevazicumab is tolerated acceptably. TTP and OS in 

our 1°/2°-line HCC patients on Tx is comparable to sorafenib monotherapy 

in the SHARP trial (1° line only). 


Biliary tract cancer: A large institutional experience. Presenting Author: 

Mairead Geraldine McNamara, Princess Margaret Hospital, Toronto, ON, 

Canada 

Background: Biliary tract cancers (BTCs) encompass both cholangiocarcinoma 

(CC), arising in intrahepatic, perihilar (klatskin), or distal biliary tree, 

ampulla of vater and gallbladder carcinoma (GBC). Prognosis is poor for 

majority of these patients (pts). Aim: To retrospectively review outcomes of 

pts, as practices/treatments evolve, who presented to a multidisciplinary 

team at tertiary referral center Princess Margaret Hospital, Toronto, with a 

diagnosis of BTC. Methods: 1057 pts were followed from 01/87 - 09/11. 

Complete demographics, performance status (PS), disease site, histological 

diagnosis, percentage receiving surgery with curative intent, chemotherapy 

(CT), radiotherapy (RT), recurrence patterns and overall survival 

(OS) were analyzed. Results: The cohort includes 549 (52%) males, PS of 

0-1 in 850 (80%), 2-3 in 87 (8%) pts. A histological diagnosis of 

adenocarcinoma was confirmed in 885 (84%), 106 (10%) non diagnostic, 

66 (6%) other. Definitive surgery was performed in 41% and adjuvant CT or 

concurrent CT/RT given in 20% and 8% respectively. CT or CT/RT was 

given for unresectable/metastatic disease in first line palliative setting in 

395 (37%) and 18 pts (5%) respectively. Response to first line CT in GBC 

was 33% vs. 24% in CC (p�0.005) and med survival was 8.4 and 13.1 mo 

respectively (p�0.001). The OS for entire cohort of 1057 pts was 19.3 mo 

with survival for breakdown of tumor type, stage detailed in the table. At 

this time, 207 (20%) are still alive, 609 (58%) deceased, status unknown/ 

pending in 241 (22%). Conclusions: This represents a large biliary cancer 

cohort with survival benchmarks obtained in modern era of multidisciplinary 

care. Different subsites clearly present at different stages and have 

different prognosis with treatments. Despite better responses for advanced 

disease on CT in GBC, survival was better in CC consistent with reported 

literature. Therapeutic advancement mandates finding additional drug 

options and appropriate adjuvant care. 

Location N (%) 

Stage I 

(%) 

Stage II 

(%) 

Stage III 

(%) 

Stage IV 

(%) 

Median 

survival 

(mo) 

Gallbladder 304 (29) 8 12 17 63 13.0 

Distal bile duct 248 (23) 32 32 6 30 22.2 

Ampulla of vater 186 (18) 51 23 13 13 46.8 

Klatskin 162 (15) 14 10 24 52 16.5 

Intrahepatic 157 (15) 13 18 10 59 20.4 

Overall 1,057 (100) 19.3 


265s 


A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, 

RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma 

(HCC). Presenting Author: Thomas Cheung Yau, Department of Surgery, 

The University of Hong Kong, Hong Kong, China 

Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal 

role in tumor cell proliferation, migration and invasion in HCC and 

circulating levels of HGF correlate with poor prognosis. This phase I/II trial 

(MET111645) evaluated foretinib, an oral multikinase inhibitor targeting 

MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced- 

HCC patients. Methods: Asian patients with measurable, unresectable/ 

metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG 

PS 0-1, adequate organ function and Child-Pugh grade A were recruited. 

The phase I was a standard 3�3 dose escalation design with a phase II 

cohort expansion. The primary endpoint was safety and tolerability at the 

maximum tolerated dose (MTD) and the secondary endpoints included 

antitumor activity (objective response rate [ORR], disease stabilization rate 

[DSR; confirmed CR/PR or SD for at least 12 weeks], and time to 

progression [TTP] evaluated by central review according to modified 

RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics 

(PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting 

toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once 

daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was 

determined to be 30 mg QD. A further 32 patients were enrolled at the 

MTD, for a study total of 39 patients treated at 30 mg QD. The most 

common AEs, independent of causality,were hypertension (36%), decreased 

appetite (23%), and pyrexia (21%). The most common SAEs were 

hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued 

foretinib due to AEs. No dose reductions were reported. Thirty-eight 

patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), 

DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 

2.7-7.5). Mature OS data will be presented. Mean steady-state exposures 

(AUC/Cmax) were comparable after administration of foretinib at 30 and 45 

mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK 

profile in an Asian HCC population. It has demonstrated promising 

antitumor activity that warrants further testing in a randomized setting. 


Adjuvant chemotherapy following curative intent hepatectomy for intrahepatic 

cholangiocarcinoma: Results from a multi-institutional analysis of 

575 patients. Presenting Author: Dario Ribero, Ospedale Mauriziano, 

Torino, Italy 

Background: Surgical resection alone is the standard of care for patients 

with resectable intrahepatic cholangiocarcinoma (IHC). This study evaluates 

the benefit of adjuvant chemotherapy ( AdjCTx) following curative intent 

hepatectomy for IHC. Methods: Clinicopathologic and long-term outcome 

data of 575 consecutive patients treated with curative intent hepatectomy 

for IHC (1995-2011) were extracted from a multi-institutional registry. 

After excluding operative mortality and M1 (n�46), Cox regression analysis 

was used to identify independent determinants of early recurrence (i.e., 

within 3 years). Propensity scores, which are used in observational studies 

to reduce selection bias by equating groups on the basis of relevant 

covariates, were calculated and utilized to match patients who had or had 

not AdjCTx (one-to-one match). Cases whose propensity score deviated more 

than 0.10 were considered unmatched and excluded from the analysis. 

Primary end-point was recurrence-free survival (RFS) at 3-years. Results: At 

a median FU of 42 months, 247 patients had recurred. Predictors of 

recurrence were LN metastases (HR 1.83 [1.36-2.44]), radical resection 

(HR 0.64 [0.45-0.9]), an elevated preoperative CA19.9 (HR 1.54 [1.15- 

2.07]), vascular invasion (HR 1.97 [1.49-2.61]), multiple tumors (HR 

2.21 [1.71-2.86]), and size (analysed as continuous variable) (HR 1.01 

[1.01-1.01]). After matching, no difference was observed between patients 

who had or had not AdjCTx (n�155 per group; 3-yrs RFS 28.3% vs. 38.0%, 

respectively; p�NS). When the analysis was restricted to patients who had 

gemcitabine, GEMOX or FOLFOX for 3 or more cycles (n�64 per group) 

again no difference emerged between patients who had or had not AdjCTx 

(3-yrs RFS 27.7% vs. 40.0% respectively, p�NS ). Conclusions: Our data 

suggest that AdjCTx following resection of IHC does not increase 3-years 

RFS. 




A phase II trial of gemcitabine, irinotecan, and panitumumab in advanced 

cholangiocarcinoma, with correlative analysis of EGFR, KRAS, and BRAF: 

An interim report. Presenting Author: Davendra Sohal, Abramson Cancer 

Center at the University of Pennsylvania, Philadelphia, PA 

Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy 

approaches achieve modest results. The epidermal growth 

factor receptor (EGFR) pathway appears to be associated with tumor stage, 

prognosis and response to therapy. This trial was designed to evaluate the 

tolerability and efficacy of the combination of panitumumab, a monoclonal 

anti-EGFR antibody, with gemcitabine and irinotecan, in patients with 

advanced cholangiocarcinoma. Molecular analysis of EGFR pathway genes 

was planned as well. Methods: Patients with advanced (unresectable or 

metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney 

and bone marrow function were treated with panitumumab (9 mg/kg) on 

day 1, and gemcitabine (1000 mg/m2 ) and irinotecan (100 mg/m2 ) on days 

1 and 8 of a 21-day cycle. Tissue specimens were collected at diagnosis for 

correlative molecular analyses. Primary objective is to evaluate the 5-month 

progression-free survival (PFS) rate. Secondary objectives include overall 

response rate (ORR), overall survival (OS) and toxicity of the combination. 

Mutational analysis of EGFR (del 19; 858), KRAS (codons 12, 13) and 

BRAF (V600E) was done on samples with adequate material for testing. 

Results: There have been 26 (of planned 42) patients recruited to the study. 

A median of 6 (0-30) cycles were administered. There were no treatment 

related deaths. The most common gr 3 or higher toxicities were neutropenia 

(10 pts, 38%), thrombocytopenia (10 pts, 38%), skin rash (10 pts, 38%) 

and diarrhea (3 pts, 12%). During the study, there were 3 CR, 6 PR, 10 SD 

(disease control rate of 90%), and 2 PD (by RECIST) in 21 evaluable pts. 

Two pts went on to have surgical resection. Median OS is 12.7 months. Of 

13 testable samples, no EGFR or BRAF mutations were identified; however, 

there were 7 KRAS mutations. Retrospective analysis showed no difference 

in OS by KRAS mutation status. Conclusions: Interim evaluation of this 

ongoing study showed encouraging tolerability and efficacy of this regimen. 

Several patients have KRAS mutations; there appears to be no association 

with response, however. The pre-specified efficacy criteria to continue 

enrollment were met. 


SWOG 0941: A phase II study of sorafenib and erlotinib in patients (pts) 

with advanced gallbladder cancer or cholangiocarcinoma. Presenting 

Author: Anthony B. El-Khoueiry, University of Southern California Norris 


Background: The treatment of pts with advanced biliary cancers represents 

a therapeutic challenge. The vascular endothelial growth factor and 

epidermal growth factor receptor pathways play an important role in biliary 

carcinogenesis, as evidenced by their up-regulation and prognostic impact. 

Methods: The primary objective was progression free survival (PFS) (improvement 

in PFS from 4 to 8 months); secondary endpoints included overall 

survival (OS), objective response rate, and toxicity. A two-stage design was 

used; if 13 or more eligible pts of the 25 initially accrued were alive without 

progression at 4 months, an additional 25 were to be accrued. Eligibility 

criteria included no prior treatment for advanced or metastatic disease, 

histologic diagnosis of gallbladder cancer or cholangiocarcinoma, presence 

of measurable disease, Zubrod performance status 0-1, AST/ALT � 5 

IULN, total bilirubin �1.5 IULN, adequate hematologic function. Pts were 

treated with sorafenib 400 mg PO BID and erlotinib 100 mg PO q daily 

continuously. Restaging scans were performed every 8 weeks. Results: 32 

eligible pts were accrued. 30 pts were evaluable for response. 2 patients (7 

%) had an unconfirmed partial response (95% CI:1%-23%), and 8 pts 

(27%) had stable disease. Median PFS was 2 months (95% CI: 2-3 

months). 22/32 patients progressed or died within 4 months of registration. 

Median OS was 6 months (95% CI: 3 -7 months). The study failed to meet 

its primary endpoint to proceed to the second stage of accrual. There were 3 

deaths on study, 1 of which was possibly related to treatment. 19 patients 

(59%) had grade 3 or 4 toxicities: AST/ALT (22%), bilirubin (16%), 

alkaline phosphatase (16%), hypertension (16%), diarrhea (9%), hepatic 

infection (6%). Conclusions: This multicenter study was the first to evaluate 

the combination of sorafenib and erlotinib in pts with advanced biliary 

cancers. Despite manageable toxicity, the study failed to meet its primary 

endpoint. Correlative studies on collected tissue and blood are ongoing; 

improved pt selection based on tumor biology and molecular markers is 

necessary for future evaluation of targeted therapies in this disease. 


Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of 

cediranib in advanced hepatocellular carcinoma (HCC): A phase II study 

(CTEP 7147). Presenting Author: Andrew X. Zhu, Division of Hematology 

and Oncology, Massachusetts General Hospital, Boston, MA 

Background: Sorafenib remains the only approved systemic therapy in HCC. 

We performed a phase II study of cediranib (AZD2171)—a more potent and 

selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). 

Methods: Eligibility criteria included unresectable or metastatic measurable 

HCC, ECOG PS �2, CLIP score �3, and adequate organ function. 

Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The 

primary endpoint was progression free survival (PFS). We also assessed 

overall survival (OS) and response rates, steady-state PK of cediranib, and 

blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the 

targeted 17 pts required for the first stage of the planned study: ECOG 

0/1/2�5/11/1, CLIP 1/2/3�6/4/7, Child A/B�14/3, BCLC C�17. Nine 

pts had prior sorafenib. The best response was stable disease in five pts 

(29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median 

OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included 

hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one 

pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and 

proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage 

occurred in 1 pt each. Steady-state PK parameters (mean�SD) were, Cmin, 22�21 ng/mL; Cmax, 55�33 ng/mL; AUC�, 887�503 ng*h/mL. Plasma 

levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 

decreased significantly after cediranib treatment (p�0.05). PFS was 

inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and 

OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, 

TNF-alpha and CD34�CD133� hematopoietic progenitor cells (p�0.05). 

Conclusions: Cediranib at 30 mg daily is associated with high frequency of 

grade 3 hypertension and shows preliminary evidence of antitumor activity 

in advanced HCC pts. Exploratory studies confirmed potential PD and 

response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in 

HCC pts as in those with other tumor types and normal/near normal hepatic 

function. This study was stopped by AstraZeneca after discontinuation of 

cediranib development for unrelated factors. 


Multiparametric quantitative functional MRI for assessing early changes in 

volumetric functional tumor burden in hepatocellular carcinoma treated by 

intra-arterial therapies. Presenting Author: Vivek Gowdra Halappa, The 

Johns Hopkins Hospital, Baltimore, MD 

Background: Hepatocellular carcinoma (HCC) is the most common primary 

malignant disease of the liver. Intra-arterial therapy (IAT) has been shown 

to improve survival and is commonly used in unresectable HCC. Assessing 

response to IAT as early as possible using objective criteria is paramount for 

clinical care. The purpose of this study was to evaluate volumetric diffusion 

weighted (DWI) and contrast Enhanced MR imaging (CE-MRI) changes for 

assessing early treatment response to IAT in hepatocellular carcinoma. 

Methods: This study included 177 lesions of HCC in 107 patients (85 Male, 

mean age 64 years) with BCLC A (19) B (44) C (36) D (8) treated by IAT. All 

patients had pre-IAT and 3-4 weeks follow up MRI with DWI and CE-MR. 

Tumors were segmented using semi automated software to provide volumetric 

functional analysis of DWI and CE- MRI as well as percent tumor 

burden. Statistical analyses include paired t-test, Kaplan-Meier curves, log 

rank test and multivariate analysis with cox model. Results: There was 

significant increase in volumetric ADC and significant decrease in volumetric 

arterial (AE) and venous (VE) enhancement after IAT. Patients with 

tumor burden of � 10% had improved survival compared to patients with 

high tumor burden of �10% (log rank p �.008 ) This survival benefit was 

larger among patients with tumor burden of � 10% who demonstrated an 

increase in volumetric ADC (�20%. Overall survival (OS) 33.5 mo) and 

decrease in volumetric VE (�50% OS 35.2 mo) compared to patients with 

high tumor burden �10% who no favorable response in ADC ( OS 14.1 mo) 

or VE (OS 16.5 mo) (Log rank p � .001) . In multivariate analysis factors 

associated with favorable prognosis were: increased ADC, (Hazard Ratio 

(HR) � 0.44, 95% CI �0.24 - 0.80) decreased VE, (HR � 0.43, 95% CI � 

0.22 - 0.84) and BCLC A and B (HR � 0.31, 95% CI �0.18 - 0.54). 

Conclusions: Volumetric functional analysis of DWI and CE-MR are reliable 

imaging biomarkers of treatment response and tumor necrosis were able to 

differentiate responders and non responders. Early assessment of treatment 

response by volumetric functional MRI predicts prognosis in patients 

undergoing IAT in HCC. 



Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in 

sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER 

study. Presenting Author: Michael Bitzer, Medical University Clinic, Eberhard-Karls-University, 

Tuebingen, Germany 

Background: Resminostat (R), an oral HDAC inhibitor, was studied in the 

SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) 

refractory to sorafenib (S). R was explored as monotherapy and within a 

novel resensitization approach to overcome tolerance to S by the combination 

of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were 

included in a multi-center, two-arm trial. Radiologic progression under S 

firstline therapy had to be confirmed by central review (RECIST) prior to 

study entry. A dose escalation of R (range 200 to 600 mg) combined with S 

(400 or 800 mg) was performed. Arm A investigated the drug combination 

(R�S), Arm B the monotherapy of R (600 mg). Primary objective was the 

progression-free survival rate (PFSR) after 12 weeks (w). Secondary 

objectives included safety, tolerability, tumor response, PFS, TTP, OS and 

the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme 

inhibition, histone acetylation and gene expressions in peripheral blood. 

Results: 50 pts were enrolled, dose escalation determined 600 mg R and 

400 mg S for Arm A. Clinical activity results of 15 evaluable pts from 

combination treatment revealing a PFSR of 66.6% after 12 w, not all 

patients in Arm B already reached the 12 w staging. Most frequent AE were 

CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, 

pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of 

non-hematological events mostly related to tumor disease. Plasma concentrations 

of both drugs correlated with administered doses and were in the 

expected range without obvious influence of preexisting liver disease. BM 

investigations revealed effective target modulation by R in both arms. 

Conclusions: The primary study objective was achieved for both treatment 

arms. R demonstrated a favorable PK, safety and tolerability profile, even in 

combination with S and despite preexisting liver disease, includig cirrhosis. 

The observed clinical activity emphazises the resensitizing activity of R by 

an epigenetic mode-of-action to overcome tolerance to S and warrants 

further development, in particular for combination therapy in both, first and 

second line HCC treatment. 


Updated results from a phase III trial of sunitinib versus placebo in patients 

with progressive, unresectable, well-differentiated pancreatic neuroendocrine 

tumor (NET). Presenting Author: Aaron Vinik, EVMS Strelitz Diabetes 

Research Center and Neuroendocrine Unit, Norfolk, VA 

Background: In a double-blind phase III trial, sunitinib (Sutent; SU) 

improved progression-free survival (PFS) vs placebo (PBO; 11.4 vs 5.5 

mos; HR: 0.42, 95% CI: 0.26–0.66; P�0.0001) and was well tolerated in 

patients (pts) with unresectable, well-differentiated pancreatic NET that 

had progressed �12 mos before baseline. Initial overall survival (OS) 

revealed a benefit for SU vs PBO, although median OS had not been 

reached. We now report PFS assessed by blinded independent central 

review (BICR) and updated OS. Methods: Pts were randomized 1:1 to SU 

37.5 mg or PBO on a continuous daily dosing schedule, each with best 

supportive care. The primary endpoint was investigator-assessed PFS; OS 

was a secondary endpoint to be evaluated every 2 yrs for 5 yrs, or until 95% 

of pts had died. Additionally, BICR was performed retrospectively; baseline 

and on-study CT/MRI scans were evaluated by a 2-reader, 2-time-point 

lock, followed by a sequential locked-read, batch-mode paradigm by 

blinded, third-party radiologists. Results: 171 pts were randomized (SU, 

n�86; PBO, n�85) from Jun 2007 to Apr 2009. The trial ended when an 

independent data monitoring committee noted efficacy favoring SU and 

more serious AEs and deaths with PBO. The study was unblinded at 

closure; pts were offered open-label SU and followed for survival. Median 

PFS by BICR was 12.6 mos (SU) vs 5.8 mos (PBO) (HR: 0.32, 95% CI: 

0.18–0.55; P�0.00001). At study closure, there were 9 and 21 deaths in 

the SU and PBO arms (HR: 0.41, 95% CI: 0.19–0.89; P�0.02). By Apr 

2011 (2 yrs additional follow-up) a total of 87 deaths occurred (51%), 

median OS was estimated at 33.0 mos in the SU arm, and 26.7 mos in the 

PBO arm (HR: 0.71, 95% CI: 0.47–1.09; P�0.11 [Table]). 69% of pts 

crossed over to SU on progression. Conclusions: BICR confirmed investigator 

assessment of PFS and demonstrated a 6.8-mo improvement in median 

PFS with SU. Updated OS favors SU, although this result is non-significant 

for reasons that may include crossover of treatment and limited statistical 

power. 

2-yr OS update, Apr 2011 

Deaths, n 

Censored, n 

Median OS (95% CI), mos 

SU 

n�86 

40 

46 

33.0 (25.6–NR) 

HR (95% CI) 0.71 (0.47–1.09) 

P 0.11 


PBO 

n�85 

47 

38 

26.7 (16.4–35.3) 

267s 


Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with 

sorafenib in patients (pts) with hepatocellular carcinoma (HCC) from a 

phase I study. Presenting Author: Robert E. Martell, Tufts Medical Center 

Cancer Center, Boston, MA 

Background: The multikinase inhibitor sorafenib is standard of care for pts 

with advanced HCC. Tivantinib, an oral, selective MET inhibitor, demonstrated 

synergistic antitumor activity when combined with sorafenib in 

several tumor models. The phase 1 dose-escalation study assessed the 

safety profile of tivantinib plus sorafenib in pts with advanced solid tumors. 

Methods: Endpoints were safety, the recommended phase 2 dose (RP2D) of 

tivantinib plus sorafenib, and antitumor activity. Dose escalation previously 

established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 

400 mg BID. Extension cohorts enrolled � 20 pts each with HCC or other 

tumors. Patients were treated until disease progression or unacceptable 

toxicity. After a safety review in HCC pts in other studies and a report of 

febrile neutropenia in this study, the tivantinib dose for newly enrolled pts 

was reduced to 240 mg BID. Results: 20 pts with HCC (mean age, 62 yr; 

Child-Pugh [CP] A [n � 14], or CP B [n � 6]) were treated at the RP2D (n � 

10) or at the reduced tivantinib dose plus sorafenib (n � 10). 10 pts 

received � 1 previous systemic anticancer treatment (median, 0.5; range, 

0-3). The most common adverse events (� 25%) were rash (40%), 

palmar-plantar erythrodysesthesia syndrome (35%), fatigue and diarrhea 

(30% each), and nausea and anorexia (25% each). Neutropenia was 

reported in 2 pts. Best response was 1 complete response (CR), 1 partial 

response (PR), and 12 stable disease (SD). Overall response rate and 

disease control rate were 10% and 70%, respectively. Median progressionfree 

survival (mPFS) was 3.5 mo (95% CI, 2.8-11.1 mo). Among 8 pts 

previously treated with vascular endothelial growth factor (VEGF) inhibitors 

(6 sorafenib; 1 sunitinib; 1 sorafenib plus sunitinib), best response was 1 

CR, 1 PR, and 3 SD, and mPFS was 15.9 mo (95% CI, 1.6-15.9 mo). 2 pts 

are still on study. Conclusions: The combination of tivantinib (360 mg BID) 

plus sorafenib (240 mg BID) was well tolerated. Preliminary evidence of 

antitumor activity indicates that combined inhibition of MET and angiogenic 

signals may have therapeutic potential in this setting, including pts 

pretreated with VEGF inhibitors. 


PAZONET: Results of a phase II trial of pazopanib as a sequencing 

treatment in progressive metastatic neuroendocrine tumors (NETs) patients 

(pts), on behalf of the Spanish task force for NETs (GETNE)— 

NCT01280201. Presenting Author: Enrique Grande Pulido, Hospital 

Ramon y Cajal, Madrid, Spain 

Background: Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, 

PDGFR and KIT that has demonstrated clinical activity in NETs. The aims 

of our study were to assess efficacy, safety and potential predictive 

biomarkers of pazopanib in pts with NETs who had previously failed to at 

least one antiangiogenic or mTOR inhibitor treatment. Methods: Pts 

presented locally-advanced or metastatic gastrointestinal or pancreatic 

NET disease documented as progressive. Pazopanib 800 mg was given 

daily until disease progression (DP) or unacceptable toxicity. Primary 

endpoint was Clinical Benefit Rate (CBR) defined as Complete Response 

plus Partial Response (PR) plus Stable Disease (SD) at 6 months by 

RECIST-V-1.0. Optimal two-stage Simon design was utilized with H1 and 

H0 set at 70 % and 50 % respectively, Kaplan-Meier estimates waere used 

for the analysis of time-to-event variables: 95% CI. Results: 33 pts were 

evaluable for response per protocol. 54.5% males, mean age 60.7�10.3 

years. At 6 months, 2 pts had PR (6%), 26 SD (79%), and 5 DP (15%), 

thus the CBR was 85%. By subgroups, CBR was 100% in pts with no 

previous targeted therapy (7 pts), 89% in pts with previous mTOR 

inhibitors (9 pts), 83% in pts with previous antiangiogenics (12 pts), and 

60% in pts with previous antiangiogenics and mTOR inhibitors (5 pts). The 

sum of the longest diameter of target lesions had a decrease over 10% in 

22% of pts (29% without previous biological treatment, 22% mTOR 

without prior multitarget, 18% prior multitarget without mTor, and 20% 

with previous multitarget and mTOR. Median PFS was only reached in the 

subgroup of pts (26 pts) with previously treated with antiangiogenics and 

mTOR inhibitors (20.6 weeks, 95% CI, 10.4-30.8). Most frequent toxicities, 

any grade: asthenia (75%), diarrhoea (63%), nausea (42%). Translational 

studies on angiogenesis and inmunohistochemistry biomarkers and 

CTCs are ongoing. Conclusions: Pazopanib at 800 mg daily has promising 

activity in advanced NET regardless of previous treatment with other 

targeted therapies. This trial may introduce the concept of treatment 

sequencing with novel targeted agents in NETs. 




Merkel cell polyomavirus in gastrointestinal neuroendocrine tumors. Presenting 

Author: Salvatore Lorenzo Renne, European Institute of Oncology, 

Milan, Italy 

Background: Cutaneous Merkel cell carcinoma (MCC) is a high grade 

neuroendocrine carcinoma potentially induced by Merkel Cell Polyomavirus 

(MCPyV), a clonally integrated host in the tumor cell genome. 

Integration of viral DNA and truncating mutations in the helicase domain of 

the large T (LT) antigen, a protein implicated in the viral life cycle, have 

been detected in all MCPyV associated MCCs. These results suggest a role 

of the virus in tumor pathogenesis according to a two step model: a 

necessary but not sufficient integration of viral DNA followed by LT antigen 

premature truncations. Gastrointestinal neuroendocrine tumors (GI-NETs) 

share common phenotypical features with MCCs, therefore we evaluated 

whether MCPyVs may be present in GI-NET. Methods: Formalin–fixed and 

paraffin-embedded samples from 14 cases of liver metastases of G2 

GI-NETs, 9 small cell lung cancer (SCLCs) and 4 MCCs of the skin were 

screened for MCPyV-DNA positivity using two PCR primer sets mapping the 

LT antigen gene. Then to confirm the putative pathogenetic role of the 

virus, we seeked for premature truncation of LT antigen by sequencing the 

helicase portion using seven amplicons mapping 1356-2210 region of the 

MCPyV complete genome (RefSeq: NC_010277.1). Results: Viral DNA was 

detected in 7/14 GI-NETs, in 0/9 SCLCs and in 4/4 MCCs. We found a 

premature stop codon truncating the helicase domain in two GI-NETs. Both 

the patients had a rapid disease progression. We also found previously not 

reported alterations in MCCs: a single aminoacid deletion in 3 cases and a 

point mutation causing a single aminoacid substitution in another case. 

Conclusions: For the first time the potential tumorigenic signature of MCPyV 

has been detected in GI-NETs, suggesting a possible role in pathogenesis. 

The study is ongoing to confirm these observations that could support new 

diagnostic and therapeutical perspectives of a subset of GI NETs. Moreover 

we have shown that the clonal integration of MCPyV in MCCs produces 

different genetic alterations with unknown effects on cell biology. 


RAMSETE: A single-arm, multicenter, single-stage phase II trial of RAD001 

(everolimus) in advanced and metastatic silent neuro-endocrine tumours in 

Europe. Presenting Author: Marianne E. Pavel, Charite Universitatsmedizin, 



is involved in the pathogenesis of neuroendocrine tumors (NET). 

Everolimus (RAD001), an oral mTOR inhibitor, has antitumor activity in 

patients (pts) with advanced NET. In this open-label, multicenter, phase II 

study (RAMSETE), the safety and efficacy of everolimus monotherapy was 

evaluated in pts with advanced nonsyndromic, nonpancreatic NET. Methods: 

Pts with advanced (unresectable or metastatic), progressive, nonsyndromic, 

nonpancreatic NET received everolimus (10 mg/day) as monotherapy. 

The primary endpoint was objective response rate (proportion of 

pts with best overall complete response [CR] or partial response [PR] per 

RECIST v1.0) by central radiologic review. A secondary endpoint included 

progression-free survival (PFS). Results: By database soft lock (December 

1, 2011), 73 pts from 16 European clinics received everolimus (median 

duration of treatment: 193 days). Fifty-five (75%) pts discontinued; 

reasons included disease progression (n�23), adverse events (AEs [n�23]), 

withdrawal of consent (n�4), death (n�3), and protocol deviation (n�2). 

In the per protocol population (N�60), 32 (53%) pts received prior 

antineoplastic therapy. The best response by central review was stable 

disease in 55%. By local review, 3 (5%) pts had a PR, with SD in 39 (65%) 

pts. Median PFS by central review was 185 days (95% CI: 158-255). 

Median PFS by local investigator review was 285 days (95% CI: 231-not 

estimable). 69 (95%) pts reported treatment-related AEs of any grade, 

including rash (n�28; 38%), diarrhea (n�20; 27%), mucosal inflammation 

(n�18; 25%), and decreased appetite (n�17; 23%). Treatmentrelated 

grades 3 and 4 AEs and serious AEs were reported by 27 (37%) and 

18 (25%) pts, respectively.Conclusions: In this open-label trial of everolimus 

in pts with advanced, nonsyndromic, extrapancreatic NET, a high rate 

of disease stabilization was achieved after prior tumor progression with 

favorable median PFS. This study further supports efficacy of everolimus in 

types of NET other than those studied in RADIANT-3 (pancreatic NET) and 

RADIANT-2 (NET associated with carcinoid syndrome). 


Treatment of advanced neuroendocrine tumors: Results of the UKINETS 

and NCRI randomized phase II NET01 trial. Presenting Author: Philippa 

Corrie, Oncology Centre, Cambridge University Hospitals NHS Foundation 

Trust (Addenbrooke’s Hospital), Cambridge , United Kingdom 

Background: Chemotherapy is widely used for advanced, unresectable 

neuroendocine tumours (NETs) but only four randomised trials are published. 

The first combined streptozocin (strep) and 5fluorouracil (5FU), 

reporting 63% response rate (RR), but subsequent retrospective studies 

had lower RRs (6-45%). Cisplatin has been combined with strep�5FU in a 

retrospective study with promising activity in NETs and capecitabine (cap) 

has been effectively substituted for 5FU in many tumours. The NET01 trial 

was designed to investigate whether cap�strep � cisplatin warrant further 

evaluation. Methods: Patients (pts) with histologically confirmed, unresectable, 

advanced and/or metastatic NETs of foregut, pancreatic or unknown 

primary site were randomised (ratio 1:1) to 6 cycles of 3-weekly cap 625 

mg/m2 po bd daily (D1-21), strep 1.0g/m2 IV (D1), with cisplatin 70mg/m2 IV(D1) (Cap-cist) or without (Cap-strep). The primary outcome measure was 

RR using RECIST criteria (v 1.0). 84 pts were required to test a RR of 

�40% vs �60% with a significance level of 5% and 80% power in each 

arm. Central pathology review was performed; retrospective central radiology 

review was undertaken on 10% of randomly selected cases. Results: 86 

pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42 

Cap-cist) with primary site – foregut 20%, pancreatic 48% and unknown 

33%. The grade was low 8 (11%), intermediate 47 (67%) and high 15 

(21%). Baseline characteristics were balanced between the 2 arms. 60% 

Cap-strep pts received �6 cycles compared with 33% Cap-cist pts. 17 

Cap-strep and 26 Cap-cist pts experienced grade �3 toxicities. Outcome 

results are summarised in the table. Ki67, mitotic index or primary site of 

origin did not appear to predict for response. Conclusions: The novel 

Cap-strep � cisplatin regimens were associated with overall disease control 

and survival durations consistent with published studies. Cap-strep was 

better tolerated than Cap-cist. Further prospective randomised studies are 

required to determine optimal NET chemotherapy. 

Cap-cist Cap-strep 

Response 

14% 

8% 

PR 

64% 

74% 

SD 

22% 

18% 

PD 

PFS 33 (79) 

30 (68) 

No. progressions/deaths, n (%) 

9.7 

10.2 

Median (mo) 

OS 34 (40) 

No. deaths, n (%) 

34.7 

Median (mo) 


Circulating tumor cells as prognostic and predictive markers in neuroendocrine 

tumors. Presenting Author: Mohid Shakil Khan, University College 

London, London, United Kingdom 

Background: Neuroendocrine tumors (NETs) are a heterogeneous group of 

tumors with variable survival. While Ki67 in tumour tissue is prognostic, 

there have been no prospectively validated circulating prognostic or 

predictive markers. Here we present results from a large prospective study 

of circulating tumor cells (CTCs) in patients with NETs. Methods: Patients 

about to commence therapy had a 7.5 ml blood sample taken at baseline 

with additional samples taken at 3-5 weeks after commencing treatment. 

CTCs were enumerated using the CellSearch system and counted independently 

by two observers. Radiological response was classified according to 

RECIST 1.1. PFS and OS were measured from start date of therapy, to date 

of progression and date of death, respectively. In order to define a 

prognostic cut off value for CTCs, 90 patients were enrolled in a training set 

and 85 patients in a validation set. The optimal cut-off level validated was 

CTC�1. Prognostic factors including Ki67 were evaluated using Cox 

regression. Changes in CTCs after treatment were divided into tertiles. 

Results: 138 patients with metastatic NET (31 pancreatic, 81 midgut, 12 

bronchopulmonary, 11 unknown primary, 3 hindgut) were recruited who 

were about to undergo treatment with somatostatin analogues(34), chemotherapy(28), 

PRRT(40), TAE(18), RFA(3), Sunitinib(4), interferon(4) and 

surgery(7). Median follow-up was 9.7 months (range 5-29). Patients with 

baseline CTC�1 had significantly worse PFS (HR 4.3 95%CI 1.8-10.3), 

and OS (HR 6.1 95%CI 1.8-20.3) than those without CTCs. In multivariate 

analysis CTC presence was associated with worse PFS (HR 3.7 95%CI 

1.5-8.9) and OS (HR 5.1 95%CI1.5-7.3). Changes in CTCs predicted 

response to therapy (Fisher’s exact p�0.001) and those with increase in 

CTCs by �33% post-therapy had significantly worse PFS (HR 23.1 95%CI 

5.37-99.0) and OS (HR18.9 95%CI 2.4-146) than a fall or �33% 

increase. Conclusions: In metastatic NETs, CTCs are a promising prognostic 

marker and may be an early marker of response to therapy. Further 

evaluation of CTCs in the context of therapeutic trials is required. 



Prevalence and prognostic significance of FGF receptor 2 (FGFR2) gene 

amplification in Caucasian and Korean gastric cancer cohorts. Presenting 

Author: Elaine Kilgour, AstraZeneca, Oncology Innovative Medicines, 

Macclesfield, United Kingdom 

Background: Gastric adenocarcinoma is the 4th most common cancer, and 

many patients present with metastatic or recurrent disease. The prognosis 

for these patients is poor, with median survival times of 11–12 months. 

Hence there is a need for identification of potential new drug targets. We 

have determined the prevalence of FGFR2 gene amplification (FGFR2amp) 

and its relationship to clinicopathological parameters and survival in 

Caucasian (n�408) and Korean (n�356) gastric cancers (GC) and determined 

the overlap with HER2 or cMET gene amplification. Methods: 

FGFR2, HER2 and cMET gene amplification was assessed by fluorescence 

in situ hybridisation in GC tissue microarrays from Caucasian and Korean 

surgically resected gastric carcinomas. Gene amplification was defined as a 

gene/centromeric probe ratio of �2.0 after measuring at least 50 tumour 

cells. Results: 7% (30/408) of Caucasian and 4% (15/356) of Korean GC 

showed FGFR2amp, and the incidence was not significantly different 

between these cohorts (p�0.092). FGFR2amp was significantly associated 

with lymph node status in both cohorts (p�0.0007, multivariate analysis), 

and in the Korean cohort with diffuse-type histology, but not with depth of 

tumour invasion, age or gender. Patients with FGFR2amp showed significantly 

shorter overall survival in both the Caucasian (HR 2.37, 95% CI 

1.6–3.5; p�0.0001) and Korean (HR 2.33, 95% CI 1.28–4.25; 

p�0.0129) cohorts, by multivariate analysis. There was no overlap 

between FGFR2amp and HER2 or cMET amplification in the Korean 

cohort, but two of twenty-six FGFR2amp Caucasian gastric tumours also 

showed HER2 amplification. Conclusions: This is the first study to demonstrate 

FGFR2amp, at a prevalence of 4% and 7%, in two large GC cohorts of 

Asian and Caucasian origin and that FGFR2amp is prognostic and significantly 

associated with lymph node metastasis. Furthermore, FGFR2amp is 

generally mutually exclusive with HER2 and cMET amplifications. Based 

on these observations, FGFR2 inhibitors warrant further investigation in the 

treatment of FGFR2 amplified GCs. 


Prevalence of functional tumors in neuroendocrine carcinoma: An analysis 

from the NCCN NET database. Presenting Author: Michael A. Choti, The 

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 

Baltimore, MD 

Background: Neuroendocrine tumors (NETs) are increasing in incidence 

and prevalence. Identification and treatment of specific clinical NET 

syndromes are established, yet there is uncertainty regarding the prevalence 

of NET with hormone-related symptoms versus nonfunctional tumors. 

Methods: The National Comprehensive Cancer Network (NCCN) 

created a comprehensive database to characterize patients (pts) treated for 

NETs. This database was queried to identify pts presenting to 7 NCCN 

institutions with a confirmed NET diagnosis: including carcinoid (cNET), 

pancreatic NET (pNET), NET not otherwise specified (NOS), and pheochromocytoma 

(PCC) between 2004 and 2010. The primary aim of this analysis 

was to describe demographic and clinical characteristics of NET pts by 

functional (fxn) status at diagnosis (dx). Results: Among 1244 NET pts, 

26% (n�327) had an fxn tumor. Carcinoid syndrome (CS) occurred in 28% 

of cNET pts. The most common primary tumor sites among CS pts were 

small bowel (69%) and unknown (15%). Prevalence of hormonal syndrome 

(HS) among pNET pts was 22%, 24% among NOS pts and 37% among 

PCC pts. The majority of CS pts (74%), pNET HS pts (67%), and NOS HS 

pts (91%) had distant disease at dx, in contrast to 31% of PCC HS patients. 

Among CS pts with a known histologic grade, 91% were well differentiated 

(G1). Similarly, 86% of pNET HS and 67% of NOS HS pts with a known 

histologic grade had G1 NETs. The most common symptoms at dx among 

pts with CS included abdominal cramping (53%), change in bowel habits 

(48%), and flushing (40%). Among those tested, 85% of CS pts had a 

positive 5-HIAA test at dx. Among pNET HS pts, the most common 

symptoms present at dx were abdominal cramping (39%) and change in 

bowel habits (46%). The most common symptoms present at dx among 

NOS HS pts were abdominal cramping (35%), change in bowel habits 

(47%) and flushing (38%). Conclusions: Prevalence of CS in this NCCN 

database (28%) was slightly higher than the 10% previously reported in the 

literature. In contrast, the prevalence of HS among pNET pts (22%) was 

lower than previously reported. Approximately one quarter of cNET pts 

without metastatic disease had CS, warranting further analysis as CS most 

often occurs in the presence of liver metastasis. 


269s 


A multi-institutional phase II open-label study of AMG 479 in advanced 

carcinoid and pancreatic neuroendocrine tumors. Presenting Author: Matthew 

Kulke, Dana-Farber Cancer Institute, Boston, MA 

Background: The IGF pathway is thought play an important role in 

neuroendocrine tumor progression. We therefore investigated AMG 479, a 

human monocolonal antibody against IGF1-R, in patients with metastatic 

progressive carcinoid and pancreatic neuroendocrine tumors (NETS). 

Methods: This open-label phase II study enrolled patients (�18 yrs) with 

metastatic low and intermediate-grade carcinoid and pancreatic NETs. Key 

inclusion criteria included evidence of progressive disease (by RECIST) 

within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar 

�160mg/dL. Prior treatments were allowed, and concurrent somatostatin 

analog therapy was permitted as long as patients remained on a stable 

dose. The primary endpoint was objective response rate. Secondary 

endpoints included overall survival (OS), progression-free survival (PFS), 

and safety. Results: 60 patients (30 carcinoid, 30 pancreatic NET) were 

treated with AMG 479 18mg/kg every 3 weeks and 54 patients were 

evaluable for response. There were no objective responders by RECIST. 

When best response to therapy was evaluated, 10/27 (37%) evaluable 

carcinoid patients and 8/26 (31%) evaluable pancreatic NET patients 

experienced 1-29% tumor shrinkage, while 17/27 (63%) of the carcinoid 

patients and 15/26 (58%) of the pancreatic NET patients appeared to 

experience continued tumor growth. Median PFS was 6.3 months (95% CI 

4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients and 4.2 

months for pancreatic NET patients. The OS rate at 12 months was 70% 

(55%-81%) for the entire cohort. Median OS has not been reached. 

Treatment related grade 3/4 AEs were rare and consisted of hyperglycemia 

(4%), neutropenia (4%), thrombocytopenia (4%) and infusion reaction 

(1%). Conclusions: While well-tolerated, single-agent AMG 479 was not 

found to result in major tumor responses among patients with metastatic 

low-intermediate grade carcinoid or pancreatic NET. Subgroup analysis to 

identify characteristics of patients who may have benefited from therapy 

with AMG 479 is ongoing. 


Bevacizumab, pertuzumab, and sandostatin for patients (pts) with advanced 

neuroendocrine cancers (NET). Presenting Author: Irfan Firdaus, 

Sarah Cannon Research Institute/Oncology Hematology Care, Inc, Cincinnati, 

OH 

Background: Targeted agents are used to treat well-differentiated NET. 

Octreotide binds somatostatin receptors and improves time to progression 

(TTP) of carcinoid tumors, and VEGF pathway targeting improves TTP of 

pancreatic NET. HER2 overexpression is reported in NET, and pertuzumab 

blocks HER2 receptor dimerization. This phase II trial combined bevacizumab, 

pertuzumab, and octreotide LAR for pts with advanced NET. 

Methods: Pts with advanced well-differentiated NET were enrolled. Pts had 

ECOG 0-1, and normal end-organ function, including left ventricular 

ejection fraction (LVEF) �50%. Pts received bevacizumab 15 mg/kg IV, 

pertuzumab 420 mg IV (following an 840 mg loading dose) day 1 of a 21 

day cycle, and octreotide LAR 30 mg IM every 28 days. Primary endpoint 

was objective response rate (ORR). Results: Between 6/10 and 4/11, 43 pts 

enrolled. 22 M/21 F, med age 62 (33-88), 32 (74%) carcinoid, 11 (26%) 

PNET. 26% had prior sandostatin, 72% prior surgery, 19% prior radiation, 

23% with � 2 previous systemic therapies. Treatment-related grade 3 

toxicities included: hypertension (28%), LVEF dysfunction (9%) (reversible 

with trial drug hold), and diarrhea (7%). No grade 4 toxicity was 

reported. Median treatment duration was 38 weeks (range: 0 – 76). 

Chromogranin A values were elevated in 27 pts; 59% had decreases during 

treatment. Seven pts (16%) achieved objective response [CR: 1 carcinoid 

(2%), PR: 6 (4 carcinoid, 2 PNET) (14%)]. ORR for carcinoid pts was 

15.6%. Median PFS for the entire group was 8.2 months (95% CI: 6.3 – 

NA). PFS for carcinoid pts was 8.5 months (95% CI: 6.3 – NA); PFS for 

PNET pts was 6.4 months (95% CI: 3.9 – NA). Median OS has not been 

reached at 14.3 months followup. Conclusions: The ORR of the combination 

of bevacizumab, pertuzumab, and octreotide LAR in NET pts was 

encouraging. Particularly the response rate in carcinoid pts appears higher 

than historical data, warranting further investigation of this regimen in 

these pts. 




Prognostic relevance of circulating PIGF levels in patients with neuroendocrine 

tumors. Presenting Author: Christian Fischer, Charité-Universitätsmedizin, 


Background: Placental growth factor (PlGF), a VEGF homolog implicated in 

tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging 

as candidate target in malignancies. As antiangiogenic treatments are 

introduced in the management of neuroendocrine tumors (NETs), we 

addressed the expression and function of PlGF in NETs. Methods: Serum 

levels of PlGF were determined in two independent cohorts of NET patients 

collected retrospectively and prospectively (n�87 and n�84) using Roche 

Elecsys and correlated with clinical data. Expression of PlGF in tumors was 

evaluated by immunohistochemistry. PlGF effects on proliferation and 

migration were examined in vitro using NET cell lines. Results: Circulating 

and tumoral PlGF were found elevated in NET patients as compared to 

control sera and pancreatic tissues in a retrospective analysis restricted to 

patients with pancreatic NETs (pNETs). De novo expression of PlGF 

occurred primarily in the tumor stroma, suggesting paracrine stimulatory 

circuits. Indeed, PlGF enhanced proliferation and migration of NET cells, 

and elevated circulating PlGF levels correlated with advanced tumor 

grading, suggesting that PlGF supported a more aggressive phenotype. In 

line with this notion, circulating PlGF levels above median predicted 

reduced tumor related survival in pNET patients (p�0.012). Furthermore, 

pathologic PlGF levels were associated with poor prognosis within the 

subgroup of grade 2 tumors. Subsequent prospective PlGF determinations 

confirmed and extended our observation of elevated PlGF levels for both, 

pNETs (n�32, p�0.001) and midgut NETs (n�58, p�0.001). Since 

median follow up was too short to determine survival, time to progression 

(TTP) was analyzed instead. Most pNETs were progressive at the time of 

sample collection, precluding an informative evaluation of TTP in this 

subgroup. However, PlGF levels above median were correlated with shorter 

TTP in midgut NETs (p�0.0091; TTP 27 months versus undefined, HR 

3.802). Conclusions: These data assign to PlGF a novel function in the 

pathobiology of NETs and propose PlGF as a prognostic parameter in 

patients with NETs. 


Patients with carcinoma of unknown primary and “colon cancer profile”: 

Clinicopathologic features and survival data. Presenting Author: Gauri R. 

Varadhachary, University of Texas M. D. Anderson Cancer Center, Houston, 

TX 

Background: We have previously proposed a “colon cancer profile” (CCP- 

CUP) favorable subset. CCP-CUP is ~ 8% of all CUP with features 

resembling lower gastroinestional cancers. Distinguishing this entity from 

other CUP pts is of significance given the progress in the treatment of 

metastatic colorectal cancer (CRC). Additionally, emerging data suggests a 

high level of agreement between histology�IHC and tissue of origin 

profiling for CCP-CUP. Methods: The retrospective cohort includes 74 pts 

from MD Anderson (50) and Sarah Cannon (24) Cancer Centers from 2004 

-2010. Pts with CDX2� tumors and pathology suggesting a �GI profile� 

were chosen. All pts met the definition of CUP and most had a negative 

colonoscopy. Results: 2 cohorts were created - Cohort 1 (34 pts), labeled 

“consistent with lower GI profile” [CDX2�, CK20�, CK7-] and Cohort 2 

(40 pts), labeled “probable lower GI profile” [CDX2�, irrespective of 

CK7/CK20 status]. Most pts had a good PS; 58% women, median age 59 

yrs; 20 (27%) pts had ascites on presentation and the predominant sites of 

metastases included liver (30%), carcinomatosis (50%), and nodes (51%). 

53 pts received first line CRC regimens (FOLFOX or FOLFIRI based), 15 pts 

received gemcitabine or taxane based and 3 ‘other’ regimens. OS was 37 

mo (C.I 22- 52). 6 of these were �outliers� (Stage 4 NED or indolent 

pathology). Excluding these, cohorts 1 and 2 had 32 and 36 pts - their OS 

were 37 and 21 mo respectively. There was no difference in OS of pts with 

or without ascites on presentation. Kras data was available for 17; 12 were 

Kras mutant. On multivariate analysis, the factors found to negatively 

influence survival were age, PS (of 2) and 3 or more sites of disease. 

Conclusions: Survival of IHC defined CCP-CUP pts (which may include 

colorectal, appendiceal and small bowel profile) exceeds historical control 

and illustrates a new �favorable� subset. IHC is not without its limitations – 

nonetheless, pts with CDX2 � tumors and CUP should undergo evaluation 

for GI cancers and likely best served with an armamentarium of drugs used 

for CRC. Since carcinomatosis and liver mets are predominant sites, all 

patients with abdominal CUP should undergo optimal IHC (CDX-2, CK7, 

and CK20) testing to rule out a CCP-CUP. 


Well-differentiated grade 3 digestive neuroendocrine tumors: Myth or 

reality? The PRONET study group. Presenting Author: Jean-Yves Scoazec, 

Hôpital Edouard Herriot, Lyon, France 

Background: In contrast to the 2000 World Health Organization (WHO) 

classification of digestive neuroendocrine tumors (NET) in which morphologic 

differentiation was the first criterion, the 2010 WHO classification of 

NET is based mostly on histologic grade. NET are now classified into three 

main categories: NET G1 (mitotic count �2/10 HPF and/or �2% Ki67 

index), NET G2 (2-20/10 HPF and/or 3-20%), and neuroendocrine 

carcinoma (NEC) of small or large cell type. While NET G1 and G2 are 

well-differentiated tumors, NEC are considered poorly differentiated G3 

tumors. We looked at the agreement between grade and differentiation to 

determine whether all NET can be readily classified according to the 2010 

WHO classification. Methods: We designed a 1-year prospective, epidemiologic 

study to assess the characteristics of newly diagnosed NET, including 

diagnostic pathology. From August 2010 to July 2011, all pathology 

laboratories in France were invited to register all incident cases of 

gastroenteropancreatic (GEP) and thoracic NET, excluding small cell 

carcinoma. For GEP-NET, investigators were asked to indicate morphologic 

differentiation (according to WHO 2000) and elements of histologic grade 

(mitotic index, Ki67 index), according to ENETS. Results: Of 500 invited 

centers, 80 participated; 1417 incidental cases were included and 77 

excluded (duplicates or exclusion criteria), totaling 1340 cases; 778 

(58.1%) were GEP-NET; 660/778 (85%) were well differentiated, 72 (9%) 

poorly differentiated, and 46 (6%) adenocarcinoid, nonclassified, or not 

evaluable; 422 (54.2%) were G1, 220 (28%) G2, 104 (13.5%) G3, and 

32 (4.1%) had missing grades. Of those deemed G3, 72 (69%) were 

described as poorly differentiated, 21 (20%) as well differentiated (mean 

Ki67 index 35%, range 25%-60%), and 11 (10.5%) as adenocarcinoid. 

Conclusions: In this prospective, epidemiologic study, overall agreement 

between grade and differentiation was good. However, a significant 

proportion of G3 NET were classified as well differentiated and thus 

unclassifiable by 2010 WHO classification. This group of tumor deserves to 

be included in future classifications to help the clinician decide whether 

they should be treated as NET G1/G2 or NEC G3. 


Mutation profling in patients with carcinoma of unknown primary using the 

Sequenom MassARRAY system. Presenting Author: Katherine Stemke 

Hale, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: CUP management may be viewed as an epitome of personalised 

medicine as we apply our understanding of biological markers to this 

heterogeneous disease. There is a significant interest in evaluating actionable 

mutations in various signaling pathways, receptors and downstream 

effectors in CUP that may help us understand its biology and serve as the 

basis for unique targeted therapeutic approaches. Sequenom (SQM) 

Massarray platform enables rapid mutation profiling in solid tumors which 

we applied to CUP. Methods: 83 CUP samples were sent for DNA mass array 

analysis. Sequenom was run on 60 samples; 23 samples lacked sufficient 

quantity or quality of DNA. Data on clinicopathological features was 

collected. Results: Of the 60 patient samples run on SQM, 16 patients had 

changes including 11 mutations and 6 polymorphisms . The 6 polymorphisms 

were in MET . The mutations reported were :RAS (7; 6 KRAS, 1 

NRAS), IDH1 (2), PI3K (1) and MET (1). Atleast 50% of the tumors were 

poorly differentiated. Interestingly, the 2 patients with IDH1 mutations 

presented with osseous predominant metastatic disease. Of the 6 patients 

with KRAS mutations, 4 presented with a gastrointestinal profile ( CDX2� 

or CK20�) on IHC; in all 4, the DNA sequencing analysis results matched 

the sequenom results. Conclusions: The (all-comers) overall mutation rate 

in a heterogenous CUP population is low (11/60, 18%). No �new� low 

frequency mutations were found using the current panel (Table). Rare and 

potentially targetable mutations may be identified with a larger panel. 

Focusing on CUP subsets using this approach may also provide a higher 

mutational yield. 

P13K/AKT pathway MEK pathway Receptors Downstream effectors 

AKT1, 2, 3 BRAF EGFR CDK4 

PIK3CA KRAS ALK CTNNB1 

PHLPP2 MEK1,2 KIT IDH1,2 

FRAP (mTOR) NRAS MET JAK2 

RICTOR PRKAG1/2 PDGFRA RET 

PDPK1 BRAF FLT3 

PIK3R1 TNK2(ACK1) 



Final results of a phase Ib study of tivozanib and FOLFOX6 in patients (pts) 

with advanced gastrointestinal (GI) tumors. Presenting Author: Ferry 

Eskens, Erasmus University Medical Center, Daniel den Hoed Cancer 

Center, Rotterdam, Netherlands 

Background: Tivozanib is a potent, selective, oral small-molecule tyrosine 

kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 

with a long half-life. A Phase I study found tivozanib’s maximum tolerated 

dose (MTD) to be 1.5 mg/d and responses were observed in pts with 

colorectal cancer (CRC) and other tumors. Tivozanib has shown additive 

anti-tumor activity with 5-fluorouracil in a preclinical breast tumor model. 

FOLFOX6 is a standard chemotherapy for GI cancers. This open-label, 

Phase Ib study (NCT00660153) sought to determine the MTD, doselimiting 

toxicities (DLTs), pharmacokinetics (PK), and anti-tumor activity 

of escalating doses of tivozanib combined with a modified (m) FOLFOX6 

regimen (85 mg/kg2 oxaliplatin) in pts with advanced GI tumors. Methods: 

Tivozanib was administered once daily in 4-week cycles (3 weeks on, 1 

week off) with mFOLFOX6 administered on Days 1 and 15 of each cycle. 

Pts also received a single dose of tivozanib on day -5 for PK analysis. Pts 

were allowed to continue tivozanib following discontinuation of mFOL- 

FOX6. Results: Twenty two pts (14:8 male:female; median age 58 years; 

91% Caucasian) received tivozanib 0.5 mg (n�9), 1.0 mg (n�3), or 1.5 

mg (n�10) and mFOLFOX6. Pts received a median of 5.2 (range 0.0 to 

25.1) months of treatment. DLTs were observed in 2 pts on tivozanib 0.5 

mg (reversible Grade [Gr] 3 diarrhea and Gr 3/4 transaminase elevations) 

and in 2 pts on tivozanib 1.5 mg (Gr 3 seizure and reversible Gr 3 vertigo). 

Other Gr 3/4 drug-related adverse events (AEs) included neutropenia, 

fatigue, and hypertension (n�2 each). Eight pts discontinued treatment 

due to AEs. The MTD for tivozanib with mFOLFOX6 was 1.5 mg. The 

disease control rate was 63% (�1% complete response, 27% partial 

response, 36% stable disease). Preliminary PK data showed no interaction 

between tivozanib and mFOLFOX6. Eight additional pts enrolled at the 1.5 

mg dose level are currently being evaluated. Final results will be presented. 

Conclusions: Tivozanib can be combined at its recommended dose of 1.5 

mg/day with mFOLFOX6 for pts with advanced GI tumors. The combination 

was tolerable and showed encouraging anti-tumor activity. A Phase II study 

of this combination for mCRC is ongoing. 


Dasatinib combined with gemcitabine (Gem) in patients (pts) with locally 

advanced pancreatic adenocarcinoma (PaCa): Design of CA180-375, a 

placebo-controlled, randomized, double-blind phase II trial. Presenting 

Author: T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre, 

Glasgow, United Kingdom 

Background: Dasatinib, a potent oral BCR-ABL and SRC family kinase 

(SFK) inhibitor, is approved for first- and second-line therapy of Philadelphia 

chromosome-positive chronic phase chronic myeloid leukemia (CML) 

in pts with newly diagnosed CML or CML resistant/intolerant to prior 

therapy. SRC expression and activity is upregulated in PaCa and correlates 

with reduced survival in resected high-grade PaCa (Morton, Gastroenterology 

2010) and resistance to Gem, a PaCa standard of care (Duxbury, J Am 

Coll Surg 2004). In preclinical PaCa studies, inhibition of SFKs with 

dasatinib reduces tumor cell proliferation, migration, and invasion; increases 

apoptosis; sensitizes cells to Gem; and inhibits development of 

metastases in vivo either alone or in combination with Gem (Duxbury, Clin 

Cancer Res 2004; Duxbury, J Am Coll Surg 2004; Nagaraj, Mol Cancer 

Ther 2010; Morton, op cit). Phase I clinical studies of dasatinib and Gem 

therapy in PaCa have demonstrated feasibility and suggested efficacy of the 

combination (Uronis, ASCO 2009, abstract e15506). Methods: This 

double-blind phase II study tests whether addition of dasatinib to Gem is 

tolerable and improves efficacy in pts with histologically/cytologically 

confirmed unresectable locally advanced nonmetastatic PaCa. Eligible pts, 

aged �18 years with Eastern Cooperative Oncology Group performance 

status �1 and adequate organ function, are randomized 1:1 to Gem 1000 

mg/m2 IV once weekly (Weeks 1–3 of a 4-week cycle) plus either dasatinib 

100 mg once daily or matched placebo. Pts are treated until progression, 

unacceptable toxicity, withdrawal of consent, or study termination. The 

primary endpoint is OS, and secondary endpoints are progression-free 

survival and safety. Exploratory endpoints include freedom from distant 

metastases, measures of pain and fatigue, overall response rate, and 

carbohydrate antigen 19-9. Final study analysis will be conducted after 

135 deaths; all pts will be followed for survival. To date, 23/200 pts have 

enrolled; estimated primary completion date is March 2013. ClinicalTrials. 

gov identifier: NCT01395017. 


271s 


Methylguanine DNA methyl transferase (MGMT) expression to predict 

response to temozolomide (TMZ) in patients with digestive neuroendocrine 

tumors (NETs). Presenting Author: Pascal Hammel, Beaujon, Paris, France 

Background: TMZ is an orally given drug used in patients (pts) with NETs, 

with encouraging results in pancreatic NETs in a recent study (Strosberg et 

al, 2011). Higher treatment efficacy seems to be correlated to MGMT 

tumor deficiency (Kulke et al, 2010). Aim-To assess MGMT expression in 

digestive NETs and to correlate with the efficacy of TMZ-based therapies. 

Methods: All pts with well differentiated, progressive, non resectable NETs 

treated with TMZ-based chemotherapy were included. Treatment efficacy 

was defined according to RECIST. Pts with progression or only stable 

disease were considered as “non-responders”. Nuclear expression of 

MGMT was assessed by immunohistochemistry on primary tumors or 

metastases and graded according the product of the intensity of staining (0 

to 3) and the rate of positive cells (%), leading to a score comprised 

between 0 and 300. A score � 80 was defined as “high” staining. Results: 

22 pts (age 59 years (36-81)) with pancreatic (14 pts), small bowel (5 pts) 

or other (3 pts) NETs, grade 1 (5 pts) or 2 (17 pts) (WHO 2010 

classification) were included. They received TMZ alone (19 pts) or 

combined with capecitabine (3 pts) as first line (3 pts) or 2� line (19 

pts).After a median of 6 cycles (3-16), objective response, stable disease 

and progression rates were seen in 32 % (7 pts, all with pancreatic NETs), 

41% (9 pts, 5 pancreatic) and 27% (6 pts, 4 small bowel), respectively. 

Median (range) MGMT score was 10 (0-300). A “High” MGMT score was 

seen in 36% of pts (small bowel 4, pancreas 3 pts) ; it was correlated with 

primary tumor location (more frequent in small bowel NETs, p�0.02) and 

predictive of the absence of response (p�0.02). A “Low “MGMT score 

tended to be associated with objective response (p�0.06) whereas none of 

the pts with “high” score had tumor response. Response rate in pts with 

“low” MGMT score was 50%. Conclusions: MGMT deficiency is more 

frequent in pancreatic than small bowel NETs. Patients with pancreatic 

NET and low MGMT score are good candidates for TMZ, whereas those with 

high score should be treated with other drug in first intention. In patients 

with small bowel NET with most often high MGMT score, tumor stabilization 

using TMZ seems to be rare. 


A phase III, multicenter, randomized, double-blind, placebo-controlled 

trial of ganitumab or placebo in combination with gemcitabine (G) as 

first-line therapy for metastatic adenocarcinoma of the pancreas: The 

GAMMA trial. Presenting Author: Charles S. Fuchs, Dana-Farber Cancer 


Background: Ganitumab (AMG 479) is an investigational, fully human, 

monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study 

in patients with metastatic pancreatic cancer, addition of ganitumab 12 

mg/kg every 2 weeks (Q2W) to G prolonged progression-free survival (PFS) 

and overall survival (OS) (Kindler. Ann Onc. 2010;21:741P). Exposureefficacy 

analysis showed that patients with higher ganitumab exposure 

levels (AUCss at or above median) had longer PFS and OS (Lu. JCO. 

2011;29:4049). Methods: In this phase III study, patients are randomized 

2:2:1 to placebo � G, ganitumab 12 mg/kg � G, or ganitumab 20 mg/kg � 

G. Patients receive ganitumab or placebo IV days (D) 1 and 15 and G 1000 

mg/m2 IV D 1, 8, and 15 every 28 D. Patients receiving 20 mg/kg 

ganitumab are expected to achieve ganitumab levels above the median in 

phase 2. Key eligibility criteria: untreated metastatic adenocarcinoma of 

the pancreas; ECOG score 0 or 1; � 18 years old; adequate organ function; 

and fasting (or non-fasting) glucose � 160 mg/dL. The primary endpoint is 

OS. A log-rank test stratified by ECOG, presence of liver metastases, and 

geographic region will compare OS independently for each ganitumab arm 

at an overall one-sided 2.5% significance level for declaring superiority of 

ganitumab � G vs placebo � G. Key secondary endpoints include PFS, 

objective response, safety, and patient-reported outcomes. An additional 

objective is to define a subpopulation with improved OS based upon 

baseline levels of circulating biomarkers. Enrollment began in April 2011. 

As of January 23, 2012, 463 of 825 patients have been enrolled. The study 

is overseen by an independent data monitoring committee. Status: open. 

Supported by Amgen Inc. in collaboration with Takeda Global Research & 

Development Center, Inc.; ClinicalTrials.gov: NCT01231347. 




Gemcitabine with nab-paclitaxel in neoadjuvant treatment of pancreatic 

adenocarcinoma: GAIN-1 study. Presenting Author: Neelam Vijay Desai, 

University of Florida, Gainesville, FL 

Background: Pancreatic adenocarcinoma remains a deadly disease with a 

dismal prognosis. Only 15% of patients present with resectable disease 

with 5-year survival only 20% despite adjuvant therapy. Neoadjuvant 

treatment may improve R0 resection rates, allows more patients curative 

surgery, is cost effective, and may improve overall survival by incorporating 

earlier systemic therapy. Methods: This is a prospective single arm 

open-label phase II trial using gemcitabine (G) and nab-paclitaxel (A) in the 

neoadjuvant treatment of resectable and borderline-resectable pancreatic 

cancer. Patients are stratified by risk group as defined by a predictive model 

published by Bao et al and the NCCN expert consensus statement (Table): 

low-risk resectable (Group 1) and high-risk resectable or borderlineresectable 

(Group 2). Group 1 receives 3 cycles of G�A then surgical 

resection. 1 cycle � G 1000mg/m2 �A 100mg/m2 IV on Days 1, 8, 15 Q28 

days. Group 2 receives 2 cycles of G�A followed by 2 weeks of hypofractionated 

IMRT (50.4Gy in 10 fx) with G 400mg/m2 IV weekly, then surgical 

resection. The primary endpoints are R0 resection rate and overall response 

rates. Secondary endpoints are PFS, OS, 30-day post-op mortality, toxicity, 

QOL and molecular analysis including DPC4 and SPARC levels in tumor 

and stroma. Enrollment has just begun with a total accrual goal of 60 

patients. This platform will allow targeted systemic therapy and tailored 

treatment stratification to optimize outcomes in curable pancreatic cancer. 

This study is registered with Clinicaltrials.gov (NCT01470417). 

Risk stratification Definition 

Low-risk -EUS Stage � IA OR 

-No vascular involvement on CT & 

a. EUS stage IB or IIA OR 

b. EUS stage � IIB but tumor � 2.6cm 

High-risk -EUS stage IB or IIA but vascular involvement on CT 

-No vascular involvement but EUS stage � IIB & tumor � 2.6 cm 

-(�) nodes on PET or FNA 

Borderline -Involvement of SMV/portal vein but w/o encasement of arteries, or 

short segment venous occlusion 2/2 tumor thrombus 

or encasement but w/ suitable vessels to allow 

resection & reconstruction 

-Gastroduodenal artery encasement up to hepatic artery 

w/ short segment involvement of hepatic artery, 

w/o extension to celiac axis 

-Tumor abutment of SMA �180 degrees of vessel wall 


PaFLO: Pazopanib with 5-fluorouracil, leucovorin, and oxaliplatin (FLO) as 

first-line treatment in advanced gastric cancer: A randomized phase II 

study of the Arbeitsgemeinschaft internistische Onkologie (AIO). Presenting 

Author: Kirstin Breithaupt, Charité-Universitätsmedizin Berlin, Campus 

Virchow-Klinikum, Med Klinik m. S. Hämatologie u. Onkologie, Berlin, 

Germany 

Background: VEGF inhibition in gastric cancer shows promising improvement 

of remission rate and progression-free survival (Ohtsu et al., JCO 

2011). Pazopanib is an orally available tyrosine kinase inhibitor (TKI) 

selectively inhibiting VEGFR-1, -2, -3, c-kit and PDGFR. It is approved for 

treating renal cell cancer. A phase-I trial showed good tolerability of 

pazopanib with full-dose FOLFOX in solid tumors (Brady et al., ASCO, 

2009). FLO is a widely used combination for advanced gastric cancer 

recommended in national guidelines. Methods: 75 Patients with HER-2negative 

locally advanced or metastatic adenocarcinoma of the stomach or 

the gastro-esophageal junction will be randomized in a 2:1 ratio to A: FLO 

(F 2600mg/m2 as 24h infusion, L 200mg/m2, O 85 mg/m2) d1 � 

pazopanib (800mg) d1-14 and B: FLO; repeated for 12 2-week cycles, 

followed by a maintenance therapy with pazopanib alone in A and an 

observation period in B until disease progression. Primary endpoint is 

progression-free survival rate (PFSR) at 6 months, secondary endpoints are 

PFSR at 9 and 12 months, median PFS, response rate, duration of 

response, toxicity, tolerability and overall survival. Additionally, we evaluate 

the predictive and prognostic relevance of PIGF, VEGF, and the 

respective soluble receptors sVEGFR1 and sVEGFR2 as biomarkers for 

clinicopathological parameters, clinical response to treatment and tumor 

volume change. Based on a phase-III trial demonstrating a 6-month PFSR 

of 44% with FLO (Al-Batran et al., 2008), we estimate a 6-month PFSR of 

55% in the experimental group. Given an alpha error of 0.1 and a beta error 

of 0.2 in a Simon 2-stage minimax design, in the first stage �12 of 30 

patients need to be progression free at 6 months to continue and after the 

second stage �25 of 50 patients should be progression free at 6 months to 

justify further evaluation. Randomization is performed to estimate selection 

bias according to pazopanib-specific exclusion criteria for comparison 

with historical data. Study protocol received ethics committee approval in 

November 2011 and is currently recruiting patients in 15 AIO centers. 


PAN1: A randomized phase II study evaluating potential predictive biomarkers 

in the treatment of metastatic pancreatic cancer. Presenting Author: Yu 

Jo Chua, Medical Oncology Unit, The Canberra Hospital, Garran, Australia 

Background: Biomarker-based selection of cancer treatments has already 

entered routine clinical practice in some cancer types. Recent retrospective 

data suggests the human equilibrative nucleoside transporter 1 (hENT1) to 

be promising predictive marker for benefit from gemcitabine in pancreatic 

cancer, at least in resected disease. Methods: 80 patients will be randomised 

to receive either gemcitabine or FOLFOX chemotherapy (folinic 

acid (FOL) fluorouracil (F) and oxalipatin (OX)) with stratification based on 

hENT1 status. All patients will be required to have tumour samples tested 

for hENT1 prior to randomisation, with both hENT1 positive and negative 

patients eligible for inclusion. Patients will continue their assigned 

treatment until progression, or unacceptable toxicity. Primary endpoint: 

Progression free survival in each chemotherapy arm (FOLFOX/gemcitabine). 

Secondary endpoints: efficacy/activity of gemcitabine and FOLFOX 

as assessed by OS (overall survival), TTP (time to progression), RR 

(response rate according to RECIST v1.1), CA19.9 response; Percentage of 

eligible patients able to be randomised within 14 days of screening; PFS in 

each biomarker-selected cohort (hENT1 positive/negative); Treatment 

related toxicity in each chemotherapy group (CTCAE v4.0) and in biomarker 

cohorts (hENT1 positive/negative); establishment of a tissue bank from 

patients treated with and without gemcitabine for further biomarker 

studies. Eligibility: Adult patients with radiologically and histologically 

confirmed metastatic pancreatic adenocarcinoma who have not previously 

received treatment for metastatic disease, and who have tumour tissue 

available for hENT1 testing are eligible for the study. Patients who do not 

have tumour tissue available will be required to undergo core biopsy to 

obtain tissue for hENT1 testing. Status: Opened to accrual July 2011. 


A randomized, multicenter, double-blind, placebo (PBO)-controlled phase 

III study of paclitaxel (PTX) with or without ramucirumab (IMC-1121B; 

RAM) in patients (pts) with metastatic gastric adenocarcinoma, refractory 

to or progressive after first-line therapy with platinum (PLT) and fluoropyrimidine 

(FP). Presenting Author: Hansjochen Wilke, Kliniken Essen Mitte 

Center of Palliative Care, Essen, Germany 

Background: Vascular endothelial growth factor (VEGF) expression in gastric 

cancer (GC) is associated with more aggressive clinical disease. VEGF 

expression in resected GC is associated with tumor recurrence and shorter 

survival. Data from Phase 2 and 3 studies suggest that agents targeting the 

VEGF pathway improve the efficacy of some chemotherapy regimens in 1stand 

2nd-line treatment of patients with gastric or gastroesophageal 

carcinomas. RAM, a fully human monoclonal antibody, binds to the VEGF 

receptor-2 (VEGFR-2), potently blocks the binding of VEGF to VEGFR-2, 

inhibits VEGF-stimulated activation of VEGFR-2, and neutralizes VEGFinduced 

mitogenesis of human endothelial cells. Methods: Pts are randomized 

1:1 to receive PTX � RAM or PTX � PBO until disease progression or 

intolerable toxicity (28-day cycle; RAM/PBO 8 mg/kg Days 1, 15; PTX 80 

mg/m2 Days 1, 8, 15). Eligibility includes metastatic or locally advanced, 

unresectable gastric or gastroesophageal junction adenocarcinoma; prior 

first-line therapy with any PLT/FP doublet with or without anthracycline; 

progressive disease during or following first-line therapy; ECOG PS 0-1; 

bilirubin � 1.5 � upper limit of normal (ULN), transaminases � 3 � ULN 

for ALAT/ASAT if no liver metastases, � 5 � ULN if liver metastases; 

creatinine � 1.5 � ULN; absolute neutrophil count � 1.5 � 109 /L, 

hemoglobin � 9 g/dL; platelets � 100 � 109 /L. The primary endpoint is 

overall survival (OS). Secondary endpoints include progression-free survival, 

time to progression, best overall response, objective response rate, 

safety, patient-reported outcome measures, pharmacodynamics, immunogenicity, 

and pharmacokinetics. This study, powered at 90% to show an 

increase in OS (mdn: 7mPTX�PBO, 9.33 m PTX � RAM) at a 1-sided 

2.5% significance level, will randomize 663 pts. As of 18 January 2012, 

approximately 58% of planned pts were randomized. The IDMC reviewed 

this study 23 June and 01 December 2011 and recommended the study 

continue unmodified. 



Lapatinib in combination with ECF/x in EGFR1 positive first-line metastatic 

gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 

40071). Presenting Author: Markus Hermann Moehler, University of 

Mainz, Mainz, Germany 

Background: Survival of HER2� metastatic GC is prolonged by trastuzumab 

when administered with CF/X (VanCutsem, ASCO 2009). Lapatinib inhibits 

both EGFR1 and HER2, is active in HER2� GC lines, and has shown 

clinical activity in uncontrolled phase II GC trials. A phase III trial of 

lapatinib with X � oxaliplatin in HER2� (FISH) GC is closed to recruitment. 

Additional unaddressed questions include the efficacy and safety of 

lapatinib with ECF/X (epirubicin � cisplatin � 5-FU or capecitabine (X), 

which is a preferred chemotherapy (CT) regimen in GC), and its activity in 

patients (pts) with discordant FISH or IHC HER2 status or EGFR1�. 

Methods: This is a phase II, randomized, double- blind, placebo controlled, 

multicenter trial sponsored by the EORTC. About 480 pts with adenocarcinoma 

of the stomach or esophagogastric junction not amenable to curative 

surgery and without prior palliative CT are screened centrally for HER2/ 

EGFR1 by FISH and IHC. Patients are enrolled into one of two strata: 1) 

HER2 FISH- and IHC 2/3�, or 2) HER2 IHC 0/� and EGFR1 FISH� or IHC 

2/3�. Pts HER2 FISH�/IHC 2/3� and pts without HER2/EGFR1 by 

FISH/IHC will be excluded. 168 pts are anticipated to be randomized to 

lapatinib 1,250 mg cont. until progression or placebo, administered 6 

cycles of ECF or ECX (72/96 in stratum 1/2, respectively).The primary 

endpoint is progression-free survival (PFS) in stratum 2 and 77 events are 

needed for 80% power to detect an increase in PFS from 4 to 6.5 months 

with lapatinib (HR�0.615, one-sided alpha 10%). Secondary endpoints 

include PFS, toxicity, response rate, overall survival, and correlation of 

HER2/EGFR1 status with response. Currently, half of all screened patients 

(19/38) have been randomized. So far, 8/38 (21%) pts were HER2� 

according TOGA criteria. By FISH or IHC, 14/38 were EGFR1�, with 4/14 

pts double HER2/EGFR�. Enrolment continues in 5 centers with about 

4-10 patients per month. A safety cohort analysis will be performed in the 

first 15 pts receiving lapatinib. Conclusions: This is the first trial to analyze 

prospectively and separately the role of lapatinib combined with chemotherapy 

in EGFR1� GC pts stratified by FISH/ IHC. 


Postoperation chemotherapy with S1 and docetaxel in curatively resected 

gastric cancer of stage III (POST trial). Presenting Author: Minkyu Jung, 

Gachon University Gil Hospital, Incheon, South Korea 

Background: Complete surgical resections remains the only chance for cure 

in patients with gastric cancer, but approximately from 40% to 80% of 

patients still have recurrences and most patients ultimately die from their 

disease. The recent adjuvant trials in gastric cancer showed significantly 

improved survival in patients with adjuvant chemotherapy than those with 

surgery alone. However, further studies need for the effect of adjuvant 

chemotherapy following D2 dissected gastric cancer patients, especially in 

advanced gastric cancer. S-1 is an oral anticancer drug, a prodrug of 

fluorouracil, very effective in gastric cancer. Docetaxel is the first drug that 

showed survival benefits when added to the two drugs in advanced gastric 

cancer patients. And docetaxel is also synergistic anti-cancer effect with 

S-1 in advanced gastric cancer. Base on this background, the aim of this 

study is to detect a significant increase in 3 –year disease free survival 

(DFS) of adjuvant chemotherapy with docetaxel and S-1(DS) relative to 

those with S-1 and cisplatin (SP) in patients with stage III gastric cancer 

Methods: This study is an open-label, phase 3, randomized controlled trial, 

multicenter in South Korea. Patients with stage III (AJCC 7th edition) 

gastric cancer who had had curative D2 gastrectomy is randomly assigned 

to receive adjuvant chemotherapy of eight 3-week cycles of intravenous 

docetaxel (35 mg/m2 on day 1 and 8 of each cycle) plus oral S-1 (35 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months (DS) or 

chemotherapy of eight 3-week cycles of oral S1 plus intravenous cisplatin 

(60 mg/m2 ). After satisfying the screening criteria, patients have been 

randomized to the SD or SP arm in a 1:1 ratio. The randomization is 

stratified by institution and stage of disease (IIIA vs. IIIB vs. IIIC). The each 

stratum has been randomized by using the method of randomly permuted 

block. The primary endpoint is 3 year DFS, will analyze by intention to treat. 

A total of 290 patients will be enrolled, 67 patients have been treated to 

day, with continuing accrual. The trial is registered at ClinicalTrials.gov 

(NCT01283217). 


273s 


TOPGEAR: An international randomized phase III trial of preoperative 

chemoradiotherapy versus preoperative chemotherapy for resectable gastric 

cancer (AGITG/TROG/EORTC/NCIC CTG). Presenting Author: Trevor 

Leong, Peter MacCallum Cancer Centre, Melbourne, Australia 

Background: Optimal management of patients with resectable gastric 

cancer remains unknown. Since the INT0116 and MAGIC trials, there are 2 

standards of care for adjuvant therapy: postoperative chemoradiotherapy 

(CRT) and perioperative ECF chemotherapy. The important question arising 

from these studies is whether CRT is superior to chemotherapy alone as 

adjuvant therapy. This randomized phase II/III trial will compare CRT to 

chemotherapy alone in the preoperative setting. Methods: Patients with 

resectable adenocarcinoma of the stomach or gastroesophageal junction 

will be randomized to receive either preoperative chemotherapy alone 

(ECFx3 as per MAGIC regimen) or preoperative CRT (ECFx2 followed by 

45Gy of radiation with concurrent 5-FU). Following surgery, both groups 

will receive 3 further cycles of ECF. The trial is being conducted in two 

Parts; Part I (phase II component) will recruit 120 patients with the aim of 

demonstrating sufficient efficacy and safety of preoperative CRT, as well as 

trial feasibility. Part II (phase III component) will recruit a further 632 

patients to provide a total of 752. The primary endpoint for Part I is 

pathological complete response rate, and for Part 2 it is overall survival. 

The trial includes formal quality of life and biological sub-studies. In 

addition, the trial incorporates a rigorous quality assurance program that 

includes real time central review of radiotherapy plans and central review of 

surgical technique. Current status: This study is an international, intergroup 

trial led by the Australasian Gastro-Intestinal Trials Group (AGITG), 

in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), 

European Organisation for Research and Treatment of Cancer (EORTC) and 

the NCIC Clinical Trials Group. To date, 36 patients have been recruited 

from 20 sites in Australia and New Zealand; European and Canadian sites 

will commence recruitment in 2012. 


ST03: A randomized trial of perioperative epirubicin, cisplatin plus 

capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with 

operable gastric, oesophagogastric junction (OGJ) or lower oesophageal 

adenocarcinoma. Presenting Author: Elizabeth C Smyth, The Royal Marsden 

Hospital, Sutton, United Kingdom 

Background: Perioperative ECX chemotherapy is a standard of care for 

localised gastric/OGJ/lower oesophageal adenocarcinoma (Cunningham 

NEJM 2006). B is a monoclonal antibody targeting VEGF-A, and in 

combination with chemotherapy results in improved response rates (RR) 

and progression free survival in advanced gastric cancer (Ohtsu JCO 2011). 

The aim of ST03 is to assess the safety and feasibility (stage I, first 200 pts) 

and efficacy (stage II) of the addition of B to perioperative ECX chemotherapy. 

Methods: ST03 is a multicentre, open-label, phase II/III randomised 

trial ongoing at 92 UK centres; sites in Germany will open in 

2012. Eligibility criteria are histologically proven, untreated, resectable, 

lower oesophageal, OGJ or gastric adenocarcinoma; age �18 years; WHO 

PS 0-1; and adequate cardiac ejection fraction (EF). Exclusion criteria are 

TIA/CVA or MI �1 year; uncontrolled hypertension; �Grade II NYHA heart 

failure; recent gastrointestinal inflammatory conditions or major surgery/ 

trauma/open biopsy �28d of study entry. Pts receive 3 pre- and 3 

postoperative ECX (epirubicin 50 mg/m2 iv D1, cisplatin 60 mg/m2 iv D1 

and capecitabine 1250mg/m2 /D1-21) �/- B 7.5mg/kg D1 q3wk during 

chemotherapy, then 6 Bev q3wk (investigational arm). Surgery is prespecified 

and laparoscopic procedures allowed only after quality assurance 

review. All specimens undergo central pathology review; blood and tissue 

collection for translational correlates is ongoing. The primary outcome 

measures for Stage I (safety results including cardiac EF) have been 

reported (Okines ASCO 2011). The stage II primary outcome measure is 

overall survival. Secondary outcome measures are RR, resection rate, 

disease free survival, toxicity, and QoL. An MRI substudy is open, a PET 

substudy is planned. 558 of ~950 pts required have been recruited, 

accrual expected to complete in 2013. An embedded pilot study within 

ST03 randomising HER2 positive patients to ECX � lapatanib will open in 

2012. Trial sponsored and co-ordinated by the MRC Clinical Trials Unit and 

funded by Cancer Research UK (CRUK06/025, NCT00450203). 




A phase II study of afatinib (BIBW 2992) in patients with advanced 

HER2-positive trastuzumab-refractory esophagogastric cancer. Presenting 

Author: Yelena Yuriy Janjigian, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: Trastuzumab, approved by the FDA, has been the standard of 

care for patients (pts) with HER2-positive esophagogastric cancer. Acquired 

and de novo resistance to trastuzumab is an important clinical issue. 

Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase 

receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination 

with cetuximab, demonstrated a 40% partial response (PR) rate, with 

clinical benefit in �90% in lung cancer patients with acquired resistance 

to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive 

NCI-N87 gastric cancer xenograft showed that while trastuzumab alone 

was minimally effective, single-agent afatinib resulted in near complete 

tumor regression by inducing apoptosis and downregulation of HER2, 

p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In 

light of these data and the efficacy of afatinib in patients with trastuzumabrefractory 

breast cancer, we designed a phase II study to determine if 

afatinib will benefit patients with trastuzumab-refractory HER2-positive 

esophagogastric cancer. We hypothesize that simultaneous inhibition of 

ErbBB receptor family components with afatinib will overcome trastuzumab 

resistance. Molecular bases of trastuzumab resistance will be 

examined. Methods: Pts with metastatic HER2-positive (IHC 3� or FISH 

�2.0) esophagogastric cancer with disease progression on a trastuzumabcontaining 

regimen will receive afatinib 40 mg once daily. Primary 

endpoint RECIST 1.1 response (SD�CR�PR) at 4 months, with imaging 

every 8 wks. 13 pts will be enrolled in the 1st stage and if �1 responses are 

observed, additional 14 ps (total of 27) will be treated. An initial biopsy 

prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis 

of archival pre-trastuzumab tissue and blood sample for matched normal 

DNA control are mandated. Changes in signaling following afatinib therapy 

will provide insight into response heterogeneity. Degree of target inhibition 

will be correlated with responses. Archival baseline (pre-trastuzumab) and 

pre-afatinib tissue will be assessed for abnormalities in pathways implicated 

in trastuzumab resistance. 


A multicenter, randomized, double-blind, phase III study of ramucirumab 

(IMC-1121B; RAM) and best supportive care (BSC) versus placebo (PBO) 

and BSC as second-line treatment in patients (pts) with hepatocellular 

carcinoma (HCC) following first-line therapy with sorafenib (SOR). Presenting 

Author: Andrew X. Zhu, Division of Hematology and Oncology, Massachusetts 


Background: Blockade of vascular endothelial growth factor (VEGF) signaling 

in HCC has been shown in preclinical models with monoclonal 

antibodies and small molecule multikinase inhibitors, and in clinical trials 

with SOR, to have anti-tumor activity and improve survival. RAM, a fully 

human monoclonal antibody, binds to the VEGF receptor-2 (VEGFR-2), 

potently blocks the binding of the VEGF ligand to VEGFR-2, inhibits 

VEGF-stimulated activation of VEGFR-2, and neutralizes VEGF-induced 

mitogenesis of human endothelial cells. In a single-arm, Phase 2 study of 

RAM as 1st-line monotherapy in 42 pts with advanced HCC (Zhu, ILCA 

2010, abstr. O-033), preliminary results included median progression-free 

survival (PFS) of 4 months (m), time to progression (TTP) of 4.2 m, overall 

survival (OS) of 12 m and disease control rate of 70% (best overall 

response: 10% partial response, 60% stable disease). Methods: Pts with 

HCC with disease progression during or following 1st-line therapy with SOR 

(or who were intolerant to SOR) are randomized 1:1 to receive RAM (8 

mg/kg) or PBO once every 2 weeks, with BSC, until disease progression or 

intolerable toxicity. Eligibility includes prior SOR as 1st-line systemic 

treatment for HCC, Child-Pugh A, B7 or 8 cirrhosis, ECOG PS 0-1, bilirubin 

� 3 mg/dL, transaminases � 5 � upper limit of normal (ULN), creatinine 

� 1.2 � ULN, and platelets � 75�103 /�L. The primary endpoint is OS. 

Secondary endpoints include PFS, best objective response rate, TTP, 

patient-reported outcome measures of disease-specific symptoms and 

health-related quality of life, safety, and RAM pharmacokinetics, pharmacodynamics, 

and immunogenicity. With 544 patients, this study is designed 

to detect an increase in OS (median 6 m with PBO to 8 m with RAM; 

1-sided �� 2.5%, 85% power). As of 18 January 2012, approximately 

52% of planned pts have been randomized. The IDMC reviewed this study 

on 21 June and 3 November 2011 and recommended the study to continue 

unmodified. 


DOCTOR: A randomized phase II trial of preoperative cisplatin, 5-fluorouracil, 

and docetaxel with or without radiotherapy based on poor early response 

to standard chemotherapy for resectable adenocarcinoma of the esophagus 

and/or OG junction. Presenting Author: Andrew Barbour, University of 

Queensland, Brisbane, Australia 

Background: Surgery forms the mainstay of curative treatment for oesophageal 

and gastro-oesophageal junction adenocarcinoma (OAC). Preoperative 

chemotherapy (CTX) with or without concurrent radiotherapy (CRT) have 

resulted in modest improvements in outcome. Patients who demonstrate a 

histological response in the resected specimen following pre-operative 

therapy (CTX or CRT) have consistently better survival than non-responders. 

Recent data suggests that early metabolic response, assessed by FDG-PET 

scan performed 14�/-1 days after the start of CTX compared with a 

baseline PET scan, is predictive of a histological response and improved 

survival. Increasing the proportion of responders to pre-operative therapy 

remains one of the major challenges facing patients with localised OAC. 

Methods: 150 patients with resectable adenocarcinona of the oesophagus 

or GOJ will be registered and given 1 cycle of cisplatin and 5FU (CF). 

Patients will undergo a series of baseline tests including endoscopy, 

endoscopic ultrasound and 18FDG-PET. At Day 15 of the initial CF cycle 

the PET will be repeated. Patients with a PET response (� 35% reduction 

in SUVmax) to initial treatment will continue with CF as standard treatment 

prior to surgery. PET non-responders (� 35% reduction in SUVmax) will be 

randomized equally to receive either docetaxel, cisplatin and 5FU (DCF) or 

DCF plus radiatiotherapy. Following completion of the preoperative chemotherapy 

/chemoradiotherapy patients will have their cancer surgically 

removed. The primary end point is major histological response (�10% 

residual viable tumour) and secondary endpoints of progression-free and 

overall survival, toxicity, quality of life and feasibility of response-based 

therapy. Eligibility: T2 or greater tumours (by EUS or CT), or T1 tumours 

that are poorly differentiated, or T1 node positive, histologically proven 

invasive adenocarcinoma of the oesophagus or GOJ, technically resectable 

tumour which is sufficiently FDG avid on the initial PET staging scan. 

Status: Opened to accural 2009. 


An open-label, randomized phase II study comparing first-line treatment 

with dovitinib (TKI258) versus sorafenib in patients with advanced hepatocellular 

carcinoma. Presenting Author: Ann-Lii Cheng, National Taiwan 

University Hospital, Taipei, Taiwan 

Background: Hepatocellular carcinoma (HCC) is a highly vascularized tumor 

that may rely on tumor angiogenesis for growth, invasion, and metastasis. 

Inhibition of the vascular endothelial growth factor receptor (VEGFR) and 

platelet-derived growth factor receptor (PDGFR) pathways temporarily 

prevents HCC tumor progression. However, because the fibroblast growth 

factor receptor (FGFR) pathway can serve as an escape pathway for these 

tumors, simultaneous inhibition of FGFR may be required to provide a 

sustainable antitumor response. Dovitinib (TKI258) has been shown to be a 

potent oral tyrosine kinase inhibitor that inhibits multiple angiogenic 

factors, including FGFR, VEGFR, and PDGFR, with IC50 values of � 20 nM. 

Preclinical studies in HCC xenograft models have demonstrated that the 

antitumor effects of dovitinib are superior to those of the kinase inhibitor 

sorafenib, which is approved for use in advanced HCC. These data support 

additional testing of dovitinib in advanced HCC patients. Methods: This 

study (NCT01232296) is an open-label, randomized phase II trial being 

conducted at multiple centers in the Asia-Pacific region. Adult patients are 

eligible if they have advanced HCC (Barcelona Clinic Liver Cancer stage C) 

with Child-Pugh class A cirrhotic status. Patients must also have an Eastern 

Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 

cannot be eligible for (or have had disease progression after) surgical or 

locoregional therapies. Patients are randomized 1:1 to receive dovitinib 

(500 mg/day on a 5-days-on/2-days-off dosing schedule) or sorafenib (400 

mg twice daily). Patients will be treated until disease progression, unacceptable 

toxicity, death, or discontinuation for any other reason. No treatment 

crossover will be permitted. The primary end point of this trial is overall 

survival. Secondary end points include time to tumor progression, disease 

control rate, time to definitive deterioration in ECOG status, safety, and 

pharmacokinetics. The pharmacodynamic effects of dovitinib and sorafenib 

on plasma/serum biomarkers will also be explored. As of 30 January 2012, 

93 of the planned 150 patients have been enrolled. 



Sorafenib in combination with local microtherapy guided by gadolinium- 

EOB-DTPA enhanced MRI in patients with inoperable hepatocellular 

carcinoma (HCC) (SORAMIC). Presenting Author: Jens Ricke, Otto-von- 

Guericke-University Magdeburg, Magdeburg, Germany 

Background: HCC is a leading cause of cancer-related mortality in both men 

and women. It represents the fifth most common cancer worldwide with an 

increasing incidence. For the individual patient tumor stage at diagnosis 

(number and size of nodules, presence or absence of vascular invasion, 

presence or absence of extrahepatic spread), liver function and general 

health status are the principal prognostic factors. The clinical management 

of HCC requires a comprehensive, multidisciplinary approach. In early HCC 

curative treatment can be achieved by local ablation, resection or liver 

transplantation. In intermediate stages patients (pts) are offered locoregional 

treatment with palliative intent (transarterial chemoembolisation 

(TACE), Yttrium-90-radioembolisation (SIRT)). In advanced disease systemic 

therapy with sorafenib (sor) has the potential to prolong survival of 

pts and is standard of care in pts with preserved liver function. Studies on 

the combined use of locoregional and systemic therapy with their potential 

of a beneficial synergism are few and conducted in a small number of pts. 

Methods: This phase II-study is composed of three substudies with the 

following primary objectives: 1. In pts in whom local ablation is appropriate 

to determine if sor in combination with RFA prolongs the time-torecurrence 

in comparison with RFA plus placebo. Primary endpoint (PEP): 

time to recurrence, n � 290 pts 2. In pts in whom RFA is not appropriate 

(palliative treatment group) to determine if the combination of SIRT and sor 

improves the overall survival in comparison to sor alone. PEP: overall 

survival, n � 375 pts 3. To confirm in a 2-step procedure that Gd-EOB- 

DTPA enhanced MRI is non-inferior or superior compared with contrastenhanced 

multislice CT for stratification of pts to a palliative or a local 

ablation treatment strategy. PEP: correct stratification of pts to a palliative 

versus local ablation treatment strategy; n � 830 pts The trial has started 

in December 2010 as a multinational and multicentric study. 90 pts have 

been enrolled until January 31st 2012 with 51 pts randomized in the 

palliative arm and 14 pts treated in the curative arm. 


TACE 2: A randomized placebo-controlled, double-blinded, phase III trial 

evaluating sorafenib in combination with transarterial chemoembolisation 

(TACE) in patients with unresectable hepatocellular carcinoma (HCC). 

Presenting Author: Tim Meyer, University College London, London, United 

Kingdom 

Background: TACE is regarded as the standard of care for patients with 

intermediate stage HCC (BCLC B), while sorafenib (S) is the current 

standard for advanced disease (BCLC C). The combination of S with TACE 

for intermediate disease is rational since sorafenib inhibits the action of 

VEGF which may be induced by tumour hypoxia following TACE, and S also 

has direct anti-tumour effect. The combination has been shown to be safe 

in and active in phase I and II studies. Phase III trials are now required to 

determine whether TACE � S is superior to TACE alone in terms of survival. 

Methods: We are conducting a double blind multicentre trial to determine if 

the addition of S to TACE is superior to TACE alone. This is a UK NCRI trial 

sponsored by University College London (UCL) (EudraCT 2008-005073- 

36). Patients with intermediate stage HCC are randomised 1:1 to continuous 

S (400mg BD) or placebo (P). Key inclusion criteria include unresectable 

HCC confined to the liver, patent main portal vein, ECOG PS �1 and Child 

Pugh A liver score. After randomisation patients commence study drug and 

TACE is performed at 2-5 weeks using drug eluting beads loaded with 

150mg doxorubicin (Biocompatibles UK Ltd) according to a standard 

protocol. Further TACE is performed at the discretion of the investigator 

based on radiological response and patient tolerance. The primary outcome 

measure is progression free survival and central, external, real time 

radiology review is required to confirm progression. Secondary outcome 

measures are overall survival, time to progression, toxicity, disease control, 

quality of life and number of TACE procedures performed in 12 months. 

The target recruitment is 412 in order to detect a hazard ratio of 0.72 using 

a 2-sided level of significance of ��0.05 with 85% power. The trial was 

reviewed by the IDMC after the presentation of the SPACE trial (Lencioni et 

al J Clin Oncol 30, 2012). The IDMC concurred with the conclusion of the 

SPACE investigators that the combination is tolerated and results required 

confirmation in a phase III trial. Thus recruitment into the TACE2 trial will 

continue as planned. 


275s 


Randomized phase II trial of TACE plus everolimus as first-line therapy in 

localized unresectable hepatocellular carcinoma (HCC): The TRACER trial. 

Presenting Author: Ronnie Tung Ping Poon, Department of Surgery, 

University of Hong Kong, Hong Kong, China 

Background: Transcatheter Arterial Chemoembolization (TACE) has shown 

benefit in improving survival and is a widely used treatment for unresectable 

HCC. However, TACE induces hypoxia leading to up-regulation of 

HIF-1� and VEGF signaling, and tumor progression. Everolimus is an oral 

inhibitor of mammalian target of rapamycin (mTOR) and its downstream 

signaling including HIF-1�. Everolimus has also been shown to increase 

chemosensitivity of HCC in preclinical study (Cancer Lett; 273(2):201-9). 

Combining everolimus with TACE may delay tumor progression. TRACER 

(Tace with Rad001 in Asian Centers for Evaluation and Research) aims to 

evaluate the efficacy and safety of everolimus plus TACE in patients with 

localised unresectable HCC. Methods: TRACER is a multinational, randomized, 

double-blind, placebo-controlled phase II trial. Patients aged �18 

years newly diagnosed with localized unresectable Child A HCC; ECOG PS 

of �2; �1 unidimensional lesion measurable according to RECIST; and 

adequate bone marrow, liver, and renal function. Exclusion criteria include 

main portal vein invasion and/or extrahepatic spread; prior local or systemic 

treatment for HCC, or contraindications to TACE. Eligible patients who have 

successfully undergone the first TACE are randomized 1:1 to oral everolimus 

7.5mg or matching placebo daily. TACE is repeated every 10 weeks or 

so. A short everolimus dose interruption of 48 hours before and after each 

TACE has been designed to allow recovery from complications of TACE. For 

standardization, doxorubicin-eluting beads are being used in every TACE. 

Patients shall exit the trial upon tumor progression, unacceptable toxicity, 

death, or trial discontinuation. All endpoints will be assessed on an ITT 

basis. The primary endpoint is time to progression base on Modified 

RECIST Criteria. Secondary endpoints include objective response rate, 

overall survival, and incidence of extrahepatic spread, safety and exploratory 

biomarkers. An independent data monitoring committee has been 

established to safeguard the trial subjects. Estimated total enrollment is 

80, of which 12 subjects have been enrolled. (Clinical Trial Registry 

Number: NCT01379521.) 


A randomized phase III trial comparing sorafenib plus best supportive care 

(BSC) versus BSC alone in Child-Pugh B patients (pts) with advanced 

hepatocellular carcinoma (HCC): The BOOST study. Presenting Author: 

Bruno Daniele, G. Rummo Hospital, Benevento, Italy 

Background: The efficacy of sorafenib in pts with advanced HCC has been 

demonstrated in two randomized phase III trials (Llovet JM, NEJM 

2008;359:378; Cheng AL, Lancet Oncol 2009;10:25), both restricted to 

pts with well-preserved liver function (Child-Pugh A). Child-Pugh B (CPB) 

pts, that represent a relevant proportion of pts with advanced HCC in 

clinical practice, were not eligible. Despite this limitation, the marketing 

authorization of sorafenib by the main regulatory agencies was not 

restricted to Child A pts. CPB pts are different in terms of prognosis, and 

are potentially different in terms of balance between treatment efficacy and 

toxicity. Large observational studies [Marrero JA, ASCO 2011 (abstr 

4001)] are producing quite reassuring data about sorafenib tolerability in 

CPB pts, but the real efficacy of the drug in this setting remains 

substantially unknown, due to the lack of randomized trials. Methods: 

BOOST (B Child HCC patients – Optimization Of Sorafenib Treatment) is a 

randomized phase III trial comparing sorafenib � best supportive care 

(BSC) vs. BSC alone in CPB pts with advanced HCC. Pts are eligible if older 

than 18, with ECOG performance status 0-2. Pts assigned to experimental 

arm receive sorafenib 400 mg twice daily, with dose reductions and 

interruptions according to toxicity. Overall survival (OS) is the primary 

endpoint. In order to demonstrate a Hazard Ratio of death 0.70 in favor of 

sorafenib (2-month improvement in median OS, from 4.5 to 6.5 months), 

with 80% power and � 0.05, 320 pts have to be randomized, 160 per arm. 

The BOOST trial (ClinicalTrials.gov Identifier NCT01405573; Eudract 

number 2009-013870-42) is approved by the Ethical Committee of the 

National Cancer Institute, Napoli, Italy, as coordinating centre, and is 

currently under evaluation by several other Institutions. BOOST is a 

non-profit, academic trial. The trial has received a financial support by 

Italian Ministry of Health (FARM84SA2X), although the support is not 

enough to supply sorafenib to participating centers. BOOST is partially 

supported by AIRC (grant IG2009-9316). The study is open to all 

international Centers wishing to participate. 




Phase IIb randomized trial of JX-594, a targeted multimechanistic oncolytic 

vaccinia virus, plus best supportive care (BSC) versus BSC alone in 

patients with advanced hepatocellular carcinoma who have failed sorafenib 

treatment (TRAVERSE). Presenting Author: James M. Burke, Jennerex, 

Inc., San Francisco, CA 

Background: JX-594 is a first-in-class targeted oncolytic poxvirus designed 

to selectively replicate in and destroy cancer cells with epidermal growth 

factor receptor (EGFR)/ ras pathway activation. Direct oncolysis plus 

GM-CSF expression stimulates tumor vascular disruption and anti-tumor 

immunity (Nature Rev Cancer 2009). JX-594 was well-tolerated in Phase 1 

trials and was shown to replicate in metastatic tumors following intratumoral 

(IT) or intravenous (IV) administration (Lancet Oncol 2008 and 

Nature 2011). A randomized dose-finding Phase 2 trial has been completed 

with JX-594 in 30 patients with advanced HCC. Treatment with 

high-dose JX-594 was associated with prolonged survival vs low-dose 

JX-594 (median survival 14.1 mo vs 6.7 mo; Hazard Ratio 0.39, p�0.02) 

(AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b 

randomized, open-label, multi-center trial of JX-594 plus BSC versus BSC 

in patients with advanced HCC who have failed sorafenib treatment. 

Approximately 120 patients will be randomized 2:1 to experimental and 

control arm respectively. Randomization will be stratified by region (Asian 

vs non-Asian); sorafenib intolerant vs refractory; and presence vs absence 

of extra-hepatic disease. The primary objective is to determine overall 

survival in the 2 arms. Assuming a control median overall survival of 4.0 

months and a target hazard ratio of 0.57 (corresponding to an experimental 

arm median survival of 7.0 months), 73 events (deaths) will provide 70% 

power at 1-sided alpha � 0.05 to detect a difference in overall survival 

between the treatment groups using a stratified logrank test. Patients 

randomized to JX-594 will receive a dose of 109 plaque forming units (pfu) 

IV on Day 1 followed by five IT treatments between Day 8 and Week 18. 

Main inclusion criteria are advanced HCC having failed sorafenib (intolerance 

or radiographic progression during or � 3 months following last 

sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. 

Enrollment has begun on this study with clinical trial registry number 

of NCT01387555. 


The CLARINET study: Assessing the effect of lanreotide autogel on tumor 

progression-free survival in patients with nonfunctioning gastroenteropancreatic 

neuroendocrine tumors. Presenting Author: Patrick Delavault, Ipsen 

Innovation, Paris, France 

Background: Somatostatin analogs (SSAs) provide good symptom control in 

patients with neuroendrocine tumors (NETs). Clinical studies suggest SSAs 

also stabilize tumor growth. In a previous double-blind study (PROMID) in a 

mixed functioning and non-functioning gastroenteroNET population (n�85), 

octreotide LAR significantly increased time to tumor progression compared 

with placebo. The CLARINET study is being undertaken to explore the 

antiproliferative effects of SSAs in a more homogeneous population. 

Specifically, the CLARINET study is a double-blind, placebo-controlled 

trial assessing the effect of 120 mg of lanreotide Autogel (lanreotide Depot 

in the USA) on progression-free survival in patients with non-functioning 

gastroenteropancreatic NETs (GEP-NETs). Methods: CLARINET is a 96week, 

multinational study being conducted in collaboration with UKI NETS 

and ENETS in patients with well or moderately differentiated nonfunctioning 

GEP-NETs and a proliferation index (Ki67) of �10%. Patients 

are stratified by prior tumor progression status and presence/absence of 

previous therapies, and treated with lanreotide Autogel 120 mg or placebo. 

The primary endpoint is time to either disease progression (using Response 

Evaluation Criteria In Solid Tumors) or death. Two baseline computed 

tomography scans (�12 weeks apart) are being performed, followed by 

additional scans at intervals up to 96 weeks. Secondary endpoints include 

proportion of patients alive and without tumor progression at 48 and 96 

weeks, time to progression, overall survival, safety, quality of life, plasma 

chromogranin A levels, tumor markers, and pharmacokinetic parameters. 

The primary study population for the analysis will be the intention-to-treat 

population. Recruitment is now complete (n�204) and, thus far, the drug 

safety monitoring committee has identified no safety concerns. The trial is 

registered with ClinicalTrials.gov (NCT NCT00353496). 



Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib 

(SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma 

(RCC). Presenting Author: Naomi B. Haas, Abramson Cancer Center at the 


Background: We performed a cardiac analysis of E2805, a well population 

of pts with resected high risk RCC. The objectives were to determine if pts 

treated with SU or SO had clinically significant decreases in left ventricular 

(LV) ejection fraction (EF) and to describe the frequency of clinically 

significant heart failure (HF). We also report the frequency of other events 

including (un)stable angina or myocardial infarction. Methods: EF was 

measured by multiple gated acquisition scan (MUGA) at baseline, 3, 6, and 

12 months (mo), and end of treatment, if symptoms developed, and 3 mo 

after the last abnormal assessment. The primary cardiac endpoint was 

defined as an EF decline � the institutional lower limit of normal (ILN) that 

was a � 16% decline from baseline, and that occurred � 6 mo into 

therapy. Clinically significant HF was � Grade 3 LV systolic or diastolic 

dysfunction (severe symptoms with any activity or from drop in EF 

responsive (Grade 3) or refractory (Grade 4) to therapy. Late LVEF events 

were a drop in LVEF of � 16% occurring after 6 mo of therapy. Event rates 

on each treatment arm were calculated, with 90% exact binomial confidence 

intervals (CI). Results: Post-baseline MUGAs are available for 1589 

of 1943 total pts accrued. 1293 pts had MUGA assessment � 6 mo. 21 pts 

had primary events (Table). 71 pts had worst LVEF declines of �16% from 

baseline, including 52 of which occurred � 6 mo from baseline, with the 

majority not meeting full primary event criteria. There were 11 reported 

grade 3 LV systolic events (5 SU, 4 SO and 2 PLC). 8 pts had cardiac 

ischemia possibly or probably from agent. Only one grade 4 event followed a 

primary LVEF event. 4 of 7 pts who began treatment with LVEF �ILN had 

primary LVEF events. Conclusions: In detailed followup of SU and SO use, 

cardiac function in pts starting with normal EF, was not impaired 

significantly over placebo. Ischemic events were uncommon and not clearly 

associated with treatment. The data demonstrate that SU or SO for 

adjuvant therapy will likely not cause significant cardiac toxicity. 

Arm Pts assessed 1° Cardiac endpt Rate 90% CI 

SU 397 9 2.3% 1.2-3.9% 

SO 394 7 1.8% 0.8-3.3% 

PLC 502 5 1.0% 0.4-2.1% 

CRA4502 Oral Abstract Session, Sat, 3:00 PM-6:00 PM 

Patient preference between pazopanib (Paz) and sunitinib (Sun): Results of 

a randomized double-blind, placebo-controlled, cross-over study in patients 

with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 

01064310. Presenting Author: Bernard J. Escudier, Institut Gustave 









277s 


Tivozanib versus sorafenib as initial targeted therapy for patients with 

advanced renal cell carcinoma: Results from a phase III randomized, 

open-label, multicenter trial. Presenting Author: Robert John Motzer, 


Background: Tivozanib, a potent, selective, long half-life tyrosine kinase 

inhibitor targeting all three VEGF receptors, showed activity and tolerability 

in a Phase II trial (JCO 2011;29[18S]:4550). Methods: Patients (pts) with 

clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, 

RECIST-defined measurable disease, and Eastern Cooperative Oncology 

Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib 

(T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib 

(S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment 

naïve or received no more than 1 prior systemic therapy for metastatic 

disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. 

The primary endpoint was progression-free survival (PFS) per 

blinded, independent radiological review. 500 pts were to be enrolled to 

observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 

months (m) with 5% type I error (2-sided). Results: A total of 517 pts were 

randomized to T (n�260) or S (n�257). Demographics were well balanced 

between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p�0.035). 

Median PFS was 11.9 m for T vs 9.1 m for S (HR�0.797, 95% CI 

0.639–0.993; p�0.042). In the treatment-naïve stratum (70% of pts 

enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 

0.756, 95% CI 0.580–0.985; p�0.037). In all pts, objective response 

rate (ORR) for T was 33% vs 23% for S (p�0.014). The most common 

adverse event (AE; all grades/�grade 3) for T was hypertension (T: 

46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% 

vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 

32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 

10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. 

Overall survival data are not mature. Conclusions: Tivozanib demonstrated 

significant improvement in PFS and ORR compared with sorafenib as initial 

targeted treatment for advanced RCC. The safety profile of tivozanib is 

favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, 

and hand-foot syndrome. 


Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall 

efficacy and pharmacokinetic (PK) analyses from a randomized phase II 

study. Presenting Author: Brian I. Rini, Cleveland Clinic Taussig Cancer 

Institute, Cleveland, OH 

Background: Axitinib is a potent, selective, second-generation inhibitor of 

vascular endothelial growth factor receptors with efficacy in mRCC. Due to 

PK and pharmacodynamic variability, some patients have sub-optimal drug 

exposures at the standard 5-mg twice daily (BID) dose. Prior analyses 

indicated higher drug exposure enhanced efficacy; thus, dose titration 

based on individual tolerability may optimize exposure and improve 

outcomes. A randomized phase II trial evaluated the efficacy and safety of 

axitinib dose titration from 5 mg BID to a maximum of 10 mg BID in 

first-line mRCC. Methods: Patients with treatment-naïve mRCC received 

axitinib 5 mg BID for a 4-week lead-in period (cycle 1). Then, patients with 

2 consecutive weeks of blood pressure (BP) �150/90 mmHg, no axitinibrelated 

toxicities �grade 2, no dose reductions, and �2 antihypertensive 

medications were randomized in a double-blind fashion to axitinib 5 mg 

BID � dose titration with either axitinib (arm A) or placebo (arm B); those 

ineligible for randomization continued with same dose (arm C). Primary 

endpoint is objective response rate (ORR). Serial 6-hr PK sampling and 

24-hr ambulatory BP monitoring (ABPM) were performed on cycle 1 day 15 

in a subset of patients. Results: In all, 203 patients were accrued; 112 

randomized to arms A or B, and 91 in arm C. As of July 1, 2011, ORR (95% 

confidence interval [CI]) was 40.2% (31.0, 49.9) in A�B (blinded pooled 

analysis) and 56.0% (45.2, 66.4) in C. Median progression-free survival 

(mPFS) (95% CI) was 13.7 mo (9.2, not estimable [NE]) in A�B and 12.2 

mo (8.6, 16.7) in C. Patients with drug exposure above therapeutic 

threshold (AUC24 �300 ng·h/mL; n�27) on cycle 1 day 15 had longer 

mPFS and higher ORR than those with sub-therapeutic exposure (n�25) 

(mPFS [95% CI]: 13.9 mo [12.2, NE] vs 8.3 mo [5.5, NE]; ORR: 59% vs 

48%). Patients with mean increases of diastolic BP (�dBP) �15 mmHg 

(n�18) per ABPM had higher ORR than those with �dBP �15 mmHg 

(n�36) (61% vs 53%). Conclusions: Axitinib is effective in first-line 

treatment of mRCC, with high ORR and mPFS �1 yr. Preliminary results 

suggest therapeutic drug exposure and �dBP �15 mmHg on cycle 1 day 

15 may be associated with better outcomes. 


278s Genitourinary Cancer 


Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory 

renal cell carcinoma (RCC). Presenting Author: Toni K. Choueiri, Lank 

Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham 

and Women’s Hospital, Harvard Medical School, Boston, MA 

Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and 

VEGFR2 that is currently undergoing evaluation in several oncology 

indications. Renal cell carcinoma (RCC) was chosen as an indication in this 

drug-drug interaction (DDI) study based on involvement of the MET and 

VEGFR signaling pathways in this disease. The primary objective of this 

study is to determine the effect of cabo on single dose PK of the CYP2C8 

substrate rosiglitazone (rosi). Anti-tumor activity was also evaluated. 

Methods: Eligible pts were required to have RCC with clear cell components 

with metastases, Karnofsky performance status of �70 and measurable 

disease by RECIST. Pts needed to have experienced PD following standard 

therapies. Cabo was given daily at a dose of 140 mg free base (equivalent to 

175 mg salt form) starting at Day 2. Rosi (4 mg) was given Day 1 and Day 

22 to complete PK assessment for DDI. Cabo was continued until PD. On 

Day 57 and every 8 weeks thereafter subjects underwent tumor assessments 

by mRECIST. Results: Enrollment is complete at 25 RCC pts; 17/25 

(64%) RCC pts had received � 2 prior agents; 13/25 (52%) with at least 1 

VEGF pathway inhibitor and 1 mTOR inhibitor. The majority of pts were in 

an intermediate (21/25) or poor (3/25) prognostic category (1/25 in 

favorable category) per Heng et al (JCO, 2009, v27, p5794). ORR by 

mRECIST: 7/25 (28%). Disease control rate (PR � SD): 72% at 16 weeks; 

19/21 (90%) pts with �1 post-baseline scan experienced tumor regression 

(range: 4 - 63% reduction in measurements). 10/25 (36%) pts remain on 

cabo. Median PFS is 14.7 months (95% CI: 7.3, upper limit not reached) 

with a median follow-up of 7.7 months. AEs � Grade 3 severity: 

hypophosphatemia (36%), hyponatremia (20%), and fatigue (16%). PK 

data suggest that clinically relevant doses of cabo do not alter the Cmax or 

AUC of rosi, consistent with no inhibition of CYP2C8. Conclusions: Cabo 

0-24h 

demonstrates encouraging anti-tumor activity in heavily pretreated RCC pts 

with a toxicity profile similar to that of other VEGFR TKIs. PK data suggest 

no DDI between cabo and rosi (CYP2C8 substrate). 


Randomized phase II trial of gemcitabine/cisplatin (GC) with or without 

cetuximab (CET) in patients (pts) with advanced urothelial carcinoma (UC). 

Presenting Author: Petros Grivas, University of Michigan, Ann Arbor, MI 

Background: In UCpts EGFR over-expression correlates with high grade, 

stage, progression, short survival. Preclinical data show enhanced antitumor 

effect with CET � chemotherapy (CT). In several solid tumors CET 

added to CT improved survival. CET is hypothesized to improve UC 

response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, 

unresectable, locally recurrent or metastatic UC were stratified by disease 

state and randomized (1:2) to C 70mg/m2 d1, G 1000mg/m2 d1, d8, d15 

(Arm A) or same CT � CET 500mg/m2 d1, d15 (Arm B) q28 days. Due to 

high thromboembolic events rate in Arm B, G dose was reduced to 800 

mg/m2 . 6 GC cycles were planned. Arm A pts progressing after 2 GC cycles 

had CET added. Arm B pts were to continue on CET monotherapy after 4-6 

CT cycles. Imaging was q8 weeks. Primary endpoint: RECIST response rate 

(RR); secondary: safety, PFS, survival. Since E-cadherin impacts UC 

response to CET in vitro, serum level (sE-cad) was assessed at baseline, 

after 2 cycles, end of CT and at progression. With 1-stage design, assuming 

RR 50% (Arm A) and at least 65% (Arm B), planned sample size was 27/54 

pts. RR improvement of 5% has 81% probability if true difference is 15%. 

Results: 88 pts were eligible and randomized, Arm A/B: median age 66/61 

years; bladder primary 71.4%/77.2%; metastatic disease 92.9%/89.5%, 

median CT cycles number 6/5. 28 Arm B pts continued CET (median 3 

cycles, range 1-29); 1 Arm A pt had CET added. Most common G3/4 

adverse events (AEs) (Arm A, B): neutropenia (34.5%, 33.9%), anemia 

(10.3%, 5.1%), thrombocytopenia (27.6%, 22%), thromboembolism 

(6.9%, 18.6%), hyponatremia (3.5%, 10.2%); Arm B only: rash 28.8%, 

fatigue 11.9%, hypomagnesemia 11.9% and 2 deaths. 84 pts were 

response evaluable (see table below). sE-cad did not correlate with 

outcome. sE-cad increased in Arm A, but decreased in Arm B over time. 

Conclusions: GC/CET was feasible with no outcome improvement but higher 

AEs. sE-cad did not correlate with outcome. Decreased sE-cad in Arm B 

suggests potential EGFR-mediated E-cad proteolysis. 

Endpoint Arm A (N�28) Arm B (N�56) 

RR% (95%CI) 57 (37-76) 62.5 (49-75) 

Median PFS (months) (95%CI) 8.5 (6-10) 7.6 (6-10) 

Median survival (months) (95%CI) 14 (13-unreached) 14 (12-22) 


Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in 

patients with previously treated metastatic renal cell carcinoma (mRCC). 

Presenting Author: David F. McDermott, Beth Israel Deaconess Medical 


Background: BMS-936558 is a fully human monoclonal antibody that 

blocks the programmed death-1 co-inhibitory receptor (PD-1) expressed by 

activated T cells. In the initial portion of a phase I study, BMS-936558 

showed promising activity in patients (pts) with various solid tumors, 

including mRCC. We expanded accrual in order to better characterize 

antitumor and dose effects. Methods: RCC pts were treated with BMS- 

936558 administered IV Q2WK at 10 mg/kg initially, followed by additional 

pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/cycle) of 

treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. 

Results: Of 240 pts treated as of July 1 2011, 33 had mRCC and were 

treated at 1 (n�17) or 10 mg/kg (n�16). ECOG performance status was 

0/1 in 13/19 pts. The number of prior therapies was 1 (n�10), 2 (n�9), or 

�3 (n�14), and included prior immunotherapy (n�20) or antiangiogenic 

therapy (n�24); 31 pts had prior nephrectomy. Sites of metastatic disease 

included lymph node (n�26), liver (n�7), lung (n�28), and bone (n�10). 

Median duration of therapy was 19 wk (max 96 wk). The incidence of grade 

3-4 related AEs was 12% and included hypophosphatemia (6%), elevated 

ALT (3%), and cough (3%). Clinical activity was observed at both dose 

levels (Table). Some pts had a persistent reduction in overall tumor burden 

in the presence of new lesions and were not categorized as responders. 

Responses were noted in pts with visceral and bone metastases. Among the 

responders who were first treated �1 yr prior to data lock, 4 of 5 pts treated 

at 10 mg/kg had OR duration �1 yr, and 1 of 2 pts treated at 1 mg/kg was 

still on study with OR duration of 17.5 mo. Although the data for pts treated 

at 1mg/kg are not mature, the estimated progression-free survival (PFS) 

rate at 24 wk in pts receiving 10 mg/kg was 67% (Table). Conclusions: 

BMS-936558 is well tolerated and has durable clinical activity in pts with 

previously treated mRCC. Further development of BMS-936558 in pts with 

mRCC is ongoing. 

Dose 

(mg/kg) n a OR b uPR c RR d (%) 

PFS rate 

at 24 wk (%) 

1 16 3 2 31 TBD e 

10 16 5 - 31 67 

a Response evaluable pts. 

b CR or PR. 

c Unconfirmed PR. 

d Response rate [(OR � uPR) ÷ n]. 

e To be determined (follow up ongoing). 


Biomarker analysis and final results of INT70/09 phase II proof-of-concept 

study of pazopanib (PZP) in refractory urothelial cancer (UC). Presenting 

Author: Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, 

Milan, Italy 

Background: Discouraging results have been achieved with standard and 

novel compounds in refractory UC. The final results with biomarker analysis 

of INT70/09 trial with pazopanib are presented. Methods: Pts failing � 1 

chemotherapy regimen for metastatic disease underwent PZP 800 mg once 

daily until PD or unacceptable toxicity. CT scan and PET scan were planned 

at baseline and q4weeks thereafter. Independent review of all CT scans was 

made and � 5 RECIST CR�PR were required to conclude for activity 

according to Simon’s 2-stage design. 50 mL of EDTA blood samples were 

collected at baseline and q4wks in all pts to analyze plasma VEGF, 

sVEGFR-1,-2 and -3, c-Kit, IL-6, 8 and 12 by multiplex ELISA plates. 

Results: 41 pts were enrolled from 02/2010 to 07/2011. 15 pts (37%) had 

UC of the upper urinary tract. 20/41 pts were treated in 3rd line or beyond. 

19 pts (46%) were CDDP-refractory and 22 (54%) had hepatic metastases. 

27 (66%) had ECOG PS 1-2. 7 pts (17%) had a confirmed PR, 24 had a SD 

(76% clinical benefit). 20 pts (49%) had a confirmed necrotic evolution of 

metastases and/or a decreased SUV at PET consistent with PR. Median PFS 

and OS (95% CL) were 2.6 (1.7-3.7) and 4.7 mos (4.2-7.3), respectively 

but 7 pts (17%) had long-term cure for �10mos (4/7 beyond 2nd line). G3 

hypertension occurred in 2 pts, diarrhoea in 5, anemia and hand-foot 

syndrome in 3 pts each. Significant increase from T0 (baseline) to T1 

(�4wks) level was observed for VEGF (p�0.0001), IL6 (p�0.0129) and 

IL8 (p�0.0013) and decrease for VEGFR2 and c-Kit (p�0.0001 each). 

Rising IL8T1 levels significantly associated with RECIST progression at 

covariance analysis (p�0.0104). Elevated IL8T1 levels (IQ range, 

HR�2.11), liver mets (HR�2.33), PS (HR�3.73) and upper tract UC 

(HR�0.33) were significant variables for OS at multivariate Cox analysis. 

Conclusions: This is the 1st trial ever presented to meet the primary 

endpoint with a targeted drug in UC. A role for antiangiogenesis in UC has 

been set. Increasing levels of IL8 were associated with PD and worse 

outcome and may be included in a new prognostic model. Future investigation 

should aim at targeting IL8 to improve efficacy results by prolonging 

responses. 



Bilateral testicular cancer within two prospective, population-based SWENO- 

TECA protocols in clinical stage I nonseminoma. Presenting Author: 

Torgrim Tandstad, St. Olav’s Hospital, Trondheim, Norway 

Background: Contralateral tumor (CLT) occurs in 3.5-5% in men diagnosed 

with testicular cancer. The precursor lesion, ITGCNU, transforms into 

invasive germ cell cancer in 50-100%. Although radiotherapy eradicates 

ITGCNU effectively, mandatory biopsy of the contralateral testis to detect 

ITGCNU is controversial. Whether, adjuvant chemotherapy (ACT) reduces 

the incidence of bilateral cancer is also uncertain. Methods: 988 patients 

with clinical stage 1 nonseminoma were included in two prospective, 

population-based SWENOTECA protocols. Thirteen patients were excluded 

due to previous contralateral biopsy, synchronous bilateral cancer or 

protocol violations. Treatment was either adjuvant chemotherapy (n�490), 

or surveillance (n�485). Contralateral testicular biopsy was recommended, 

but performed only in 283 patients. In case of ITGCNU radiotherapy 

to 16 Gy was recommended.The estimated cumulative incidence of 

CLT was calculated using the Kaplan-Meier method. Results: With a median 

follow-up of 6.3 years, twenty-nine (3.9%) patients developed CLT including 

five patients with synchronous cancer. Biopsies showed ITGCNU in 

3.2%. The incidence of CLT was similar following ACT, 3.7 % (11/490), 

and surveillance, 3.1% (12/485), p�0.99. Biopsied patients had a risk of 

developing CLT of 4.3% (9/283), and seven patients treated for CIS never 

developed CLT. Unbiopsied patients had a risk of 3.0 % (14/668). The 

proportion of bilateral cancers was similar in biopsy negative patients 3.6% 

(7/274) and unbiopsied patients 3.0 % (14/668). Young age at orchiectomy 

was a significant risk factor for metachronous cancer, HR 0.94 (CI: 

0.89-0.99), p�0.04. All patients with ITGCNU were offered RT. One 

irradiated patient developed CLT cancer, and one developed CLT before RT 

was given. Conclusions: In this selected population ACT did not reduce the 

incidence of CLT. There was a high proportion of false negative biopsies, 

which might explain why biopsy negative patients had the same risk of CLT 

as patients not undergoing biopsy. Young patients had the highest risk of 

developing contralateral cancer, the risk of CLT decreased by 6% yearly. 


Effect of denosumab on prolonging bone-metastasis free survival (BMFS) 

in men with nonmetastatic castrate-resistant prostate cancer (CRPC) 

presenting with aggressive PSA kinetics. Presenting Author: Fred Saad, 

University of Montreal Hospital Center, Montreal, QC, Canada 

Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has 

been shown to prolong BMFS by a median 4.2 months and with a 15% risk 

reduction vs. placebo in men with non-metastatic CRPC and baseline PSA 

value � 8.0 ng/mL and/or PSA doubling time (PSADT) �10.0 months. To 

determine the efficacy of denosumab in men at greatest risk for bone 

metastases, we evaluated BMFS in a subset of men with PSADT �6 months 

(previously reported in Smith MR, et al: J Clin Oncol. 23:2918-2925, 

2005). Methods: 1,432 men with non-metastatic CRPC (baseline medians: 

PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were 

randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or 

placebo. The first patient enrolled February 2006; primary analysis cut-off 

was July 2010, when �660 men had developed bone metastasis or died. 

The primary endpoint was BMFS (time to first bone metastasis or death 

from any cause). BMFS results are presented for men with baseline PSADT 

�6 months. Results: Median BMFS in the placebo group of men with 

PSADT �6 months was 6.5 months shorter than for the placebo group in 

the full population (18.7 months vs. 25.2 months), indicating that these 

men are at particularly high risk. In this group of men with PSADT �6 

months, denosumab prolonged BMFS by a median of 7.2 months and with 

a 23% reduction in risk compared with placebo (Table). Conclusions: 

Patients with shortened PSADT are at higher risk of developing bone 

metastasis and denosumab is markedly effective at prolonging BMFS in 

this subset of patients. 

BMFS 

median 

(months) 

Population 

Sample 

size 

All patients D: 716 D: 29.5 

P: 716 P: 25.2 

PSADT


LBA4512 Oral Abstract Session, Tue, 9:45 AM-12:45 PM 

Updated analysis of the phase III, double-blind, randomized, multinational 

study of radium-223 chloride in castration-resistant prostate cancer 

(CRPC) patients with bone metastases (ALSYMPCA). Presenting Author: 

Chris Parker, The Royal Marsden NHS Foundation Trust, Sutton, United 

Kingdom 








A randomized phase II study of OGX-427 plus prednisone (P) versus P 

alone in patients (pts) with metastatic castration resistant prostate cancer 

(CRPC). Presenting Author: Kim N. Chi, British Columbia Cancer Agency, 


Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone 

protein that regulates cell signaling and survival pathways implicated 

in cancer progression. In prostate cancer models, Hsp27 complexes with 

androgen receptor (AR) and enhances transactivation of AR-regulated 

genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits 

Hsp27 expression with in vitro and in vivo efficacy and was well tolerated 

with single agent activity in phase I studies. Methods: Chemotherapy-naïve 

pts with no/minimal symptoms were randomized to receive OGX-427 600 

mg IV x 3 loading doses then 1000 mg IV weekly with P5mgPOBIDorP 

only. Primary endpoint was the proportion of pts progression free (PPF) at 

12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 � 5%, HA �20%, ��0.1, ��0.1) with 32 pts/arm provides 70% power to detect the 

difference at 0.10 1-sided significance. Secondary endpoints include PSA 

decline, measurable disease response, and circulating tumour cell (CTC) 

enumeration. Results: 38 pts have been enrolled; 1st stage of accrual 

completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to 

OGX-427�P, 15 to P), baseline median age was 71 years (53-89), ECOG 

PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in 

bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, 

and 93% had �5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions 

(chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts 

receiving OGX-427�P. One pt on OGX-427�P developed hemolytic 

uremic syndrome. A PSA decline of �50% occurred in 41% of pts on 

OGX-427�P, and 20% of pts treated with P. A measurable disease partial 

response was seen in 3/8 (38%) evaluable pts on OGX-427�P and 0/9 pts 

on P. CTC conversion from �5 to�5/7.5 ml occurred in 50% of pts on 

OGX-427�P and 31% treated with P. Thus far, in 26 evaluable pts the PPF 

at 12 weeks was 71% (95% CI: 42-92) in OGX-427�P treated pts and 

33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical 

evidence for the role of Hsp27 as a therapeutic target in prostate cancer 

and support continued evaluation of OGX-427 for pts with CRPC. Funded 

by a grant from the Terry Fox Research Institute. 


Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration 

resistant prostate cancer (mCRPC): Results from a phase II nonrandomized 

expansion cohort (NRE). Presenting Author: Matthew R. Smith, Massachusetts 


Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of 

bone scan resolution, pain relief and overall disease control, independent 

of PSA changes, were previously reported in a phase II study in mCRPC 

patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a 

novel primary endpoint of bone scan response based on computer-aided 

quantitative assessment of bone scan lesion area (BSLA) and a doublereader, 

independent, blinded review (Nucl Med Commun, in press). 

Methods: D-pretreated (�225 mg/m2 ) CRPC pts with bone metastasis were 

required to have progressed in soft-tissue or bone within 6 months of last 

dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6 

wks. Bone scan response (BSR) was defined by a �30% decline in BSLA. 

Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and 

interference with sleep and daily activity were prospectively assessed using 

an IVR system. Analgesic use was collected by diary. Bone turnover markers 

and CTCs were assessed. Results: 93 D-pretreated pts were enrolled (89 

evaluable with �6 wks f/u). Median age was 67, 46% received cabazitaxel 

and/or abiraterone, 32% had visceral disease, 51% had fatigue, and 18% 

had anemia. 44% had worst pain �4 of which 95% were taking narcotics. 

Median CTC count was 49 and 80% had �5. Median f/u was 125 days 

(range, 23-305). Of 85 pts evaluable for BSR, 51 (60%) had a PR, 24 

(28%) SD, 5 (6%) PD and 5 (6%) d/c’d prior to f/u scan. 21/30 pts (70%) 

had reduction of measurable disease.16/33 pts (49%) with BPI �4 and 

�12 wks f/u had pain reduction durable for �6 wks; 46% had decreased 

narcotic use, including 27% who discontinued use. Sleep and daily activity 

were improved in pts with pain relief. Among pts with elevated serum 

levels, 74%, 67% and 47% had declines on treatment of �30% in CTx, 

NTx and bALP, respectively. In 59 pts with CTCs �5, 92% had a decrease 

of �30% and 39% converted to �5 CTCs at weeks 6 or 12. 12% 

discontinued cabo due to AEs. Most common Gr 3/4 AEs were fatigue 

(19%), nausea (10%) and anemia (10%). Conclusions: Cabo treatment 

resulted in high rates of bone scan response, durable pain relief, and 

reductions in bone turnover markers and CTCs in D-pre-treated CRPC pts 

with bone metastases. 


Prostate-specific antigen decline (PSA) as a surrogate for overall survival 

(OS) in patients (pts) with metastatic castrate-resistant prostate cancer 

(mCRPC) who failed first-line chemotherapy. Presenting Author: Susan 

Halabi, Duke University Medical Center, Durham, NC 

Background: PSA kinetics, and more specifically a 30% decline in PSA 

following initiation of first-line chemotherapy with docetaxel, has been 

reported to be a surrogate endpoint for OS in mCRPC pts. The objective of 

this analysis was to evaluate PSA kinetics as surrogate endpoints for overall 

survival (OS) in patients who were receiving second line chemotherapy 

following progression after docetaxel front line therapy. Methods: Data from 

a phase III trial of 755 mCRPC pts randomized to treatment with 

cabazitaxel in combination with prednisone (C�P) every 3 weeks or 

mitoxantrone in combination with prednisone (M�P) were used. All pts 

were previously treated with a docetaxel-containing regimen. PSA decline 

(�30% and �50% ) and PSA velocity within the first three months of 

treatment were evaluated as potential surrogate endpoints for OS. The 

proportional hazards (PH) model was used to test for Prentice’s criteria and 

the proportion of treatment explained (PTE) was computed as a second test 

of surrogacy. PTE was defined as one minus the ratio of the treatment 

coefficient in the adjusted PH model (includes PSA decline or velocity) to 

the treatment coefficient in the unadjusted PH model. Results: Of 755 

men, 654 had sufficient PSA data to be included in the analysis. Treatment 

arm (C�P vs. M�P) was prognostic of OS with a hazard ratio (HR) of 0.65 

(95% CI�0.54-0.79, p�0.001). A 30% PSA decline within three months 

of treatment was associated with a HR of 0.46 (95% CI 0.37-0.57, 

p-value�0.001) for OS. After adjusting for treatment effect, the HR for 

30% PSA decline was 0.50 (95% CI� 0.40-0.62, p�0.001) but treatment 

arm remained statistically significant thus failing Prentice’s third 

criterion. The PTE for �30% decline in PSA within three months was 0.39 

(95% CI� 0.36-0.42) indicating a lack of surrogacy for OS. Similar results 

were observed for pts who experienced �50% decline in PSA and PSA 

velocity. Conclusions: Neither PSA decline (�30% and �50%) nor PSA 

velocity within the first three months of therapy are surrogate endpoints for 

OS in pts receiving second line chemotherapy. 



A validated whole-blood RNA transcript-based prognostic model that 

predicts survival in men with castration-resistant prostate cancer. Presenting 

Author: William K. Oh, Division of Hematology and Medical Oncology, 

The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 

Background: Survival for patients with castration resistant prostate cancer 

(CRPC) is highly variable. We developed a whole blood RNA transcriptbased 

model as a prognostic biomarker in CRPC. Methods: Peripheral blood 

was collected from 62 men with CRPC in a training set and from 140 

patients with CRPC in a validation set on various treatment regimens. A 

panel of 168 inflammation and prostate cancer-related genes was evaluated 

using optimized quantitative polymerase chain reaction to assess 

biomarkers predictive of survival. A 2-class proportional hazard model was 

developed from time of CRPC diagnosis and time of blood draw. Results: A 

6-gene model (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, 

CDKN1A) separated CRPC patients into two classes: higher risk men who 

died within 2·2 years of developing CRPC and lower risk men who lived over 

2·2 years (log rank p�0·00083). The results were similar regardless of the 

survival time definition (CRPC diagnosis versus blood draw) and did not 

depend on whether they received chemotherapy in addition to hormone 

treatment. The model successfully validated in an independent cohort of 

men with CRPC (p� 0.000001·7). Conclusions: Transcriptional profiling of 

whole blood yields critical prognostic information in men with CRPC 

independent of treatment. The 6-gene model suggests possible dysregulation 

of the immune system, a finding that warrants further study. This 

model may play an important role in patient counseling, in patient 

stratification for clinical trials, and potentially as a predictive biomarker for 

immune-based therapeutic strategies. 

LBA4518 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM 

Interim analysis (IA) results of COU-AA-302, a randomized, phase III study 

of abiraterone acetate in chemotherapy-naive patients (pts) with metastatic 

castration-resistant prostate cancer (mCRPC). Presenting Author: Charles 

J. Ryan, University of California, San Francisco, San Francisco, CA 








281s 


18F-16�-fluoro-5�-dihydrotestosterone (FDHT) PET as a prognostic biomarker 

for survival in patients with metastatic castrate-resistant prostate 

cancer (mCRPC). Presenting Author: Karen A. Autio, Memorial Sloan- 


Background: At present there is no imaging biomarker for patients with 

mCRPC as the disease primarily metastasizes to bone, which is difficult to 

visualize and quantify using standard techniques. We have conducted 

clinical trials in which patients with progressive mCRPC are scanned using 

FDG-PET to examine glucose metabolism, and FDHT-PET. FDHT is a novel 

tracer and structural analog of dihydrotestosterone that binds to the 

androgen receptor (AR) to demonstrate AR overexpression, a key biologic 

feature of mCRPC. We previously reported an association between baseline 

FDG-PET and overall survival in mCRPC. We now present the prognostic 

utility of baseline FDHT-PET. Methods: We prospectively scanned mCRPC 

patients with FDG and FDHT-PET prior to a change in therapy as part of 

imaging clinical trials. PET results were represented as the hottest lesion 

(SUVmax), or average of the five hottest lesions (SUVmaxavg). Five lesions 

per patient were recorded. If less than 5 lesions were captured, a value of 1 

was imputed for the remaining lesions. Clinical and lab parameters were 

collected. Univariate analysis was performed on PET, clinical and lab 

variables for association with overall survival (OS). Multivariate models of 

prognostic factors were constructed. Results: 170 mCRPC patients were 

imaged with FDG and 116 also had FDHT-PET at baseline. Median survival 

was 21.2 months (95%CI: 19.1-24.0). On univariate analysis, FDHTmax, 

FDHTmaxavg, FDGmaxavg, PSA, hemoglobin, alkaline phosphatase, and 

LDH were associated with OS. FDHTmax and FDHTmaxavg were significantly 

correlated with one another. In a multivariate model, FDHTmaxavg 

and LDH were prognostic of survival. In a separate model assessing FDG, 

FDGmaxavg and LDH were also prognostic. Conclusions: FDHT not only 

allows for a visual assessment of the AR axis in prostate cancer, but appears 

to associate with overall survival in mCRPC. Increased AR activity as 

measured by FDHT SUVmaxavg held greater prognostic value than PSA or 

Gleason score. FDHT is also being evaluated as a clinical response indicator 

and pharmacodynamic measure with AR directed therapies. 

4519^ Clinical Science Symposium, Sat, 8:00 AM-9:30 AM 

Primary, secondary, and quality-of-life endpoint results from the phase III 

AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. 

Presenting Author: Johann Sebastian De Bono, The Institute for Cancer 

Research, London, United Kingdom 

Background: MDV3100, a novel androgen receptor signaling inhibitor 

(ARSI), inhibits: 1) binding of androgens to AR, 2) AR nuclear translocation, 

and 3) association of AR with DNA. MDV3100 was active in a phase 

I-II trial enrolling pre- and post-docetaxel castration-resistant prostate 

cancer (CRPC) patients. The AFFIRM trial evaluated whether MDV3100 

could provide benefit to men with post-docetaxel CRPC. Methods: In this 

double-blind, multinational phase III study, patients who had received 

docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 

mg/day or placebo. Treatment with corticosteroids was allowed but not 

required. Patients were stratified by baseline ECOG and mean brief pain 

inventory score. The primary endpoint was overall survival (OS). Other 

efficacy endpoints included radiographic progression-free survival (rPFS), 

time to PSA progression (TTPP), soft tissue objective response (PR�CR), 

PSA response, and quality of life (QoL) response (FACT-P). Results: 800 

patients were randomized to MDV3100 and 399 to placebo with respective 

median treatment durations of 8.3 and 3.0 months.Based on a planned 

interim analysis at 520 deaths, the Independent Data Monitoring Committee 

recommended the study be unblinded and placebo patients offered 

MDV3100. Efficacy results are presented (Table). The most common 

MDV3100 events with an incidence higher than placebo were fatigue (34% 

vs 29%), diarrhea (21% vs 18%), and hot flush (20% vs 10%). Grade �3 

events of interest were cardiac disorders (0.9% MDV3100 vs 2% placebo), 

fatigue (6% MDV3100 vs 7% placebo), seizure (0.6% MDV3100 vs. 0% 

placebo), and LFT abnormalities (0.4% MDV3100 vs 0.8% placebo). 

Conclusions: MDV3100, a novel ARSI, is well-tolerated and significantly 

prolongs OS, slows disease progression, and improves QoL in men with 

post-docetaxel CRPC. 

MDV3100 Placebo HR (95% CI) P value 

OS, median 18.4 months 13.6 months 0.631 (0.529, 0.752) �0.0001 

rPFS, median 8.3 months 2.9 months 0.404 (0.350, 0.466) �0.0001 

TTPP, median 8.3 months 3.0 months 0.248 (0.204, 0.303) �0.0001 

PR�CR 25.1%� 3.8% 2.9%�1.0% - �0.0001 

PSA response 54.0% 1.5% - �0.0001 

QoL response 43.3% 17.8% - �0.0001 




Neoadjuvant androgen pathway suppression prior to prostatectomy. Presenting 

Author: Elahe A. Mostaghel, Fred Hutchinson Cancer Research Center, 

Seattle, WA 

Background: Optimizing tissue androgen suppression may provide better 

local and systemic control of prostate cancer (PCa). Standard androgen 

deprivation therapy (ADT) has limited effect on tissue androgens which 

remain in a range which supports tumor survival. We determined whether 

targeting androgen metabolism using CYP17 and 5a-reductase (SRD5A) 

inhibitors would more effectively suppress tissue androgens and tumor 

volume. Methods: Open label, multicenter neoadjuvant study in men with 

localized PCa treated for 3 months prior to prostatectomy with zoladex and 

1) avodart 3.5 mg QD; 2) avodart and casodex 50 mg QD; or 3) casodex, 

avodart and ketoconazole 200 mg TID. Serum and tissue androgens were 

measured by LC/MS/MS. Data were compared to men treated with standard 

ADT (LHRH agonist plus Casodex), and untreated prostatectomy tissue. 

The primary outcome measure was suppression of tissue dihydrotestosterone 

(DHT). Results: 35 men with intermediate/high risk PCa were enrolled. 

Tissue DHT was suppressed 30 fold (� 95%) in all groups vs. LHRH 

agonist/Casodex (0.92 � 0.20 pg/mg vs. 0.03� 0.03 for all groups 

combined, p�0.0001). Tissue testosterone was 3-4 fold higher (consistent 

with SRD5A inhibition) in all treatment groups vs. LHRH agonist/Casodex 

(0.33 vs. 0.07 pg/mg, p � 0.05). Differences in DHT/T between groups 1 

through 3 were not statistically significant. There was no correlation 

between tissue and serum androgens, or tissue androgen and tumor volume 

(p� 0.05). In subset analysis, total serum DHEA declined significantly in 

group 3, with free DHEA unchanged, suggesting differential effect on free 

and total DHEA. Pathologic complete response (CR) was seen in 2 men, 

and an additional 8 men had �0.2 cc of tumor, with the largest number of 

CR or near CR in the cohort treated with ADT, CYP17 and SRD5A inhibitor, 

4 of 12 men (33%). Due to small cohort size, differences were not 

statistically significant. Conclusions: Addition of high dose SRD5A inhibition 

(with and without CYP17 inhibition) achieves prostate DHT levels 30 

fold below standard ADT. In this relatively high risk population, CR or near 

CR was seen in 10 of 35 men receiving protocol therapy. Further 

suppressing the androgen receptor signaling axis may provide better local 

and systemic control of PCa. 


12:00 PM-1:00 PM 

Time from prior chemotherapy (TFPC) as a prognostic factor in advanced 

urothelial carcinoma (UC) receiving second-line systemic therapy. Presenting 

Author: Gregory R. Pond, McMaster University, Hamilton, ON, Canada 

Background: Prognostic factors for overall survival (OS) in patients receiving 

second-line chemotherapy for advanced platinum-pretreated UC include 

ECOG performance status (PS) �0, hemoglobin (Hb) �10g/dL and the 

presence of liver metastasis (LM) (Bellmunt J, J Clin Oncol 2010). We 

hypothesized that time from prior chemotherapy (TFPC) independently 

impacts OS. Methods: Of 11 available phase II trials evaluating second-line 

therapy for advanced UC (n�698), 6 trials with available baseline Hb, PS 

and LM were utilized (n�534). The trials evaluated vinflunine (2 trials), 

docetaxel plus vandetanib or placebo, paclitaxel-gemcitabine, nanoparticlealbumin-bound 

paclitaxel and paclitaxel-cetuximab. The Kaplan-Meier 

method was used to estimate OS from date of starting second-line therapy. 

Cox proportional hazards regression stratified for trial was used to evaluate 

the prognostic effect of factors on OS. TFPC was evaluated as a continuous 

variable, and based on cutpoints of 3, 6, 9 and 12 months (mo) from prior 

chemotherapy to first study treatment. The choice of optimal cutpoint for 

TFPC was determined by the maximum likelihood ratio �2 statistic. Results: 

Overall, 513 patients were evaluable. 64.1% received prior chemotherapy 

for metastatic disease. Median OS was 6.8 mo (95% CI: 6.1 to 7.4); range 

was 0 to 84.2 mo. Median OS was 5.2, 7.1, 8.8, 7.6 and 10.6 mo 

respectively for TFPC �3 (n�181), 3 to �6 (n�133), 6 to �9 (n�77), 9 

to �12 (n�45) and �12 (n�77) mo, respectively. Shorter TFPC was 

independently prognostic for decreased survival. The optimal cutpoint for 

TFPC was �3 mo, but no well-defined plateau was observed. PS�0 

(HR�1.72, p�0.001), LM (HR�1.41, p�0.002), Hb �10 g/dl (HR�1.59, 

p�0.001) and TFPC �3 mo (HR�1.67, p�0.001) were significantly 

prognostic in the multivariate model. Timing of prior chemotherapy 

(metastatic disease vs. perioperative) was not prognostic. Conclusions: A 

shorter duration of TFPC exhibited a significant negative prognostic impact 

on OS independent of known prognostic factors in patients receiving 

second-line therapy for advanced UC. If externally validated, TFPC should 

be a stratification factor in trials of second-line therapy for advanced UC. 


Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate 

(LHRHa) on PSA, pathological complete response (pCR), and near pCR in 

localized high-risk prostate cancer (LHRPC): Results of a randomized 

phase II study. Presenting Author: Mary-Ellen Taplin, Dana-Farber Cancer 


Background: LHRPC is infrequently cured with prostatectomy (RP). To date 

neoadjuvant androgen deprivation therapy (ADT) has not improved outcomes 

and residual intra-prostatic androgens remain. AA lowers serum 

testosterone (T) and DHT to � 1 ng/dL and has improved survival in 

advanced PC. Methods: We conducted a neoadjuvant, phase II trial of 

AA/LHRHa in LHRPC. The primary aim was to evaluate intra-prostatic 

T/DHT with LHRHa vs LHRHa/AA. We report secondary endpoints of PSA, 

pCR and near pCR ([� 5mm residual tumor]) and safety. Eligibility: � 3 

positive biopsies and either Gleason � 7(4�3), T3, PSA � 20 ng/mL or 

PSA velocity � 2 ng/mL/year. For the first 12 wks men were randomized to 

LHRHa or LHRHa/AA/prednisone (P) 5mg qd. After 12 wks, a prostate 

biopsy was done to measure T/DHT. Men received 12 more wks of 

LHRHa/AA/P followed by RP. Results: 58 men enrolled: 28 to initial LHRHa 

and 30 to initial AA/LHRHa. 2 withdrew prior to RP (1/group). Median age 

was 58 (50-75). pCR/near pCR was 14/56 (25%). Grade 3 AEs included 

elevated AST/ALT 5/58 (9%) and hypokalemia 3/58 (5%). No grade 4 

mineralocorticoid-related AEs were observed. Conclusions: Neoadjuvant 

ADT with AA was well tolerated in LHRPC. PSA (�0.2) declines were high 

and achieved earlier on AA/LHRHa compared to LHRHa. The pCR/near pCR 

rates were higher for 24 wks AA (34%) than 12 wks AA (15%). No new 

safety signals were seen with AA used with P 5 mg. These results support 

further evaluation of aggressive ADT as neoadjuvant/adjuvant therapy for 

LHRPC. 

Baseline 

12 wks AA/ 

24 wks LHRHa 

n� 28 

24 wks AA/ 

24 wks LHRHa 

n�30 

Gleason: 7/8/9/10 8/10/10/0 9/7/11/3 

PSA (median) 10.6 6.8 

PSA: < 10/10-20/> 20 12/9/7 20/6/4 

Elevated PSA velocity 6 3 

Stage T3 8 6 

Results n�27 n�29 

PSA: wk 4/8/12/16/20/24 4.34/1.35/1.06/0.20/0.09/0.06 0.65/0.17/0.10/0.09/0.06/0.05 

12 wk nadir PSA < 0.2 1/27 (4%) 26/29 (90%) p�0.0001 

24 wk nadir PSA < 0.2 23/27 (85%) 25/29 (86%) p�0.9131 

pCR 1/27 (4%) 3/29 (10%) p�0.3349 

Near pCR (tumor < 5mm) 3/27 (11%) 7/29 (24%) p�0.2034 

Total pCR/near pCR 4/27 (15%) 10/29 (34%) p�0.0894 

pT3 16/27 14/29 

Positive nodes 3/27 (11%) 7/29 (24%) 

Positive margins 5/27 (19%) 5/29 (17%) 


12:00 PM-1:00 PM 

Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk 

urothelial cancer: Results from a phase II trial at the University of Texas 

M. D. Anderson Cancer Center. Presenting Author: Arlene O. Siefker- 

Radtke, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: DD-MVAC has shown an improved 5-year survival in metastatic 

urothelial cancer; however, there is no prospective data on its use in the 

neoadjuvant setting. Previous work suggested that over-expression of VEGF 

was associated with a high risk of relapse in our neoadjuvant patients, 

leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy 

may improve patient outcomes. Methods: Between 8/07 and 

12/10, 60 patients with urothelial carcinoma of the bladder or upper tract 

tumor were enrolled on a prospective phase II clinical trial. Eligibility 

requirements included at least one of the following: 3-D mass on EUA 

(cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a 

diverticula, and for upper tract tumors a high grade tumor or radiographically 

measurable sessile mass. The primary endpoint was pathologic 

down-staging to ��pT1N0M0. Results: Forty-four patients with bladder/ 

urethral tumors and 16 patients with upper tract tumors were enrolled. 

Pathologic down-staging to �� pT1N0M0 occurred in 53% of patients 

overall (bladder/urethra 45%, upper tract 75%), and to �� pT0N0M0 in 

38% overall (bladder/urethra 39%, upper tract 38%). At a median 

follow-up of 26 months, the 2-year OS and DSS was 78% and 82%, 

respectively (bladder 2-yr OS and DSS 75%, 78%; upper tract 93%, 93%). 

The median OS and DSS have not yet been reached. The most common 

grade 3 or greater toxicity was neutropenia in 27% of patients, followed by 

fatigue in 10%. The following grade 3 toxicities were observed in � 10% of 

patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. 

One patient experienced cardiac ischemia. Conclusions: Neoadjuvant 

chemotherapy leads to pathologic down-staging in 45% of patients 

with bladder cancer. DD-MVAC appears an acceptable alternative to 

traditional M-VAC in the neoadjuvant setting. Although bevacizumab did 

not impact down-staging based upon historical expectations, determining 

the effect on recurrence requires longer follow-up. 



12:00 PM-1:00 PM 

Prognostic model for overall survival in patients with metastatic urothelial 

cancer treated with cisplatin-based chemotherapy. Presenting Author: 

Matt D. Galsky, Division of Hematology and Medical Oncology, The Tisch 

Cancer Institute, Mount Sinai School of Medicine, New York, NY 

Background: Patients with metastatic urothelial cancer (UC) treated with 

cisplatin-based chemotherapy have heterogeneous clinical outcomes. Pretreatment 

prognostic variables have previously been defined (Bajorin, JCO, 

1999) but have not been extensively validated or expanded upon. Methods: 

Pretreatment clinical parameters from 400 international patients with 

metastatic UC treated on phase II and III first-line clinical trials with 

cisplatin-based chemotherapy from 11/1997 to 10/2011 were evaluated 

(cisplatin � gemcitabine �/- paclitaxel or �/- antiangiogenic agent � 235; 

MVAC � 83; cisplatin � 5FU �/- paclitaxel � 79). Parameters were 

subjected to multivariable regression analysis to determine which patient 

characteristics had independent prognostic significance for survival. Results: 

Complete data were available on 361 patients, median survival was 13.9 

months (95% CI 12.4, 16.5); 247 have died. In multivariable analysis, 

ECOG performance status (�1), visceral metastases (lung, liver, bone), and 

white blood count (WBC, continuous variable) were significantly associated 

with poor survival (P � .05), whereas perioperative chemotherapy, hemoglobin, 

platelets, creatinine clearance, site of primary tumor, and number of 

metastatic sites were not (Table). The cut-off for WBC was established at 

10. Median survival times for patients with 0, 1, 2, or 3 risk factors were 

26.9, 16.8, 12.8, 9.7 months (log rank p value � 0.0001). When 

subjected to internal validation, the model achieved a bootstrap-corrected 

c-index of 0.60. External validation is ongoing utilizing data from a phase 

III trial (n�186) of MVAC versus docetaxel plus cisplatin. Conclusions: A 

model derived from pretreatment parameters from an international cohort 

of patients was constructed that confirmed, and expanded upon, known 

prognostic factors in metastatic UC. This model may be useful for patient 

counseling and clinical trial design. Better predictions require the identification 

of additional factors that affect survival. 

Prognostic model for overall survival. 

Parameter Hazard ratio 95% CI P 

WBC > 10 1.66 1.27, 2.18 0.0002 

Visceral metastases 1.49 1.15, 1.93 0.0024 

ECOG > 1 1.52 1.16, 2.00 0.0028 


12:00 PM-1:00 PM 

Neoadjuvant accelerated MVAC (AMVAC) in patients with muscle invasive 

bladder cancer: Results of a multicenter phase II study. Presenting Author: 

Elizabeth R. Plimack, Fox Chase Cancer Center, Philadelphia, PA 

Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin 

(MVAC) demonstrates a survival benefit in the neoadjuvant setting for 

patients (pts) with muscle invasive bladder cancer (MIBC). Compared with 

standard MVAC, AMVAC yielded higher response rates with less toxicity in 

the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with 

CrCl ��50 and adequate hepatic and marrow function were eligible. Pts 

received 3 cycles of AMVAC (methotrexate 30 mg/m2 , vinblastine 3 mg/m2 , 

doxorubicin 30 mg/m2 , cisplatin 70mg/m2 ) on day 1, with pegfilgrastim 6 

mg day 2 or 3, every 2 weeks. Pts with CrCl � 60 could receive cisplatin 

split over 2 days. Radical cystectomy (RC) with lymph node dissection was 

performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint 

was pathologic complete response (pCR) rate. Results: Accrual is complete 

with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month 

period. Median age 64 (range 45-83). Three withdrew from study early and 

are not evaluable for response (2 physician discretion, 1 withdrawal of 

consent). An additional 8 are currently receiving treatment on study with 

toxicity and response data pending. Of the 33 evaluable pts for whom final 

data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts 

received � 3 cycles due to grade 3 fatigue (1), low platelets (1), and 

disease progression precluding RC (1). 32/33 pts underwent RC, all within 

8 weeks of last chemotherapy. Median time from start of chemotherapy to 

RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI, 

22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non 

muscle invasive disease. For the intent to treat cohort (n�36) 8 pts had 

grade 3-4 AMVAC related adverse events, the most common being anemia 

(3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95% 

CI, 20.4-51.8%). All pts will have completed study treatment by April 

2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is 

well tolerated and preliminary results show a pCR rate similar to that 

reported for standard 12-week MVAC, suggesting that AMVAC for three 

cycles (6 weeks) is a safe and efficient alternative. 


283s 


12:00 PM-1:00 PM 

Correlation of progression-free survival at 6 months (PFS6) with overall 

survival at 12 months (OS12) in an analysis of 10 trials of second-line 

therapy for advanced urothelial carcinoma (UC). Presenting Author: Benjamin 

Maughan, University of Utah, Salt Lake City, UT 

Background: Second-line therapy of advanced UC is a significant unmet 

need. While phase II trials have relied on response rate (RR) as a primary 

endpoint, response may not be suitable for assessing cytostatic agents and 

does not capture duration of benefit. We hypothesized that PFS6 correlates 

with OS12 and may be a robust intermediate endpoint for phase II trials. 

Methods: Ten trials with individual patient progression and survival data 

(n�646) evaluating chemotherapy and/or biologics following chemotherapy 

were combined. Progression was defined as tumor progression 

(RECIST 1.0 in 9 trials, WHO in 1 trial), or death from any cause. 

Unadjusted and adjusted binomial confidence intervals for PFS6, OS12 

and response were reported, with adjustment for variability between trials 

using random effects models. The relationship between PFS6 and OS12 

was assessed at the trial level using Pearson correlation and weighted linear 

regression with larger studies having more influence. The relationship 

between PFS6 and OS12 at the individual level was assessed using 

Pearson chi-square test with Yates continuity correction. Statistical analyses 

employed “R” statistical computing software, version 2.8.0. Results: 

59% had visceral metastasis and performance status was 0, 1 and 2 in 50, 

39 and 8%, respectively. Median age was 65 years (31-88) and 77% were 

male. PFS6 was 22% (95% CI: 17-24%), and adjusted PFS6 was 23% 

(95% CI: 15-34%). The OS12 was 20% (95% CI: 17-24%), and adjusted 

OS12 was 21% (95% CI: 15-29%). The Pearson correlation between trial 

level PFS6 and OS12 was 0.66 (p � 0.037). The individual level 

agreement between PFS6 and OS12 was seen in 82% of patients (kappa � 

0.45). Among 560 patients evaluable for response and OS, the RR was 

22% (95% CI: 18-25%) and adjusted RR was 21% (95% CI: 13-32%). 

Trial level Pearson correlation between response and OS12 was 0.37 (p � 

0.30), and individual level agreement was seen in 78% (kappa�0.36). 

Conclusions: PFS6 is associated with OS12 at the trial and individual levels 

in patients receiving second-line therapy for advanced UC. The association 

of response with OS was suboptimal. Validation of PFS6 is warranted. 


12:00 PM-1:00 PM 

Defining the genetic basis of everolimus sensitivity in metastatic bladder 

cancer (MBC) by whole-genome sequencing (WGS). Presenting Author: 

Gopa Iyer, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: MBC is rarely cured with standard chemotherapy and novel 

agents are clearly needed. A phase II trial of everolimus in MBC resulted in 

1 near-complete response (CR), 1 partial response, and 3 minor responses. 

We used WGS and a Next Generation exon capture assay to identify the 

genetic aberrations underlying treatment response. Methods: In the near-CR 

case, tumor and peripheral blood DNA was subjected to WGS (Illumina) 

using 2x100 bp paired-end libraries for 40X haploid coverage. Raw 

sequence data was aligned to hg19 and somatic point mutation detection 

was performed. Tumor DNA from 13 additional patients on the trial was 

analyzed using an exon capture sequencing assay. Results: 184 exonic 

somatic mutations were identified in the everolimus complete responder by 

WGS, including a2bpframeshift truncation in TSC1 and a nonsense 

mutation in NF2. Sanger sequencing of an additional 96 high-grade 

bladder tumors found 5 (6.2%) tumors containing TSC1 alterations and no 

NF2 mutations. Of the 13 patients on the trial who underwent targeted 

exon sequencing, 3 (23%) possessed nonsense TSC1 mutations and 2 had 

minor treatment responses (17% and 24% tumor regression). 1 patient 

with a 7% tumor regression had a somatic missense TSC1 variant. 8 (89%) 

of 9 patients with tumor progression as best response were TSC1 wild-type. 

Patients with TSC1-mutant tumors remained on drug for longer duration 

(7.7 vs. 2 months, p�0.004, Wilcoxon rank sum test). Conclusions: 

Everolimus is an active agent in MBC in patients with TSC1 mutant tumors. 

The pattern of co-mutation in patients with TSC1 mutant tumors is complex 

and combination therapies will likely be required to achieve durable 

responses in most patients. Our results also highlight the potential utility of 

WGS in identifying novel predictors of response to targeted inhibitors. 




12:00 PM-1:00 PM 

Association of long-term exposure to circulating platinum with adverse late 

effects in testicular cancer survivors. Presenting Author: Hink Boer, Department 

of Medical Oncology, University Medical Center Groningen, Groningen, Netherlands 

Background: Successful platinum(Pt)-based chemotherapy for testicular cancer 

(TC) comes at the price of late cardiovascular morbidity and neurotoxicity. 

Damage induced by circulating Pt could be an etiological mechanism. We 

investigated the relation between circulating Pt and late effects. Methods: In 96 

consecutive TC patients (med age 29 [17-53] at chemotherapy), 3 serum 

samples and a 24h-urine sample were collected on several time-points med 5 yrs 

(1-13) after treatment. Pt concentrations ([Pt]) were measured with a sensitive 

voltammetric method (Lancet 2000, 355:1075). Measured [Pt] combined with 

cisplatin dose, age, weight and height were analyzed simultaneously to construct 

a population pharmacokinetic (PK) model using NONMEM. Based on the PK 

parameters of each patient, individual [Pt] at 1, 3, 5, 10 yrs after start and AUC 

were calculated. Cardiovascular status, paresthesia and markers of vascular 

damage were assessed after a med follow-up (FU) of 9 yrs (3-15). Results: Decay 

of [Pt] was best described by a two compartment model. Mean terminal T1/2 was 

3.7 (�0.3) yrs. At all time-points [Pt] correlated with cisplatin dose and renal 

function during treatment. [Pt] at 3 yrs correlated with systolic blood pressure 

(BP) (r�.32, p�0.01) and creatinine clearance (CRCL) (r�-.25, p�0.02) at FU. 

Patients with increased BP had higher Pt AUCs than patients with normal BP 

(table). Pt AUCs were higher in patients with paresthesia (table). Conclusions: 

Known late effects of cisplatin-based chemotherapy such as hypertension and 

paresthesia are related to higher circulating [Pt]. Long-term exposure to Pt is 

involved in healthy tissue damage in TC survivors. 

[Pt] pg/g serum (mean�SD) 

AUC 1-5 yrs 

(pg/g •day)•103 n 3 yrs 5 yrs 

Cisplatin dose 

800mg 

43 

.048* 

53 

379 �118 

.028 

433 �140 

189 �55 

.013 

218 �66 

960 �250 

1109 �316 

CRCL (mL/min) 

>120 


12:00 PM-1:00 PM 

Serum tumor marker (STM) decline rates during high-dose chemotherapy 

(HDCT) to predict outcome for germ cell tumor (GCT) patients (pts). 

Presenting Author: Darren Richard Feldman, Memorial Sloan-Kettering 


Background: STM decline rates predict outcome for GCT pts during 1st-line conventional-dose chemotherapy. We investigated the importance of STM 

decline rates during salvage HDCT. Methods: HDCT included an initial low 

dose (LD) portion (1-2 cycles of paclitaxel plus ifosfamide [TI] � G-CSF) for 

stem cell collection followed by a high-dose (HD) portion (3 cycles of 

carboplatin � etoposide or TI � carboplatin). Eligible pts had elevated STM 

(AFP �15 and/or HCG �2.2) at the start of LD and completed �1 HD 

cycle. Slope and t1/2 were calculated for HCG and AFP for cycles 1-2 of LD 

and HD starting with the peak value during days (d) 1-6 of LD and HD to 

avoid interference from lysis. T1/2 for AFP �7d and HCG �3.5d were 

categorized as satisfactory (SAT); normalization within 7d was also considered 

SAT, regardless of t1/2. Pts with elevated AFP and HCG had to have 

adequate decline in both to be considered SAT. Progression-free (PFS) and 

overall survival (OS) were compared for SAT vs. unsatisfactory (UNSAT) pts 

using the log-rank test. Results: Of 117 pts (115 male, 105 nonseminoma), 

the most common primary sites were testis (81) and mediastinum (26). 93, 

19, and 5 pts completed 3, 2, and 1 HD cycles, respectively. Overall, 

19/117 had SAT decline during LD (19/77 for HCG; 7/57 for AFP). For LD, 

there was no significant difference in PFS or OS for SAT vs. UNSAT decline. 

For HD, 17/96 had SAT decline (11/59 for HCG; 9/47 for AFP). SAT overall 

decline (HCG and AFP) during HD predicted superior PFS (p�0.0025) and 

OS (p�0.0046) with 2-year (yr) PFS 0.88 (0.59, 0.97) vs. 0.37 (0.26, 

0.47) and 3yr OS 0.82 (0.55, 0.94) vs. 0.37 (0.26, 0.48). SAT HCG 

decline alone also predicted superior PFS (p�0.0018) and OS (p�0.004) 

with 2yr PFS 0.91 (0.51, 0.99) vs. 0.32 (0.19, 0.46) and 3yr OS 0.91 

(0.51, 0.99) vs. 0.35 (0.22, 0.50) whereas only a non-significant trend for 

improved PFS (p�0.14) and OS (p�0.16) was seen for AFP alone. 

Conclusions: STM decline rates during the HD portion of salvage HDCT 

predicts favorable PFS and OS, mostly driven by HCG. However, UNSAT 

STM decline does not exclude long-term PFS/OS. STM decline rates during 

the initial LD portion of HDCT programs do not predict outcome; thus, 

UNSAT LD decline should not prohibit subsequent HDCT. 


12:00 PM-1:00 PM 

A retrospective analysis of patients with intermediate-risk germ cell tumor 

(IRGCT) treated at Indiana University from 2000 to 2010. Presenting 

Author: Costantine Albany, Indiana University Melvin and Bren Simon 

Cancer Center, Indianapolis, IN 

Background: Based on the International Germ Cell Cancer Collaborative 

Group (IGCCCG), IRGCT represents 26% of non-seminomas and 10% of 

seminomas with 2 year PFS of 74% (63-85%). Most patients are treated 

with 4 cycles of Bleomycin, Etoposide and Cisplatin (BEP). However, the 

optimal therapy for this heterogeneous group is not well defined. Our 

hypothesis was that many patients with IRGCT may not require BEPx4 as 

they are clinically closer to good risk rather than to poor risk disease. 

Methods: We conducted a retrospective analysis of all patients with 

testicular cancer seen at Indiana University (IU) between 2000- 2010. We 

identified 170 pts with IRGCT of whom 84 consecutive pts received their 

therapy at IU. 2 chemotherapy categories were identified: BEP (or equivalent) 

x4 or BEPx3 (�/-EPx1). Results: 45 pts received either BEPx4 (41), 

VIPx4 (2) or BEPx2 followed by HDCTx2 (2). 39 pts received BEPx3 (9) or 

BEPx3�EPx1 (30). Treatment decisions were based on clinical characteristics 

and markers amplitude. There were 78 (93%) non-seminoma, 6 (7%) 

seminoma. 27 (32%) stage II and 57 (68%) stage III. Mean AFP 3899 

(range 1000-9550; n�50), mean hCG 16354 (range 5000-49000; 

n�34). The overall 1 and 2 year Kaplan-Meier estimates were 93% and 

87% for PFS and 98% and 92% for OS. Results are depicted below. 

Conclusions: Our results for patients with IRGCT treated from 2000-2010 

are superior to the IGCCCG pts treated from 1975-1990. Routine administration 

of BEPx4 probably represents overtreatment in a substantial 

percent of IRGCT. 

BEPx3 (�/- EPx1) BEPx4 /other p value 

Number 39 45 

AFP mean (range) 3890 (1009- 8300) n�23 3907 (1000- 9550) n�28 

hCG mean (rRange) 16074 (5000-49000) n�14 16549 (5000- 36800) n�20 

Persistent GCT on post 

5 2 

chemo RPLND 

Salvage high dose 

4 6 

chemotherapy (HDCT) 

Death 2 2 

PFS 1 yr, 2 yrs 95%, 89% 91%, 85% 0.60 

OS 1 yr, 2 yrs 100%, 94% 96%, 90% 0.86 


285s 


12:00 PM-1:00 PM 

Phase II trial of bevacizumab (BEV)/high-dose chemotherapy (HDC) for 

refractory germ-cell tumors (GCT). Presenting Author: Yago Nieto, University 


Background: HDC is a curative therapy for relapsed GCT. However, multiple 

prior relapses, cisplatin refractoriness (relapse/progression (PD) within 4 

weeks) or absolute refractoriness (no prior response), or very high tumor 

markers at relapse predict poor early event-free survival (EFS). The 

validated Beyer model (JCO 1996;14:2638) identifies groups with poor 

risk (5% EFS at 1-year post-HDC), intermediate risk (25% EFS) or good risk 

(�50% EFS). Given high VEGF expression in metastatic GCT and synergy 

between BEV and chemotherapy, we studied concurrent BEV/HDC in 

refractory GCT. Methods: Eligibility includes � 1st relapse/PD, poor/interm 

risk and no contraindications to HDC or BEV. Treatment consisted of 2 

cycles of HDC with stem-cell support following BEV (5 mg/kg) 1 week 

before each cycle. HDC-1 consists of a novel regimen of infusional 

gemcitabine with docetaxel/melphalan/carboplatin (BBMT 2005;11:297). 

HDC-2 includes ifosfamide/carboplatin/etoposide. Target accrual is 25 pts, 

to distinguish a 1-yr expected EFS of 15% (median time to progression 

[TTP], 9 months) from 50% 1-year EFS (median TTP, 2 years). Results: 21 

pts have been treated, median age 22 (range, 19-45) poor risk (N�15) or 

interm risk (N�6), cisplatin refractoriness (N�9) or absolute refr (N�12), 

median 3 prior relapses (1-4), median 3 prior regimens (2-6), PD at HDC: 

11 pts. Tumor sites: lungs (N�15), liver (8), bones (5), brain (5), retroperit 

(15), mediast (12). Histol at Dx: embryonal ca (4), chorio (3), mixed with 

teratoma (14). Prior surgery for metastases: 8 pts (6 abdomen, 1 liver, 1 

brain). Prior radiation: 6 pts. Toxicity of HDC-1: grade 3 mucositis in all 

pts, rash (8 G2, 2 G3) and transaminase elevation; 2 pts with marginal 

baseline renal function died from early sepsis; 1 pt died from late fungal 

pneumonia. After HDC-1, markers normalized in 14/17 evaluable pts. 15 

pts received HDC-2 at a median 49 (38-66) days after 1st stem cell 

infusion, which was well tolerated. 8 pts had residual lesions resected with 

findings of either teratoma (N�2) or no viable tumor (N�6). With median 

follow-up of 23 (3-43) months, 14 pts are alive in CR (67% EFS). 

Conclusions: BEV with HDCx2 shows encouraging preliminary results in 

heavily pretreated refractory GCT. 


12:00 PM-1:00 PM 

Large retroperitoneal lymph nodes (RPLN) as a novel risk factor for venous 

thromboembolism (VTE) in germ cell tumor (GCT) patients (pts) receiving 

first-line chemotherapy (chemo). Presenting Author: Ben Tran, Princess 


Background: VTE causes substantial morbidity and mortality in GCT pts. 

The Khorana model is a validated predictive model that stratifies VTE risk in 

cancer pts receiving chemo; Khorana score �3 (K3) identifies pts at high 

risk. Many GCT pts have bulky RPLN that can cause venous stasis in the 

lower limbs. This study examines the incidence of VTE in GCT pts and 

assesses large RPLN as a novel predictor of VTE risk. Methods: Retrospective 

data from the Princess Margaret Hospital GCT database was complemented 

by review of medical records. GCT pts receiving 1st line chemo 

between 2000-2010 were included. Pts diagnosed with VTE prior to chemo 

and pts receiving thromboprophylaxis (TP) were excluded. Pts diagnosed 

with VTE during or within 3 months of completing chemo were identified. 

Large RPLN were defined as having maximal diameter �5cm. Odds ratios 

for VTE risk with large RPLN and K3 were calculated. Discriminatory 

accuracy (DA) of each predictor was calculated using area under the 

receiver operating characteristic curves (AUROC). An external cohort from 

London Regional Cancer Program, with similarly collected data, was used 

to validate results. Results: In the test cohort 21 (10%) of 216 pts 

developed VTE. Both large RPLN (OR 6.2, p�0.001) and K3 (OR 11.8, 

p�0.001) were significantly associated with VTE. Positive predictive value 

(PPV) was lower for large RPLN compared to K3 (21% v 44%, p�0.014) 

but sensitivity was greater (71% v 40%, p�0.001), while DA showed no 

difference (AUROC 0.73 v 0.67, p�0.46). In the validation cohort 10 (9%) 

of 111 pts developed VTE. There was a non significant trend for associations 

between VTE and both large RPLN (OR 2.54, p�0.16) and K3 (OR 

4.5, p�0.13). When compared to K3, sensitivity was greater for large 

RPLN (60% v 20%, p�0.003), but there was no difference in PPV (14% v 

29%, p�0.25) or DA (AUROC 0.61 v 0.57, p�0.72). Conclusions: VTE 

occurs in 1 in 10 GCT pts receiving curative chemotherapy. Large RPLN is 

a novel and clinically applicable predictor of VTE risk, although prospective 

validation would be beneficial. Randomized controlled trials of TP in GCT 

pts should be considered in pts at high risk of VTE, identified by large RPLN 

or K3. 




12:00 PM-1:00 PM 

An in-depth multicentered population-based analysis of outcomes of 

patients with metastatic renal cell carcinoma (mRCC) that do not meet 

eligibility criteria for clinical trials. Presenting Author: Daniel Yick Chin 

Heng, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, 

Canada 

Background: Clinical trials have strict eligibility criteria that exclude many 

patients to whom the trial results are later extrapolated to in clinical 

practice. Methods: mRCC patients treated with VEGF targeted therapy were 

retrospectively deemed ineligible for clinical trials (according to commonly 

used inclusion/exclusion criteria) if they had a Karnofsky Performance 

Status (KPS) �70%, brain metastases, non-clear cell histology, hemoglobin��9 

g/dL, creatinine �2x the upper limit of normal, platelet count of 

�100x103 /uL, neutrophil count �1500/mm3 or corrected calcium��12 

mg/dL. Results: 894/2076 (43%) patients were deemed ineligible for 

clinical trials by the above criteria. Between ineligible versus eligible 

patients, the response rate, median progression free survival (PFS) and 

median overall survival of first-line targeted therapy were 21% vs 29%, 5.2 

vs 8.8 months and 14.5 vs 28.8 months (all p�0.0001), respectively. 

Second-line PFS (if applicable) was 3.2 months in the trial ineligible vs 4.4 

months in the trial eligible patients (p�0.0074). Patients who were 

excluded due to KPS�70, hemoglobin��9 g/dL, calcium ��12, brain 

metastases, and non-clear cell histology, had a hazard ratio (HR) for death 

of 2.8 (95%CI 2.4-3.4), 1.8 (95%CI 1.4-2.2), 1.8 (95%CI 1.2-2.7), 1.4 

(95%CI 1.1-1.8), and 1.4 (95%CI 1.1-1.7), respectively (all p�0.01). 

When adjusted by the Heng et al prognostic categories, the HR for death 

between trial ineligible vs trial eligible patients was 1.511 (95%CI�1.335- 

1.710, p�0.0001). Conclusions: The number of patients that are ineligible 

for clinical trials is high and their outcomes are inferior. Specific trials 

addressing the needs of protocol ineligible patients and assessing OS are 

required. 

Clinical trial 

ineligible N�894 

Clinical trial 

eligible N�1,182 P value 

Parameter 

Heng et al prognosis 

�0.0001 

Favorable 

9% 

25% 

Intermediate 

48% 

59% 

Poor 

43% 

16% 

Median KPS (%) (range) 80 (20-100) 90 (70-100) �0.0001 

Anemia (below LLN) 68.7% 51.4% �0.0001 

Hypercalcemia (above ULN) 14.5% 6.8% �0.0001 

Brain metastases present 19% 0% �0.0001 

Non-clear cell histology 26% 0% �0.0001 


12:00 PM-1:00 PM 

Characteristics of long-term and short-term survivors of metastatic renal cell 

carcinoma (mRCC) treated with targeted therapy: Results from the International 

mRCC Database Consortium. Presenting Author: Wanling Xie, Dana-Farber 


Background: Patients with mRCC have variable courses in terms of survival and 

response to targeted therapy. The patients at the two extremes of the survival 

spectrum need to be characterized. Methods: 2,161 patients with mRCC treated 

with targeted therapy were examined. 152 patients who survived 4 years or more 

after the initiation of targeted therapy (long-term) were compared with 218 

patients who survived 6 months or less (short-term) over the same time period 

(2004-2007). Results: Long-term survivors had fewer poor prognostic factors 

(PFs) such as Karnofsky performance status (KPS) �80%, diagnosis to treatment 

interval�1 yr, hypercalcemia, anemia, thrombocytosis and neutrophilia 

(all p�0.0001). Patients with favorable prognosis who responded to targeted 

therapy were more likely to be long term survivors. For those in the intermediate 

risk group, patients who were long-term survivors were more likely to have only 1 

poor prognostic factor (73% vs. 28%, p�0.0001) and KPS�80% (88% vs. 

69%, p�0.009) compared to those in the short term survivor group. On 

multivariable analysis adjusting for PFs, response to targeted therapy (PR or 

better) significantly predicted long term survivor status (odds ratio�6.3, 95% 

CI: 2.3,17.4, p�0.0004). Conclusions: Long term survivors had a higher 

response rate to targeted therapy, a longer treatment duration and more use of 

second-line targeted therapy. Baseline prognostic criteria may be able to 

discriminate between long- and short- term survivors. 

Long-term Short-term 

survivor 

survivor 

Characteristic 

(N�152) (N�218) P value 

Median age (years) 61 61 0.26 

Heng et al prognostic category 

�0.0001 

Favorable 

42% 

2% 

Intermediate 

49% 

34% 

Poor 

3% 

60% 

Unknown 

5% 

4% 

KPS < 80% 7% 53% �0.0001 

Prior nephrectomy 95% 65% �0.0001 

>1 site of metastases 73% 83% 0.02 

Best response 

�0.0001 

Complete response 

4% 

0% 

Partial response 

34% 

4% 

Stable disease 

53% 

19% 

Progressive disease 

3% 

43% 

Unknown 

6% 

34% 

Median duration of targeted 

therapy (months) 

23.6 2.0 - 

Median duration of second-line 

11.5 

0.8 

- 

targeted therapy (months) 

(N�90) 

(N�20) 

Median overall survival (months) 69.3 3.1 - 

LBA4537 Poster Discussion Session (Board #16), Sat, 8:00 AM-12:00 PM 

and 12:00 PM-1:00 PM 

Axitinib versus sorafenib as second-line therapy in Asian patients with 

metastatic renal cell carcinoma (mRCC): Results from a registrational 

study. Presenting Author: Shukui Qin, Nanjing Bayi Hospital, Nanjing, 

China 








12:00 PM-1:00 PM 

Phase III randomized sequential open-label study to evaluate efficacy and 

safety of sorafenib (SO) followed by sunitinib (SU) versus sunitinib followed 

by sorafenib in patients with advanced/metastatic renal cell carcinoma 

without prior systemic therapy (SWITCH Study): Safety interim analysis 

results. Presenting Author: Maurice Stephan Michel, University Hospital 

Mannheim, Mannheim, Germany 

Background: Several retrospective studies have investigated the sequential 

use of SO and SU. Some smaller trials support the use of SO followed by SU 

forming the rationale for this study. Methods: Pts with metastatic RCC 

unsuitable for cytokines without prior systemic therapy, ECOG PS 0/1, 

MSKCC score low or intermediate, and �1 measurable lesion (CT/MRI 

every 12 weeks) were randomized to SO-�SU or SU-�SO in standard 

dosage (primary endpoint total PFS from randomization to event during 2 nd 

line therapy). Treatment continues until progression or intolerability. 

Monitoring includes echocardiography and NT pro-BNP. Results: Baseline 

characteristics of 361 randomized pts (116 completed) are balanced 

between arms. Safety data of 333 pts are evaluable. AE occurring in �10% 

of pts are listed in tab. 1. Left-ventricular ejection fraction (LVEF) at 

screening, switch of treatment, and end of study are given in tab. 1. AE 

occurred in 93.4% and 92.8%; grade 3/4 AE in 59.9% and 50%; and SAE 

in 46.7% and 42.2% in the SO-�SU and SU-�SO arm, respectively. 

Updated results will be presented. Conclusions: AE frequencies are higher 

in 1 st than in 2nd line treatments. Typical AE profiles for SO and SU are 

observed. LVEF values are in a similar range. 

SO 1st SU 2nd SU 1st SO 2nd 

(n�167) % % (n�71) % % (n�166) % % (n�47) % % 

CTCAE All G 3/4 All G 3/4 All G 3/4 All G 3/4 

Hematotoxicity 6.6 1.2 19.7 5.6 16.9 9.0 0 0 

Hypertension 26.9 7.2 7.0 1.4 29.5 9.0 4.3 2.1 

Fatigue 28.1 5.4 22.5 2.8 31.3 5.4 17.0 0 

Weight loss 12.6 0.6 4.2 0 4.2 0.6 4.3 0 

Hair loss 28.1 0 1.4 0 3.0 0 4.3 0 

Rash 10.8 1.2 4.2 0 3.0 0 6.4 0 

Hand-Foot Skin Rct. 41.3 13.8 7.0 1.4 15.1 4.2 21.3 8.5 

Diarrhea 45.5 4.8 14.1 2.8 30.1 1.2 29.8 4.3 

Mucositis 4.8 0 4.2 0 13.8 2.4 2.1 0 

Nausea 18.6 1.2 15.5 1.4 22.9 0.6 4.3 0 

Vomiting 6.6 0 12.7 2.8 14.5 1.8 4.3 0 

SO->SU N Mean LVEF % �SD 

Screening 151 63.0 � 7.6 

Day of stopping 1st-line treatment 46 62.7 � 8.9 

End of study 

SU->SO 

23 60.3 � 10.5 

Screening 149 64.1 � 8.2 

Day of stopping 1st-line treatment 28 62.6 � 10.1 



12:00 PM-1:00 PM 

The use of tumor growth rate (TGR) in evaluating sorafenib and everolimus 

treatment in mRCC patients: An integrated analysis of the TARGET and 

RECORD phase III trials data. Presenting Author: Charles Ferte, Department 

of Medical Oncology, Institut Gustave Roussy, Villejuif, France 

Background: RECIST criteria may not be sufficient to evaluate targeted 

therapies in mRCC. TGR includes the time between each evaluation and is 

expected to overcome some of the RECIST pitfalls. How TGR is modified 

under targeted therapies and how it correlates with outcome in mRCC 

remains unknown. Methods: Medical records from all patients (pts) prospectively 

treated at Institut Gustave Roussy (IGR) in the TARGET (n�84) and 

in the RECORD (n� 52) phase III trials were extracted. Results were 

subsequently validated in the entire TARGET cohort (TARGET) (n�902). 

TGR was computed by dividing tumor shrinkage by the time between the 

two related evaluations (% RECIST x 100 / days). Typical treatment periods 

were assessed: BEFORE treatment (wash-out), UNDER treatment (first 

cycle), at PROGRESSION (pts still receiving the drug) and AFTER treatment 

interruption (wash-out). Results: As compared to placebo, TGR 

UNDER was significantly decreased following sorafenib (-23.6 vs. 20 (IGR) 

and -19 vs. 22 (TARGET)) and everolimus (-5.2 vs. 30 (IGR)). The great 

majority of pts (IGR) had a decrease in the TGR UNDER vs. BEFORE, 

regardless of the RECIST evaluation, both with sorafenib (28/29) or 

everolimus (36/37). TGR AFTER sorafenib or everolimus interruption was 

significantly higher than TGR at PROGRESSION in both settings (IGR) 

(14.6 vs. 31 and 17.9 vs. 32.1 respectively). No significant difference was 

observed between TGR AFTER vs. BEFORE either in sorafenib or in 

everolimus pts (IGR). High TGR UNDER is associated with poor progression 

free survival (HR� 2.6) and overall survival (HR� 2.3) in sorafenib-treated 

pts (multivariate analysis, trained in IGR and validated in TARGET cohorts) 

and with poor overall survival in everolimus-treated pts (IGR)(HR� 1.2). 

Conclusions: Adding TGR assessment in mRCC unravels interesting traits 

that make it potentially adaptable for clinical practice: (i) better evaluation 

of the tumor response, regardless of RECIST criteria, (ii) independent 

prognosis value, (iii) it suggests that maintaining sorafenib or everolimus 

after disease progression might benefit to patients and should be prospectively 

evaluated. 


12:00 PM-1:00 PM 

Sunitinib objective response (OR) in metastatic renal cell carcinoma 

(mRCC): Analysis of 1,059 patients treated on clinical trials. Presenting 

Author: Ana M. Molina, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: Sunitinib achieves robust OR and improved progression-free 

survival (PFS) in mRCC patients (N Engl J Med 2007;356:115). A 

retrospective analysis was performed to characterize the OR rate with 

sunitinib treatment (Tx) and OR-associated patient features and survival. 

Methods: Data from six phase II and III trials were pooled from 1,059 

patients who received sunitinib on the approved 50 mg/d 4-week-on/2-weekoff 

schedule (n�689; 65%) or at 37.5 mg continuous once-daily dosing 

(n�370; 35%), in both the 1st- (n�783; 74%) and 2nd-line (n�276; 

26%) Tx settings. Median PFS and overall survival (OS) were estimated by 

the Brookmeyer and Crowley method, and compared between responders 

and nonresponders, and early and late responders (response � and �12 

weeks, respectively), by a log-rank test. Baseline characteristics were 

compared by Fisher-exact Test, T-Test, or Wilcoxon Rank-sum Test. 

Results: Of 1,059 patients, 398 (38%) had a confirmed investigatorassessed 

OR by RECIST (including 12 with a complete response), of whom 

105 (26%), 243 (61%), 314 (79%), and 342 (86%) had a response by 6, 

12, 18, and 24 weeks, respectively. Median (range) time to tumor response 

(TTR) in all patients was 10.6 (2.7–94.4) weeks, which was similar in the 

1st- and 2nd-line Tx settings. Responders had better baseline ECOG 

scores, more favorable risk factor classification based on published MSKCC 

data, a longer interval since initial diagnosis, more prior nephrectomy, and 

less presence of baseline bone metastases (all p�0.05). Early responders 

had more lung metastases (p�0.01). Median PFS (16.3 vs. 5.3 months) 

and OS (40.1 vs. 14.5 months) were significantly longer in responders vs. 

nonresponders (both p�0.001), with similar results regardless of 1st- or 

2nd-line Tx setting. Median OS did not differ between early and late 

responders (p�0.1438). Conclusions: OR was achieved in 38% of 1,059 

mRCC patients treated with sunitinib and was predicted by favorable 

pretreatment prognostic factors. Patients with OR had longer PFS and OS. 

Median TTR was 10.6 weeks, and characteristics and outcome of early and 

late responders were similar, except for higher frequency of lung metastases 

among early responders. 



12:00 PM-1:00 PM 

PFS to predict long-term OS after first-line treatment for advanced renal 

cell carcinoma (aRCC): Correlation and power analysis of randomized trials 

(RCT). Presenting Author: Michele Milella, Regina Elena National Cancer 

Institute, Rome, Italy 

Background: Targeted agents (TA) have become standard 1st line aRCC 

treatment based on evidence of PFS advantage. Retrospective series 

indicatePFS as a reliable intermediate end-point in this setting; however, 

correlation, surrogacy testing, and validation are required. Methods: RCT 

evaluating the efficacy of TA as 1st line treatment for aRCC were eligible. 

PFS/OS Response/Disease Control rates (ORR, DCR) and HR were extracted 

from papers/updated presentations. Correlations between 6-, 9-, 

and 12-mo PFS and OS rates according to parametric (Pearson’s r) and 

non-parametric (Spearman’s Rho and Kendall’s Tau) coefficients (with 

95% CI) were analyzed to avoid lead-time biases. Regression analysis 

(parametric R2) and a power-analysis-model to determine patients’ sample 

necessary to detect 3%, 5% and 10% OS gain were developed. Results: Six 

RCT (4096 pts) were gathered. The best overall correlation between PFS 

and OS at concurrent timepoints was found at 9 mos. With regard to overall 

rates, 3- and 6-mo PFS significantly correlated with 9-mo OS, as shown in 

the table below. Pearson’s coefficients for the correlation between 3-mo 

PFS and 6- and 12-mo OS were 0.70 (p�0.01) and 0.67 (p�0.01); the 

correlation between 6-mo PFS and 12-mo OS was also significant (Pearson 

0.74, p�0.005; Spearman 0.83, p�0.005; Tau 0.71, p�0.001). The 

regression equation was: Y�0.391861 � 0.4914X [R2 0.44, 

p(slope)�0.01]; based on this model, the demonstration of a 3-mo PFS 

absolute difference of 6%, 10% and 21% (corresponding to a 9-mo OS 

benefit of 3%, 5% and 10%) would require 2043, 696 and 155 patients, 

respectively. A significant correlation was also found between DCR and OS. 

Conclusions: Early PFS is an acceptable intermediate end-point for OS in 

the context of 1st line TA for aRCC. Individual patient data analysis to verify 

Prentice criteria would be required for definitive confirmation. 

Correlation coefficient (p value) 

Sample 

Pearson Rho Tau 

Overall 0.66 (0.01) 0.78 (�0.01) 0.67 (0.03) 

0.75 (0.004) 0.91 (0.002) 0.79 (0.004) 

TA arm 0.69 (n.s.) 

0.94 (0.03) 0.85 (0.02) 

0.90 (0.01) 0.90 (0.04) 0.82 (0.03) 

Control arm 0.76 (n.s.) 

0.84 (n.s.) 

0.69 (n.s.) 

0.68 (n.s.) 

0.89 (0.04) 0.82 (0.03) 


12:00 PM-1:00 PM 

Association of inherited genetic variation with clinical outcome in patients 

with advanced renal cell carcinoma treated with mTOR inhibition. Presenting 

Author: Mark M. Pomerantz, Lank Center for Genitourinary Oncology, 

Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard 


Background: Mammalian target of rapamycin (mTOR)-targeted therapy is 

standard in patients with metastatic renal cell carcinoma (mRCC). Predictive 

biomarkers for response are lacking. We sought to characterize 

outcome after mTOR inhibition based on germline variation in 2 critical 

genes in the mTOR pathway: phosphoinositide-3-kinase catalytic alpha 

(PIK3CA) and mTOR. Methods: 76 Americans of European ancestry treated 

with temsirolimus or everolimus for mRCC were included. Germline DNA 

was genotyped for all common genetic variation (minor allele frequency 

[MAF] �0.05) across PIK3CA and mTOR, tagging with single nucleotide 

polymorphisms (SNPs) at r2�0.8. Associations between genotype and 

progression-free survival (PFS) and overall survival (OS) from the start of 

mTOR-targeted therapy were measured using univariate Cox model. Results: 

Among 76 patients, 66% were poor or intermediate risk and 89% received 

prior systemic therapies. Median follow up was 23.7 months. Median PFS 

and OS were 4.3 and 12.7 months, respectively. Two intronic PI3KCA 

SNPs were significantly associated with PFS and OS, and a SNP in the 5’ 

UTR of mTOR was associated with OS. Associations were maintained when 

adjusted for age, gender and MSKCC RCC risk categories using Cox PH 

model (Table). The PI3KCA SNPs are in modest linkage disequilibrium (r 2 

~0.36). Conclusions: We suggest that inherited variation at PIK3CA is 

associated with PFS and OS after mTOR inhibition. If results are validated, 

prospective studies could explore the role of genotyping in treatment 

selection for mRCC. Further work will be needed to identify causal alleles 

and define the mechanism underlying the associations. 

PFS and OS after mTOR-targeted therapy by genotype. 

Gene SNP MAF 

Median PFS 

Genotype (months) 

HR 

(95% CI) 

Median OS 

P value* (months) 

HR 

(95% CI) P value* 

PIK3CA rs2699905 0.25 TC, TT 6 1 13.1 1 

CC 4.4 2.1 0.006 12.2 1.86 0.03 

(1.23,3.57) (1.05,3.3) 

PIK3CA rs13082485 0.08 AA, AG 10.6 1 33.9 1 

GG 4.2 3.1 

(1.37,7) 

0.007 12.2 4.11 

(1.46,11.61) 0.008 

mTOR rs12732063 0.07 AA, AG 3.5 1 7.7 1 

GG 4.8 0.58 

(0.28,1.2) 

0.14 12.9 0.36 

(0.16,0.8) 

Abbreviations: HR, hazard ratio; CI, confidence interval. * Adjusted for age, gender, MSKCC risk groups. 


287s 

0.01



12:00 PM-1:00 PM 

Phase II trial of RAD001 in renal cell carcinoma patients with non-clear 

cell histology. Presenting Author: Youngil Koh, Department of Internal 

Medicine, Seoul National University College of Medicine, Seoul, South 

Korea 

Background: In non-clear cell renal cell carcinoma (ncRCC), the efficacy of 

VEGF tyrosine kinase inhibitor (TKI) is controversial. In the while, a mTOR 

inhibitor, temsirolimus showed a promising efficacy in ncRCC patients in 

ARCC trial. Hence, we investigated the role of everolimus in ncRCC with 

this phase II trial. Methods: ncRCC patients received everolimus 10 mg 

once daily until disease progression or unacceptable toxicity. We included 

patients who had received VEGF TKI previously, while excluded patients 

who received previous mTOR inhibitor. The primary end point was progression 

free survival (PFS). Results: A total of 49 patients were enrolled from 5 

centers. Their median age was 57 years (range 24-75 years) and male to 

female ratio was 37:12. Histology of the patients included papillary 

(n�29), chromophobe (n�8), collecting duct (n�2), sarcomatoid (n�4), 

and unclassifiable (n�6) RCC. Twenty-three patients had been treated with 

VEGF-TKI prior to the study enrollment. Among 49 patients, 46 patients 

underwent radiologic response assessment after everolimus treatment. 

Partial response was observed in 5 patients (10.2%) and stable disease in 

25 patients (51.0%). Diseases of 16 patients (32.7%) progressed despite 

of everolimus administration. Histology of 5 patients who showed objective 

response to everolimus included chromophobe carcinoma (n�2), papillary 

carcinoma (n�2) and unclassifiable carcinoma (n�1). During the study 

period, 34 patients experienced PFS events and median PFS was 5.2 

months. Patients with chromophobe histology showed longer PFS than 

patients with the other histologies (median PFS 18.8 months vs. 3.5 

months, p�0.027). Estimated median PFS were not significantly different 

between patients VEGF-TKI treatment and patients without previous 

VEGF-TKI treatment (median PFS 7.1 vs. 3.7 months, p�0.110). Toxicity 

profiles were commensurable with previous reports. Conclusions: Everolimus 

shows considerable efficacy in ncRCC. Patients with chromophobe 

histology might earn benefit from everolimus treatment especially. Previous 

treatment with VEGF-TKI seems not to significantly influence outcome of 

everolimus therapy in these patients. (ClinicalTrials.gov number, 

NCT00830895) 


12:00 PM-1:00 PM 

Phase III AXIS trial of axitinib versus sorafenib in metastatic renal cell 

carcinoma: Updated results among cytokine-treated patients. Presenting 

Author: M. Dror Michaelson, Massachusetts General Hospital Cancer 


Background: Axitinib, a potent and selective second-generation inhibitor of 

vascular endothelial growth factor receptors, improved progression-free 

survival (PFS) compared to sorafenib in patients with metastatic renal cell 

carcinoma (mRCC) in the phase III AXIS trial. In patients previously treated 

with cytokines, median PFS (mPFS) was 12.1 mo. In a prior phase II study 

of axitinib for cytokine-refractory mRCC, mPFS was 13.7 mo and the 5-yr 

overall survival (OS) rate was 20.6%. We report updated PFS and OS for 

cytokine-treated patients from the AXIS trial. Methods: 723 patients with 

clear-cell mRCC and progressive disease after 1 systemic therapy were 

enrolled, of whom 251 received prior interleukin-2 (IL-2) or interferon-� 

(IFN-�). Patients were randomized 1:1 to axitinib (5 mg twice daily [BID] 

starting dose) or sorafenib (400 mg BID). Results: As of Jun 3, 2011, mPFS 

(95% confidence interval [CI]) for cytokine-treated patients was 12.0 mo 

(10.1, 13.9) with axitinib (n�126) vs 6.6 mo (6.4, 8.3) with sorafenib 

(n�125): hazard ratio [HR] (95% CI) 0.519 (0.375, 0.720); p�0.0001. 

For those treated with an IL-2-containing regimen, mPFS (95% CI) was 

15.7 mo (8.3, 19.4) with axitinib (n�37) vs 8.3 mo (4.7, 15.7) with 

sorafenib (n�38). For those treated with IFN-� alone, mPFS (95% CI) was 

12.0 mo (10.0, 13.8) with axitinib (n�89) vs 6.5 mo (6.4, 8.2) with 

sorafenib (n�87). As of Nov 1, 2011, median OS (95% CI) in the 

cytokine-treated subgroup was 29.4 mo (24.5, not estimable) with axitinib 

vs 27.8 mo (23.1, 34.5) with sorafenib: HR (95% CI) 0.813 (0.555, 

1.191); p�0.144. Adverse event (AE) profiles were similar in both arms. 

Few cytokine-treated patients (5.6%) discontinued axitinib due to toxicity. 

AEs reported in �25% of cytokine-treated patients receiving axitinib were 

diarrhea (49.2%), hypertension (47.6%), fatigue (35.7%), dysphonia 

(29.4%), and hand–foot syndrome (28.6%). Conclusions: Axitinib showed 

median PFS and OS of 1 and 2.5 yr, respectively, in cytokine-treated 

patients, confirming prior phase II study results, and was well tolerated. 

PFS was superior to that of sorafenib in second-line mRCC and compares 

favorably with historical results of other agents in second-line mRCC. 


12:00 PM-1:00 PM 


sorafenib in patients (pts) with renal cell carcinoma (RCC) from a phase I 

study. Presenting Author: Igor Puzanov, Vanderbilt University Medical 

Center, Nashville, TN 

Background: Inhibitors of vascular endothelial growth factor (VEGF) and 

VEGF receptor are standard therapy for RCC, and the MET signaling 

pathway is implicated in tumor angiogenesis. Tivantinib is an oral, selective 

MET inhibitor. In several tumor models, tivantinib plus sorafenib exhibited 

synergistic antitumor activity vs single-agent activity. This phase I doseescalation 

study assessed the safety of tivantinib plus sorafenib in pts with 

advanced solid tumors. Methods: Endpoints were safety, the recommended 

phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. 

Previously, dose escalation established the RP2D as tivantinib 360 mg 

twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled � 

20 pts each with RCC or other tumors. Patients were treated until disease 

progression or unacceptable toxicity. Results: 20 pts (mean age, 60 yr) 

including 16 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts 

received treatment at the RP2D (n � 19) or tivantinib 360 mg BID plus 

sorafenib 200 mg BID (n � 1). 4 pts are still on study. 16 pts (13 with clear 

cell RCC) received � 1 previous systemic therapy (median, 2; range, 0-4) 

including VEGF (14 pts) and/or mTOR (5 pts) inhibitors. The most common 

(� 25%) adverse events were rash (65%), diarrhea (45%), alopecia (40%), 

hypophosphatemia (35%), and fatigue, stomatitis, palmar-plantar erythrodysesthesia 

syndrome, and pruritus (25% each). Best response was partial 

response (PR) in 3 pts (all clear cell RCC pts) and stable disease (SD) in 15 

pts (11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts). 7 pts 

with SD had � 10% tumor size reduction. The overall response rate (ORR) 

and disease control rate (DCR; PR � SD) were 15% and 90%, respectively. 

Median progression-free survival (mPFS) was 12.7 mo (95% CI, 7.1-14.5 

mo). In 14 pts previously treated with a VEGF inhibitor, best response was 2 

PR and 10 SD, the ORR and DCR were 14% and 86%, respectively, and 

mPFS was 12.7 mo (95% CI, 5.3-NR mo). Conclusions: Oral combination 

therapy with tivantinib plus sorafenib was well tolerated and exhibited 

preliminary anticancer activity in pts with RCC, including pts pretreated 

with VEGF inhibitors. 

4547 Poster Discussion Session (Board #1), Mon, 8:00 AM-12:00 PM and 

11:30 AM-12:30 PM 

SWOG 0421: Prognostic and predictive value of bone metabolism biomarkers 

(BMB) in castration resistant prostate cancer (CRPC) patients (pts) with 

skeletal metastases treated with docetaxel (DOC) with or without atrasentan 

(ATR). Presenting Author: Primo Lara, University of California, Davis, 


Background: S0421, a phase III study of DOC �/- the endothelin antagonist 

ATR in CRPC pts with bone metastases, showed no overall survival (OS) 

benefit for DOC�ATR. While BMB may have a prognostic role in CRPC, 

their predictive role vis a vis bone-targeted therapy such as ATR is 

unknown. We prospectively assessed pre-treatment serum BMB from 

S0421 pts to validate their prognostic and predictive value. Methods: BMB 

for resorption (N-telopeptide, NTX and Pyridinoline, PYD) and formation 

(C-terminal collagen propeptide, CICP and bone alkaline phosphatase, 

BAP) were assayed [Quidel (PYD, CICP, BAP) and Wampole (NTX)]. Cox 

regression models for OS based on BMB adjusted for clinical variables were 

developed. An adjusted Cox model was fit with main effects and BMB x 

Treatment interaction to assess predictive value of ATR on OS. Results: Of 

1,038 pts, 855 (82%) submitted baseline serum: 778 (91%) were usable 

and analyzable. Pt characteristics: median age � 69 years; PS 0-1 � 91%, 

Bisphosphonate use � 61%; Gleason �7 � 56%; median PSA � 68; and 

bone mets only � 45%. BMB values (median; range): NTX (14 nM; 

9.3-23.9), BAP (64.7 u/L; 35-164), CICP (9.5 ng/mL; 6.5-17.4), and PYD 

(2.8 nmol/L; 2.2-3.9). Table below shows prognostic role of BMB. Pts with 

very high BMB (upper 25 %ile, n�47) not only have poor prognosis (HR � 

4.3, p�0.001) but have OS benefit from ATR (HR�0.34, median OS � 

13.6 vs. 6.7 months; interaction p�0.002**). Conclusions: S0421 validates 

the strong independent OS prognostic value of BMB in CRPC. Very 

high BMB levels appear to be significantly predictive of OS benefit with 

ATR. Further study of endothelin antagonists in CRPC should focus on this 

high-risk pt subset. (5R01-CA120469) 

Biomarker 

Hazard ratio 

(95% CI) 

Median survival, 

months ( median) p-value* 

BAP (u/l) 1.23 (1.14, 1.32) 22.8 vs. 15.4 �0.001 

CICP (ng/ml) 1.38 (1.26, 1.51) 24.5 vs. 14.6 �0.001 

NTx (nM) 1.40 (1.27, 1.54) 22.4 vs. 15.5 �0.001 

PYD (nmol/l) 1.52 (1.28, 1.81) 22.0 vs. 15.3 �0.001 

* Significance set at � 0.006 to control 2-sided error rate at 0.05. **Significance set at 

�0.01 to control overall 2-sided error rate at 0.05 (Bonferroni adjustment). 



11:30 AM-12:30 PM 

A phase I study of the androgen signaling inhibitor ARN-509 in patients 

with metastatic castration-resistant prostate cancer (mCRPC). Presenting 

Author: Dana E. Rathkopf, Sidney Kimmel Center for Prostate and Urologic 

Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: ARN-509 is a novel small molecule AR antagonist that impairs 

AR nuclear translocation and binding to DNA, inhibiting tumor growth and 

promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) 

We conducted a phase I trial to assess safety, pharmacokinetics (PK), and 

determine the recommended phase II dose (RP2D). Methods: Eligible 

patients with mCRPC received ARN-509 orally on a continuous daily dosing 

schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were 

tested using standard 3x3 dose escalation criteria. Once drug concentrations 

were achieved that met or exceeded optimal levels predicted 

preclinically, an additional 2 dose levels were tested to further confirm the 

safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was 

assessed by PSA, radiographic responses, and FDHT-PET imaging. Results: 

Thirty patients were enrolled. The most common grades 1-2 treatmentrelated 

adverse events were fatigue (38%), nausea (29%), and pain (24%). 

There was only 1 treatment-related grade 3 adverse event (abdominal pain) 

at 300 mg, possibly related to a higher pill burden. PK was shown to be 

linear and dose-dependent. At 12 weeks, 42% of patients have had � 50% 

PSA declines. Eleven (37%) patients have discontinued the study due to 

progression, with the longest patient still on study for more than 16 

months. FDHT-PET imaging demonstrated AR blockade at 4 weeks across 

multiple dose levels. Conclusions: In this phase I study, ARN-509 was 

shown to be safe and well tolerated with linear PK. Based on promising 

activity across all dose levels and pharmacodynamic evidence of AR 

antagonism, an optimal biologic dose of 240 mg daily was selected for 

phase II investigation. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. 


11:30 AM-12:30 PM 

Tasquinimod and survival in men with metastatic castration-resistant 

prostate cancer: Results of long-term follow-up of a randomized phase II 

placebo-controlled trial. Presenting Author: Andrew J. Armstrong, Duke 

Cancer Institute, Durham, NC 

Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative 

that binds S100A9 protein and has preclinical anti-angiogenic and 

anti-tumor activity. Between 12/07-6/09, 201 (134 T, 67 Placebo (P)) 

men with metastatic CRPC were randomized and received treatment 

once-daily at an initial dose of 0.25 mg/day escalated to 1.0 mg/day over 4 

weeks. Placebo patients could cross over to T after 6 months or at disease 

progression. The primary endpoint of improved PCWG2 criteria-defined 

progression at 6 months was met (69 vs. 37% of patients (T/P) were 

progression free) with PFS of 7.6 vs. 3.3 months for pts on T vs. P1 with 

acceptable toxicity. This abstract provides the first analysis on symptomatic 

progression, overall survival (OS) as well as a multivariate analysis for PFS 

and OS. Methods: Survival data were collected between June 2011 and 

January 2012 with a median time to censoring of 32 months. Survival data 

was also evaluated in an exploratory multivariate model of known prognostic 

factors in CRPC. Results: An imbalance of several baseline prognostic 

criteria favored placebo (e.g. baseline PSA of 29 vs. 19 (T/P)) (JCO 

2011;20:4022). Time to symptomatic progression was longer in T treated 

patients (p�0.039, HR�0.42). Record of death (97 events) or survival 

�13 months was documented in 182 patients. Median time to death was 

34.2 vs. 30.2 months (T/P). Median time to death in the PCWG2 

bone-metastatic subgroup (N�92/44) was 34.2 vs. 25.6 months. A 

multivariate analysis of known prognostic factors including PSA, LDH, PSA 

kinetics, and hemoglobin demonstrated an adjusted HR for PFS of 0.54 

(95% CI 0.37,0.81) and OS of 0.72 (95% CI 0.46,1.12) in the total 

population and 0.63 (95% CI 0.37,1.07, n�136) in the bone-metastatic 

group. Conclusions: OS observed after tasquinimod treatment is longer than 

previously reported in this patient population. The current exploratory data 

indicates that the prolongation in PFS observed with tasquinimod treatment 

may lead to a survival advantage in men with metastatic CRPC. A 

phase III placebo-controlled study (NCT01234311) is ongoing in men with 

bone-metastatic CRPC powered to detect an OS improvement. 


289s 


11:30 AM-12:30 PM 

Safety and activity of the investigational agent orteronel (ortl) without 

prednisone in men with nonmetastatic castration-resistant prostate cancer 

(nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a 

phase II study. Presenting Author: Daniel J. George, Duke University 

Medical Center, Durham, NC 

Background: Ortl is an investigational, oral, non-steroidal selective 17,20lyase 

inhibitor that suppresses androgen production. Ortl affects cortisol 

synthesis less than similar agents due to limited inhibition of 17�hydroxylase, 

and may permit steroid-free dosing. Ortl 300 mg BID was 

examined in patients (pts) with nmCRPC and rising PSA. Methods: Eligible 

pts had nmCRPC with PSA �2 ng/mL (PSA �8 ng/mL if doubling time �8 

mo), and surgical/medical castration, with testosterone (T) �50 ng/dL. 

Prior chemotherapy, ketoconazole, or concomitant corticosteroids were 

excluded. Starting dose of ortl was 300 mg BID and continued until PSA 

progression, metastases, or unacceptable toxicity. The primary endpoint 

was the percentage of pts with PSA �0.2 ng/mL after 3 mo. Secondary 

endpoints included safety, PSA kinetics, time to metastases, changes in 

endocrine markers and circulating tumor cells (CTCs). Results: 39 pts were 

enrolled with baseline demographics including median age 71 y, ECOG PS 

�1, median PSA 12.1 ng/mL (range 2.6-67.8), T 7.9 ng/dL (1.4–17.3), 

and ACTH 19 ng/L (n�33; 0-47); 3 pts had dose reduction due to adverse 

events (AEs). Gr �3 AEs occurred in 16 pts (drug-related in 14); Gr �3 AEs 

�5% were dyspnea (8%), hypertension (13%), fatigue, hypokalemia, 

pneumonitis (5% ea). 7 pts (18%) had serious AEs; most common was 

pneumonitis (2�Gr 3, 1�Gr 2). 8 pts discontinued due to AEs; 2 pts 

required corticosteroids. At 3 mo, 6 pts (16%) achieved PSA �0.2 ng/mL; 

PSA50 and PSA90 rates were 76% and 32%, respectively; median PSA 

declined by 83% (n�34); median T declined by 89% to 0.78 ng/dL 

(n�31), and median ACTH increased by 171% to 43 ng/L; median cortisol 

declined by 21%. At 6 mo, PSA50 and PSA90 rates were 45% and 21%, 

respectively. Median time to PSA progression was 14.8 mo. 17 pts (44%) 

were on treatment �6 mo. Of 37 pts with baseline CTC/7.5 mL assessed, 

only 1 had CTC �5 and converted to �5; 6 had 1–4 CTCs at baseline, none 

converted to �5 during treatment. Conclusions: Ortl without steroids 

produces marked and durable declines in T and PSA, has manageable 

toxicities, and is feasible in men with nmCRPC. 


11:30 AM-12:30 PM 

Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) 

and ECOG performance status (PS) in patients with castration-resistant 

prostate cancer (CRPC) with bone metastases: Interim results of a phase III 

trial (ALSYMPCA). Presenting Author: A. Oliver Sartor, Tulane Cancer 

Center, New Orleans, LA 

Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone 

metastases (mets) with high-energy alpha-particles of short range (�100 

�m). ALSYMPCA, a phase III, double-blind, randomized, multinational 

study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) 

plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint 

was OS; secondary endpoints included SREs and ECOG PS. Methods: 

Eligible pts had progressive, symptomatic CRPC with � 2 bone mets on 

scintigraphy and no known visceral mets; were receiving BSC; and either 

previously received docetaxel, were docetaxel ineligible, or refused docetaxel. 

Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) 

q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP 

level, and current bisphosphonate use. Results: 921 pts were randomized 

from 6/2008-2/2011. In a planned interim analysis (n � 809), Ra-223 

significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively; 

two-sided P � .00185; HR � .695; 95% CI, .552-.875).SREs were lower 

in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed 

(median time to SRE 13.6 mo v 8.4 mo, respectively; P � .00046; HR � 

.610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration 

(� 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%, 

15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time 

to ECOG PS deterioration (� 2 points) was significantly delayed by Ra-223 

v pbo (P � .003; HR � .62; 95% CI, .46-.85). Conclusions: Ra-233 

significantly delayed time to 1st SRE and SRE components, notably SCC. 

Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223 

improves OS with excellent safety and may provide a new standard of care 

for CRPC pts with bone mets. 

Time to 1st event 

No. (%) of patients 

(Ra-223 vs Pbo) 

Ra-223 Pbo 

HR 

SRE component 

n � 541 n � 268 p value* (95%CI) 

External beam radiotherapy 122 (23) 72 (27) .0038 .65 

(.48-.87) 

Spinal cord compression 17 (3) 16 (6) .016 .44 

(.22-.88) 

Pathologic bone fracture 20 (4) 18 (7) .013 .45 

(.24-.86) 

Surgical intervention 9 (2) 5 (2) .69 .80 

(.27-2.4) 

*Not adjusted for multiplicity. 




11:30 AM-12:30 PM 

Development of a nomogram model using a very large sample of patients 

(pts) to predict the risk of 99mTc-bone scan (BS) positivity in pts receiving 

androgen deprivation therapy (ADT) for prostate cancer (PCa). Presenting 

Author: Geoffrey Gotto, Southern Alberta Institute of Urology, Calgary, AB, 

Canada 

Background: Decisions to start imaging pts with PCa can be difficult due to 

the heterogeneous nature of the disease. Nomograms can combine information 

on multiple disease factors to improve predictive accuracy and are not 

influenced by subjective confounders that may affect clinical judgment. 

However, currently available nomograms for PCa predict current or future 

risk of positive BS in ADT-naive pts only. We have developed a new 

nomogram to predict current BS positivity in ADT-treated pts with PCa 

using a very large pt sample. Methods: All BS records from 1650 

ADT-treated pts who received treatment at the Memorial Sloan-Kettering 

Cancer Center from 2000 to 2011 were analyzed. Pts were followed up 

from the start of ADT until the first positive BS or last hospital visit. 

Multivariate logistic regression analysis was used to model the variables 

that could be used for predicting likelihood of metastases and the variables 

were incorporated into the nomogram model. The current probability of 

bone metastasis was generated by the nomogram using the pt variables at 

each BS and the predictive accuracy was quantified by calculating the 

concordance index (C-index). Results: In total, 3949 BS records were 

analyzed and 950 pts had a positive scan. There was an average of 1.1 prior 

negative scans before a positive result was recorded. Median prostatespecific 

antigen (PSA) was 2.5 ng/mL and mean PSA doubling time 

(PSADT) was 7.8 months. At the same time of the positive scans, 49.4% of 

pts had a PSA �10 ng/mL. Based on clinical relevance and data 

availability, 13 variables were included in the nomogram model: number of 

previous negative BSs, PSA, PSADT, prostatectomy, radiotherapy, brachytherapy, 

chemotherapy, immunotherapy, estrogen therapy, cryotherapy, 

clinical trial enrollment, and most recent primary and secondary Gleason 

grades. C-index for the nomogram was 0.76. Conclusions: This is the first 

nomogram to predict current BS positivity in pts with PCa following ADT. 

The nomogram was devised from a very large data set from a single center 

and provides high predictive accuracy. 


11:30 AM-12:30 PM 

Abiraterone in patients with metastatic castration-resistant prostate cancer 

progressing after docetaxel and MDV3100. Presenting Author: Ecaterina 

Ileana, Institut Gustave Roussy, Villejuif, France 

Background: Chemotherapy with docetaxel is the standard first-line treatment 

in patients with metastatic castration-resistant prostate cancer 

(mCRPC). In patients progressing after docetaxel, both abiraterone and 

MDV3100 have yielded improved survival for patients with mCRPC. The 

efficacy of abiraterone in patients pre-treated with MDV 3100 is unknown. 

Methods: We investigated abiraterone-prednisone in 24 patients with 

cancer progression after docetaxel followed by MDV3100. All patients 

received abiraterone 1000 mg/day plus prednisone 10mg/day. Prostatespecific 

antigen (PSA) response, symptom response, and time to progression 

were assessed. Results: Patient characteristics were as follows: median 

age: 74 years (53-84), median PSA: 108 ng/mL (2-2541), metastatic 

sites: bone: all 24 patients, liver/lung: 6 patients (25%), and lymph nodes : 

9 patients (38%). Five patients (21%) had a PSA decrease on abirateroneprednisone. 

Three patients (13%) achieved a PSA response, defined as a 

decrease of �50% in PSA, confirmed after� 4 weeks. The duration of PSA 

response was 2, 3 and 4.5 months. Six patients (29%) had a symptomatic 

response on the pain score and analgesic consumption was decreased. 

Treatment was well tolerated. Abiraterone-prednisone was discontinued in 

one patient due to edema and hypokaliemia. Conclusions: This study shows 

preliminary evidence that abiraterone-prednisone yields activity in patients 

with mCRPC pretreated with docetaxel and MDV3100. 


11:30 AM-12:30 PM 

Durable radiologic and clinical disease stability beyond PSA progression in 

patients with metastatic castration-resistant prostate cancer (mCRPC) 

treated with abiraterone acetate (AA). Presenting Author: Diletta Bianchini, 

The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, 


Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment 

of mCRPC with a survival advantage of 4.9 months. In clinical practice, 

response evaluation remains challenging for pts with mCRPC. CTC conversion 

from CTC � 5toCTC�5with treatment predicts for improved overall 

survival in mCRPC. We hypothesized that pts continue to have durable 

disease stability beyond PSA progression on AA. Methods: Prostate Specific 

Antigen (PSA) responses, radiological responses and CTC conversion rates 

were retrospectively analysed in pts treated on AA at our institution. CTCs, 

PSA and imaging were obtained at predefined time points during these 

studies. Radiological and PSA progression were defined by standard 

Prostate Cancer Working Group Criteria II. Clinical progression consisted of 

worsening disease related pain, skeletal events or declining performance 

status.Pearson’s chi-squared test and the Kaplan-Meier method were used 

for this analysis. Results: 141 patients [ECOG Performance Status 0-2; 

Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 predocetaxel] 

received AA. The median duration of clinical and radiological 

stable disease (SD) was 16.8 months (n�55) and 5.6 months (n�75) in 

patients with a baseline CTCs count of � 5 cells/7.5mls and � 5 cells/7.5 

mls respectively. In the 105 patients with documented PSA progression on 

AA there was a median 5.7-month delay in detecting radiological and/or 

clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological 

and clinical SD of � 1 year, � 2 years and � 3 years on AA was observed 

in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. 

Conclusions: Radiological and clinical disease stabilization beyond PSA 

progression is maintained in a high proportion of mCRPC patients treated 

with AA. Future studies should evaluate whether continued AA treatment 

beyond PSA and radiological progression can impact outcome. 


11:30 AM-12:30 PM 

Association of metabolic syndrome with poorer prostate cancer and overall 

survival in men receiving androgen deprivation therapy (ADT) for biochemical 

relapse. Presenting Author: Sarah Maria Rudman, Division of Cancer 

Studies, King’s College London, Guy’s Hospital, London, United Kingdom 

Background: The metabolic syndrome (MS) has been implicated in the 

development of prostate cancer (PC). In our previous study of a Veterans’ 

Administration (VA) cohort, MS was associated with a shorter duration of 

PC control with ADT. We report the impact of MS on overall survival (OS) 

and PC specific death for a cohort of patients with biochemical relapse. 

Methods: 273 pts (64 VA pts and 209 pts from Health Professionals Follow 

up Study) treated with ADT for biochemical recurrence post radiation or 

prostatectomy for PC were included. The modified Adult Treatment Panel 

III criteria for MS was used to identify patients with MS status prior to the 

commencement of ADT. Cox models tested for association of MS status 

with OS or time to PC specific death. With 42% overall death rate, 31% MS 

prevalence, there was 90% power to detect HR� 1.81 (type I error rate 

�0.05). Results: 31% pts (84/273) had MS and 15% pts (40/273) died of 

PC. Median follow-up was 9.5 years. The median OS with and without MS 

was 7.4 and 11.2 years respectively. Patients with hypertension, being 

African American, having diabetes and age were associated with increased 

risk of death from any causes, while hypertension and being African 

American were also associated with increased risk of PC specific death. A 

multivariate Cox regression model adjusted for age at diagnosis, race, 

definitive local therapy (RT vs. RP), PSA at diagnosis and Gleason score 

revealed MS was associated with a significantly increased risk of death from 

any cause and PC specific death (Table). Conclusions: In men receiving ADT 

for biochemically recurrent androgen dependent PC, the presence of MS at 

the commencement of ADT is associated with an increased risk of death 

from any cause as well as prostate cancer specifically. 

Overall (N�273) 

Comparison Median (years) Event Adjusted HR 

Endpoint (MS status) OS, (95%CI) (patient) (95% CI) P value* 

OS No (ref) 11.17 74 (189) 1 

(10-13.9) 

Yes 7.42 (5.33-12.1) 40 (84) 2.12 

(1.42, 3.16) �0.001 

PCa death No (ref) 25 (189) 1 

Yes 15 (84) 2.03 0.036 

(1.05, 3.94) 



11:30 AM-12:30 PM 

Cytoreduction and androgen signaling modulation by abiraterone acetate 

(AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk 

prostate cancer (PCa): Preliminary results of a randomized preoperative 

study. Presenting Author: Eleni Efstathiou, University of Athens, Athens, 

Greece; University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Endocrine to “intracrine” androgen signaling transition, a 

milestone in the lethal progression of PCa, has not been characterized in 

localized high risk disease. Signaling heterogeneity under the selective 

pressure of castration may account for response differences. Methods: A 

single institution preoperative study of 12 weeks AA 1g/prednisone 5 mg � 

LHRHa compared to LHRHa (randomized 2:1) was conducted in patients 

(pts) with high risk PCa (clinical stage �T1c and biopsy Gleason score �8, 

or �T2b, Gleason � 7 and PSA � 10ng/ml). Primary aim: Assess 

difference in down staging (� ypT2) and safety. Secondary aims: Assess 

difference in androgen biosynthesis, androgen signaling (AR, AR variants, 

NKX 3.1, ERG, PSA) proliferation apoptosis and candidate treatment 

resistance pathways. Results: We report on 37 (50 enrolled) pts who had 

prostatectomy. AA�LHRHa was given to 25pts, LHRHa to 12. Median age 

is 61 ys (46-74). Preoperative PSA was �0.1ng/ml in 17/25 (68%) 

AA�LHRHa vs 0/12 LHRHa (p 0.0001). ypT2N0 occurred in 15/25 (60%) 

AA�LHRHa treated pts vs 4/12 (33%) LHRHa (p 0.17). Near complete 

cytoreduction (�6mm scattered cells) occurred in 6/25 (24%) AA�LHRHa 

vs 1/12 (8%) LHRHa. Lymph node infiltration in 7/25 (28%) AA�LHRHa 

vs 6/12 (50%) LHRHa. Margin positivity in 2/25 (8%) AA�LHRHa vs 4/12 

(33%) LHRHa (p 0.07). Grade 3 AA related AEs: elevated AST/ALT 4 

(discontinued AA), hypertension 3. One AA�LHRHa pt had postop pulmonary 

embolism. Androgen signaling and proliferation suppression is more 

profound in AA�LHRHa treated remaining tumor cells (Table). Conclusions: 

Addition of AA to LHRHa results in greater cytoreduction, suppression of 

PSA and androgen signaling compared to LHRHa in high risk PCa. Findings 

support the hypothesis that intracrine androgen signaling is a therapy target 

in patients with untreated PCa and form the foundation for a marker driven 

treatment strategy. 

Mean tumor expression (involvement)% by IHC (standard deviation). 

Marker AA�LHRHa LHRHa P value Wilcoxon 

AR 27 (26) 69 (22.3) 0.0001 

Nkx3.1 50 (29.8) 83 (14.3) 0.002 

CYP17 64 (22) 75 (14.4) 0.13 

Ki67 3.4 (5) 8.6 (5.7) 0.003 


11:30 AM-12:30 PM 

Exploratory analysis of survival benefit and prior docetaxel (D) treatment in 

COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone 

(P) in metastatic castration-resistant prostate cancer (mCRPC). Presenting 

Author: Oscar B. Goodman, National Cancer Institute, Las Vegas, NV 

Background: AA, a selective androgen biosynthesis inhibitor, blocks the 

action of CYP17, thereby inhibiting adrenal and intratumoral androgen 

production. AA has demonstrated improved overall survival (OS) by 4.6 

months (mos) vs placebo (HR�0.74) in patients (pts) previously treated 

with D. Methods: COU-AA-301 is a randomized double blind study of AA (1 

g) � P (5 mg po BID) vs placebo � P administered to mCRPC pts post-D 

with a primary endpoint of OS. To further evaluate primary survival result 

robustness, we performed post hoc exploratory analyses to assess whether 

the timing of first and last dose of D and reason for D discontinuation 

impacted OS. Results: At randomization, treatment arms were balanced 

with respect to baseline characteristics, prior D use, and reasons for 

discontinuation. In both arms, almost half (45%) discontinued D due to 

progressive disease (PD); remainder discontinued D after completing all 

planned cycles (37%), due to toxicity (12%), or for other reasons (5%) per 

investigator. Median OS from first and last dose of D were longer with AA vs 

placebo (Table). Median OS was longer with AA vs placebo in pts who 

discontinued D for PD, or for all other reasons. Conclusions: These 

exploratory analyses suggest that the OS benefit of AA in mCRPC was 

maintained when calculated from first or last dose of prior D, and whether 

or not pts discontinued D for PD. Pts in AA arm of this study had a 

prolonged median OS of � 32 mos from time of initial D therapy. Congruity 

among these analyses and lack of dependence on D timing demonstrate 

robustness of the primary survival result. 

Median OS, mos (95% CI) 

Category a 

AA 

(N�797) 

Placebo 

(N�398) 

Time from D b 

From first dose D 32.6 (30.7, 35.0) 27.6 (25.9, 30.3) 

HR � 0.75 (0.65, 0.88); p�0.0002 

From last dose D 23.2 (22.4, 24.5) 19.4 (17.5, 20.8) 

HR � 0.74 (0.64, 0.86); p �0.0001 

Reason for D discontinuation c 

PD 14.2 (12.0, 15.8) 10.5 (9.3, 11.8) 

HR � 0.77 (0.62, 0.97); p�0.0222 

All other reasons 17.0 (15.6, 18.2) 12.6 (10.4, 14.9) 

HR � 0.73 (0.59, 0.89); p�0.0025 

a 

Investigator reported (limited source verification); 

b 

calculated from first or last dose of D; 

c 

calculated 

from randomization. 



11:30 AM-12:30 PM 

Time to testosterone (T) and PSA rises during first “off treatment” interval 

(1OFF-2ON) of intermittent androgen deprivation (IAD) as prognostic for 

time to castration resistance (CRPC) and prostate cancer mortality (PCM) in 

men with biochemical relapse (BR). Presenting Author: Evan Y. Yu, Fred 

Hutchinson Cancer Research Center, Seattle, WA 

Background: A recent phase III trial of intermittent vs. continuous AD 

supports IAD as standard of care for men treated with AD for BR. To identify 

potential prognostic factors during 1OFF, times to T and PSA rises from our 

prospective trial of IAD in men with BR were analyzed in relation to times to 

CRPC and PCM. Methods: 72 men with BR after definitive local therapy 

were treated with IAD, each cycle consisting of 9 months of leuprolide and 

flutamide followed by a variable “off treatment” interval. T and PSA were 

followed monthly; AD was resumed when PSA reached a pre-specified 

value. Cycles repeated until CRPC, defined as �2 PSA rises with T�50 

ng/dL. Markers of interest from 1OFF-2ON were time to first T�50, time 

from first T�50 to first PSA rise �0.1 ng/mL, time to first PSA rise �0.1, 

and PSA doubling time (PSAdt), calculated using the first 3 PSA measurements 

starting from first PSA �0.1. The associations of these markers with 

CRPC and PCM were evaluated using Cox proportional hazards models (or 

logistic regression if the Cox proportional hazards assumption was not met), 

controlling for age at study entry and Gleason score categorized to �7 or 

�7. Results: A 30-day increase in time to first T�50 was significantly 

associated with a 75% increase in the risk of PCM. A 30-day increase in 

time to PSA rise from 1OFF or after T�50 was significantly associated with 

a 23% or 72% reduction in the risk of CRPC, respectively. While neither of 

the associations of PSAdt with CRPC or PCM were significant, they were of 

moderate size: PSAdt displayed a moderate reduction in risk of CRPC by 

35% and PCM by 38%. Conclusions: During the first “off treatment” 

interval of IAD, the time to first T�50 is prognostic for PCM. Time to first 

PSA rise after 1OFF and after first T�50 are both prognostic for CRPC. 

Time to CRPC Time to PCM 

Marker 

N HR P value 95% CI N HR P value 95% CI 

1OFF to T>50 

T>50 to PSA>0.1 

46 

45 

1.1 

0.28 

0.67 

0.05 

(0.71, 1.7) 

(0.08, 0.99) 

49 

48 

1.75 

0.28 

0.01 

0.19 

(1.14, 2.68) 

(0.03, 1.63) �� 

1OFF to PSA>0.1 57 0.77 0.01 (0.63, 0.93) 60 0.85 0.24 (0.65, 1.11) 

PSAdt 49 0.65 0.08 (0.4, 1.06) 52 0.62 0.29 (0.26, 1.5) 

�� Odds ratio. 

291s 


11:30 AM-12:30 PM 

The effect of PSA frequency and duration on PSA doubling time (PSADT) 

calculations in men with biochemically recurrent prostate cancer (BRPC) 

after definitive local therapy. Presenting Author: Channing Judith Paller, 

The Johns Hopkins Hospital, Baltimore, MD 

Background: The prognostic nature of PSADT in men with BRPC makes it an 

attractive intermediate endpoint for assessing novel therapies in these 

patients. Although a number of investigational agents appear to favorably 

modulate PSADT, slowing in PSADT has also been observed in placebotreated 

men. We aimed to determine whether PSADT calculations could be 

influenced by the frequency and duration of PSA measurements. Methods: 

We performed a retrospective analysis of men with BRPC who chose to 

defer hormonal therapy. Eligible men were those with PSA values �0.2 

ng/mL and at least 6 values taken on average 3 mo apart, and whose local 

prostate cancer therapy was completed �1 year prior. To examine the 

influence of PSA frequency and duration on PSADT, we calculated median 

PSADT using different subsets of available PSA values (e.g. each vs every 

other; and first 3 vs. remaining PSA values). Results: After a median 

follow-up of 58 mo (range, 6-185 mo), 213 men with BRPC had �6 PSA 

values and 127 men had �9 PSA values for analysis. Men (77% white, 

23% black/other) had a median age of 61 y with Gleason score distribution 

as follows (�6: 30%; 7: 40%; �8: 18%; NOS: 12%). For men with �6 

data points: PSADT calculated using earlier values ranged from 13.2 to 

16.6 mo, compared to 16.6 to 17.8 mo, respectively, for the remaining 

values (within-patient change range: 0.6-1.2 mo). For men with �9 data 

points: PSADT calculated using earlier values ranged from 15.3 to 19.9 mo 

compared to 22.1 to 22.3 mo, respectively, for the remaining values 

(within-patient change range: 3.5 to 4.5 mo). When we examined the 

frequency of PSADT by using every other value, we found little difference 

(22.3 vs 22.1 mo). Conclusions: These data show that PSADT appears to 

increase even in the absence of therapy, and may be influenced by duration 

of PSA follow up. This finding explains PSADT slowing on placebo arms and 

calls into question the utility of PSADT as a surrogate endpoint. Placebocontrolled 

trials and the use of standard clinical endpoints are recommended 

to screen novel agents in men with BRPC to mitigate bias because 

of natural PSADT variability. 




11:30 AM-12:30 PM 

Development of a needle biopsy-based genomic test to improve discrimination 

of clinically aggressive from indolent prostate cancer. Presenting 

Author: Eric A. Klein, Glickman Urological and Kidney Institute, Cleveland 

Clinic, Cleveland, OH 

Background: Standardized, quantitative tools are needed to improve discrimination 

of clinically aggressive from indolent prostate cancer at diagnosis. 

We previously identified multiple genes and biological pathways in radical 

prostatectomy (RP) specimens associated with clinical recurrence and 

adverse pathology. We evaluated whether measurement of these genes in 

prostate needle biopsy (Bx) specimens predicts adverse pathology - high 

grade (GS � 4�3) and/or non-organ-confined disease (pT3) - in a separate 

study of AUA low-intermed risk pts treated w/ RP. Methods: All AUA 

low-intermed risk (cT1-T2a, GS 3�3/3�4) pts treated w/ RP �6 mos from 

Bx at Cleveland Clinic (1999-2007) w/ available Bx tissue and �3 pos 

cores were evaluated. Expression of 81 prognostic genes identified in 

previous RP studies and 5 reference genes was quantitated by RT-PCR in 

60 �m manually microdissected FPE prostate needle Bx tissue. Association 

of gene expression w/ adverse pathology was analyzed by logistic 

regression controlling false discovery rate (FDR) using Storey’s method. 

Results: RT-PCR was successful for 167 of 171 (98%) pts (92 AUA low, 75 

intermed). At RP, 58 pts (35%) had high-grade and/or non-organ confined 

disease. 58 of 81(72%) genes predicted high grade and/or non-organconfined 

disease (FDR�10%), including all stromal response and androgen 

genes and the majority of cellular organization genes (82%). 

Proportionately fewer proliferation (40%), stress response (29%), and 

basal epithelial (25%) genes were associated w/ adverse path. Androgen 

and cellular organization genes consistently predicted lower risk; stromal 

response and proliferation genes predicted higher risk; (majority of std odds 

ratios �1.5, comparable to the prognostic strength of ER in breast cancer). 

Conclusions: Genes and biological pathways associated w/ clinically aggressive 

prostate cancer in RP specimens can be reliably measured by RT-PCR 

from fixed prostate needle biopsies and predict high-grade, non-organconfined 

disease. These results support the potential value of a Bx-based 

assay to inform selection of immediate treatment or active surveillance for 

pts diagnosed with prostate cancer on needle Bx. 


11:30 AM-12:30 PM 

Predictive biomarkers in circulating tumor cells (CTC) from patients with 

castration-resistant prostate cancer (CRPC) through genomic analysis. 

Presenting Author: Daniel Costin Danila, Sidney Kimmel Center for 

Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: Mutations in the ligand binding domain of androgen receptor 

(AR) in prostate cancer cells may alter their sensitivity to treatment with 

specific antiandrogens. To predict for tumor sensitivity to treatment with 

novel AR targeted therapies, we explored the frequency of mutation 

detection and copy number alteration in CTC isolated from patients with 

CRPC enrolled on trials with these targeted therapies. Methods: We used 

fluorescence-activated cell sorting (FACS) methodology to enrich EpCAM� , 

CD45- , DAPI- cells. For mutation detection and genomic copy number 

alteration in CTC in low number of cancer cells found in clinical samples, 

we optimized next-gen deep sequencing by Illumina. Results: In patients 

with progressive CRPC , �10 or �50 EpCAM� events (EPE) were isolated 

by FACS in 88% or 58% of patients, in whom 32% and 10% had 

unfavorable (�5 cells/7.5 ml) CTC counts using CellSearch. EPE, expressing 

prostate-specific mRNAs, provide sufficient high quality DNA for 

genomic sequencing and copy number analysis. Adequate coverage was 

obtained from as few 50 EPE, with a recovery rate of 89% from FACS sorted 

samples. The detection threshold of a mutation was established at 1:4 

alleles. To further expand genomic profiling in CTC, we optimized Nimblegen 

exome mutation detection by deep sequencing on HiSeq PE101. Our 

initial analysis established the polymorphism frequency detection thresholds 

in heterogeneous cell populations, and confirmed the sequencing 

coverage. Somatic missense mutations in AR, APC and TP53 found in CTC 

but not in paired WBC were confirmed by Sanger sequencing. In parallel, 

copy number alterations in CTC are studied. Conclusions: Somatic mutations 

detected in CTC isolated from patients with CRPC can serve as 

predictive markers of tumor sensitivity to targeted therapies. We established 

standard operating procedures for specimen processing, and confirmed 

the sequencing coverage and polymorphism detection thresholds in 

heterogeneous cell population. Currently we are proceeding to clinical 

samples to study the associations between specific molecular alterations in 

CTC as predictive markers of sensitivity and clinical outcomes. 


11:30 AM-12:30 PM 

Gene expression biomarkers to predict overall survival of prostate cancer 

patients. Presenting Author: Chunde Li, Department of Clinical Oncology, 

Karolinska University Hospital, Stockholm, Sweden 

Background: Current clinical parameters are not accurate in the prediction 

of overall survival of prostate cancer patients. Methods: Driven by cancer 

stem cell hypothesis and by using a simple bioinformatics analysis, we 

identified 641 genes with either consistently high or low level of expression 

in human embryonic stem cells. We showed that these 641 genes had 

strong power to classify cancers into different biological subtypes and 

named them as embryonic stem cell gene predictors (ESCGPs). Nineteen 

selected ESCGPs and five control genes were analyzed by multiplex 

quantitative PCR in prostate fine needle aspiration (FNA) samples taken at 

diagnosis. The cohort included 189 patients diagnosed during 1986- 

2001. Of these patients, 97.9% had overall and cancer specific survival 

data and 77.9% were treated by medical or surgical castration as the 

primary treatment. The cohort was divided into a discovery and two 

validation subsets. The univariate and multivariate Cox proportional hazards 

and Kaplan-Meier plots were used in the survival analysis. A published 

dataset was used for an external validation. Results: Ten gene markers F3, 

WNT5B, VGLL3, CTGF, IGFBP3, c-MAF-a, c-MAF-b, AMACR, MUC1 and 

EZH2, showed a significant correlation to overall or cancer specific survival. 

Four of these genes, F3, IGFBP3, CTGF and AMACR, were independent of 

all clinical parameters. An expression signature of F3, VGLL3 and IGFBP3 

characterized patients into three subtypes. The median overall survival was 

2.60 years in the high risk, 3.85 years in the intermediate risk and 7.98 

years in the low risk subtype, corresponding to a HR of 5.86 (95% CI 

2.91-11.78, p�0.001) for the high risk and 3.45 (95% CI 1.79-6.66, 

p�0.001) for the intermediate risk over the low risk subtype. Two gene 

markers, F3 and EZH2, were further verified by the external validation. 

Conclusions: The new ESCGP gene markers and the expression signatures 

can be used to predict the overall and cancer specific survival of prostate 

cancer patients. 


11:30 AM-12:30 PM 

Generation of a prognostic cancer stem-like gene expression signature in 

men undergoing radical prostatectomy for localized prostate cancer. 

Presenting Author: Adrian Stuart Fairey, University of Southern California, 

Los Angeles, CA 

Background: Novel biomarkers are needed to predict recurrence after 

radical prostatectomy for localized prostate cancer. Recent data suggest 

that cancer stem-like cells (CSC) are present in prostate tumors, and the 

CSC phenotype has been associated with an aggressive cancer phenotype. 

We investigated whether tumor mRNA levels of genes typically expressed 

by CSC are associated with disease recurrence. Methods: Clinically annotated 

prostatectomy specimens (FFPE) were used for this nested casecontrol 

study. Samples represented men who underwent radical 

prostatectomy and either experienced a recurrence (PSA or clinical; 

n�152) or no recurrence (controls; n�124) with minimum 5-year followup. 

Men were excluded if they received neoadjuvant hormone therapy. 

Cases and controls were frequency matched based on D’Amico risk group. 

Laser capture microdissection with mRNA extraction and quantitative 

RT-PCR were used to quantify the expression of 12 candidate CSCassociated 

genes (ALDH1A1, Axin2, Bmi1, CD133, CD44a, CTNNB1/�catenin, 

ITGA2/integrin �2, NANOG, Nkx3-1, Notch1, OCT 4, TACSTD2/ 

Trop2). Univariable and multivariable analyses were conducted to measure 

associations with recurrence. Results: mRNA data were evaluable for 241 of 

276 patients. Univariate Wilcoxon analysis showed that 4 genes (Axin2, 

p�0.001; CD44a, p�0.036; OCT 4, p�0.017; TACSTD2, p�0.008) were 

expressed at low levels in tumors of patients whose disease recurred. 

Recursive partitioning analysis identified 3 genes significantly predictive of 

disease recurrence (Axin2, NANOG, CTNNB1), with cutpoints yielding 

odds ratios (OR) of 8.5 (Axin2low /NANOGhigh ;n�94, 95%CI 3.7-19.2) and 

5.1 (Axin2low /NANOGvery high /CTNNB1low ; n�26, 95%CI 1.7-14.8). 

Conclusions: We identified a novel CSC-associated 3 gene expression 

signature with the potential to predict recurrence after radical prostatectomy. 

Axin2 is known to interact with CTNNB1/�-catenin in the Wnt 

signaling pathway, which in turn has been shown to regulate expression of 

NANOG, a key protein that mediates pluripotency. In vitro experiments and 

an independent cohort validation study are planned based on these novel 

findings. 



11:30 AM-12:30 PM 

Pretreatment (pre-tx) neutrophil to lymphocyte ratio (NLR) in metastatic 

castration-resistant prostate cancer (mCRPC) patients (pts) treated with 

ketoconazole (keto): Association with outcome and predictive model. 

Presenting Author: Avishay Sella, Assaf Harofeh Medical Center, Zerifin, 

Israel 

Background: The CYP17 inhibitor keto is active in mCRPC. The NLR, an 

index of systemic inflammation, is associated with prognosis in several 

types of cancer. We assessed the association between pre-tx NLR and 

outcome of mCRPC pts treated with keto. Methods: We performed an 

international multicenter retrospective study of pts with mCRPC, who were 

treated with keto. We analyzed the pre-tx NLR and previously described 

factors associated with keto tx outcome as prior response to hormonal tx, 

pre-tx PSADT, and extent of metastatic disease (limited vs extensive). 

Progression free survival (PFS) was determined by the Kaplan-Meier 

method. Multivariate analyses using Cox regression model were performed 

to determine their independent effect, and to form a predictive model. A 

survival tree analysis was used to find the best NLR cut-off value. Results: 

From 1999-2011, 156 mCRPR pts (median age 69) were treated with 

keto. 78/156 (50%) had � 50% PSA decline. Overall median PFS was 8 

months (mos) (range 1-144). Excluded from the analysis were 23 pts 

without available data on pre-tx NLR, and those with recent (�1 mos) 

health event or tx (surgery, steroids, radiation) associated with a change of 

blood counts. 133 pts were included in the analysis. 62 (47%) had an 

elevated pre-tx NLR �3. Risk factors associated with PFS (table) were 

pre-tx NLR �3, prior response to GnRH-a �24 mos and to antiandrogen 

(AA) �6 mos, and pre-tx PSADT �3 mos. The number of risk factors was 

used to categorize patients into three risk groups (table): favorable (0-1 

factors), intermediate (2 factors), and poor (3-4 factors). Conclusions: In 

mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, 

and pre-tx PSADT are associated with PFS, and may be used to categorize 

pts into risk groups. 

Factor PFS (mos) (HR, p value) 

NLR < 3vs>3 14 vs 3, (0.353, �0.0001) 

Response to prior GnRH-a 

12 vs 5, (0.513, 0.035) 

> 24 vs < 24 mos 

Response to prior AA 

18 vs 3, (0.445, 0.003) 

>6vs3vs



11:30 AM-12:30 PM 

Dual antiangiogenic therapy using lenalidomide and bevacizumab with 

docetaxel and prednisone in patients with metastatic castration-resistant 

prostate cancer (mCRPC). Presenting Author: Bamidele Adesunloye, Medical 

Oncology Branch, National Cancer Institute, National Institutes of 


Background: Previously, we had shown the potent anti�tumor activity of 

dual anti-angiogenic therapy by combining bevacizumab (B) and thalidomide 

(T) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 

2010). We hypothesized that combining lenalidomide (L), an analogue of 

T, with B, D, and P would have a more favorable efficacy/toxicity profile. 

Methods: All patients (pts) had chemotherapy�naïve mCRPC. Among the 

first 52 pts, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 

25 mg daily for 14 days of every 21�day cycle (C). The protocol was 

recently amended to enroll 11 more pts at L 15 mg; 2 pts have now been 

enrolled in this expansion cohort. All pts received D 75 mg/m2 and B 15 

mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. 

Pegfilgrastim was given on day 2. PSA each C with imaging after C2 and 

after every 3C. Dental exams with mandible CT scan at baseline, after C5, 

and every 6C. Results: 54 of 62 pts have been enrolled. Median age 65.5 

(51�82), Gleason score 8 (5�10), on�study PSA 85.2 ng/ml 

(0.15�3520), and pre�study PSA doubling time 1.49 months 

(0.52�6.73). Median number of Cs was 16 (3�38). PFS was 22 months 

and probability of survival at 12 months was 90%. Forty-six (85.2%) and 

42 (77.8%) pts had PSA declines of �50% and �75%, respectively. Of 30 

pts with measurable disease there were 1 CR and 25 PR (86.7% overall 

RR). 17/54 pts were off study for radiographic disease progression and 

8/54 for other reasons. Grade �2 toxicities included neutropenia (34/54), 

anemia (23/54), thrombocytopenia (7/54), hypertension (12/54), perianal 

fistula (3/54), rectal fissure (1/54), myocardial infarction (1/54), and 

osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of 

ONJ, 7/12pts were on bisphosphonates (BP), 2/12 had used BP previously, 

and 3/12 never used BP. The incidence of ONJ was comparable to 18.3% 

reported by Ning et al. A recent study of carboplatin plus weekly docetaxel 

reported an incidence of 29.3%. Conclusions: Dual anti-angiogenic therapy 

with, B and L, plus D and P was associated with high PSA (85.2%) and 

tumor (86.7%) responses in mCRPC, with manageable toxicities. The 

incidence of ONJ is comparable to other studies. 


11:30 AM-12:30 PM 

Preliminary quality-of-life outcomes for SWOG-9346: Intermittent androgen 

deprivation in patients with hormone-sensitive metastatic prostate 

cancer (HSM1PC)—Phase III. Presenting Author: Carol Moinpour, Fred 


Background: The relative quality of life (QOL) for patients with newly 

diagnosed, metastatic prostate cancer, treated with intermittent androgen 

deprivation (IAD) has been assumed and hypothesized, yet never compared 

in a well-powered randomized trial (RT) to continuous androgen deprivation 

(CAD). SWOG-9346 provided such a RT in which to test QOL differences 

between CAD and IAD in men with metastatic prostate cancer. Methods: 

Patients were randomized to CAD or IAD. Patients completed the SWOG 

QOL Questionnaire (SF-20/SF-36, Symptom Distress Scale, treatmentspecific 

symptoms, global QOL) at randomization and months (mo) 3, 9, 

and 15 post-randomization. Five QOL change scores at one time point (mo 

3) were designated as primary for the QOL endpoint and are reported in this 

abstract: impotence, libido, energy/vitality (E/V), physical function (PF), 

and emotional function (EF). Significance level was adjusted for 5 

comparisons (used p�0.01). Results: 615 patients in the CAD arm and 

633 in the IAD arm completed the QOL questionnaire at baseline. Change 

between baseline and 3 months differed for the two arms with CAD 

reporting statistically significantly more impotence and less libido than 

IAD. EF was also slightly better for the IAD arm. Conclusions: These results 

indicate better sexual function in men receiving IAD versus CAD through 

post-randomization month 3. Additional benefits for IAD may include 

better PF, E/V and EF. Ongoing analyses will address the role of missing 

data, additional follow-up assessments, and resumption of therapy in the 

IAD arm. 

Baseline treatment arm 

Impotence % 

(n) 

Libido % 

(n) 

EF^ score 

(n) 

PF^ score 

(n) 

E/V^ score 

(n) 

Descriptive results 

3-mo 

CAD IAD CAD IAD T-test p values* 

.85 

(546) 

.03 

(560) 

80.0 

(568) 

70.2 

(569) 

59.8 

(557) 

.82 

(585) 

.04 

(580) 

77.9 

(595) 

70.7 

(591) 

59.7 

(586) 

.87 

(487) 

.04 

(481) 

79.0 

(491) 

69.3 

489) 

58.9 

(478) 

.73 

(494) 

.11 

(486) 

79.6 

(500) 

71.3 

(500) 

60.0 

(489) 

*T-test of arm difference in baseline to 3-month change for patients with both assessments; ^0-100 scale. 

� 0.01 

� 0.01 

� 0.01 

0.08 

0.23 


11:30 AM-12:30 PM 

A multinational phase III adjuvant study of immediate (I) versus deferred 

(D) chemotherapy (C)/hormone therapy (HT) after radical prostatectomy 

(RP): TAX-3501. Presenting Author: Mario A. Eisenberger, Sidney Kimmel 

Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 

Background: TAX 3501 was designed to test I or D C/HT after RP. No 

adequately designed prospectively randomized surgical systemic adjuvant 

studies have ever been successfully completed. Methods: TAX-3501 was a 

randomized phase III study. Eligibility included post-operative predicted 

probability of 5-year freedom from progression of �60% (Kattan et al) 

after central pathology review, no prior C/HT, undetectable PSA, M0, 

normal hematology/chemistries, signed consent. Pts were randomized 

within 120 days after RP to I or D (at 1st progression) Rx with HT (leuprolide 

acetate 22.5mg S.C. q.3 months x6)�/- C (docetaxel 75mg/m2 q.3wks x 

6). F/U included a physical exam, PSA, CBC/chemical profile, serum T, 

scans yearly or at progression (PSA� 0.4ng/ml, clinical or radiographic 

and death). Main objectives comparing PFS and 5-year progression-free 

rates after systemic treatment (2 � 2 factorial design, 4 arms). 1,696 

subjects would provide 90% power to detect the targeted treatment effect 

at a 5% 2-sided type I error level. Results: From 12/2005-9/2007399 

pts were registered, 228 randomized after central path review ICHT�55, 

IHT�55, DCHT�56, DHT�62, median age 62 (41-76), pre-op PSA 

(ng/ml) 9.38 (2.2 - 90.0), Gleason score- 8,T3a (19.6%), 

R�(65%),S.V.�(50%),N�(19.7%%), all had undetectable post op PSA. 

Predicted probability of no progression was 21% on 228pts. Study was 

terminated by sponsor (9/2007) due to poor accrual F/U continued from 

2007-2010. Small sample size precludes reliable analyzes 37/118 (31.3%) 

on the D arms received CHT/HT (all PSA progressions); ICHT 10/55, IHT 

14/55, DCHT 9/56, DHT 8/62 met progression endpoint after I/D Rx (1/31 

bone). AEs were characteristic and reversible (no grade 5). Leading causes 

of accrual impediment were inadequate site selection, no consensus 

regarding patient and treatment selection for this pt population, physician 

and patient bias re: treatment and evolving changes in the adjuvant 

treatment landscape during follow-up time (adjuvant RT). Conclusions: The 

role of adjuvant systemic treatment after RP remains undefined. Clinical 

trials in this pt population are challenging. Supported by Sanofi 

NCT000283062. 

4572 General Poster Session (Board #1A), Sun, 8:00 AM-12:00 PM 

Intravesical sequential BCG and electromotive mitomycin versus BCG 

alone in high risk non-muscle invasive bladder cancer. Presenting Author: 

Savino Mauro Di Stasi, Department of Surgery/Urology, Tor Vergata 

University, Rome, Italy 

Background: In 2006, we reported that intravesical sequential bacillus 

Calmette-Guérin (BCG) and electromotive mitomycin in high risk nonmuscle 

invasive bladder cancer leads to higher disease-free interval, lower 

recurrence and progression, and to improved overall survival and diseasespecific 

survival compared with BCG alone. After an additional 6 years of 

follow-up, we now report estimated 16-year results. Methods: From 1994 

through 2002, we randomly assigned 212 patients with high risk non- 

.muscle invasive bladder cancer to 81 mg BCG infused over 120 min once 

a week for 6 weeks (n�105) or to 81 mg BCG infused over 120 min once a 

week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical 

electric current 20 mA for 30 min) once a week as one cycle for three cycles 

(n�107). Complete responders underwent maintenance treatment: those 

assigned BCG alone had one infusion of 81 mg BCG once a month for 10 

months, and those assigned BCG and mitomycin had 40 mg electromotive 

mitomycin once a month for 2 months, followed by 81 mg BCG once a 

month as one cycle for three cycles. The primary endpoint was disease-free 

interval. Analyses were done by intention to treat. Results: Median follow-up 

was 121 months (IQR 70.5–163.5). Patients assigned sequential BCG and 

electromotive mitomycin had higher disease-free interval than did those 

assigned BCG alone (79 months [95% CI 27–139] vs 26 months 

[11–113]; difference between groups 53 months [39–67], log-rank 

p�0.0002). Patients assigned sequential BCG and electromotive mitomycin 

also had lower recurrence (45% [35–55] vs 62% [50–72], difference 

between groups 17% [6–28], log-rank p�0.0002); progression (12% 

[3–21] vs 28% [17.5–38.5], difference between groups 16% [5–27], 

log-rank p�0.003); overall mortality (44% [33–55] vs 59% [43–75], 

difference between groups 15% [2–28], log-rank p�0.01); and diseasespecific 

mortality (9% [2.5– 15.5] vs 23% [11–34], difference between 

groups 14% [4–24], log-rank p�0.0055). Conclusions: In patients with 

high risk non-muscle invasive bladder cancer intravesical BCG combined 

with electromotive mitomycin provided better results than BCG alone in 

terms of higher remission rates and longer remission times. 


4573 General Poster Session (Board #1B), Sun, 8:00 AM-12:00 PM 

Expression of MET and HGF in bladder cancer tumorigenesis and invasion. 

Presenting Author: Randy F. Sweis, University of Michigan, Ann Arbor, MI 

Background: The human MET gene encodes the hepatocyte growth factor 

(HGF) tyrosine kinase receptor. Limited studies in human bladder cancer 

have demonstrated that expression of MET protein is linked with disease 

progression and survival. We hypothesized that the expression of both MET 

and its ligand HGF are altered in bladder cancer. Methods: Expression of 

MET and HGF in human bladder tissues was explored using Oncomine, an 

online compendium of cancer transcriptome profiles. The largest relevant 

dataset was identified and contained 157 samples (Sanchez-Carbayo, et al. 

2006). Normalized and log2 transformed mRNA expression values for 

Affymetrix U133 microarray probe sets corresponding to the genes of 

interest were compiled and averaged for each gene. Mann-Whitney U 

testing was used to compare means. Nominal and standard least squares 

logistic regression was used to evaluate the predictive significance of, and 

relevance of clinicopathologic variables on, gene expression. Statistical 

analyses were carried out using JMP 9.0.2. Results: Expression of MET and 

HGF was compared across subsets of normal bladder tissue (n�48), 

superficial tumors (n�28), and invasive tumors (n � 81). Relative to 

normal tissue, MET expression was greater in superficial (p � 0.0008) and 

invasive tumors (p�0.0001). HGF expression was reduced in both invasive 

and superficial tumors vs. normal tissue (both p� 0.0001), but was higher 

in invasive vs. superficial tumors (p� 0.0007). In a logistic regression 

model of tumor samples, both MET and HGF correlated with tumor invasion 

(model p�0.0003). Interaction between MET and HGF was not significant 

(p�0.55). Neither MET nor HGF expression was predicted by regression 

using age, gender, grade, or nodal stage (p�0.16 and 0.27, respectively). 

Conclusions: Decreased HGF expression and MET over-expression are 

strongly associated with tumorigenesis and invasion in bladder cancer. The 

reduction in HGF expression is blunted in invasive vs. superficial tumors, 

suggesting a potential loss of negative feedback in more aggressive tumors. 

Expression of both genes could not be predicted by modeling clinicopathologic 

variables. MET signaling represents a potential therapeutic target in 

bladder cancer. 

4575 General Poster Session (Board #1D), Sun, 8:00 AM-12:00 PM 

Defining a nine-biomarker panel for predicting bladder cancer outcome in 

combination with smoking intensity: A report from the Los Angeles Cancer 

Surveillance Program. Presenting Author: Anirban Pradip Mitra, University 

of Southern California Keck School of Medicine and Norris Comprehensive 


Background: Urothelial carcinoma of the bladder (UCB) is a disease of 

alterations in several cellular pathways. Routine molecular profiling studies 

do not account for smoking, a well established risk factor for UCB, and its 

influence on outcome. This study assessed the prognostic potential of a 

multi-pathway protein panel across all UCB stages in a population-based 

cohort after accounting for clinicopathologic factors and smoking history. 

Methods: 212 UCB patients from the LA CSP, part of the NCI/SEER cancer 

registry, were included. �Smoking intensity� analyzed biologic and molecular 

impact of smoking by combining smoking status, duration of smoking 

and number of cigarettes smoked daily into a composite covariate. Tumors 

were profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, COX2, VEGF 

and E-cadherin alterations by IHC. Univariate analyses and multivariable 

modeling examined associations with outcome. Results: Median follow up 

was 13.2 years. Age, pathologic stage, adjuvant therapy (all p� 0.001) and 

surgical modality (p � 0.05) were associated with survival. Increasing 

smoking intensity was associated with worse outcome (P � 0.001). Apaf-1 

(p � 0.005), E-cadherin (p � 0.014) and p53 (p � 0.032) were 

univariately prognostic; E-cadherin remained prognostic after multivariate 

analysis (p � 0.04). Combined alterations in all 9 biomarkers were 

prognostic by univariate (p � 0.001) and multivariate (p � 0.006) 

analysis. A multivariate model that included all 9 biomarkers and smoking 

intensity was more accurate in predicting prognosis than models comprising 

of standard clinicopathologic covariates without (p � 0.001) or with (p 

� 0.018) smoking intensity. Conclusions: The study confirms detrimental 

effects of smoking on UCB prognosis. Apaf-1, E-cadherin and p53 

individually predicted UCB survival. Increasing number of biomarker 

alterations was significantly associated with worsening survival, although 

markers contained in the panel were not necessarily prognostic individually. 

Predictive value of the nine-biomarker panel with smoking intensity 

was significantly higher than that of routine clinicopathologic parameters 

alone. 


4574 General Poster Session (Board #1C), Sun, 8:00 AM-12:00 PM 

Results of a phase II study of pralatrexate in patients with advanced/ 

metastatic relapsed transitional cell carcinoma of the urinary bladder. 

Presenting Author: Yohann Loriot, Institut Gustave Roussy, Villejuif, France 

Background: Antifolate agents have demonstrated activity in transitional 

cell carcinoma (TCC), a disease with very poor outcomes in advanced 

stages. Pralatrexate (FOLOTYN, Allos Therapeutics, Inc., Westminster, 

CO), a folate analogue targeting dihydrofolate reductase, is designed for 

enhanced uptake and accumulation in tumor cells. The objective of this 

study was to examine the activity and safety of pralatrexate in patients (pts) 

with advanced/metastatic TCC of the urinary bladder after failure of prior 

chemotherapy. Methods: Pts with histologically confirmed TCC (�50% TCC 

in tumor) received pralatrexate 190 mg/m² intravenously on days 1 and 15 

of a 28-day cycle supplemented with vitamin B12 and folic acid. Included 

pts had Eastern Cooperative Oncology Group performance status of 0–1, 

measurable disease, and prior treatment with �1 platinum- and/or methotrexate-based 

regimen in the recurrent/metastatic setting. Results: Thirty 

pts were enrolled and treated. All pts received prior platinum-based 

therapy, and 7 pts (23%) received methotrexate in a multidrug regimen. 

One pt had a confirmed partial response (PR); 4 additional pts had 

unconfirmed PRs. Twelve pts had stable disease. The median number of 

cycles received was 2 (range, 1–24), and median time on treatment was 56 

days (range, 1–714). The median progression-free survival (PFS) and 

overall survival for all pts was 4.0 months (95% confidence interval [CI], 

2.1–4.5) and 9.3 months (95% CI, 5.6–13.2), respectively. Eight pts 

(27%) had PFS �6 months and 3 pts (10%) had PFS �12 months. Eight 

pts (27%) underwent dose reductions, all due to mucositis. Six pts (20%) 

discontinued the study due to treatment-related adverse events (AEs)— 

mainly mucositis. The most frequent treatment-related AEs were stomatitis 

(77%), asthenia (30%), vomiting (27%), and anemia, nausea, and 

neutropenia (23% each). Conclusions: Pralatrexate showed evidence of 

activity and durable disease control when used as a single agent in pts with 

advanced bladder cancer, although the overall response rate was modest. 

Further study of pralatrexate in this setting should focus on improving drug 

delivery and evaluation of novel combination approaches. 

4576 General Poster Session (Board #1E), Sun, 8:00 AM-12:00 PM 

The impact of preoperative ASA score and serum albumin on early 

complication and survival rate of patients undergoing radical cystectomy 

for bladder cancer. Presenting Author: Hooman Djaladat, Institute of 

Urology, University of Southern California, Los Angeles, CA 

Background: American Society of Anesthesiologist Score (ASA-S) is used to 

evaluate patient physical status before surgery. Serum albumin (Alb) is also 

a marker of nutritional status. We evaluated the impact of preoperative 

ASA-S and Alb on early complication rate and survival of patients who 

underwent radical cystectomy for bladder cancer. Methods: 1964 patients 

with primary bladder cancer underwent radical cystectomy between 1971 

and 2008 at USC. Preoperative serum Alb and ASA-S were available in 

1471 and 1140 patients respectively. Post cystectomy early complication 

was defined as any surgery related/unrelated event leading to lengthening 

hospital stay or re-admission within 90 days of surgery. Recurrence free 

survival (RFS) and overall survival (OS) for these cohorts were reviewed 

using a Kaplan-Meier and Cox proportional hazards models. Results: The 

demographic data of patients based on their serum Alb and ASA-S is 

presented in the Table. The median follow up was 12.4 years (0 - 36.6 yrs). 

Low serum Alb (�3.4 g/dL) and high ASA-S (3 or 4) were associated with 

higher early complication rate (43% vs. 33%, p� 0.03 and 40% vs. 28%, 

p� 0.0001 respectively). In multivariable analysis, low serum Alb level was 

an independent predictor of RFS (HR 1.35, 95% CI 1.00-1.81) and OS 

(HR 1.62, 95% CI 1.29-2.04). High ASA-S was an independent predictor 

of OS (HR 1.45, 95% CI 1.13-1.85), but not RFS. Conclusions: Preoperative 

low serum Alb and high ASA-S are independently predictive of post 

cystectomy decreased OS. Low serum Alb is also a risk factor for recurrence 

after cystectomy. These parameters potentially could be used in nomograms 

to predict post-cystectomy prognosis. 

Demographic data in patients who underwent cystectomy for bladder 

cancer based on preoperative serum Alb and ASA-S respectively. 

Pts No Male sex 

Alb< 3.4 137 92 

(67%) 

Alb> 3.4 1334 1062 

(79%) 

ASA�1, 2 400 320 

(80%) 

ASA�3, 4 740 574 

(78%) 

Median age 

(range) LVI 

74 

(51-90) 

67 

(30-93) 

60 

(35-90) 

69 

(33-92) 


62 

(45%) 

373 

(28%) 

98 

(25%) 

226 

(30%) 

Multi 

focality 

46 

(33%) 

497 

(37%) 

150 

(38%) 

275 

(37%) 

High 

grade 

126 

(92%) 

1101 

(82%) 

317 

(79%) 

608 

(82%) 

295s 

Stage 

> pT3 

87 

(63%) 

461 

(35%) 

116 

(29%) 

258 

(35%)


4577 General Poster Session (Board #1F), Sun, 8:00 AM-12:00 PM 

FGFR3 protein expression and gene mutation in primary and metastatic 

urothelial carcinoma (UC) tumors. Presenting Author: Jonathan E. Rosenberg, 

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/ 

Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 

Background: FGFR3 protein expression may represent a valid therapeutic 

target in metastatic UC. The prevalence of both mutation and overexpression 

is unknown in metastatic UC. Methods: Tissue microarrays of formalin 

fixed paraffin-embedded urothelial carcinomas (UC) were stained for 

FGFR3 by immunohistochemistry (IHC) [primary (n�250); metastatic 

(n�31); of which (n�14) were paired]. FGFR3 immunostaining was scored 

as negative or positive based on previously reported scoring systems. 

FGFR3 mutation in primary tumors was assessed by iPlex and confirmed by 

hME sequencing (n�141) or Affymetrix OncoScan FFPE Express 2.0 

(primary: n�17; metastases n�31). Results: FGFR3 IHC positivity was 

present in 48% of metastases (95% CI�32-65%) and 26% of primary 

tumors, (95%�CI 21-32%), though strong staining was rare (�1%). 

Paired primary and metastatic tumors were both negative in 50% of cases, 

with 14% positive only in the metastasis, 14% positive only in the primary 

tumor, and 21% positive in both. If the primary tumor showed staining, 

71% of the metastases showed staining. FGFR3 IHC staining did not 

impact overall survival (p�0.8). FGFR3 mutations were observed in 9.6% 

of metastatic tumors (95% CI�3.3-25%), compared to 3.5% of primary 

tumors (95% CI�1.5%-8%). Co-occurrence of mutation and FGFR3 DNA 

copy number gain was observed in one specimen. Conclusions: FGFR3 IHC 

staining is present 26 % of primary tumors of patients who go on to develop 

metastatic disease, and nearly half of metastatic tumor sites. FGFR3 

mutation frequency in primary and metastatic tumor specimens is low. 

Further investigation of the frequency of FGFR3 protein expression in 

metastases is needed. The presence of FGFR3 protein by IHC staining in 

primary and metastatic specimens suggests that FGFR3 may represent a 

therapeutic target even in the absence of mutation. Further functional 

studies are needed. 


BRCA1, RAP80, and AEG-1 mRNA expression in resectable muscleinvasive 

bladder cancer (MIBC) patients (p) treated with neoadjuvant 

cisplatin-based chemotherapy. Presenting Author: Albert Font Pous, Institut 

Catala d’ Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain 

Background: Cystectomy remains the standard treatment in MIBC and only 

a minority of p are treated with neoadjuvant chemotherapy, suggesting that 

predictive markers of chemotherapy outcome are needed. Low BRCA1 

mRNA expression is associated with an improvement in survival in bladder 

cancer p treated with cisplatin-based chemotherapy. However, BRCA1 

function can be modulated by other DNA repair genes. RAP80 is required 

for the accumulation of BRCA1 to sites of DNA breaks, and cells depleted 

of RAP80 exhibit hypersensitivity to irradiation. AEG-1 can induce BRCA1 

expression and cause chemoresistance. Methods: Paraffin-embedded pretreatment 

tumor samples were collected by transurethral resection from 65 

p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatinbased 

chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 

were quantified by real-time quantitative PCR. Expression levels were 

divided into terciles and correlated with median survival (MS). Results: 33 p 

were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p 

with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy 

in 60 p. Overall MS was not reached and 5-year survival was 51%. MS was 

45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 

mRNA levels vs 168 m and 59% in 44 p with low and intermediate levels 

(p�0.05). MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with 

intermediate levels, and was not reached in 18 p with low levels, although 

these differences were not statistically significant (p�0.3). No differences 

in MS were observed according to RAP80 mRNA levels. Conclusions: 

BRCA1 can be a useful marker to predict the efficacy of neoadjuvant 

chemotherapy. Cisplatin-based chemotherapy should be recommended in 

p with low/intermediate BRCA1 expression. Further studies with larger 

numbers of p are warranted to elucidate the role of AEG-1 in this setting. 

4578 General Poster Session (Board #1G), Sun, 8:00 AM-12:00 PM 

A pre-cystectomy decision model to predict pathologic upstaging and 

oncologic outcomes in clinical stage T2 bladder cancer. Presenting Author: 

Siamak Daneshmand, University of Southern California Keck School of 

Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA 

Background: Neoadjuvant chemotherapy is the standard for advanced 

bladder cancer (BC), although its benefit in lower risk clinically organconfined 

muscle-invasive (cT2N0M0) BC is uncertain. This study aimed to 

define pre-cystectomy factors in cT2N0M0 BC that could predict pathological 

upstaging at cystectomy and oncological outcomes. Methods: 1,964 

institutional BC patients were reviewed. Neoadjuvant chemotherapy-naïve 

cT2N0M0 patients who underwent cystectomy were included. A multivariate 

classification and regression decision tree was used to assess hierarchical 

interactions of univariately significant variables, thereby identifying 

patients at greatest risk for upstaging and poor outcome. Results: 948 

cT2N0M0 patients were identified; 512 (54%) were upstaged at cystectomy. 

Pathological upstaging was associated with poor RFS and overall 

survival (OS) (both p � 0.001). Age, lymphovascular invasion (both P � 

0.01), multifocality (p � 0.004), deep muscle invasion, tumor growth 

pattern and hydronephrosis (all p � 0.001) were associated with upstaging. 

When these factors were included in a multivariate decision tree 

model, 71% of patients with hydronephrosis were upstaged and had the 

worst outcome (p � 0.001). In patients without hydronephrosis, tumor 

growth pattern was a second-tier discriminator; only 37% of patients with 

papillary tumors were upstaged. In patients with non-papillary tumors, 

deep muscle invasion was a third-tier discriminator; 70% of patients with 

invasion were upstaged. Age was a third-tier discriminator in patients with 

papillary � non-papillary features; 33% of patients �65 years were 

upstaged compared to 47% of patients �65 years. The decision tree was 

cross-validated and resulted in 3 risk groups – 5 year RFS/OS for low risk 

patients was 66%/48% versus 46%/27% for high risk patients (p � 

0.001). Conclusions: This study identified pre-cystectomy variables that 

predict upstaging and poor outcomes in cT2N0M0 BC. The decision tree 

approach highlighted the most crucial prognostic variables, and can aid in 

identifying low risk patients in a stepwise fashion who have lower probability 

of upstaging and better outcomes. 


Multidimensional investigation of HER2 in advanced urothelial carcinoma 

(UC). Presenting Author: Rachel S. Park, Lank Center for Genitourinary 

Oncology, Dana-Farber Cancer Institute, Boston, MA 

Background: Incidence of Her2 positivity and association with overall 

survival (OS) are controversial in advanced UC. Activating Her2 mutations 

have been identified in other cancers, but they have not been previously 

reported in UC. We determined Her2 status by immunohistochemistry 

(IHC), fluorescence in situ hybridization (FISH), and copy number gain 

(CNG) via array CGH of primary UC tumors from patients (pts) with 

metastatic disease. Targeted Her2 sequencing was performed at known 

mutation hotspots, and mutation effect was investigated in vitro. Methods: 

Tissue microarrays of formalin fixed paraffin-embedded tumor from 98 UC 

pts treated with platinum-based combination chemotherapy for metastatic 

disease were evaluated for Her2 protein and for Her2 gene amplification by 

using standard clinical protocols. Positive staining was defined as an IHC 

score of 3� or a FISH ratio of �2 using scoring criteria established for 

evaluation of breast cancer. Her2 CNG was evaluated by aCGH with cutoff 

log base 2 ratio � 0.9. Mutation status was validated by hME sequencing. 

OS was measured from start of treatment for metastatic disease. Association 

of OS and Her2 status was assessed by a Cox regression model. 

NIH-3T3 cells with Her2 V777L were assessed for growth, invasion, and 

Her2 kinase activation. Results: 22% of pts had 3� Her2 staining by IHC. 

21% of pts had FISH amplification. These were concordant in 78% of pts. 

CNG was identified in 16% and was concordant with FISH and IHC 85% 

and 88% of the time, respectively. Her2 status by any modality showed no 

significant association with OS in either univariate [HR�0.94, 95% CI: 

(0.52, 1.70), p�0.83] or multivariate [HR�1.12, 95% CI: (0.61, 2.06), 

p�0.72] analysis. Her2 mutations (V777L and L755S) were identified in 2 

pts (2%). In vitro analysis of V777L results in transformation of NIH-3T3 

cells, leading to increased growth, invasion on soft agar, and Her2 kinase 

constitutive activation. Conclusions: Her2 overexpression or amplification 

in the primary tumor does not predict OS in pts with metastatic UC. Other 

research has suggested that V777L sensitizes cells to lapatinib, while 

L755S leads to lapatinib resistance. These rare oncogenic Her2 mutations 

occur and may be therapeutic targets in selected pts. 


4581^ General Poster Session (Board #2C), Sun, 8:00 AM-12:00 PM 

Phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) with 

sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC). 

Presenting Author: Arjun Vasant Balar, Memorial Sloan-Kettering Cancer 


Background: Response to neoadjuvant chemotherapy (NC) prior to radical 

cystectomy (RC) predicts improved overall survival (OS) in MIBC. Associations 

with enhanced survival include complete pathologic response (pT0; 

Grossman, NEJM 2003) and eradication of the muscle-invasive component 

(�pT2; Splinter, J Urol 1992). Sunitinib (S) is active in pretreated pts with 

advanced disease. We tested if S added to GC was safe, improved the rate 

of pT0, and improved the rate of �pT2. Methods: Cisplatin-eligible pts with 

cT2-4aN0 bladder cancer received G 1000 mg/m2 and C 35 mg/m2 on day 

(D) 1 and D8 with S 25 mg orally daily D1-14 of a 21D cycle for 4 cycles. 

RC plus pelvic lymph node dissection was required to assess response of 

pT0 or �pT2. A Simon’s Minimax 2-stage design was used to test a null 

(H0) pT0 rate � 20% against alternative (H1) pT0 rate � 40% with Type I 

and II error rates of 0.05 and 0.10 respectively. Enrollment to the 2nd stage 

of 45 patients was planned if � 6 of the initial 24 evaluable pts achieved 

pT0. Primary endpoint was pT0N0 and secondary endpoints were: response 

defined as �pT2N0; safety; time to progression (TTP), and OS. 

Results: 18 pts (15M, 3F), median age 63 (54-76) were enrolled from 6/09 

and 10/11 after which financial support was withdrawn. 3 pts were 

inevaluable for response endpoints due to: 1.) withdrawal of consent, 2.) 

declining any surgery, 3.) partial cystectomy instead of RC. All 18 were 

evaluable for safety, TTP and OS. 1 of 15 pts had pT0N0 (6.6%; 95% CI 

0.34 – 29.8%) and 5 had �pT2N0 (33%; 95% CI 15-58%). 4 of 5 pts 

with status �pT2N0 were pTisN0. Median TTP was 10 months (95% CI 

3.5-NR). 3 pts were deceased at time of analysis; median OS not reached. 

Neutropenia due to the 3 drug combination required routine GCSF support 

on day 8 of each cycle. Grade 3/4 toxicities were anemia (11 pts), 

neutropenia (6), thromboembolic events (2), febrile neutropenia (2) and 

infection (2). Conclusions: Despite incomplete accrual, the pT0 rate was 

low suggesting that S does not add to GC. Residual non-invasive disease 

(�pT2) was common, including a large proportion of pts with pTisN0. 

Given these findings, response criteria for future NC studies should 

consider either �pT2 or � pTis as the primary endpoint. 

ABSTRACT 

WITHDRAWN 


297s 


PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic 

target? Presenting Author: Joaquim Bellmunt, University Hospital del 

Mar-IMIM, Barcelona, Spain 

Background: PI3KCA is frequently mutated in human cancer; however, 

information is scarce regarding its relevance in urothelial carcinoma (UC). 

We determined the prevalence of mutation and impact on clinical outcome 

of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K 

and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with 

either H1047R or E545K mutation. Methods: 141 samples from invasive 

UC were scanned for mutations. Of those, complete clinical data was 

available from 85 cases treated with platinum-based combination chemotherapy 

for advanced or metastatic disease. DNA was extracted from FFPE 

material. Mutation status was determined by iPLEX sequencing and 

confirmed with hME sequencing. Overall survival (OS) was measured from 

beginning of treatment for metastatic disease to time of death or censored 

on the last known alive date. Cox proportional hazard model was used to 

assess the associations of PI3K mutational status and OS. Growth 

inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR 

inhibitor (both from Selleck) on UC cell lines with or without mutations 

were tested using MTT assays. Results: Mutations in the PI3KCA gene were 

observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in 

all 14 specimens, though one specimen contained mutation at both E545K 

and H1047R. Among patients with clinical data, there was no statistically 

significant association between PI3KCA mutational status and OS (HR for 

having PI3KCA�0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in 

vitro experiments showed that cell growth was more potently inhibited with 

dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations 

in the PI3KCA gene were detected in 10% of invasive UC and did not 

correlate with OS in patients with metastatic UC treated with platinumbased 

chemotherapy. PI3K inhibition in vitro impacts UC cell growth, 

though dual PI3K/mTOR inhibitors may have more significant effects than 

PI3K inhibition alone. 


PIK3CA gene alterations in bladder cancer: Analysis of correlative series of 

transurethral resection (TUR)—Correlation with grade histology and tumor 

size. Presenting Author: Daniel E. Castellano, University Hospital 12 de 

Octubre, Madrid, Spain 

Background: PI3K pathway involvement in bladder cancer is well documented 

and activating mutations of the gene have been identified, 

particularly in tumors of low grade and stage. We have analyzed hot spot 

mutations and copy number in PIK3CA gene as well as mRNA expression 

levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods: 

90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent 

normal tissue was collected. All pts signed an informed consent and basic 

demoghrapics data were collected. Histology confirmation of UCC was 

required. PIK3CA alterations were analyzed by quantative-PCR. Results: 

Patient«s characteristics were: median age 73 years, Ta 45.5%, T1 

41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP 

4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences 

were observed. 13% normal tissue and 51,8% tumor samples harbored 

alterations in PIK3CA gene, including alterations affecting the helical 

domain (mutations 65%, amplifications 60%, both 21%). According to T 

stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p�0.05). When 

analyzing factors related to tumor recurrence, it was found that PIK3CA 

gene mutations in E542 or E545 had a lower recurrence risk (p-value 

²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray) 

showed that tumors bearing altered PIK3CA gene are more 

similar to non-tumoral samples comparing with tumors bearing wtPIK3CA 

gene. Moreover, overexpressed genes in mutant samples are mainly 

involved in G-protein and Wnt signaling, whereas underexpressed genes are 

involved in cell morphogenesis and cell polarity. Conclusions: We observed 

that PIK3CA gene alterations is an early carcinogenesis event in UCC pts, 

and more frequently found in larger tumor stages. These data support that 

PIK3CA status may constitute a good prognostic tool, as well as a 

therapeutic target in stratified groups for bladder cancer. 




External validation of somatic copy number alteration (SCNA) at chromosome 

1q23.3 in advanced urothelial carcinoma (UC). Presenting Author: 

Markus Riester, Department of Biostatistics and Computational Biology, 


Background: Advanced UC is associated with multiple SNCAs. To identify 

SCNA predictors of poor survival in advanced UC, we evaluated SCNAs in 

two cohorts of high-risk urothelial carcinoma of the bladder. Methods: We 

obtained DNA copy number data from bladder cancer patients in two 

independent cohorts [Spanish cohort (n� 93, Agilent aCGH 180k array) 

and Brigham and Women’s/Dana-Farber (BW/DF) cohort (n � 48, Affymetrix 

OncoScan FFPE Express 2.0)]. For the BW/DF cohort, we acquired 

copy number information from 30 primary tumors and 33 metastases. For 

12 patients, both primary and matched metastases were available. The 

GISTIC method was used on GLAD segmented data to identify driver copy 

number lesions, and the NBC algorithm to identify recurrent breakpoints. 

Cox proportional hazards models were used to estimate the effect of the 

identified SCNAs on overall survival, defined as time from start of 

chemotherapy for metastatic disease (Spanish) or from metastatic recurrence 

(BW/DF). Copy numbers were incorporated in the Cox models as 

continuous measures. Statistical significance of optimal cutpoints was 

estimated with permutation tests. Copy number profiles of primary tumors 

and metastases were compared with hierarchical clustering. Results: 

Amplification of 1q23.3 was independently associated with overall survival 

in both cohorts (Spanish cohort: HR 3.98; 95% 1.64-9.67; p � 0.03; 

C-statistic 0.54, 95% 0.45-0.65. BW/DF cohort: HR 6.28; 95% 1.84- 

21.4; p � 0.042; C-statistic 0.62, 95% 0.48-0.76). Amplifications at 

22q12.2 were enriched in patients who developed metastasis (p � 0.05). 

A breakpoint analysis identified possible truncations of ITPR1 (Spanish: 

15%; BW/DF: 25%) and PRIM2 (Spanish: 31% BW/DF: 12.5%) in large 

numbers of samples. For primary tumors with matched metastases, we 

observed that metastases clustered together with their primary tumors. 

Conclusions: External validation of the 1q23.3 amplification demonstrates 

the association of this SCNA with poor outcomes in advanced UC; the 

identification of the target of this copy number gain is ongoing. Gene 

truncations and their biological significance require further experimental 

investigation. 


Long-term progression-free survival (PFS) and overall survival (OS) to 

pemetrexed (P) as single agent in metastatic urothelial carcinoma (MUC): A 

Spanish Oncology Genitourinary Group (SOGUG) systematic review. Presenting 

Author: J. M. Cervera Grau, ITIC Benidorm, Valencia, Spain 

Background: The effect of pemetrexed in MUC is not well characterized. 

Vinflunine is the standar second-line in MUC with adjusted benefits and no 

more drugs have been aproved. SOGUG reports a systematic review of MUC 

patient series with high activity of P in monotherapy. Methods: Patients with 

locally advanced urothelial carcinoma and/or MUC whom received P 500 

mg/m(2) every 21 days with folic acid and vitamin B12 supplementation, 

were elected. These patients received P in second, third or fourth-line of 

chemotherapy. Results: 44 patients have been reported (39males), median 

age 62 [41-82]. Of all 44 patients; 21, 22, and 1 patients received P as 

second-line, third and fourth-line respectively. A median of 4 courses were 

administered [1-12] and disease control (SD�PR�CR) was achieved in 19 

patients for an overall control rate of 43.2%. Four groups with significant 

differences in PFS (p�.033) were established (1.bone-metastasis, 2.visceral-metastasis, 

3. nodal-visceral-metastasis and 4.nodal-metastasis). OS 

was significant between 2nd and 4th group (p�.036) . Mean PFS and OS 

were 125days [17-606] and 219days [17-1168] respectively for all 44 

patients. Mean PFS and OS of 8 patients with bone metastasis were 75 

days and 134 days. Mean PFS and OS of 10 patients with visceral 

metastasis were 65 days and 144 days. Mean PFS and OS of 8 patiens with 

nodal�visceral metastasis were 154 and 228 days. Mean PFS and OS of 

18 patients with nodal metastasis were 166 days and 299 days. Conclusions: 

Our longer and multicenter follow-up shows that single agent P in 

monotherapy as second, third and fourth line in MUC is associated with 

high activity and long-time survival specially in metastatic nodal MUC. 

These results suggest that P as monotherapy requires to be further studied, 

more patients are being collected. 


A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive 

urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group 

GU07-122 trial. Presenting Author: Noah M. Hahn, Indiana University 

Melvin and Bren Simon Cancer Center, Indianapolis, IN 

Background: Neoadjuvant chemotherapy (NC) preceding radical cystectomy 

(RC) is an accepted standard for miUCB patients (pts). Dasatinib (D) is an 

oral tyrosine kinase inhibitor of Src mediated signaling, and has demonstrated 

promising preclinical anti-tumor activity, providing a rationale to 

evaluate Neo-D in human miUCB. Methods: A phase II trial was conducted 

to assess the safety and biologic activity of Neo-D in miUCB. Key eligibility 

criteria included: miUCB (T2-T4a, N0, M0), unsuitable or willing to forego 

platinum-based NC, adequate TURBT tissue available, ECOG PS 0-1, 

creatinine � 2 x ULN. Pts received D 100 mg po once daily for 28 �/- 7 

days followed by RC 8-24 hours after the last dose. The primary endpoint 

was feasibility defined as � 60% of pts completing therapy without 

treatment-related dose limiting toxicity (DLT) specified as grade 4 hematologic 

toxicity, grade 3 non-hematologic toxicity, or any grade 2 toxicity � 14 

days. Secondary endpoints included the assessment of biologic activity as 

assessed by pre- and post-treatment tumor tissue immunohistochemistry 

analysis of Src, pSrc, EPHA2, pEPHA2, FAK, pFAK, AKT, pAKT, CD31, 

Ki67, TUNEL. Results: The study completed accrual with enrollment of 

25pts. 22 and 24 pts were respectively evaluable for feasibility and toxicity 

endpoints. Patient demographics included: median age – 62, M/F – 20/5, 

ECOG PS 0/1 – 19/6. Baseline tumor staging included: T2 – 17, T3 – 7. 

The study achieved its primary endpoint with 15 pts (68%) completing 

therapy without treatment related DLT’s. DLT’s included: fatigue (2 pts), 

DVT/PE, abdominal pain, supraventricular tachycardia, enteric fistula, and 

hematuria (1 pt each). Frequency of highest observed toxicity on study 

included: Grade 1 – 13%, Grade 2 – 38%, Grade 3 – 46%, Grade 4–4%. 

Among 22 patients, pathologic stage at RC was T1/Tis in 3 pts (14%), �T2 

in 19 pts (86%), and node positive in 6 pts (27%). Correlative analyses of 

pre- and post-treatment tumor Src signaling are ongoing and will be 

updated at the meeting. Conclusions: Neoadjuvant dasatinib preceding RC 

is feasible in miUCB patients. Tumor tissue correlative studies may provide 

directions for further development. 


Clinical validation of the 7th AJCC-TNM nodal staging system in lymph 

node-positive patients undergoing radical cystectomy. Presenting Author: 

Eila C. Skinner, USC Institute of Urology, University of Southern California, 


Background: The AJCC TNM staging system for bladder cancer has recently 

been updated. In the new 7th edition, staging of lymph node (LN) 

metastases is based on anatomical location instead of size as in the former 

6th edition. This study evaluated whether the prognostic value of nodal 

staging according to the 7th edition is superior to the 6th edition. Methods: 

Prospectively collected data of patients who underwent radical cystectomy 

(RC) at a high-volume center between 2002 and 2008 were reviewed. 

Patients who underwent RC for non-urothelial cancer, received neoadjuvant 

therapy or had non-LN metastatic disease at the time of RC were 

excluded. All patients underwent RC with extended lymphadenectomy up 

to the inferior mesenteric artery. LNs were submitted in predesignated 

anatomically defined packets. Detailed data on the number, size and 

location of LN metastases were recorded. Both the 6th and 7th edition AJCC 

TNM editions were used to stage LN positive (LN�) disease. Median 

follow-up time was 2.8 years. Kaplan-Meier analysis was used to estimate 

overall survival (OS) and recurrence-free survival (RFS). Results: A total of 

637 patients were identified of whom 141 patients (22.1%) had LN� 

disease. In total, 83 patients (58.9%) received adjuvant chemotherapy. 

Administration of adjuvant chemotherapy did not differ significantly per 

N-stage according to both editions. Based on the 6th edition, 31 patients 

(22.0%) had N1 disease, 105 patients (74.5%) N2 disease and 5 patients 

(3.5%) N3 disease. Three-year RFS rates for N1, N2 and N3 disease were 

51%, 43% and 0% respectively (p � 0.87). Based on the 7th edition, 29 

patients (20.6%) had N1 disease, 60 patients (42.6%) N2 disease and 52 

patients (36.9%) N3 disease. Three-year RFS rates for N1, N2 and N3 

disease were 51%, 42% and 45%, respectively (p � 0.84). Conclusions: 

Neither the AJCC-TNM 7th edition (location-based) LN staging nor the 6th edition (size-based) staging performed well as a prognostic tool for the 

patients in this cohort. The new staging system moved a large percent of 

patients into the N3 category, which did not have a worse prognosis than 

either the N1 or N2 categories. A better staging system for LN� bladder 

cancer patients needs to be developed. 



Mortality from other malignancies in bladder cancer survivors. Presenting 

Author: Hamed Ahmadi, USC Institute of Urology, University of Southern 

California, Los Angeles, CA 

Background: Other-cause mortality represents a considerable proportion of 

overall long-term mortality in bladder cancer (BC) patients who underwent 

curative radical cystectomy (RC). Other malignancies besides BC are 

reportedly among the most common etiologies of other-cause mortality. We 

report on mortality from other malignancies in BC survivors who have 

undergone prior RC. Methods: Data on BC patients who died of other 

malignancies were derived from a cohort of 1964 patients with pathologic 

diagnosis of urothelial carcinoma of bladder who underwent RC with intent 

to cure due to BC at University of Southern California between 1971 and 

2008. For subsequently developed malignancies, the time interval between 

RC and occurrence of malignancy was calculated. Other malignancies 

mortality was evaluated with respect to gender, pathological stage of 

BC, and type of malignancy. Results: Other malignancies were diagnosed in 

463 (23.5%) patients. They were the cause of death in 122 (6.21%) 

patients (109 male) who had a median age of 68.6 (range 43.4 – 88.7) at 

time of RC. Of all 122 patients with other malignancies, 22(18%) patients 

were diagnosed prior to RC, 5 (4%) concurrently with BC diagnosis, and 94 

(77%) subsequent to RC. At the time of cystectomy, 87/122 (71.3%) 

patients had lymph node-negative organ-confined disease, compared to 

56.3% in the whole cohort; and 18 (14.7%) patients had nodal disease, 

compared to 23.2% in the whole cohort. 116/122 (95%) of these patients 

had no evidence of BC recurrence at time of death. Secondary cancers 

occurred at a median of 7.7 years (Range 3 months – 29.9 years) after RC. 

Most common sites and types of malignancies that led to death were lung in 

43/122 (35.2%), predominantly non-small cell carcinoma in 17/ 

43(39.5%); hematologic in 15/122 (12.3%), largely lymphoma in 6/15 

(40%); and colon in 11/122 (9%), primarily adenocarcinoma in 8/11 

(72.7%) patients. Conclusions: Lung, hematologic, and colon cancers are 

the most common causes of death due to other malignancies in BC 

survivors and more commonly found in male patients with lymph nodenegative 

organ-confined tumor. Continued screening for other cancers in 

the follow-up of BC survivors may be warranted. 


Novel oncogenic function of ATDC in bladder cancer. Presenting Author: 

Phillip Lee Palmbos, University of Michigan Health System, Ann Arbor, MI 

Background: Bladder cancer is a common and deadly disease, but the 

molecular events leading to its initiation and progression are incompletely 

understood. We recently identified Ataxia-Telangiectasia Group D Associated 

(ATDC) as a novel oncogene which drives tumor proliferation and 

invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we 

describe the role of ATDC as an oncogene in bladder cancer. Methods: To 

further determine the oncogenic role of ATDC, we generated ATDC 

transgenic (tg) mice in which ATDC expression was driven by a CMV 

promoter and characterized the resulting tumors. Results: Interestingly, the 

dominant phenotype in these mice was the development of both noninvasive 

and invasive urothelial carcinomas (9% and 20% respectively, 

average age of onset 10-12 months of age). Histologically, these tumors 

were indistinguishable from human urothelial carcinomas. Gene expression 

profiling of invasive tumors derived from ATDC tg mice demonstrated a 

marked overlap with gene signatures of human invasive bladder cancers. 

ATDC was the 11th most highly up-regulated gene in bladder cancers 

represented in the Oncomine gene expression database. Analysis of a 

human bladder cancer tissue microarray (311 samples) by IHC showed 

elevated expression in 70% (173/252) of muscle-invasive carcinomas, 

22% (5/23) of papillary tumors and little or no expression in normal 

bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of 

p53 signaling and down-regulation of PTEN expression, which correlated 

with ATDC induced methylation of the PTEN promoter by DNMT3A. 

Furthermore, ATDC knock-down in invasive cancer cell lines resulted in 

decreased proliferation, invasion and reactivation of p53-mediated signaling 

and PTEN expression. Conclusions: ATDC is a novel oncogene that is 

highly expressed in human bladder cancers and is sufficient to drive the 

development of invasive bladder tumors in tg mice. The mechanism by 

which ATDC drives bladder cancer formation involves alterations in p53 

and PTEN pathways known to be important in bladder tumorigenesis. 


299s 


Second-line treatment of advanced urothelial cancer with paclitaxel and 

RAD001 (everolimus) in a German phase II trial (AUO trial AB 35/09). 

Presenting Author: Guenter Niegisch, Department of Urology, Heinrich- 

Heine-University, Duesseldorf, Germany 

Background: Efficacy of second-line treatment after cisplatinum failure in 

patients (pts) with advanced urothelial cancer is limited. Based on 

encouraging preclinical data and results from several phase I trials in solid 

cancers, we evaluated the safety and efficacy of the combination of 

paclitaxel and RAD001 (everolimus) in these pts. Methods: In this singlearm, 

multicenter phase II trial, pts failing prior cisplatinum based combination 

treatment for advanced urothelial cancer were treated with paclitaxel 

(175 mg/m² i.v., three-weekly) and the mTOR-inhibitor RAD001 (10 mg 

p.o., once daily). Pts were treated until tumor progression by RECIST 

criteria or until a maximum of 6 cycles was completed. A one-stage design 

was used to evaluate the overall response rate (ORR) as primary endpoint. 

Results: 27 pts (18 men, 9 women; median age 63 (35-76) years; ECOG � 

1: 11/27pts, hepatic metastases: 10 pts, Hb�10 g/dl: 8 pts; upper urinary 

tract: 9 pts, lower urinary tract 15 pts, both: 3 pts) were enrolled between 

07/09 and 12/11. As of 01/12, 19 pts are evaluable for the primary 

endpoint and the toxicity profile (6 pts still on treatment, 1 patient has 

withdrawn consent). Main toxicities (all CTCAE grades) were anemia 

(10/19 pts), leucopenia (8/19 pts), and neuropathy (9/19 pts). Grade III/IV 

toxicities were anemia (4/19 pts) and leucopenia (4/19 pts). No treatment 

related deaths were observed. Median number of cycles was 4 (1-6). 

Complete remission (CR) and partial remission (PR) was observed in 0/19 

and 3/19 pts, respectively (ORR 16%). Stable disease (SD) was observed in 

10/19 pts. Median time-to-progression (TTP) was 2.7 months (95% 

confidence interval [CI] 1.6 – 4.4), median overall survival (OS) was 6.5 (CI 

4.5 – 9.2) months. Conclusions: Frequency and severity of toxicities were 

acceptable. Using the combination of RAD001 and paclitaxel as secondline 

treatment for advanced urothelial cancer after cisplatinum-failure, 

response rates and survival times comparable to vinflunine were observed. 


External validation of prognostic models for overall survival (OS) in patients 

(pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy. 

Presenting Author: Andrea Borghese Apolo, Medical Oncology 

Branch, National Cancer Institute, National Institutes of Health, Bethesda, 

MD 

Background: The most commonly used model predicting OS for UC pts 

treated with cisplatin-based chemotherapy is based on 2-variables (visceral 

metastases and performance status), developed at MSKCC in 1999, and 

validated in a phase III study (DeSantis JCO 2011). A prognostic model of 

OS for advanced UC pts based on 4 variables (visceral metastases, 

albumin, performance status, and hemoglobin) was developed using 308 

pts from MSKCC (ASCO 2007 abstr 5055). We report the discriminative 

ability of the 4- and 2- variable models for advanced UC pts using an 

independent dataset from CALGB 90102. Methods: The analysis was 

performed using an external multi-institutional dataset from CALGB 

90102. The primary measurement of predictive discrimination was Harrell’s 

c-index which was computed with 95% confidence interval (CI). To 

assess whether there was a statistically significant difference in discrimination 

between the two models, the U statistic was used to test whether the 

predictions of the 4-variable model in all possible pairs were more 

concordant with actual observations than the 2-variable model in the same 

pairs. Results: CALGB 90102 included 74 UC pts (58 males, 16 females), 

median age 64 years, treated with cisplatin, gemcitabine and gefitinib, 

enrolled from 7/02 to 4/05 with a median follow-up of 72.5 months. 

Visceral metastases were present in 64% (bone, 18%, liver, 31%, lung, 

43%), median KPS 90%. The MSKCC 2-variable risk group distribution 

was 30% �0, 65%� 1 and 5%�2. The median OS �12.7 months (95% 

CI�10.4-20.5) with 68 deaths observed. When applied to the CALGB 

cohort, the predictive accuracy for the 4- and 2-variable models were 0.63 

(95 CI� 0.56- 0.69) and 0.58 (95% CI� 0.52-0.65), respectively. There 

was a statistically significant difference in discrimination between the two 

models (p �0.019), with superiority of the 4-variable model compared to 

the 2-variable model. Conclusions: A 4-variable prognostic nomogram for 

survival in pts with advanced UC was superior to a 2-variable risk-group 

model. The 4-variable prognostic model may replace the widely used 

2-variable model and can be used in the design and conduct of future 

phase II and III trials in advanced UC. 



4593 General Poster Session (Board #3H), Sun, 8:00 AM-12:00 PM 

Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer 

after BCG failure: Updated results of a phase I/II trial. Presenting Author: 

Terence W. Friedlander, University of California, San Francisco, San 

Francisco, CA 

Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs 

commonly in bladder cancer and leads to upregulation of the E2F-1 

transcription factor. CG0070 is a replication-competent oncolytic adenovirus 

genetically modified to express GMCSF under control of the human 

E2F-1 promoter. Updated results from a phase I study of CG0070 in 

patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG 

treatment are presented here. Methods: The V-0046 phase I/II study 

previously reported the safety and evidence of efficacy of single and 

multiple doses of intravesical CG0070. Efficacy was determined using 

quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was 

assessed immunohistochemically in 18 tumors. Results: 35 patients were 

treated with either a single dose (n�13) of CG0070 ranging from 1x1012 to 

3x1013 viral particles (vp) or with weekly x6(n�9) or every 4 week x 3-6 

doses (n�13) ranging from 1x1012 to 1x1013 vp per dose. The most 

common adverse events regardless of schedule were flu-like illness, 

dysuria, hematuria, bladder spasm, and nocturia. No maximum tolerated 

dose was reached. Urine GMCSF and CG0070 levels were detectable in 

almost all patients suggesting in-vivo viral replication. The CR rate in the 

single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose 

cohorts. The CR rate for patients with either CIS or Ta tumors was 65% 

(15/23). Of all responders, 11 recurred with a remission duration ranging 

from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, 

remain in remission as of last follow-up with a remission duration ranging 

from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 

of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a 

complete response. All patients (5/5, 100%) with known phosphorylated 

Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 

was well tolerated with minimal toxicities. Complete responses were more 

frequently observed in the multiple-dose cohorts, including durable CRs in 

patients with inactive Rb and in patients with CIS. Further study in 

Rb-inactive superficial tumors is warranted. 


Late gastrointestinal (GI) complications in patients with stage I-II testicular 

seminoma treated with radiotherapy (RT). Presenting Author: Christopher 

Leigh Hallemeier, Mayo Clinic, Rochester, MN 

Background: For stage I-II testicular seminoma, RT is highly effective at 

eradicating disease in the abdominopelvic lymph nodes, but results in 

unnecessary exposure to normal tissues including the GI tract. The purpose 

of this study was to define the incidence and risk factors for late GI 

complications in this patient population. Methods: A retrospective review 

was performed of 251 patients with stage I-II testicular seminoma treated 

with curative intent RT at our institution from 1974-2009. All patients 

underwent orchiectomy and postoperative external beam RT to the involved 

and/or at-risk nodal basins. Potential late GI complications that were 

assessed included endoscopically-confirmed gastric or duodenal ulceration, 

small bowel obstruction (SBO), and biopsy-confirmed malignancy of 

the GI tract. Risks were estimated using the Kaplan-Meier (KM) technique 

and univariate/multivariate analyses were performed using the Cox proportional 

hazards model. Results: Median age at diagnosis was 36 years (range 

18 – 80). Clinical stage was I (n�199) or II (n�52). Median abdominopelvic 

RT dose was 26 Gy (interquartile range 25 – 30). Median follow-up was 

15 years (range 0.1 – 38). KM estimates for any GI complication (ulcer, 

SBO, or GI malignancy) at 10, 20, and 30 years were 7, 10 and 24%, 

respectively. Four patients died as result of a GI complication. KM 

estimates for ulcer at 10, 20, and 30 years were 4, 7, and 9%, respectively. 

Age at RT (Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.00 – 

1.10, p�0.03) and RT total dose (per Gy, HR 1.20, 95% CI 1.09 – 1.31, 

p�0.01) were associated with risk of ulcer. KM estimates for SBO at 10, 

20, and 30 years were 2%, 2%, and 3%, respectively. History of 

inflammatory bowel disease was associated with risk of SBO (HR 43, 95% 

CI 7-325, p�0.01). KM estimates for GI malignancy at 10, 20, and 30 

years were 0.5, 3 and 16%, respectively. Age at RT was associated with risk 

of GI malignancy (HR 1.07, 95% CI 1.02-1.14, p�0.01). Conclusions: In 

patients with stage I-II testicular seminoma treated with RT, late GI 

complications were a relatively uncommon, but clinically significant source 

of late morbidity. Use of low dose, limited field, and/or proton RT may 

reduce these risks. 


Utilization and predictors of neoadjuvant chemotherapy for muscleinvasive 

bladder cancer in the Veterans Health Administration. Presenting 

Author: Gurdarshan Singh Sandhu, Washington University School of 

Medicine, St. Louis, MO 

Background: The survival benefit with neoadjuvant chemotherapy for 

bladder cancer was established in 2003. However, adoption of this 

paradigm in clinical practice has been slow. We explored the use of 

neoadjuvant chemotherapy and identified predictors of its use in a 

contemporary cohort in the Veterans Health Administration (VA). Methods: 

Using the national VA Clinical Cancer Registry, all patients diagnosed with 

clinical stage T2-4, N0 or Nx, M0 bladder cancer from 1997 to 2007 were 

stratified into surgically (radical cystectomy [RC], n�1,211) and nonsurgically 

managed groups (n�2,125). Receipt of neoadjuvant chemotherapy 

was defined as chemotherapy treatment up to 6 months before RC as well 

as initial treatment only with chemotherapy (without subsequent surgery or 

radiation) in the nonsurgical group. Temporal trends in neoadjuvant 

chemotherapy use were evaluated with a chi square test. Predictors of 

neoadjuvant chemotherapy were examined using a multivariable logistic 

regression model incorporating demographic, socioeconomic, comorbid, 

pathologic and hospital factors. Results: 6.3% and 8.3% of patients 

received neoadjuvant chemotherapy in the surgical and non-surgical group, 

respectively. Analysis of temporal trends in chemotherapy use demonstrated 

an increase in neoadjuvant chemotherapy use over time (p�0.0001); 

from 3% (2003 and before) to 14% annually (2007). On multivariable 

analysis of both groups, older age and more recent diagnosis were 

predictive of neoadjuvant chemotherapy use (Table). Other covariates did 

not predict receipt of neoadjuvant chemotherapy. Conclusions: While 

overall use of neoadjuvant chemotherapy in the VA population with bladder 

cancer remains low, use thereof is slowly increasing, with a more recent 

diagnosis most strongly predicting its use. 

Multivariable predictors of neoadjuvant chemotherapy in bladder cancer. 

OR 95% CI P value 

Age (per year older) 

Year of diagnosis (reference 2003 and before) 

1.02 1.00-1.04 �.0001 

2004 1.56 0.98-2.47 0.06 

2005 1.23 0.76-2.00 0.39 

2006 1.66 1.09-2.52 0.02 

2007 2.38 1.59-3.57 �0.0001 


Interim results of phase II trial of the cyclin-dependent kinase 4/6 inhibitor 

PD-0332991 in refractory retinoblastoma protein positive germ cell 

tumors. Presenting Author: David J. Vaughn, Abramson Cancer Center at 

the University of Pennsylvania, Philadelphia, PA 

Background: Deregulation of the retinoblastoma pathway in germ cell 

tumors (GCT) has been well documented. We previously reported that 

PD-0332991, a selective oral inhibitor of cyclin-dependent kinase 4/6, led 

to prolonged disease control in 3 patients (pts) with unresectable growing 

teratoma syndrome (NEJM, 2009). For these reasons, we initiated a phase 

II trial of PD-0332991 in pts with refractory retinoblastoma protein (Rb) 

positive (�) GCT. Methods: Pts with incurable refractory GCT that expressed 

Rb by immunohistochemistry were treated with PD-0332991 125 mg 

orally daily for 21 days followed by a 7 day break (cycle � 28 days). Tumor 

assessments were performed every 2 cycles. The primary endpoint was 

6-month progression-free survival (PFS) rate. Results: As of 1/12/2012, 

archived tumors from 36 pts with refractory GCT were stained for Rb and 35 

had � 1� staining. 18 of planned 24 pts have been enrolled and treated. 

Pt characteristics: 17 male, 1 female; median age, 31 years (range, 

17-56); median ECOG performance status, 1 (range, 0-1); median number 

of prior chemotherapy regimens, 2 (range, 1-6); median number prior 

surgeries, 3 (range, 1-6). Pt pathology: mature teratoma (MT), 7; teratoma 

with malignant transformation (TMT), 7; mixed GCT, 2; late relapse (LR), 

2. 16 pts are evaluable; 2 pts are too early to evaluate. 5 of 16 evaluable pts 

achieved 6-month PFS (3 MT, 1 TMT, 1 LR). Median PFS was 2 months 

(range, 0-17). No objective radiological responses were observed; 7 

patients had best response of stable disease by RECIST criteria (3 MT, 3 

TMT, 1 LR). Grade 3 toxicity included neutropenia (4 pts), thrombocytopenia 

(3 pts), anemia (1 pt), mucositis (1 pt). No grade 4 toxicity was seen. 

Analysis of archival tumor for predictive biomarkers including Rb and p16 

expression is being performed. Conclusions: PD-0332991 has resulted in 

6-month PFS in pts with refractory Rb � GCT, including pts with incurable 

teratomas. 



Bone metastases in patients with relapsed/refractory germ cell tumors 

(GCT) undergoing first salvage chemotherapy: A retrospective analysis of a 

large international database. Presenting Author: Karin Oechsle, University 

Medical Center Eppendorf, Hamburg, Germany 

Background: Bone metastases (mets) are rare events in GCT patients (pts) 

and data on characteristics, risk factors, treatment and outcome in these 

pts are largely missing. Methods: A subgroup of 104 ptswith bone metsfrom 

the IPFSG database was analyzed. All patients experienced unequivocal 

relapse/progression after � 3 cycles of cisplatin-based chemotherapy and 

received conventional-dose (CDCT) or high-dose salvage chemotherapy 

(HDCT). Results: 104 / 1594 pts presented with bone mets (6,5%) at first 

relapse. Histology was pure seminoma in 26%, and non-seminoma in 74%. 

At initial diagnosis, 54% of pts had presented with �poor risk� according to 

IGCCCG. Overall response rate (ORR; CR�PR) to 1st-line chemotherapy 

was 89%. Median PFS after primary treatment was 3 months (range 0 - 

140). Bone mets at first relapse were accompanied by abdominal, lung, 

mediastinal, liver and brain mets in 54%, 48%, 28%, 36%, and 14%, 

respectively. Tumor marker profiles were heterogeneous (elevation of AFP / 

ß-HCG: 51% / 37%). Salvage treatment was CDCT in 34%, and HDCT in 

66% of pts. ORR to salvage chemotherapy was 68% for the total cohort, 

and 43% vs. 81% for CDCT vs. HDCT (p�.01). For the total cohort, 2y-PFS 

and 5y-OS were 24% and 16%, respectively. 2y-PFS and 5y-OS were 

significantly higher in pts after HDCT compared to CDCT (2y-PFS 29% vs. 

14%, p�.01; 5y-OS 19% vs. 9%, p�.04). Conclusions: Pts relapsing with 

bone mets after platinum-based CTX were characterized by �poor risk� 

disease at initial diagnosis, but characteristics at first relapse were 

heterogeneous. Treatment response and outcome was improved in pts with 

HDCT compared to CDCT. Further prospective evaluation of characteristics 

and treatment approaches in GCT pts with bone mets is warranted. 


Clinical relevance of specialist pathologic testicular tumor review. Presenting 

Author: David N. Church, Oxford Cancer Centre, University of Oxford, 

Oxford, United Kingdom 

Background: Therapeutic options in stage IA/B testicular cancer include 

surveillance, retroperitoneal lymph node dissection, and adjuvant chemotherapy/radiotherapy; 

clinician and patient choice is guided by recurrence 

risk. Specialist pathologic review is important in informing this decision as 

it may alter diagnosis and staging. Methods: Analysis of a prospective 

supraregional database of 627 testicular tumors diagnosed in Oxford or 

referred for central review between 2004 and 2012. Tumor histology, stage 

(AJCC 7th ed.), and other factors predictive of relapse were compared 

between referring and final pathology reports. Results: Of 402 cases 

referred from 11 hospitals during the study period, 370 primary testicular 

tumors with an informative initial pathology report were analysed. There 

was a discrepancy between referring and final reports in 116 cases 

(31.4%), with significant variation between referring units in the frequency 

of discordance (20.0-89.9%, p�0.0001, x2 ). Changes to histological 

diagnosis in 34 cases (9.2%) were minor alterations in type and proportion 

of non-seminomatous germ cell tumor (NSGCT) elements of no clinical 

significance, with exception of one classical seminoma reclassified as 

spermatocytic seminoma. For seminomas (n�201) the commonest discrepancies 

were in identification of rete testis invasion (RTI) (15.9%); lymphovascular 

invasion (LVI) (9.5%); and spermatic cord invasion (SCI) (5.0%). 

RTI was more frequently under-reported (14.4%), and LVI over-reported 

(8.0%) on initial assessment. Disparity of tumor size in 2 cases (1.0%) was 

of no clinical significance. For NSGCT (n�150) the commonest discrepancies 

were in RTI (9.3%), LVI (7.3%) and SCI (6.7%), with LVI typically 

over-reported (4.0%) and RTI and SCI under-reported (6.7%, 5.3% 

respectively) on primary analysis. Central review resulted in change of 

primary tumor stage in 45 cases (12.1%). 12 (6.0%) and 16 (8.0%) 

seminomas, and 12 (8.0%) and 5 (3.3%) NSGCTs were upstaged and 

downstaged respectively. Conclusions: Central pathology review results in 

frequent alteration of factors predictive of relapse in stage IA/B testicular 

cancer. Particular attention should be directed to review of RTI, LVI and 

SCI to ensure accurate prognostication. 


301s 


Metastatic malignant transformation of teratoma to primitive neuroectodermal 

tumor (PNET): Results with PNET-based chemotherapy. Presenting 

Author: Amit Jain, Indiana University Melvin and Bren Simon Cancer 

Center, Indianapolis, IN 

Background: Metastatic germ cell cancers are highly chemosensitive and 

have 80% cure rate with cisplatin based chemotherapy. Post-chemotherapy 

teratoma can usually be surgically resected. However, teratoma, 

which is pleuripotent tissue, can undergo malignant transformation along 

mesodermal elements to PNET. Unlike teratoma, PNET can metastasize 

and render a patient unresectable and incurable. We report the results of 

treatment of patients with PNET with cyclophosphamide � doxorubicin � 

vincristine (CAV) alternating with ifosfamide � etoposide (IE). Methods: We 

reviewed 81 patients with histologically confirmed PNET transformed from 

testicular teratoma at Indiana University from 1998 to 2011. We identified 

13 cases who were treated with chemotherapy comprising cyclophosphamide 

1000-1200 mg/m2 , doxorubicin 50-75 mg/m2 , and vincristine 2 mg 

alternating with ifosfamide 1.8 grams/m2 plus etoposide 100 mg/m2 for 5 

days. Treatment was given every 3 weeks with a maximum of 6 cycles or 

until progression or undue toxicity. Hematopoeitic growth factors were 

usually incorporated. The remaining 68 patients underwent surgical 

resection. Results: Ten patients had unresectable disease and 3 were 

treated in an adjuvant setting. Median age was 31 years (range 20-53). Ten 

of 13 patients had received prior platinum based chemotherapy. Eight of 

10 evaluable patients achieved objective response. Five of those were 

rendered with no evidence of disease(NED) with further surgery. Although 4 

of the 5 patients subsequently relapsed, 1 patient remains alive with NED 

at 69 months. The 3 patients who received adjuvant treatment after 

retroperitoneal lymph node dissection (RPLND) are alive with NED at 1, 4 

and 8 years. Conclusions: CAV and IE alternating chemotherapy has high 

objective response rate for PNET transformed from teratoma and results in 

occasional long term disease free survival when combined with subsequent 

resection. We recommend adjuvant CAV alternating with IE chemotherapy 

for patients with PNET after RPLND due to the high probability of recurrent 

disease and their high chemosensitivity to this regimen. 


Quality of life and late toxicities in germ-cell cancer patients after 

high-dose chemotherapy. Presenting Author: Thomas Wuendisch, University 

Hospital Marburg, Marburg, Germany 

Background: The number of long term survivors after treatment for relapsed/ 

refractory germ cell cancer (GCC) is increasing but little is known about 

quality of life (QOL) and late toxicities (LT). Methods: We assessed LT and 

QOL in GCC patients (pts), treated in a prospective, randomized, multicenter, 

phase III trial comparing single versus sequential high-dose 

chemotherapy (HDCT) (Lorch 2007). All 216 pts were asked to complete 

the European Organization of Research and Treatment of Cancer Quality of 

Life Questionnaire (EORTC QLQ-C30) prior to HDCT, 6 weeks after and 

yearly thereafter. Results were analyzed according to standard methods 

(Fayers 2001). In addition pts were contacted at a median of 76 months 

(range 45-109) after HDCT to obtain information about current social and 

professional activities as well as LT. Results: Among 216 pts, 92/216 

(42%) were alive and without evidence of disease one year after randomization. 

Median age of pts was 34 years (range 15-56). A median of 4 

conventional-dose cisplatin-based treatment cycles had been given prior to 

HDCT. Questionnaires and response to the survey were evaluable in 86/92 

(93%) pts overall and in 59/86 (69%) pts more than 3 years after HDCT. 

Values for global health status, role functioning and emotional functioning 

declined during the first year after HDCT, increased in the following years, 

but did not reach the reference values from large samples of the general 

population in Norway (Hjermstad 1998). Pts after sequential HDCT scored 

better in a number of items (e.g. emotional-, cognitive-, social-functioning, 

fatigue and dyspnoea) in comparison to single HDCT including high-dose 

cyclophosphamide. Persisting polyneuropathy was reported in 59%, ototoxicity 

or tinnitus in 56%, erectile dysfunction in 24%, hypertension in 23%, 

hypercholesterinemia in 17%, diabetes mellitus in 6%, nephrotoxicity in 

6%, myocardial infraction in 2% and second cancers in 1% of pts. Overall 

82 % of pts were employed, 30% exercised regularly. Conclusions: HDCT 

has a negative impact on QOL, including social and professional life. Most 

common late toxicities were ototoxicity and polyneuropathy. Sequential 

HDCT without cyclophosphamide seems to result in a better outcome in 

respect to QOL. 




Residual tumor resections (RTR) in patients with germ cell tumors (GCT) 

after salvage chemotherapy. Presenting Author: Christian Winter, University 

of Duesseldorf, Duesseldorf, Germany 

Background: Residual tumor resections (RTR) after salvage chemotherapy 

are of utmost importance due to a much higher rate of vital carcinoma in 

the residual tumor. A complete RTR may lead to an improved long term 

survival of such patients (pts). Methods: A retrospective analysis was 

performed in 197 pts who underwent 209 RTRs in 2 referral centers 

(2003-2011) with identical surgical technique (2 surgeons). The RTR 

database was queried for pts who received salvage chemotherapy (conventional 

salvage chemotherapy (CCT) or high-dose salvage chemotherapy 

(HDCT)) and a subsequent RTR. Results: Sixty (29%) of all RTRs were 

performed after salvage chemotherapy. In 31 pts (52%) and 29 pts (48%) 

a CCT and HDCT was used as salvage regimen, respectively.Vital cancer 

was found in 48% and 45% of pts with CCT and HDCT. Respectively, vital 

cancer consisted of germ cell cancer and malignant transformed teratoma 

in 61% and 39% of the cases. In contrast, the percentage of vital cancer in 

pts after 1st-line treatment was 30% (p� 0.0365).This comparatively high 

rate is due to a 55% rate of intermediate/poor prognosis pts in the whole 

group of 209 RTRs. To date we have evaluated the oncological outcome in 

171 of 197 pts with a median follow-up of 23 months (1-227). In 142 pts 

no relapse was observed, whereas in 29 pts a GCT relapse occured (17%), 7 

(4.6%) of all evaluated pts had an “in-field”-relapse. 7 pts died due to 

tumor progression. The relapse rate in pts with RTR after salvage regime 

was significantly higher compared to RTR pts after primary chemotherapy 

(37% vs. 13%, p� 0.0008). The „in-field“-relapse rate in pts with RTR 

after salvage was only in 3.9%, 2 pts died due to tumor progression. 

Conclusions: Every second pts with RTR after salvage chemotherapy 

showed vital cancer in the residual tumor. The relapse rate in pts with RTR 

after salvage chemotherapy was significantly higher compared to RTR pts 

after first-line chemotherapy (p�0.0008) but the “infield” relapse rate was 

similar. A complete resection of all residual lesions after salvage chemotherapy 

is necessary to potentially improve the long-term disease-free 

survival. This is especially true for pts with malignant transformed teratoma 

and restricted options for repeated salvage chemotherapy. 


Phase I results of a phase I/II trial of BNC105P with everolimus in 

metastatic renal cell carcinoma (mRCC) patients previously treated with 

VEGFR tyrosine kinase inhibitors. Presenting Author: Thomas E. Hutson, 

US Oncology Research, LLC, McKesson Specialty Health, The Woodlands, 

TX, and Baylor Sammons Cancer Center-Texas Oncology PA, Dallas, TX 

Background: BNC105P is an investigational agent that destabilizes tubulin 

polymers leading to selective damage of tumor vasculature, causing 

disruption of blood flow to tumors, hypoxia and associated tumor necrosis. 

BNC105P also has a direct anti-proliferative action on cancer cells. 

Preclinical investigations have demonstrated that BNC105P is effective at 

selectively damaging the vasculature in both primary and metastatic 

lesions. Up regulation of the mTOR pathway has been identified as a 

survival response by the tumor to hypoxic insult. It follows that the 

combined use of BNC105P with an agent active against mTOR may 

improve clinical outcome in patients with progressive mRCC who are 

refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A 

phase I/II study in mRCC patients who have received 1-2 prior TKIs was 

undertaken. Using a classic 3�3 design, the phase I component of this 

study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 

16 mg/m2 ; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus 

was administered concurrently (10 mg p.o.). PK analysis was performed 

during Cycle 1. Results: The phase I component has been completed. The 

BNC105P / everolimus combination was well tolerated. No DLTs (drugrelated, 

during cycle 1) were observed in any of the phase I subjects. 

Toxicities on study deemed to be drug-related (either single agent or 

combination) included single grade 3 events of anemia and pericardial 

effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia and 

oral mucositis were also observed. Seven phase I subjects achieved at least 

disease stabilization with a minimum time on therapy of 18 weeks (6 

cycles). Across all subjects a median of 6 cycles (range: 1-15) was 

administered. PK analysis confirmed no drug-drug interaction. The randomized 

phase II component of the study continues and will compare 

everolimus given in combination with BNC105P to a sequential approach 

(everolimus followed by BNC105P). Conclusions: The MTD of BNC105P 

(16 mg/m2 ) can be combined with full dose everolimus and is being 

evaluated in the randomized phase II study. 


Can abdominal ultrasound replace CT scanning in long-term follow-up of 

male patients with germ cell tumor? Presenting Author: Arthur Gerl, 

Oncology Practice, Ludwig Maximilians University Munich (LMU), Munich, 

Germany 

Background: To date, there is no international consensus on how best to 

follow patients (pts) with GCT after their initial management. In the 

absence of a generally accepted follow-up schedule the possible benefits of 

regular CT scanning must be weighed against their cost, potential contrast 

media reactions and the long term risk of cumulative X-ray exposure. The 

present study focuses on the role of abdominal ultrasound in the follow-up 

of males with GCT and raises the question whether CT-scanning may be 

replaced by abdominal ultrasound. Methods: This retrospective singlecenter 

cohort study included 887 GCT pts followed between January 2001 

and November 2011. The follow-up schedule was predominately based on 

abdominal ultrasound performed by the same physician (A.G.). Patterns of 

recurrence and the long-term outcome were analyzed. Results: 462 of 887 

pts (52.1%) had stage I, 258 (29.1%) stage II and 130 (14.7%) stage III 

disease (not evaluable in 37 pts). The median time between baseline and 

the most recent follow-up examination was 5.0 years. A total of 14.604 

abdominal ultrasound examinations (16.5/pt.), 1170 CT scans (1.32/pt.), 

and 956 chest X-rays (1.08/pt) were performed. A relapse occurred in 58 

pts (6.5%) with 11 of 58 pts experiencing multiple relapses. 34 of 58 

relapses (58.6%) were detected in pts with stage I GCT. The sites of relapse 

included the abdomen (n�42), other sites (n�10), and marker elevation 

only (n�10). 33 of 42 abdominal relapses (78.6%) were detected by 

abdominal ultrasound. The median size of abdominal lymph nodes was 25 

mm (range, 6-67mm). After a median follow-up of 5 years the GCT 

specific survival of the entire cohort was 98.4%. Regarding the subgroup of 

pts with relapse the GCT specific survival was 94.7%. Conclusions: 

Ultrasound appears to be an appropriate method to detect abdominal 

recurrences in pts with GCT. However, training and cumulative experience 

is necessary to detect retroperitoneal recurrences at an early stage. The 

number of expensive and potentially harmful CT scans may be markedly 

decreased by abdominal ultrasound. 


Genetic determinants of long-term response to rapalog therapy in advanced 

renal cell carcinoma (RCC). Presenting Author: Martin Henner Voss, 


Background: Temsirolimus (T) and everolimus (E) are rapalog inhibitors of 

the mammalian target of rapamycin (mTOR) with efficacy in advanced RCC 

[NEJM;356(22):227-81; Lancet;372(9637):449-56]. With reported median 

progression-free survival (PFS) of 5.5 and 4.9 months (mo), respectively, 

benefit is typically modest, yet a subset of patients (pts) achieves 

long-term disease control evident by extended PFS. The oncogenomic 

background for this is unclear. Methods: We analyzed frozen specimens of 

tumor and adjacent normal kidney from pts with advanced RCC and 

documented long-term response to T or E, defined as PFS of � 20mo. 

Samples from pts with PFS � 2mo served as comparators. Specimens were 

subjected to whole exome sequencing; a targeted next-generation sequencing 

platform was used for deep sequencing and investigation of copy 

number variations (CNV) in 230 genes of interest. Results: In 5 pts with 

long-term response to T [n�3] or E [n�2], histologic subtypes were clear 

cell [n�3] and unclassified [n�2] RCC. Median number of prior treatments 

was 2 (1-3). Two pts remain on therapy, 3 have stopped drug for disease 

progression; treatment duration was 20, 25�, 27, 28, and 28� mo. Three 

control pts progressed after 1, 2, and 2 mo on therapy. Mean target 

coverage was 86x for whole exome and 443x for targeted sequencing. Three 

of 5 long-term responders harbored acquired somatic mutations and/or 

CNV in genes encoding for members of the Phosphoinositide 3-Kinase 

(PI3K) / mTOR pathway. Effects on amino acid sequence and gene function 

suggest a hyperactive pathway in all 3. For the other 2 long-term responders 

genomic changes with possible indirect link to the pathway, but no 

apparent determinants of treatment response were seen. In 3 control 

patients with rapid disease progression no genomic alterations suggesting 

hyperactivation of the pathway were seen. Conclusions: In this retrospective 

discovery set of RCC pts with unusually long response to rapalog therapy, 

next generation sequencing using pre-treatment tissue specimens revealed 

plausible oncogenomic determinants of treatment benefit in 3 of 5 cases. 

These findings provide basis for further biomarker development and studies 

in a larger sample set are ongoing. 



Correlation of chromosome (Chr) 14 loss and 5q gain with outcomes of 

pazopanib treatment in patients (pts) with metastatic clear cell renal cell 

carcinoma (mRCC). Presenting Author: Gary R. Hudes, Fox Chase Cancer 


Background: The identification of molecular prognostic and/or predictive 

determinants of outcome in pts with mRCC is an important challenge. We 

hypothesized that specific tumor DNA copy number alterations (CNAs) - 

loss of chr 14 or 14q (14/14q-), and gain of chr 5q (5q�) may predict 

likelihood of pazopanib treatment benefit in pts with mRCC. Methods: Pts 

DNA samples from the Phase II (VEG102616) pazopanib trial were 

analyzed by using Affymetrix OncoScan. Copy no. data were moving 

smoothed and normalized. The copy no. and allele difference were profiled 

according to their chromosome locations to interrogate CNA and LOH. 

Objective response (OR, RECIST) and progression free survival (PFS) were 

determined by investigators (IN) and an independent review (IR) committee. 

OR and PFS data were analyzed using exact and Kaplan-Meier tests. 

Results: Tumor DNA samples from 75 pts were adequate for CNA analysis. 

14/14q- was found in 35/75 pts (46.7%), and 5q� was found in 37/75 

(49.3%). 14/14q- was present in the tumors of 12/31 pts (39%) with OR 

by IR compared with 23/44 (52%) nonresponding pts (p�0.347). 14/14qdid 

not affect PFS. 5q� was present in tumors of 17/31 pts (55%) with OR 

and 20/44 (45%) nonresponding pts (p�0.486). PFS was longer in pts 

with 5q� tumors compared with those without 5q� (log rank p�0.026), 

with median PFS of 66 vs 35 wks, respectively. The odds of achieving OR 

decreased as the total number of chromosomal gains/losses increased 

(p�0.032, odds ratio 0.49), but this had no effect on PFS. In exploratory 

analysis, we examined the combined effect of both 14/14q- and 5q� on 

PFS (Table). Conclusions: Pts with 5q� tumors have significantly longer 

PFS, with no effect on OR rate. While 14/14q- alone had no effect on 

outcomes, the combination of 5q� and no 14/14q- was associated with 

significantly greater PFS. Pts with more genetically complex tumors were 

less likely to obtain OR with pazopanib. 

Median PFS wks (95% confidence limits) 

Copy no. change No. pts 

By IN By IR 

14/14q- , no 5q� 14 18 (8, 52) 28 (18, -) 

No 14/14q-, no 5q� 24 36 (20, 60) 44 (20, 84) 

14/14q-, 5q� 21 36 (24, -) 60 (28, -) 

No 14/14q-, 5q� 16 83 (36, 100) 84 (43, -) 

Total 75 p�0.005 p�0.071 


Evolving trends in non-clear cell renal cell cancer (RCC) epidemiology: A 

large registry analysis of 4,483 patients. Presenting Author: Ashok P. Pai, 

University of California, Davis, Sacramento, CA 

Background: Non-clear cell (ncc) RCC is uncommon but includes a 

heterogeneous group of histologic subtypes such as papillary, chromophobe 

(Chr), medullary (Med), and collecting duct (CD) cancers. We used a 

large cancer registry to define nccRCC clinical features and outcomes, 

identify prognostic variables, and to generate hypotheses for further study. 

Methods: Invasive RCC tumors in the California Cancer Registry from 

1998-2009 among adults � 18 years of age (n�38,251) were analyzed. 

Baseline clinical and tumor variables were collected. Primary outcome 

measures were 3-year cause-specific (CSS) and overall survival (OS). Uniand 

multivariate survival analysis were used to identify predictors of CSS 

and OS. Results: Of 38,251 RCC cases, 19,149 (50%) were of clear cell 

type; 14,619 (38.2%) were “unclassified.” Thus, 4,483 (11.7%) nccRCC 

cases were identified and included in this analysis. Of these, 3,304 

(73.7%) were diagnosed in 2004-09, suggesting a shift to more precise 

coding of histologic subtypes starting in the early 2000s. Histology 

distribution (n, %): papillary - 2,863 (63.9%); Chr - 1,507 (33.6%); and 

other including Med and CD - 113 (2.5%). Variables associated with 

significantly better OS and CSS (univariate analysis) were Chr histology, 

female sex, and higher socioeconomic status (SES). Significantly worse OS 

and CSS were seen in Med�CD, age � 65 yrs, no nephrectomy (Nx), and 

higher stage. Non-hispanic blacks had significantly worse OS and CSS, 

while the “targeted therapy era” (2004-2009) was associated with better 

OS. Multivariate analysis showed the following to be independently 

associated with outcomes (all p �0.001; Hazard Ratios [HR] shown for 

CSS and OS): Chr histology (0.48, 0.56), Med�CD histology (2.99, 2.42), 

no Nx (2.84, 3.18), regional stage (5.84, 1.98), distant stage (25.7, 

7.67); and non-hispanic blacks (1.5,2 p�0.006; 1.25, p�0.03). Age � 

65 yrs (HR 1.78, p�0.001) and high SES (HR 0.88, p�0.001) were 

associated with OS but not CSS. Conclusions: This is among the largest 

registry analyses of nccRCC ever performed, showing emerging trends in 

this uncommon RCC subset. Clinical variables associated with CSS and OS 

were identified that can inform the design of future clinical trials in 

nccRCC. 


303s 


Safety and efficacy of AMG 386 in combination with sunitinib in patients 

with metastatic renal cell carcinoma (mRCC) in an open-label multicenter 

phase II study. Presenting Author: Michael B. Atkins, Beth Israel Deaconess 

Medical Center, Boston, MA 

Background: AMG 386, an investigational peptide-Fc fusion protein, 

inhibits angiogenesis by disrupting the angiopoietin/Tie2 axis. We evaluated 

the safety and efficacy of AMG 386 plus sunitinib in patients (pts) with 

mRCC. Methods: Adults with mRCC who were naïve to angiogenesis 

inhibitors were sequentially enrolled to 2 cohorts: sunitinib 50 mg PO QD 

(4 wks on, 2 wks off) plus AMG 386 at 10 mg/kg (A) or 15 mg/kg (B) IV QW. 

Primary endpoints: adverse events (AEs), dose interruptions/reductions due 

to AEs in the first 12 wks of treatment; secondary endpoints included: 

progression-free survival (PFS) and response rate (ORR). Results: 85 pts 

received �1 dose of study medication (A/B, n�43/42). In A/B, 88%/76% 

were male and 30%/36% were age �65; MSKCC risk scores were low 

(40%/36%) or intermediate (60%/62%). For A/B: median follow-up time 

was 19.6/12.0 mos; AMG 386 discontinuations due to AEs were 16%/ 

29%; and grade �3 treatment-related AEs occurred in 72%/74% with 

virtually all attributed to sunitinib. Grade 3 AEs occurring with �5% 

frequency were hypertension, hand foot syndrome, asthenia, fatigue, 

elevated lipase, diarrhea, mucositis, vomiting, thrombocytopenia, and 

neutropenia, with no distinction between dose levels. The percentage of pts 

with sunitinib dose interruptions within the first 12 wks (A/B, 58%/57%) 

met the prespecified criteria. One pt in B had fatal acute pulmonary edema. 

No pt developed anti-AMG 386 antibodies. The Kaplan-Meier estimate 

(95% CI) of PFS was 13.9 (10.4, 19.2) mos in A; PFS in B is not yet mature 

with only 21% of pts having disease progression. ORR (95% CI) was 58% 

(42, 73) in A including 1 CR, and 59% (42, 74) in B. Conclusions: In pts 

with mRCC, AMG 386 at 10 and 15 mg/kg combined with sunitinib 

appeared to be tolerable. Reported sunitinib dose modifications for the 

observation period were within the prespecified range. Efficacy results 

suggest potential benefit for the addition of AMG 386 to sunitinib. 


Selecting renal cell carcinoma therapy: Ranking of patient perspective on 

toxicities. Presenting Author: Michael K.K. Wong, Norris Comprehensive 

Cancer Center, University of Southern California, Los Angeles, CA 

Background: Oral therapies (angiogenesis inhibitors and mammalian target 

of rapamycin (mTOR) inhibitors) for renal cell carcinoma (RCC) have 

demonstrated significant improvements in progression-free survival but 

also possess toxicities. The objective of this study was to evaluate whether 

different toxicities of oral RCC therapies had equal importance to patients. 

Methods: US adults from the Kidney Cancer Association with a self-reported 

diagnosis of RCC completed a web-enabled survey. Respondents were 

asked to select the 3 most and 3 least troublesome toxicities from a list of 

20 common RCC therapy toxicities. For each respondent, a value of 1 was 

assigned to each of the 3 most troublesome toxicities, a value of -1 was 

assigned to each of the 3 least troublesome toxicities, and a value of 0 was 

assigned to the remaining toxicities. A straight count method was applied to 

estimate the mean relative importance of each toxicity. Respondents also 

answered 10 treatment-choice questions, each of which included a pair of 

hypothetical RCC medication profiles described by survival, toxicities, and 

serious adverse events. Four toxicities including fatigue, mouth sores, 

hand-foot syndrome, and stomach problems were included in both exercises. 

Results: 264 of the 272 respondents completed the entire ranking 

exercise. Among the 20 toxicities, stomach problems was the most 

troublesome and was assigned an importance of 10. Changes in hair color 

was the least troublesome and was assigned an importance of 0. Patients 

ranked fatigue (8.2), mouth sores (7.7), hand-foot syndrome (6.6) by order 

of importance. When given choices among eliminating severe toxicities, 

fatigue was as important as stomach problems, both fatigue and stomach 

problems were more import than mouth sores, and mouth sores was more 

important than hand-foot syndrome; although not statistically significant. 

Conclusions: This statistical approach offers insight into those toxicities 

important to patients on chronic RCC therapies. 




Post-axitinib systemic therapy in metastatic renal cell carcinoma (mRCC). 

Presenting Author: Housam Haddad, Cleveland Clinic Taussig Cancer 

Institute, Cleveland, OH 

Background: Axitinib is a potent and selective inhibitor of the VEGF receptor 

family with efficacy as a second-line therapy in mRCC. Evaluation of further 

systemic therapy following axitinib has not been previously reported. 

Methods: The medical records ofmRCCpatients (pts) treated at The Cleveland 

Clinic or MD Anderson Cancer Center who received axitinib were 

retrospectively reviewed. Patient characteristics including best response 

and duration of treatment on axitinib and each subsequent line of therapy 

were recorded. Results: Eighty-one patients were initially identified; 29 

patients received at least one approved targeted agent following axitinib 

and are included in this analysis. The remainder of pts were excluded due 

to ongoing axitinib (n�16), lack of subsequent therapy (n�13), lost to 

follow up (n�11), received experimental agents post-axitinib (n�7) or were 

inevaluable (n�2). Three pts were excluded due to � 21 days on axitinib. 

Pt characteristics at start of axitinib included 76% male, median age 59 

(range, 44-78); 97% clear cell; 93% prior nephrectomy; 64% previouslytreated. 

Pts were favorable (39%) or intermediate (60%) risk based on 

Heng criteria. Overall response rate to axitinib was 52% and median 

duration of treatment of 11.2 months (range, 1.1-90). Thirty eight percent 

of patients had new brain, bone, and/or liver metastases at disease 

progression on axitinib. For the first subsequent therapy post axitinib 

(n�25), pts were treated with tyrosine kinase inhibitors (72%) or mTOR 

inhibitors (28%). Overall 8% of pts achieved partial responses (one pt each 

to sunitinib and pazopanib) and 52% had a best response of stable disease. 

Estimated median duration of therapy was 4.4 months (range, 0.2-27.5�). 

Fifteen pts received a second post-axitinib targeted therapy with mTOR 

inhibitors (60%) or TKIs (40%). One patient (7%) achieved a partial 

response to pazopanib and 8 patients (53%) had a best response of SD. 

Estimated median treatment duration was 4.8 months (range, 0.7-19.1�). 

Conclusions: There are objective responses and stable disease to postaxitinib 

targeted therapies, consistent with previous series and trials in 

refractory RCC patients. 


Outcome of rapid disease progression in the treatment break following 

cytoreductive nephrectomy (CN) after presurgical sunitinib in patients with 

primary metastatic renal cell carcinoma (RCC). Presenting Author: Axel 

Bex, The Netherlands Cancer Institute, Amsterdam, Netherlands 

Background: There is concern that interruption of tyrosine kinase inhibitors 

(TKI) triggers disease progression (PD) and metastasis. This is based on 

preclinical models and observation of rapid PD in the postsurgical treatment 

break in patients pretreated with TKI. Little is known about the 

frequency of PD during postsurgical TKI interruption and its outcome. 

These data may have implications for neoadjuvant or presurgical treatment 

concepts. Methods: Of 66 patients from two closed phase II trials 

investigating 2-3 months presurgical sunitinib for primary metastatic 

clear-cell RCC, 45 were evaluated in this retrospective analysis because 

they had absence of PD prior to planned surgery and underwent CN (35 

[78%] MSKCC intermediate and 10 [22%] poor risk). Patients had CT 

scans at the end of pretreatment and at 4 weeks post-nephrectomy before 

restarting sunitinib. In patients with postsurgical RECIST PD at 4 weeks 

when compared to the preoperative CT scan overall survival (OS) was 

measured from the time of nephrectomy and compared to patients without 

treatment break PD. Results: Median OS of 45 patients from the time of 

surgery was 22 months (13.0-31.5 months). Overall 14 patients progressed 

during treatment break (31%), with new sites of disease in 5/14 

(35%). Reintroduction of sunitinib resulted in disease stabilisation or 

better in 13. Patients with poor risk were represented in the progressors 

(n�4[28%]) and non-progressors (n�6 [19%]) (p�0.7 fishers exact test). 

The hazard ratio (HR) for death associated with PD during treatment break 

was 1.90 (95% CI 0.89-4.08). OS for non-progressors was 25 months 

(15-NA) and 13 months (6-27) for progressors. Conclusions: A significant 

proportion of patients develop PD upon sunitinib withdrawal in a 4 week 

recovery period following CN. In view of the small sample size these data 

suggest a strong trend toward treatment break PD being associated with a 

poor outcome. It is not clear whether this PD is related to interruption of 

TKI, surgery or a combination of factors. The EORTC SURTIME trial 

investigates treatment break PD after immediate CN and CN after sunitinib 

and may answer this question. 


Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma 

(RCC) patients treated with targeted therapies. Presenting Author: Philip S. 

Hall, Stanford University, Internal Medicine Residency Program, Stanford, 

CA 

Background: Almost all patients with advanced RCC are treated with 

therapies targeting the hypoxia inducible factor axis. The potential for these 

agents to cause cardiovascular (CV) toxicity has been increasingly recognized 

but the overall incidence and extent have not been well described. We 

sought to identify and characterize the incidence and severity of CV toxicity 

among RCC patients treated with targeted therapies. Methods: Between 

2004 and 2011, all RCC patients treated with targeted therapies directed 

against the VEGF or mTOR axes were identified at our institution. The 

incidence of hypertension, left ventricular (LV) dysfunction, changes in 

serum markers of CV toxicity (e.g., troponin I, NT-proBNP) and heart failure 

were assessed and graded according to the Common Terminology Criteria 

for Adverse Events (CTCAE v.4.0). Results: Cardiovascular toxicity developed 

in 116 of 159 patients (73%). Excluding hypertension, 52 of 159 

(33%) developed cardiovascular toxicity. Cardiac toxicity ranged from 

asymptomatic drops in LV ejection fraction (LVEF) to rises in NT-proBNP to 

severe heart failure. Asymptomatic cardiotoxicity as defined by decrease in 

LVEF or increase in NT-proBNP occurred in 43 patients (27%). Symptomatic 

heart failure (grade 2-3) and grade 3-4 decrease in LVEF each occurred 

in 4%. Sunitinib was the most frequently used and most common offending 

agent, with 66 of 101 sunitinib-treated patients (65%) developing a form 

of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was 

notable that CV toxicity was observed in 68%, 66%, and 51% of patients 

treated with bevacizumab, sorafenib, and pazopanib as well. The mTOR 

inhibitors elicited significantly less CV toxicity, but sample sizes were 

small. Conclusions: Cardiovascular toxicity is an important adverse event 

related to targeted therapy administration. Close monitoring for the 

development of CV toxicity with the use of these agents should become 

standard of care as early detection of asymptomatic patients could preempt 

symptomatic toxicity and reduce treatment-related morbidity and mortality. 


Overall and progression-free survival with everolimus, temsirolimus, or 

sorafenib as second targeted therapies for metastatic renal cell carcinoma: 

A retrospective U.S. chart review. Presenting Author: Hongbo Yang, 

Analysis Group, Inc., Boston, MA 

Background: Tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib) 

and inhibitors of the mammalian target of rapamycin (mTORs) 

(everolimus, temsirolimus) are used for treating metastatic renal cell 

carcinoma (mRCC) following initial treatment with a TKI. This study’s 

objective was to establish the effectiveness of the most commonly used 2nd line treatments based on real-use data. Methods: mRCC patients who 

received a TKI as their 1st targeted therapy and everolimus, temsirolimus or 

sorafenib as their 2nd therapy were identified by oncologists (85% in 

community practice) throughout the US as part of an online chart review 

study. Baseline characteristics were assessed prior to 2nd targeted therapy, 

including type and duration of initial TKI, response, histological subtype, 

performance status, and sites of metastasis. Overall survival (OS) and 

progression free-survival (PFS) were assessed after initiating 2nd targeted 

therapy. OS and PFS were compared between treatment groups using Cox 

proportional hazards models adjusted for baseline characteristics. Results: 

Charts were reviewed for 233, 178, and 123 mRCC patients receiving 

everolimus, temsirolimus, and sorafenib after an initial TKI, respectively. 

Median age was 64 years and 70.4% were male. Prior to initiating a 2nd targeted therapy, 86.0% used sunitinib and 85.9% had disease progression. 

After adjusting for baseline characteristics, everolimus was associated 

with significantly prolonged OS compared to temsirolimus (hazard 

ratio [HR] 0.56; CI 0.40-0.78; p�0.001) and sorafenib (HR 0.65; CI 

0.42-0.99; p�0.047). Everolimus was associated with significantly longer 

PFS compared to temsirolimus (HR 0.73; CI 0.55-0.96; p�0.025), and 

non-statistically significant longer PFS compared to sorafenib (HR 0.75; CI 

0.53-1.07; p�0.110). Results were similar in the subgroup with sunitinib 

as 1st targeted therapy and the subgroup with progression on 1st TKI. 

Conclusions: Among mRCC patients with prior TKI treatment, everolimus 

was associated with significantly prolonged OS and PFS compared to 

temsirolimus and significantly prolonged OS compared to sorafenib. 



Xp11.2 translocations in adult renal cell carcinomas with clear cell and 

papillary features. Presenting Author: Susanne M. Chan, Department of 

Anatomical Pathology, Sunnybrook Health Sciences Centre, University of 


Background: Xp11.2 translocation renal cell carcinoma (RCC) is a rare 

tumor with unpredictable clinical course and prognosis in adults. Recognition 

of these tumors depends on the identification of a RCC with unique 

histology, particularly clear cell and papillary (CCP) features. Our objectives 

were to determine the incidence of Xp11.2 translocations in adult 

RCCs with clear cell and papillary features, and to characterize the 

clinicopathological features and prognosis of adult Xp11.2 RCCs. Methods: 

Slides for 1047 RCCs in adults (1999-2009) were retrieved from multiple 

institutions. Cases were reviewed histologically in order to detect any 

degree of clear cell and papillary change. Tissue microarrays were constructed 

from the clear cell and papillary RCCs as well as 40 non-papillary 

clear cell, 5 papillary, 3 chromophobe and 2 unclassified RCCs. Immunohistochemistry 

using TFE3, a marker highly sensitive (97.5%) and specific 

(99.6%) for Xp11.2 translocations was performed. Four pathologists 

independently reviewed the TFE3 results. Clinical and pathologic data were 

also retrieved. Results: Out of 1047 RCCs, 140 (13%) exhibited clear cell 

and papillary features. Four out of these 140 (3%) were positive for TFE3. 

All of the non-papillary clear cell, papillary, chromophobe and unclassified 

RCCs were negative for TFE3. Mean follow up for TFE3� RCCs was 55 

months. Conclusions: Xp11.2 translocation RCCs diagnosed by TFE3 

immunohistochemistry were identified in 3% of adult RCCs that had clear 

cell and papillary changes. These tumors appear to present with smaller 

tumour size, lower stage and better prognosis in comparison to non-Xp11.2 

CCPRCC and clear cell RCCs. In addition to Xp11.2 translocation carcinoma, 

coexistence of clear cell and papillary features may be present in 

other subsets of tumors that have yet to be characterized. 

Comparison of clinicopathological features and prognosis. 

TFE3� CCPRCC TFE3- CCPRCC Non-papillary clear 

(n�4) 

(n�136) 

cell RCC (n�40) 

Average age 54 62 60 

Average tumor size 4.1 6.0 5.2 

pT1 4 (100%) 80 (60%) 28 (70%) 

pT2 0 (0%) 17 (13%) 2 (5%) 

pT3 0 (0%) 35 (26%) 10 (25%) 

pT4 0 (0%) 1 (1%) 0 (0%) 

Local recurrence 0 (0%) 13 (10%) 9 (23%) 

Distant metastasis 0 (0%) 31 (23%) 5 (13%) 

Death due to RCC 0 (0%) 11 (8%) 4 (10%) 


Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) 

treated with pazopanib after progression on other targeted therapies (TT): A 

single-institution experience. Presenting Author: Marc Ryan Matrana, 


Background: Pazopanib is an approved multi-tyrosine kinase inhibitor that 

prolongs progression-free survival (PFS) compared to placebo in treatmentnaive 

and cytokine-refractory mRCC. Outcomes and safety data on its use 

after TT are limited. Methods: We retrospectively reviewed pts with mRCC 

who received salvage pazopanib between 11/09-11/11. Kaplan-Meier 

method was used to estimate survival outcomes. PFS was calculated from 

start of pazopanib until progressive disease (PD) or death. Univariable and 

multivariable Cox proportional hazards models were fitted to evaluate 

associations of PFS with covariables. Results: 114 consecutive pts met 

inclusion criteria (median age 62.6 years, 66% males, 83% clear cell). All 

pts had PD after other TT (median # of prior TT 2, range 1-5; median time 

on prior TT 23.3 mos). 79% of pts had PD on sunitinib, 39% on sorafenib, 

19% on temsirolimus, 59% on everolimus, and 23% on bevacizumab. 

25% received prior chemotherapy and 16% received prior cytokines in 

addition to TT. 87% had prior nephrectomy. 11% had favorable-risk, 68% 

intermediate-risk, and 21% poor-risk per MSKCC criteria. 85 events (PD or 

death) occurred. Median OS was 17 mos (95% CI: 10.3-NA). Median PFS 

was 6.4 mos (95% CI: 4.5-9.5). By multivariable analysis, PFS was 

associated with male gender (HR�0.433, 95%CI: 0.269-0.696; 

p�0.0006), # of metastatic sites (HR�1.252; 95%CI: 1.04-1.503; 

p�0.016), hypertension exacerbation (HR�0.378; CI: 0.175-0.813; 

p�0.0128) and PS 2� vs.0-1 (HR�2.067; CI: 1.243-3.437; p�0.0052). 

58% discontinued pazopanib due to PD, 12% died of PD on treatment, and 

11% discontinued pazopanib due to adverse events (AEs), mostly GI 

complaints or fatigue. There were no treatment related deaths. Common 

AEs included: fatigue (44%), diarrhea (29%), nausea/vomiting (15%), 

anorexia (14%), hypertension exacerbation (11%), hypothyroidism (11%), 

hand-foot skin reaction (9%), and increase LFTs (4%). 86% of AEs were 

grade 1/2. Conclusions: In this retrospective study, pazopanib demonstrated 

efficacy in mRCC following PD with other TT. AEs were mild/ 

moderate and manageable. 


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A phase I study of pazopanib (P) combined with bevacizumab (B) in 

patients with metastatic renal cell carcinoma (mRCC) or other advanced 

refractory tumors. Presenting Author: Sylvie Negrier, Léon-Bérard Cancer 

Centre, Lyon, France 

Background: Since previous experiments of B with VEGFR tyrosine kinase 

inhibitors showed overlapping and limiting toxicities, a dose-finding study 

was designed to explore the safety and feasibility of the combination of a 

new VEGFR inhibitor P with B, in mRCC treatment-naive patients (pts) or in 

pts with other advanced refractory solid tumors. Methods: This bicentric 

trial is conducted with 3�3�3 escalation doses of P � B. The MTD is the 

highest dosage not expected to cause a dose limiting toxicity (DLT) in more 

than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. The 

effect of B on steady-state pharmacokinetic (PK) of P is also investigated. 

Major inclusion criteria are: ECOG PS �1, ALT and AST ��2.5 x ULN, 

serum creatinine ��1.5 mg/dL or creatinine clearance ��50 mL/mn and 

absence of uncontrolled hypertension. Results: 15 pts were enrolled with 

mRCC (n�7), melanoma (n�2), adrenocortical carcinoma (n�1), mesothelioma 

(n�1), pancreatic cancer (n�1), oesophageal cancer (n�1), bladder 

cancer (n�1) and seminoma (n�1). Median age is 61 (43-78), 12 pts are 

male. No DLT were reported at DL1 (P 400 mg/d � B 7.5 mg/kg q2w) (n � 

9), or at the first step of DL2 (P 600 mg/d � B 7.5 mg/kg q2) (n�3), but the 

3 following nephrectomized pts experienced DLT: a grade 3 transaminitis, 

a grade 3 pulmonary embolism and a reversible microangiopathic hemolytic 

anemia. Inclusion of nephrectomized pts was completed, but enrolment 

of 3 additional non-nephrectomized pts at DL2 was approved by 

IDSMB in November 2011 and these treatments are ongoing. Preliminary 

results of PK analysis showed a significantly higher P AUC at steady-state in 

pts with DLT. Moreover, lower P apparent clearance was observed in 

nephrectomized pts. Conclusions: The MTD of the combination of P and B is 

400 mg/d and 7.5mg/kg respectively, in nephrectomized patients, but is 

not yet reached in other patients. Unexpected effect of nephrectomy status 

was observed on P pharmacokinetics. 


Circulating mir-21 and mir-378 are predictive of progression-free survival 

(PFS) in patients treated with everolimus in metastatic renal cell cancer 

(mRCC). Presenting Author: James Lin Chen, The University of Chicago, 

Chicago, IL 

Background: The oral mTOR inhibitor, everolimus, affects tumor growth by 

targeting cellular metabolic proliferation pathways and modestly delays 

RCC progression. We hypothesized that circulating microRNAs, which have 

been associated with renal cancer and inflammation, may serve as 

predictive biomarkers to help better define a population more sensitive to 

treatment. Methods: Plasma from mRCC pts refractory to VEGF inhibition 

were obtained prior to treatment with standard dose everolimus as part of a 

clinical trial examining FDG-PET as a potential predictive biomarker. As we 

were specifically interested in tumor response to drug, only pts who died, 

remained on trial, or had radiographic progression by RECIST criteria were 

profiled. Pts who were unable to tolerate drug were excluded. MicroRNAs 

were extracted and profiled without pre-amplification using Exiqon LNA 

PCR panels. Crossing point (Cp) values within 5 of the negative control were 

removed. MicroRNAs must have been present in �90% of samples and 

varied at least p � 0.10 from mean to be further analyzed. Cox-proportional 

hazards model and Kaplan-Meier analyses were performed. Results: 28 

patients had available plasma and met criteria for profiling. Pt characteristics 

included: 20 (71%) clear cell histology, median age 57.7 (43 – 76), 

median number of prior systemic therapies 2 (1 – 3). 103 microRNAs were 

expressed in at least 90% of all samples. Mir-21 and mir-378 were 

independently correlated with PFS (FDR: 0.02 and 0.06, respectively). 

Low circulating plasma mir-21 and mir-378 levels resulted in a median 

PFS prolongation of 370d vs. 101d (p�0.027) and 368d vs. 106d 

(p�0.001). Analysis of the clear cell cohort for mir-21 and mir-378 also 

demonstrated a significant median PFS difference of 350d vs. 173d 

(p�0.045) and 345d vs. 147d (p�0.004). Conclusions: Elevated levels of 

circulating mir-21 and mir-378 have been associated with systemic 

inflammatory states, and in our study are correlated with decreased PFS in 

mRCC pts undergoing everolimus therapy. Further prospective studies will 

be required to validate these exploratory results for their potential role as 

prognostic or predictive biomarkers. 




Evaluation with DCE-US of antiangiogenic treatments in 539 patients 

allowing the selection of one surrogate marker correlated to overall survival. 

Presenting Author: Nathalie Lassau, Institut Gustave Roussy, Villejuif, 

France 

Background: A prospective study of dynamic contrast-enhanced ultrasound 

(DCE-US) with quantification for the evaluation of antiangiogenic treatments 

was launched (19 centers), supported by the French National 

Cancer Institute. The objectives were the diffusion of the standardized 

method, a cost evaluation and the identification of perfusion parameters 

predicting tumor response. Methods: All patients had DCE-US at baseline, 

D7, D14, D30, D60 and every two months. Each examination included a 

bolus injection of sonovue (Bracco) and 3 minutes of raw linear data with an 

Aplio (Toshiba). Raw data were analyzed with a mathematical model 

(patent PCT/IB2006/003742) to evaluate 7 parameters characterizing the 

tumor perfusion curve. Response to treatment was evaluated every 2 

months with RECIST criteria. In order to have sufficient follow-up data, the 

statistical analysis has to be performed more than 6 months after the 

inclusion of the last analyzed patient. Inclusions were closed in March 

2010. Results: A total of 539 patients have been included (mainly RCC 

(157) and HCC (107)); more than 2 000 DCE-US and 1700 CT-scan were 

performed. A follow-up more than 12 months showed that 3 parameters 

have a strong significant difference (p�0.0003) according to the response 

at 6 months. The decrease of more than 40% of AUC at one month is 

correlated to the TTP (p� 001) and OS (p� 0.04). Conclusions: Final 

results confirm the usefulness of this tool to monitor anti-angiogenic 

treatments. The criteria: the decrease of more than 40% of AUC at one 

month is predictive of response. 


Prospective exploratory analysis of the association between genetic polymorphisms 

and sunitinib toxicity and efficacy in metastatic renal-cell carcinoma. 

Presenting Author: Carlos Alberto Farfan, Hospital Universitario 12 

de Octubre, Madrid, Spain 

Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase 

inhibitor treatment that is approved for metastatic renal cell carcinoma 

(mRCC). However, several patients either do not respond to treatment or 

they experience significant toxicity.Our study aims to find genetic markers 

of toxicity and efficacy using a commercially available DNA microarray 

genotyping system. Methods: 30 patients with newly diagnosed mRCC, 

from January 2010 to May 2011, were evaluated prospectively at Hospital 

12 de Octubre (Madrid, Spain). Pts received SU 50 mg/day, 4 wks on / 2 

wks off treatment schedule. A total of 92 of single nucleotide polymorphisms 

(SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic 

pathways of drugs were analyzed using Drug inCode pharmacogenetic 

service. SNPs in candidate genes, together with clinical characteristics 

were tested univariately for association with the number of days of SU 

treatment until the first reduction of dose, PFS and OS. Results: Complete 

analysis was possible in 25 pts. Pts with CYP1A2*1/*1.a low metabolizing 

genotype, had an increased risk of dose reductions due to toxicity compare 

to allele *1F (Median time to dose reduction : 2.33 months vs NR; 

p�0.006). Pts with CYP2C19*1/*1 , wild type genotype, had an increased 

risk of dose reductions due to toxicity vs. other genotypes (Median time to 

dose reduction: 2.8 vs 9.73 months; p�0.021). Catechol-O-methyltransferase 

(COMT) V158M polymorphisms, was associated with PFS and OS 

(Met/Met carriers median PFS and OS NR; Met/Val pts PFS� 15 months; 

OS�17.2 months and Val/Val pts PFS�3.3 months; OS� 4.4 months ; 

p�0.005 for PFS and p�0.003 for OS). Conclusions: This preliminary 

analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with 

toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 

activity could be affected by a variety of non-genetic factors, if these is 

confirmed, it could lead to the necessity of controlling toxic and dietary 

habits of pts treated with SU. SNPs associated with toxicity and survival in 

this preliminary analysis are being validated in an independent cohort of 

RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011). 


Use of bisphosphonates (Bis) combined with sunitinib (Su) to improve the 

response rate (RR), progression-free survival (PFS), and overall survival 

(OS) of patients (pts) with bone metastases (mets) from renal cell 

carcinoma (RCC). Presenting Author: Avivit Peer, Rambam Health Care 

Campus, Haifa, Israel 

Background: Bis are used to prevent skeletal events of bone mets, and may 

exhibit anti tumor effects. We aimed to evaluate whether Bis can bring a 

RR, PFS, and OS benefit to pts with bone mets from RCC that are treated 

with Su. Methods: We performed an international multicenter retrospective 

study of pts with bone mets from RCC who were treated with Su. Pts were 

divided into Bis users (group 1) and nonusers (group 2). The effect of Bis on 

RR, PFS and OS, was tested with adjustment for known prognostic factors 

using a chisquare test from contingency table and partial likelihood test 

from Cox regression model. Results: Between 2004-2011, 244 pts with 

metastatic RCC were treated with Su. 92 pts had bone mets, 41 group 1 

and 51 group 2. The groups were balanced regarding the following known 

prognostic factors: past nephrectomy, clear cell vs non clear cell histology, 

initial diagnosis to sunitinib treatment (tx) time, presence of � 2 mets 

sites, presence of lung/liver mets, ECOG performance status, anemia, 

calcium level � 10 mg/dL, elevated alkaline phosphatase (AP), pre-tx 

neutrophil to lymphocyte ratio (NLR) �3, sunitinib induced HTN, and the 

use of angiotensin system inhibitors. They were also balanced with regard 

to past cytokines/targeted tx, and mean sunitinib dose/cycle. Objective 

response was partial response/stable disease 85% (n�35) vs 71% (n�36), 

and progressive disease 15% (n�6) vs 29% (n�15) (OR 3.287, p�0.07) 

in group 1 vs 2 respectively. Median PFS was 15 vs 5 months (HR 0.433, 

p�0.035), and median OS not reached with a median folloup time of 43 

mos vs 12 months (HR 0.398, p�0.003), in favor of group 1. In 

multivariate analysis of the entire pt cohort (n�92), factors associated with 

PFS were Bis use (HR 0.433, p�0.035), pre-tx NLR �3 (HR 0.405, 

p�0.016), and elevated AP (HR�3.63, p�0.012). Factors associated 

with OS were Bis use (HR 0.32, p�0.003), elevated AP (HR 3.18, 

p�0.002), and Su induced HTN (HR 0.193, p� 0.001). Conclusions: Bis 

may improve the outcome of Su tx in RCC with bone mets. This should be 

investigated prospectively, and if validated applied in clinical practice and 



Prognostic role of body composition parameters in renal cell carcinoma 

(RCC). Presenting Author: Emilie Lanoy, Biostatistics and Epidemiology 

Unit, Institut Gustave Roussy, Villejuif, France 

Background: Previous studies have shown that body component i.e. muscle 

tissue (MT) and adipose tissue (AT) are linked to overall survival (OS) and 

progression free survival (PFS). The aim of our study is to analyze whether 

MT and AT have a prognostic role in metastatic RCC treated with targeted 

therapy. Methods: We investigated body mass index (BMI), MT and AT in 

RCC pts. Analysis of CT image was used to evaluate cross-sectional areas 

(cm2 ) of total AT (TAT), MT, and the grey level image (GLI) of MT, reflecting 

physical properties of the scanned tissue and used as a proxy to describe 

the quality of muscle. The 3rd lumbar vertebra (L3) was chosen as a 

landmark since L3 and whole-body measurements are linearly related. 

Images were analyzed using Slice-O-Matic software V4.3 (Tomovision). 

Indexed on height MT (cm2 /m2 ), indexed on height TAT (cm2 /m2 ) and 

mean GLI of MT were computed and described stratified on sex. For each 

measurement, population was divided in two groups: patients with values � 

or �� median observed in patient of the same gender and OS and PFS were 

estimated using Kaplan-Meier method and compared with the log-rank 

test. Multivariable Cox proportional hazards model were adjusted for 

modified MSKCC risk group and treatment (active versus placebo). Results: 

There were 113 men aged of 60 (interquartile range�52-56) years with 

BMI of 26 (24-29) kg2 /m2 and 36 women aged of 58 (54-65) years with 

BMI of 23 (20-26) kg2 /m2 . After adjustment for MSKCC (OS and PFS) and 

active treatment (PFS), GLI of MT over the median was associated with 

longer OS (HR�1.85, 95%CI�[1.22;2.82], p�.004) and PFS (HR�1.81, 

95%CI�[1.22;2.65], p�.002) Conclusions: Quality of muscular tissue is 

independently associated with better outcome in RCC. Surprisingly, adipose 

tissue as well as BMI is not associated with survival in this study. 

OS in months PFS in months 

Label 

Median P25 P75 p Median P25 P75 p 

Indexed MT>� 14 cm 2 /m 2 (men) 

or 13 cm 2 /m 2 24 14 49 .1213 6 4 13 .3128 

(women) 

Indexed MT< 14 cm 2 /m 2 (men) 

or 13 cm 2 /m 2 19 10 39 5 3 9 

(women) 

Mean GLI >� 38 (men) or 36 (women) 29 18 62 .0011 8 4 15 .0007 

Mean GLI < 38 (men) or 36 (women) 14 7 30 4 3 8 

Indexed TAT >�326 cm 2 /m 2 (men) 

or 231 cm 2 /m 2 24 14 45 .1725 6 4 11 .6124 

(women) 

Indexed TAT


Adherence to oral anticancer drugs (OAD) in patients (pts) with metastatic 

renal cancer (mRCC): First results of the prospective observational multicenter 

IPSOC study (Investigating Patient Satisfaction with Oral Anticancer 

Treatment). Presenting Author: Pascal Wolter, Department of 

General Medical Oncology, University Hospitals Leuven, Leuven, Belgium 

Background: Patient adherence to oral therapy is a critical issue in cancer 

treatment. The aim of this study is to investigate the prevalence and 

severity of non-adherence to OAD in mRCC and to identify factors 

predictive of non-adherence. Methods: Prospective observational multicenter 

trial performed at 11 Belgian academic and non-academic centers. 

All pts with mRCC starting OADs (sunitinib, pazopanib, everolimus or 

sorafenib) are eligible for the study. Pts are contacted by phone at baseline 

and at 1, 3, 6 and 12 months. At each contact, pts are asked to complete 

questionnaires investigating 1) medication adherence (MMAS), 2) patient 

satisfaction with treatment (CTSQ) and with treatment education (PS- 

CaTE), 3) the extent of information desire (EID), 4) quality of life (FACT-G 

and FKSI) and 5) the role of the pharmacist (SWiP). Adherence is measured 

using an electronic medication event monitoring system (MEMS, Aardex). 

Results: Between 02/2011 and 11/2011, 49 pts (m: 33, f: 16) with a 

median age of 63 years (range 25 - 87) have participated in the IPSOC 

study. Twenty-nine pts (64%) were treated with an OAD in first-line, 15 pts 

(33%) in second-line. With a median follow-up of 131 days (range 2 - 313) 

45 pts (92%) claimed to be fully adherent to their treatment (based on 

MMAS and CTSQ data). Four patients indicated to have missed at least one 

dose, of whom two indicated they occasionally forgot their medication and 

two others interrupted treatment because of side effects. Based on MEMS 

data, mean adherence, defined as the percentage of days with at least the 

prescribed number of dosage taken, was 98.91%. Conclusions: The IPSOC 

study, the first to examine adherence to OAD among mRCC pts, shows that 

mRCC pts are almost fully adherent to treatment recommendations. This 

seems to be in contrast to adherence data for other, long-lasting, anticancer 

treatments. Further investigations will focus on the question 

whether extensive counseling and participation in side-effect programs 

contribute to the high percentage of adherence in this study. 


Molecular characterization of SETD2, a histone methyltransferase, in clear 

cell renal cell carcinoma (ccRCC). Presenting Author: Thai Huu Ho, 


Background: Although the von Hippel-Lindau (VHL) tumor suppressor is 

mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for 

tumorigenesis. Sequencing of ccRCC tumors identified mutations in 

SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. We hypothesize 

that loss of SETD2 methyltransferase activity decreases H3K36 

trimethylation (H3K36Me3) in ccRCC, and contributes to the cancer 

phenotype. Methods: H3K36Me3 immunohistochemical (IHC) staining was 

quantitated in wild-type and mutant SETD2 nephrectomy tissue. To 

establish frequency of SETD2 loss of heterozygosity (LOH), genomic DNA 

was isolated from 51 VHL deficient ccRCC specimens and analyzed with 

Affymetrix single-nucleotide polymorphism (SNP) arrays. To evaluate 

alterations of histone modifications in advanced ccRCC, H3K36Me3 IHC 

was quantitated on tissue microarrays (TMAs) representing 28 paired 

ccRCC specimens with unaffected kidney parenchyma and 40 metastases. 

To identify kidney-specific H3K36Me3 binding sites, chromatin immunoprecipitation 

(ChIP) sequencing was performed on nephrectomy specimens. 

Results: Nephrectomy specimens with SETD2 truncating mutations 

have decreased H3K36Me3 (�50%) compared to uninvolved kidney 

tissue. Using SNP arrays, LOH at chromosome 3p (location of VHL and 

SETD2 genes) was detected in �90% of the tested tumors. IHC reveals a 

27.4% and 52.0% decrease in H3K36Me3 positive nuclei in primary 

ccRCC and metastases, respectively, when compared to matched adjacent 

unaffected kidney tissue (p �0.0001). Using ChIP sequencing, 421 and 

1,718 genomic regions were upregulated in the tumor and unaffected 

kidney tissue. Conclusions: SETD2 truncating mutations in patient-derived 

tissue have decreased H3K36Me3 indicating that SETD2 is a nonredundant 

H3K36 methyltransferase. LOH of VHL and SETD2 occurs in 

�90% of tested ccRCC tumors. Genomic regions enriched for H3K36Me3 

binding are being validated in additional patient-derived tissues. H3K36Me3 

is decreased in primary ccRCC and even more in metastases, suggesting 

that SETD2 methyltransferase activity is progressively misregulated in 

RCC. Loss of SETD2 activity may cooperate with VHL silencing to promote 

tumorigenesis. 


307s 


Trends in the use of cytoreductive nephrectomy for metastatic renal cell 

carcinoma in the VEGFR tyrosine kinase inhibitor era. Presenting Author: 

Che-Kai Tsao, Division of Hematology and Medical Oncology, The Tisch 

Cancer Institute, Mount Sinai School of Medicine, New York, NY 

Background: Two large randomized trials (SWOG, EORTC) published in 

2001 established the role of cytoreductive nephrectomy (CyNx) for the 

treatment of metastatic renal cell carcinoma (mRCC) in the cytokine era. A 

paradigm shift occurred in 2005 with the approval of VEGFR tyrosine 

kinase inhibitors (TKIs). We hypothesized that uncertainty regarding the 

role of CyNx in the VEGFR TKI era has resulted in a change in practice 

patterns. Methods: Using the Surveillance, Epidemiology and End Results 

(SEER) registry, we identified 2780 patients with histologically-confirmed 

mRCC between 2000 and 2008 who underwent CyNx or no surgery. 

Patients were separated into pre- or VEGFR TKI-eras (2000-2005 vs. 

2006-2008). Differences in baseline characteristics between these patient 

groups were assessed and controlled for in a logistic regression analysis to 

determine the likelihood of undergoing CyNx. Results: Overall, 1202 of 

2780 patients (43%) underwent CyNx. CyNx increased from 41% in 2000 

to 49% in 2005, and decreased to 35% in 2008, with a 20% decreased 

likelihood of undergoing CyNx in the VEGFR TKI era compared to the 

pre-VEGFR TKI era. Logistic regression analysis showed that tumor size, 

age, race, marital status and pre- versus post-2005 periods were independent 

predictors of CyNx (Table). Patients who were non-Caucasian, single, 

with primary tumor �3cm, or older were less likely to undergo CyNx. 

Conclusions: Use of CyNx increased after supporting level I evidence was 

published in 2001, and decreased after regulatory approval of VEGFR TKIs 

in 2005. Racial and demographic differences exist in the utilization of 

CyNx. The results of pending randomized trials evaluating the role of CyNx 

in the TKI-era are awaited to optimize use of this modality and address 

potential disparities. 

Logistic regression model for use of CyNx in 2000-2008. 

Variable (reference) Odds ratio Std error p value 

Post-2005 (Pre-2005) 0.802 0.092 0.0161 

Primary tumor size >3cm (



Impact of maximum standardized uptake value (SUVmax) evaluated by 

18-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography 

(FDG PET/CT) on survival for patients with advanced renal cell 

carcinoma. Presenting Author: Noboru Nakaigawa, Department of Urology, 

Yokohama City University Graduate School of Medicine, Yokohama, Japan 

Background: In this era of molecular targeting therapy when various 

systematic treatments can be selected, prognostic biomarkers are required 

for the purpose of risk-directed therapy selection. Numerous reports of 

various malignancies have revealed that 18-Fluoro-2-deoxy-D-glucose 

( 18F-FDG) accumulation, as evaluated by positron emission tomography, 

can be used to predict the prognosis of patients. The purpose of this study 

was to evaluate the impact of the maximum standardized uptake value 

(SUVmax) from 18-fluoro-2-deoxy-D-glucose positron emission tomography/ 

computed tomography (FDG PET/CT) on survival for patients with advanced 

renal cell carcinoma (RCC). Methods: A total of 67 patients with advanced 

or metastatic RCC were enrolled in this study. The FDG uptake of all RCC 

lesions diagnosed by conventional CT was evaluated by FDG PET/CT. The 

impact of SUVmax on patient survival was analyzed prospectively. Results: 

The mean duration of observation was 461 days (range, 7-1229 days). The 

SUVmax before treatment of 67 patients ranged between undetectable 

level and 16.6 (mean 7.6�3.6). The patients with RCC tumors showing 

high SUVmax before treatment demonstrated poor prognosis (p�0.001 

hazard ratio 1.289, 95% CI 1.161-1.430). The median survival time of 36 

patients with RCC showing SUVmax less or 7.0 was 1229�991 days, that 

of 21 patients with RCC showing SUVmax between 7.0 and 12.0 was 

446�202 days, and that of 10 patients RCC showing SUVmax higher than 

12.0 was 95�43 days (�7.0 vs. 7.0� �12.0 p�0.0052, 7.0� �12.0 vs. 

12.0�:p�0.0169, log-rank test). SUVmax demonstrated a tendency to 

predict the survival compared with the Memorial Sloan-Kettering Cancer 

Center classification (p �0.015 vs 0.315, multivariate Cox analyses). 

Conclusions: The survival of patients with advanced RCC can be predicted 

by evaluating their SUVmax using FDG PET/CT. FDG PET/CT has potency as 

an “imaging biomarker” to provide helpful information for the clinical 

decision-making. 


Sorafenib treatment of Asian patients with advanced renal cell carcinoma 

(RCC) in daily practice: Subset analysis of the large non-interventional 

PREDICT study. Presenting Author: Dingwei Ye, Cancer Hospital, Fudan 

University, Shanghai, China 

Background: Previous studies with sorafenib in Asian patients with advanced 

RCC were relatively small and used strict entry criteria. Here we 

investigated safety and efficacy in a large subset of Asian patients in the 

prospective, non-interventional PREDICT study of sorafenib in routine 

practice (NCT 00895674). Methods: Patients were eligible based on a 

diagnosis of advanced RCC and the decision by the investigator to prescribe 

sorafenib under compliance of the local product label. Tumor status, 

patients’ performance and physician assessment of efficacy and tolerability 

were collected up to 12 months. Results: Between Jan 2007 and June 

2010, 1092 patients were enrolled in China (n�1033), South Korea 

(n�55), the Philippines (n�3) and Indonesia (n�1). In the efficacy 

population (n�909), baseline characteristics were: 71% male; 89% �70 

years old; 89% clear cell histology; 78% prior nephrectomy; 56% prior 

systemic therapy; 16% high MSKCC risk; 35% ECOG PS �2; 5% brain 

metastases. Overall, 19% of patients had �1 concomitant disease at 

baseline; the most frequent concomitant diseases were hypertension 

(14%) and diabetes (6%). Initial sorafenib dose was 800 mg daily in 97% 

of patients, of whom 91% were also receiving 800 mg daily as last dose. 

Median duration of sorafenib treatment was 9.7 months (range 0.2–24.1), 

and in clinically relevant subgroups was as follows: treatment-naïve, 9.7 

months; high MSKCC risk, 9.3 months; brain metastases, 8.4 months; age 

�70 years, 7.6 months; ECOG PS 2, 9.7 months; ECOG PS 3, 6.1 months. 

At last follow up, 63% of physicians reported good/very good efficacy and 

59% good/very good tolerability. Sorafenib was well tolerated; �2% of the 

safety population (n�1022) reported serious drug-related adverse events 

(SDRAEs) and only 3% discontinued due to DRAEs. In all, 35% of patients 

reported a DRAE, with the most frequent being hand-foot skin reaction 

(21%), diarrhea (7%), rash (7%), alopecia (5%), hypertension (3%). 

Conclusions: In this large subset of Asian patients with advanced RCC 

treated in daily practice settings, sorafenib was well tolerated and provided 

benefit, including in clinically relevant patient subgroups. 


Natural history of malignant bone disease in renal cancer: Final results of 

an Italian bone metastases survey. Presenting Author: Daniele Santini, 

Dipartimento di Medicina Oncologica, Università Campus Bio-Medico di 

Roma, Rome, Italy 

Background: bone metastases (mts) are an emerging clinical problem in 

renal cancer patients related to survival increase. We report the final data of 

largest survey never published in literature. Methods: 398 renal cancer 

patients (pts) with evidence of bone mts, all died at the moment of study 

inclusion, have been included. Clinico-pathological data, data on survival 

and Skeletal Related Events (SRE) data and skeletal related therapies have 

been collected and statistically analyzed. Results: 286 males/112 females; 

median age: 63 (16-87); pts with bone mts at the moment of renal cancer 

diagnosis: 31.4%; pts with single bone mts: 31.1%. Type: lytic 77%, 

mixed: 14.6%, blastic: 7.6 %. Sites: spine (65.8%), pelvis (38.4%), long 

bones (31.6%), other (18.8%). Median time to bone mts: 8 months 

(0-288) (all patients); 24 months (1-288) (pts without bone mts at 

diagnosis). Pts with at least 1 SRE: 71.1%. Types of SREs: pathologic 

fracture (12.6%), radiotherapy (61.8%), spinal compression (7.6%), bone 

surgery (14.8%), hypercalcaemia (3.2%). Median number of SRE for 

patient: 1 (0-4). Median time to first SRE: 2 (0-72), to second SRE: 4 

(0-113), to third SRE: 11 (1-108). Median survival after bone mts 

diagnosis: 12 (1-178). Median survival after first SRE: 10 (0-144). Median 

survival in pts with at least one SRE: 14 (1-178); median survival in pts 

without SREs: 9 (0-62). In according with MKSCC criteria median time to 

skeletal disease was in patients with good prognosis was 24 (0-288), 

intermediate was 5 (0-180) and poor prognosis was 0 (0-77). A total of 168 

pts received zoledronic acid until performance status worsening or death. 

162 pts have been analysed as control group. The median time to first SRE 

in the zoledronic treated pts was 3 mths (0-101) compared with 1 mth (0 - 

25) in the control group (p� 0.05). 5 cases of ONJ have been diagnosed. 

Conclusions: The present survey is the largest descriptive study concerning 

the natural history of bone disease in renal cancer patients. The effects of 

biological therpies on bone met will be presented during the meeting. 


Overall survival (OS) in metastatic renal cell carcinoma (mRCC) sequentially 

treated with different targeted therapies (TTs): Results from a large 

cohort of patients. Presenting Author: Giuseppe Procopio, Fondazione 

IRCCS Istituto Nazionale dei Tumori, Milan, Italy 

Background: Targeted Therapies (TTs) have definitely improved survival in 

patients with mRCC. However the optimal therapeutic strategy is not 

shared. This study was performed to assess the overall survival (OS) in a 

consecutive series of mRCC patients receiving TTs. Methods: Characteristics 

and outcomes of 336 patients affected by mRCC receiving TTs were 

collected from the database of Istituto Nazionale Tumori of Milan. The 

main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131 

(39%)/19 (6 %); clear-cell histology 291 (87%); previous nephrectomy 

293 (87%). According to Motzer criteria 32% of patients showed low risk, 

48% intermediate risk and 20% poor. Overall, 167 (50%) patients 

received one TTs, while 116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 

and 4 TTs, respectively. 245 (73%) patients received sorafenib (So), 212 

(63%) sunitinib (Su), 33 (10%) a bevacizumab regimen and 73 (22%) 

other TTs, including everolimus, temsirolimus and axitinib. The Kaplan 

Meier curves were used to describe the survival.The uni- and multi-variate 

analyses for OS were carried out by means of Cox proportional hazard 

regression analysis. Results: Ata median follow-up of 43 months, 199 

patients (57 %) had died. The median OS was 24 months (95%CI: 

20.0-27.0) and the 5-year OS was 24.6 % (95 %CI: 18.7-30.8). In 

univariate analyses, there were no significant differences in the hazard 

ratios (HR) for So followed by Su compared to Su followed by So 

(HRSU-SO / SO-SU � 1.16; 95%CI: 0.57-2.33) or compared with other 

therapies (HROther sequential th. / SO-SU � 1.21; 95%CI: 0.78-1.88; 

p�0.674).In the multivariate analysis, in terms of OS any statistical 

difference was reported as regards the sequence used (Su/So vs So/Su; 

p�0.05) or bevacizumab regimen as compared to Su and/or So used 

sequentially (p�0.05). In the uni and multivariate analysis ECOG PS, 

nephrectomy, Fuhrman grade and number of sites of disease are independent 

predictive factors of outcome (p� 0.01). Conclusions: These data 

suggest that TTs improve OS in mRCC without any statistical difference 

when using different sequences of TTs. No cross-resistance between 

several sequences of TTs was documented. 



Hypoxia-inducible factor (HIF) 1� and 2� as predictive markers of outcome 

to VEGFR tyrosine kinase inhibitors (TKI) in renal cell carcinoma (RCC). 

Presenting Author: M.I. Saez, Hospital Universitario Virgen de la Victoria, 

Malaga, Spain 

Background: Relevant biomarkers in RCC are needed to identify appropriate 

candidates for selected targeted therapies. Mutations in the von Hippel- 

Lindau (VHL) gene result in the accumulation of HIF and increased 

expression of proangiogenic factors, including VEGF. Methods: Metastatic 

clear RCC patients with available baseline tumor samples who received 

first-line oral VEGFR-TKI were included in this analysis. VHL mutation/ 

hypermethylation status and HIF1� and HIF2� immunohistochemical 

staining were analyzed from paraffin-embedded tumors. Additionally, a 

panel of candidate VEGF and VEGFR2 genetic SNPs was determined from 

peripheral blood samples. HIF was scored as negative or positive based on 

staining intensity (0-10% and � 10%, respectively). Results were evaluated 

for associations with clinical outcome. Results: 80 patients were 

included: 71 evaluable for HIF expression, 63 for VHL status and 52 for 

SNPs. 73% received treatment with sunitinib and median follow-up was 

21.5 months. Unlike VHL status, HIF1 and HIF2 positive expression 

showed a significant correlation with PFS and OS. HIF1� was also 

predictive for response rate (RR). On multivariate analysis adjusting for 

other prognostic factors, HIF1� and HIF2� remained the most significant 

independent predictive factors for survival (adjusted HR 0.09, 95% CI 

0.03-0.28, p � 0.0001 and HR 0.13, 95% CI 0.04-0.37, p � 0.0001; 

respectively). We did not find any statistically significant differences based 

on the VEGF and VEGFR2 SNPs analyzed. Conclusions: HIF1� and HIF2� 

levels represent the most important independent predictive factors of 

outcome for VEGFR-TKI therapy in metastatic RCC. These findings may 

contribute to optimize treatment with targeted agents. 

HIF1� HIF2� 

HIF1� � HIF1� - HIF2� � HIF2� - 

N (%) 38 (53.5) 33 (46.5) 46 (64.8) 25 (35.2) 

RR (%) 67 27 55 37 

OR (p value) 0.18 (p�0.001) 0.50 (p�0.20) 

Median PFS (months) 22.8 13.6 21.4 9.6 

HR (p value) 0.36 (p�0.0001) 0.61 (p�0.04) 

Median survival (months) 43.7 16.6 42.5 20.3 

HR (p value) 0.31 (p�0.0001) 0.52 (p�0.04) 


Updated safety results from EXIST-2: Everolimus therapy for angiomyolipoma 

(AML) associated with tuberous sclerosis complex (TSC) or sporadic 

lymphangioleiomyomatosis (sLAM). Presenting Author: John Bissler, Cincinnati 

Children’s Hospital Medical Center, Cincinnati, OH 

Background: EXIST-2 (NCT00790400) is a randomized, double-blind, 

placebo-controlled, phase 3 trial assessing the efficacy and safety of 

everolimus, an oral mTOR inhibitor, for treating AML in patients with TSC 

or sLAM. We have previously reported that everolimus resulted in a 

significantly higher AML response rate vs placebo (41.8% vs 0%; 95% CI: 

23.5–58.4; p�0.0001) with a consistent safety profile (Bissler et al. JAm 

Soc Nephrol. 22, 2011, Abstract LB-PO3159). Here we present a 90-day 

safety update. Methods: 118 eligible patients were randomized 2:1 to 

receive everolimus 10 mg daily (n�79) or placebo (n�39). The primary 

efficacy endpoint was AML response rate (proportion of patients with best 

overall AML response status of “response”). Original cut-off date for data 

analysis was 30 Jun 2011. An updated analysis of the safety data for the 

safety set (all patients receiving �1 dose of double-blind study drug with a 

valid post-baseline assessment) to 14 Oct 2011 are presented here. 

Results: As of 14 Oct 2011, median treatment duration was 48.1 and 45.0 

weeks for everolimus and placebo arms, respectively. Discontinuations in 

the double-blind period were the same in the everolimus arm as the initial 

analysis, but had increased by 4 patients in the placebo arm since initial 

analysis (3 due to disease progression, 1 withdrew consent). The majority of 

adverse events (AEs) continued to be grade 1 or 2; the incidence of serious 

AEs was slightly higher than initially reported, particularly in the placebo 

arm (everolimus 20.3%, placebo 23.1%). AE incidence leading to discontinuation 

was the same as initially reported (everolimus 3.8%, placebo 

10.3%). In the updated data, 3 additional everolimus patients required 

dose interruption or reduction due to AEs; dose reduction/interruption 

remained more common in the everolimus arm (51.9% vs. 20.5%). 

Conclusions: Overall, the 90-day updated safety data analysis from the 

EXIST-2 trial has not revealed any additional safety concerns. No other 

patients receiving everolimus withdrew for any reason, whereas 3 more 

patients receiving placebo withdrew due to disease progression. 


309s 


Use of early tumor shrinkage as a response to VEGF inhibitors as a predictor 

of progression-free survival (PFS) and overall survival (OS) in patients with 

metastatic renal cell carcinoma (mRCC). Presenting Author: Viktor Gruenwald, 

Department of Hematology, Hemostasis, Oncology and Stem Cell 

Transplantation, Hannover Medical School, Hannover, Germany 

Background: Several novel targeted agents significantly prolong overall 

survival (OS) in metastatic renal cell cancer (mRCC) patients (pts.). 

Translational research, however, has not identified any prospectively 

validated prognostic or predictive biomarkers. Recently, progression free 

survival (PFS), overall response rate (ORR) and early tumor shrinkage were 

proposed as putative predictors for clinical outcome. In this study we aim to 

explore the potential role of treatment induced tumor remission as a 

prognostic or predictive parameter in mRCC. Methods: In our analyses we 

investigated the putative prognostic role of best response according to 

RECIST 1.1 criteria (complete remission (CR), partial remission (PR), 

stable disease (SD), progressive disease (PD)) in first line Tyrosine-kinase 

inhibitor (TKI) treatment in n�83 pts. Responders were defined by 

achieving CR, PR or SD at any time during the course of treatment. 

Furthermore, we tested whether tumor shrinkage of 10% or more within 12 

weeks of treatment qualifies as a potential cut-off-parameter to predict PFS 

or OS. Uni- and multivariate analyses were performed using Log-rang test, 

Kaplan-Meier-, and Cox-regression analysis. Results: Univariate analyses 

revealed that first-line treatment non-responders had a significantly shorter 

OS than responders (p �0.0001). Tumor shrinkage of �10% or �10% 

also correlated with an OS of 14.5 vs. 29.1 mo. (p�0.001) and a PFS of 

3.0 vs. 11.5 mo. (p �0.001). In multivariate analyses tumor shrinkage of 

�10% was tested with other common variables such as ECOG, MSKCCscore, 

histology, and metastatic sites and proved to be a significant 

independent prognostic (HR 0.361; 95% CI 0.156-0.833) and predictive 

(HR 0.306; 95% CI 0.152-0.612) parameter. Conclusions: Our results 

outline that sensitivity to first line treatment of mRCC is an important 

prognostic factor in mRCC. Hereby tumor shrinkage of �10% within 12 

weeks of treatment reveals a novel cut-off-parameter, which showed to be a 

promising prognostic and predictive marker in mRCC. Further investigations 

are needed to validate this parameter. 


Use of miRNA profiling in metastatic renal cell carcinoma to reveal a tumor 

suppressor effect for mir-215. Presenting Author: George M. Yousef, 

Department of Laboratory Medicine and Keenan Research Centre, St. 

Michael’s Hospital, Toronto, ON, Canada 

Background: Renal cell carcinoma (RCC) is the most common neoplasm of 

the adult kidney. Metastatic RCC is difficult to treat. The five-year survival 

rate for metastatic RCC is �10%. Recently, microRNAs (miRNAs) have 

been shown to have a role in cancer metastasis and potential as prognostic 

biomarkers in cancer. Methods: We performed a miRNA microarray to 

identify a miRNA signature characteristic of metastatic compared to 

primary RCC. Results were validated by quantitative real time PCR. Target 

prediction analysis and gene expression profiling identified many of the 

dysregulated miRNAs could target genes involved in tumor metastasis. The 

effect of miR-215 on cellular migration and invasion was shown in a RCC 

cell line model. Results: We identified 65 miRNAs that were significantly 

altered in metastatic when compared to primary RCC. Nine (14%) miRNAs 

had increased expression while 56 (86%) miRNAs showed decreased 

expression. miR-10b, miR-196a, and miR-27b were the most downregulated 

while miR-638, miR-1915, and miR-149* were the most upregulated. 

A non-supervised 2D-cluster analysis showed that a sub-group of the 

primary tumors clustered under the metastatic arm with a group of miRNAs 

that follow the same pattern of expression suggesting they have an 

inherited aggressive signature. We validated our results by examining the 

expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in 

two independent cohorts of patients. We also showed that overexpression of 

miR-215 decreased cellular migration and invasion in a RCC cell line 

model. In addition, through gene expression profiling, we identified direct 

and indirect targets of miR-215 that can contribute to tumor metastasis. 

Conclusions: Our analysis showed that miRNAs are altered in metastatic 

RCC and can contribute to kidney cancer metastasis through different 

biological processes. Dysregulated miRNAs represent potential prognostic 

biomarkers and may have therapeutic applications in kidney cancer. 




Evaluation of selective inhibitors of nuclear export (SINE) CRM1 inhibitors 

for the treatment of renal cell carcinoma (RCC). Presenting Author: Hiromi 

Inoue, University of California, Davis, Davis, CA 

Background: For the ~30% of patients who present with RCC at the 

metastatic stage, multi-kinase inhibitors have been used with moderate 

success: progression-free survival remains at only one to two years, and 

thus it is imperative to discover novel therapeutic approaches for metastatic 

disease. We asked whether (1) SINE inhibitors of chromosome region 

maintenance protein 1 (CRM1) attenuate key cell cycle regulatory and 

apoptotic molecules and whether these compounds exert salutary effects in 

a human RCC xenograft mouse model. Methods: Four RCC cell lines (ACHN, 

Caki-1, 786-O, and A498) with distinct genotypes, and primary normal 

human kidney (NHK) cell lines, were used in this study. The cells were 

treated with the chemically related SINE CRM1 inhibitors KPT-185 or 251 

and MTT assays were performed. In addition, cell cycle analyses, immunofluorescence 

for p53 and p21, and immunoblotting for CRM1, p53, p21, 

p27, and p-MDM2 were performed for all cell lines. RCC mice with Caki-1 

xenografts were treated with vehicle, the orally-available CRM1 inhibitor 

KPT-251, or sorafenib for 26 days. Tumor volume was measured over 

several days. Results: Both KPT185 and 251 specifically reduced CRM1 

protein levels in RCC cells. KPT-185 caused dose-dependent cytotoxicity 

in RCC cells, which was greater than sorafenib in RCC cell lines but less in 

NHK cells, suggesting a possible clinical advantage of KPT-185 over 

sorafenib. By FACS analysis, we showed that KPT-185 arrests the cell cycle 

in both G2/M and G1, and increased the sub-G0 cell population. KPT-185 

and 251 both increased p53 and p21 in RCC cells, and KPT-185 confined 

these proteins to the nucleus. In vivo, KPT-251 inhibited Caki-1 xenografts 

in mice compared to both vehicle and sorafenib without obvious systemic 

adverse effects. Conclusions: We introduce a completely novel therapeutic 

approach to the treatment of RCC based on inhibition of the nuclear export 

of key cell cycle regulatory proteins. Inhibition of CRM1 leads to forced 

nuclear retention, and thereby activation, of several key p53-pathway 

proteins, leading to cell cycle arrest and apoptosis in RCC cell lines in vitro 

and tumor growth inhibition in vivo. 


Efficacy and safety of cancer vaccine with 4-fold gene-modified allogeneic 

tumor cells: Results of the phase I/II ASET study in patients with advanced 

renal cell carcinoma. Presenting Author: Steffen Weikert, Department of 

Urology, Charité-University Medicine Berlin, Berlin, Germany 

Background: MGN1601 was tested in the first-in-man phase I-II clinical 

study in patients with advanced renal cell carcinoma (RCC) who failed 

several previous therapy lines and had no further standard therapy 

available. MGN1601 consists of two active pharmaceutical ingredients in 

fixed combination: fourfold gene-modified allogeneic tumor cells expressing 

IL-7, GM-CSF, CD80 and CD154 through MIDGE vectors and a TLR-9 

agonist, the immunomodulator dSLIM. Methods: The ASET study is a 

multicentric, single-arm phase I-II clinical trial. Clinical response was 

evaluated using CT scans (RECIST 1.1 or immune related Response 

Criteria, irRC). Efficacy data were evaluated in terms of PFS and OS for the 

intended to treat and the treated per protocol (TPP) populations, clinical 

parameters and quality of life. Immune response was determined using 

DTH to MGN1601, LTT assay, frequency and activation of blood cells, and 

mRNA, chemokine and cytotoxic T cells analysis as well as tumor tissue 

evaluation. Results: Nine of 19 included patients completed the TPP, the 

others discontinued the study earlier due to PD. Median PFS in the TPP 

group was 12 wks (3 months) and OS (not reached yet) 46 wks (11 

months). Three patients achieved disease control (1 PR, 2 SD) after 12 

wks. Two patients are continuing treatment in the extension phase and are 

progression free since 37 and 46 wks, respectively. Re-evaluation of tumor 

response data using irRC revealed 1 additional patient with a delayed tumor 

response 4 wks after treatment stop. Herewith, 4 out of 9 TPP patients 

(45%) achieved disease control. Of 7 patients receiving targeted therapy 

upon stop of study treatment, 4 had substantial objective responses, 

providing evidence that the study drug is able to render their tumors more 

vulnerable to subsequent therapies. Immune analysis showed trends 

towards increases of T-, NKT-cell and pDC frequencies and other immune 

parameters in those patients with clinical responses, indicating anti-tumor 

immunity of study treatment. Conclusions: The therapeutic cancer vaccine 

MGN1601 shows promising efficacy in late stage mRCC patients. Results 

warrant further clinical studies with MGN1601. 


Genetic polymorphisms’ influence in outcome of metastatic renal cell 

cancer patients treated with VEGF-targeted agents. Presenting Author: 

Fabio Augusto Barros Schutz, Lank Center for Genitourinary Oncology, 

Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard 


Background: Single nucleotide polymorphisms (SNP) in critical signaling 

pathways may impact the outcome of metastatic renal cell cancer (mRCC) 

patients (pts) treated with VEGF targeted agents. Methods: Germline DNA 

was extracted from 263 pts of European-American ancestry enrolled in a 

prospective protocol with full baseline and follow up clinical data. A total of 

113 common SNPs within select genes involved in RCC pathogenesis, 

angiogenesis and drugs metabolism were genotyped and associations 

sought with clinical outcome. The primary endpoint was progression free 

survival (PFS), defined as time from VEGF targeted therapy to progression 

or death. Cox model tested for the association between SNPs with PFS in 

univariate and multivariate model that adjusted for age, gender, type of 

VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was 

used to control for the number of tests performed. Results: The median 

follow-up time was 51.6 months (mo), 81% of pts had progression or death 

events. All patients were treated with an approved VEGF targeted agent 

(bevacizumab, sunitinib, sorafenib or pazopanib). Fifty three percent 

(140/263) of pts were treated with sunitinib. Two SNPs, one in HIF2� and 

one in VEGFR2, showed a significant association with the risk of progression. 

Compared to the dominant genotype (frequency 83%, median PFS 

10.1mo), the VEGFR2 rs2305948 variant genotype (frequency 17%) 

showed a superior PFS (median 19.2mo) corresponded to an adjusted 

hazard ratio (HR) of 0.56 (95%CI: 0.37-0.84; p�0.005). Similarly and 

compared to the dominant genotype (frequency 94%, median PFS 10.6mo), 

the HIF2a rs11687512 variant genotype (frequency 6%) had a superior 

PFS (median 26.5mo) with an adjusted HR of 0.33 (95%CI 0.16-0.68; 

p�0.002). The analysis adjusted for age, gender, type of VEGF targeted 

therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate 

was �20% with both SNPs. Conclusions: Inherited variants may influence 

the PFS of pts with mRCC treated with VEGF targeted agents. Validation of 

these findings in an independent cohort is required. If validated, these 

results could help identifying subset of pts that are more likely to remain 

progression free on treatment. 


Longitudinal serum testosterone levels (T) in long-term testicular cancer 

survivors (TCSs) in relation to testicular cancer (TC) treatment, aging, and 

TC diagnosis itself. Presenting Author: Mette Sprauten, OUS, The Norwegian 

Radium Hospital, Oslo, Norway 

Background: Low T may increase the risk of cardiovascular disease, 

osteoporosis, and reduced quality of life. T might be reduced by TC, its 

treatment, ageing, and particularly their combination. Methods: T was 

retrieved from 311 TCSs after orchiectomy and prior to subsequent 

management with either surveillance/surgery only (S), radiotherapy (RT) or 

cisplatin based chemotherapy (CT). Human Chorionic Gonadotropin (hCG) 

was available for 211 TCSs. T was reassessed at surveys performed 9 (S9) 

and 18 years (S18) after treatment. T values were categorized into quartiles 

according to cut-off values derived from 570 healthy controls (C) for each 

decadal age group. Statistical associations were assessed with Chi2 tests. 

Results: In TCSs about to receive RT or CT, T and hCG were higher when 

compared to those subsequently managed by S. TCSs were more likely to 

belong to the lowest T quartile, more so with increasing treatment intensity 

(table). The proportions of TCSs belonging to the corresponding T quartiles 

displayed no significant changes from S9 to S18. Conclusions: TCSs had 

lower T than C of similar age already after orchiectomy, possibly related to 

removal of the affected testicle and/or testicular dysgenesis syndrome. 

TCSs who were to receive RT or CT had slightly increased T when compared 

to S, probably due to hCG stimulation. T reduction by RT or CT has been 

described previously but rarely in longitudinal studies. Of note, longitudinal 

assessment of T without comparison to C might result in overestimation of 

the treatment burden. Relatively stable age adjusted T levels from S9 to 

S18 for the TCSs independent of treatment are encouraging. 

C: n�570, 

(100%) 

S: n�69, 

(100%) 

RT: n�133, 

(100%) 

CT: n�109, 

(100%) 

Pretreatment 

75% 141 (24.7) 3 (4.3) 18 (13.5) 18 (16.5) 

OR(95%CI) Referent (R) 13.2 (4.0- 43.7) 3.5 (2.0- 6.2) 2.4 (1.3- 4.3) 

S9 

75% 141 (24.7) 9 (13.0) 12 (9.0) 12 (11.0) 

OR(95%CI) R 3.2 (1.4- 7.0) 5.2 (2.7- 10.0) 5.0 (2.6- 9.7) 

S18 

75% 141 (24.7) 6 (8.7) 9 (6.8) 10 (9.2) 

OR(95%CI) R 4.4 (1.8- 11.0) 6.9 (3.3- 4.4) 6.8 (3.4- 13.7) 



Epidermal growth factor receptor (EGFR) expression and KRAS mutations 

in penile squamous cell carcinoma: Analysis of potential application of 

anti-EGFR monoclonal antibodies. Presenting Author: Hongfeng Gou, 

Department of Abdominal Cancer, Cancer Center, West China Hospital, 

Sichuan University, Chengdu, China 

Background: Penile squamous cell carcinoma (SCC) is a rare cancer with 

poor prognosis and limited response to conventional chemotherapy. Anti- 

EGFR monoclonal antibodies (mAbs) have exhibited significant anti-tumor 

activities in several cancers such as colorectal carcinoma, head and neck 

cancer. KRAS mutations are linked to a poor response to mAbs and may 

thereby result in resistance to anti-EGFR agents. This study was aimed to 

examine EGFR expression and KRAS, BRAF mutations in penile SCC and to 

analyze the potential application of anti-EGFR monoclonal antibodies 

(mAbs) for this disease. Methods: Totally 150 penile SCC specimens from 

patients undergone surgical resection were included. EGFR expression was 

evaluated by immunohistochemistry. KRAS mutations at codons 12 and 

13, and the BRAF mutation at codon 600 were analyzed on DNA isolated 

from formalin fixed paraffin embedded tissues by direct genomic sequencing. 

Results: EGFR expression was positive in all specimens, and its 

overexpression rate was 92%. We failed to observe a significant correlation 

between EGFR expression and tumor grade or lymph node metastases. The 

detection of KRAS and BRAF mutations analysis were performed in 94 and 

83 tumor tissues, respectively. KRAS mutation was detected in only one 

sample and no patient was found to harbor BRAF V600E point mutation. 

Conclusions: We found the overexpression of EGFR and the absence of 

KRAS and BRAF mutations in penile SCC. This suggests that anti-EGFR 

mAbs may be potentially considerable therapeutic agents in penile SCC. 


Dynamic sentinel lymph node biopsy in patients with invasive squamous 

cell carcinoma of the penis: A prospective study of the outcome of 500 

inguinal basins assessed in a single institution. Presenting Author: Wayne 

Lam, St. George’s Hospital, London, United Kingdom 

Background: Dynamic sentinel node biopsy (DSNB) in combination with 

ultrasound scan (USS) has been the technique of choice at our centre since 

2004 for the assessment of non palpable inguinal lymph nodes in patients 

with squamous cell carcinoma of the penis (SCCp). Sensitivity/falsenegative 

rates may vary depending on whether results are reported per 

patient or per node basin and with and without USS. The purpose of this 

study was to determine the long-term outcome of DSNB and ultrasoundguided 

fine needle aspiration cytology (FNAC) in our cohort of newly 

diagnosed patients and to analyse any variation in sensitivity of the 

procedure. Methods: A prospective cohort study over 6 years (2004 to 

2010). Inclusion criteria: New diagnosis SCCp, T1G2 or greater definitive 

histology, non-palpable nodes in inguinal basin. Exclusion: patient with 

persistent/untreated local disease. Sensitivity of the procedure was calculated, 

per node basin, per patient, DSNB alone, USS/DSNB combined. 

Minimum follow up 12 months. Results: 500 inguinal basins in 264 

patients underwent USS�/-FNAC and DSNB. 70 (14%) positive inguinal 

basins in 57(22%) patients were identified. 9 (2%) inguinal basins had no 

tracer uptake. 2 inguinal basins were confirmed false negative at 8 and 12 

months. 2 inguinal basins had positive USS�FNAC and negative DSNB. 

Overall sensitivity of the technique is reported in the table. Conclusions: 

DSNB in combination with USS has excellent performance characteristics 

to stage patients with clinically node-negative penile cancer with a 3% 

false negative rate. USS improves performance by 4% over DSNB alone. 

There is no difference in performance of the combined technique if it is 

reported per node basin or per patient. 

USS�/-FNAC � DSNB DSNB alone 

Technical (per inguinal basin) 97% 95% 

Clinical (per patient) 97% 93% 


311s 


Activity of insulin growth factor-receptor (IGF-1R) antibody cixutumumab 

combined with the mTOR inhibitor temsirolimus in patients with metastatic 

refractory adrenocortical carcinoma. Presenting Author: Aung Naing, 

Department of Investigational Cancer Therapeutics (Phase I Program), 


Background: Adrenocortical carcinoma (ACC) is a rare and aggressive 

endocrine malignancywithout an available effective systemic chemotherapy. 

IGF-R2 overexpression leading to the activation of the IGF1R/ 

mTOR pathway is well described in ACC. Cixutumumab, a fully human IgG1 

monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), 

was combined with temsirolimus on the basis of preclinical data. Methods: 

Patientsreceived cixutumumab, 3-6 mg/kg IV weekly, and temsirolimus, 

25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. 

Results: Twenty-six patients were enrolled (13 [50%] men); median age, 47 

years; median number of prior therapies, 4. Five patients previously 

received an IGF-1R inhibitor and one, temsirolimus. The most frequent 

toxicities, at least possibly drug-related, were grade 1-2 thrombocytopenia 

(38%), mucositis (58%), hypercholesterolemia (31%), hypertriglyceridemia 

(35%), and hyperglycemia (31%). Eleven of 26 patients (42%) 

achieved stable disease (SD) � 6 months (duration range � 6to21 

months) with 3 of the 11 having received a prior IGF-1R inhibitor. 

Conclusions: Cixutumumab combined with temsirolimus was well tolerated 

and more than 40% of patients achieved prolonged SD. This study was 

supported by R21CA13763301A1 (AN), U01CA62461 (RK), and 

U01CA62487 (PL). 


Adjuvant radiotherapy after primary surgical resection in patients with 

adrenocortical carcinoma: Retrospective cohort analysis. Presenting Author: 

Mouhammed Amir Habra, University of Texas M. D. Anderson Cancer 


Background: Adrenocortical carcinoma (ACC) is a rare malignancy with high 

recurrence and mortality rates. The role of adjuvant radiotherapy (RT) to 

improve outcome remains unclear. Considering the rarity of ACC, we 

conducted a historical cohort study to ascertain the effect of adjuvant RT 

on overall survival and recurrence rates. Methods: Patients were selected 

from the MD Anderson Cancer Center (MDACC) ACC registry (1998- 2011) 

who had primary tumor resection with no evidence of distant metastasis at 

the time of initial diagnosis and a minimum follow-up of 6-months. The 

adjuvant RT group included patients who received adjuvant RT within 3 

months of diagnosis. Control group included patients who did not receive 

RT and matched based on resection margin status and stage at diagnosis. 

Results: There were no significant differences between the adjuvant RT 

group (n�15) and comparison group (n �45) in gender distribution, age, 

tumor size, functional status, and use of adjuvant mitotane therapy. On 

multivariate Cox proportional hazard model for overall survival, the adjuvant 

RT group had hazard ratio of 1.981(95% confidence interval [CI] 0.894- 

4.391, p�0.0922) compared to the control group. The differences in 

median time to local recurrence, distant recurrence and of recurrence free 

survival were not significant between the two groups. In subgroup analysis 

including only the patients whose initial treatments were from outside of 

MDACC, RT group (n�15) had hazard ratio of overall survival of 1.604 

(95% CI 0.712- 3.613, p�0.2543) compared to group without adjuvant 

RT (n� 32). Median times to local recurrence, distant recurrence, or of 

recurrence free survival were also not significantly different between the 

two groups. Conclusions: To our knowledge, this is the largest single 

institution report about adjuvant RT use in ACC. In our study, RT did not 

appear to cause a significant difference in overall survival, recurrence rate, 

or time to recurrence. However, it is still possible that patients offered 

adjuvant RT and control groups may have been inherently different. Hence, 

a prospective study is needed to clarify the role of adjuvant RT in patients 

with resectable ACC. 




Baseline covariates impacting overall survival (OS) in a phase III study of 

men with bone metastases from castration-resistant prostate cancer. 

Presenting Author: Karim Fizazi, Institut Gustave Roussy, Villejuif, France 

Background: Prognostic models of OS in men with metastatic castrateresistant 

prostate cancer (M�CRPC), have been limited. Here we present 

an analysis of baseline covariates associated with OS from an international 

phase 3 study that demonstrated superiority of denosumab over zoledronic 

acid for prevention of skeletal-related events (SRE) in this population 

(Fizazi et al., Lancet 2011;377:813-822). Methods: Patients had confirmed 

bone metastases (BM) from CRPC (a rising PSA despite castrate 

testosterone levels) and no prior bone anti-resorptive therapy. Proportional 

hazards modeling with various selection strategies was used to assess the 

prognostic significance of baseline covariates in multivariate analyses. 

Study-specified factors (previous SRE [Y vs N], PSA level [�10 vs �10 ng 

/mL]) and additional variables (Cook et al., Clin Cancer Res 2006;12:3361- 

3367; Halabi et al., J Clin Oncol 2003;21:1232-1237; Halabi et al., J Clin 

Oncol 2008;26:2544-2549) were explored. As no difference in OS was 

observed between treatment arms, analyses were performed using the 

pooled overall patient population. Results: Analyses included all randomized 

subjects with available baseline covariate data (n�1745). At the 

primary analysis date (median study duration 12.2 months), OS was 51%. 

Various selection strategies produced consistent results. In multivariate 

analysis, bone-specific alkaline phosphatase (BAP) �146 �g/L (p�0.0001) 

and corrected urinary N-telopeptide (uNTx) �50 nmol/mmol (p�0.0008) 

were associated with shorter OS, as were prior SRE (p�0.0002), PSA �10 

ng /mL (p�0.0001), visceral metastases (p�0.0002), greater time from 

either diagnosis to first BM or first BM to randomization (p�0.0001 for 

both), ECOG performance status 2 vs. 0/1 (p�0.017), BPI-SF pain score 

�4 (p�0.0001), age (p�0.008), alkaline phosphatase �143 U/L 

(p�0.0001), and hemoglobin �128 g/L (p�0.0001). Conclusions: Besides 

known factors previously associated with OS in men with CRPC 

(Halabi et al., 2003), we show that bone-associated covariates (pain, prior 

SRE, BAP, and uNTx) are also important and independent prognostic 

factors for OS. 


Prognostic stratification of post-docetaxel metastatic castration resistant 

prostate cancer (mCRPC) from a phase III randomized trial. Presenting 

Author: Guru Sonpavde, Texas Oncology, Houston, TX, and Department of 

Medicine, Section of Medical Oncology, Michael E. DeBakey Veterans 

Affairs Medical Center, Baylor College of Medicine, Houston, TX 

Background: A prognostic model for mCRPC post docetaxel is necessary to 

guide therapy. We retrospectively analyzed a phase III trial enrolling 

progressive mCRPC following docetaxel to construct a prognostic model. 

Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a 

potential marker for inflammatory and immune state. Methods: A phase III 

trial (SUN-1120) comparing prednisone combined with sunitinib (N�584) 

or placebo (N�289) for mCRPC following docetaxel-based chemotherapy 

was evaluated. The treatment arms were combined for analysis, since no 

statistical difference was observed in the primary endpoint of overall 

survival (OS). A logarithmic transformation was applied to non-normal 

factors. The Kaplan-Meier method was used for OS estimation. To identify 

an optimal prognostic model for survival, we used a Cox proportional 

hazards regression methods with forward stepwise selection, stratifying for 

ECOG PS, progression type (PSA or radiographic) and treatment group. A 

risk score was calculated and patients were categorized into risk groups to 

assess model performance. Results: Data from patients without missing 

data (n�806) were used to construct an optimal model. The factors used in 

the model that remained individually significant in multivariate analysis 

were: log-LDH (HR 2.77 [95% CI�2.23, 3.44], p�0.001), hemoglobin 

(0.81 [0.76, 0.87], p�0.001), log-NLR (1.63 [1.38, 1.92], p�0.001), 

�1 organ involved (1.53 [1.24, 1.88], p�0.001), log-alkaline phosphatase 

(1.14 [1.01, 1.30], p�0.041) and log-PSA (1.07 [1.00, 1.13], 

p�0.036). No clear cutpoints were identified; thus, these prognostic 

factors were used to group patients into 3 equally sized risk categories. 

Low, medium and high risk patients (n�268-270 per group) had median 

(95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and 

7.3 (6.3-8.4) months, respectively. Conclusions: A prognostic risk model 

with readily available variables significantly discriminated between outcomes 

in post-docetaxel mCRPC and may provide valuable information in 

future studies. High NLR was associated with an independent poor 

prognostic impact, and warrants prospective validation. 


Phase I trial of NY-ESO-1/LAGE1 peptide vaccine for metastatic castration 

resistant prostate cancer (mCRPC). Presenting Author: Teresa Gray Hayes, 

Michael E. DeBakey VA Medical Center and Baylor College of Medicine, 

Houston, TX 

Background: The NY-ESO-1 and LAGE-1 antigens are amplified in malignancies 

including prostate cancer. Preclinical induction of immune responses 

and anti-tumor activity has been demonstrated upon administration of 

these peptides. A phase I/II clinical trial evaluated the feasibility of a 

combined HLA class-I and class-II peptide vaccine in mCRPC. Methods: 

Men with progressive mCRPC, Performance Status �2, PSA �10 ng/ml 

and had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4, 

DR13) were eligible. Three groups with 3 patients each received the 

vaccine subcutaneously every 2 weeks for 6 doses. Group 1 was treated 

with a peptide directed at a HLA class I haplotype (HLA A2), Group 2 was 

treated with a peptide reacting to a HLA class II haplotype (DR4, DP4, or 

DR13), and Group 3 received peptides directed at both Class I and II 

haplotypes. Group I and Group II received 1 dose of 1000 mcg and Group 

III received doses of 1000 mcg for each of 2 peptides. Androgendeprivation 

was continued. Results: Of 14 patients enrolled, all were 

evaluable for toxicities and 9 patients completed all 6 treatments per 

amended protocol and were evaluable for efficacy. The median baseline 

PSA was 85.19 ng/ml. Four patients were chemo naive and 5 were 

post-docetaxel. One patient had a grade 5 event (myocardial infarction) 

unlikely therapy-related. Potential therapy related toxicities were local 

grade 1 injection site erythema (n�5), fatigue (n�2), flu-like symptoms 

(n�1), myalgias (n�1), anorexia (n�1), nausea (n�1) and leukocytosis 

(n�1). The median PSA doubling time pre-therapy and during therapy were 

3.1 and 4.92 months, respectively. The PSA-DT was prolonged compared 

to baseline in 6 patients, including a negative PSA slope in 2 patients. 

Antigen-specific immune response determined by ELISPOT was observed, 

and its association with slowing of PSA-doubling time will be further 

examined. Conclusions: In men with mCRPC, HLA class-I and/or class-II 

restricted NY-ESO-1 and LAGE-1 peptides administered subcutaneously 

demonstrated excellent tolerability, slowing of PSA doubling time and 

antigen-specific immune responses. Further development of peptide vaccines 

alone or in combination with other regimens may be warranted. 


Inhibition of 3�-hydroxysteroid dehydrogenase by abiraterone: A rationale 

for increasing drug exposure in castration-resistant prostate cancer. Presenting 

Author: Nima Sharifi, University of Texas Southwestern Medical Center, 

Dallas, TX 

Background: Treatment with abiraterone acetate (abi) increases the survival 

of men with castration-resistant prostate cancer (CRPC). Resistance to abi 

invariably occurs, probably due in part to up-regulation of steroidogenic 

enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone 

(DHT), which raises the possibility of reversing resistance by 

concomitant inhibition of other required steroidogenic enzymes. The 1,000 

mg daily abi dose was selected for the phase III trials despite the absence of 

dose-limiting toxicities at higher doses. Based on the 3�-hydroxyl, �5- structure, we hypothesized that abi also inhibits 3�-hydroxysteroid dehydrogenase/isomerase 

(3�HSD), which is absolutely required for the intratumoral 

synthesis of DHT in CRPC, regardless of origins or routes of synthesis. 

Methods: We tested if abi inhibits recombinant 3�HSD2 activity in vitro or 

endogenous 3�HSD activity in LNCaP and LAPC4 cells, including conversion 

of [ 3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), 

androgen receptor (AR) nuclear translocation, expression of AR-responsive 

genes, and LAPC4 xenograft growth in orchiectomized mice supplemented 

with DHEA. Results: Abi has a mixed inhibition pattern of 3�HSD2 in vitro, 

blocks the conversion from DHEA to AD and DHT with an IC50 of � 1 �Min 

CRPC cell lines, inhibits AR nuclear translocation and expression of 

TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented 

mice. Conclusions: Abi blocks 3�HSD enzymatic activity, synthesis of AD 

and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at 

concentrations that are clinically achievable. Variable abi inhibition of 

3�HSD might account in part for the heterogeneous clinical response to 

abi. More importantly, 3�HSD inhibition with abi might be clinically 

harnessed to reverse resistance to CYP17A1 inhibition at the standard dose 

by dose-escalation, or simply by administration with food to increase drug 

exposure. 



Polymorphisms in fragile histidine triad gene (FHIT) associated with 

aggressive prostate cancer and cancer specific mortality. Presenting 

Author: Yan Ding, City of Hope, Duarte, CA 

Background: FHIT is a 1.5 Mb gene encoding a 16.8 kD triphosphatase 

known to promote apoptosis responding to DNA damage in epithelial cells. 

It resides in the most frequently observed fragile site in the human genome, 

FRA3B, and is frequently deleted in early development of multiple cancer 

types. More importantly, down regulation of FHIT protein has been 

associated with clinical features of tumors, such as the presence of 

extraprostatic extension and Gleason Score � 8 in prostate cancer (CaP), 

advanced diseases in breast cancer, and shorter survival after platinumbased 

treatment for advanced non-small cell lung cancer. Previously, a 

genetic locus for CaP has been reported in FHIT. Here we evaluated 

association of aggressive CaP and death due to CaP with Single nucleotide 

polymorphisms (SNPs) in FHIT using cases and controls of European origin 

nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer 

Screening trial with 13 years of follow-up. Methods: We analyzed 659 SNPs 

on FHIT in 1,164 CaP patients (476 with nonaggressive CaP, Gleason � 7 

and stage � III; 688 with aggressive CaP, Gleason �� 7 and/or stage III/IV; 

63 with death due to CaP) and 1,167 controls using an incidence density 

sampling strategy. Stratified Cochran-Mantel-Haenszel test and logistic 

regression were performed to test association. Results: We detected 

significant association (p � 0.05) of incident CaP to 48 SNPs and 

aggressive CaP to 52 SNPs. After 50,000 permutations, two SNPs within a 

7 kb region, one for incident CaP and the other for aggressive CaP, 

remained marginally significant (corrected p � 0.053 and 0.093, respectively). 

The same risk allele for aggressive CaP was also associated with 

CaP-specific mortality (OR � 1.50, p � 0.027). The association was 

stronger after adjusting for Gleason, stage, and PSA at diagnosis, treatment 

options after diagnosis. Test on imputed SNPs within the 7 kb intronic 

region identified 7 additional SNPs in 2 linkage disequilibrium groups at 

higher risk to CaP-specific death (OR � 1.98, p � 0.00015 and OR � 

2.51, p � 0.0027). Conclusions: Risk SNPs in FHIT were implicated for 

aggressive disease and CaP specific death. Replication of these SNPs in 

other populations is warranted. 


Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An 

exploratory analysis from the phase III IMPACT trial. Presenting Author: 

Gerald Chodak, Weiss Memorial Hospital, Chicago, IL 

Background: Sipuleucel-T is an autologous cellular immunotherapy approved 

for asymptomatic or minimally symptomatic metastatic castrateresistant 

prostate cancer. In the IMPACT trial, sipuleucel-T showed a 

22.5% reduction in risk of death vs the control group (hazard ratio 

[HR]�0.775 [95% CI 0.614, 0.979]; P�0.032). A pre-specified subgroup 

analysis for baseline prognostic variables showed homogeneous 

treatment effects consistently favoring sipuleucel-T. In patients (pts) with 

baseline PSA below vs above the median, there was a trend toward greater 

treatment effect (HR�0.685 vs. 0.865). In this exploratory analysis, we 

further sub-divide baseline PSA into quartiles to evaluate potential treatment 

effect patterns. Methods: The analysis included all randomized pts 

from IMPACT (n�512). Pts were categorized by baseline PSA quartile 

(Table), ECOG PS and by median for other baseline prognostic variables 

(i.e., LDH, PAP, ALP in bone-only disease, and Hgb). Median OS and HR 

were estimated using Kaplan-Meier and Cox models, respectively. Results: 

Increasing baseline PSA quartile was associated with markers of advanced 

disease. HRs suggest a consistent treatment effect in all subsets, although 

there is inadequate power to show significant results within each quartile. 

There was a trend toward an increased magnitude of treatment benefit in 

pts with a lower baseline PSA (Table). Results for other baseline prognostic 

variables also suggest a trend toward greater benefit in subjects with better 

prognostic features. However, results for baseline Hgb indicated an 

opposite trend. Conclusions: Although not adequately powered for significance, 

the results of this analysis support a consistent OS benefit with 

sipuleucel-T across PSA quartiles. The greater magnitude of benefit in pts 

with lower baseline PSA suggests that pts with less advanced disease may 

benefit more from treatment with sipuleucel-T. 

Baseline PSA (ng/mL) 

22.1–50.1 >50.1–134.1 >134.1 

n 128 128 128 128 

Median OS, months 

Sipuleucel-T 41.3 27.1 20.4 18.4 

Control 28.3 20.1 15.0 15.6 

Difference 13.0 7.1 5.4 2.8 

HR (95% CI) 0.51 (0.31, 0.85) 0.74 (0.47, 1.17) 0.81 (0.52, 1.24) 0.84 (0.55, 1.29) 


313s 


Guideline-discordant androgen deprivation therapy (ADT) use in localized 

prostate cancer (CaP) and cost implications: A population-based study. 

Presenting Author: Adam Rea Kuykendal, University of North Carolina at 

Chapel Hill, Chapel Hill, NC 

Background: ADT use in localized CaP has increased overall survival and is 

recommended by National Comprehensive Cancer Network (NCCN) guidelines 

in certain clinical situations. However, ADT may cause harm and is 

without benefit in other situations. Prior studies showed a decline in 

“inappropriate” ADT use coinciding with Medicare reimbursement changes 

in 2004-2005. This study examines recent trends in ADT use and 

quantifies the cost of guideline-discordant ADT. Methods: Patients in the 

Surveillance Epidemiology and End Results (SEER)-Medicare database 

diagnosed with non-metastatic CaP between 2004 and 2007, ages 66-80 

were included for analysis. PSA, Gleason score and clinical stage were used 

to define D’Amico risk categories. Logistic regression was used to examine 

factors associated with guideline-discordant ADT use. Annual direct cost 

was estimated using the current Medicare reimbursement amount for ADT. 

Results: Of 24,280 men included, 13% received guideline-discordant ADT. 

Discordant use declined from 15% in 2004 to 11% in 2007. In low-risk 

patients, 15% received discordant ADT, mostly due to simultaneous ADT 

with radiation. Discordant use was seen in 7% of intermediate and 16% of 

high-risk patients, mostly from ADT monotherapy. African American (AA) 

(p�.001), older patients (p�.001) and those with more comorbidities 

(p�.001) were more likely to receive discordant ADT (Table). The estimated 

annual direct cost to Medicare from discordant ADT is $43,500,000. 

Conclusions: Approximately one in eight patients received ADT discordant 

with published guidelines, with AA and elderly patients disproportionately 

affected. Elimination of discordant use would result in substantial savings 

in healthcare costs. 

Covariate OR p value 

AA (vs. Caucasian) 1.35 �.001 

Age (vs. 65-69) 

70-74 1.58 �.001 

75-79 3.22 �.001 

Modified Charlson comorbidity (vs. 0) 

>0 1.34 �.001 

Diagnosis (vs. 2004) 

2005 .86 .008 

2006 .78 �.001 

2007 .71 �.001 

Risk group (vs. low risk) 

Intermediate .40 �.001 

High .88 .003 

Controls for SEER region, regional socioeconomic indicators, and marital status. 


Targeted next-generation sequencing (NGS) of advanced prostate cancer 

(PCA) using formalin-fixed tissue. Presenting Author: Himisha Beltran, 

Weill Cornell Medical College, New York, NY 

Background: The genomic landscape of advanced PCA is not well characterized, 

partly due to limited availability of frozen metastatic tissue. This has 

created a gap in our knowledge of treatment related and potentially 

targetable genomic alterations. The purpose of this study was to demonstrate 

feasibility of performing NGS to molecularly characterize advanced 

PCA using formalin-fixed paraffin embedded (FFPE) tissue. Methods: 25 

metastatic CRPC, 4 metastatic hormone naïve PCA, 3 primary localized 

PCA, and 18 benign matched prostates were evaluated (40mm FFPE tissue 

per case). High-density foci were captured and sequenced for 3230 exons 

of 182 cancer-related genes and 37 introns of 14 genes often rearranged in 

cancer to an average depth of �800x in a CLIA lab (Foundation Medicine). 

Recurrent mutations, copy number alterations, and fusions were validated 

using PCR and FISH. Results: In �90% of samples, there was sufficient 

DNA (�50 ng) for analysis. Recurrent high confidence cancer alterations in 

CRPC included: TMPRSS2-ERG fusion (44%), PTEN loss (44%), TP53 

mutation (40%), AR mutation (24%), AR gain (24%), RB mutation (28%), 

MYC gain (12%), and BRCA2 loss (12%). Overall 48% of CRPC harbored 

AR gene alterations. Additionally, there were mutations in CTNNB1 (12%), 

ATM (8%) and PIK3CA (4%). Copy number alterations not previously 

described in PCA included CCND1, CDK4/6 gains and CDKN2A/CDKN2B 

deletions. Hormone naïve metastatic and high risk localized PCA demonstrated 

similar frequency of TMPRSS2-ERG gene fusion, BRCA2 deletion, 

and TP53 mutations as CRPC, but AR alterations and MYC gain were not 

seen. Conclusions: This study demonstrates feasibility of in-depth, NGS 

based DNA analysis using FFPE tissue, even biopsy material. Frequent AR 

alterations in CRPC, mutations associated with disease progression, and 

potential drug targets were identified. Focused NGS has clinical potential 

to identify actionable genomic alterations in advanced PCA that can impact 

patient participation in trials as well as treatment and outcome. Treatment 

options include PARP inhibitors for patients with BRCA2 and ATM 

alterations (20% of cases) and PI3K/AKT inhibitors for PIK3CA mutations. 




Correlation of increased eosinophil count following sipuleucel-T treatment 

with outcome in patients (pts) with metastatic castrate-resistant prostate 

cancer (mCRPC). Presenting Author: Douglas G. McNeel, University of 

Wisconsin-Madison, Madison, WI 

Background: Sipuleucel-T is the first autologous cellular immunotherapy 

approved for asymptomatic or minimally symptomatic mCRPC. In the 

IMPACT trial, pts treated with sipuleucel-T had transient increases in 

eosinophil counts compared with control. In this retrospective analysis, we 

assess potential correlations between eosinophilia, overall survival (OS), 

prostate cancer-specific survival (PCSS) and immune response following 

sipuleucel-T. Methods: Data from three phase III trials (D9901, D9902A, 

and IMPACT) were pooled. The analysis included CBCs performed at 

baseline and wks 2–34. Eosinophilia was defined as either �ULN (with 

normal baseline), or a max change from baseline within the top quartile, at 

any time between wks 2–16. Results: Increased eosinophil counts were 

seen in sipuleucel-T pts by wk 6, decreasing to near baseline by wk 14; 

eosinophil counts in control pts were stable. Of 377 sipuleucel-T pts 

eligible for analysis, 105 (27.9%) had eosinophilia. Baseline disease 

characteristics associated with eosinophilia were indicative of better 

prognosis (i.e., longer Halabi predicted survival [p�0.007], lower PSA 

[P�0.033], higher Hgb [p�0.001], and no prior docetaxel [p�0.012]). In 

univariate analyses, eosinophilia correlated with improved OS (HR�0.75; 

95%CI: 0.56–1.01; p�0.057) and PCSS (HR�0.71; 95%CI: 0.53– 

0.97; p�0.031); trends persisted after adjusting for Halabi. The magnitude 

of eosinophilia positively correlated with antigen-specific humoral 

responses (p �0.039 for wks 6, 14 and 26) and elevations in the cytokines 

at wk 6 (IL2 [p�0.011], IL5 [p�0.038] and TARC [p�0.001]). AEs 

occurring more frequently (p�0.05) in pts with eosinophilia were infusionrelated: 

pyrexia (33.3 v 21.3%) and nausea (19.0 v 10.7%). No cases of 

hypereosinophilic syndrome were reported. Conclusions: Increases in eosinophils 

after sipuleucel-T correlated with improved OS and PCSS. Large 

increases in eosinophil counts were associated with humoral responses and 

Th2-type cytokine production. Further studies of eosinophilia as a biomarker 

for sipuleucel-T response, particularly in earlier disease settings, 

are of interest. 


Comparing the ability of clinicians and a nomogram model at predicting 

future 99mTc-bone scan (BS) positivity in patients (pts) with rising prostatespecific 

antigen (PSA) following radical prostatectomy (RP) for prostate 

cancer (PCa). Presenting Author: Michael W. Kattan, Department of 

Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 

Background: Nomograms that assist clinicians in predicting which PCa pts 

have a high risk of developing M1 disease have been developed, but 

clinicians still tend to use their own judgment of risk when managing 

individual pts. This is the first study to compare the ability of clinicians vs a 

nomogram at predicting future BS positivity in pts with PCa. Only androgen 

deprivation therapy- (ADT-) naive post-RP pts were considered, as there are 

currently no nomograms for predicting M1 disease in pts receiving ADT. 

The Slovin nomogram (Slovin et al. Clin Cancer Res 2005; 11: 8669- 

8673) was chosen based on considerations of the numbers of pts analyzed 

and the follow-up intervals used in its development. Methods: During an 

advisory board in June 2011, 24 PCa experts were given details of 25 

ADT-naive post-RP PCa pts with biochemical recurrence who were randomly 

selected from the Cleveland Clinic Database of 759 pts. The 

predicted 1-yr from today probability of freedom from metastasis was 

generated using the Slovin nomogram and estimated by the clinicians. The 

predictive accuracy was quantified using the concordance index (C-index). 

Results: All pts were Caucasian and median age was 62 yrs. Median PSA 

level at biochemical recurrence was 1.2 ng/mL and PSADT varied between 

1.3 and 11.7 months. The data used for each of the pts was acquired 

between 4 and 133 months after the RP procedure. Eight pts had a positive 

BS within 1 yr. Considerable variation between the clinicians’ predictions 

for each pt was observed. The nomogram gave a higher C-index compared to 

the clinicians (0.812 and 0.628, respectively; p�0.003). The clinicians 

typically overestimated the risk of developing M1 disease. The nomogram 

outperformed all of the clinicians (C-index range: 0.47 to 0.75). Urologists 

predictions were superior to those of oncologists (p�0.048). Conclusions: 

The Slovin nomogram was more accurate than expert clinicians in predicting 

1-yr BS positivity. We suggest nomograms should become an integral 

part of the clinical decision process in the PCa setting. 


Proton radiotherapy for prostate cancer in the Medicare population: 

Patterns of care and comparison of early toxicity with IMRT. Presenting 

Author: James B. Yu, Yale University School of Medicine, New Haven, CT 

Background: Proton radiotherapy (PRT) is a costly treatment used for 

prostate cancer despite little evidence supporting its use. We examined 

patterns of PRT use in the Medicare program and assessed the short-term 

toxicity of PRT vs. intensity modulated radiation therapy (IMRT). Methods: 

Using national Medicare claims from 2008-2009, we identified a sample 

of prostate cancer patients ages 66-94 who had received PRT or IMRT. We 

used multivariable logistic regression to identify patient and regional 

factors associated with receipt of PRT. We searched claims for procedure 

and diagnosis codes indicative of treatment-related complications and 

grouped the complications into genitourinary (GU), gastrointestinal (GI), 

and other complications. To compare the effect of PRT and IMRT on 

short-term toxicity, we used a Mahalanobis distance approach to match 

each PRT patient to two IMRT patients, achieving balanced distribution of 

clinical and sociodemographic characteristics. We compared six-month 

and one-year outcomes between the two treatment groups using conditional 

logistic regression. Results: We identified 27,647 men; 421 (2%) 

received PRT and 27,226 (98%) received IMRT. Patients who received 

PRT were widely geographically distributed, with some patients traveling 

�500 miles for treatment. PRT patients were younger, healthier, and of 

higher socioeconomic status. Although PRT was associated with a significant 

reduction in GU complications at six-months compared with IMRT 

(6.1% vs. 12.0%, OR 0.60 [95% CI 0.38-0.96], p�0.03), at one-year 

post-treatment there was no longer any difference in cumulative complication 

rates (18.9% vs. 21.9%, OR 0.96 [95% CI 0.61-1.53], p�0.88). 

There was no significant difference in GI or other complications at 

six-months or one-year post-treatment. Conclusions: Although PRT remains 

a scarcely used treatment, some prostate cancer patients traveled great 

distances for treatment. While PRT was associated with a reduction in 

six-month GU toxicity, there were no differences in toxicity at one-year. 

Further study on longer-term effects and other clinical and patient-reported 

outcomes is needed to inform the widespread application of PRT. 


Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role 

for EN2? Presenting Author: Emma Killick, Institute of Cancer Research, 


Background: EN2 is part of the HOX gene family and plays a role in foetal 

development. More recently a potential oncogenic role for the protein has 

been postulated and its utility as a cancer biomarker has been explored in 

prostate cancer (PrCa) and breast cancer. Carriers of mutations in the 

BRCA1 and BRCA2 genes have an increased risk of PrCa (1.8-fold and 

5-fold respectively) and their tumours tend to be more aggressive and 

advanced than sporadic cases. Currently there is no national screening 

program for BRCA mutation carriers in the UK, and the IMPACT study was 

set up to evaluate PSA screening in this particular group. Here we analyse 

the efficacy of the urinary EN2 protein as a marker of early cancer detection 

within this higher risk group. Methods: First pass urine (without preceding 

digital rectal examination) was collected as part of the IMPACT screening 

study which enrolled individuals aged between 40 and 69 who were 

unaffected by PrCa at time of enrolment into the study (n� 418). All 

participants were from families harbouring a BRCA1 or BRCA2 mutation 

and were either BRCA mutation carriers themselves or controls with a 

negative predictive BRCA genetic test. They underwent annual PSA test 

with a PSA of � 3.0 ng/ml triggering a diagnostic biopsy. EN2 protein was 

measured in the urine using an ELISA; (positive ��42.5ng/ml). Results: 

Our initial results demonstrated urinary EN2 had a sensitivity of 66.67% 

and a specificity of 89.29% when discriminating which men had been 

diagnosed with PrCa; the ROC AUC was 0.816. The difference in EN2 level 

between those diagnosed with cancer and those who were not was 

significant (p ��0.001). There was trend towards higher EN2 levels in 

those with more aggressive tumours (median EN2 84.5ng/mL in Gleason 

�3�4 vs 111ng/mL in Gleason �4�3), however this was not statistically 

significant. In one PrCa case EN2 rise preceded PSA rise by 2 years. 

Further samples are in the process of being analysed, results from these will 

be included. Conclusions: Urinary EN2 protein measurement warrants 

further investigation as a PrCa biomarker in this higher risk group with 

genetic predisposition to PrCa. 



A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin 

polymerization, in men with bone-metastatic castration-resistant prostate 

cancer (CRPC): A PCCTC trial. Presenting Author: Emmanuel S. Antonarakis, 

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 

University, Baltimore, MD 

Background: KX2-391 is an oral small molecule inhibitor of Src kinase and 

tubulin polymerization. In phase 1 trials, PSA declines were seen in men 

with advanced prostate cancer. Methods: A single-arm phase 2 study of 

KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted 

at 5 PCCTC sites. Men received oral KX2-391 (40 mg BID) until 

disease progression or unacceptable toxicity. The primary endpoint was 

progression-free survival (PFS) at 24 wk (progression � clinical/ 

radiographic progression or death, but not rising PSA; PCWG2 criteria); a 

50% success rate was predefined as clinically significant. Secondary 

endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA 

progression � 25% PSA rise above nadir; PCWG2 criteria); median PFS; 

median PPFS; and max PSA decline. Exploratory outcomes included PK 

studies, CTC enumeration, and analysis of markers of bone resorption 

(urinary N-telopeptide [uNTx]; C-telopeptide [CTx]) and formation (bone 

alk phos [BAP]; osteocalcin). Results: The trial closed early after accrual of 

31 men, due to a prespecified futility rule. In all, 26/31 men were 

evaluable for the primary endpoint; efficacy results are shown below. Also, 

2/11 men (18%) with unfavorable (�5) CTCs at baseline converted to 

favorable (�5) CTC counts on study, and 18/19 men (95%) with baseline 

favorable CTC counts maintained them. The proportion of men with 

declines in bone turnover markers was 32% (8/25) for uNTx, 21% (6/29) 

for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK 

studies, median Cmax was 61 (range 16–129) ng/mL, and AUC was 156 

(35–348) ng*hr/mL. Common toxicities (�10%) included LFT elevations, 

leukopenia, thrombocytopenia, fatigue, nausea and constipation. 

Conclusions: KX2-391 dosed at 40 mg BID lacks antitumor activity in men 

with CRPC, but modulates bone turnover markers in some men. Because a 

Cmax of �142 ng/mL is required for tubulin polymerization inhibition, 

higher once-daily dosing will be used in future trials. 

Endpoint Value 95% CI 

Primary 

PFS at 24 wk (%) 7.7 2.3 – 24.3 

Secondary 

PPFS at 24 wk (%) 0 0 – 13.2 

Median PFS (wk) 18.6 12.1 – 24.0 

Median PPFS (wk) 5.0 4.1 – 11.4 

>30% PSA decline (%) 9.7 3.5 – 25.0 


Phase I results from a phase I/II study of orteronel, an oral, investigational, 

nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in 

metastatic castration-resistant prostate cancer (mCRPC). Presenting Author: 

Daniel Peter Petrylak, Columbia University Medical Center, New York, 

NY 

Background: The investigational agent orteronel (ortl, TAK-700) is a 

selective 17,20-lyase inhibitor that blocks androgen production. Since DP 

is standard chemotherapy in mCRPC, this phase 1/2 study examined ortl � 

DP in men with mCRPC. Methods: The primary phase I objective was to 

determine the maximum dose of ortl 200–400 mg BID that can be 

administered safely with DP in castrate men (testosterone [T] �50 ng/dL) 

with mCRPC, �1 prior chemotherapy and no ketoconazole/abiraterone 

�30 d prior. A 3�3 dose escalation was used with ortl 200 then 400 mg 

BID. Ortl dosed daily and D (75 mg/m2 q3w) � P (5 mg BID) was started on 

d8 of cycle 1 (28 d); cycles �2 � 21 d. Results: 14 men, median age 68 yrs 

(range 53–81), ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL 

(5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable disease, were 

treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men 

received ortl 200 and 400 mg BID � DP, in cohorts 1 and 2, respectively. 

No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3 pts); in cohort 

2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no 

DLTs occurred in group 2. 3 pts discontinued due to AEs (2 D infusion 

reactions, 1 at each dose; 1 unrelated cardiorespiratory death at 200 mg). 

All men had at least 1 AE Gr �3 which were treatment-related in 11 men. 

The most common Gr �3 AEs were seen at both doses and included 

neutropenia 50% (n � 7), hyperglycemia 21% (n � 3), febrile neutropenia, 

infusion reaction, hyponatremia, decreased neutrophil count (2 each); at 

400 mg only: fatigue, hypophosphatemia, and decreased WBC count (2 

each). 7 men had serious AEs (SAEs), which were drug-related in 5. The 

most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and 

PSA90 rates were 86% and 36%, respectively; 12/14 men had a median 

PSA decline �70%; and median T declined to �0.2 ng/dL (0–10.7). The 

Cmax of D � ortl was similar to D alone. Conclusions: Ortl 200 mg and 400 

mg BID � DP appears safe and tolerable with androgen-lowering activity at 

the maximum planned dose in mCRPC. There is no evidence of AE 

potentiation when ortl is administered with DP. The phase II portion of the 

study will use ortl 400 mg BID � DP. 


315s 


Liver metastases (LM) to predict for short overall survival (OS) in metastatic 

castration-resistant prostate cancer (mCRPC) patients (pts). Presenting 

Author: William Kevin Kelly, Kimmel Cancer Center at Thomas Jefferson 

University, Philadelphia, PA 

Background: Patients withCRPC with LM represent a subset of patients with 

a poor prognosis. An exploratory analysis was performed to evaluate the 

difference in baseline characteristics and clinical outcomes in patients 

with and without LM from a randomized phase III trial (CALGB 90401) in 

men with mCRPC. Methods: Data from 1,050 men treated with docetaxel, 

prednisone with either bevacizumab or placebo were used. Pts were 

chemotherapy naïve, and had evidence of progressive mCRPC despite 

castrate testosterone levels and anti-androgen withdrawal, ECOG performance 

status � 2, and adequate bone marrow, hepatic and renal functions. 

The proportional hazards model was used to assess the prognostic significance 

of LM in predicting OS and progression free survival (PFS) adjusting 

for stratification factors. Results: Fifty-nine (5.6%) of the 1045 pts with a 

complete data set had documented LM. Patients with LM had higher 

baseline alkaline phosphatase (ALK, 167 vs 117 U/L, p �0.0205) and 

lactate dehydrogenase (LDH, 262 vs 205 U/L, p �0.0001) compared to 

patients without LM. There were strong associations between LM status 

and lung metastasis (p�0.0004) and other visceral disease (p��0.001) 

but not with bone disease. Clinical outcomes as a function of LM status are 

listed in the table. The median OS time in LM pts was 14.4 compared to 

22.6 months, with a hazard ratio (HR) 1.4. The HR for treatment effect 

(DP�B vs. DP) for LM was not statistically significant for either group. 

Conclusions: Compared to pts without LM, mCRPC with LM are characterized 

by higher LDH and ALK and have a poor OS despite having similar PFS 

and objectivebiochemical response to docetaxel based therapy. 

Clinical outcomes Liver mets at baseline 

No 

Yes 

HR* 

(n�986) (n�59) (95% CI) p value 

Median OS (months) 22.6 

14.4 

1.4 0.019* 

(95% CI ) 

(21.5-24.1) (13.3-17.8) (1.1-1.8) 

Median PFS (months) 7.6 

5.7 

1.1 0.672* 

(95% CI) 

(7.2-8.1) (2.5-7.1) (0.7-1.7) 

>50% decline in PSA 64% 

55% 

0.216 

(95% CI) 

(60-67) (42-69) 

Objective response 

41% 

53% 

0.097 

(95% CI) 

(37-46) (39-67) 

* stratified log-rank p value 


A national survey of radiation oncologists and urologists on active surveillance 

for low-risk prostate cancer. Presenting Author: Simon P. Kim, Mayo 

Clinic, Rochester, MN 

Background: While active surveillance (AS) is well recognized as an 

acceptable treatment strategy for low-risk prostate cancer (PC), the extent 

to which radiation oncologists and urologists perceive AS as effective and 

routinely recommend it to patients is unknown. Therefore, we sought to 

assess the attitudes and treatment recommendations for low-risk PC from a 

national survey of PC specialists. Methods: A mail survey was sent to a 

population-based sample of 1,439 physicians in the U.S. from late 2011 

and early 2012. Physicians were queried about their attitudes regarding AS 

and treatment recommendations for patients diagnosed with low-risk PC 

(PSA�10 ng/dl; T1c; Gleason 6 in one of twelve cores). Pearson Chi-square 

and multivariate logistic regression were used to test for differences in 

attitudes and treatment recommendations by physician demographics, 

compensation structure, primary place of employment, and specialty. 

Results: Overall, 321 radiation oncologists and 322 urologists completed 

the survey for a 45% response rate. Most physicians reported that AS is 

effective for low-risk PC (71%) and stated that they were comfortable 

routinely recommending AS (67%). Urologists were more likely to agree 

that AS is effective (77% vs. 67%; p�0.005) and were comfortable 

recommending AS (74% vs. 61%; p�0.001) compared with radiation 

oncologists. Most physicians recommended radical prostatectomy (47%) 

or radiation therapy (32%), but fewer endorsed AS (21%) for low-risk 

disease. After adjusting for physician covariates, radiation oncologists were 

more likely to recommend radiation therapy (OR: 10.97; p�0.001), while 

urologists were more likely to recommend surgery (OR: 4.69; p�0.001) 

and AS (OR: 2.18; p�0.001) for low-risk PC. Conclusions: Although AS is 

widely viewed as effective by both radiation oncologists and urologists, 

most urologists continue to recommend surgery, while most radiation 

oncologists recommend radiation therapy. Our results may explain in part 

the relatively low contemporary use of AS in the U.S. 




Prostate-specific antigen (PSA) screening in the United States: Patterns of 

use and PSA outcomes in screened versus unscreened men. Presenting 

Author: Ian M. Allen, UNC-CH School of Medicine, Chapel Hill, NC 

Background: PSA screening is a subject of substantial controversy. We 

examined patterns of PSA screening using a recent cohort from the 

population-based National Health and Nutrition Examination Survey 

(NHANES) study and compared PSA levels of previously screened vs. never 

screened men. Methods: NHANES is a cross-sectional study which collects 

health-related information (including cancer screening history, family 

history and socioeconomic variables) and blood samples from nationally 

representative samples of the US population. We included 2,078 previously 

screened men and 1,902 never screened men surveyed from 2003-8. 

Statistical analysis accounted for sampling weights. Results: 25% of men 

age 40-49 years had prior PSA screening; 56% age 50-59, and 72% age 

60-69. Screening rates were higher for men with family history (68% vs. 

50% no history, p�.001), health insurance (58% vs. 21% no insurance, 

p�.001), and Caucasians (59% vs. 44% non-Caucasian, p�.001). No 

significant differences were seen in the PSA values of screened vs. never 

screened men stratified by age (Table), or by race/ethnicity, insurance 

status, or family history. Conclusions: Rates of PSA screening in the US 

differ by age, family history, race/ethnicity and insurance status. However, 

no significant differences were seen in PSA values of screened vs. 

unscreened men, and very few patients under 60 years of age had PSA 

values �10. Despite questions about the appropriate role of PSA testing, 

population-based prostate cancer screening is routinely conducted among 

Caucasian and non-Caucasian men 50 years of age and older. 

PSA in screened versus unscreened individuals stratified by age. 

Screened (%) Unscreened (%) p value 

Age 49-49 

PSA 0-3.99 98.9 98.7 0.927 

PSA 4-9.99 0.7 0.9 

PSA >10 0.3 0.3 

Age 50-59 

PSA 0-3.99 92.9 94.6 0.066 

PSA 4-9.99 6.4 4.1 

PSA >10 0.6 1.2 

Age 60-69 

PSA 0-3.99 81.9 83.3 0.136 

PSA 4-9.99 15.7 12.2 

PSA >10 2.3 4.4 


A first-in-human phase I imaging study using hyperpolarized 1c-13 pyruvate 

(h-Py) in patients (pts) with localized prostate cancer (l-PCa). 

Presenting Author: Andrea Lynne Harzstark, University of California, San 

Francisco, San Francisco, CA 

Background: Preclinical studies demonstrated that the conversion of h-Py to 

hyperpolarized 13C lactate (h-lac) is detectable on MRI-spectroscopy and is 

a useful marker of differentiation in PCa. H-Py MRI provides more than 

10,000-fold enhancement in signal to noise ratio (SNR), allowing for rapid 

detection of metabolic alterations in vivo. Hyperpolarized compounds have 

not been previously studied in man. Methods: Pts with biopsy-proven 

untreated l-PCa were enrolled in a phase I study of h-Py MRI. Following a 

modified 3�3 design, 6 pts were enrolled at each dose level (0.14, 0.28 

and 0.43 mL/Kg): 3 to monitor kinetics of h-Py, and 3 to evaluate the 

spatial distribution of metabolism in PCa and normal prostate (nl-P). An 

expansion cohort of 15 pts explored the biological variability of metabolism. 

A dynamic nuclear polarization (DNP) system, the first human system 

anywhere, generated and delivered 230 mM sterile h-Py. IV injection of 

h-Py was followed by imaging with a 3T MR scanner with custom transmit 

and receive coils. Monitoring included EKG, vital signs, and laboratory 

testing. Results: 31 pts were imaged. 23 pts had Gleason (G) 6, 6 pts G7, 

and 2 pts G8 PCa. Median age was 63 years (range 45-75); median PSA 

was 5.9 ng/mL (1.88-20.2). No dose limiting toxicities or �grade (gr) 2 

toxicity was observed. Toxicity included: gr 1dysgeusia (6 pts), gr 1 

hypokalemia, gr 1 hypocalcemia, gr 1 dizziness, and gr 2 diarrhea (1 pt 

each). Median time from dissolution of the agent to delivery into patients 

was 66 seconds (43-88). Signals from h-Py and h-Lac were seen in PCa 

and nl-P at all doses; 0.43 mL/Kg showed the best SNR and discrimination 

between PCa and nl-P and was therefore established as the phase II dose. 

There appeared to be an association between h-Lac levels and PCa grade. 

Conclusions: H-py metabolic imaging has minimal toxicity and provides the 

ability to discriminate Ca from nl-P based on increased levels of h-lac. The 

correlation with grade and changes with therapy require further study. 


Prevalence of nonmetastatic (M0) prostate cancer (PC) patients on continuous 

androgen deprivation therapy (ADT) in the United States. Presenting 

Author: Karynsa Cetin, Center for Observational Research, Amgen Inc, 

Thousand Oaks, CA 

Background: ADT is the cornerstone treatment of metastatic PC, but the 

nature and extent of its use in the M0 setting is less well-described. We 

sought to estimate the current prevalence of M0 PC patients actively 

receiving continuous ADT (�6 months) in the US. Methods: Two pointprevalent 

cohorts on 12/31/2008 with continuous insurance coverage in 

2008 were assembled: men aged 45-64 years (yrs) enrolled in commercial 

health plans (MarketScan) and men aged �67 yrs enrolled in fee-forservice 

(FFS) Medicare (Medicare 5% sample). Among those with evidence 

of PC and no evidence of metastases, we selected men who had continuous 

exposure to gonadotropin-releasing hormone agonists during at least the 

last 6 months of 2008 or received bilateral orchiectomy prior to 7/1/2008. 

The number of prevalent ADT users was extrapolated to the entire national 

commercially insured population aged 45-64 yrs and to the entire Medicare 

FFS population aged �65 yrs using person-level weights. Applying agespecific 

prevalence estimates to the US Census population on 12/31/ 

2008, we estimated the number of prevalent ADT users in the total US 

male population aged �45 yrs. Results: An estimated 11,935 (95% 

confidence interval [CI]: 11,310-12,561) commercially insured men aged 

45-64 yrs and 115,468 (95% CI: 112,304-118,633) Medicare FFS men 

aged �65 yrs were M0 PC patients actively receiving continuous ADT for 

�6 months on 12/31/2008. Extrapolated to the total US male population 

aged �45 yrs, this estimate was 188,916 (95% CI: 184,104-193,727). 

Age-specific prevalence (N [95% CI]) on 12/31/2008 is presented in the 

table. Conclusions: We projected nearly 190,000 US men with M0 PC were 

actively receiving continuous ADT for �6 months at the end of 2008, and 

the vast majority (91%) of these men were aged �65 yrs. Additional work 

will address timing of initiation, duration, and other aspects of ADT use in 

this large population of M0 PC patients. 

Age, yrs Commercial and FFS Medicare males US males 

45-64 11,935 (11,310-12,561) 17,163 (16,264-18,062) 

65-74 28,087 (26,272-29,902) 43,851 (41,017-46,686) 

75-84 51,541 (49,549-53,532) 76,157 (73,214-79,100) 

>85 35,841 (34,195-37,487) 51,745 (49,368-54,121) 


Correlation of UHRF1 expression in primary prostate cancer patients with 

adverse prognosis. Presenting Author: Enrico Roggero, IOSI International 

Prostate Research Group, Bellinzona, Switzerland 

Background: Cancer of the prostate is a leading cause of cancer death in 

western countries. There is a great need to understand the clinical course of 

the disease and to distinguish the indolent tumors from those with 

aggressive behavior. Epigenetic mechanisms play an essential role in 

cancer initiation and progression. Our groups have recently provided 

evidence that over-expression of UHFR1 (ubiquitin-like with PHD and ring 

finger domain) leads to prostate cancer progression by activating a robust 

epigenetic switch involving silencing of a network of tumor suppressor 

genes. The purpose of this study was to evaluate in a clinical setting the 

prognostic impact of UHFR1 expression. Methods: In a series of 225 

eligible patients (median age 63 years, range 44-75) with prostate cancer 

treated in a single institution with prostatectomy between 1990 and 1999 

we evaluated the tumor nuclear expression of UHRF1 by immunohistochemistry 

(IHC). Clinical and histological data of the series were also reviewed. 

The UHFR1 expression (evaluated in tissue microarrays by immunohistochemistry) 

and prognostic factors were analyzed using univariate analyses 

and multivariate logistic regression analysis to identify association with 

overall survival (OS). Results: The median FU for the series was 137 months 

(range 1-229), eighty-one patients died (median FU 85 months). In 

Ninety-seven patients (43%) the UHRF1 expression was positive. In 

univariate analyses Gleason Score (�7 vs 7-9), Stage Risk Group (TNM 

Stage �III vs Stage III and/or N�) and UHFR1 expression (negative vs 

positive) were significant prognostic factors for OS with p-value �0.0001. 

In multivariate analyses Gleason Score, Stage Risk Group and UHFR1 

expression were independent predictors for OS with respectively HRs of 

2.77 (95% CI 1.72-4.46) p�0.0001, HRs of 1.96 (95% CI 1.14-3.37) 

p�0.014 and Hrs 1.35 (95% CI 1.02-1.78) p�0.030. Conclusions: Our 

results indicate that expression of UHFR1 protein, independently from 

historical prognostic factors, is linked with adverse prognosis for overall 

survival in a homogeneous primary prostate cancer treated group with 

long-term follow-up. 



Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): 

A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) 

previously treated with a taxane. Presenting Author: Anthony E. Mega, 

Brown University Oncology Group, Providence, RI 

Background: The abundant expression of prostate specific membrane 

antigen (PSMA) type II transmembrane glycoprotein on prostate cancer 

cells provides a rationale for antibody therapy. PSMA ADC, a fully 

humanized antibody to PSMA linked to the potent antitubulin agent 

monomethyl auristatin E (MMAE), binds PSMA and is internalized within 

the prostate cancer cell where cleavage by lysosomal enzymes and releases 

free MMAE, causing cell cycle arrest and apoptosis. We report results from 

an ongoing phase 1 dose escalation study of PSMA ADC in subjects with 

taxane-refractory mCRPC. Methods: Eligibility requirements include progressive 

mCRPC following taxane-containing chemotherapy and ECOG status of 

0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. 

Adverse events, pharmacokinetics (PK), PSA, circulating tumor cells, 

clinical disease progression and immunogenic response to PSMA ADC were 

assessed. Serum PSMA ADC and total antibody were measured by ELISA, 

and free MMAE was measured by LC/MS/MS.The dosing cohorts range from 

0.4 mg/kg to 2.8 mg/kg, with dose escalation continuing. Results: 40 

subjects have been dosed in nine dose levels (0.4, 0.7, 1.1, 1.6, 1.8, 2.0, 

2.2, 2.5, 2.8 mg/kg). To date, PSMA ADC has been well tolerated with the 

most commonly seen adverse events being anorexia and nausea, and the 

most common laboratory abnormalities being reversible hematologic parameters 

and liver function tests. Antitumor activity has been manifested as 

reductions either in PSA or circulating tumor cells in the higher dose 

cohorts. Exposure to PSMA ADC increased with dose and was ~1,000-fold 

greater than MMAE exposure. Similar PK metrics were observed after the 

first and third doses. Dosing at the 2.8 mg/kg cohort is continuing and an 

MTD has not yet been reached. Conclusions: PSMA ADC is generally well 

tolerated in subjects with mCRPC, previously treated with taxane in doses 

up to 2.8 mg/kg. Antitumor activity at higher dose levels has been observed. 

The MTD has not yet been reached and enrollment is ongoing at higher dose 

levels. 


Response to ketoconazole (keto) or docetaxel (D) following clinical progression 

on abiraterone acetate (AA) in castrate-resistant prostate cancer 

(CRPC). Presenting Author: Rahul Raj Aggarwal, University of California, 

San Francisco, San Francisco, CA 

Background: Patients (pts) with CRPC treated with keto often experience a 

rise in serum adrenal androgen levels upon progression and may subsequently 

respond to more potent adrenal suppression with AA. In contrast, 

pts treated with AA do not have a rise in serum androgen levels upon 

progression, and thus may not respond to further androgen synthesis 

inhibition with keto but require other treatment modalities such as 

chemotherapy instead. The goal of this analysis is to report the outcomes of 

pts with CRPC progressing on AA subsequently treated with either keto or 

D. Methods: Pts with chemotherapy-naïve CRPC were treated on previously 

reported phase 1 and 2 trials of AA, with doses ranging from 250 to 1000 

mg/day. Subsequent treatment following progression on AA was per 

individual investigator discretion, including treatment with either keto or D. 

Results: To date, following disease progression on AA, 6 and 14 pts have 

been subsequently treated with either keto or D respectively. Of the 14 pts 

treated with D, 11 (79%) had exposure to keto prior to AA. The keto- and 

D-treated cohorts were similar with respect to other baseline factors, 

including prior response to AA (4/6 (67%) pts with � 50% PSA decline on 

AA in keto cohort; 10/14 (71%) pts in D cohort); though pts treated with D 

were more likely to require opioid analgesics (0 pts in keto cohort; 7 (50%) 

in D). For pts treated with keto, none experienced a decline in PSA, 

improvement in bone scan, or an objective response; all had disease 

progression by 12 weeks. In contrast, for pts treated with D, 10 (71%) had 

a decline in PSA; 6 (43%) with a � 50% maximum PSA decline. Of 6 pts 

with measurable disease, 2 (33%) had an objective response. The median 

time to progression for the D cohort was 129 days (range 60 – 294). 

Conclusions: Although the cohort size is small, and post-AA therapy was not 

randomized, these data provide preliminary support for the hypothesis that 

CRPC progressing on AA is cross-resistant to further androgen synthesis 

inhibition with keto. Contrary to other reports, prior treatment with AA does 

not appear to decrease the likelihood of subsequent response to D, but this 

observation requires prospective validation. 



Results of telomerase activity measurements from live circulating tumor 

cells captured on a slot microfilter in a phase III SWOG-coordinated 

prostate cancer trial (S0421). Presenting Author: Amir Goldkorn, University 

of Southern California Norris Comprehensive Cancer Center, Los 

Angeles, CA 

Background: Analysis of circulating tumor cells (CTC) is a promising 

biomarker strategy in advanced prostate cancer, and telomerase activity 

(TA) is a recognized cancer marker. To test whether CTC TA is prognostic for 

survival (OS), we developed a novel Parylene-C slot microfilter capable of 

capturing live CTC and used it to measure CTC TA as part of a Phase III 

SWOG-coordinated therapeutic trial in metastatic castration resistant 

prostate cancer (S0421). Methods: Blood samples were drawn into EDTA 

tubes and shipped overnight to a central processing site. After Ficoll 

centrifugation, low constant pressure was used to pass the mononuclear 

cell layer through two slot microfilters in series as published previously 

(filter1 captures CTC � background white blood cells; filter2 captures only 

background white blood cells). Filter-trapped cells were lysed in CHAPS 

buffer and assayed for TA using qPCR-based telomeric repeat amplification. 

In parallel, CTC were enumerated using CellSearch (J&J). Cox 

regression was used to evaluate the association between baseline (pretreatment) 

TA and OS overall, and within subgroups characterized by good 

prognosis (�5) vs. poor prognosis (��5) baseline CTC counts. CART 

regression was used to explore potential prognostic subgroups based on 

baseline PSA, CTC, and TA cutpoints. Results: Samples were obtained from 

263 patients. While no association was observed between TA and OS 

overall, in patients with baseline CTC ��5 (108 of 263 or 41% of 

patients), TAfilter2 –TAfilter1 representing high CTC TA relative to background 

blood cells was associated with a hazard ratio (HR) of 1.14 (95% CI 

1.05-1.23, p�0.001) for OS after adjusting for risk factors and remained 

significant when also adjusting for CTC: HR 1.14 (95% CI 1.04-1.23; 

p�0.005). Exploratory CART regression assessing baseline PSA, CTC, and 

TA identified risk groups based only on CTC and TA values. Conclusions: 

Baseline TA from CTC live-captured on a new slot microfilter is the first CTC 

biomarker shown to be prognostic of OS in men with CTC counts ��5 ina 

prospective clinical trial. CTC TA may be useful for further identifying 

prognostic groups in this population. 


Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen 

and CYP17 inhibitor in castration resistant prostate cancer (CRPC). 

Presenting Author: Robert B. Montgomery, University of Washington, 

Seattle, WA 

Background: Galeterone is an oral steroid analog that suppresses prostate 

cancer growth by inhibiting CYP17, blocking androgen receptor and 

reducing androgen receptor levels. Methods: Open label, multicenter 

dose-finding study assessing the safety, pharmacokinetics and clinical 

effect of escalating doses of galeterone in chemotherapy naïve CRPC 

patients (pts). Pts were enrolled in cohorts from 650-2,600mg of galeterone 

daily for 12 wks. Study also explored effects of food supplement and 

scheduling. Pts remained on study until disease progression or dose 

limiting toxicity. Results: Pt characteristics included median age 69 

(47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49 

pts completed 12 wks of study with early discontinuation for toxicity (6), 

progression (5), or withdrawal of consent (2). Maximal tolerated dose was 

not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8% 

grade 3 and 1% grade 4. Transient LFT elevations were seen in 15 men (5 

with suspected or confirmed Gilberts). There was no trend for increasing 

toxicity with dose escalation and no PK difference in Gilberts pts. 9 SAEs 

were reported with one considered related to galeterone (rhabdomyolysis 

with acute renal failure in the context of high dose statin use). Overall 

11/49 pts (22%) demonstrated �50% PSA decline and an additional 

13/49 (26%) had 30-50% declines. Partial response by RECIST was seen 

in 2 pts. Consistent with lyase inhibition, increased corticosteroids and 

suppressed androgens were seen with dose escalation. Analysis of limited 

plasma collected 4 - 30 hours after dosing showed high interpatient 

variability with no consistent relationship to dose or time after dosing. 

Conclusions: Galeterone was well tolerated in CRPC pts and demonstrated 

clinical activity. Galeterone is being reformulated with additional PK and 

phase II trials planned. 

PSA response to galeterone. 

Dose (mg/day) N 

Duration on 

treatment 

(months) 

>50% PSA 

decline 

% (n) 

317s 

>30% PSA 

decline 

% (n) 

650 6* 2-16 20% (1) 20% (1) 

975 with and w/out supplement 12* 1-21 18% (2) 55% (6) 

1,300 6 2-21 0% (0) 17% (1) 

1,950 single/split 13 1-12 23% (3) 54% (7) 

2,600 single/split 

*One pt nonevaluable. 

12 1-8 42% (5) 75% (9) 




Regional variation in survival after metastatic prostate cancer diagnosis. 

Presenting Author: Darius Lakdawalla, University of Southern California, 


Background: Survival after diagnosis of metastatic prostate cancer (mPC) 

averages 2-3 years. Substantial regional differences in survival have been 

documented for PC prior to 2000. We investigated the extent to which 

regional variation exists in survival for mPC patients during 2000-2007. 

Methods: Using the Surveillance, Epidemiology, and End Results (SEER) 

database linked to Medicare claims, we identified men (mean age, 77.6 

years) continuously enrolled in Medicare Parts A/B who were diagnosed 

with mPC between 2000 and 2007 and not diagnosed with another 

malignancy. The base-case model was limited to hospital service areas with 

�50 patients. A Cox proportional hazards model was used to estimate 

hazard ratios (HR) for overall survival (OS), adjusting for year of diagnosis, 

age, marital status, poverty and education covariates, Gleason score, 

comorbidities, and region covariates. Sensitivity of results was tested by 

limiting the analysis to patients surviving at least 6 months after diagnosis 

and by removing regional sample size limits. We report HRs for covariates, 

results of a Wald test of joint significance for region effects, and percentage 

difference from the mean for each region’s HR for death. Results: A total of 

2696 patients with mPC met the inclusion criteria. OS was 37% at 3 years 

and mean HR for death was 4.8 (sd 2.1). HRs for death were positively 

correlated with age (HR�1.96, 95% CI: 1.6-2.3 for �80 years), PCspecific 

comorbidity index (HR�1.2, 95% CI: 1.1-1.3), and Gleason score 

(HR�6.6, 95% CI: 2.4-17.8 for poorly differentiated). Year of diagnosis, 

race, and socioeconomic status were not significantly associated with 

mortality. Wald test of joint significance for survival across regions of 

P�.019 indicated significant differences in survival across regions and was 

robust in sensitivity analyses. Patients living in regions with the worst 

survival rates had HRs for death that were 20% higher than the mean 

(HR�5.8) and those living in regions with the best survival rates had HRs 

30% lower than the mean (HR�3.4). Conclusions: There are significant 

regional differences in survival for mPC patients in the 2000s. Further 

research is needed to determine if treatment differences play a role in this 

disparity. 


Incidence-based analysis of lethal prostate cancer in Swedish counties 

with high versus low incidence of prostate cancer in nationwide, populationbased 

registries. Presenting Author: Pär Stattin, Department of Surgery, 

Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Current data from randomized trials differ in the ratio of 

benefit to harms from screening for prostate cancer (PC) using prostate 

specific antigen (PSA) testing and it is further unclear if decreases in PC 

mortality in the US can be attributed to introduction of screening or to 

changes in treatment. The aim of this study was to investigate if rapidly 

increased incidence of PC diagnosis due to early and rapidly increased rate 

of PSA testing, is associated with decreased incidence of lethal PC. 

Methods: In this incidence-based study using highly representative data 

from nation-wide population-based registries we analysed the incidence of 

lethal prostate cancer in eight Swedish counties with the most rapid and 

largest increased incidence of PC diagnosis (high incidence counties) from 

1995 through 2002, and six counties with the smallest increased PC 

incidence (low incidence counties). We analysed the rate ratio (RR) in high 

vs. low incidence counties of cases with metastatic PC at diagnosis, 

(positive bone scan or PSA above 100 ng/ml), PC-specific mortality, and 

excess mortality (death among PC cases regardless of cause). Participants 

were men aged 50-74 years during 2000 to 2009 in the high versus low 

incidence counties contributing 4,528,134 versus 2,471,373 personyears 

at risk, respectively. There were 33,780 incident PC diagnoses and 

1,577 PC deaths in high incidence counties and 16,377 PC cases and 985 

PC deaths in low incidence counties. Results: In high vs. low incidence 

counties, RR of metastatic PC was 0.85 (95% confidence interval [CI] � 

0.79 to 0.92), RR of PC-specific mortality was 0.87 (95% CI � 0.81 to 

0.95) and RR of excess mortality in men with PC was 0.75 (95 %CI � 0.66 

to 0.86). Conclusions: Our study provides data on a population-level 

indicating a decreased incidence of lethal PC in areas with rapid and large 

increase in incident PC diagnosis due to increased rates of PSA testing, 

early diagnosis, and treatment with curative intent. 


The impact of prior therapy with ketoconazole (keto) on clinical outcomes 

after subsequent docetaxel treatment in metastatic castration-resistant 

prostate cancer (mCRPC) patients: Results from a randomized phase III 

trial (CALGB 90401). Presenting Author: Eric Jay Small, University of 

California, San Francisco, San Francisco, CA 

Background: Small retrospective reviews have suggested the possibility of a 

decreased benefit of docetaxel in mCRPC patients (pts) previously treated 

with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). 

CALGB 90401 was an intergroup (CALGB, ECOG) randomized phase 3 trial 

in which 1050 mCRPC pts were treated with docetaxel, which offered the 

opportunity to evaluate the effect of prior treatment with keto, an earlier 

generation ASI, on clinical outcomes following docetaxel treatment in 

mCRPC pts. Methods: Data from 1,050 men randomized on CALGB 90401 

to treatment with docetaxel and prednisone with either bevacizumab or 

placebo were used. Pts were chemotherapy naïve, had evidence of 

progressive mCRPC, an ECOG performance status � 2, and adequate bone 

marrow, hepatic and renal function. Randomization was stratified by age, 

prior history of a thromboembolic event, and 24-month predicted survival 

using the CALGB nomogram. The effect of prior keto use on overall survival 

(OS), progression-free survival (PFS), PSA decline, and objective response 

rate (RR) was estimated using proportional hazards and logistic regression 

models. Results: 277/1050 pts (26%) had received prior keto. Baseline 

characteristics including the 3 stratification factors, race, performance 

status, measurable disease, and baseline alkaline phosphatase and Hgb 

were balanced between prior keto treated pts and keto untreated pts. LDH 

and PSA were higher in the keto treated patients (211 vs. 201, p � 0.01; 

and 121 vs. 73, p � .0001; respectively.) There were no statistically 

significant differences in keto vs. non-keto treated patients with regards to 

OS (21.1 vs. 22.3 m, p � 0.643); PFS (8.1 vs. 8.6m p � 0.394 ); �50% 

decline in PSA (61% vs. 66% p�.112); or objective response (39% vs. 

43% p � 0.34). Conclusions: As measured by OS, PFS, PSA and RR, prior 

treatment with the ASI ketoconazole has no impact on the subsequent 

clinical impact of docetaxel in mCRPC pts. 


Association of decreased expression of protein phosphatase 2A subunit 

PR55� (PPP2R2C) with an increased risk of metastases and prostate 

cancer-specific mortality. Presenting Author: Elysia Sophia Spencer, Fred 


Background: The protein phosphatase 2A (PP2A) holoenzyme complex 

negatively controls cell growth, differentiation and apoptosis. Down regulation 

of PP2A activity is associated with oncogenic transformation of 

papillomas and is a target for the small-T viral oncogene. The PR55� 

(2R2C) subunit regulates PP2A target specificity, inhibiting c-Src activity 

in some cell lines. c-Src activity enhances growth and invasion in prostate 

cancer. This study evaluates whether PPP2R2C protein levels in radical 

prostatectomy (RP) specimens were predictive for the development of 

metastases or prostate-cancer specific mortality (PCSM). Methods: From 

1954-1997, 1004 consecutive patients underwent RP at Virginia Mason 

Medical Center in Seattle. Metastases were confirmed radiographically or 

by tissue diagnosis. Death certificates confirmed PCSM. Patients without 

stored tissue were excluded. 34 patients with metastases or PCSM were 

matched to patients without recurrence (NR) at a 1:2 ratio. Paraffinembedded 

tissue was stained with anti-PPP2R2C monoclonal antibody, 

clone 6D1 (Abnova, Taiwan). A pathologist evaluated the percentage and 

intensity of nuclei stained using a 4-point scale. Statistical analysis was 

performed on SAS. Results: Mean follow up was 10.26 years. PPP2R2C was 

detected in 13/18 (72.2%) PCSM, 18/22 (81.8%) metastases and 45/49 

(91.8%) NR patients. Mean expression was lower in cancerous vs benign 

glands, 1.74 vs 2.04 (p � 0.001). Expression intensity from PCSM vs NR 

was 1.45 vs 1.80 (p � 0.041). On multivariate analysis, expression was 

lower in metastases or PCSM versus NR 1.79 vs 2.35 (p � 0.002), 

independent of pre-op PSA and Gleason grade. Conclusions: PPP2R2C loss 

was highly correlated with metastasis and PCSM. Patients with the lowest 

levels of expression were at the highest risk for PCSM. As tissue was 

obtained at time of surgery, this analysis reflects a truly prognostic 

biomarker, independent of Gleason grade and PSA. We have shown that 

PPP2R2C scoring is a useful metric to identify patients at high risk of 

developing advanced disease. With further validation may allow for more 

accurate individual patient treatment plans and counseling. 



African American race to predict for earlier failure of active surveillance: 

Results from the Duke Prostate Center. Presenting Author: Mitchell 

Bassett, Duke University Medical Center, Durham, NC 

Background: As concerns mount regarding overtreatment and overdiagnosis 

of prostate cancer (CaP), active surveillance (AS) is increasingly 

utilized in low risk patients. While African-American (AA) race is associated 

with adverse outcomes after prostatectomy, its effect on patients managed 

with AS is not known. Methods: A retrospective review identified 222 

patients managed with AS at the Duke Prostate Center from January 2005 

to September 2011. All men had CaP diagnosed on biopsy performed at our 

center, and elected AS over treatment. Failure was defined as progression 

to treatment. In men who failed AS, the reasons for failure, follow-up PSA 

and biopsy characteristics were analyzed. The primary outcome - time from 

diagnosis to failure of AS for a reason other than patient choice - was 

analyzed with univariable and multivariable Cox proportional hazards 

models. Results: In our AS cohort, 73% are Caucasian and 23% AA. Median 

follow-up is 25.4 months. Age, household income, BMI, PSA, clinical 

stage, family history, prostate volume, number of cores with cancer, and 

Gleason grade on initial biopsy did not differ by race. The number of 

biopsies and PSA tests performed on AS did not differ by race. A higher 

proportion of AA men tended to fail from biopsy progression (72.7% vs. 

63.8%) while a lower proportion failed by choice (9.1% vs. 14.9%) 

compared to Caucasians (p � 0.114). AA men had a significantly shorter 

time to failure (HR 1.74, p � 0.045) compared to Caucasians. There was a 

trend toward increased Gleason grade 8 or higher cancer on follow-up 

biopsy in AA compared to Caucasian men (10% vs. 2.5%, p � 0.08). AA 

race remained a predictor (HR 1.76, p � 0.058) of failure on multivariable 

analysis, as did initial PSA (HR 1.90, p � 0.031) and number of cores with 

cancer on initial biopsy (HR 1.29, p � 0.013). Conclusions: AA race was 

associated with higher risk for failure of AS. There was a trend toward AA 

men failing due to biopsy progression and with higher grade cancer. 

Additional follow-up is necessary to determine how this affects the long 

term outcomes of these men. 

TPS4672 General Poster Session (Board #13G), Sun, 8:00 AM-12:00 PM 

Phase II trial of cabazitaxel in patients with advanced or metastatic 

transitional cell carcinoma of the urothelial tract who have progressed 

within less than 12 months after cisplatin-based chemotherapy: A Spanish 

Oncology Genitourinary Group (SOGUG) study. Presenting Author: Jose 

Angel Arranz Arija, Hospital General Universitario Gregorio Marañón, 

Madrid, Spain 

Background: Advanced transitional cell carcinoma of the urothelium (TCCU) 

on progression after previous cisplatin-based combination is generally an 

incurable disease. The appropriate management of these patients is still an 

unmet need. Many drugs have shown modest or no activity in previous 

phase 2 trials. Population heterogeneity in these studies emerges as one of 

the key determinants that could explain the variable outcomes. Recently, in 

a phase III study in this setting, prognostic factors (PF) for overall survival 

were identified (Bellmunt J et al, JCO 2010). Taxanes are active drugs in 

2nd-line metastatic TCCU. Cabazitaxel (C) is a semi-synthetic taxane that 

is a poor substrate for the multidrug resistance system. C could be a valid 

alternative in this patient population. Methods: This is an open label phase 

II study of C in patients (pts) with advanced or metastatic TCCU who have 

progressed within 12 months after receiving a 1st-line platinum based 

chemotherapy. There are three treatment arms as patients will be assigned 

to one of three groups previously defined based on the presence of 0, 1 or 

2-3 PFs as defined by Bellmunt et al. The activity of C will be assessed 

separately in each group and overall. The primary endpoint is response rate 

(RR) evaluated according to RECIST 1.1, a maximum of 35 pts are needed 

in each subgroup (maximum number of pts required: 105). Secondary 

objectives are RR in the whole population, toxicity, progression-free 

survival and overall survival. In addition, an external validation of the 

prognostic model proposed by Bellmunt will be conducted, as well as a 

pharmacogenomic study in order to better define the toxicity profile of the 

drug and the potential responders. 


319s 


Activity of oral VT-464, a selective CYP17-lyase inhibitor, in the LNCaP 

prostate cancer xenograft. Presenting Author: William Douglas Figg, 

Medical Oncology Branch, National Cancer Institute, National Institutes of 


Background: With the FDA approval of abiraterone acetate, inhibition of 

CYP17 (17� hydroxylase/C17, 20-lyase) is now a validated approach to the 

treatment of castration-resistant prostate cancer. VT-464 is a novel, 

selective CYP17-lyase inhibitor with decreased activity against CYP17 

hydroxylase (less mineralcocorticoid and glucocorticoid effects). The study 

objectives were to observe the effects of VT-464 in a prostate cancer 

xenograft model and to compare its activity to abiraterone acetate and 

surgical castration. Methods: SCID mice were implanted subcutaneously 

with LNCaP cells. When tumors reached 100 mm3 , mice were randomized 

to receive vehicle (0.5% CMC in saline, 5 mL/kg), VT-464 at 15, 50, or 100 

mg/kg p.o. b.i.d. A second cohort of LNCaP tumor-bearing mice received 

vehicle, surgical castration, or VT-464, or abiraterone acetate at 100 mg/kg 

p.o. b.i.d. for 28 days. Terminal blood and tumor concentrations were 

analyzed on day 28, four hours after the last dose. Results: In the first 

LNCaP xenograft cohort, percent growth inhibition (� S.E.) of 9.6 (�15.6), 

38.5 (�12.4), and 73.9 (�13.2) was observed on day 21 of treatment for 

VT-464 doses of 15, 50, and 100 mg/kg, respectively. Growth reduction at 

100 mg/kg was statistically significant compared to vehicle control from 

day 7 to 28. VT-464 was well tolerated with insignificant weight loss at all 

doses. In the second cohort, VT-464-treated (100 mg/kg) mice had 

significantly reduced tumor volumes on day 28 compared to control and 

abiraterone acetate (p�0.05, p�0.01, respectively). Reduction in tumor 

volumes were similar between VT-464-treated (100 mg/kg) and castrate 

animals. Plasma and tumor analyses revealed much greater plasma and 

tumor exposure of VT-464 compared to abiraterone acetate. Conclusions: 

VT-464 exhibited dose-dependent growth inhibition with significantly 

reduced tumor volumes at the highest dose compared to abiraterone 

acetate. The activity in VT-464-treated animals was similar to that of 

castrate animals. These preclinical results show promising activity of 

VT-464 in the treatment of prostate cancer. 

TPS4673 General Poster Session (Board #13H), Sun, 8:00 AM-12:00 PM 

Design of a phase II randomized, open-label trial of DN24-02, an 

autologous cellular immunotherapy targeting HER2/neu, in patients with 

surgically resected urothelial cancer at high risk of recurrence. Presenting 

Author: Dean F. Bajorin, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: Despite surgical resection and the use of (neo)adjuvant 

chemotherapy, up to 50% of patients with invasive urothelial carcinoma 

will have disease recurrence and eventually die of metastatic disease. New 

approaches are needed for these patients. Approximately 50% of patients 

with high-risk pathologic features have evidence of HER2 expression in the 

primary tumor or involved lymph nodes. DN24-02 is an autologous cellular 

immunotherapy targeting HER2, which is based on Dendreon’s Antigen 

Delivery Cassette technology – the same platform used for sipuleucel-T (an 

FDA-approved treatment for asymptomatic or minimally symptomatic 

metastatic castrate-resistant prostate cancer). Each dose of DN24-02 is 

manufactured by culture of peripheral blood mononuclear cells obtained by 

leukapheresis with a recombinant antigen that comprises components of 

the intra- and extracellular domains of the HER2 antigen linked to GM-CSF. 

A product similar to DN24-02 has shown evidence of safety and immune 

response in phase I studies. Objectives: The primary objective is to 

determine whether DN24-02, given as adjuvant therapy following surgical 

resection, can prolong survival compared to standard of care (SOC). 

Secondary objectives are to evaluate disease-free survival, safety, and 

immune responses to DN24-02. Methods: Eligible patients will have 

undergone surgical resection of a primary urothelial cancer, with either 

�pT2 or pN� staging, and HER2 expression �1� by IHC based on 

pathologic review. Approximately 180 patients will be randomized (1:1) to 

receive three IV infusions of DN24-02 as adjuvant therapy approximately 

every 2 weeks, or SOC. Stratification will include 1) neoadjuvant chemotherapy 

vs surgery alone; and 2) positive (pN�) vs negative lymph node 

involvement (pN0). Other adjuvant chemotherapy will not be allowed. 

Patients can be treated per SOC if there is disease recurrence. Patients will 

be monitored for evidence of recurrence by imaging, and followed for 

survival. Cellular and serological immune responses will be assessed at 

baseline and post-DN24-02 therapy. 



TPS4674 General Poster Session (Board #14A), Sun, 8:00 AM-12:00 PM 

Vinflunine maintenance therapy versus best supportive care (BSC) after 

platinum combination in advanced bladder cancer: A phase II, randomized, 

open-label study (MAJA study)—SOGUG 2011-02. Presenting Author: 

Sonia Maciá, Hospital General de Elda, Elda, Spain 

Background: Vinflunine is a novel microtubule inhibitor currently approved 

by EMA as treatment after platinum progression, in metastasic bladder 

cancer. It is distinguished from the other vinca-alkaloids because it binds 

relatively weakly to tubulin, suggesting an improved tolerance profile as a 

result of less neuropathy. Based on the fact that no cumulative toxicity is 

expected and the results reported in second-line, we aim to test the role of 

vinflunine in first line therapy, as maintenance treatment for patients who 

obtain clinical benefit after platinum. Methods: This is a multicenter, 

randomized, open label, proof-of-concept study that will be performed in 

20 institutions members of the Spanish Oncology Genitourinary Group 

(SOGUG). Subjects will be randomized in a 1:1 ratio to receive vinflunine 

320 mg/m2 every 21 days plus BSC vs BSC alone until disease progression. 

Vinflunine dose will be 280mg/m2 for patients with PS�1, age � 75 years, 

prior pelvic radiotherapy or creatinine clearance Cr �60ml/min. Stratification 

factors are: 1) Scheduled dose at randomization (320 vs 280mg/m2) 

2) Liver metastasis (Y/N). Main inclusion criteria are: Subjects �18 and� 

80 years of age with histological diagnosis of transitional cell carcinoma of 

the urothelial tract and measurable disease with radiological response or 

stabilization after 6 cycles of a platinum containing doublet for metastasic/ 

advanced disease. Primary objective will be progression free survival (PFS), 

considering as clinically relevant 6 months in experimental arm. To 

guarantee an overall type-1 � error (one side) no greater than 0.05 and a 

type II (�) error 0.1 for the primary endpoint of PFS, a sample size of 86 

patients allocated in a 1:1 ratio is planned. Recruitment is scheduled to 

start by February 2012. A pharmacogenomic translational study will also 

be conducted. 

TPS4676 General Poster Session (Board #14C), Sun, 8:00 AM-12:00 PM 

Phase II trial of gemcitabine and cisplatin plus ipilimumab as first-line 

treatment for metastatic urothelial carcinoma. Presenting Author: Benjamin 

Adam Gartrell, Division of Hematology and Medical Oncology, The 

Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 

Background: While metastatic urothelial carcinoma is a chemosensitive 

neoplasm, current therapeutic approaches are inadequate. Preclinical and 

clinical data suggests that bladder cancer is immunogenic. For example, 

CD8� tumor infiltrating lymphocytes correlate with survival in patients 

with muscle-invasive disease (Sharma, PNAS, 2007). However, immunotherapeutic 

approaches have been rarely investigated for advanced urothelial 

cancer. CTLA4 blockade with ipilimumab is a novel approach to 

immunotherapy that interrupts T-cell pathways responsible for immune 

down-regulation or tolerance. In a proof of concept study, ipilimumab was 

administered to 12 patients with muscle-invasive disease preoperatively 

(Carthon, Clin Can Res, 2010). Treatment resulted in perivascular infiltration 

of cells positive for CD3, CD8, CD4, and granzyme and intriguing 

evidence of antitumor activity. In the current trial, we will explore a 

“phased” schedule of chemotherapy and ipilimumab with the goal of 

“autovaccinating” patients to tumor antigen with chemotherapy prior to 

introduction of immune checkpoint blockade. Methods: We have initiated a 

phase II clinical trial of gemcitabine (G), cisplatin (C), plus ipilimumab in 

chemonaive patients with unresectable and/or metastatic urothelial cancer 

within the Hoosier Oncology Group network. During cycles 1 and 2, G 

(1000 mg/m2 D day 1 � 8) and C (70 mg/m2 D 1) will be administered 

every 21 days without ipilimumab. During cycles 3-6, GC plus ipilimumab 

(10 mg/kg day 1) will be administered every 21 days. Patients without 

evidence of disease progression after completion cycle 6 will continue 

single-agent ipilimumab “maintenance” every 3 months. The primary 

objective is to determine the 1-year overall survival. The trial will enroll 36 

patients and is powered to detect an improvement in 1-year survival from 

60% to 80%. Secondary objectives include progression-free survival, 

disease control rate, safety, and immunologic outcomes. Correlative 

studies will include serial measurements of the global composition of 

immune cells in the blood by polychromatic flow cytometry, whole blood 

transcriptional profiling, and tumor-antigen specific CD8� T cells assays. 

TPS4675^ General Poster Session (Board #14B), Sun, 8:00 AM-12:00 PM 

Randomized phase II study of docetaxel with or without ramucirumab 

(IMC-1121B) or icrucumab (IMC-18F1) in patients with urothelial transitional 

cell carcinoma (TCC) following progression on first-line platinumbased 

therapy. Presenting Author: Daniel Peter Petrylak, Columbia 


Background: The vascular endothelial growth factor (VEGF) pathway may 

play an important role in the pathogenesis of bladder cancer. Two 

antibodies (ramucirumab or icrucumab) in combination with docetaxel are 

being tested in this clinical study. Ramucirumab is a fully human IgG1 

monoclonal antibody (MAb) that specifically binds with high affinity to 

VEGF receptor-2 (VEGFR-2), thereby blocking the interaction of VEGF 

ligands. Ramucirumab inhibits VEGF-mediated proliferation of human 

endothelial cells and migration of human leukemia cells. Icrucumab is a 

fully human IgG1 MAb that specifically binds with high affinity to VEGFR-1 

and blocks the binding of VEGF-A, VEGF-B, and placental growth factor 

(PlGF) to the receptor, thereby inhibiting subsequent signaling. Blockage 

of VEGFR-1 and VEGFR-2 by antibodies demonstrates antiangiogenic and 

antitumor activity and prevents dissemination and growth of lung metastases 

in several tumor xenograft models. Methods: This study includes 

patients (pts) with TCC with progressive disease after prior platinum-based 

therapy. Pts are randomized equally to 1 of 3 open-label treatments given 

on a 21-day cycle: docetaxel (75 mg/m2 ) on Day 1 (Arm A); docetaxel on 

Day 1 and ramucirumab (10 mg/kg) on Day 1 (Arm B); or docetaxel on Day 

1 and icrucumab (12 mg/kg) on Days 1 and 8 (Arm C). Randomization is 

stratified by the absence/presence of visceral metastases and receipt of 

prior antiangiogenic therapy. The primary endpoint is progression-free 

survival (PFS). Secondary outcome measures include response rate and 

duration of response, overall survival, and pharmacodynamic markers, 

including circulating levels of PlGF, VEGF-A, VEGF-B, soluble VEGFR-1, 

and soluble VEGFR-2. Exploratory analyses of VEGF, VEGFR-1, and 

VEGFR-2 genetic polymorphisms will be performed. As of 12 January 

2012, approximately 20% of 138 planned pts were randomized in the US 

and Canada. The sample size will allow differentiation of an expected 

increase in median PFS from 3.0 months to 4.5 months with a one-sided 

alpha of 0.1 and a power of 71%. ClinicalTrials.gov identifier: 

NCT01282463. 

TPS4677 General Poster Session (Board #14D), Sun, 8:00 AM-12:00 PM 

Phase II study of everolimus (E) in refractory germ cell tumors (GCTs). 

Presenting Author: Michal Mego, Department of Medical Oncology, School 

of Medicine, Comenius University, National Cancer Institute, Bratislava, 

Slovakia 

Background: GCTs represent a model for the cure of cancer. Nonetheless, a 

small proportion of patients (pts) develop disease recurrence. Because of 

insufficient results in the treatment of relapsed GCTs, evaluation of new 

treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase 

and tensin homolog) marks the transition from intratubular germ cell 

neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly 

expressed in germ cells whereas it was virtually absent from 56% of 

seminomas as well as from 86% of embryonal carcinomas and virtually all 

teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating 

that loss of PTEN expression is not in early event in GCTs development, but 

is associated with disease progression. PTEN inactivation is associated 

with dysregulation of PI3K/Akt pathway and increased mTOR signalling. 

We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN 

inactivation in GCTs suggests that these pts could have greater benefit from 

mTOR inhibition. Methods: In December 2011, National Cancer Institute of 

Slovakia launched an one arm, two-staged phase II study aimed to evaluate 

the efficacy and toxicity of E in pts with refractory GCTs. The primary 

objective is to determine the efficacy of E in patients with refractory GCTs. 

Secondary objectives includes favourable response rate, time to progression 

and safety. The pts with radiological and/or serological proof of 

relapsed GCTs, who were not amenable to be cured by chemotherapy or 

surgery and who failed at least two platinum-based regimens or one 

platinum regimen in case of platinum-refractory disease or primary mediastinal 

non-seminomatous GCTs were eligible. All other standard inclusion 

and exclusion criteria for study of salvage treatment in refractory GCTs pts 

were applied. E will be administered at a dose of 10mg daily until 

progression or unacceptable toxicity. Assuming a response rate of clinical 

interest of �40%, a minimal response rate of 20%, a probability of 5% for 

rejecting an active drug, and a probability of 20% to further evaluate an 

ineffective drug, 18 pts will be enrolled into the first cohort. If �4 

responses will be observed, the study will be terminated, otherwise, it will 

be continued with a second cohort of 20 pts. 


TPS4678 General Poster Session (Board #14E), Sun, 8:00 AM-12:00 PM 

Neoadjuvant therapy preceding cytoreductive nephrectomy to develop 

individualized first-line therapy with everolimus for advanced renal cell 

carcinoma (RCC). Presenting Author: Guru Sonpavde, Texas Oncology, 

Houston, TX, and Department of Medicine, Section of Medical Oncology, 

Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of 

Medicine, Houston, TX 

Background: Everolimus (E), an orally administered mTOR inhibitor, is the 

conventional agent for progressive disease following vascular endothelial 

growth factor (VEGF) inhibitors for advanced RCC. Given the excellent 

tolerability and convenient oral administration, a rationale may be made to 

develop E as first-line therapy for selected patients. The period between 

diagnosis and cytoreductive nephrectomy (CN) may be utilized for brief 

therapy to capture biologic activity in tumor tissue and facilitate individualized 

systemic therapy. The agent may be resumed following CN and 

continued until progression. Pharmacodynamic (PD) alterations from 

baseline to CN tumor tissue may predict progression-free survival (PFS). 

We hypothesized that the application of this paradigm to E may enable the 

employment of first-line E in patients predicted to optimally benefit. 

Methods: This is a 27-patient phase II trial being conducted at the Baylor 

College of Medicine and University of Texas Southwestern, and 5 patients 

have been enrolled currently. Patients with �3 poor risk factors or those 

who refuse or are ineligible for VEGF inhibitors and have untreated 

metastatic RCC are eligible. Adequate hematologic, renal and hepatic 

function is required. The primary endpoint is PFS and secondary endpoints 

are response, survival and toxicities. Exploratory endpoints are tumor 

tissue, peripheral blood mononuclear cell (PBMC) and plasma PD studies 

and pharmacokinetic (PK) studies, and their association with PFS. PD 

studies include DNA, mRNA, protein and miRNA studies to evaluate the 

mTORC1 among other pathways. Patients initially undergo 4 core biopsies 

of the primary renal mass for fresh frozen tumor. Patients then receive E 10 

mg orally once daily for 3-5 weeks. CN is performed within 24-48 hours 

after the last dose of E. At the time of CN and before separation from the 

vascular supply, 3 core biopsies are performed. E is resumed 2-4 weeks 

after CN and continued until progression or intolerable toxicities. Clinical 

and laboratory assessments are performed every 4-5 weeks, and imaging is 

performed every 8 weeks. A progressing metastatic site will be biopsied (4 

core biopsies). 


A phase II study of bevacizumab and erlotinib in subjects with advanced 

hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic 

papillary renal cell cancer (RCC). Presenting Author: Eric A. Singer, 

Urologic Oncology Branch, Center for Cancer Research, National Cancer 

Institute, National Institutes of Health, Bethesda, MD 

Background: There are currently no treatment options of proven efficacy for 

patients with advanced papillary RCC. The evaluation of families with 

inherited forms of RCC has allowed for the identification of genetic 

alterations associated with papillary RCC. HLRCC is one such familial 

condition with a propensity for the development of a clinically aggressive 

variant of papillary RCC characterized by unique histopathologic features. 

Germline mutations in the gene for the Krebs cycle enzyme fumarate 

hydratase (FH) are the genetic hallmark of HLRCC. Mutational inactivation 

of FH leads to von Hippel-Lindau-independent upregulation of hypoxia 

inducible factors (HIF) and their downstream transcriptional targets such 

as vascular endothelial growth factor (VEGF) and transforming growth 

factor-alpha (TGF-�) / epidermal growth factor receptor (EGFR). Upregulation 

of the HIF pathway may also be important in sporadic papillary RCC, 

although the prevalence of FH inactivation in these patients is unknown. 

We propose to evaluate the activity of dual VEGF/EGFR blockade with 

bevacizumab/erlotinib in patients with HLRCC-associated RCC and sporadic 

papillary RCC. Methods: This is a single arm phase II study based on 

an open label Simon two-stage minmax design with a maximum accrual of 

20 patients in each of two cohorts: Cohort 1- patients with HLRCC; Cohort 

2- patients with sporadic papillary RCC. The primary endpoint is RECIST 

overall response rate, assessed independently in each cohort. Patients will 

receive bevacizumab (10mg/Kg IV every 2 weeks) and erlotinib (150mg PO 

daily). Dose reductions and drug interruptions for toxicity are allowed. 

Patients will be evaluated for response every 8 weeks. Major eligibility 

criteria include: advanced RCC associated with HLRCC or sporadic papillary 

RCC; age �18 years; ECOG 0-2; measurable disease by RECIST; no 

brain metastases; no more than 2 prior regimens containing a VEGF 

inhibitor; and no prior therapy with bevacizumab. The prespecified activity 

goal for the first stage of accrual has been met for both cohorts. 

NCT01130519. 


321s 

TPS4679 General Poster Session (Board #14F), Sun, 8:00 AM-12:00 PM 

An observational study of metastatic renal cell carcinoma patients prior to 

initiation of initial systemic therapy. Presenting Author: Elizabeth R. 

Plimack, Fox Chase Cancer Center, Philadelphia, PA 

Background: The biology of metastatic RCC is extremely diverse, including a 

subpopulation of patients with indolent growth of metastases. Because of 

the acute and chronic toxicity and assumed non-curative nature of current 

systemic targeted therapy, a select subset of patients may be better served 

with initial surveillance. Such an approach may allow for deferral of 

systemic therapy to minimize overall treatment-related toxicity burden 

while maintaining treatment benefit. Methods: A prospective phase II trial is 

being conducted to characterize the clinical course of patients with mRCC 

who defer initial systemic treatment. Appropriate patients are selected by 

the treating physician based on an observed indolent growth pattern. As 

such, there is a 12 month window allowed between the first diagnosis of 

metastatic disease and study entry. Patients must be treatment-naïve, 

asymptomatic, with histologically confirmed mRCC and clinically-evident, 

measurable disease to be eligible. Radiographic assessment is performed 

at baseline, every 3 months for year 1, every 4 months for year 2, then every 

6 months. The primary objective is to characterize the clinical outcome of 

patients on observation in terms of time to RECIST defined disease 

progression and time to initiation of systemic treatment. Secondary 

endpoints include measurement of disease-related symptoms and depression/anxiety 

using standardized questionnaires (FKSI-DRS and HADS), as 

well as correlative endpoints analyzing the immune response over time for 

which blood is being collected for immune assays (TH1/TH2 phenotype, 

Tregs). Pts remain on study until initiation of systemic therapy due to 

radiographic disease progression, development of disease-related symptoms, 

withdraw of consent or clinical change that renders the patient 

unacceptable for further observation. Local therapy (e.g. surgery, radiation) 

during the observation period is permitted. Currently, 29 patients have 

been accrued at 5 collaborating sites. The target accrual of 50 pts provides 

adequate power for the primary descriptive endpoint as well as 80% power 

to detect changes from baseline for the correlate endpoints based on a 

two-sided Wilcoxon signed rank test. 


EVERSUN: A phase II trial of everolimus alternating with sunitinib as 

first-line therapy for advanced renal cell carcinoma (RCC) (ANZUP trial 

0901). Presenting Author: Ian D. Davis, Austin Health, Heidelberg, 

Australia 

Background: Treatment of RCC has improved due to better understanding of 

its biology. New targeted therapies have improved time to progression and 

overall survival but the optimal sequencing of agents is unknown. Currently 

drugs are given sequentially, usually starting with sunitinib and often 

followed by an mTOR inhibitor or another VEGFR-targeted therapy, but 

resistance to both drugs eventually occurs probably due to host adaptive 

responses. We hypothesize that resistance might be delayed by planned 

alternation of treatments. Methods: EVERSUN is a single-arm, two-stage, 

multicenter, phase II clinical trial aiming to determine the activity and 

safety of an alternating regimen of two therapies with different targets 

(sunitinib and everolimus) in patients with advanced RCC. Key eligibility 

criteria: RCC with a clear cell component; metastatic or locally advanced 

disease not suitable for resection; ECOG performance status 0-1; low or 

intermediate MSKCC prognostic score. The primary endpoint is the status 

of being alive and progression-free (RECIST 1.1) 6 months after registration. 

Target accrual of 55 subjects gives 95% power and 95% confidence 

to distinguish between 6-month progression free survival rates of 64% or 

lower vs 84% or higher using a Simon 2-stage minimax design. The criteria 

for further evaluation come from the pivotal trial of single agent sunitinib as 

first line therapy for RCC, in which the 6-month progression free survival 

rate was 74%. Trial treatment is administered in 12-week (wk) cycles 

consisting of 4 wks of sunitinib (50 mg daily) followed by 2 wks rest, 

followed by 5 wks of everolimus (10 mg daily) followed by 1 wk rest. 

Disease progression is interpreted as failure of the most recent drug taken. 

Participants who stop one drug because of toxicity or disease progression, 

on or before the 6 month assessment, will continue the other drug until 

subsequent progression or prohibitive toxicity on the second drug. EVER- 

SUN is an ANZUP Cancer Trials Group Ltd. trial coordinated by the NHMRC 

Clinical Trials Centre. Accrual commenced in September 2010 with 38/55 

participants recruited as of the 31-Jan-12 from 17 Australian sites 

(ACTRN12609000643279). 




Treatment of refractory metastatic renal cell carcinoma (RCC) with lenvatinib 

(E7080) and everolimus. Presenting Author: Ana M. Molina, Memorial 


Background: Lenvatinib (E7080) is an oral tyrosine kinase inhibitor targeting 

vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast 

growth factor receptor 1-4, RET, KIT and platelet-derived growth factor 

receptor beta. Lenvatinib has demonstrated acceptable toxicity and antitumor 

activity in Phase I and II studies (Glen H et al. JCO 2008, 26;15S: 

3526;Yamada K et. al. Clin Cancer Res 2011, 17:2528-2537; Sherman S 

I et al. JCO 2011, 29; 15S: 5503). Improved understanding of the 

molecular basis of renal cell carcinoma (RCC) has led to the development of 

targeted therapies (inhibitors of mTOR and of the VEGF pathway) that have 

shown clinical benefit in patients with metastatic RCC. However patients 

develop resistance and ultimately progress during treatment with available 

single agents. Combination therapy targeting different pathways have the 

potential to improve efficacy. Methods: This multicenter, randomized, 

open-label, phase Ib/II study is investigating everolimus (an oral mTOR 

inhibitor) in combination with lenvatinib in RCC patients with unresectable 

or metastatic disease (NCT01136733). The study is being conducted in 

two phases. The phase Ib dose-escalation component will determine the 

maximum tolerated dose (MTD) of the combination; starting doses are 12 

mg/day lenvatinib and 5 mg/day everolimus. A cohort expansion will follow 

to confirm the MTD and establish a recommended phase II dose (RP2 

dose). Approximately 150 patients will be enrolled in phase II and 

randomized 1:1:1 to receive: lenvatinib and everolimus at the RP2 dose 

(Arm A); lenvatinib 24 mg/day (Arm B); or everolimus 10 mg/day (Arm C). 

Patients with clear cell RCC, ECOG performance score �2 and progression 

during or after one prior VEGF-targeted treatment are eligible for phase II. 

The primary endpoint for Phase II is to compare progression-free survival of 

the investigational arms (A and B) with single agent everolimus (Arm C). 

Three phase Ib dose escalation cohorts have completed enrollment, and 

enrollment of the expansion cohort commenced in November 2011. 

Participating phase II centers will be located in the US, UK, Spain, Poland 

and Czech Republic and are expected to enroll patients throughout 2012. 


A phase II study of intermittent sunitinib in previously untreated patients 

(pts) with metastatic renal cell carcinoma (mRCC). Presenting Author: 

Laura S. Wood, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 

Background: Sunitinib is a standard of care initial treatment in mRCC. One 

challenge is balancing the acute and chronic toxicity of therapy with 

clinical benefit. Pre-clinical and retrospective clinical data support the 

concept that treatment breaks are feasible and not associated with a 

reduction in efficacy of sunitinib. It is hypothesized that an intermittent 

dosing regimen of sunitinib in mRCC pts is feasible, and may lead to 

prolonged duration of disease control with improved tolerance. Methods: 

Eligibility criteria include treatment-naïve clear cell mRCC, measurable 

disease, and adequate organ function. Pts will be treated for 4 cycles of 

sunitinib (50 mg 4/2) in the absence of unacceptable toxicity or RECISTdefined 

progression. Pts with � 10% reduction in tumor burden per 

RECIST following 4 cycles will have sunitinib held, with re-staging CT scans 

approximately every 10 weeks thereafter to assess tumor burden. Sunitinib 

will be re-initiated in those patients with an increase in tumor burden of 

10% or greater (per RECIST) compared to the scan obtained just prior to 

holding sunitinib. Pts who have RECIST tumor burden reduction of 10% or 

more compared to scans at the start of the most recent treatment period will 

again have sunitinib held. This intermittent sunitinib dosing will continue 

until RECIST-defined disease progression while on sunitinib. Patients not 

initially achieving at least a 10% reduction in tumor burden will continue 

sunitinib. The primary objective is the feasibility of intermittent sunitinib, 

defined as the proportion of patients eligible for and who undergo 

intermittent therapy. The alternative hypothesis is a feasibility rate of � 

80% vs. the null hypothesis of � 50%. Thirty pts provides 80% power 

based on a two-sided exact test with a .05 type I error. Secondary endpoints 

include PFS and toxicity. Twenty five of planned 30 patients have been 

enrolled. 

TPS4683 General Poster Session (Board #15B), Sun, 8:00 AM-12:00 PM 

Phase III trial of dovitinib (TKI258) versus sorafenib in patients with 

metastatic renal cell carcinoma after failure of anti-angiogenic (VEGFtargeted 

and mTOR inhibitor) therapies. Presenting Author: Robert John 

Motzer, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Standard first- and second-line treatments in metastatic renal 

cell carcinoma (mRCC) target the vascular endothelial growth factor (VEGF) 

and mammalian target of rapamycin (mTOR) signaling pathways. However, 

signaling through other pathways, including the fibroblast growth factor 

receptor (FGFR) pathway, may account for tumor resistance to these 

standard therapies. Dovitinib (TKI258) is an oral FGF, VEGF, and plateletderived 

growth factor (PDGF) receptor tyrosine kinase inhibitor, with IC50 values of � 10 nM. In a phase II study of 59 RCC patients, many of whom 

had failed prior VEGF-targeted and mTOR inhibitor therapies, dovitinib 

(500 mg/day on a 5-days-on/2-days-off schedule) was well tolerated and 

demonstrated promising anti-tumor effects, with progression-free survival 

(PFS) of 5.5 months (Angevin et al, ASCO 2011). Methods: Approximately 

550 patients from over 26 countries will be randomized 1:1 in this 

multicenter, open-label, randomized phase III trial (NCT01223027) to 

receive dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) or 

sorafenib (400 mg twice daily). Eligible mRCC patients must have failed 1 

VEGF-targeted therapy and 1 mTOR inhibitor (disease progression on or 

within 6 months of stopping the prior treatment). Patients will remain on 

study until disease progression, unacceptable toxicity, death, or discontinuation 

for any other reason. No treatment crossover is planned. The primary 

endpoint is PFS as determined by central radiology assessment according 

to RECIST v1.1, with evaluations performed every 8 weeks. Secondary 

endpoints include overall survival, overall response rate, safety, patientreported 

outcomes, and pharmacokinetics. The pharmacodynamic effects 

of dovitinib on plasma/serum biomarkers will also be explored. The data 

monitoring committee last reviewed the trial on 20 December 2011 and 

recommended that the trial continue as planned. This is the first third-line 

randomized clinical trial in mRCC to evaluate a multitargeted inhibitor of 

FGFR. 


Prospective assessment of circulating endothelial cells (CECs) as early 

markers of clear cell renal cell carcinoma (CCRCC) progression in first line 

setting: The Circles study (SOGUG 2011-01). Presenting Author: Daniel E. 

Castellano, University Hospital 12 de Octubre, Madrid, Spain 

Background: Since the identification of Von Hippel Lindau (VHL) gene 

mutations as a critical step in the development of most Clear Cell Renal Cell 

Carcinomas (CCRCC), neoangionesis inhibition has become a cornerstone 

in their treatment. Despite the proven efficacy of antiangiogenic drugs, 

most patients will not achieve partial response by RECIST criteria. Thus, to 

accurately determine tumor progression is a challenging question incompletely 

answered by traditional radiological assessment. In recent years 

CECs counts have been proposed as surrogate biomarkers of angiogenesis 

that could be used for monitoring tumor evolution while on targeted 

therapies. We aim to figure out if CECs elevations could anticipate 

radiological progression in CCRCC. Methods: An observational prospective 

study is being performed in 10 institutions members of the Spanish 

Oncology Genitourinary group (SOGUG). Patients older than 18 years with 

histologically proven CCRCC on first line treatment with any targeted drug 

who have not progressed after 3 months of therapy are considered elegible. 

Recruitment begun on August the 1st 2011 and 15 of the 75 scheduled 

patients have been included so far. CECs are periodically collected in 

peripheral blood every 6 weeks for 15 months or radiological tumor 

progression, whatever occurs first. Median CEC values will be calculated 

and stated by descriptive statistics (Cellsearch, VERIDEX). To explore the 

evolution of CECs counts along treatment a linear model will be constructed. 

An association among CECs counts changes and time to progression 

will be analyzed with Cox model. 



A phase II biomarker assessment of tivozanib in oncology (BATON) trial in 

patients (pts) with advanced renal cell carcinoma (RCC). Presenting 

Author: Thomas E. Hutson, Texas Oncology–Baylor Charles A. Sammons 

Cancer Center, Dallas, TX 

Background: Tivozanib is an oral, potent, and selective tyrosine kinase 

inhibitor targeting all three vascular endothelial growth factor (VEGF) 

receptors; it showed efficacy and tolerability in a Phase II trial in pts with 

advanced RCC (Nosov et al. JCO 2011;29[18S]:4550). Preclinical studies 

have identified a 42-gene tivozanib resistance signature (Jie et al. EORTC- 

NCI-AACR 2010; abstract 608) that may be predictive of tivozanib 

sensitivity. This study (NCT01297244) is designed to evaluate these 

potential biomarkers for tivozanib activity in pts with advanced RCC. 

Methods: Pts with advanced RCC (stratified as clear cell or non-clear cell) 

who underwent nephrectomy and received �1 prior systemic treatment (no 

prior VEGF- or mammalian target of rapamycin–targeted therapy) entered 

this open-label, single-arm study conducted in the United States and 

Canada beginning January 2011. Pts receive tivozanib 1.5 mg/d orally (3 

weeks on, 1 week off schedule). Primary objectives include correlation of 

biomarkers in blood (e.g. VEGF, hepatocyte growth factor [HGF]) and tumor 

tissue (e.g. CD68, hypoxia-induced factor, VEGF, HGF, and gene expression 

profiles) with clinical activity and/or treatment-related toxicity, and 

6-month progression-free survival (PFS) rate. Secondary objectives include 

overall response rate (ORR), PFS, safety and tolerability, and pharmacokinetics. 

Contingency table methods will be used for biomarker correlation 

with ORR, and Cox proportional-hazards regression for correlation with 

PFS. Sample size (100 pts) is estimated based on clinical considerations 

and the precision with which 6-month PFS can be estimated. Biomarkers 

were defined at study outset; the requirement of prior nephrectomy ensured 

availability of primary tumors as controls for correlative analysis. As of 

January 2012, the study completed enrollment of 100 pts, demonstrating 

a large number of pts can be enrolled to a biomarker study with well-defined 

candidate genes and critical inclusion criteria to facilitate compliance. 

Tivozanib biomarkers evaluated in this study, along with those evaluated in 

other solid tumors, may play an important role in optimizing patient 

selection. 


Phase II study of dovitinib in first-line metastatic or nonresectable primary 

adrenocortical carcinoma (ACC): SOGUG study 2011-03. Presenting 

Author: Paula Jimenez, Hospital Universitario Central de Asturias, Oviedo, 

Spain 

Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, 

among other tyrosin kinases, the fibroblast growth factor receptor (FGFR). 

Since this pathway has been proposed to play a major role in ACC, we aim to 

test the clinical efficacy of dovitinib in this tumor. Methods: An open label 

phase II trial has been designed in patients with advanced non-resectable 

ACC. The objective will be to obtain at least a 15% response rate according 

to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 

patients would need to be included in the first stage to demonstrate a 

treatment efficacy of at least 15%. Sample size calculation was done based 

on the following parameters, probability of Type I error � � 0.05, power of 

the test (1 - �) � 0.8. Main inclusion criteria are advanced non-resectable 

disease and no prior therapy (other than mitotane). Dovitinib scheduled 

dose matches currently employed standard in the drug development 

(500mg daily for 5 days then 2 days off) for 6 months. If clinical benefit is 

obtained longer treatment will be allowed for particular patients. Since this 

is an extremely unfrequent disease 7 institutions, members of the SOGUG 

(Spanish Oncology Genitourinary Group), will participate. The active 

support of a big collaborative group will guarantee candidate patients to be 

refereed to such institutions. Starting January 26th 2012 recruitment is 

scheduled to last around 12 months. A translational research, including 

whole exome analysis, will be performed in order to improve our scarce 

knowledge of ACC. 


323s 


Phase I/II study of high-dose interleukin 2, aldesleukin, in combination 

with the histone deacetylase inhibitor entinostat in patients with metastatic 

renal cell carcinoma. Presenting Author: Roberto Pili, Roswell Park Cancer 

Institute, Buffalo, NY 

Background: Immunosuppressive factors such as regulatory T cells (Tregs) 

limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors 

have been shown to have anti-tumor activity in different malignancies 

and to induce immuno-modulatory effects. We have previously reported 

that a class I specific HDAC inhibitor, entinostat, has synergistic anti-tumor 

effect in combination with high dose interleukin-2 (IL-2) in a renal cell 

carcinoma model (Kato Y et al Clinical Cancer Res 2007). Our group has 

also recently showed that low dose entinostat induces STAT3 acetylation, 

down-regulates Foxp3 expression in Tregs, and blocks Tregs suppressive 

function without affecting T effector cells (Shen Li et al PLoSONE 2012). 

Methods: Based on these preclinical evidences we have initiated a Phase 

I/II clinical study with entinostat and high dose IL-2 in patients with 

metastatic renal cell carcinoma. The primary objective of the study is to 

evaluate the safety, tolerability and efficacy of this combination strategy. 

The main eligibility criteria are clear cell histology, no prior treatments and 

being fit to receive high dose IL-2. The Phase I portion consists of two dose 

levels of entinostat (3 and 5 mg) and a fixed standard dose of IL-2 

(600,000 units/Kg every 8 hrs.) according to a 3�3 design. The sample 

size of 36 patients in the Phase II portion is powered to detect an increase 

in objective response rate from 20% to 40% as compared to historical data 

with high dose IL-2 alone. Correlative studies include assessment of CD4�, 

CD8�, CD4�/Foxp3, NK cells in tumor and blood samples by immunohistochemistry 

and FACS analysis, and tumor metabolism by FDG PET. We are 

also exploring the relationship between entinostat exposure with pharmacodynamic 

endpoints. To date dose level one has been completed without 

DLT. Enrollment to dose level two has begun in the Fall 2011. The results 

from this study may confirm the role of entinostat in enhancing the effect of 

IL-2 and may be translated into other combination strategies involving 

immunotherapies. The clinical trial and correlative studies are supported 

by the National Cancer Institute- R21CA137649. 


CA184-043: A randomized, double-blind, phase III trial comparing ipilimumab 

versus placebo following a single dose of radiotherapy (RT) in 

patients (pts) with castration-resistant prostate cancer (CRPC) who have 

received prior treatment with docetaxel (D). Presenting Author: Charles G. 

Drake, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 

University, Baltimore, MD 

Background: Ipilimumab (Ipi), a fully human monoclonal antibody which 

blocks CTLA-4, augments antitumor immune responses. Ipi has shown 

antitumor effects in prostate cancer model systems and clinical activity (via 

prostate-specific antigen [PSA] declines and RECIST response) in Phase 

1/2 investigations in CRPC, with a side effect profile reflective of its 

mechanism of action. Preclinical data suggest that RT given prior to 

CTLA-4 blockade may increase antitumor activity. Methods: In this study, 

pts with CRPC who have progressed during or after D are randomized 1:1 to 

receive either a single dose of bone-directed RT followed by Ipi 10mg/kg, or 

RT followed by placebo. Within 2 days of RT administration (up to 5 lesions 

at 8 Gy on a single day) patients receive their initial dose of Ipi/placebo; 

Ipi/placebo is then given every 3 weeks for a total of 4 doses. Eligible pts 

may continue to receive blinded study drug every 12 weeks until they meet 

treatment stopping criteria, withdraw consent, are lost to follow-up, or 

study closure. The primary endpoint is overall survival (OS). Secondary 

endpoints include progression-free survival, pain response, and safety. The 

study is designed to detect a 3.8 month difference (HR�0.76) in median 

OS with 90% power and 0.05 2-sided type one error. The enrollment goal is 

800 randomized patients, with a single interim analysis for superiority of 

OS planned at 435 events at approximately 33 months from first patient 

first visit (ClinicalTrials.gov identifier: NCT00861614). 

Key inclusion criteria 

Metastatic CRPC 

At least 1 bone metastasis appropriate for RT 

Testosterone 2 prior cytotoxic chemo regimens for CRPC 




What is optimal timing of post prostatectomy radiotherapy? Is adjuvant 

radiotherapy equivalent to early salvage radiotherapy? The “RAVES” phase 

III randomized clinical trial. Presenting Author: Maria Pearse, Auckland 

City Hospital, Auckland, New Zealand 

Background: Three randomised trials have demonstrated a significant 

benefit of adjuvant post prostatectomy radiotherapy in patients with 

positive margins, extra capsular extension or seminal vesicle involvement, 

and it should be regarded as current standard of care. However, adopting 

this approach will expose nearly half of such patients to unnecessary 

radiotherapy and potential treatment morbidity. Salvage radiotherapy, if 

given early, is recognised to be effective. The RAVES trial is designed to 

compare these two approaches, and was developed in collaboration with 

the Trans Tasman Radiation Oncology Group (TROG), Australian and New 

Zealand Urogenital and Prostate Trials Group (ANZUP) and the Urological 

Society of Australia and New Zealand (USANZ). It aims to test the 

hypothesis that active surveillance with early salvage radiotherapy is 

non-inferior to adjuvant radiotherapy with respect to risk of biochemical 

failure (defined as PSA level � 0.40 ng/mL and rising). Methods: Patients 

must have at least one of the following risk factors: positive margins, 

extracapsular extension or seminal vesicle involvement. They must start 

radiotherapy within 4 months of radical prostatectomy (RP) and have an 

undetectable PSA (� 0.10 ng/ml) prior to randomisation. Patients receiving 

androgen deprivation or who have an artificial hip are excluded. Eligible 

patients are randomised to either: Arm 1: Adjuvant RT (64Gy in 32#) 

commenced within 4 months of RP, or Arm 2: Active surveillance with 3 

monthly PSA tests and commencement of early salvage RT (64Gy in 32#) if 

PSA rises � 0.20 ng/ml. Stratification is by seminal vesicle invasion, 

Gleason Score, pre-operative PSA, margin positivity (no/yes) and radiotherapy 

institution. A sample size of 470 patients is required to detect a 

10% non-inferiority margin in the 5-year biochemical failure-free rate 

between the adjuvant and active surveillance arms. As of 31 Jan 2012, 

186 patients have been recruited across 26 centres in Australia and New 

Zealand. A meta analysis with the MRC RADICALS and GETUG-17 trials 

will be prospectively designed to detect a survival difference between the 

two approaches. 

TPS4692^ General Poster Session (Board #16C), Sun, 8:00 AM-12:00 PM 

Comparison of two doses of cabazitaxel plus prednisone in patients (pts) 

with metastatic castration-resistant prostate cancer (mCRPC) previously 

treated with a docetaxel (D)-containing regimen. Presenting Author: Mario 

A. Eisenberger, Sidney Kimmel Comprehensive Cancer Center at Johns 

Hopkins University, James Buchanan Brady Urological Institute, Baltimore, 

MD 

Background: The phase III TROPIC study (NCT00417079) reported a 

significant improvement in overall survival (OS) for cabazitaxel (Cbz) � 

prednisone (P;CbzP) (25 mg/m2 IV Q3W/10 mg PO QD) vs mitoxantrone 

(M) � P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P � 0.0001) in pts 

with mCRPC (also known as hormone-refractory prostate cancer) previously 

treated with a D-containing regimen. CbzP is approved by the FDA, EMA 

and other health authorities for the treatment of pts with mCRPC that has 

progressed after a D-containing regimen. Cbz toxicity is consistent with 

other taxanes; compared with M, more hematologic toxicities are reported 

(primarily Grade 3–4 neutropenia). Phase I/II studies identified 20 and 25 

mg/m2 as recommended doses; 25 mg/m2 was selected for the phase III 

TROPIC study. As pooled data show Grade 3–4 neutropenia incidence is 

lower with Cbz � 25 mg/m2 (61%) vs � 25 mg/m2 (74%), it is of interest to 

assess if reducing the Cbz approved dose in mCRPC lessens hematologic 

toxicity and is non-inferior in terms of efficacy. Methods: PROSELICA 

(NCT01308580) is a randomized, open-label, multinational, phase III 

study comparing 20 mg/m2 and 25 mg/m2 Cbz for efficacy and tolerability. 

Pts with a life expectancy � 6 mos, ECOG PS � 2, histologically/ 

cytologically confirmed metastatic prostate adenocarcinoma resistant to 

hormone therapy and previously treated with a D-containing regimen are 

eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV 

Q3W � P 10 mg PO QD, treated until disease progression, unacceptable 

toxicity or withdrawal of consent (max 10 cycles), and stratified according 

to ECOG PS, measurable disease (yes/no) and region. The primary endpoint 

is OS (non-inferiority design). Secondary endpoints include safety, progression-free 

survival (PCWG2 criteria), PSA and pain progression and response, 

tumor response in pts with measurable disease and health-related 

quality of life. Cbz PK and pharmacogenomics will be assessed in pt 

subgroups. Planned enrollment is 1,200 pts. Study start was in May 2011; 

as of Jan 2012, 270 pts had been enrolled. The first DMC meeting 

recommended continuing the study without change. 


CA184-095: A randomized, double-blind, phase III trial to compare the 

efficacy of ipilimumab versus placebo in asymptomatic or minimally 

symptomatic patients (pts) with metastatic chemotherapy-naive castrationresistant 

prostate cancer (CRPC). Presenting Author: Tomasz M. Beer, 

Oregon Health & Science University Knight Cancer Institute, Portland, OR 

Background: Ipilimumab (Ipi), a fully human monoclonal antibody which 

blocks CTLA-4, augments antitumor immune responses. Ipi has demonstrated 

overall survival (OS) benefit in two Phase 3 trials for advanced 

melanoma, with side effects that were managed using product-specific 

treatment guidelines. In addition, in Phase 1/2 trials in metastatic CRPC, 

Ipi has shown clinical activity (as measured by prostate-specific antigen 

[PSA] declines and RECIST response) with no unexpected toxicities. While 

docetaxel is standard therapy for metastatic CRPC, its use may be delayed 

until pts develop symptoms. As such, this global (~150 sites in 25 

countries) Phase 3 study (ClinicalTrials.gov identifier: NCT01057810) is 

evaluating Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or 

minimally symptomatic CRPC without visceral metastases. Methods: The 

primary endpoint is OS; secondary endpoints include progression-free 

survival, time to pain progression, and time to non-hormonal systemic 

therapy. The study is designed to detect a 9.3 month difference (HR�0.7) 

in OS with 90% power and 0.05 two-sided significance. Pts are randomized 

at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or 

placebo, respectively, as induction therapy. Eligible pts will continue to 

receive maintenance therapy of blinded study drug every 12 weeks until 

treatment stopping criteria are met, withdrawal of consent, or study 

closure. The accrual goal is 600 pts randomized. 

Inclusion criteria 

Metastatic CRPC 

Asymptomatic or minimally symptomatic 

Progression during prior hormonal therapy 

Discontinuation of anti-androgens 

Testosterone < 50 ng/dl 

ECOG Performance Status 0-1 

Exclusion criteria 

Liver, lung, or brain metastases 

Prior immunotherapy or chemotherapy for metastatic CRPC 

Autoimmune disease 

HIV, Hep B, or Hep C infection 

Pelvic targeted radiotherapy within 3 months of study 


A phase III, randomized, double-blind, multicenter trial comparing the 

investigational agent orteronel (TAK-700) plus prednisone (P) with placebo 

plus P in patients with metastatic castration-resistant prostate cancer 

(mCRPC) that has progressed during or following docetaxel-based therapy. 

Presenting Author: Robert Dreicer, Cleveland Clinic, Cleveland, OH 

Background: The investigational agent orteronel is a selective inhibitor of 

17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a 

phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific 

antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent 

with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 

abst 98). Docetaxel-based chemotherapy is an effective but noncurative 

therapy for mCRPC that has progressed on hormonal therapy; new therapeutic 

options are needed. Methods: This double-blind, multicenter study is 

assessing orteronel � P vs placebo � P in men with mCRPC 

(NCT01193257; C21005). Patients must have evidence of disease progression 

during or after receiving a total of �360 mg/m2 docetaxel within a 

6-mo period. Patients who are clearly intolerant to docetaxel or have 

progressive disease before receiving �360 mg/m2 are also eligible if they 

have received at least 225 mg/m2 of docetaxel within a 6-mo period and 

meet the other inclusion criteria. Other eligibility criteria include radiographically 

documented metastatic disease and baseline testosterone �50 ng/dL 

following surgical or medical castration. Prior adrenal-targeted therapies 

are not permitted. Men may have opioid-requiring bone pain. The planned 

sample size is 1083; men will be randomized 2:1 to receive orteronel 400 

mg twice daily (BID) plus P5mgBIDorplacebo plus P. The primary 

endpoint is overall survival; other endpoints are radiographic progressionfree 

survival, PSA decrease of �50% at 12 wks, pain response at 12 wks, 

safety, time to PSA progression, objective response by RECIST, circulating 

tumor cell and endocrine marker changes, and patient-reported outcomes. 

After disease progression, men may continue to receive study drug. Tumor 

specimens will be analyzed for biomarkers that may predict orteronel 

antitumor activity, including the TMPRSS2:ERG fusion gene. The same 

regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve 

men with mCRPC (NCT01193244). 



A phase I/IIa study of the safety and efficacy of radium-223 chloride 

(Ra-223) with docetaxel (D) for castration-resistant prostate cancer (CRPC) 

patients with bone metastases. Presenting Author: Michael J. Morris, 


Background: Ra-223is a first-in-class alpha-pharmaceutical that targets 

bone metastases (mets) with high energy alpha-particles of short range (� 

100 �m). In the ALSYMPCA trial, Ra-223 plus best standard of care (BSC) 

significantly improved OS vs placebo plus BSC in CRPC patients (pts) with 

bone mets (Parker et al. ECCO/ESMO 2011), and was shown to have an 

excellent safety profile. Since D is an approved chemotherapy with 

demonstrated survival benefit for pts progressing after castrating hormone 

therapy, it is logical to explore combining Ra-223 plus D in pts with CRPC 

and bone mets. This study is being conducted in the Prostate Cancer 

Clinical Trials Consortium with an aim to establish the safe dose of Ra-223 

and D when used in combination in pts with bone mets with CRPC. 

Methods: This ongoing phase I/IIa trial (NCT01106352) is enrolling pts 

with bone mets from CRPC intended for treatment with D. D naïve pts are 

preferred, although up to 10 previous infusions of D are acceptable if D was 

well tolerated and the patient is in good condition and fulfills all eligibility 

criteria at study entry. Phase I dose-escalation study: minimum of 9 pts 

(max. 18 pts) will be included if no dose limiting toxicity (DLT) is observed. 

Dose escalation will follow a ‘3�3’ design, with no intra-patient dose 

escalation or overlapping of cohorts permitted. Ra-223 doses are 25 or 50 

kBq/kg, with number of Ra-223 injections (inj) (2, 4, 5, or 10) and interval 

between inj (3 or 6 wks) varying by escalation schema; D doses are 60 or 75 

mg/m2 q3wk. DLT will be assessed when 6 wks post-inj safety data are 

available after 1st Ra-223 �D inj. Phase IIa open-label expanded safety 

study: pts will be randomized 2:1 to the recommended dose of Ra-223 to 

be used with D or to treatment with D alone (approx. 42 pts will be 

included). Primary endpoint is to assess safety of combining Ra-223 with 

D. Exploratory efficacy endpoints for the open-label expanded safety 

portion of the study include change in disease-related biomarkers, time to 

1st radiological or clinical progression, CTC and pain assessment. Enrollment 

in dose-escalation portion of the study is complete; expanded safety 

cohort to begin enrolling in March 2012. 

TPS4696^ General Poster Session (Board #16G), Sun, 8:00 AM-12:00 PM 

First-line use of cabazitaxel in chemotherapy-naive patients with metastatic 

castration-resistant prostate cancer (mCRPC): A three-arm study in 

comparison with docetaxel. Presenting Author: Stephane Oudard, Georges 

Pompidou European Hospital, Paris, France 

Background: Docetaxel (D) in combination with prednisone (P) as first-line 

(1L) chemotherapy in patients (pts) with mCRPC is the current standard of 

care. However, treatment is not curative and D-resistant disease typically 

develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and 

-resistant tumor models. Clinical activity of Cbz plus P (CbzP) was 

demonstrated in the Phase III TROPIC study in mCRPC pts previously 

treated with a D-containing regimen; CbzP showed a significant overall 

survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs 

12.7 months; HR 0.70; P � 0.0001). Therefore, it is of interest to 

determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. 

Methods: The phase III FIRSTANA study (NCT01308567) is a randomized, 

open-label, multinational trial in 1L mCRPC pts, designed to compare the 

efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm 

B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given 

concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable 

disease (yes/no) and region (depending on availability of Cbz as 2L). Pts 

with ECOG PS � 2, histologically/cytologically confirmed metastatic 

prostate adenocarcinoma, with no prior chemotherapy and with disease 

progression following medical or surgical castration are eligible. The 

primary endpoint is OS. Secondary endpoints include progression-free 

survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable 

disease (RECIST 1.1), PSA response and PSA PFS, pain response and 

pain PFS, time to occurrence of any skeletal-related events, safety profile 

and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics 

will be assessed in pt subgroups. Pts will be treated until 

progression, unacceptable toxicity or pt request. Planned enrollment is 

1,170 pts; study size was calculated to achieve 90% power for OS. Study 

start was in May 2011; at January 2012, 219 pts were enrolled. The first 

DMC meeting recommended continuing the study without change. 


325s 


A randomized, open-label, phase II study of MDV3100 alone or in 

combination with leuprolide and dutasteride as neoadjuvant therapy to 

prostatectomy in intermediate and high-risk prostate cancer. Presenting 

Author: Robert B. Montgomery, University of Washington School of 

Medicine, Seattle, WA 

Background: MDV3100 is a potent androgen receptor (AR) signaling 

inhibitor (ARSI) that inhibits AR signaling via three mechanisms: inhibition 

of androgen binding to AR, inhibition of AR nuclear translocation, and 

inhibition of nuclear AR-DNA binding. In vivo, MDV3100 induces significant 

prostate cancer apoptosis, an effect not seen with anti-androgens. To 

date, the use of neoadjuvant androgen deprivation therapy has not led to an 

improvement in time to PSA progression (Soloway 2002; Aus 2002). While 

serum androgens may be suppressed using luteinizing hormone-releasing 

hormone agonists, intratumoral levels of androgens remain, driving continued 

AR signaling and prostate cancer survival. More effective inhibition of 

AR signaling may improve local and systemic disease control. Methods: 

MDV3100-07 will assess the effect of 6 mos of neoadjuvant AR blockade 

with AR inhibition alone (MDV3100) or in combination with maximal 

suppression of androgens (MDV3100 �leuprolide [L] � dutasteride [D]). 

Eligible patients will have treatment-naive localized prostate cancer and be 

candidates for radical prostatectomy. Patients must have either PSA � 10 

ng/mL or Gleason score � 7(4� 3) with �3 cores containing tumor. 

Patients with evidence of metastatic/nodal disease are excluded. All 

patients receive MDV3100 (160 mg/d PO); those randomized to 

MDV3100�L�D therapy also receive L (22.5mg IM q3m) and D (0.5 

mg/day PO). Serum/tumor androgen levels will be serially assessed. Tissue 

from the diagnostic and prostatectomy specimens will be evaluated for 

androgen levels, AR signaling profiles, and selected markers of apoptosis 

and mitotic indices. The primary efficacy endpoint is pathological complete 

response (pCR) rate at time of radical prostatectomy. For each arm, the 

percent of patients who achieve a pCR will be compared to the percent pCR 

in patients treated with neoadjuvant leuprolide, estimated to be 5% in a 

mixed low-to-intermediate risk population. Target Accrual: 40 pts will be 

randomized 1:1 to MDV3100 or MDV3100�L�D therapy. Keywords: 

MDV3100, prostate cancer, androgen receptor, anti-androgen, Phase 2, 

neoadjuvant. 


A phase II study of the androgen signaling inhibitor ARN-509 in patients 

with castration-resistant prostate cancer (CRPC). Presenting Author: Dana 

E. Rathkopf, Sidney Kimmel Center for Prostate and Urologic Cancers, 


Background: ARN-509 is a novel small molecule androgen signaling 

inhibitor that impairs AR nuclear translocation and binding to DNA, 

inhibiting tumor growth and promoting apoptosis, with no partial agonist 

activity. Preclinical data suggests that the maximal therapeutic index of 

ARN-509 can be achieved at low steady state plasma levels with minimal 

toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose escalation 

study of ARN-509 in patients with progressive CRPC with and without prior 

chemotherapy was completed in January 2012. The recommended Phase 2 

dose of 240 mg was determined based on safety, PSA kinetics, and 

pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU 

ASCO, 2012). Methods: The primary objective of this Phase 2 study is to 

determine the PSA response at 12 weeks according to Prostate Cancer 

Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion 

cohorts will enroll a total of 80-90 patients for treatment with 240 mg 

continuous oral ARN-509 daily. These cohorts include: 1) non-metastatic 

treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic 

(m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone 

mCRPC (10-20 patients). The effect of food on the PK of ARN-509 and the 

effect of ARN-509 on ventricular repolarization will also be evaluated. 

Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon 

Pharmaceuticals. NCT01171898. 



TPS4698^ General Poster Session (Board #17A), Sun, 8:00 AM-12:00 PM 

TERRAIN: A randomized, double-blind, phase II study comparing MDV3100 

with bicalutamide (Bic) in men with metastatic castrate-resistant prostate 

cancer (CRPC). Presenting Author: Edwina S. Baskin-Bey, Astellas Pharma 

Europe, Ltd., Staines, United Kingdom 

Background: MDV3100 is a novel androgen receptor (AR) signaling inhibitor 

(ARSI) in clinical development for treatment of prostate cancer (PCa). 

Compared with Bic in nonclinical CRPC models, MDV3100 showed higher 

affinity AR binding, inhibited nuclear translocation and AR-DNA binding, 

showed no evidence of AR agonism, and caused tumor regression in 

Bic-resistant xenografts. MDV3100 has shown antitumor activity in men 

with advanced PCa. We present the study design of a trial comparing 

MDV3100 and Bic in men with progressive metastatic PCa. Methods: 

Multinational study (Table) with planned enrollment of 370 patients 

(randomized 1:1 to MDV3100 160 mg/d or Bic 50 mg/d). Inclusion criteria 

include metastatic (�2 bone lesions or soft tissue disease at screening) 

progressive CRPC (�3 rising prostate-specific antigen [PSA] levels or new 

bone/soft tissue disease), ongoing stable gonadotropin-releasing hormone 

(GnRH) analog therapy or surgical castration (serum testosterone �50 

ng/dL), Eastern Cooperative Oncology Group performance status 0–1, and 

life expectancy �1 year. Exclusion criteria include previous chemotherapy, 

current/prior antiandrogens (except if administered for �12 wk and 

discontinued no less than 6 mo before study). Patients will be stratified by 

time of bilateral orchiectomy or GnRH analog initiation (before/after 

diagnosis of metastases) and will receive treatment until occurrence of 

radiographic progression/skeletal-related event, start of new antineoplastic 

therapy, or development of an adverse event requiring discontinuation. 

Results: The primary endpoint is progression-free survival; secondary 

endpoints are safety, PSA response, and time to PSA progression. Exploratory 

endpoints include circulating tumor cell conversion rate and quality of 

life. Patients are currently enrolling. Conclusions: This ongoing, head-tohead, 

phase II trial is the first to prospectively assess whether MDV3100 

can provide improved antitumor effects vs Bic in men with metastatic 

CRPC. 

Country Sites, n 

Canada 4 

US-East 12 

US-Midwest 13 

US-South 11 

US-West 10 

France 9 

Germany 6 

Romania 3 

UK 5 

Belgium 5 


Targeting castration resistant prostate cancer (CRPC) with autologous 

PSMA-directed CAR� T cells. Presenting Author: Susan F. Slovin, Sidney 

Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan- 


Background: Based on our preclinical animal models, we initiated a phase I 

dose-escalating study to assess safety, dose requirement and targeting 

efficiency of genetically directed autologous human T cells targeted to 

Prostate Specific Membrane Antigen (PSMA). Our approach is based on the 

infusion of autologous PSMA-targeted T cells utilizing the P28z second 

generation chimeric antigen receptor (CAR) in patients (pts) with metastatic 

CRPC, following iv cyclophosphamide (Cy) (trial NCT01140373). 

For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is 

co-expressed with the P28z receptor, and renders T cells sensitive to 

ganciclovir for immediate T cell elimination if needed. The expression of 

hsvtk enables PET imaging using radiolabeled FIAU to localize adoptively 

transferred T cells. The aims of the trial are to assess: (1) safety of 

PSMA-targeted T cells; (2) biologic and anti-tumor effects; (3) T cell 

persistence at tumor site; and (4) immune response. Methods: Autologous T 

cells are activated from a leukapheresis product using anti-CD3/CD28 

Dynabeads. Release criteria include mean vector copy number by Q-PCR 

and vector identity by Southern blot, absence of Replication Competent 

Retrovirus and residual Dynabeads. Pts will be treated at 3 dose levels from 

107 to 108 CAR� T cells/kg. Four patients have been enrolled; 3 have been 

treated with 300mg/m2 of Cy one day before infusion of 107 CAR� T 

cells/kg. Pts underwent baseline and post treatment CT, bone and PET 

scans. Pts are followed weekly, then monthly with blood work including 

immune and vector sequence monitoring. Results: The first 3 pts within the 

first cohort were successfully treated without toxicity. Two had stable 

disease for greater than 6 months with the third patient having disease 

progression. There were no acute adverse events. Conclusion: We have 

established an ex vivo transduction, expansion and therapeutic protocol for 

the generation and testing of safe, clinical-grade, PSMA targeted T cells. 

Pts enrolled at the next dose level of 3x107CAR� T cells/kg will be 

assessed as described and by imaging the transduced T cell population 

using 18F-FIAU as a radiotracer. The data pertaining to the planned T cell 

imaging will be presented as well. 


Prospect: A randomized, double-blind, phase III efficacy trial of PROST- 

VAC. Presenting Author: Olga Bandman, BN ImmunoTherapeutics, Mountain 

View, CA 

Background: PROSTVAC is a candidate cancer vaccine comprised of two 

recombinant poxviral vectors: vaccinia (V) and fowlpox (F), each with 

insertions of four human genes: PSA and three costimulatory molecules 

(TRICOM) - LFA-3, B7.1 and ICAM-1. This off the shelf vaccine demonstrated 

a statistically significant overall survival (OS) benefit of 8.5 months 

while displaying a favorable side effect profile in patients (pts) with 

asymptomatic to minimally symptomatic prostate cancer (mCRPC) in a 

randomized, placebo –controlled 122-pt Phase II trial. Data from this 

Phase II trial supported the design of a Phase III protocol that will rigorously 

test the hypothesis of OS benefit, as well as expand our understanding of 

immune system response to cancer vaccines. Methods: 1200 pts will be 

randomized in a double-blind fashion to three arms: PROSTVAC, 

PROSTVAC�GM-CSF, or Placebo, at 1:1:1 ratio. A five-month treatment 

regimen will include a priming vaccination with PROSTVAC-V, and six 

booster vaccinations with PROSTVAC-F. Eligible pts will have asymptomatic 

or minimally symptomatic mCRPC, and progression despite androgen 

ablation and be chemotherapy-naïve. Pts with rapidly progressing disease 

will be excluded, as well as pts with risk factors for developing vacciniaassociated 

complications. The projected trial size is 400 pts per arm for at 

least 85% power. Primary endpoint is OS. The final analyses will be 

event-driven and will compare each active arm independently with placebo. 

Pts will be followed for 12 months after the projected number of events in 

each arm is realized. Secondary endpoint is proportion of event-free pts at 6 

months compared to placebo. A number of exploratory endpoints are 

planned, including immune response to immunizing antigen, non-vaccinecontained 

prostate antigens, tumor-associated antigens; changes in baseline 

biomarker levels and CTC levels, as well as characterization of T cell 

subpopulations. The thorough immune monitoring program would provide 

basis for future studies on the effects of cancer immunotherapy on immune 

system and facilitate search for potential biomarkers of such effects. The 

trial is currently open for enrollment. ClinicalTrials.gov registry number: 

NCT00450463. 


Randomized phase II clinical trial to assess MUC1 specific immune 

response to L-BLP25 vaccine in addition to standard therapy in newly 

diagnosed high-risk prostate cancer. Presenting Author: Nishith Singh, 

Laboratory of Tumor Immunology and Biology and Medical Oncology 

Branch, National Cancer Institute, Bethesda, MD 

Background: In high-risk prostate cancer, radiation therapy (RT) � androgen 

deprivation therapy (ADT) improve survival. Nonetheless, 10-year 

disease specific mortality is about 25%. L-BLP25 is a cancer vaccine 

containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may 

enhance immune targeting of cells that express MUC1 (e.g. prostate 

cancer). In murine models, RT synergizes with vaccine-induced anti-cancer 

immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular 

Fas and co-stimulatory/adhesion molecules). ADT augments T-cell 

trafficking to prostate. Immune response to combining the three (L-BLP25 

� RT � ADT) is not known. The current trial intends to study this immune 

response to L-BLP25 � RT � ADT and compare it to RT�ADT alone. Using 

ELISPOT, endo-rectal MRI and serial prostate biopsies, this trial was 

designed to correlate systemic immune response with changes in tumor 

imaging and/or tumor microenvironment after treatment with L-BLP25. 

This trial may provide insight into immune response biomarkers that are 

most appropriate in this setting. Methods: A randomized (1:1), open-label, 

phase II trial of 42 pts is planned. Eligibility: Adult males with newly 

diagnosed high-risk prostate cancer (T3 or Gleason � 8 or seminal vesicle 

involvement or N1 or PSA�20) and HLA-A2/A3 positivity (to allow for 

ELISPOT analysis). The vaccine arm will receive RT � 2-year ADT � 

L-BLP25. Standard arm will receive RT � 2-year ADT. L-BLP25 vaccine 

schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6 weekly X 4 

starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases 

suppressor T-cells) will be given 3 days before L-BLP25 to enhance 

immune response in the vaccine arm. The impact of L-BLP25 � RT�ADT 

on MUC-1-specific systemic immune response will be determined using 

interval peripheral blood ELISPOT assays. Endo-rectal coil MRI will be 

done before and after treatment to study prostate signal changes for 

correlative and predictive analysis. MRI-UltraSound guided lesion-targeted 

serial prostate biopsies will be obtained to assess immune response in 

tumor microenvironment. Two pts have been enrolled. 



Randomized phase III study of erlotinib versus observation in patients with 

no evidence of disease progression after first-line platin-based chemotherapy 

for ovarian carcinoma: A GCIG and EORTC-GCG study. Presenting 

Author: Ignace B. Vergote, University Hospital Leuven and KU Leuven, 

Leuven, Belgium 







LBA5002^ Oral Abstract Session, Sat, 3:00 PM-6:00 PM 

AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus 

chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer 

(OC). Presenting Author: Eric Pujade-Lauraine, GINECO and Université 

Paris Descartes, Paris, France 








327s 


Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance 

treatment in patients (pts) with platinum-sensitive recurrent serous 

ovarian cancer (PSR SOC): A randomized, open-label phase II study. 

Presenting Author: Amit M. Oza, Princess Margaret Hospital, Toronto, ON, 

Canada 

Background: The oral PARP inhibitor olaparib has shown antitumor activity 

in pts with SOC. Our multicenter study compared the efficacy of (Arm A) 

olaparib capsules plus P/C for 6 cycles then maintenance olaparib 

monotherapy vs (Arm B) P/C alone for 6 cycles and no further therapy in pts 

with PSR SOC (NCT01081951). Methods: Pts received 6 x 21-day(d) 

cycles of olaparib (200 mg bid, d1–10/21) � P (175 mg/m2 iv, d1) � C 

(AUC4 iv, d1), then olaparib monotherapy as maintenance (400 mg bid, 

continuous) (Arm A), or 6 x 21d cycles of P (175 mg/m2 iv, d1) � C (AUC6 

iv, d1) then no further therapy (Arm B), until progression. Randomization 

(1:1) was stratified by number of platinum treatments and platinum-free 

interval. Primary endpoint: progression-free survival (PFS) by central review 

(RECIST 1.1). Secondary endpoints: overall survival (OS), objective response 

rate (ORR), safety. Archival tissue was collected where available for 

analysis of biomarker correlation. Results: Of 162 pts randomized (n�81 

per arm), 156 received treatment (Arm A, n�81; Arm B, n�75) and 121 

began the maintenance/no further therapy phase (Arm A, n�66; Arm B, 

n�55). Olaparib � P/C (AUC4) followed by maintenance olaparib showed a 

significant improvement in PFS vs P/C (AUC6) alone (HR � 0.51, 95% CI 

0.34, 0.77; P�0.0012; median � 12.2 vs 9.6 months). OS data are 

immature (total events: 14%). ORR was similar for Arm A and Arm B (64 vs 

58%). Most common AEs during the combination phase were alopecia (74 

vs 59%), nausea (69 vs 57%) and fatigue (64 vs 57%) for Arm A vs Arm B, 

respectively. Pts with grade �3 AEs (65 vs 57%), serious AEs (SAEs: 15 vs 

21%) and AEs leading to treatment discontinuation (19 vs 16%) were 

similar for Arm A vs Arm B. Most common AEs during maintenance/no 

further therapy were nausea (50 vs 6%) and vomiting (29 vs 7%). 29 vs 

16% of pts had grade �3 AEs, 9 vs 7% had SAEs and 8% vs N/A 

discontinued due to AEs in the olaparib vs no treatment arms, respectively. 

There were no fatal AEs. Conclusions: In pts with PSR SOC, olaparib plus 

P/C (AUC4) followed by olaparib 400 mg bid monotherapy maintenance 

treatment resulted in a significant improvement in PFS vs P/C (AUC6) 

alone. 


Long-term follow-up of a randomized trial comparing conventional paclitaxel 

and carboplatin with dose-dense weekly paclitaxel and carboplatin in 

women with advanced epithelial ovarian, fallopian tube, or primary peritoneal 

cancer: JGOG 3016 trial. Presenting Author: Noriyuki Katsumata, 

Nippon Medical School Musashikosugi Hospital, Kanagawa, Japan 

Background: The primary analysis of the JGOG3016 trial (Lancet 2009, 

374:1331) showed that dose-dense weekly administration with paclitaxel 

and carboplatin (dd-TC) demonstrated statistically significant efficiency 

over tri-weekly administration withTC (c-TC) as first-line chemotherapy in 

patients with stage II-IV epithelial ovarian, fallopian tube or primary 

peritoneal cancer. We report the long-term follow-up results on progressionfree 

survival (PFS) and overall survival (OS). Methods: Patients with stage II 

to IV ovarian cancer were randomly assigned to receive c-TC (carboplatin 

AUC 6 and paclitaxel 180 mg/m2 on day 1) or dd-TC (carboplatin AUC 6 on 

day 1 and paclitaxel 80 mg/m2 on day 1, 8, 15). The treatments were 

repeated every 3 weeks for six cycles; in responding patients, additional 

three cycles were administered. Results: The analysis included eligible 631 

patients. At 6.4 years of median follow-up, there continues to be a highly 

statistically significant improvement in median PFS in favor of the dd-TC 

group compared with the c-TC group (28.1 vs. 17.5 months, hazard ratio 

[HR] 0.75, 95% CI, 0.62-0.91; P�0.0037). Median survival has not yet 

been reached in the dd-TC group, and OS at 5 years was higher in the dd-TC 

group than the c-TC group (58.6% vs. 51.0%, HR 0.79, 95% CI, 

0.63-0.99; P �0.0448). Conclusions: The dd-TC improves long-term PFS 

and OS in patients with advanced epithelial ovarian cancer. 


328s Gynecologic Cancer 


Prospective assessment of cost, morbidity, and survival associated with 

lymphadenectomy in low-risk endometrial cancer. Presenting Author: Sean 

Christopher Dowdy, Mayo Clinic, Rochester, MN 

Background: Since 1999, patients with low-risk endometrial cancer (EC) as 

defined by the Mayo criteria have preferably not undergone lymphadenectomy 

(LND) at our institution. We assess survival, sites of recurrence, 

morbidity, and cost per up-staged case in this low-risk cohort. Methods: 

Consecutive patients with Mayo-defined low-risk EC managed without 

(non-LND) and with LND were compared. Cause-specific survival (CSS) was 

estimated using the Kaplan-Meier method and compared using the 

log-rank test. 30-day cost analyses were equated to 2010 Medicare dollars. 

Results: Among 1,393 consecutive surgically managed EC cases, 385 

(27.6%) met the Mayo low-risk criteria, accounting for 34.1% of type I EC. 

The 5-year CSS of the low-risk cases was 98.6 %. There were 80 LND cases 

(median # nodes, 29) and 305 non-LND cases. Complications within 30 

days occurred in 37.5% and 19.3% of LND and non-LND cases, respectively 

(P�0.001). Nodal metastasis was identified in a single LND case 

(1.3%). There were 11 recurrences, 6 of which were vaginal. Not a single 

recurrence was detected in the pelvic or paraaortic nodal areas in these 

385 patients, with a median follow-up of 5.4 years. The estimated 

prevalence (combining surgery and surveillance) of lymph node metastasis 

was 0.3%. The 5-year CSS in LND and non-LND cases was 97.3% and 

99.0%, respectively (P�0.32). Patients were more than seven times as 

likely to die of co-morbidities than from EC. The 30-day median cost of care 

was $15,678 for LND cases compared to $11,028 for non-LND cases 

(P�0.001). The estimated cost per up-staged low-risk case was $439,990 

if performed via endoscopy and $327,866 via laparotomy. If the 305 

non-LND cases had been subjected to LND, an estimated additional 

$1,418,189 would have been expended. Conclusions: For patients with 

low-risk EC as defined by the Mayo criteria, lymphadenectomy dramatically 

increases morbidity and 30-day cost of care without discernible short- or 

long-term benefits: CSS was 99% with a 0.3% rate of nodal metastasis. In 

these low-risk patients, hysterectomy with salpingo-oophorectomy alone is 

appropriate surgical management and should be standard of care. 


A randomized, phase III trial of paclitaxel plus carboplatin (TC) versus 

paclitaxel plus cisplatin (TP) in stage IVb, persistent or recurrent cervical 

cancer: Japan Clinical Oncology Group study (JCOG0505). Presenting 

Author: Ryo Kitagawa, NTT Medical Center Tokyo, Tokyo, Japan 

Background: TC is a less toxic regimen in terms of milder nephropathy, 

neuropathy and no need of hospitalization. This multicenter phase III trial 

was designed to evaluate the clinical benefits of TC compared with TP 

which is current standard chemotherapy for stage IVB or recurrent cervical 

cancer. Methods: Patients (pts) with stage IVB or recurrent cervical cancer; 

not amenable to curative therapy; 0-1 prior platinum; no prior taxanes; were 

randomized with minimization method to either TP (T 135 mg/m2 24h d1 

� P 50 mg/m2 2h d2) or TC (T 175 mg/m2 3h d1 � C AUC5 1h d1), both 

for maximum 6 cycles every 21 days. Primary endpoint was overall survival 

(OS). Secondary endpoints were progression-free survival (PFS), toxicities, 

and the proportion of non-hospitalization periods (NHP) as a surrogate for 

QoL. The trial was powered at least 70% to confirm the non-inferiority of TC 

to TP (threshold hazard ratio [HR] 1.29) in terms of OS, and the planned 

sample size was 250 pts with one-sided alpha 5%. HR is estimated by a 

stratified Cox regression. Results: From 2/06 to 11/09, 253 pts were 

enrolled. 71% pts of TP arm and TC arm each received 6 cycles. Median 

follow-up is 17.4 mo. Results are as below. As an alpha level for an interim 

analysis was less than 0.0001, significance level for the final analysis is 

approximately 5% even after the multiplicity adjustment. Conclusions: This 

first randomized controlled trial comparing carboplatin doublet with cisplatin 

doublet showed significant non-inferiority of TC in terms of OS. More 

feasible and less toxic TC can be recommended as the new standard 

treatment for stage IVB or recurrent cervical cancer. 

TP TC 

OS (median) HR 0.99 (multiplicity adjusted 90%CI: 18.3 mo 17.5 mo 

0.79-1.25); noninferiority p�0.032 

PFS (median) HR 1.04 (95%CI: 0.80-1.35) 6.90 mo 6.21 mo 

Neutropenia G3-4 85.1% 76.4% 

Thrombocytopenia G3-4 3.3% 23.6% 

Febrile neutropenia G3-4 16.0% 7.3% 

Creatinine G2-4 9.8% 4.1% 

Neuropathy (motor) G3-4 0.8% 2.4% 

Neuropathy (sensory) G3-4 0% 4.9% 

Early treatment discontinuation (toxicity-related) 11.4% 10.0% 

NHP (p


Survival after radiation therapy for early-stage endometrial carcinoma: The 

Oslo study revisited after up to 43 years of follow-up. Presenting Author: 

Kristina Lindemann, Akershus University Hospital, Lørenskog, Norway 

Background: There is an ongoing debate regarding the benefit of radiation in 

patients with early stage endometrial carcinoma. Data on long time risk 

conferred by radiation is scarce. This study is a long-term follow-up on 

survival and secondary cancers of a previously published randomized study 

(Aalders J. et al., Obstet Gynecol 1980; 56: 419-27). Methods: Between 

1968 and 1974, 568 patients with endometrial cancer FIGO stage I 

primarily treated with abdominal hysterectomy and bilateral salpingooophorectomy 

were included in the study. Patients were postoperatively 

randomized to receive either vaginal radium brachytherapy followed by 

external pelvic radiation 40 Gy (N�288) or brachytherapy alone (N�280). 

Survival data and data on incident secondary cancers were obtained by 

individual linkage to the Registry of Statistics Norway and Cancer Registry 

of Norway. By the end of follow-up at 1 November 2011, 45 (7.9%) 

patients were still alive. We used Cox proportional hazards model to 

estimate hazard ratios (HR) with 95% confidence intervals (95% CI). We 

also conducted analyses stratified by age groups. Results: After median 21 

(range 0-43.4) years of follow-up there was no significant difference in 

overall survival or relapse free survival between treatment arms with HR of 

1.12 (95% CI: 0.95-1.33) and HR 0.88 (95% CI: 0.55-1.40), respectively. 

Patients treated with external radiation had significantly lower risk of 

developing locoregional relapse (p�0.001). However, women younger than 

60 years had a significant poorer survival after external radiation (HR 1.36; 

95% Cl: 1.06-1.76). In this patient group the risk of secondary cancer was 

significantly increased (HR 1.9; 95% CI: 1.23-3.03). Conclusions: We 

observed no survival benefit of external pelvic radiation in early stage 

endometrial carcinoma. In women younger than 60 years, pelvic radiation 

decreased survival, probably due to increased risk of subsequent second 

neoplasms. Adjuvant external radiotherapy cannot be recommended to this 

patient group. Those who have received such treatment might eventually 

benefit from prolonged post treatment surveillance with respect to secondary 

cancer. 


Molecular determinants of outcome with mTOR inhibition in endometrial 

cancer (EC). Presenting Author: Helen Mackay, Princess Margaret Hospital, 

University Health Network, Toronto, ON, Canada 

Background: Deregulation of PI3K/AKT/mTOR signaling plays a significant 

role in EC biology. NCIC CTG has completed three phase II trials of 2 mTOR 

inhibitors (temsirolimus and ridaforolimus) in EC (IND 160A, IND 160B, 

IND192) demonstrating anti-tumor activity. PTEN expression, however, 

was not associated with response. In this study we are conducting 

additional molecular analyses on samples obtained from patients (pts) 

participating in these trials to identify mutations or other findings associated 

with mTOR response. Methods: Formalin fixed paraffin embedded 

(FFPE) tumor samples were collected from pts treated on the three trials. 

Tumor DNA was isolated and mutational profiling (MP) was performed 

using theOncoCarta Panel v1.0 which can detect 238 mutations in 19 

oncogenes including AKT1, 2, BRAF, CDK-4, EGFR, ERBB2, MET, H-, K-, 

N- RAS, PDGFRA, PIK3CA, RET. All mutations were verified by Sanger 

sequencing. For each gene found to be mutated in at least 1 patient, the 

relationship between presence/absence of mutations in that gene and 

objective anti-tumor response (RR) was assessed (RR vs. no response; early 

progression (PD) vs. no PD) using Fisher’s exact test. In addition, the 

presence of any mutation vs. no mutations was assessed in relationship to 

the same clinical outcomes. Results: MP was feasible in 73 of the 94 

eligible pts treated on the three trials. 44% (32 pts) had a mutation in at 

least one gene: 21 pts (29%) in PIK3CA, 10 (14%) KRAS, 4 (5%) MET, 3 

(4%) NRAS, 3 (4%) AKT and 1(1%) EGFR. 9 pts (12%) had � 1 mutation. 

No significant correlations were seen, in individual trials or within the 

pooled data set of 3 studies, between the presence/absence of any 

mutation and RR (p�1.0) or early PD (p�1.0). No significant association 

was seen between the presence of mutations within individual genes and 

RR or PD (including PIK3CA). Of interest, no response was observed in any 

of the 13 pts with a Ras mutation (non-significant). Additional analyses 

involving gene expression (including stathmin) and correlation of MP with 

tumor morphology are underway. Conclusions: Mutations are common in EC 

but we have not identified a statistical association between presence of 

mutations in PIK3CA or any other gene and response to mTOR inhibition. 

Further analyses are ongoing. 


329s 


Impact of metformin use on risk of recurrence in high-grade endometrial 

cancers. Presenting Author: Emily Meichun Ko, University of North Carolina at 

Chapel Hill, Chapel Hill, NC 

Background: Obesity and diabetes (DM) have been linked to increased recurrence 

rates and worse survival in endometrial cancer. Metformin is widely used as the 

first line treatment for type II DM. Recent epidemiological evidence suggests 

that metformin may lower cancer risk and reduce cancer-related deaths among 

DM patients. However, no studies have assessed the effect of metformin use on 

endometrial cancer outcomes. Methods: A retrospective cohort analysis was 

conducted of all grade 3 endometrial cancer patients with DM at a single 

institution from 2005-2010. Clinical-pathologic data was abstracted, including 

metformin, insulin, sulfonamide and thiazolidinedione use at the time of cancer 

diagnosis. Statistical analysis were performed using summary statistics and 

multivariate cox analysis, with two tailed p-values �0.05 considered significant. 

Results: 55/329 patients with grade 3 cancer had DM. Mean age was 68.3 (sd 

8.4), and BMI 35.7 (sd 9.4). Stage distribution consisted of 58.2% stage I, 

7.3% stage II, 27.3% stage III, and 7.3% stage IV. Histology included 41.8% 

endometrioid, and 58.2% serous or clear cell. 56.4% of diabetics used 

metformin and 43.6% did not. Mean follow-up was 21.6 months (sd 15.0). After 

adjusting for BMI, myometrial invasion, stage, histology, adjuvant treatment, 

and non-metformin DM medications, metformin use was significantly associated 

with decreased cancer recurrence (HR 0.06, 95CI 0.01, 0.40; p�0.004). 

Conclusions: Metformin use was associated with a decreased risk of recurrence in 

high-grade endometrial cancer, suggesting that it may have a role as adjuvant 

and maintenance therapy for this obesity-driven disease. 

Metformin user (%) Metformin non-user (%) 

n�31 n�24 

Age 67.5 (9.1) 69.4 (7.4) 

BMI 

Stage 

35.4 (8.5) 36.2 (10.5) 

I 15 (48.4) 17 (70.8) 

II 3 (9.7) 1 (4.2) 

III 9 (29.0) 6 (25.0) 

IV 

Histology 

4 (12.9) 0 (0) 

Endometrioid 11 (35.5) 12 (50) 

Serous � Clear cell 

Other medications 

20 (64.5) 12 (50) 

Sulfonamide (Sulfo) 5 (16.1) 8 (0) 

Thiazolidinedione (Thz) 2 (6.5) 0 (0) 

Sulfo � Thz 2 (6.5) 2 (8.3) 

Insulin 0 (0) 4 (16.7) 

Insulin � Sulfo 1 (3.2) 0 (0) 

Insulin � Thz 

Adjuvant treatment 

0 (0) 2 (8.3) 

Chemotherapy 4 (12.9) 3 (12.5) 

Radiation 7 (22.6) 4 (16.7) 

Chemo � Radiation 11 (35.5) 7 (29.2) 


KRAS and EGFR mutations to distinguish adenocarcinomas and squamous 

cell carcinomas of the cervix. Presenting Author: Alexi Wright, Dana-Farber 


Background: Cervical adenocarcinomas (AC) have higher rates of recurrence 

and distant metastasis, compared with squamous cell carcinomas (SCC), 

and decreased survival in advanced disease. Yet, tailored treatments for 

cervical cancers have not emerged. The aim of this study was to compare 

the frequency and type of somatic mutations in cervical AC and SCC to 

identify novel therapeutic targets for both subtypes. Methods: Tumors from 

61 patients with cervical cancer (36 AC, 25 SCC) underwent genomic 

profiling by OncoMap, a multiplexed mass spectrometric genotyping 

technology that interrogates more than 400 known mutations in 33 cancer 

genes. Results: Overall, 31/61 (50.8%) tumors harbored candidate mutations, 

and 6/61 (9.8%) had �2 mutations. PIK3CA mutations were present 

in 21/64 (34.4%) of cervical cancers, with a trend towards higher rates in 

SCC compared with ACC (21/25 or 48.0% vs. 9/27 or 33.3%, p�0.10). 

KRAS mutations were present in 6/31 (16.7%) of AC, but none of the SCC 

(0%; 0/25). EGFR mutations were present in 9/25 (36.0%) of SCC, 

including G719S, but none of AC (0%; 0/31). Conclusions: The identification 

of distinct genomic alterations in SCC and AC of the cervix suggest 

different therapeutic rationales for each subtype. EGFR amplification in 

cervical SCC has been previously reported, but this is the first identification, 

to our knowledge, of activating EGFR mutations in cervical SCC. 

Together, this suggests that EGFR-inhibitors might be useful in selected 

patients with cervical SCC. Similarly, activating mutations in KRAS and 

PIK3CA in AC suggest that inhibition of the MAPK pathway (MEK 

inhibitors) and/or PI3K pathway may be beneficial in this subtype. Future 

studies should include more comprehensive genomic profiling strategies, 

such as targeted massively parallel sequencing, to detect multiple types of 

genomic alterations. 




4:30 PM-5:30 PM 

A phase II, open-label, multicenter study of IMC-1121B (ramucirumab; 

RAM) monotherapy in the treatment of persistent or recurrent epithelial 

ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) carcinoma 

(CP12-0711/NCT00721162). Presenting Author: Richard T. Penson, 

Massachusetts General Hospital, Boston, MA 

Background: VEGF receptor-mediated-signaling contributes to ovarian cancer 

pathogenesis. Elevated VEGF expression and serum levels are associated 

with poor clinical outcomes. We investigated RAM, a fully human 

VEGFR-2 antagonist antibody, in patients (pts) with persistent or recurrent 

EOC/FTC/PPC. Methods: Adult women with EOC/FTC/PPC who had completed 

�1 platinum (P)-based chemotherapeutic (ct) regimen and had a 

P-free interval (PFI) of �12 months (m), progression on, or persistent 

disease after P-based therapy were eligible. Any number of prior ct 

regimens was allowed. ECOG PS 0-1 and adequate organ function were 

required. Pts received 8 mg/kg RAM IV every 2 weeks. Primary endpoints 

were progression-free survival at 6m (PFS-6) and confirmed objective 

response rate (ORR) by RECIST 1.0. Results: 60 pts were treated; 1 

remains on study as of Dec 2011. Median age was 62 years (range 27-80). 

Median number of prior regimens was 3 (range 1– 14). 51 pts (85%) 

received � 2 prior regimens; 25 pts (42%) received �3 prior regimens. 45 

pts (75%) were P resistant or refractory, with 65% (39 pts) serous tumors. 

PFS-6: 34.2% (95% CI: 21.7% – 47%). Best overall response: 3 PR (5%), 

34 SD (57%), 20 PD (33%) and 3 not evaluable (5%). Median duration of 

PR: 5.6m (3.7, 5.6, 17.5); median PFS: 3.5m (95% CI: 2.3 – 5.3). 

Median OS: 11.1m (95% CI: 8.3 – 17.0). No unexpected toxicities were 

observed. Grade (G) 3 adverse events (AEs) observed in �5% of pts were: 

headache (10%) and fatigue (8%). No G4 AEs were observed in �5% of 

pts. 5 deaths occurred on RAM or within 30 days of discontinuation; 4 due 

to PD, and 1 due to intestinal perforation. 1 G4 bowel perforation and one 

G4 colo-vaginal fistula were noted. All 3 cases of perforation/fistula 

occurred in the setting of progressive, large-volume disease. Correlative 

biomarker studies are ongoing to identify patients most likely to benefit. 

Conclusions: Ramucirumab was reasonably tolerated and demonstrated 

single-agent activity in persistent or recurrent ovarian carcinoma, with 

approximately one-third of patients progression free at 6 months. 


4:30 PM-5:30 PM 

Phase I trial of metronomic oral topotecan in combination with pazopanib 

utilizing a daily dosing schedule to treat recurrent or persistent gynecologic 

tumors. Presenting Author: Todd D. Tillmanns, The West Clinic, Memphis, 

TN 

Background: Metronomic oral topotecan has antiangiogenic properties. Oral 

pazopanib is also a potent inhibitor of VEGF angiogenesis with clinical 

benefit. This study investigated the safety and efficacy of daily topotecan 

and pazopanib. Methods: This phase I, single-center, open-label, dose 

ranging study comprised 28-day cycles of daily oral topotecan/pazopanib at 

dose levels of 0.50/400, 0.25/800, 0.25/600, and 0.25/400 mg. A 

standard 3�3 dose escalation design was used. Dose limiting toxicity 

(DLT) was defined as � grade 3 adverse event (AE) occurring in cycle 1, 

noncompletion of cycle 1 at prescribed dose, or inability to start cycle 2 as 

scheduled due to toxicities. Imaging was conducted after every 2 cycles for 

response assessment. Confirmed responses were evaluated per RECIST 

1.0. Results: 25 extensively pretreated patients (pts) with gynecologic 

tumors (6 cervical, 7 endometrial, 8 ovarian, 4 other) were enrolled. Mean 

age was 61 years; 19 Caucasian, 6 African American. Median number of 

cycles received was 4 (range 1-19). DLTs occurred � 2 pts for A (2/6), B 

(2/7), C (3/7). For level D, 1/5 had a DLT, but one dose level C pt with a DLT 

received level D dosing due to unavailability of pazopanib. 9/25 pts had any 

serious adverse event (SAE), and respiratory SAEs were most common 

(4/16 SAEs). Nausea, fatigue, dysgeusia, diarrhea, and vomiting were the 

most common conditions reported as non-serious AEs. The Table shows 

best overall response (28%) by dose level. Conclusions: DLTs in dose levels 

C and D were effectively managed with minor dose and schedule adjustments. 

4 pts with DLTs at these doses remained on treatment for 4, 5, and 

6 months, with one pt still on treatment at 9 months. Given the initial 

biologically favorable signal in this heavily pretreated group and low 

toxicity, we recommend a randomized phase II trial to define efficacy using 

the 0.25/600 regimen allowing for dose reduction if needed. 

Dose level CR PR SD PD NE 

A 0.50/400 0 0 2 (33.3%) 4 (66.7%) 0 

B 0.25/800 2 (28.6%) 2 (28.6%) 0 1 (14.3%) 2 (28.6%) 

C 0.25/600 1 (14.3%) 0 1 (14.3%) 4 (57.1%) 1 (14.3%) 

D 0.25/400 1 (20.0%) 1 (20.0%) 0 0 3 (60.0%) 

Overall 4 (16.0%) 3 (12.0%) 3 (12.0%) 9 (36.0%) 6 (24.0%) 


4:30 PM-5:30 PM 

Phase II trial of bevacizumab and pemetrexed for recurrent or persistent 

epithelial ovarian, fallopian tube, or primary peritoneal cancer. Presenting 

Author: Andrea R. Hagemann, Washington University School of Medicine 

and Siteman Cancer Center, St. Louis, MO 

Background: This phase II clinical trial evaluated the efficacy and safety of 

the combination of bevacizumab, a VEGF inhibitor, and pemetrexed, a 

multi-targeted antifolate agent inhibiting thymidylate synthase, for recurrent 

or persistent epithelial ovarian, fallopian tube (FT) or primary peritoneal 

(PP) cancer. Methods: Patients with measurable recurrent/persistent 

epithelial ovarian, FT or PP cancer after at least one prior platinum- and 

taxane-containing regimen were eligible. Patients might have received � 2 

prior cytotoxic chemotherapy regimens but no prior bevacizumab. Pemetrexed 

500 mg/m2 IV and bevacizumab 15 mg/kg IV were given every 3 

weeks until progression, unacceptable adverse effects, or patient/physician 

choice. 32 patients were needed to have 90% power to detect the primary 

endpoint of 6-month PFS � 40% with a two-sided 0.05 significance. 

Secondary endpoints included toxicity and response by RECIST and 

CA-125 criteria. Results: Thirty-four patients received a median of 7 

treatment cycles (range, 2-26). Twenty-eight patients (82%, 95% CI: 

66-92) were platinum-sensitive. Median follow-up was 17.1 months 

(range, 2.7-31.2). The 6-month PFS was 58.2% (95%CI: 40-73) for all 

patients and 50% (19-81) for platinum-resistant patients. Objective 

response rates by RECIST criteria included (%; 95%CI): 0 CR, 14 PR 

(41%; 25-59), 18 SD (53%; 35-70) and 2 PD (6%; 1-20). Of 27 patients 

evaluable by CA-125, levels declined �50% in 17 (62%; 44-79), and 

�75% in 8 (30%; 16-49). 12-month OS was 88% (95%CI: 71-95) and 

median PFS was 7.8 months (95%CI: 4.7-10.7). Of the 34 patients, grade 

3-4 hematologic toxicities occurred in 53% (neutropenia 50%, leukopenia 

26%, thrombocytopenia 12%, anemia 9%). Other grade 3-4 toxicities 

included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal 

(15%). No bowel perforations occurred. Conclusions: Combined 

bevacizumab/pemetrexed is well tolerated and highly active for the treatment 

of recurrent ovarian cancer. The dose and schedule tested here 

warrant further investigation in phase III trials. 


4:30 PM-5:30 PM 

Randomized phase II study of docetaxel plus vandetanib (D�V) versus 

docetaxel followed by vandetanib (D-V) in patients with persistent or 

recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma 

(OC): SWOG S0904. Presenting Author: Robert L. Coleman, University of 


Background: Antiangiogenesis therapy has led to antitumor effects both 

preclinically and clinically. Vandetanib (V) is an oral tyrosine kinase 

inhibitor of VEGFR-2/3, EGFR and RET. These targets are of interest in OC 

care, as targeting has shown anti-tumor efficacy, particularly in combination 

with taxanes. We explored the efficacy, safety, and toxicity of docetaxel 

(D) and V in women with recurrent OC. Methods: Women with resistant, 

refractory, or progressive/persistent OC were eligible for this randomized 

phase II study provided they had not received D or V for recurrent disease. 

Patients were allowed to receive other anti-VEGF targeted agents for 

primary therapy (stratification variable). Up to 3 additional cytotoxic 

regimens for recurrence were allowed. Patients were allocated 1:1 to D(75 

mg/m2 , I.V.)�V (100 mg daily, p.o.) or D(75 mg/m2 ). Patients receiving 

single agent D were allowed to crossover to V upon progression (D-V). The 

primary endpoint was PFS. Other objectives were: OS, objective response 

(ORR), and frequency/severity of adverse events. The study was designed 

with 84% power to detect a 1.55 PFS hazard ratio using a one-sided P of 

0.1. Results: 131 patients were enrolled; 5 were excluded (1 ineligible, 4 

eligible but untreated). 9% had received prior anti-angiogenic therapy. 61 

patients on D�V were assessable for toxicity; 19 (31%) had treatmentrelated 

G4 events, primarily hematologic. Similarly, 17 (26%) of 65 

patients receiving D alone had G4 events, primarily hematologic. 34 (52%) 

patients crossed over to V; no G4 events were recorded among 32 evaluable 

patients. G3 diarrhea was observed in 14% of D�V patients; 5% D-V 

patients. G3 acneiform rash occurred in 2% and 0%, respectively. The 

median PFS estimates were 3.0 mos (D�V) vs 3.5 (D-V); HR (PFS): 0.98 

(80% CI:0.75-1.27). For OS, the median estimates were 14 mos (D�V) vs 

12 mos (D-V); HR (OS):0.84 (80% CI:0.56-1.28). ORR was 14% and 

17%, respectively. Crossover V response was 4% (1/27 measurable 

patients). Conclusions: D�V was well tolerated in this population however, 

did not prolong PFS with respect to D. 



4:30 PM-5:30 PM 

Phase II trial of irinotecan plus bevacizumab for heavily pretreated 

recurrent ovarian cancer. Presenting Author: Salvia Sanjay Jain, New York 

University School of Medicine, New York, NY 

Background: Irinotecan and bevacizumab have single agent activity in 

platinum sensitive (PSen) and resistant (PRes) ovarian cancer patients 

(pts). We sought to evaluate the efficacy and toxicity of irinotecan plus 

bevacizumab in these pts. The trial was designed to evaluate whether the 

progression free survival (PFS) at 6 months is at least 40% and with 

secondary objectives of estimating response rate (RR), duration of response 

(DoR), time to progression and toxicity. Methods: No limitation on number 

of prior regimens was placed, and prior use of study drugs was allowed. 

Irinotecan 250mg/m2 and bevacizumab 15mg/kg every 3 weeks were 

given. Due to treatment-related grade 3 toxicity (diarrhea and neutropenia) 

experienced by the first 5 pts on the study, the dose of irinotecan was 

amended to 175mg/m2. Results: 20 pts with recurrent ovarian cancer 

[PSen 5, PRes 15] of a planned 35 have been recruited thus far. Median 

age is 59 (45-78). Median number of prior regimens is 5 (3-12) with 9 pts 

demonstrating progressive disease (PD) on prior topotecan-containing 

regimens and 7 pts exhibiting PD on prior bevacizumab-containing regimens. 

4 pts discontinued treatment before 2 cycles (2 for protocol defined 

toxicity, 2 by patient/physician choice). Partial response (PR) was observed 

in 2 PSen pts and 1 PRes pt, while stable disease (SD)was seen in 9 (2 

PSen, 7 PRes) out of the 15 pts assessable for response at this time. 3 pts 

demonstrated PD after 2 cycles of treatment. 12 of 13 pts with PR or SD by 

RECIST also had response by CA125 criteria. Median DoR thus far (SD plus 

PR) is 18 weeks (4-37). 6 pts have ongoing response (4-18 weeks). Of 19 

pts that received � 2 cycles, 3 had grade 3 diarrhea (2 before protocol 

amendment and 1 after). 2 pts had grade 3/4 neutropenia (1 before and 1 

after protocol amendment). Median PFS is 9.6 months (mts). Median 

overall survival is 15.5 mts. PFS rate at 6 mts is 61% with 95% confidence 

interval: (40%, 92%). Conclusions: Results of the trial to date suggest the 

hypothesis that the PFS at 6 mts is less than 40% can be rejected. Activity 

of this regimen is encouraging given the heavily pretreated nature of the 

pts. Dose-limiting diarrhea and neutropenia required protocol amendment. 

We continue to accrue study subjects at the amended dosing. 


4:30 PM-5:30 PM 

Lenalidomide (REV) in asymptomatic late recurrent ovarian cancer (ROC) 

patients with increasing CA 125: A GINECO phase II trial. Presenting 

Author: Frédéric Selle, Universite Pierre et Marie Curie, Oncology, GHU-Est 

Tenon, Paris, France 

Background: REV is a thalidomide analogue, with both immunomodulatory 

and anti-angiogenic properties that could confer antitumor effect in ROC. 

Methods: The aim of this study was to evaluate REV efficacy as single agent 

in patients (pts) with asymptomatic late ROC (�6mos) with increasing CA 

125, in 2nd or 3rd line. Primary endpoint was to estimate the rate of 

non-progressive disease at 4 mos. Pts were treated with REV 20 mg daily in 

oral continuous regimen with systematically recommended anti-thrombotic 

prophylaxis (ATP). Imagery and CA 125 were performed every 8 weeks. 

Results: From 05/2009 to 09/2010, 45 pts were included with a median 

age of 63 years. Pt characteristics were: serous (78%), previous lines (one 

73%, two 27%), median platinum-free interval (PFI) (11.3 mos), PFI � 12 

mos (42%), measurable disease (73%), and ECOG performance status 0 

(84%). Efficacy: Rate of non progressive disease at 4 mos was 38% 

(95%CI, 23-53), 59 % (95%CI, 36-82) and 24 % (95%CI, 7-41) for the 

global population, pts relapsing over 12 mos and those relapsing between 

6-12 mos, respectively. Results were independent of the number of 

previous lines. Median progression-free survival was 3.8 mos (95%CI, 

2.1-5.6) and 6.4 mos in the subset of pts with PFI � 12 mos. Response 

evaluation according to CA 125 (Rustin criteria) was: complete response 

(CR) 2.4%, partial response (PR) 17%, stable disease (SD) 71%. When 

using RECIST criteria alone, response evaluation was: 9.5% PR and 45% 

SD. Median duration of biological response was 6.6 mos. REV efficacy will 

be correlated to immunological parameters (lymphocyte phenotypes and 

cytokines). Safety: Grade 3-4 toxicity in more than 5% of pts was 

neutropenia (29%) and thrombo-embolic events (TEE) (11%). TEE occurred 

only in pts without ATP. Reasons for stopping treatment due to 

toxicity were TEE (3), allergy (2), arrhythmia (1), dyspnea (1) and 

neutropenia (1). Conclusions: REV demonstrated encouraging activity in 

ROC with good tolerability and manageable adverse events. A phase I of 

REV combined with platinum-based chemotherapy is currently being 

conducted. 


331s 


4:30 PM-5:30 PM 

Safety of front-line bevacizumab (BEV) combined with weekly paclitaxel 

(wPAC) and q3w carboplatin (C) for ovarian cancer (OC): Results from 

OCTAVIA. Presenting Author: Antonio Gonzalez-Martin, GEICO and Medical 

Oncology Service, Centro Oncológico M. D. Anderson International 

Spain, Madrid, Spain 

Background: In two randomized phase III trials in OC (GOG218 and ICON7), 

front-line BEV � q3w PAC � q3w C followed by BEV alone significantly 

improved progression-free survival (PFS) vs chemotherapy (CT) alone. In 

the Japanese NOVEL trial, wPAC � q3w C was more effective than q3w 

PAC � C, but toxicity limited CT delivery. The single-arm OCTAVIA study 

evaluated front-line BEV � wPAC � q3w C. Methods: Patients (pts) 

received 6–8 cycles of BEV (7.5 mg/kg, d1) � wPAC (80 mg/m2 d1, 8, 15) 

� C (AUC6, d1) iv q3w, with BEV q3w continued alone for a total of up to 

17 cycles (1 y) as front-line therapy for newly diagnosed OC (FIGO stage 

I–IIa [grade 3/clear cell] or stage IIb–IV [any grade]). The trial was designed 

to recruit a pt population similar to that enrolled in ICON7. The primary 

endpoint was PFS. Secondary endpoints included response rate, duration 

of response, overall survival, biological progression-free interval, and 

safety. Previously we reported safety findings from the concurrent CT 

phase. Here we present final safety results from the entire treatment period. 

Results: Between Jun 2009 and Jun 2010, 189 eligible pts were enrolled. 

Baseline characteristics: median age 55 y (range 24–79 y); ECOG 0 74%; 

FIGO stage I/II/III/IV 10%/10%/63%/17%; serous/clear cell/mixed 65%/ 

6%/6%; 71% optimally debulked. Pts received a median of 6 CT cycles 

(range 1–8) and 17 BEV cycles (range 0–18). Of the 168 pts who received 

single-agent BEV, 135 completed 1yoftherapy. In the entire treatment 

period, BEV was discontinued for adverse events (AEs) in 12% and disease 

progression (PD) in 10%. The most common grade �3 hematologic AEs 

were neutropenia (60%), anemia (8%), and thrombocytopenia (7%). The 

incidences of grade �3 AEs of special interest for BEV were: hypertension 

4.2% (grade 2/3/4: 9.0%/3.2%/1.1%); thromboembolic events 6.3% 

(grade 3/4: 3.7%/2.6%); bleeding 0.5% (grade 3), wound-healing complications 

0.5% (grade 3), and GI perforation 0.5% (grade 4). There was no 

grade �3 proteinuria or fistula/abscess. At the time of data cut-off, 9 pts 

had died, all from PD. Conclusions: BEV combined with wPAC is feasible 

and well tolerated. BEV AEs were no more frequent with wPAC in OCTAVIA 

than with q3w PAC in ICON7. 


4:30 PM-5:30 PM 

A phase II study of RO4929097 (RO), a gamma-secretase inhibitor, in 

advanced platinum (Pt)-resistant (R) ovarian cancer (OC): A study of the 

PMH, Chicago, and California phase II consortia. Presenting Author: Ivan 

Diaz-Padilla, Princess Margaret Hospital, Toronto, ON, Canada 

Background: Notch signalling pathway plays a critical role in regulating 

cellular differentiation, proliferation, and apoptosis in preclinical cancer 

models. The Notch receptor, its ligands, and down-stream effectors are 

over-expressed in OC. Inhibition of �-secretase-mediated Notch cleavage is 

a primary focus for the development of targeted therapeutics. Methods: 

Women (pts) with progressive, measurable (RECIST), Pt-R OC treated with 

� 2 chemotherapy regimens for recurrent disease were treated with oral RO 

at 20mg od, 3 days on/4 days off every week, q3w. The primary objective 

was to determine the antitumor efficacy of RO in Pt-R OC by the 

progression-free survival (PFS) rate at the end of 4 cycles. Secondary 

objectives were to assess the safety of RO and to explore molecular 

correlates of outcome in archival tumor tissue. A Simon two-stage design 

was used. The study would open to second stage accrual if � 4 pts of the 

first 17 accrued remain progression-free at the end of 4 cycles. Results: 39 

pts have been enrolled after first-stage criteria were met. Median age was 

59 (range 26-81). Median number of cycles was 2 (range 1-18). 30 (83%) 

pts had high-grade serous OC. 34 pts were evaluable for response. 8 pts 

(20%) were progression-free after 4 cycles.12 pts (35%) had stable 

disease, with a median duration of 3.9 months (range 2.5-12.2). Median 

PFS was 1.3 months (1.2-2.3). The most common drug-related adverse 

events (AEs) of any grade (% pts) were: nausea (36), fatigue (28), anorexia 

(15), hypophosphatemia (15), anemia (13), and increased alanine aminotransferase 

[ALT] (13). There were 5 G3-4 AEs at least possibly related with 

RO: increased liver transaminases (2), diarrhea (1), headache (1), and 

hypophosphatemia (1). Intracellular Notch (NIC) and JAG1 protein expression 

on high-grade serous OC were correlated with response in 17 pts. 

Median PFS for pts with high NIC (n�6) was 3.3 months (1.0-not reached), 

compared to 1.3 months (1.1-2.6) for pts with low NIC (n�11), p�0.09. 

Conclusions: RO has limited clinical activity in unselected Pt-R OC as a 

single agent. Future studies need to assess potential for cohort enrichment 

using NIC expression. 




4:30 PM-5:30 PM 

Randomized trial of oral cyclophosphamide (C) with or without veliparib 

(V), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with 

recurrent BRCA-positive ovarian, or primary peritoneal or high-grade serous 

ovarian carcinoma. Presenting Author: Shivaani Kummar, Developmental 

Therapeutics Clinic, National Cancer Institute, Bethesda, MD 

Background: V�C was well tolerated in a phase I trial and responses and 

prolonged disease stabilization were observed in BRCA � patients (pts).To 

assess the relative contribution of the PARP inhibitor to the efficacy 

observed for the combination, we conducted a randomized multicenter trial 

comparing the response rate (RR) of V and C to the RR of C alone in patients 

with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, 

fallopian tube or high-grade serous ovarian cancer. Methods: Pts were 

� 18 yrs, KPS � 70%, had adequate organ function, prior therapy with 

PARP inhibitors was allowed.Both drugs were administered orally qd; C 50 

mg, V 60 mg; 21 day cycles. Pts were randomized to receive either C alone 

or V�C. At disease progression, pts on C alone were allowed to cross over to 

the combination. Radiologic imaging was performed at baseline and q 3 

cycles for assessment of response. Dose reduction of V was allowed to 40 

mg for gr 3 non-hematologic or gr 4 hematologic toxicities. The study 

design had an 88% power to detect the difference between a 15% RR for C 

alone versus 35% for V�C, early closure if fewer responses were observed 

on the combination arm in the first 65 pts enrolled (half of the total 

projected accrual). Results: Total of 74 pts were enrolled (36 pts C, 38 pts 

V�C), median age 58 (37-79 yrs), # of prior therapies: median 4 (1-9), 2 

pts had prior PARP therapy. Treatment was well tolerated, Gr � 2 toxicities 

per arm for initial regimen (# of pts): C alone: lymphopenia (2), mucositis 

(1); V�C: lymphopenia (4), anemia (2), leucopenia (2), neutropenia (2). Of 

the 74 pts evaluable for response at the interim analysis, 3 PRs observed in 

36 pts on V�C and 5 PRs of 38 pts on C alone arm; thus accrual was 

stopped. PAR levels assessed by validated ELISA were inhibited (�80%) in 

PBMCs in 9/10 pts 4 hours post V, no inhibition with C alone. Conclusions: 

Addition of V, a PARP inhibitor, to C did not improve RR versus C alone. 

Exomic sequencing, gene expression studies, and Fanconi Anemia triple 

stain immunofluorescence (FATSI) assay for FancD2 nuclear foci formation 

using archival tissue are ongoing. 


4:30 PM-5:30 PM 

Use of chemotherapy (CT) in BRCA1/2-deficient ovarian cancer (BDOC) 

patients (pts) with poly-ADP-ribose polymerase inhibitor (PARPi) resistance: 

A multi-institutional study. Presenting Author: Joo Ern Ang, The 

Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, 


Background: Emerging clinical data point to the clinical utility of PARPi in 

BDOC. However, the impact of PARPi exposure on the prospects of 

response to further CT remains unclear. In our previous single centre study, 

we provided the first clinical data relating to the use of post-PARPi CT (JCO 

2010: 28(15S), A5041). Our aim here was to re-examine this issue in a 

larger multi-institutional population. Methods: We included pts with advanced 

BDOC who received CT, having progressed on �200 mg bd 

olaparib. Pt, tumor and treatment characteristics and clinical outcomes 

were documented. Relationships between post-PARPi CT overall survival 

(OS) and other variables were explored using Cox regression. Results: We 

collected data on 75 pts (median age 51 y [range 31-77], BRCA1:BRCA2 

54:21, mean 3 previous lines of CT [95% CI 2.5-3.4], pre-PARPi platinum 

(Plt) resistance rate 49% and olaparib RECIST-response rate [RR] 39% 

[95% CI 28-50]). Following olaparib, most pts received Plt alone or in 

combination with taxane (Tx) or liposomal doxorubicin (PLD). Weekly Plt 

was used in 36% of all Plt-treated pts, mainly in combination with weekly 

Tx. Overall RECIST and CA125 (GCIG) RRs were 38% and 48%, respectively; 

these responses occurred independently of PARPi response or 

pre-PARPi Plt sensitivity (all p�.1). The median progression free survival 

and OS of RECIST responders were 7.9 m (95% CI 5.8-10.9) and 10.5 m 

(95% CI 1.4-19.6), respectively. In all pts, the median OS from the start of 

post-PARPi CT was 7.9 m (95% CI 5.7-10.1) while that from diagnosis was 

64.9 m (95% CI 52.9-76.9). Factors associated with improved OS on 

post-PARPi CT in the MVA included best olaparib response of non-disease 

progression (p�.003, HR 0.28), optimal initial debulking (p�.01, HR 

0.36) and pre-PARPi Plt sensitivity (p�.05, HR 0.46). Conclusions: These 

data indicate potential for meaningful responses to CT in BDOC pts with 

PARPi resistance. Analysis to identify molecular predictors of response is 

ongoing. 

RR ([n responses]/[n evaluable]) 

Regimen 

RECIST GCIG 

Plt single agent/combination 16/37 20/35 

Tx single agent 4/9 3/7 

PLD single agent 1/8 4/11 

Others 1/4 1/5 

Total 22/58 (38%) 28/58 (48%) 


4:30 PM-5:30 PM 

Phase I/II study of weekly paclitaxel with or without MLN8237 (alisertib), 

an investigational aurora A kinase inhibitor, in patients with recurrent 

epithelial ovarian, fallopian tube, or primary peritoneal cancer (OC), or 

breast cancer (BrC): Phase I results. Presenting Author: Gerald Steven 

Falchook, Department of Investigational Cancer Therapeutics, University of 


Background: Preclinical data indicate that inhibiting aurora A kinase (AAK), 

a key mitotic regulator, in OC can enhance the activity of taxane-based 

chemotherapy. This is the first clinical study to evaluate the AAK inhibitor 

MLN8237 (A) in combination with paclitaxel (P). Methods: Eligible women 

(aged �18 y) had previously treated, metastatic or locally recurrent OC or 

BrC. OC pts had previously received a platinum and taxane, and had 

disease recurrence within 12 mo of discontinuing platinum. Pts received IV 

P (D1, 8, 15) with oral A (enteric coated tablet, 3 d on, 4 d off, wkly for 3 

wks) in 28-d cycles. Doses were escalated in a 3�3 schema. Phase I 

endpoints were safety, response by RECIST and CA125, and pharmacokinetics 

(PK). Results: 28 pts were treated at doses of P80 mg/m2 � A10 mg 

BID (n�5), P80�A20 (n�6), P60�A20 (n�4), P60�A30 (n�6), 

P60�A40 (n�4) and P60�A50 (n�3). 25 pts had OC (20 ovarian, 4 

primary peritoneal, 1 mullerian) and 3 BrC. Median age was 59 y (range 

37–72). Pts received a median of 2.5 (1–16) and 2.5 cycles (1–15) of A 

and P, respectively. 11 pts are ongoing. 3 pts had DLTs: Gr 4 diarrhea 

(P80�A20), Gr 3 stomatitis (P80�A20) and Gr 4 neutropenia for �7 d 

with fever (P60�A30). MTD has not yet been reached. 27 pts had �1 

drug-related adverse event (AE); most common were neutropenia (n�18), 

anemia (n�13) and nausea (n�12). 21 pts had Gr �3 drug-related AEs; 

the most common was neutropenia (n�15). 5 pts had drug-related SAEs. 

No pts have died on study. Preliminary PK data (n�24) indicated fast 

absorption of A with a median Tmax of 3 hr. Geometric means of A AUC0–12hr on D3 were 3740 nM*hr (CV: 22%), 7180 nM*hr (31%), 11,900 nM*hr 

(49%) and 15,100 nM*hr (72%) at 10, 20, 30 and 40 mg BID, 

respectively. A exposures increased approximately dose proportionally. 

Partial responses by RECIST (n�5) and/or CA125 (n�7) in 8 pts (29%; 7 

OC, 1 BrC); 3 pts had stable disease �6 mo. Conclusions: Emerging data 

from this first combination study suggest that P�A is generally well 

tolerated and has antitumor activity in pts with OC/BrC. Dose-escalation is 

ongoing to determine the recommended phase II dose. 


4:30 PM-5:30 PM 

A novel autologous oxidized whole-tumor antigen vaccine therapy for 

recurrent ovarian cancer. Presenting Author: Lana Kandalaft, University of 

Pennsylvania, Philadephia, PA 

Background: Despite surgical and chemotherapeutic advances, the death 

rate from ovarian cancer has not changed. We report here an enhanced 

dendritic cell vaccine platform developed for clinical testing. Furthermore 

we report the application of this novel platform comprising of dendritic cell 

(DC)-based autologous whole tumor antigen vaccination in a pilot study of 

patients with recurrent ovarian cancer. Methods: To determine the optimal 

tumor lysate preparation for loading DCs, ovarian tumor lines were prepared 

by HOCl-oxidation, UVB-irradiation or freeze and thaw. Normal donor DCs 

were evaluated for tumor lysate uptake, cytokine and chemokine productions 

and phenotype. The optimal lysate preparation, was used in a phase I 

study where five patients with recurrent ovarian cancer with available tumor 

lysate from secondary debulking surgery underwent intranodal vaccination 

with OC-DC, an autologous DC preparation pulsed with HOCL oxidized 

autologous tumor cells. Feasibility, safety, and biological and clinical 

efficacy were evaluated. Results: Normal donor DCs pulsed with HOCloxidized 

tumor lines demonstrated the highest tumor lysate uptake, 

matured efficiently after LPS and IFN-gamma stimulation, and produced 

higher levels of proinflammatory cytokines and chemokines. In vitro, these 

lysates loaded DCs primed T cell responses against ovarian tumor associated 

antigens and effectively expanded against tumor specific T cells from 

donors and patients. Therapy was feasible and well tolerated in all subjects. 

Vaccination with OC-DC produced limited grade 1 toxicities and elicited 

tumor-specific T cell responses. Moreover specific HLA-A2-restricted 

responses were documented following vaccination and HER-2/neu specific 

T cells were expanded following 10 days of in vitro culture. Patients 

exhibiting immune response demonstrated clinical benefit including two 

patients who demonstrated remission inversion on vaccine maintenance. 

Conclusions: We developed a DC-HOCl oxidized whole tumor lysate vaccine 

which was safe and well-tolerated by patients. The vaccine was highly 

proinflammatory and elicited cellular and humoral anti-tumor responses 

establishing a platform for immune-combinatorial therapy. 



4:30 PM-5:30 PM 

Phase II trial of temsirolimus and bevacizumab for initial recurrence of 

endometrial cancer. Presenting Author: Mark H. Einstein, Albert Einstein 

College of Medicine, Bronx, NY 

Background: We report the interim results of the endometrial arm of a 

multi-tumor protocol using temsirolimus and bevacizumab in endometrial 

cancer (EMCA) patients at the time of their initial recurrence. The primary 

aim of this trial is to assess treatment efficacy in terms of both confirmed 

tumor response and 6-month progression free survival (PFS). Methods: 

Women with a performance status of 0 or 1 who have had their first 

recurrence for EMCA were eligible. Subjects who had chemotherapy as part 

of their adjuvant treatment after front line surgical staging were also 

eligible. The regimen included Temsirolimus 25 mg IV weekly followed by 

bevacizumab 10mg/kg IV on days 1 and 15 of a 28 day cycle. A modified 

two-stage Simon design with fixed sample size was adopted with the null 

hypothesis being that the true tumor response rate is at most 25% and the 

true 6 month PFS rate is at most 50%. Results: We enrolled 26 evaluable 

subjects to the first stage of which one did not proceed with treatment. The 

median age at enrollment was 60 (range 40-80). 22 (85%) were white and 

19 (73%) were not Hispanic/Latino. 19 (73%) of subjects had prior 

raditation therapy, with 4 having a prior para-aortic boost. 5 (20%) subjects 

had a confirmed PR and 12 (48%) were progression-free at 6 months, 

which fell short of the futility stopping rule. An additional 5 (20%) subjects 

had a best response of confirmed SD, so 10 (40%) had overall clinical 

benefit from this regimen. AEs attributable to treatment were modest and 

included 16 grade 3 adverse events, of which the most common ones 

included hypertension, hyperglycemia, and neutropenia. There were 2 

grade 4 events that were possibly treatment related including a duodenal 

perforation and an anorectal infection. Conclusions: While there was 

clinical benefit of this regimen in women at the time of their first recurrence 

of EMCA, the combination of temsirolimus and bevacizumab did not 

achieve our prespecified efficacy assumptions. This differs from what has 

been reported with this combination as a second line therapy for recurrent 

EMCA, where prespecified response assumptions differ. Also, the regimen 

had comparable safety and toxicity to other cytotoxic chemotherapy 

regimens used in this setting. 


4:30 PM-5:30 PM 

Efficacy and safety of the APE (actinomycin D, cisplatin, etoposide) 

regimen for the management of high-risk gestational trophoblastic neoplasia. 

Presenting Author: Catherine Lhomme, Institut Gustave Roussy, 


Background: Patients (pts) with high risk gestational trophoblastic neoplasia 

(GTN) or who fail low risk single agent chemotherapy (CT) require multi 

agent CT to be cured. The most common regimen is etoposide (E), 

methotrexate and actinomycin D (A) alternating weekly with cyclophophamide 

and vincristine (EMA/CO). Cisplatin (P) is a very active drug but its 

role is controversial and usually restricted to second line. We report results 

of a platinum based therapy: APE. Methods: We evaluated the efficacy and 

safety on 103 pts treated at Institut Gustave Roussy (IGR) (n�80) or other 

French centers (n�23) between 1983 and 2010 with APE for high risk 

GTN (defined by IGR criteria [Azab, Cancer, 1988] and/or FIGO score �6). 

Pts with brain metastasis were excluded. Results: Efficacy was evaluated on 

59 pts treated for high risk GTN in first line, and on 39 pts in �2nd line 

including 13 pts after multi agent CT. We excluded pts with placental site 

trophoblastic tumors (n�2), or with FIGO score �7 and without IGR criteria 

(n�3). Complete remission (CR) rate was 95%. Seven pts (7 %) relapsed 

and a second CR was obtained for all with surgery and/or CT. Only one 

patient died due to GTN, after successive CRs obtained with 3 regimens. 

Five year overall survival (median follow-up 6.6 years) was 98%. Toxicity 

was evaluated on 95 pts. No toxic death occurred. Given good efficacy and 

to avoid acute hematotoxicity and long-term G�1 neuro and ototoxicity 

APE regimen was modified as detailed in the Table (below). Long-term 

neuro (5 pts, G1), oto (2 pts, G1 and 2 pts, G2) and renal toxicities (1 pt, 

G1 ) were recorded. No long-term G2 toxicities were observed with APE3. 

One pt developed an AML 4 after 4cy APE and 6 cy EMA/CO. 37 pts of 40 

who wished to be pregnant succeeded and all of them had at least one live 

birth. Conclusions: With a 98% long-term overall survival rate, an excellent 

reproductive outcome, and no detectable long-term toxicity, APE-3 should 

be regarded as an alternative standard option to EMA/CO for high-risk GTN. 

A 0.3 mg/m2 /J E 100 mg/m2 /J Cisplatin Cycles N 

APE 1 J1–3,J14-15 J1–3,J14-15 100 mg/m²/J, J1 J1 � J28 38 

APE 2 J1–3 J1–3 100mg/m²/J, J1 J1 � J21 34 

APE 3 J1–3 J1–3 75mg/m²/J, J1 J1 � J21 23 


333s 


4:30 PM-5:30 PM 

Brief family history questionnaire for identification of Lynch syndrome in 

women with newly diagnosed endometrial cancer. Presenting Author: Sarah 

E. Ferguson, Princess Margaret Hospital, Toronto, ON, Canada 

Background: Endometrial cancer (EC) is often the sentinel cancer for 

women with Lynch syndrome (LS); however, it is underappreciated in this 

population. The Brief Family History Questionnaire (bFHQ) was developed 

to identify women with EC who have family histories suggestive of LS. The 

objective of our study was to evaluate the bFHQ compared to an extended 

family history (eFHQ) and medical record in identifying women with EC who 

may benefit from genetic cancer risk assessment. Methods: All women with 

newly diagnosed EC from July 2010 to June 2011 were asked to participate 

in a prospective screening protocol for LS which included completing two 

family history questionnaires; the bFHQ which is a 4-item self-report 

measure and the 37-item eFHQ administered by a research assistant. 

Family history was also extracted from the medical record. Using the bFHQ 

women were flagged as requiring additional investigation for LS based on 

predetermined criteria and the predictive ability of the flag was evaluated 

treating eFHQ as the gold standard. Comparisons were made between the 

bFHQ, eFHQ and medical record for families meeting Amsterdam II, 

Society Gynecologic Oncologist (SGO) 20-25% or the Ontario Ministry of 

Health (MOH) testing criteria for LS, using generalized estimating equation 

logistic regression models. Results: 119 (N � 182, 65%) consented to the 

study and 106 (89%) completed the bFHQ. The median age was 61 

(26-91). The number of women who met testing criteria by the eFHQ was 

17 (16%) and 33 (31%) were flagged by the bFHQ. The sensitivity, 

specificity, PPV and NPV of the bFHQ was 88.2%, 79.8%, 45.5% and 

97.3%. There was no significant difference in the number of women who 

met Amsterdam II or SGO 20-25% testing criteria between the bFHQ, 

eFHQ and medical record (P � 0.05). The numbers of women meeting 

MOH criteria using the bFHQ (N�16, 15%) and the eFHQ were similar 

(N�17, 16%) (P � 0.7); however, more women met MOH criteria using the 

bFHQ and the eFHQ compared to the medical record (N�8, 7.6%) (P � 

0.011; P � 0.006). Conclusions: The patient-administered bFHQ is a 

highly effective tool in identifying women who meet MOH testing criteria for 

LS and is a good screening tool to identify women with EC for further 

genetic assessment. 


4:30 PM-5:30 PM 

A snapshot of potentially personalized care: Molecular diagnostics in 

gynecologic cancer. Presenting Author: Elizabeth Sales, Massachusetts 


Background: Genetic abnormalities underlie the development of cancer. It 

has been proposed that tumors be recategorized by gene mutation such as 

BRAF in LG serous, TP53 in HG serous, and PIK3CA in clear cell and 

endometrioid tumors. These targets potentially represent an opportunity for 

personalizing cancer therapy. Methods: Gynecologic Oncology patients at 

the MGH Cancer Center can have their tumor genotyped for a panel of 

mutations by SNaPshot, a validated, CLIA approved assay developed by 

MGH that uses DNA from FFPE tissue to interrogate 160 site-specific 

mutations across 15 genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, 

IDH1, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, PTEN, TP53). At 

present SNaPshot has no validated endpoints in GYN Cancers but may help 

identify a useful clinical trial. Results: Between 5/17/10 and 10/17/11, 

125 patients consented to SNaPshot genotyping. Patients had a median 

age of 59 (24-78) yrs. Tumors were ovarian 70(56%), uterine clear, UPSC, 

or MMMT 16(13%), uterine endometrioid 10(8%), fallopian tube 8(6%), 

PPC 7(6%), cervical 6(5%), uterine sarcomas (3), ACUP (2), vulvovaginal 

(2), metastatic (1). A mutation was identified in 41(33%), with 9 of these 

(23%) having 2 or 3 (n�2) mutations. In the 85 ovarian, FT, and PPC 

cancers 33% were �ve, but 50% were in TP53. The low mutation rate for 

TP53 is likely explained by copy number abnormalities (Amplification). 

50% of the 10 uterine tumors were �ve, with 3 of those 5 having multiple 

mutations in the PIK3CA pathway, while 69% of the non-endometrioid 

uterine tumors had mutations. Only 20% of the vulvo-vaginal and Cx 

tumors had mutations, both PIK3CA. 19% of the purely serous tumors 

(n�58) had TP53 mutations, and 37% of the purely clear/endometrioid 

tumors (n�19) had mutations in PIK3CA, PTEN or AKT. Certain rare 

tumors did not have identifiable mutations: granulosa cell tumors (2), 

ovarian small cell (2). 5 pts with a PIK3CA mutation were enrolled on a 

clinical trial (2 phase II, 3 phase I, 3 uterine, 1 ovary, 1 cervix). 

Conclusions: SNaPshot can identify potentially important therapeutic 

targets. However, the incidence of �drugable� targets in ovarian cancer is 

low, and �5% subjects eventually were treated on a relevant clinical trial. 




4:30 PM-5:30 PM 

A comprehensive analysis of BRAF and KRAS mutation status in low-grade 

serous (LGS) and serous borderline (SB) ovarian cancer (OC). Presenting 

Author: Rachel Nicole Grisham, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: LGS OC develops in a step-wise pattern from serous cystadenoma 

to SB tumor to invasive LGSOC. LGSOC accounts for 6-22% of serous 

OC and is a chemoresistant disease. Prior studies have reported that 

LGS/SB ovarian tumors harbor BRAF mutations in 28-35% of cases, 

suggesting that LGS/SB OC may respond to mutant BRAF inhibitors. 

Methods: We genotyped 75 LGS and SB ovarian tumors for BRAF and KRAS 

hotspot mutations using a mass spectrometry based Sequenom assay. All 

samples were collected at MSKCC between 2000-2010. All specimens 

underwent two independent pathologic reviews for diagnostic confirmation 

and macrodissection to ensure 80% cellularity. The incidence and identity 

of BRAF and KRAS mutations were defined and results were correlated with 

stage, response to treatment, and outcome. Exon capture sequencing is 

underway to sequence all coding exons of 230 cancer associated genes to 

identify additional targetable alterations in LGS/SB OC. Results: Of 75 

samples examined, 56(75%) were SB and 19(25%) LGS histology. 57% of 

samples showed KRAS mutation (KRAS�)(n�17, 23%) or BRAF mutation 

(BRAF�)(n�26, 35%). Mutation status was mutually exclusive. All BRAF 

� were V600E, KRAS� were G12D (n�9) or G12V (n�8). BRAF� was 

associated with early stage (I-II) at presentation and SB histology. 22 

(29%) patients were treated with chemotherapy, 2 (9%) with KRAS � and 

0 with BRAF�. 4(15%) BRAF� patients underwent resection of recurrent 

disease. All BRAF� patients are alive without evidence of disease at a 

median follow-up of 43.3 months (range 1.9- 129.3 months). Conclusions: 

V600E BRAF mutations are present in 35% of cases of SB/LGS ovarian 

cancer. Presence of BRAF � in SB/LGS OC is associated with good 

prognosis and surgical cure of disease. Patients with SB/LGS OC who 

require systemic therapy are unlikely to have BRAF�. Our group is 

performing a detailed search for additional targetable alterations in 

multiple signal transduction pathways through next generation sequencing 

technology. 

KRAS� BRAF� WT for KRAS/BRAF p value 

Stage 

I/II 10 (58.8%) 24 (92.3%) 11 (34.4%) �0.001 

III/IV 7 (41.2%) 2 (7.7%) 21 (65.6%) 

Histology 

SB 14 (82.4%) 25 (96.2%) 17 (53.1%) �0.001 

LGS 3 (17.6%) 1 (3.8%) 15 (46.9%) 


4:30 PM-5:30 PM 

Application of micro-RNA (miRNA) expression profiles for prognostication 

in low-risk endometrial carcinoma (LEC). Presenting Author: Johanne 

Ingrid Weberpals, The Ottawa Hospital, Ottawa, ON, Canada 

Background: Reliably predicting which LEC patients are most likely to recur 

is a challenge for the clinician with implications on adjuvant therapy. 

MiRNAs have been exploited for diagnosis and prognostication in a number 

of malignancies. We hypothesize that miRNA expression profiles differ in 

tumors from patients with recurrence compared to those without recurrence. 

Methods: The inclusion criteria for this study are informed consent, 

stage 1 disease, grade 1 or 2 tumors and endometrioid histology. RNA was 

extracted from formalin-fixed paraffin-embedded tissues and miRNA profiling 

was done using Agilent Human miRNA. Differentially expressed 

miRNAs were identified using GeneSpring GX software and the two groups 

were compared using the student t-test. Results: The expression levels of 

866 miRNAs were determined from LEC patients with recurrence (n�15) 

and without recurrence (n�16). The mean follow-up interval was 61.5 

months. The average age of cancer diagnosis for patients with and without 

recurrence was 60.2 (range 42-75) and 59.7 (range 44-86), respectively 

(p�0.91). Three of 15 patients with recurrence and 6 of 16 patients 

without recurrence received adjuvant brachytherapy following their primary 

surgery (p�0.43). 17 miRNAs were identified which can distinguish 

between the tumors with recurrence and those without recurrence (p�0.05). 

MiR-146a, miR-18a, miR-222, and miR-30a showed the highest fold 

change difference (�5 fold) in the tumors with recurrence compared to that 

did not recur. A decision tree prediction model for recurrent LEC was 

developed where a miRNA cutoff was used as a branch in the decision tree. 

This model identified those patients who were most likely to recur based on 

the expression of 4 dysregulated miRNAs (miR-222, miR-361-3p, miR- 

181c and miR-125b). Conclusions: These preliminary results show the 

miRNA expression profile differs among LEC and can be used to distinguish 

an aggressive sub-group. Should future validation studies confirm this 

result, this information would be valuable in the design of a biomarker 

study to help decide which patients would benefit most from extended 

adjuvant treatment. 


4:30 PM-5:30 PM 

Topotecan plus carboplatin versus standard therapy with paclitaxel plus 

carboplatin (PC) or gemcitabin plus carboplatin (GC) or carboplatin plus 

pegylated doxorubicin (PLDC): A randomized phase III trial of the NOGGO- 

AGO-Germany-AGO Austria and GEICO-GCIG intergroup study (HECTOR). 

Presenting Author: Jalid Sehouli, Department of Gynecology, European 

Competence Center for Ovarian Cancer, Charité Campus Virchow Klinikum, 


Background: We present the efficacy data from a phase III study of 

topotecan (T) plus carboplatin (C) versus standard therapy with paclitaxel 

plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin 

plus pegylated doxorubicin (PLDC). Methods: From 02/07 to 12/09, 590 

pts were screened and 550 pts were randomized to either T (0.75mg/m²/d1- 

3/q21d) � C (AUC 5/d1/q21d) or to standard therapy with CP or GC or 

PLDC based on patient preference. Progression free survival at 1 year was 

defined as primary endpoint. Results: Median number of cycles was 6 

(range 0-9) in both arms. Most patients preferred GC (78%) in the standard 

therapy arm.. Best Response (CR�PR) was 73.1% (95%CI) and 75.1% 

(95%CI) for the CA. Median follow-up was 18 (0-52) months for TC and 20 

(0-48) months for standard therapy. TC failed to show any advantage 

regarding 1-yr.-PFS or OAS. Conclusions: The combination of topotecan 

plus carboplatin failed to improve PFS or OAS in platinum sensitive 

relapsed ovarian cancer. In addition, carboplatin plus gemcitabine was well 

tolerated with lower rates of severe and long-lasting (neuropathy) toxicities 

compared to paclitaxel-carboplatin. 

1 year PFS rate (%): p�0.215 

PFS, median months (95%); p�0.472 

OAS, median moths (95%), 

p�0.340 

TC 

arm 

37.0% 

10 mo 

(9.2-10.8) 

25 mo 

(22.4-27.6) 

CP 

arm 

49.3% 

12 mo 

(9.1-14.9) 

29 mo 

(23.4-34.6) 

GC 

arm 

36.8% 

10 mo 

(9.1-10.9) 

33 mo 

(26.8-39.7) 

Neutropenia G3–4; p�0.015 27.8% 34.2% 40.7% 

Thrombocytopenia G3–4; p2; p2; p�0.073 10.0% 17.7% 8.5% 

Hand-foot syndrome G>2 0% 0% 0% 

Mucositis G>2p�0.380 3.0% 6.3% 3.7% 

Hypersensitivity, allergic reaction G>2; 

p�0.100 

15.2% 12.7% 8.5% 

Early treatment discontinuation 

(toxicity related, < 6 cycles); p�0.162 

15.9% 7.6% 13.2% 


4:30 PM-5:30 PM 

Randomized, phase III study of carboplatin plus paclitaxel for 8 cycles 

(CP8) versus carboplatin x 8 cycles plus paclitaxel x 4 cycles (C8P4) in 

advanced ovarian, fallopian, or primary peritoneal carcinoma. Presenting 

Author: Aristotelis Bamias, HECOG and University of Athens, Athens, 

Greece 

Background: The combination of carboplatin/paclitaxel represents the 

standard 1st-line chemotherapy in advanced OC, FC, and PPC. The optimal 

duration of paclitaxel treatment has not been defined, while its use is 

associated with cumulative neurotoxicity in about 50% of patients, which 

becomes long-term in 15-20% of cases. We, therefore, designed a 

randomized study to investigate the effect of administering 4 instead of 8 

cycles of paclitaxel in the combination carboplatin/paclitaxel on efficacy 

and tolerability of this treatment. Methods: Patients with FIGO stages IIC-IV 

OC, FC, PPC were included. Carboplatin AUC 6 and paclitaxel at 175 

mg/m2 were used. Both agents were administered for 8 cycles in the CP8 

arm, while paclitaxel was administered only for 4 cycles in the C8P4. The 

study was powered to detect a � 15% difference in survival rate to a 

baseline rate of 50 % at the 3-year time point. Results: 389 pts were 

randomized (2/2004-1/2008) and 380 were eligible for analysis (CP8: 

192, C8P4:188). The distribution (CP8 vs C8P4) of baseline characteristics 

were: stage III: 78% vs. 76%; IV: 12% vs. 15%, residual disease 0 cm: 

25% vs. 22%, ECOG PS 0: 68% vs. 64%, serous carcinomas: 79% vs. 

68%, tumor grade III: 56% vs. 63%. During a median follow up of 72.3 

months 231 patients (111 [58%] in CP8 arm and 120 [64%] in the C8P4 

arm) have died. Median PFS was significantly shorter in the C8P4 arm 

(21.41 vs. 16.46 months, HR [95% CI]: 1.36 [1.07-1.71], Wald’s 

p�0.011), while OS was similar between the two arms (53.41 vs. 46.59 

months, HR [95% CI]: 1.18 [0.91-1.53], Wald’s p�0.211). Lower grade 3 

or 4 neurotoxicity (1.9% vs. 10.8%, p� 0.001) but higher myelotoxicity 

(neutropenia 38.8% vs. 28.8%, p�0.031; thrombocytopenia 20% vs. 

8.3%, p�0.004) was observed in the C8P4 arm. Conclusions: Lowering the 

total number of cycles of paclitaxel in 1st-line chemotherapy of advanced 

OC, FC, PPC resulted in similar OS but shorter median PFS and is not 

recommended in this setting. The reduction of neurotoxicity by limiting the 

total paclitaxel cycles to 4 is achieved at the expense of higher myelotoxicity. 



4:30 PM-5:30 PM 

Use of HE4 and CA125 to predict surgical outcome and for prognostic 

value for progression-free survival (PFS) and overall survival (OS) in primary 

epithelial ovarian cancer (EOC) patients (pts). Presenting Author: Ioana 

Braicu, Charité University Department of Gynecology, Campus Virchow 

Clinic , Berlin, Germany 

Background: Optimal surgical cytoreduction and response to platinum (P) 

based chemotherapy (ChTh) remain the cornerstones of therapeutic management 

of primary EOC. Aim of this study was to analyze the predictive 

role of HE4 and CA125 as biomarkers (BM) for clinical outcome in primary 

EOC pts at diagnosis and during subsequent follow-up. Methods: In the 

European OVCAD project 275 pts with primary EOC were enrolled. Pts were 

eligible if radical cytoreductive surgery and P-based ChTh were applied. 

Plasma collected at first diagnosis and 6 months after 1st line ChTh in 

P-sensitive pts was analyzed for HE4 and CA125 levels using ELISA and 

Luminex technique, respectively. Results: Complete cytoreduction with no 

residual tumor disease (RTD) was obtained in 69.9% pts. HE4 and CA125 

expression in plasma at first diagnosis correlated with RTD, p � 0.002 and 

p�0.002, respectively. The sensitivity (SE) and specificity (SP) of the 

combinative use of both BM in predicting RTD was 64.8% and 73.5%, 

respectively. Pts having over-expression of both BM in plasma had a 6.1 

greater risk for RTD (p�0.001, OR: 6.107, 95% CI 2.41-15.46). Presistance 

occurred more frequently when both BM were over-expressed 

(p�0.028, OR� 3.1, 95%CI 1.13-8.46). Elevated BM levels during 

follow-up predicted recurrence (SE 90% and SP 71% for CA125 �55U/ 

ml; SE 72.7% and SP 81.4% for HE4 �150pM) and when HE4 or CA125 

were positive, a SE of 86.4% and SP of 72.9% were achieved. Elevated 

CA125 and HE4 at 6 months following adjuvant therapy was associated 

with significantly poorer PFS (p�0.001, HR 9.6, 95%CI 3.93-23.44 with 

elevated HE4 or CA125, and HR�50.52, 95%CI 14.44-176.78, with 

elevated HE4 and CA125) and OS (p�0.001, HR�7.42 95%CI 1.43- 

38.42 with elevated HE4 or CA125 and HR�28.38 95%CI 6.50-123.97 

with elevated HE4 and CA125). Conclusions: The combinative use of HE4 

and CA125 appears to have a significant value in predicting optimal 

surgical outcome and development of P resistance disease in EOC pts. 

Elevated plasma levels 6 months after 1st line ChTh significantly correlate 

with OS and PFS in P-sensitive pts. 


4:30 PM-5:30 PM 

Use of an optimized primary ovarian cancer xenograft model to mimic 

patient tumor biology and heterogeneity. Presenting Author: Zachary C. 

Dobbin, University of Alabama at Birmingham, Birmingham, AL 

Background: Current xenograft and transgenic models of ovarian cancer are 

mainly homogeneous and poorly predict response to therapy. Use of patient 

tumors may represent a better model for tumor biology and offer potential to 

test personalized medicine approaches, but poor take rates and questions 

of recapitulation of patient tumors have limited this approach. We have 

developed a protocol for improved feasibility of such a model and examined 

its similarity to the patient tumor. Methods: Under IRB and IACUC approval, 

23 metastatic ovarian cancer samples were collected at the time of tumor 

reductive surgery. Samples were implanted either subcutaneously (SQ), 

intraperitoneally (IP), in the mammary fat pad (MFP), or in the subrenal 

capsule (SRC) and monitored for tumor growth. Cohorts from 8 xenolines 

were treated with combined carboplatin and paclitaxel or vehicle, and 

response to therapy compared between xenografts and patients. Expression 

of tumor-initiating cell (TIC) markers ALDH1, CD133, and CD44 was 

assessed by immunohistochemistry in tumors from patients and treated 

and untreated xenografts. Results: At least one SQ implanted tumor 

developed in 91.3% of xenografts, significantly higher than in the MFP 

(63.6%), IP (23.5%), or SRC (8%). Xenografts were similar in expression 

of putative TIC’s compared to patient tumors. The patients and the 

xenografts also have similar responses to chemotherapy in that xenografts 

from patients with a partial response responded more slowly than those 

from patients achieving a complete response (45 vs 21 days, p�.004). 

Treated xenografts were more densely composed of TICs. ALDH1 increased 

to 36.1% from 16.2% (p�0.002) and CD133 increased to 33.8% from 

16.2% (p�0.026). Conclusions: Xenoline development can be achieved at 

a high rate when tumors collected from metastatic sites are implanted SQ. 

These xenografts are similar to patient tumors with regard to chemotherapy 

response and TIC expression.. This model may be a more accurate model 

for in vivo pre-clinical studies as compared to current models. Also, as 

treated xenografts become chemoresistant, this model is well positioned to 

evaluate targeted therapies aimed at the most aggressive populations in a 

heterogeneous tumor. 


335s 


4:30 PM-5:30 PM 

Functional profiling of clear cell ovarian cancer. Presenting Author: Rowan 

Miller, The Institute of Cancer Research, London, United Kingdom 

Background: Clear cell ovarian cancer represents up to 15% of epithelial 

ovarian cancers. In comparison to other subtypes, clear cell ovarian 

carcinomas have a poorer prognosis and are relatively resistant to standard 

platinum based chemotherapy. Recently, loss of function mutations in the 

tumour suppressor gene ARID1A were identified in up to 50% of ovarian 

clear cell carcinomas. We have adopted an integral functional and 

molecular profiling approach as a route to identify new genetic dependencies 

and therapeutic targets for this disease. Methods: Clear cell ovarian 

cancer cell lines were functionally profiled using high throughput screening 

with chemical and siRNA libraries. This has been integrated with molecular 

profiling data generated from exome and transcriptome sequencing to aid 

the discovery of novel targets. Results: Using functional screens we have 

now identified critical gene dependencies and potential therapeutics in a 

series of clear cell ovarian cancer models. The comparison of functional 

viability profiles for models characterized by ARID1A loss of function 

mutations is now enabling an analysis of synthetic lethal effects that could 

be used to target clear cell ovarian cancers carrying these mutations. 

Conclusions: The work undertaken so far provides the framework for the 

discovery of therapeutic targets for clear cell ovarian cancer using an 

integrated approach. Revalidation of these preliminary results is now 

underway to characterize new genetic dependencies for this disease. 


Effect of weekly administration of bevacizumab, gemcitabine, and oxaliplatin 

in patients with heavily pretreated ovarian cancer. Presenting Author: 

Yuji Ikeda, Ohki Memorial Cancer Center for Women, Tokorozawa, Japan 

Background: The combination therapy of gemcitabine with oxaliplatin 

(GEMOX) has high activity in patients with ovarian cancer. Bevacizumab 

(B), a vascular endothelial growth factor specific antibody, enhances 

chemotherapeutic efficacy through its anti-angiogenic function in various 

types of tumors. We evaluated the effect of weekly administration of B and 

GEMOX in heavily-pretreated patients with recurrent or refractory ovarian 

cancers (ROC). Methods: Nineteen patients with ROC received at least three 

or more cycles of weekly-B and GEMOX consisting of B (2mg/kg), 

gemcitabine (300mg/m2 ) and oxaliplatin (30mg/m2 ). The treatment was 

continued until the development of progressive disease. The response and 

adverse effects (AE) were evaluated using the response evaluation criteria 

in solid tumors (RECIST), CA125 Gynecologic Cancer Intergroup (GCIG) 

criteria, and common terminology criteria for adverse events (CTCAE) 

version 3.0. Results: Seventeen (89%) of the 19 patients were primarily 

stage 3 or 4. Fifteen patients (79%) had received more than three regimens 

of chemotherapy. All patients were pretreated with a platinum-containing 

regimen within 6 months and 16 of these patients (84%) were pretreated 

within 3 months. According to the RECIST evaluation, 2 patients (11%) 

had a complete response (CR), 6 patients (32%) had a partial remission 

(PR) and 5 patients (26%) had a stable disease (SD). The response rate 

(RR; CR�PR) and clinical benefit rate (CBR; CR�PR�SD) were 42% and 

68%, respectively. In 10 patients with serous adenocarcinoma, RR was 

60%. In 6 patients pretreated with weekly B and pegylated liposomal 

doxorubicin (PLD), RR was 50%. Median progression-free survival was 5 

months (range: 2-11 months). Hematological adverse effects (AE) with 

grade 3/4 were leukopenia (16%), neutropenia (10%), thrombocytopenia 

(5%), however, all AE were manageable. Conclusions: Weekly B and 

GEMOX administration had significant activity with mild AE in patients with 

ROC especially in serous adenocarcinoma. Notably, the activity was also 

observed in patients pretreated with weekly B and PLD. These results 

warrant further prospective study. 




Phase Ib study of AMG 386 in combination with paclitaxel (P) and carboplatin 

(C) in high-risk stage I and stages II-IV epithelial ovarian, primary peritoneal, or 

fallopian tube cancers. Presenting Author: Antonio Casado, Hospital Clínico San 

Carlos, Madrid, Spain 

Background: AMG 386 is a first-in-class investigational peptibody that inhibits 

angiopoietin-1/-2 binding to Tie2. We report on an ongoing, 2-part, open-label 

phase 1b study of AMG 386 � PC as first-line treatment of high-risk ovarian 

cancer. Methods: Part 1 enrolled women, GOG performance status 0/1, with 

newly diagnosed, FIGO high-risk stage I or stages II, IIIA-B (primary debulking 

surgery; PDS) or IIIC & IV (PDS or interval debulking surgery; IDS) ovarian 

cancer. Patients (pts) received AMG 386 at 15 mg/kg QW IV � P at 175 mg/m2 Q3W � C at AUC 6 Q3W for 6 cycles (or until disease progression or 

unacceptable toxicity); AMG 386 was withheld 4 weeks pre-/post-debulking. Pts 

completing 6 cycles continued AMG 386 QW as maintenance for up to 18 

months. Part 1: incidence of dose-limiting toxicities (DLTs) dictated expansion 

to 25 pts (part 2). Primary endpoint: DLT incidence; secondary: adverse events 

(AEs), PK and efficacy measures. Results: At the time of analysis, 16 pts had 

received �1 dose of AMG 386 � PC and completed �2 cycles of therapy (PDS, 

n�8; IDS, n�8). No DLTs occurred in part 1. 15 pts continue on-study; 6 pts 

have received a median of 6 doses of maintenance AMG 386. One pt 

discontinued due to progression. AEs are tabulated below. One serious AE 

(decreased appetite; maintenance phase) required hospitalization. AE incidence 

and type were similar for PDS or IDS. Combination therapy did not affect the PK 

of AMG 386 or PC. Non-neutralizing antibodies against AMG 386 were detected 

in 2 pts. Conclusions: AMG 386 at 15 mg/kg QW � PC is tolerable in pts with 

high-risk ovarian cancer. AMG 386 maintenance was tolerated and associated 

with few AEs. Updated toxicity and efficacy data will be presented. 

AEs 

Any; n (%) 

Of specific interest (grade 3 

Neutropenia 

Decreased appetite 

Localized edema 

Syncope 

Thrombocytopenia 

Anemia 

Ascites 

Hypertension 

Hypokalaemia 

Psoriasis 

All grade >4 

Neutropenia 


Grade 5 

AMG 386 � PC 

n � 16 

16 (100) 

1(6) 

1(6) 

1(6) 

8 (50) 

5 (31) 

0 

0 

2 (13) 

2 (13) 

1(6) 

1(6) 

1(6) 

1(6) 

1(6) 

4 (25) 

3 (19) 

1(6) 

0 

AMG 386 maintenance 

n � 6 

4 (67) 

0 

0 

0 

2 (33) 

0 

1 (17) 

1 (17) 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 


ESA use in women with cancer: Consequences of the 2008 FDA clinical 

alert. Presenting Author: Kimberly M. Dickinson, Warren Alpert Medical 

School of Brown University, Providence, RI 

Background: Erythropoietin stimulating agents (ESA) are used clinically as 

an alternative to blood transfusions in cancer patients suffering from 

symptoms of anemia. However, more recent randomized controlled trials of 

ESA usage concluded that its use is associated with an increased risk of 

tumor progression and death. As a result, in July 2008 the FDA issued a 

clinical alert restricting the use of ESA. A reduction in the prescribing of 

ESA was immediately seen but changes in blood transfusion rates have not 

been examined. Methods: A retrospective chart review was conducted 

drawing from patients under treatment in the Program in Women’s 

Oncology at Women and Infant’s Hospital from one year before the clinical 

alert (August 2007-July 2008) to one year afterward (August 2008-July 

2009). The primary outcomes were blood transfusion and ESA administration 

rates compared across the two time periods. Results: The study 

population (n�776) included patients with a cancer diagnosis who 

received chemotherapy during one or both time periods. 165 (21.3%) 

patients received ESA treatment. The total number of ESA treatments 

administered in the study period of interest was 1,277, with the majority 

(60%) given prior to the FDA alert. The mean number of ESA treatments in 

the first time period was 6.39 per person as compared to 0.61 per person in 

the second time period. Of the study population, 186 (23.8%) patients 

received at least one blood transfusion. A total of 463 blood transfusions 

were administered during the entire study period but a significant difference 

was not observed in the proportion of those delivered prior to the FDA 

alert (52%) versus after the FDA alert (48%). The average number of 

transfusions given in the first time period was 2.34 per person, as 

compared to 2.17 per person in the second period. Conclusions: Our results 

indicate that despite a steep decline in the use of ESA for chemotherapyinduced 

anemia, blood transfusion rates were not significantly different 

between the two periods. Interestingly, a slight downward trend was 

observed from before the FDA alert to after the alert. While more work is 

needed to understand the implications of these findings, it suggests that 

resource utilization did not increase despite the reduction in ESA use. 


The combination of intravenous bevacizumab and metronomic oral cyclophosphamide 

for recurrent platinum-resistant ovarian cancer. Presenting 

Author: Emma L. Barber, Northwestern University, Department of Gynecologic 

Oncology, Chicago, IL 

Background: This study was undertaken to determine the progression free 

survival and overall survival in heavily pre-treated patients with recurrent 

ovarian carcinoma treated with bevacizumab and metronomic oral cyclophosphamide. 

Methods: An IRB-approved retrospective review was performed 

for all patients with recurrent ovarian, fallopian tube or primary 

peritoneal carcinomas treated with intravenous bevacizumab 10mg/kg 

every 14 days and oral cyclophosphamide 50mg daily between January 

2006 and December 2010. Response to treatment was determined by 

change in disease status according to RECIST criteria and/or CA-125 

levels. Results: Sixty-six eligible patients were identified with a median age 

of 58 years. Fifty-five patients (83%) originally had optimal cytoreduction 

and all were platinum resistant. Median time from diagnosis to beginning 

bevacizumab and cyclophosphamide was 36 months. Median number of 

prior chemotherapy treatments was 7.5 (range 3-16). Eight patients 

(12.1%) had side effects which required discontinuing bevacizumab and 

cyclophosphamide, most common were hypertension, proteinuria, and 

fatigue. There was one bowel perforation (1.5%). A complete response was 

noted in 7 patients (10.6%), partial response was seen in 21 patients 

(31.8%) with an overall response rate of 42.4%. Fifteen patients (22.7%) 

had stable disease and 23 (34.8%) had disease progression. Median 

progression free survival (PFS) for responders was 5 months (range 2-14) 

and 11 months (range 4-14) for those with a complete response. Median 

overall survival (OS) from start of bevacizumab and cyclophosphamide for 

responders was 20 months (range 2-56) and 9 months (range 1-51) for 

nonresponders. Conclusions: Bevacizumab and cyclophosphamide is an 

effective, well-tolerated chemotherapy regimen in heavily pre-treated 

patients with recurrent ovarian carcinoma which significantly improves PFS 

and OS in responders. Response rates were significantly better than the 

rates we have reported in this same group of patients receiving topotecan 

(22%) or liposomal doxorubicin (25%) and were superior to reported rates 

for single agent bevacizumab (18%) in patients with only 2-3 prior 

regimens. 


Carboplatin dosing in the treatment of epithelial ovarian cancer (EOC): A 

Gynecologic Oncology Group (GOG) study. Presenting Author: Roisin Eilish 

O’Cearbhaill, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Optimal carboplatin dosing (CPRx) for patients (pts) with renal 

dysfunction or low creatinine (Cr) values in the setting of malnutrition and 

ascites is unknown. Multiple methods have been utilized to estimate Cr 

clearance (CrCl) but these perform differently in pts with abnormal Cr 

values. We sought to determine 1) the relationship between adverse events 

(AE) and baseline CrCl used for CPRx; 2) the effect on CPRx of using 

Cockcroft-Gault (CG) �/- the NCI/CTEP recommended limits (CGL), Modification 

of diet in renal disease (MDRD) or Jelliffe Formula (J) renal function 

estimates. Methods: Retrospective data were drawn from pts treated on 

GOG 182, a phase III trial of carboplatin doublet vs triplet or sequential 

doublet combinations in stage III/IV EOC. For patient safety, the protocol 

was amended to assign the lower limit of Cr at 0.6mg/dl for CPRx. Area 

under the receiver operating characteristic curve (AUC) was used to 

describe associations between CrClJ and various AE. Sensitivity and 

positive predictive values (PPV) described the AE rate in pts with CrClJ �60ml/min. CPRx for each pt was calculated using J, CG, CGL and MDRD. 

Results: 3830 evaluable pts had a mean age 58.7yrs, mean BMI 26.8kg/m2 and mean baseline CrClJ 81.9ml/min (range 23.4-239). The AUC statistics 

(range 0.52-0.64) show that the log(CrClJ) was not a good predictor of 

grade �3 AE (anemia, thrombocytopenia, febrile neutropenia, auditory, 

renal, metabolic, neurologic). A cutoff value of CrClJ �60 ml/min would 

have deemed 15% of pts treated on GOG182 ineligible. The range of PPV 

for the above AEs in pts with CrClJ �60 ml/min was 1.8-15%. Using CG, 

CGL, MDRD instead of J for CPRx would have resulted in �10% decrease 

in CPRx in 21%, 32% and 12% of pts, respectively. Using CG, CGL, MDRD 

instead of J for CPRx would have resulted in �10% increase in CPRx in 

45%, 9.6% and 5.2% of pts, respectively. Conclusions: Our data do not 

support excluding patients with CrClJ �60ml/min from clinical trials. The 

new GOG guidelines replacing J with CGL affect CPRx. The clinical 

significance of this change with regards to toxicity, particularly in pts with 

abnormally low Cr values, is yet to be determined. 



Detection of disseminated tumor cells in bone marrow as an independent 

prognostic factor in primary ovarian cancer patients. Presenting Author: 

Pauline Wimberger, AGO and Department of Gynecology and Obstetrics, 

University of Duisburg-Essen, Essen, Germany 

Background: Detection of disseminated tumor cells (DTC) in the bone 

marrow (BM)of breast cancer patients is associated with poor outcome. 

Recent studies demonstratedthat DTC may serve as a prognostic factor in 

ovarian cancer.The aim of our study was to evaluate the impact of BM 

status on survival in a large cohort of ovarian cancer patients. Methods: 365 

patients with primary ovarian cancer were included into this three-center 

prospective study. BM aspirates were collected preoperatively from iliac 

crest. Disseminatedtumor cells were identified by immunocytochemistry 

using the pancytokeratin antibodyA45B/B3 and by cytomorphology. Patient 

outcomes were evaluated using a multivariable Cox regression model. 

Results: Disseminated tumor cells were detected in 28% of all BM 

aspirates. The number of CK-positive cells ranged from 1 to 42 per 2x106 mononuclear cells. DTC status did not correlate with any of the established 

clinicopathogical factors. The overall survival was significantly shorter 

among DTC-positive patients compared to DTC-negative patients (51 mo, 

95% CI: 35 – 67 mo versus 32 mo, 95% CI: 22 – 42 mo; p � 0.003). 

However, disease-free survival was not related to DTC-positivity. In the 

multivariable analysis, BM status, FIGO stage, nodal status, resection 

status and age were independent predictors of reduced overall survival. 

Interestingly, a subset of DTCs may have stem cell properties since a subset 

of these cells (128 out of 228 cases) were SOX2 positive, which is an 

embryonic stem cell marker. Conclusions: Tumor cell dissemination into 

bone marrow is a common phenomenon in ovarian cancer. DTC detection 

has the potential to become an important biomarker for prognostication and 

may be included as a therapeutic target in future concepts. 


What do 676 primary and recurrent ovarian cancer (OC) patients expect 

from their doctors and therapy management? Results of a German survey of 

the northeastern German Society of Gynecological Oncology (NOGGO). 

Presenting Author: Gülten Oskay-Özcelik, NOOGO, Berlin, Germany 

Background: The primary aim of this study was to investigate information 

needs and preferences among patients with ovarian cancer, focusing 

especially on doctor-patient relationships and therapy management. 

Methods: A 42-item questionnaire was developed and validated in a 

mono-centre phase I study and was then provided to primary and recurrent 

ovarian cancer patients via internet (online) or as a print-version. In the first 

part basic data (age, tumour status, therapy) were requested. In the second 

part, most of the questions try to evaluate the expectations and needs 

concerning their therapy management and doctor-patients communication. 

Results: From January to November 2009, a total of 676 (201 online; 475 

print version) patients with ovarian cancer from 44 German centres took 

part in the survey.The median age of the online group was 49 years (range 

19-84), for the print group 62 years (26-92). Nearly all patients (98.7%) 

had a primary surgery and a primary chemotherapy (89%). Asked for side 

effects during therapy, the most frequent answers were alopecia, paraesthesia/dysaesthesia 

and fatigue. Most of the patients were content with the 

completeness and understandability of the explanations about the therapies 

from their doctors . The three most important aspects, which were 

proposed by patients to improve therapy against ovarian cancer were: 

“Doctors should have more time for explanations”, “The therapy should not 

lead to any loss of hair”, and “The therapy should be more effective”. 

Conclusions: This study underlines the high need of ovarian cancer patients 

to discuss all details concerning treatment options and clinical management. 

As matter of fact, the physician involved in the treatment is the most 

important source of information. 


337s 


BRCA1 immunohistochemistry in high-grade serous ovarian cancers 

(HGS-OC) characterized for BRCA1 germ-line mutations. Presenting Author: 

David Michael Hyman, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: The optimal use of BRCA1 germline testing in patients with 

HGS-OC is unclear. Moreover, BRCA1 germline testing does not provide 

information on non-germline mechanisms of BRCA1 loss. We investigated 

the performance of BRCA1 immunohistochemistry (IHC) testing in HGS-OC 

with known BRCA1 mutation status. Methods: Eligible patients had 

HGS-OC, underwent surgery at a single institution between 1997 and 

2010, and were tested for germline BRCA1 mutations under IRB-approved 

protocols. FFPE tumor tissue was used in triplicate to construct a tissue 

microarray (TMA). Two pathologists, blinded to BRCA1 status, independently 

scored each sample as BRCA1 IHC present (normal) or absent 

(abnormal). Whole sections were stained for all samples with absent 

BRCA1 staining on TMA. A commercially available monoclonal antibody 

against BRCA1, clone MS110 from Calbiochem (OP92) was used with 

previously optimized conditions. Results: 123 samples (30 BRCA1 �; 93 

BRCA1 wild-type) were analyzed and 47 (38%) had abnormal BRCA1 IHC. 

Inter-observer agreement on BRCA IHC was high (kappa�0.87). BRCA IHC 

had a sensitivity of 83.3% (CI: 70.0-96.7%), specificity of 76.3% (CI: 

67.7-85.0%), PPV of 53.2% (CI: 38.9-67.5%), and NPV of 93.4% (CI: 

87.9-99.0%) for BRCA1 germline mutation. There was a trend towards 

improved overall survival in the BRCA IHC abnormal vs. normal patients 

(median survival 82 vs 61 wks, HR 0.70, p�0.12). Conclusions: BRCA1 

IHC is a reproducible and inexpensive test with a high NPV for absence of a 

BRCA1 germline mutation. The 22 (17.7%) cases with abnormal BRCA1 

IHC and wild-type BRCA1 germline status may have other mechanisms of 

protein loss such as promoter hypermethylation or somatic mutation and 

are currently being tested for these changes. This rate of non-germline 

BRCA1 loss in HGS-OC is consistent with data generated by the Tumor 

Cancer Genome Atlas Network. BRCA1 IHC may be useful as a reliable 

biomarker for risk stratification in HGS-OC. 

Germline BRCA1 status 

Wild-type Mutated 

BRCA1 IHC 

Normal 71 (57.2%) 5 (4.0%) 

Abnormal 22 (17.7%) 25 (20.2%) 


Correlative study of low serum creatinine and hematological toxicities in 

Japanese patients with ovarian cancer treated by dose dense TC therapy. 

Presenting Author: Koji Matsumoto, Medical Oncology Division, Hyogo 

Cancer Center, Akashi, Japan 

Background: Dose dense TC (ddTC) is a novel standard therapy for patients 

(pts) with advanced ovarian cancer, although hematological toxicities 

(hemTX), especially anemia, may increase as observed in NOVEL trial 

(JGOG3016). Low serum creatinine (LCr), especially below 0.7 mg/dl, may 

lead to overestimation of GFR. GOG announced that pts with LCr should use 

a minimum value of 0.7mg/dl to estimate GFR. The correlation between 

LCr and hemTX treated by ddTC is unknown. Methods: GFR was determined 

using the Cockcroft-Gault formula. Serum creatinine concentrations were 

measured using enzymatic assays. Minimum value of 0.7 mg/dl was not 

used during this period of time. The carboplatin clearance was then 

calculated by Calvert equation. HemTX were defined as, Grade 3 or 4 (by 

CTC-AE ver.4) neutropenia, anemia, and thrombocytopenia. Using electrical 

chart, frequency of hemTX and correlation between serum creatinine 

(less than 0.7 or not) were examined. Results: From Feb. 2010 to Dec. 

2011, 61 consecutive pts were treated with ddTC. LCr was observed in 

73% of pts. No treatment related death occurred. Among 61 pts, 50 

(82%), 31 (51%), and 12 (19.6 %) pts experienced Grade3/4 neutropenia, 

anemia and thrombocytopenia, respectively. HemTX in pts with LCr and the 

others were as in the Table. Conclusions: LCr is frequent in Japanese female 

pts. ddTC in practice setting seems safe, and hemTX of ddTC are similar 

with those observed in NOVEL trial. The rationale using a minimum value of 

0.7 mg/dl should be further studied by larger population, such as pts in 

NOVEL trial. 

G3/4 neutropenia G3/4 anemia G3/4 thrombocytopenia 

Pts with LCr 36 (80%) 24 (53.3%) 9 (20%) 

Pts without LCr 14 (87.5%) 7 (44%) 3 (18.8%) 




Neo-escape: Neoadjuvant extended sequential chemotherapy with adjuvant 

postoperative treatment for epithelial nonmucinous advanced inoperable 

peritoneal malignancy. Presenting Author: Christopher John Poole, 

University Hospital Coventry and Warwickshire NHS Trust, Coventry, 


Background: Neo-Escape was designed to exploit fully the modest non-cross 

resistance of carboplatin (CBDCA) and paclitaxel (ptx) in an extended 

sequential regimen, with dose-dense ptx, and address feasibility of combining 

gemcitabine (gem) with either CBDCA or ptx. Methods: A randomised 

phase II trial in patients (pts) with untreated (FIGO stage 3C/4) inoperable 

ovarian, fallopian, or primary peritoneal carcinoma to assess feasibility of 

two regimens of sequential neoadjuvant-then-adjuvant chemotherapy (CT); 

(a) CBDCA AUC 2.5 and gem 1000mg/m2 repeated days 1 and8q3wksx 

6 cycles, then ptx 175mg/m2 q 2 wks x 6 cycles (CG-P) or (b) CBDCA AUC 6 

q 3 wks x 6 cycles, then ptx 175mg/m2 and gem 2000mg/m2 q2wksx6 

cycles (C-PG). All pts were considered for delayed 1o debulking surgery 

after neoadjuvant CT. The 1o feasibility outcome was % pts completing 12 

cycles of CT. Using Fleming’s single stage procedure 44 patients on each 

arm were needed to test null hypothesis of feasibility �60% with 5% 

1-sided significance level and 90% power. 2o outcomes included safety, 

PFS and ORR. Pts were stratified by serum albumin, stage and tumor 

differentiation. Results: 75 pts were recruited Sept 2007 - May 2011 (28 

CG-P; 47 C-PG), median age 62 yr (range 21-75). Recruitment to CG-P 

closed early due to futility. 52% had albumin �35g/L, 68% FIGO stage 3C 

and 80% poorly differentiated tumors. 64% on CG-P and 55% on C-PG had 

debulking surgery as planned and a further 4% on CG-P and 13% on C-GP 

after completion of all CT. For CG-P 35% achieved 0cm, 35% �1cm and 

30% � 1cm residuum; for C-GP 34% 0cm, 13% �1cm and 34% �1cm, 

19% TBC. 14/28 pts on CG-P completed all 12 cycles (feasibility 50%; 

95% CI 31-67%); 37/47 pts on C-PG (feasibility 79% (95% CI 64-88). 

Main reason for early discontinuation was toxicity on CG-P and disease 

progression on C-PG. Similar proportions of pts on each arm had dose 

reductions (68%) or delays (86% on CG-P; 89% on C-PG), mainly for 

toxicity. 82% of pts experienced grade 3/4 toxicity on CG-P; 72% on C-PG. 

Median PFS for CG-P is 14.3 mths (95% CI 11.6-15.7mths) and 13.0 

mths (95% CI 11.5-15.4mths) for C-PG. Conclusions: CG-P was not 

feasible at these doses using pre-specified criteria, but C-PG is feasible. 


NKTR-102 in patients with platinum-resistant ovarian cancer (PROC): 

Modeling CA125 response and its correlation with tumor response. 

Presenting Author: Yen Lin Chia, Nektar Therapeutics, San Francisco, CA 

Background: NKTR-102 is a unique topoisomerase 1 inhibitor that provides 

continuous exposure to SN38. In heavily pretreated pts with PROC (median 

of 3 prior therapies; 27 pts were platinum refractory), 145 mg/m2 NKTR-102 given q14d or q21d demonstrated significant anti-tumor 

activity (JCO 28:7s, 5013). We present a PK/PD model for CA125 kinetics 

that can be used to project GCIG response as an aide to selecting dose and 

schedule. Methods: Data from 55 pts with PROC and elevated CA125 

(median baseline � 515 U/mL) were fit with a PK/PD model developed to 

correlate CA125 dynamics with SN38 conc-time profiles predicted from 

individual pt dosing history: d[CA125]/dt � Kin*exp(beta*t)*(1-[SN38]/ 

(IC50�[SN38]))-Kout*[CA125]. Results: CA125 profiles were well described 

by the model, with a population mean SN38 IC50 of 1.1 ng/mL. 

Typical min and max SN38 conc during treatment were 1.5 and 3 ng/mL 

for q14d and 0.9 and 2.4 ng/mL for q21d, indicating that both schedules 

resulted in SN38 exposure near the IC50. The half-life of CA125 decline 

was 6.4 days, similar to literature values. 46 of 55 pts had pre- and 

post-treatment tumor measurements for correlation of CA125 response and 

tumor size. Overall best response by GCIG and RECIST correlated in 57% of 

pts. 33% of pts with GCIG response showed declines in tumor size, albeit 

insufficient to classify as RECIST response. 72% of pts with GCIG SD 

showed at least SD by RECIST. CA125 vs time was simulated for 1000 pts 

receiving 145 mg/m2 NKTR-102 q14d or q21d, to allow comparison of 

CA125 and GCIG response between schedules (see table). The % pts per 

GCIG response was comparable between schedules, supporting use of the 

better-tolerated q21d regimen. Conclusions: The PK/PD model described 

CA125 profiles well, providing a tool to predict drug response from SN38 

PK data. Close correlation of CA125 with tumor size is consistent with 

historical use of CA125 as a surrogate marker. Predicted CA125 profiles for 

NKTR-102 q14d or q21d were similar, suggesting that the better-tolerated 

q21d schedule will produce results consistent with those from Ph 2. 

Model-predicted % pts by response. 

CR PR SD PD 

q14d 19 23 44 14 

q21d 16 22 46 16 


Changes of serum glycome in patients suffering from ovarian cancer. 

Presenting Author: Veronique Blanchard, Institute of Laboratory Medicine, 

Clinical Chemistry and Pathobiochemistry, Charité Berlin, Berlin, Germany 

Background: Protein glycosylation plays an important role in many biological 

processes. Most human serum proteins, with the exception of albumin, 

are glycosylated. Glycosylation is known to be altered with development of 

diseases such as cancer. In the case of ovarian cancer, tumor markers 

among them CA-125 that are clinically used are known to have poor 

specificity. In addition, they fail to detect the disease at an early stage. 

Therefore, better biomarkers are needed. The aim of the present research 

work is to identify new potential glycan biomarkers by analyzing the serum 

N-glycome of patients suffering from ovarian cancer Methods: Serum was 

collected from 67 patients as well as from 33 healthy age-matching 

women. N-glycans were released from 10 ul serum by PNGase F digestion, 

permethylated and subsequently analyzed by means of MALDI-TOF mass 

spectrometry. The SPSS software was used for the statistical analysis. 

Results: The N-glycome of patients was found to have more fucosylated 

structures, especially in tri- and tetraantennary sialylated glycans. The PCA 

analysis indicates that there are significant differences between the 

glycome of ovarian cancer patients in all stages of the disease and the 

glycome of healthy controls. We identified 14 potential structures that were 

divided in two categories, one of monofucosylated structures with high 

antennarity (sensitivity 94%, specificity 97%) and one containing highmannose 

structures and an asialylated structures (sensitivity 97%, specificity 

97%). Conclusions: Our study is the first trial to identify major 

differences between ovarian cancer sera and control sera, which could 

potentially be used in the future as biomarkers. 


Longitudinal health-related quality of life assessment: Implications for 

prognosis in ovarian cancer. Presenting Author: Donald Peter Braun, 

Cancer Treatment Centers of America, Zion, IL 

Background: Several studies in the oncology literature have demonstrated 

the prognostic value of baseline quality of life (QoL). However, there is little 

to no information on the prognostic effects of changes in QoL during 

treatment. We investigated whether changes in QoL could predict survival 

in ovarian cancer patients treated with an integrative model of care. 

Methods: We evaluated 137 ovarian cancer patients treated at our institution 

between Jan 2001 and Dec 2009 who were available for a minimum 

follow-up of 3 months. QoL was evaluated at baseline and after 3 months of 

treatment using EORTC-QLQ-C30. The QLQ-C30 incorporates a global 

scale, 5 function scales and 8 symptom scales. Patient survival was defined 

as the time between date of first patient visit and date of death from any 

cause/date of last contact. Cox regression was performed to evaluate the 

prognostic significance of baseline and changes in QoL scores after 

adjusting for age, treatment history and stage at diagnosis. Results: Mean 

age at diagnosis was 51.1 years. 28 patients were newly diagnosed while 

109 were previously treated. Stage at diagnosis was I, 16; II, 15; III, 72; IV, 

28; and 6 indeterminate. Median overall survival was 33.5 months (95% 

CI: 11.5-55.6 months). Baseline QoL scale predictive of survival upon 

multivariate analysis was nausea/vomiting (p�0.04). Associations between 

changes in QoL and survival were observed for global function, appetite loss 

and constipation. Every 10-point increase (improvement) in global function 

from baseline to 3 months was associated with a 10% decreased risk of 

death (HR�0.90; 95% CI�0.81 to 0.99, p�0.03). The corresponding 

HRs for 10-point increase (deterioration) in appetite loss and constipation 

scales were 1.20 (1.06 to 1.35; p�0.005) and 1.13 (1.02, 1.24; 

p�0.02) respectively. Conclusions: This exploratory study provides some 

preliminary evidence to indicate that ovarian cancer patients whose QoL 

improves within 3 months of treatment have a significantly increased 

survival time compared to those who fail to demonstrate improvement. 

These findings might be used in clinical practice to systematically address 

QoL-related problems of ovarian cancer patients throughout their treatment 

course. 



Technetium-99m sulfur colloid (TSC) as a phenotypic probe for predicting 

pharmacokinetics (PK) and palmar-plantar erythrodysesthesia (PPE) toxicity 

of pegylated liposomal doxorubicin (PLD) in patients (pts) with recurrent 

epithelial ovarian cancer (EOC). Presenting Author: Hugh Giovinazzo, 

University of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: There is significant variability in the PK and PD (efficacy and 

toxicity) of PLD. Clearance (CL) of PLD has been proposed to occur 

primarily via uptake by cells of the mononuclear phagocyte system (MPS) 

mainly located in the liver, spleen, and blood. TSC is a radioactive colloid 

used clinically for diagnostic and functional imaging of the MPS. Our aim is 

to evaluate TSC as a phenotypic probe of MPS activity, which may predict 

PLD PK and PPE toxicity in pts (n�9) with EOC. Methods: Prior to 

administration of PLD on cycle 1 day 1 (C1D1), TSC was administered at 

10 mCi IVP � 1. Dynamic planar and SPECT/CT images of the liver, spleen 

and hands were acquired using a gamma camera. Blood samples were 

collected up to 60 min after TSC and analyzed for radioactivity using a 

gamma counter. On C1D1, PLD was administered at 40 mg/m2 alone or at 

30 mg/m2 in combination with carboplatin IV over 1 to 3 h. Serial PK 

samples were obtained from 0h to 672h post PLD dose. Plasma was 

processed to measure encapsulated and released doxorubicin (dox) using 

solid phase separation and HPLC. CL of PLD and TSC were calculated by 

non-compartmental analysis. The grade of PPE toxicity was determined by 

NCI CTCAE (v4.03) criteria. Results: Nine patients have undergone TSC 

imaging and eight patients completed TSC blood PK and PLD plasma PK 

studies. There was a positive linear relationship between TSC CL and 

encapsulated dox CL (R2 � 0.61, p�0.02). When patients were subdivided, 

there was a stronger relationship between TSC CL and encapsulated 

dox CL (R2 � 0.81, p�0.03) in pts receiving PLD monotherapy. A positive 

relationship using Spearman’s correlation (��0.84, p�0.006) was also 

found between maximum grade PPE toxicity developed and estimated AUC 

of encapsulated dox in hands [(TSC AUCBlood)/(TSC AUCHand)*Encapsulated Dox AUCPlasma]. Conclusions: These results suggest that TSC is a probe for 

MPS function and PLD PK and PD and may be used to individualize PLD 

therapy in pts with EOC. In addition, our findings suggest TSC may be able 

to predict the development of PPE in patients. 


Panitumumab and pegylated liposomal doxorubicin in platinum-resistant 

epithelial ovarian cancer with KRAS wild-type: The PaLiDo study, a phase II 

nonrandomized multicenter study. Presenting Author: Karina Dahl Steffensen, 

Department of Clinical Oncology and Radiotherapy, Vejle Hospital, 

Vejle, Denmark 

Background: Ovarian cancer (OC) patients with platinum-resistant recurrent 

disease have few therapeutic options and the response rates are only 

10-20% using non-cross-resistant chemotherapeutic agents. The increasing 

number of negative trials for OC treatment has prompted an evaluation 

of new biologic agents, which in combination with chemotherapy may 

result in improvement in survival. Panitumumab is a fully human monoclonal 

antibody specific to the epidermal growth factor receptor (EGFR). No 

previous studies have evaluated the effect of panitumumab in OC based on 

KRAS mutation status. The main purpose was to investigate the response 

rate in platinum-resistant, KRAS wild-type OC patients treated with 

pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. 

Methods: Major eligibility criteria were confirmed stage I-IV primary 

epithelial ovarian/fallopian/peritoneal cancer patients with progression 

either during or within 6 months after end of first or second line 

platinum-based chemotherapy. Only patients with measurable disease by 

CA125 criteria and with KRAS wild type were eligible. Patients were treated 

with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m² day 

1, every 4 weeks. Tumor assessment was performed at baseline and at every 

third cycle according to CA-125 criteria. Results: A total of 46 patients were 

enrolled by 6 study sites in this multi-institutional phase II trial. Within the 

population evaluable for response (N�33), there was 8 CA125 responders 

for an overall response rate of 24.3 %. Progression-free and overall survival 

in the intention-to-treat population (N�43) was 2.7 months (2.5-3.2 

months, 95%CI) and 8.1 months (5.6-11.7 months, 95%CI), respectively. 

The most common treatment related grade 3 toxicities included skin 

toxicity (42%), fatigue (19%) and vomiting (12%). Conclusions: The 

combination of PLD and panitumumab demonstrates efficacy in platinum 

refractory/resistant patients although the dermatologic toxicity was considerable. 


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Sexual function, sexual activity, and quality of life in women with ovarian 

and endometrial cancer. Presenting Author: Philipp Harter, Kliniken Essen 

Mitte, Essen, Germany 

Background: Gynecological cancer (GC) is generally assumed to have an 

impact on sexual function and activity. Although there are several studies 

addressing the issue, case control studies are currently limited. Methods: 

We performed a cross-sectional investigation of sexual function and activity 

utilizing the sexual activity questionnaire, the female sexual function 

index, and parts of the EORTC QLQ C30. Patients with gynecological 

cancer (GC) like ovarian and endometrial cancer were compared with a 

control group (C) of non-cancer patients. Inclusion of GC was only allowed if 

treatment was completed �12 months previously and patients were 

disease-free. Results: The questionnaires were sent out to 727 women (335 

x GC and 392 x C), 22.8% of which responded. Response rates in both 

groups were equivalent (79 pts with GC [23.6%] and 87 control subjects 

[22.2%]). Median age was 57 years (C) and 62 years (GC), respectively 

(p�0.237). 51.5% (C) and 59.5% (GC) were not sexually active, mainly 

owing to lack of a partner (37%) or lack of interest (21%) in controls and 

lack of interest (40%, p�0.05), self-reported physical problems (31.9%, 

p�0.05), and physical problems of the partner (21%, p�0.05). There 

were significant differences between both groups in the SAQ discomfort 

score (p�0.05). We did not observe significant differences in quality of life 

or other scores regarding sexuality. Conclusions: About half of the women in 

both groups were not sexually active. However, reasons for non-activity 

differ. Quality of sexuality tends to be impaired in GC patients, but this 

seems not to influence quality of life. A shift of priority caused by 

substantial anxiety regarding cancer specific survival might explain our 

findings. 


Effect of tumor-infiltrating T-lymphocytes on the aggressiveness of epithelial 

ovarian tumors. Presenting Author: Ines Vasconcelos, Department of 

Gynaecology, European Competence Center for Ovarian Cancer, Campus 

Virchow Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany 

Background: Borderline ovarian tumors (BOT) are a low-grade form of 

ovarian malignancy with significantly less aggressive behavior than epithelial 

ovarian cancer (EOC). Since there is neither convincing scientific 

evidence nor a marker capable of predicting BOT’s behavior, we analyzed 

the role of immune tolerance in differential disease outcome. EOC and BOT 

were chosen due to similar disease etiology, despite different disease 

courses. Increased numbers of T-cell subpopulations infiltrate malignant 

tumors, so we used epigenetic tests to determine the prevalence of 

regulatory T-cells (Treg) and overall-T-Lymphocytes (oTL) in EOC and BOT. 

Methods: The ovarian cancer samples were provided by the European 

multicentric OVCAD study. The BOT samples were obtained from Tumor 

Bank Ovarian Cancer at Charité Campus Virchow (Germany). Samples and 

clinical data were prospectively collected and documented using validated 

SOPs. DNA was bisulphite-converted and forwarded to methylationspecific 

RT-PCR for CD3 and FOXP3 loci. Results: We evaluated 90 

high-grade EOC, 12 BOT with invasive implants and 25 non-invasive BOT 

samples. Higher oTL-values correlate with mortality (p�0.008) and recurrence 

(p�0.001), while higher Treg levels correlate with recurrence 

(p�0.028). Patients with non-invasive BOT have lower oTL (p�0.019) and 

Treg (p�0.0005) levels than patients with invasive BOT and EOC, while 

BOT (both invasive and non-invasive) patients have lower Treg-to-oTL ratios 

than EOC patients (p�0.0005). Finally, oTL levels associate with overall 

survival in EOC (p�0.042). Conclusions: We observed a strict correlation 

between tumor-type, Treg and oTL levels, as well as Treg-to-oTL ratio. This 

is in agreement with our hypothesis that disease aggressiveness is associated 

with the amount tumor-infiltrating lymphocytes and may provide the 

explanation for differing disease courses in EOC and BOT. 




An updated safety analysis of OCEANS, a randomized, double-blind, phase 

III trial of gemcitabine (G) and carboplatin (C) with bevacizumab (BV) or 

placebo (PL) followed by BV or PL to disease progression (PD) in patients 

with platinum-sensitive (Plat-S) recurrent ovarian cancer. Presenting 

Author: Carol Aghajanian, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: OCEANS met its primary end point with a statistically 

significant and clinically meaningful hazard ratio for progression-free 

survival (PFS) of 0.484. Secondary end points included objective response 

rate, overall survival, and safety. Eleven additional months of safety data 

were collected after the data cut-off date for the final PFS analysis event 

and updated safety analyses were performed. Methods: Eligible patients 

(pts) were randomized to arm A: GC (G [1000 mg/m 2 days 1 and 8] and C 

[AUC 4, day 1], q21d for 6–10 cycles) � concurrent PL (q21d), followed 

by PL until PD or unacceptable toxicity; or arm B: GC � concurrent BV (15 

mg/kg q21d), followed by BV until PD or unacceptable toxicity. All adverse 

events (AE) were recorded and graded per NCI-CTCAE v3.0. Results: The 

incidence of any grade AE was 100% in both arms and of SAEs was 25.3% 

(PL arm) and 35.6% (BV arm). The rates of proteinuria, hypertension 

(HTN), reversible posterior leukoencephalopathy syndrome (RPLS), thrombocytopenia 

and epistaxis were higher in the BV arm. More pts in the BV 

arm (20.6%) than in the PL arm (4.7%) experienced an AE that led to 

discontinuation of study drug, in the BV arm most commonly due to HTN 

(4%), proteinuria (2.8%), epistaxis (1.2%), thrombocytopenia (1.6%) and 

RPLS (0.8%). Median number of BV cycles in pts with G �3 proteinuria 

was 22.5 and the AE resolved in 91.7% of pts. Among the pts with G �3 

HTN, the median number of BV cycles was 16.5 and the AE resolved in 

72.7% of pts. Conclusions: The overall safety profile was similar to that seen 

at the time of the final PFS analysis. Higher incidences of proteinuria and 

HTN were possibly related to longer BV treatment duration and resolved in 

the majority of pts. 

Adverse event, n (%) 

GC � PL 

(n�233) 

GC � BV 

(n�247) 

Bleeding (non-CNS), all G 64 (27.5) 158 (64) 

Bleeding (non-CNS), G >3 2 (0.9) 14 (5.7) 

Epistaxis, G >3 1 (0.4) 12 (4.9) 

HTN, all G 20 (8.6) 107 (43.3) 

HTN, G >3 1 (0.4) 44 (17.8) 

Fistula/abscess, all G 1 (0.4) 4 (1.6) 

GIP, all G 0 (0) 0 (0) 

Proteinuria, G >3 2 (0.9) 24 (9.7) 

RPLS, all G 0 (0) 2 (0.8) 

Thrombocytopenia, G >3 79 (34) 99 (40) 


The impact of interval cytoreduction and age in advanced-stage ovarian 

cancer: A GOG ancillary study. Presenting Author: Stuart M. Lichtman, 


Background: To determine if an age group exists for which interval 

cytoreductive surgery (ICS) in patients with suboptimal residual disease at 

primary surgery influences progression free survival (PFS) and overall 

survival (OS) among women with advanced ovarian cancer treated on GOG 

182. Methods: GOG 182 was a prospective, randomized trial of first-line 

chemotherapy in patients with advanced ovarian cancer. Patients with both 

optimal and suboptimal residual disease were included, and those with 

suboptimal residual were considered for ICS, with intent registered and 

stratified prior to randomization. Patients were randomized to one of five 

chemotherapy arms, employing combinations of either two or three agents 

delivered intravenously, with a control arm of paclitaxel and carboplatin. A 

retrospective analysis was approved by the GOG Ancillary Study Committee 

to investigate the influence of age on treatment and outcomes. In that 

analysis, Cox regression was used to identify independent prognostic 

factors and estimate their covariate effects on the adjusted PFS and OS of 

patients with suboptimal residual disease. Statistical significance was set 

at p�0.05. Results: Among the entire eligible study population, 28% 

(n�1,042) were registered with suboptimal residual disease (� 1 cm) and 

109 of these patients elected to undergo ICS. Hazard ratios (HR) were 

determined for patients undergoing ICS with reference to patients with 

suboptimal disease not undergoing ICS. Based on the most current 

follow-up data, the HR for progression or death was not statistically 

different between the groups, but the HR of death alone was significant at 

0.72 (95% CI: 0.57–0.92, p�0.008). There was no significant association 

of age with ICS in either the PFS or the OS model. Conclusions: In this 

trial, a patient’s age did not influence the effect of ICS on PFS or OS. There 

is no demonstrable benefit in PFS associated with ICS, but there was a 

statistically significant improvement in OS. To elucidate this finding, 

further study is warranted, likely in the form of a meta-analysis incorporating 

data from other prospective trials. 


The impact of obesity on time to recurrence in ovarian cancer: A 

retrospective study. Presenting Author: Karina E Hew, Mercy Medical 

Center, Baltimore, MD 

Background: There has been conflicting data regarding the relationship 

between obesity and progression free survival in patients with ovarian 

cancer. There has been some evidence to suggest that obesity results in 

altered tumor biology and a poorer prognosis in these patients. The aim of 

this study was to examine whether obesity is a risk factor for time to 

recurrence in primary epithelial ovarian cancer. Methods: A multicenter 

retrospective chart review was performed at Mercy Medical Center and 

University of Michigan Medical Center. 591 patients were diagnosed with 

primary epithelial ovarian cancer between 2004-2009. However, 221 

patients were excluded from the analysis because of persistent or progressive 

disease, treatment with neoadjuvant chemotherapy, presence of 

synchronous tumors or incomplete follow-up data. 370 patients were 

eligible for analysis. Data collected included: height and weight at the time 

of surgery, age, race, medical co-morbid illnesses, tumor stage, grade and 

histology. Treatment related data such as number of cycles of adjuvant 

chemotherapy; and optimal versus suboptimal tumor debulking was also 

collected. Body mass index (BMI) was defined according to WHO 2004 

criteria. Women with a BMI greater than 30 were categorized as obese. The 

diagnosis of recurrence was made by positive radiological or pathological 

diagnosis of cancer recurrence after patient had surgery, received adjuvant 

chemotherapy and had no clinical, radiological or serological evidence of 

recurrence during this time. The time to recurrence was then quantified in 

terms of months from the initial surgery. Survival analyses were performed 

with the Kaplan-Meier method and compared using log-rank testing. Time 

to recurrence was analyzed using Mann-Whitney U and Wilcox W tests. 

Results: 130 (35%) obese patients were compared with 240 (65%) non 

obese patients. A recurrence was documented in 125 (47.9%) non obese 

patients and 49 (37.7%) obese patients. Time to recurrence between both 

BMI groups was found to be identical, at 15 months (p�1.0). The 

progression free survival was similar in both obese and non obese subjects 

(p�0.118). Conclusions: Obesity does not impact the time to recurrence in 

patients with primary ovarian cancer. 


The impact of interval from surgery to chemotherapy and age in advancedstage 

ovarian cancer: A GOG ancillary study. Presenting Author: Andrew 

Menzin, North Shore University Hospital, Manhasset, NY 

Background: To determine if an age group exists for which the interval from 

surgery to the initiation of chemotherapy influences progression free 

survival (PFS) and overall survival (OS) among women with advanced 

ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, 

randomized trial of first-line chemotherapy in patients with advanced 

ovarian cancer, including those with optimal and suboptimal residual 

disease. Patients were randomized to one of five chemotherapy arms, 

employing combinations of either two or three agents delivered intravenously, 

with a control arm of paclitaxel and carboplatin. Chemotherapy was 

to be initiated within 12 weeks of primary surgery. A retrospective analysis 

was approved by the GOG Ancillary Study Committee to investigate the 

influence of age on treatment and outcomes. In that analysis, Cox 

regression was used to identify independent prognostic factors and estimate 

their covariate effects on the adjusted PFS and OS of the study 

population. Statistical significance was set at p�0.05. Results: The primary 

analysis of GOG 182 showed no differences in PFS or OS for any of the 

experimental arms when compared to the control regimen, and it was felt 

that the data from all arms could be aggregated for this analysis. Data for all 

regimens was pooled, and the time interval from surgery to chemotherapy 

was examined as a prognostic factor of survival. The interval had no 

statistically significant association with PFS (p�0.105). In the OS model, 

though, the functional form of the log interval was both significantly linear 

and nonlinear (p�0.001). After being flat until about 20 days (21.2 days; 

95% CI, 15.0–28.2 days), the plot of log interval against log hazard 

increases, suggesting a changepoint time after which the associated risk of 

death increases. Conclusions: In this study, time interval from surgery to 

chemotherapy had no impact on PFS, but there was evidence of a potential 

time-dependent relationship with OS, which might be elucidated with a 

meta-analysis incorporating data from other prospective trials. Our observations 

did not appear to be influenced by patient age. Overall, these findings 

can reassure patients who are recuperating from extensive cancer surgery. 



Treatment reality in elderly patients with advanced ovarian cancer: A 

prospective analysis of the OVCAD consortium. Presenting Author: Linn 

Lena Woelber, University Medical Center Hamburg-Eppendorf, Hamburg, 

Germany 

Background: Approximately one third of women diagnosed with ovarian 

cancer are 70 years or older. Standard therapy of ovarian cancer including 

radical cytoreduction and combination chemotherapy has considerable 

morbidity and information regarding treatment reality in elderly patients 

with ovarian cancer is very limited. Methods: Patients with primary 

epithelial ovarian cancer FIGO-stages IIB-IV were prospectively included in 

5 European cancer centers. All patients underwent surgery with the intent 

of maximal cytoreduction and platinum-based chemotherapy. To analyze 

treatment strategies and outcome in the elderly, patients were subdivided 

in �70 years and �70 years of age and compared regarding clinicopathological 

variables and prognosis. Results: A total of 275 patients were 

included and followed for a median of 25 months. Median age of the total 

cohort was 58 (18-85) years with only 47 patients (17.1%) �70 years old. 

Age itself was not a prognostic factor for progression free survival (PFS) in 

multivariate analysis. 30-days mortality rate after primary surgery was 

3.6% in elderly patients compared to 0.6% in patients �70 years 

(p�0.153). Surgery was less radical in patients �70 (e.g. fewer lymph 

node dissections p�0.001) and the percentage of patients with residual 

disease after surgery was higher in elderly (44.7%) compared to younger 

patients (28.5%) despite similar FIGO stage distribution (p�0.029). 

Furthermore, elderly received more often mono-chemotherapy (p�0.001). 

Consequently, outcome was less favorable in patients �70 compared to 

patients �70 years (75% overall survival 16 vs. 28 months; p�0.002 and 

median PFS 14 vs. 20 months; p�0.182). Conclusions: In this prospective 

European multicenter study, ovarian cancer patients age 70 and older were 

treated significantly less radical and had unfavorable outcome compared to 

younger patients. Specific trials for elderly patients focusing on surgical as 

well as chemotherapeutic aspects are therefore highly desirable to gain 

more information in an aging society. 


The effect of the APPRISE mandate on use of erythropoiesis-stimulating 

agents and transfusion rates in ovarian cancer patients. Presenting Author: 

Jonathan David Boone, University of Alabama at Birmingham, Birmingham, 

AL 

Background: Erythropoiesis-stimulating agents (ESAs) have long been used 

to support chemotherapy-induced anemia in patients with epithelial 

ovarian cancer (EOC). Recent studies have demonstrated that ESAs may 

lead to increased tumor growth and shorter survival. The FDA mandated 

new guidelines (APPRISE, for Assisting Providers and Cancer Patients with 

Risk Information for the Safe use of ESAs) for consenting patients before 

ESA administration. We sought to quantify the change in ESA use and RBC 

transfusion rates after the APPRISE mandate was instituted. Methods: A 

retrospective chart review identified patients with EOC undergoing chemotherapy 

after initiating the APPRISE mandate. A similar subset of patients 

treated prior to the APPRISE guidelines served as a control cohort. 

Abstracted data included patient demographics, primary or second line 

treatment status, chemotherapy regimen, number of patients requiring 

ESA or RBCs, or both, and a cost savings analysis. Results: 84 patients with 

EOC were identified as having undergone 367 cycles of first or second line 

chemotherapy after the APPRISE guidelines were instituted. A matched set 

of 88 patients receiving 613 cycles of chemotherapy within a year prior to 

institution of the APPRISE guidelines was analyzed for comparison. The 

two groups were statistically similar. Most patients in each group were 

initially diagnosed with advanced stage disease, were receiving primary 

chemotherapy, and were receiving taxane/platinum-based chemotherapy. 

45 of 88 patients (51%) in the pre-APPRISE group received a total of 196 

ESA injections compared to 0 of 84 patients (0%) in the post-APPRISE 

group. In spite of discontinuing the use of ESAs and no change in 

transfusion thresholds, RBC transfusion in the post-APPRISE group was 

similar to that in the pre-APPRRISE group (8.3% vs. 14.8%, p�.28). 

Omission of ESAs in the post-APPRISE group resulted in a cost-savings of 

an estimated $700,000 in billable charges. Conclusions: In our institution, 

the APPRISE guidelines resulted in complete cessation of ESA use in 

patients with EOC, resulting in considerable cost savings. Importantly, RBC 

transfusion rates did not increase after the guidelines were imposed. 


341s 


NGR-hTNF and doxorubicin in relapsed ovarian cancer (OC). Presenting 

Author: Domenica Lorusso, Department of Gynecologic Oncology, National 

Cancer Institute, Milan, Italy 

Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis 

factor) is able to promote antitumor immune responses and to improve 

the intratumoral doxorubicin (D) uptake by selectively damaging tumor 

vessels. Methods: OC patients (pts) with progressive disease (PD) after � 1 

platinum/taxane regimen and with a platinum free interval lower than 6 

months (PFI �6) or ranging from 6 to 12 months (PFI 6-12) received 

NGR-hTNF (N) 0.8 �g/m2 and D 60 mg/m2 on day 1 every 3 weeks. Primary 

endpoint of this phase 2 trial was response rate by RECIST criteria with a 

target of � 6/37 responding pts. Secondary aims were progression free 

survival (PFS) and overall survival (OS). Results: 37 pts (median age 57 

years; PS 0/1 32/5; PFI � 6/6-12 25/12; prior regimens 1-5) were 

enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 

1.6/mL (interquartile range 1.2-2.1). In all, 177 cycles were given, with 18 

pts (49%) receiving � 6 cycles and 12 pts (32%) 8 cycles. Neither grade 

3/4 adverse events (AEs) related to N nor increase of D-related AEs were 

noted. Common grade 1/2 AEs included chills (65%). Eight pts (23%; 95% 

CI 12-39) had partial response (PR; 2 with PFI � 6 and 6 with PFI 6-12; 

median duration: 8.2 months). Fifteen pts had stable disease (SD, 43%; 

10 with PFI � 6 and 5 with PFI 6-12; median duration: 4.9 months) for an 

overall disease control (DC, PR�SD) rate of 66%. Mean changes from 

baseline in target tumor size after 2, 4, 6, and 8 cycles were 2%, -54%, 

-69%, and -77%, respectively. Median PFS was 5.0 months (95% CI 

3.1-6.9) and median OS was 17.0 months (10.4-23.6). In pts with PFI � 6 

or 6-12, median PFS were 3.8 and 7.8 months (p�.03) and median OS 

were 14.3 and 20.1 months (p�.14), respectively. Pts with DC had longer 

median OS than those with early PD (24.0 and 4.9 months, respectively, 

p�.02). Longer PFI (p�.03) and higher PBLC (p�.01) were associated 

with better PFS, while OS correlated only with PBLC (p�.001). In the 

subset with PFI � 6, pts with PBLC � or � 1.2/mL (1st quartile) had 

median PFS of 4.9 and 2.6 months (p�.02) and median OS of 15.8 and 

4.3 months (p�.0001), respectivel Conclusions: A randomized phase II 

trial is currently testing D � NGR-hTNF in pts with PFI � 6 (refractory/ 

resistant). The role of PBLC as blood-based biomarker deserves further 

investigation. 


A phase Ib study of the combination of temsirolimus (T) and pegylated 

liposomal doxorubicin (PLD) in advanced or recurrent breast, endometrial, 

and ovarian cancer. Presenting Author: Marye Boers-Sonderen, Department 

of Medical Oncology, Radboud University Nijmegen Medical Centre, 

Nijmegen, Netherlands 

Background: PLD is active in metastatic breast, endometrial and ovarian 

cancer. Preclinical studies suggest that mTOR inhibitors (mTORi), such as 

T, have an additive therapeutic effect to chemotherapy and resistance to 

doxorubicin can be reversed by adding an mTORi. Therefore, the combination 

of T and PLD is highly promising. Methods: This phase I study assessed 

the maximum tolerated dose (MTD), safety and activity of the combination 

of T and PLD in advanced or recurrent breast, endometrial or ovarian 

cancer. Patients (pts) who were not previously treated with PLD or T, with 

adequate organ function were eligible. After a two week run in period with T 

iv once weekly, PLD iv once every four weeks was added. In case of clinical 

benefit, pts were treated for a maximum of 9 cycles combination therapy. T 

could be continued as monotherapy afterwards. The MTD was defined as 

the highest dose at which � 1 dose limiting toxicity (DLT) had been 

observed among 6 pts. FDG PET scans were performed at baseline and after 

2 and 6 wks to assess the effect on tumor metabolism. Pharmacokinetic 

(PK) sampling was performed during cycle 1. Results: 20 pts were enrolled. 

On the 4th dose level with 20 mg T and 40 mg/m2 PLD 2 DLTs occurred in 

6 pts: a grade 3 thrombocytopenic bleeding and a grade 3 skin toxicity. 

Therefore, the MTD was assessed at 15 mg T and 40 mg/m2 PLD. Adverse 

events (all grades/grade 3-4 in %) occurring most frequently were fatigue 

(84/5), nausea (84/16), mucositis (79/21), vomiting (74/16) and anorexia 

(74/0) Furthermore, rash and hand foot syndrome occurred both in 53% of 

pts, with 11% and 21% grade 3 respectively. 3 pts had a confirmed PR and 

9 had SD (� 3 months). The mean progression free survival (PFS) was 4.9 

months with 2 pts still on treatment. Results of FDG PET and PK data are 

currently being analyzed and will be presented. Conclusions: The combination 

of T and PLD is safe and tolerable. The MTD was assessed at PLD 40 

mg/m2 once every 4 weeks and T 15 mg weekly. The activity of this 

combination in breast, endometrial and ovarian cancer pts is promising and 

warrants further studies. 



5062^ General Poster Session (Board #20F), Sun, 8:00 AM-12:00 PM 

Phase I safety study of farletuzumab, carboplatin, and pegylated liposomal 

doxorubicin (PLD) in patients with platinum-sensitive epithelial ovarian 

cancer (EOC). Presenting Author: Kenneth H. Kim, University of Alabama 

at Birmingham, Birmingham, AL 

Background: Farletuzumab (FAR) is a humanized monoclonal antibody that 

binds to folate receptor-�, a target which is largely absent in normal 

epithelium and over-expressed in EOC. A phase I and a phase II study 

indicate potential utility of FAR in combination with carboplatin/paclitaxel 

in recurrent platinum sensitive EOC. This study assessed safety and 

efficacy of FAR in combination with PLD/carboplatin, which has been 

demonstrated to have greater efficacy than carboplatin/paclitaxel in women 

with platinum-sensitive EOC. Methods: A multicenter, single-arm study 

enrolled 15 patients with platinum-sensitive EOC in first or second relapse 

defined by either CA-125 or RECIST. The primary endpoint is to assess 

safety of FAR plus PLD/carboplatin in this population. Patients were 

treated with weekly FAR 2.5 mg/kg plus carboplatin AUC 4-5 and PLD 30 

mg/m2 every 4 weeks for 6 cycles, followed by maintenance treatment with 

single agent FAR until disease progression. Initial dosing of weekly 2.5 

mg/kg was later amended to 7.5 mg/kg every 3 weeks. Results: 13 of 15 

patients completed 6 cycles of combination therapy; one received a total of 

12 cycles of chemotherapy. Two patients progressed during combination 

therapy: one received 3 cycles, the other 5 cycles. The median number of 

subsequent single agent maintenance cycles was 8 (range 0-13). No grade 

4 toxicities were observed. Of 20 grade 3 toxicities in 14 patients, 3 (1 

fatigue; 2 small bowel obstructions in the same patient) were deemed by 

the investigator to be possibly related to FAR. These events were seen 

during the combination phase and were deemed by the investigator to be 

also possibly related to chemotherapy. All patients demonstrated clinical 

benefit: 1 complete response, 10 partial response and 4 stable disease. 7 

patients have come off study, all for disease progression; a median PFS of 

11 months was noted. 8 patients remain on study. Conclusions: These 

preliminary data indicate that the safety profile of FAR in combination with 

carboplatin and PLD is consistent with that historically recorded for 

carboplatin and PLD alone. Complete safety profile will be assessed; PK 

data and final results will be presented. 


Application of an ointment with high radical protection factor as a 

prevention strategy against PPE. Presenting Author: Franziska Kluschke, 

Center of Applied Cutaneous Physiology (CCP), Department of Dermatology, 

Charité-Universitätsmedizin Berlin, Berlin, Germany 

Background: Pegylated liposomal doxorubicin has proved to be highly 

efficient in the treatment of various tumors. Depending on the application 

protocol, up to 80% of patients develop palmar-plantar erythrodysesthesia 

(PPE). So far, a prevention strategy is still unknown. Recently, it was shown 

that parts of the chemotherapeutics were excreted with the sweat onto the 

skin surface, spreading there homogeneously and penetrating into the 

stratum corneum. The formation of free radicals in the tissue results in 

PPE. The aim of the study was to investigate if a topically applied ointment 

containing antioxidants with high radical protection factor (RPF) can be a 

PPE prevention strategy. Methods: 20 patients with ovarian carcinoma, who 

had been treated with pegylated liposomal doxorubicin (40 mg/m2 ), were 

investigated. They applied the ointment at least twice daily, 2 days before 

and during 3 cycles of chemotherapy. Their skin condition was examined by 

a trained dermatologist. Results: From 20 patients enrolled in the study, 

only 12 (60%) met the conditions by applying the cream at least twice daily 

in the palmar and plantar regions. These patients did not develop PPE. One 

patient died in the 2nd cycle of therapy. 7 patients (35%) did not follow the 

ointment application protocol for various reasons; 6 of them developed PPE 

and resumed ointment application thereafter. As a result, PPE disappeared 

or was strongly reduced in these patients so that chemotherapy could be 

continued. Due to the small group of patients, the fact that PPE was not 

induced in patients who had applied the ointment regularly can be 

generalized only restrictedly. Far more interesting are the findings in those 

patients, who had stopped ointment application during chemotherapy and 

developed PPE, which disappeared after they resumed applying the 

ointment. The regression or distinct reduction of PPE after re-application of 

the ointment clearly proves the efficacy of this strategy. Conclusions: The 

topical application of an ointment containing antioxidants with high radical 

protection factor (RPF) could be an efficient strategy against the development 

of PPE during chemotherapy. 


Factors associated with an increased risk of recurrence in women with 

ovarian granulosa cell tumors. Presenting Author: Anuj Suri, The University 

of North Carolina Hospitals, Division of Gynecologic Oncology, Chapel Hill, 

NC 

Background: There is emerging data in different malignancies, including 

gynecologic cancers, demonstrating factors independent of a patient’s 

tumor characteristics, which are associated with an increased risk of cancer 

recurrence. The goal of this study is to determine demographic and 

prognostic factors affecting recurrence of disease (RD) in women with 

ovarian granulosa cell tumors (GCT). Methods: A dual-institution retrospective 

analysis of patients diagnosed with GCT between 1995 and 2010. 

Demographics including age, race, BMI, stage, diabetes (DM), adjuvant 

treatment, and progression free survival (PFS) were extracted. Hazard 

ratios for recurrence were estimated by univariate and multivariate Cox 

regression models Results: One hundred nine women identified with a 

median age of 50 (range 12-87). Fifty-six (57.1%) were Caucasian, 32 

(32.7%) African American, and 10 (10.2%) were other. Median BMI was 

29 (range 12-57). Twenty-one patients had DM. The majority of women 

had stage I disease (89.0%), 7 (6.4%) had stage II/III disease, and 5 were 

unstaged. In univariate analysis, DM showed the strongest association with 

recurrence (HR 3.56, 95% CI: 1.57-8.11). Non-white race was also 

associated with higher risk of RD, though the association was not 

statistically significant (HR 1.74, 95% CI: 0.78-3.87). The association 

between DM and RD was also found in multivariate analysis controlling for 

all factors including non-white race and BMI (HR 2.99, 95% CI: 1.11- 

8.08). Only 19 (17%) patients received adjuvant chemotherapy consisting 

of one of two different adjuvant chemotherapy regimens bleomycin, 

etoposide, and cisplatin or paclitaxel and carboplatin, however there was no 

difference in outcome based on chemotherapy regimen (p�0.24). 

Conclusions: This is the largest study analyzing factors associated with risk 

of recurrence in women with ovarian GCT. Studies have demonstrated 

higher morbidity among diabetic patients with breast and colon cancer and 

this may be modifiable with metformin. Our results emphasize that 

diabetes is one of the strongest predictors of recurrent disease in patients 

with ovarian GCT. Further studies are necessary to evaluate the effect of 

other factors such as adjuvant chemotherapy. 


A phase I, dose escalation trial to assess the safety and biological activity of 

recombinant human interleukin-18 (SB-485232) in combination with 

pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian 

cancer. Presenting Author: Fiona Simpkins, University of Miami Miller 

School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 

Background: SB-485232, a recombinant human form of interleukin-18 

(IL-18), is being studied as a novel cytokine for tumor immunotherapy. 

IL-18 has been shown to increase the anti-tumor activity of doxorubicin in 

other cancer mouse models. Methods: This multi-center study enrolled 16 

patients (pts), and evaluated four cycles (28 days each) of standard 

pegylated liposomal doxorubicin (PLD) (40 mg/m2 day 1) in combination 

with increasing doses of IL-18 (1, 3, 10, 30, and 100 mg/kg) on days 2 and 

9 of each cycle witha1yrfollow-up to further evaluate safety and efficacy. 

Results: Of the 16 pts, 10 (63%) completed study treatment and 6 (37%) 

did not because of disease progression (5 pts) and PLD hypersensitivity (1 

pt). Thirteen (82%) were platinum resistant/refractory having received a 

median of � 3 prior lines of therapy. SB-485232 up to 100 mg/kg in 

combination with PLD had an acceptable safety profile. All 16 pts 

experienced at least 1 AE including chills (81%), nausea (75%), anemia 

(63%), fatigue (56%), hyperglycemia, and pyrexia (50% each). Eight of 16 

pts had Grade 3 AEs including anemia (19%), and 6% each for abdominal 

pain, asthenia, dehydration, PLD hypersensitivity, edema, fatigue, hyperglycemia, 

hyperkalemia, jaundice, pain, nausea, vomiting, and pyelonephritis. 

There were no grade 4/5 AEs. Four subjects experienced 10 non-fatal 

SAEs with 3 related to study drug: anemia, PLD hypersensitivity, and 

cytokine release syndrome. Maximal SB-485232 biological activity, assessed 

by peripheral blood NK and T cell markers, was observed at 

10mg/kg-100mg/kg. This drug combination resulted in a 6% partial 

response rate (RR) and a 38% stable disease rate using RECIST 1.0. 

Median (95% CI) time of progression-free survival (PFS) was 4.50 (3.52,--) 

months. Conclusions: The SB-485232/PLD combination was tolerable with 

minimal toxicity. These preliminary efficacy data are comparable to the 

historical RR and PFS observed with PLD monotherapy in platinumresistant 

ovarian cancer. However, given the small sample size, this 

combination warrants further investigation. 



Effect of BRCA mutation on prognosis in patients with ovarian cancer: A 

systematic review and meta-analysis. Presenting Author: Antonis Valachis, 

Department of Oncology Sörmland Mälarsjukhuset, Eskilstuna, Sweden 

Background: To investigate whether the germ-line mutations of BRCA 1 and 

2 in patients with ovarian cancer are associated with disease outcome. 

Methods: A systematic search of the literature was performed using search 

terms related to BRCA, ovarian cancer and prognosis. Studies were 

considered eligible if they reported the outcome of ovarian cancer in 

patients with BRCA 1 and/or 2 mutations compared with patients with 

sporadic ovarian cancer or / and no BRCA mutation. Cohort and casecontrol 

designs were included. Pooled Hazard Ratios (HR) were estimated 

with fixed or random effects models, depending on between-studies 

heterogeneity. Results: Of 2,340 titles identified, 26 articles met the 

inclusion criteria. Of these, 6 studies were excluded from the analysis due 

to duplication of results (n�1) and lack of data to calculate HR (n�5). 

Patients with BRCA 1 or 2 mutations had better survival compared with 

control group both in cohort (HR: 0.58, 95% Confidence Interval (CI) 

0.42-0.79, p-value 0.0005) and in case-control (HR: 0.65, 95% CI 

0.45-0.93, p-value � 0.02) studies. When only patients with BRCA 1 

mutation were analyzed, the survival benefit remained significant (HR: 

0.67, 95% CI 0.53-0.85, p-value � 0.001). Furthermore, the differential 

survival benefit of the mutation groups was even more evident among 

patients with BRCA 2 mutation (HR: 0.43, 95% CI: 0.30-0.63, p-value � 

0.0001). A direct comparison of patients with BRCA 1 vs. BRCA 2 

mutations (4 studies) revealed a significantly better survival for BRCA 2 

mutation carriers (HR: 0.53, 95% CI: 0.33-0.85, p-value � 0.009). 

Conclusions: Our results confirm the hypothesis that BRCA status is a 

prognostic factor in patients with ovarian cancer. Based on these results, 

the use of BRCA status as a stratifying factor in therapeutic ovarian cancer 

trials seems to be fully justifiable. The stronger association between 

survival and BRCA 2 mutation, compared with BRCA 1, suggests a different 

nature of the dysfunction of these 2 genes. 


A phase II study of pazopanib in recurrent or persistent ovarian (EOC), 

peritoneal (PPC), or Fallopian tube cancer (FTC): A Spanish Ovarian Cancer 

Group (GEICO) study. Presenting Author: Ana Oaknin, Medical Oncology 

Department, Vall d´Hebron University Hospital, Barcelona, Spain 

Background: Pazopanib (P) is a potent and selective multi-targeted receptor 

tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/�, and 

c-kit that inhibits angiogenesis. Signaling blockade of these pathways is 

associated with anti-tumor and antiangiogenesis activity. Methods: Eligible 

patients (pts) had persistent or recurrent EOC/PPC /FTC up to 2 prior 

cytotoxic regimens. They had to have received at least a platinum–based 

line and fulfill platinum resistant criteria. Treatment consisted of P 800 mg 

orally QD until disease progression or prohibitive toxicity. The primary 

endpoint was Clinical Benefit Rate (CBR) defined as Complete Response 

(CR) plus Partial Response (PR) plus Stable Disease (SD) � 8 weeks by 

RECIST v1.1.An optimal two-stage Simon design was utilized with H1and 

H0set at 60%and 40% respectively; Power �90% significance level of 5% 

(Stage 1: � 25pts; total�66). Correlative studies to identify angiogenic 

biomarkers to predict response to P were performed. Results: From 12/10 to 

7/11, 25 pts were enrolled, 21 pts had EOC, 2PPT, and 2FTC. Median age: 

64 years (range 43-81), ECOG 0/1/2:12/11/2 pts. Prior chemotherapy 

regimens 1/2:10/15 pts. Median weeks on treatment: 8 (range 4-25). Most 

frequent adverse events (AEs) were asthenia (56%), hypertension (36%) 

and diarrhea, nausea and anorexia (20% each).Grade 3 toxicities: Hypertension 

(6pts), ALT/AST elevations (3 pts), asthenia (2 pts), DVT (1pt), Fistula 

(1 pt), Anemia (1 pt). Six pts required dose reduction to 600 mg due to 

toxicity.Reasons for stopping study treatment: PD (18pts), AEs (3pts) and 

investigator decision (2pts). First stage analysis showed: PR:1/25, SD: 

9/25, CBR:10/25; 40% (95% CI 21.1%-61.3%).No correlation between 

GCIG CA-125 response and RECIST criteria was established, 8 versus 1 

response respectively. Median PFS was 1.83 months (95% CI 1.67-2). 

Conclusions: The CBR observed at the first stage did not reach the planned 

statistical hypothesis (CBR:12 pts). Therefore, the lack of activity of P in 

platinum resistant EOC/PPT/FT led to discontinuation of the study. 

Translational study results will be presented in an additional abstract. 


343s 


Management of antiangiogenics’ renovascular safety in ovarian cancer 

subgroup and intermediate results of the MARS study. Presenting Author: 

Vincent Launay-Vacher, Service ICAR, Pitie-Salpetriere Hospital, Paris, 

France 

Background: Anti-VEGF drugs (AVD) are widely used in cancer patients 

(pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of 

AVD, related to the inhibition of the VEGF pathway. The MARS study has 

been conducted to assess the renovascular tolerance of these drugs in the 

clinical setting. Methods: Hypertension (HTN) and proteinuria (Pu) are 

class-side-effects of anti-VEGF drugs (AVD), related to the inhibition of the 

VEGF pathway. The MARS study has been conducted to assess the 

renovascular tolerance of these drugs in the clinical setting. Results: Among 

77 OC pts been included, 38 completed the study to date (1-year follow-up 

(f/u)). Median age at inclusion (introduction of the AVD) was 62 years. 

Diabetes and HTN prevalences were 5.2% and 7.9%, respectively. Baseline 

renal assessment retrieved: Pu 13.2%, Hu 7.9%, mean aMDRD 80.9 

ml/min/1.73m 2 

and 3 pts with aMDRD�60. The incidence of de novo Pu 

during f/u was 36.4% (Table). All pts with Pu at inclusion improved, except 

one. Among pts with de novo Pu, 58.3% afterwards improved/normalized. 

No Grade 3/4 Pu has been reported (at inclusion or during f/u) and no Hu. 

17.1% developed HTN. In addition, a mean renal function decrease of -2.7 

ml/min/1.73m2 /year was observed and 4 pts had aMDRD�60 at the end of 

f/u. 36.4% had grade 1 SCr increase (median increase of 15.9%) No 

thrombotic micro-angiopathy (TMA) has been reported. Conclusions: The 

results of the MARS subgroup of OC pts shows that 1) TMA remains rare, 2) 

Pu develops in 36.4% of the pts, however with no Grade 3/4, 3) less than 

20% developed HTN, and 4) renal function was not especially impaired. 

Furthermore, in case of a renovascular effect, investigators followed the 

recommendations from the French Society of Nephrology (Halimi JM et Al. 

Nephrol Ther 2008) and no treatment withdrawal for unmanageable 

renovascular toxicity occurred. 

Prevalence at inclusion 

Incidence during f/u 

Renovascular effects 

(%) 

(%) 

Pu* 

Grade 1 

13.2 

10.5 

36.4 

21.2 

Grade 2 

2.7 

15.2 

Grade 3-4 

0.0 

0.0 

HTN 7.9 17.1 

Hu 

Traces/� 

7.9 

5.3 

0.0 

�� 

2.6 

SCr increase* 

- 36.4 

Grade 1 

36.4 

Grade 2-4 

*NCI-CTC v4.03. 

0.0 


A novel treatment for ovarian cancer (OC): Anti-Müllerian inhibiting 

substance type II receptor (MISRII) humanized monoclonal antibody (mAb) 

3C23K—Preclinical validation. Presenting Author: Christine Gaucher, LFB 

Biotechnologies, Loos, France 

Background: Expressed on most OC subtypes while displaying a restricted 

expression profile in adult normal tissues, MISRII represents a potentialtarget 

for OC immunotherapy. We present here the preclinical assessment of a 

humanized anti-MISRII EMABling mAb, 3C23K. Methods: Either quantitative 

RT-PCR or immunohistochemistry (IHC) studies were performed to 

confirm MISRII expression profile in Granulosa Cell Tumor (GCT) or 

Epithelial OC (EOC) patient samples and to evaluate tissue cross-reactivity. 

For in vitro and in vivo experiments, we have generated 4 patient-derived 

MISRII expressing EOC cell lines. Xenograft studies were conducted in 

swiss nude mice on established tumors (100 mm3 ). Mice received 2 to 3 

weekly i.p. injections (10 mg/kg/inj) for 4 to 6 wks and tumor volumes were 

compared with control groups. Comparison of i.p. vs i.v. injections were 

assessed as well as combination with carboplatin (once a week for 4 weeks, 

60 mg/kg/inj). In addition, 3C23K plasma level was monitored to determine 

half-life. Results: 1) Target validation: we confirmed by IHC the 

expression of MISRII in most OC tissue sections (4/4 GCT and 13/14 EOC), 

meanwhile, MISRII mRNA was only detected in 7/48 normal tissues. 2) In 

vitro assessment: tested in vitro 3C23K displayed both cytotoxic (ADCC) 

and anti-proliferative activities. 3) In vivo assessment: in the mouse 

xenograft models 3C23K exhibited a strong anti-tumoral activity as 

measured by tumor volume, with T/C ratios reaching values below 0.42 

shortly after the initiation of treatment. No differences in efficacy were 

noticed between i.p. and i.v. injections or between thrice vs twice a week 

administrations. In addition, similar half lives were observed for 3C23K 

injected either i.v. (96.9 h) or i.p (113.5 h). Finally, the combination of 

3C23K with carboplatin (CP), a standard of care in OC, exhibited an even 

stronger anti-tumor activity with T/C values at D22 of 0.06 (3C23K�CP), 

0.18 (3C23K) and 0.69 (CP) vs vehicle. Conclusions: 3C23K represents a 

promising candidate for OC targeted therapy and a dose-escalation phase I 

study is planned in patients with OC. 




BRCA1 methylation status in high-grade serous ovarian cancer (HGSOC) 

patients (pts). Presenting Author: Ilary Ruscito, Department of Gynecology 

and Obstetrics, Sapienza University of Rome, Rome, Italy 

Background: Mutations in BRCA1/2 genes contribute to increase risk for 

breast and ovarian cancer (OC).Hypermethylation of CpG islands in gene 

promoter regions is considered a frequent mechanism associated with 

inactivation of tumor suppressor genes which contributes to oncogenic 

transformation. Studies identified methylation changes in OC pts. Most of 

the studies analyzed a small cohort and combined different histological 

subtypes. HGSOC is a special entity of OC associated with poorer OS. Aim 

of this study was to analyze the clinical impact of BRCA1 promoter gene 

methylation status in HGSOC. Methods: The cohort comprised 127 HGSOC 

treated by cytoreduction followed by platinum-based chemotherapy at 

Department of Gynecology, Charité Medical University Berlin, Germany. 

Fresh frozen OC tissues provided by TOC were examined to access the 

tumoral tissue quality. Samples presenting at least 50% of tumour area 

were included within this study. DNA was extracted followed by sodium 

bisulfite conversion, and assessment of BRCA1 gene promoter methylation 

rate was determined by PCR. Statistical analisys has been carried out using 

SPSS software. Results: In our study, 14.2% of the pts presented a 

hypermethylation of the BRCA1 promoter gene. The hypermethylation of 

BRCA1 promoter gene was significantly more frequently encountered in the 

younger pts (�59 yrs: 77.8% in the Hypermethylation Group vs 47.7% in 

the Hypomethylation Group, p�0.022). No differences in methylation 

status between primary and metastatic tissue from OC pts could be 

observed. Also no correlation with FIGO stage was observed. Optimal tumor 

debulking could be reached in most of the pts (57.5%), without significant 

differences between both groups. Platinum response rates were similar 

between both groups. No differences in PFS and OS could be observed. 

Conclusions: The study shows that HGSOC pts presenting the BRCA1 gene 

promoter in the methylated status, developed the disease significantly 

earlier with respect to OC patients with unmethylated BRCA1 gene 

promoter. The clinical outcome was similar in HGSOC independently from 

BRCA1 methylation status. 


Exposure-response relationship of open-label (OL) AMG 386 monotherapy 

in patients (pts) with recurrent ovarian cancer. Presenting Author: Beth Y. 

Karlan, Cedars-Sinai Medical Center, Division of Gynecologic Oncology, 


Background: AMG 386, an investigational peptibody, inhibits tumor angiogenesis 

by preventing angiopoietins 1/2 and Tie2 receptor interaction. A 

phase II, double-blind, controlled study (NCT00479817) evaluated toxicity 

and efficacy of AMG 386 � paclitaxel (P) in recurrent ovarian cancer 

pts. Increased AMG 386 exposure in that study was associated with longer 

progression-free survival (PFS; Lu et al., JCO 2010; 28 [Suppl]: 5042). 

Here, these analyses were applied to pts electing OL AMG 386 monotherapy 

after progression in the placebo group. Methods: Pts with recurrent 

epithelial ovarian, fallopian tube, or peritoneal cancer (�3 prior anticancer 

therapies, GOG �1) were randomized 1:1:1 to P IV QW (3 on/1 off) � AMG 

386 (3 or 10 mg/kg) or placebo IV QW. In the placebo group, pts who 

progressed and stayed eligible could receive OL AMG 386 10 mg/kg IV QW 

monotherapy. In pts receiving AMG 386 monotherapy, post-hoc analyses 

evaluated PFS per RECIST, objective response rate (ORR), adverse events 

(AEs), and the relationships between high and low AMG 386 exposure 

(based on a median AUCSS of 10.6 mg*hr/mL) and efficacy (PFS per 

RECIST, ORR). Results: 161 pts were randomized. 18 pts received OL AMG 

386 monotherapy (range: 1-56 infusions). At the time of analysis, PFS was 

3.2 mo. ORR was 0%. 6 pts had stable disease (SD), 7 had progressive 

disease (PD). Common AEs were abdominal pain (n � 6), fatigue (n � 5), 

peripheral edema (n � 5), nausea (n � 5), urinary tract infection (n � 5), 

and vomiting (n � 5); grade � 3 AEs in more than 1 pt were pleural effusion 

(n � 2; all grade 3), small intestinal obstruction (n � 2; all grade 3), and 

ovarian cancer (n � 2; all grade 5). PFS was longer in the high- (n � 9) vs 

low-exposure (n � 9) group (7.2 vs 1.8 mo; HR � .266, p � .041). 

Precrossover PFS was similar between high- and low-exposure groups (5.5 

vs 4.5 mo; HR � 1.146, p � .812). For both groups, ORR was 0%. In the 

high-exposure group, 4 pts had SD, 3 had PD. In the low-exposure group, 2 

pts had SD, 4 had PD. Conclusions: In line with results from a phase II study 

of AMG 386 � P, pts with recurrent ovarian cancer who received AMG 386 

monotherapy and had high AMG 386 exposure had longer PFS than pts 

with low exposure. Toxicity was similar in both groups. 


Interval versus primary tumor debulking surgery in advanced ovarian 

cancer: Analysis of the European OVCAD data. Presenting Author: Christina 

Fotopoulou, Charité University Department of Gynecology, Campus Virchow 

Clinic, Berlin, Germany 

Background: The international scenery around optimal primary treatment of 

advanced ovarian cancer (AOC) patients (pts) is currently being discussed, 

with large discrepancies and heterogeneity still existing between the 

national guidelines worldwide. Aim of the present study was to evaluate the 

differences in outcome of AOC-pts after primary (PDS) versus intervaldebulking-surgery 

(IDS) based on a prospectively assessed multicenter 

data set. Methods: Overall outcome was analyzed from the OVCAD database; 

a prospective, observational, multicenter project. AOC-pts who 

underwent surgery in five specialized gynecological cancer centers across 

three European countries between 02/2005 and 12/2008 were evaluated. 

Overall (OS) and progression free survival (PFS) were calculated by 

Kaplan-Meier-curves. Univariate and Cox-regression-analysis were applied. 

Results: Overall, 256 AOC pts (FIGO-stage III/IV) were evaluated. Fifty pts 

(19.5%) underwent IDS and 206 pts (80.5%) PDS. Despite the nonrandomized 

setting both groups were well balanced in terms of FIGO-stage, 

grading, histological subtype and presence of ascites. Different selection 

criteria were however present for each center. PDS pts presented significantly 

higher rates of intestinal resection (44.2% vs.24%; p�0.01) and 

lymphonodectomy compared to IDS ones (72.3%vs.48%; p�0.001), by 

equivalent complete tumor resection rates (67.5% vs.68%; p�0.82). 

Platinum response was significantly higher in PDS vs. IDS pts (80.6% vs. 

54%; p�0.001). 3-years OS was with 66.7% (95%CI: 60.2-73.2%) 

significantly better in PDS- versus 48.3% (95%CI: 34.2-62.5%) in IDS pts 

(p�0.001). Also 2-years PFS was with 31.9% (95%CI:24.8-39.1%) 

significantly higher in PDS- vs. 11.4% (95%CI: 0.9-22%) in IDS-pts 

(p�0.001). In multivariate analysis PDS, but not age, ascites, FIGO-stage, 

grading, histology or residual tumor were of prognostic significance for 

platinum response. In addition, multivariate analysis identified PDS and no 

residual tumor to positively and ascites to negatively affect OS and PFS. 

Conclusions: PDS appears to be associated with a more favorable outcome 

compared to IDS in highly specialized centers according to this nonrandomized 

data set. 


Targeting therapy based on preclinical analysis of clinical, molecular, and 

functional characteristics of individual high-grade serous ovarian cancers. 

Presenting Author: Monique Topp, Walter and Eliza Hall Institute of 

Medical Research, Melbourne, Australia 

Background: Recent molecular exploration of high-grade epithelial ovarian 

cancer (OC) has revealed potential targets for novel therapy based on 

altered DNA repair function, deregulated pathways and recurrent amplifications 

(Cancer Genome Atlas Research Network. 2011. Nature 474). 

Improved pre-clinical models allowing analysis of specific molecular 

subsets of ovarian cancer are urgently required to test novel treatment 

strategies. Methods: We have generated a novel xenograft model of human 

high-grade serous OC (HG-SOC). Histologic, functional and molecular 

analysis of the novel xenograft cohort (at baseline and following xenotransplantation) 

allows stratification of individual HG-SOC for testing with 

appropriate targeted therapy. We perform functional analysis of in vitro 

Homologous Recombination (HR) DNA repair and drug response capabilities 

on fresh human HG-SOC immediately following surgical resection. 

Molecular classification (similar to Tothill [Clin Canc Res. 2008;14]); 

analysis of NHEJ pathway (Proc Natl Acad Sci. 2011;108) and other DNA 

repair genes (Proc Natl Acad Sci USA 2011;108) is performed. In vivo drug 

response is studied in murine xenografts. Results: Sixteen chemotherapynaive 

potentially HG-SOC samples and associated clinical data have been 

collected. Functional evidence of DNA repair (HR) capability and response 

to DNA damaging agents will be presented, including IHC for markers of 

DNA damage (gH2AX), DNA repair (RAD51AP1) and apoptosis (capsase 3 

cleavage). Molecular classification, DNA repair gene and DNA repair 

pathway analyses are underway. Twelve HG-SOC have been transplanted 

and 6 of the first 8 have successfully xenografted, with serial transplantation 

and phenotyping of xenograft derivatives underway. In vivo drug 

response will be presented. Conclusions: This xenograft model will enable 

us to address hypotheses generated by recent molecular analyses of human 

HG-SOC (Cancer Genome Atlas Research Network. 2011. Nature 474; Clin 

Canc Res. 2008;14). Clinical, functional and molecular annotation will 

allow pre-clinical drug testing based on the plausible hypothesis approach. 



Proliferation pathway aberration frequencies in BRCA1- and BRCA2mutated 

ovarian cancers. Presenting Author: Deborah A. Zajchowski, 

Clearity Foundation, San Diego, CA 

Background: Large-scale genomic analyses of high-grade, advanced-stage 

serous ovarian cancers by The Cancer Genome Atlas (TCGA) project 

revealed aberrations in genes comprising key proliferation and survival 

pathways (RB-E2F, RAS, PI3K) in the majority of tumors. Patients with 

germline BRCA1/2-mutations have more favorable prognoses than non- 

BRCA carriers, and recent work suggests that BRCA2 carriers do better than 

BRCA1. We hypothesized that concurrent proliferation pathway aberrations 

and BRCA1/2 mutations in tumors might play a role in patient outcome. 

Methods: Mutation, copy number, and clinical data for 309 TCGA-profiled 

serous ovarian tumors were downloaded from the MSKCC cBIO web portal. 

Each tumor was scored as aberrant for a pathway if any gene (RB: RB1, 

CDKN2A, CCND1, CCND2, E2F3, CCNE1; PI3K: PIK3CA, PTEN, AKT1, 

AKT2; RAS: KRAS, BRAF, NF1) in that pathway was mutated, amplified, or 

deleted. Results: 205 of 309 tumors had an aberration in at least one of 

these pathways. The frequency of pathway alteration differed significantly 

in BRCA1 (82%, 28/34), BRCA2 (52%, 17/33) and BRCA1/2 WT (66%, 

160/242) tumors (BRCA1 vs. BRCA2: Fisher’s p� 0.0096). BRCA1 

tumors more frequently contained alterations in multiple pathways than 

BRCA2 or WT tumors (41% vs. 24% or 25%, respectively). RB-E2F 

pathway alteration frequency was significantly different (BRCA1: 56%, 

BRCA2: 18%, WT: 43%, p�0.0043), but no significant differences in 

PI3K and RAS pathway aberration frequencies (BRCA1%: 41, 38; BRCA2%: 

36, 27; WT% 28, 27), respectively, were observed. In agreement with the 

previous report, BRCA2 patients had significantly better overall survival 

(OS) than either BRCA1 or WT patients (median OS months for BRCA1: 

35.9, BRCA2 45.4, BRCA1/2 WT 27.8; p�0.001). Presence of pathway 

alterations was not significantly associated with OS in BRCA1, BRCA2, or 

WT patients in this cohort. Conclusions: These results show a negative 

association between BRCA2 mutations and aberrations in key proliferation 

and survival pathways. Beyond BRCA1 and BRCA2 genetic mutations, the 

elevated frequency of pathway alteration in BRCA1 vs. BRCA2 tumors 

highlights differences that may be important for patient prognosis as well 

as therapy responses. 


Inflammatory and nutritional markers as predictors of longer hospital stay 

and suboptimal residual disease (RD) in ovarian cancer (OVCA). Presenting 

Author: Michelle Torres, Mayo Clinic, Rochester, MN 

Background: Advanced OVCA should be managed aggressively, and extensive 

surgery has been the most accepted initial treatment. Medically unfit 

patients or those with extensive disease, in which complete cytoreduction 

is unlikely, may not benefit from upfront radical surgery, and neoadjuvant 

chemotherapy might be an appropriate alternative. Thus, reliable preoperative 

indicators of surgical outcome are necessary for considering primary 

surgery vs. neoadjuvant chemotherapy. Our aim is to determine if Creactive 

protein (CRP), IL-6, albumin and Glasgow Prognostic Score (GPS – 

score based on CRP and albumin) correlate with overall survival (OS), 

length of hospital stay (LOS), surgical morbidity, and suboptimal cytoreduction. 

Methods: We randomly selected 50 stages III/IV OVCA who underwent 

surgery as a primary treatment between July 2002 and June 2009 at Mayo 

Clinic with serum albumin levels and frozen serum available. CRP and IL-6 

were measured in stored serum. Univariate and multivariate regression 

models were fit to evaluate associations with each of the outcomes. Results: 

Among the 50 patients, the mean age was 67.7 years. 34% had 

pretreatment albumin �3.5 g/ml, 22.4% had CRP level �10 mg/l, 26.5% 

had IL-6 �24 pg/ml and 45% had abnormal GPS score. At 1, 3 and 5 years 

following surgery, the OS was 75.6%, 49.8% and 36.9%, respectively. RD 

(0, �1, �1cm; p�0.001) was the only independent predictor of OS. Also, 

IL-6 (p�0.028) and stage (p�0.046) were independently associated with 

LOS, but no inflammatory or nutritional markers were significant associated 

with post surgical complications. Stage IV (p�0.019) and elevated CRP 

(p�0.044) were independent predictors of suboptimal surgery (RD � 

1cm). Conclusions: One-third of the patients in our series had low serum 

albumin at the time of the OVCA diagnosis, and at least one-fourth had 

elevated inflammatory markers. Advanced stage and elevated inflammatory 

markers (CRP and IL-6) were independent predictors of longer hospital stay 

and suboptimal debulking. These pilot data, if confirmed in a larger 

population, may help in the selection of candidates for neoadjuvant 

chemotherapy. 


345s 


Secondary surgery with intraoperative chemohyperthermia in recurrent 

ovarian adenocarcinoma. Presenting Author: Jean Marc Bereder, University 

Hospital Archet 2, Nice, France 

Background: Optimal treatment of peritoneal recurrences in ovarian cancer 

is debating with second line chemotherapies. We proposed association of 

secondary surgery with heated intraperitoneal per operative chemotherapy 

(HIPEC). The aim of study is to determine prognostic factors in a single 

center cohort. Methods: Retrospective study of consecutive 169 patients 

with peritoneal recurrence from ovarian cancer were performed to evaluate 

HIPEC and to identify prognostic factors. Peritoneal Cancer Index (PCI) 

assess tumor load and completeness cytoreductive score (CCS) were used 

to give quality of resection CCS0 (no visible tumor), CCS1 (persistent 

diffuse lesions � 2.5mm), CCS2 (2.5mm �CC2� 25mm) and over CCS3 

status. HIPEC is performed with platinum based regimen. Endpoint was 

survival. Cox’s regression model was used for multivariate survival analysis 

and extending Cox model for modelling survival data. Results: We have 

operated on 197 procedures (HIPEC) in 169 patients from 2000 to 2011. 

Mean age was 58 years old range [28-75]. Median PCI was 10. After 

completion of resection, allocation of CCS was CCS0�120, CCS1�70, 

CCS2 & CCS3 �7. Procedure related mortality was 1% and morbidity 21%, 

mean length of hospital stay was 17 days range [7-51]. 3 and 5 years 

overall survival were respectively 64.7% and 37.4 %. Median survival was 

47.6 months and the median disease free survival was 20 months. PCI 

�10 (even if complete resection performed) and CCS2&3 were worse 

prognostic factors (HR respectively � 2.64 IC 95% [1.29-5.36] and � 

3.31 IC 95 % [1.55-7.08]). Modelling of these factors, is very strong to 

predict risk of death over the 2 first years after HIPEC. Conclusions: The 

chemo-hyperthermia is a standardized and reproducible feasible method. 

Less extensive disease and the quality of cytoreduction remain an independent 

factor of better outcome. To date HIPEC allows to reach the longest 

median time survival in peritoneal recurrent ovarian cancer. Modelling 

survival data is useful to know the risk of dying. 


Association of SNP genotype in ABCB1 with completion of intraperitoneal 

chemotherapy in ovarian and primary peritoneal cancer. Presenting Author: 

Sergio Enderica Gonzalez, Mayo Clinic, Rochester, MN 

Background: A standard of care (SOC) for the adjuvant treatment of ovarian 

and primary peritoneal cancer is a platinum-based intravenous (IV) chemotherapy 

doublet. Intraperitoneal (IP) chemotherapy is also a SOC, but the 

high incidence of grade 3/4 adverse events has limited its acceptance 

among clinicians. To identify genetic markers for completion of IP 

chemotherapy, we analyzed SNPs in four genes known to play a role in 

metabolism of platinum or taxane drugs. Methods: Patients diagnosed with 

primary or recurrent stage III or IV epithelial ovarian or primary peritoneal 

cancer who had primary or secondary debulking surgery at Mayo Clinic 

(Rochester, MN) between January 2007 and February 2009 followed by IP 

chemotherapy were included in this study. A cycle was defined as IV 

paclitaxel (135mg/m2 ) on day one, IP cisplatin (100mg/ m2 ) on day two, 

and IP paclitaxel (60mg/ m2 ) on day eight. With prior consent from the 

patient, peripheral blood was obtained before treatment for extraction of 

germline DNA. Using a custom Illumina BeadXpress 96-plex panel, SNPs 

in GSTM1 (N�7), ABCB1 (N�57), CYP3A4 (N�7), and CYP2C8 (N�25) 

were genotyped. The association between SNPs in these subsets of genes 

and completion of IP chemotherapy was analyzed using linear regression. 

Results: Thirty-seven patients were included in this study and 16 (43.2%) 

completed IP chemotherapy. Twenty-two out of the fifty-seven ABCB1 

SNP’s were associated with the number of cycles (p�0.15). There were no 

significant associations for GSTM1, CYP3A4 and CYP2C8 SNP’s. The 

minor A allele at missense SNP rs2229109 in the ABCB1 gene was present 

in five (31.2%) who completed treatment and only one (4.8%) who did not 

(p�0.007). However, the later was due to catheter complication. There was 

no association between rs2229109 and overall or progression-free survival. 

Conclusions: Our findings suggest that SNP rs2229109 in ABCB1 gene is 

associated with completion of IP chemotherapy, and potentially, less 

toxicity from chemotherapy. Thus, these patients may be optimal candidates 

for IP chemotherapy. Further studies in a larger population are 

needed. 




BRCA mutations and outcome in epithelial ovarian cancer (EOC): Experience 

in ethnically diverse groups. Presenting Author: Tamar Safra, Department 

of Oncology, Tel Aviv Sourasky Medical Center, Sackler School of 

Medicine, Tel-Aviv University, Tel Aviv, Israel 

Background: EOC patients with BRCA mutations have been reported to have 

better prognosis than non-hereditary (NH) matched cases, an advantage 

shown especially in the Ashkenazi-Jewish (AJ) population. We have 

analyzed our experience in our ethnically diverse patient cohort from NYC, 

Israel and Italy. Methods: A retrospective chart review of patients diagnosed 

with Stage IC-IV EOC between 1995-2008 at the NYU Cancer Institute, Tel 

Aviv Sourasky MC and Padova Clinical Cancer Centers. Out of �700 

patients, 183 were tested for BRCA mutations and evaluated. Results: 

Median age was 55.5 (range 31–83 years). Out of 183, 86 are carriers of 

BRCA1/2 mutations and 97 tested negative, 67 and 19 are carriers of 

BRCA1 and BRCA2 mutation respectively. Carrier frequency in EOC 

population is 46% (45/97) in AJ’s and 48% (41/86) in non-AJ’s. AJ 

patients had the following BRCA1 mutations: 185delAG (29), 5382insC 

(5), unknown (UK) (2) and BRCA2 mutations: 6174delT (8), UK (1). 

Non-AJ’s were divided by ethnicities into non-AJ, Caucasian, African- 

American, Hispanic, Middle Eastern or unknown. Non-AJ Jewish patients 

had BRCA1 mutations in 185delAG (7) and BRCA2 in 6174delT (1), UK 

(1). Non-Jewish Caucasians exhibited the widest variation of mutation 

types, with the following BRCA1 sites: 185delAG, K1702X (5223A�T), 

E1373X, 3829delT, 185delAT, IVS11�1G�A, 5385insC, 

5083del19�stop1670, 1720delAF�stop536, 1806C/T�Igu536Ter, del 

ex1a-2, cod1486ex14:4575delAstop1504, 5563G7A;Trp1815stop, 

5181delGTT(Val1688del) and UK and the following BRCA2 sites: 6174delT 

(2), 5301insA (1), 802delAT (1), cod2960ex22:9106C/t (1), cod68ex3: 

432delAstop79 (1), 7408A/T;Arg2394stop (1). One African-American 

patient with BRCA1 at 1294del40, 1 Hispanic BRCA1 at 185delAG. OS 

was significantly prolonged for BRCA carriers at 93.6 months versus 63.2 

months [95% CI: 44.5-91.7] (p�0.0016) for NH. Conclusions: Our data 

reports a wide variety of BRCA mutations in an ethnically diverse EOC 

population and confirms that BRCA mutations carriers have a better 

prognosis with a longer median survival compared to NH population. A 

larger cohort might manifest prognostic differences between the different 

types of mutations. 


A matched pair analysis of intra- and postoperative catumaxomab in 

patients with ovarian cancer from a multicenter, single-arm phase II trial 

versus a consecutive single-center collective of ovarian cancer patients 

without immunotherapy. Presenting Author: Klaus Pietzner, Charite University 

Medicine of Berlin, Berlin, Germany 

Background: Advanced ovarian cancer is still connected to high mortality 

rates due to intraperitoneal tumor cells that survive radical cytoreductive 

surgery as well as adjuvant chemotherapy. These persistent tumor cells 

need to be targeted in order to improve survival. Catumaxomab has 

demonstrated the ability to kill EpCAM-positive intraperitoneal tumor cells 

of ovarian cancer patients in studies aiming to controll malignant ascites in 

the recurrent setting. This analysis was conducted to investigate the 

efficacy of intraperitoneal catumaxomab at the timepoint of primary 

cytoreductive surgery and postoperative period, prior to standard adjuvant 

chemotherapy. Methods: Ovarian cancer patients undergoing radical surgery 

received one intraoperative (10 �g) followed by four subsequent 

intraperitoneal (i.p.) dosages (10, 20, 50 and 150 �g) of catumaxomab on 

days 7, 10, 13, and 16, respectively. Because of the single arm design of 

the study, the patients treated with catumaxomab were compared in a 

matched pair analysis to consecutive patients with primary ovarian cancer 

who received standard treatment without catumaxomab in a large center, in 

order to compare survival. The two main prognostic factors of stage and 

level of tumorreduction were chosen as matching criteria. Results: Of 58 

patients screened, 41 were treated with catumaxomab and available for 

survival evaluation. Median age was 57 years in the catumaxomab group 

and 59 years in the matched-pair control group. The most comon histology 

was the serous subtype with 70.7 % in the catumaxomab and 80.5 % of the 

patients in the control group. The median for overall survival was reached 

for the historical consecutive matched-pair control collective, but is not yet 

reached for the catumaxomab group. However, 3-year survival data were 

available for both groups and showed survival of 85.4% (35) in the 

catumaxomab group and 63.4% (26) in the matched-pair control group 

(p-value: 0.041; HR 2.073) Conclusions: There seems to be a trend to 

beneficial 3-year survival in the catumaxomab group, suggesting that a 

phase III trial is warranted. 


Serum IGFBP4 levels in combination with miliary disease: A candidate 

predictor of ovarian cancer progression-free survival. Presenting Author: 

Samantha Cohen, Mt Sinai School of Medicine, New York, NY 

Background: Insulin-like growth factor binding protein, IGFBP4, was shown 

to be highly expressed across all stages of epithelial ovarian cancer (EOC) 

and serum levels are elevated in EOC. Moreover, IGFBP4 levels are ~3x 

greater in women with malignant pelvic masses. We investigated whether 

ascites volume and the presence of miliary disease in combination with 

serum levels of IGFBP4 are independent predictors of survival. Methods: A 

prospective and retrospective analysis was performed. Patients were 

enrolled at the time of cytoreductive surgery. Ascites volume was either 

absent, �500 cc (low), or �� 500 cc (high), and the presence of miliary 

disease was recorded. The IGFBP4 cutoff was 1064.5 ug/ml based upon 

previous results. The Kaplan-Meier product limit method was used to 

estimate PFS probabilities. The Cox proportional hazards model was used 

to estimate hazard ratios (HR) and corresponding 95% CI. Results: 57 

cases were included in the analysis of ascites volume and miliary disease. 

Cytoreductive outcomes were complete gross resection (44.8%), optimal 

(��1cm residual disease; 44.8%), and suboptimal ( �1cm residual 

disease; 10.3%). Histologic subtypes: papillary serous (n�35; 61.4%), 

mucinous (n�15; 26.3%), endometrioid (n�4; 7.0%), and clear cell 

(n�3; 5.3%). Stage distribution was 21.1% I/II, and 78.9% III/IV. PFS 

was unaffected by ascites volume (p�0.341) or miliary disease. Among 

this cohort, 29 had IGFBP4 levels available for a separate analysis. 

Patients with high IGFBP4 and miliary disease were 5.5 times as likely to 

recur compared with patients with miliary disease and low IGFBP4 

(HR�5.55 [0.77, 39.82]), and the statistical significance was borderline 

(p�0.088). No statistically significant differences were detected between 

rates of recurrence among patients with high and low IGFBP4 values in 

combination with ascites volume. Conclusions: These exploratory studies 

suggest that patients with high IGFBP4 serum levels and miliary disease 

were � 5 times as likely to recur compared to women with miliary disease 

and low IGFBP4 levels. Future studies examining these variables using a 

larger population and examining the biologic basis of this relationship are 

planned. 


Progression-free survival (PFS) as a surrogate end point for overall survival 

(OS) in first-line treatment of advanced epithelial ovarian cancer (EOC). 

Presenting Author: Katrin Marie Sjoquist, NHMRC Clinical Trials Centre, 

University of Sydney, Sydney, Australia 

Background: The duration and cost of clinical trials of first-line chemotherapy 

in advanced EOC could be reduced if a surrogate endpoint were 

used in place of OS. The consensus of the Gynecological Cancer Intergroup 

was that PFS is the preferred primary end point for these trials due to 

potential confounding of post-progression therapy on OS. We performed a 

systematic review to assess the extent to which treatment effect on PFS is 

predictive of OS in this patient population. Methods: Randomised trials of 

first-line chemotherapy comparing platinum containing regimens in advanced 

EOC were identified; trials with non-platinum backbone, maintenance 

strategies or biological containing therapies were excluded. Summary 

data (hazard ratios (HR), median PFS and OS and the ratios of medians 

between treatment arms) were extracted. Weighted least-square (WLS) R2 by trial sample size derived using linear regression was used to report 

correlation. Results: 15 eligible trials with 19 treatment comparisons were 

identified comprising a total of 16,598 patients. There was a good 

correlation between treatment effect on PFS and OS (correlation of HR: r, 

0.88, WLS R2 , 0.71; correlation of ratios of medians: r, 0.84, WLS R2 , 

0.72). Good correlation between treatment effect on PFS and OS was also 

observed in various prognostic subgroups (Table). Conclusions: In clinical 

trials of first-line platinum based chemotherapy without biological agents 

in advanced EOC, treatment effect on PFS and OS is highly correlated. PFS 

could be considered as a primary end point when evaluating future first line 

strategies in advanced EOC. 

Prognostic factors across trials 

low vs. high split at median Correlation for HR (r) WLS R 2 

Stage IV (16%) 0.94 vs. 0.75 0.79 vs. 0.57 

Optimal debulking (62.6%) 0.86 vs. 0.95 0.69 vs. 0.83 

Age (59 years) 0.93 vs. 0.86 0.77 vs. 0.66 

ECOG performance status ECOG 2 and 3 (10.1%) 0.95 vs. 0.89 0.81 vs. 0.76 


5082^ General Poster Session (Board #23B), Sun, 8:00 AM-12:00 PM 

Final results of a phase II trial of weekly nab-paclitaxel with GM-CSF as 

chemoimmunotherapy for platinum-resistant epithelial ovarian cancer. 

Presenting Author: Ron E. Swensen, Loma Linda University, Loma Linda, 

CA 

Background: Ovarian cancer patients with an anti-tumor immune response 

have a prolonged survival, suggesting that augmenting anti-tumor immunity 

may be therapeutic. We hypothesized that weekly nab paclitaxel (nabP) 

followed by GM-CSF may enhance anti tumor immunity and prolong time to 

progression (TTP). Methods: Eligible subjects had platinum resistant 

ovarian, primary peritoneal or fallopian tube cancer, and an elevated 

CA125. Conditional power estimate after 11 subjects showed 22 subjects 

had 80% power to show a response rate (RR) �21% if the true study RR is 

35%. Study end points were RR and TTP. Progression (DP) was doubling of 

CA125 above the nadir. Complete response (CR) was a decline of CA125 

below institutional normal. Partial response (PR) was a decline of �50% 

from baseline. Stable disease (SD) was all other scenarios. Subjects 

received nabP, 100mg/m2 days 1,8,15 followed by GM-CSF 250mcg days 

16-26 of a 28 day cycle until progression or 6 cycles were complete. 

Responding subjects received up to 6 more cycles of GM-CSF on days 

14-28. Results: 21 subjects received at least one dose of study medications. 

Median age was 61 (30-91) and had a median of 3 (1-13) prior 

regimens. Among those completing the study, the median TTP was 132 

days vs. 272 days on the prior platinum regimen. 9/21 (43%) had a PR and 

4/21 (19%) had a CR. Subjects with a response had a median TTP of 140 

days. Assay of serial T-lymphocyte counts against CEA, MUC1, CA125 and 

tt and influenza controls are planned. Conclusions: Weekly nabP with 

GM-CSF had manageable toxicity and induced a high response rate (62% 

by CA125) in patients with platinum resistant ovarian cancer, however this 

regimen did not prolong the TTP beyond the TTP observed in the prior 

platinum regimen. 


Prevalence of high-risk human papillomavirus in uterine cervical lesions 

among older Japanese women. Presenting Author: Kazuhiro Takehara, 

National Hospital Organization Kure Medical Center/Chugoku Cancer 

Center, Hiroshima, Japan 

Background: To estimate the prevalence and genotypes of high-risk human 

papillomavirus (HPV) among older Japanese women, using liquid-based 

cytology (LBC). Methods: ThinPrep LBC specimens were collected from 

11,039 Japanese women (age range, 14-98 years). After classifying 

cytodiagnosis, specimens were analyzed for HPV DNA using the multiplex 

polymerase chain reaction method. Cervical smear specimens from 1,302 

women showed positive results. To examine the prevalence of HPV in 

women defined as negative for intraepithelial lesion or malignancy (NILM), 

2,563 samples were randomly selected from the remaining 9,737 women. 

Comparisons were made between women �50 years of age (older age 

group) and women �50 years of age (younger age group). Written informed 

consent was obtained from all patients. In this study, the high-risk HPV 

genotypes encountered were 16, 18, 31, 33, 35, 45, 52, and 58. Results: 

In the older age group with abnormal smear findings, HPV genotypes were 

detected in 49.7% (148/298), including high-risk HPV genotypes in 

40.9% (122/298). In the younger age group with abnormal smear findings, 

HPV genotypes were detected in 71.7% (720/1004), including high-risk 

HPV genotypes in 58.1% (583/1,004). In NILM, HPV-positive rates were 

4.5% (39/873) in the older age group and 11.8% (199/1,690) in the 

younger age group. In high-grade squamous intraepithelial lesion (HSIL) or 

more severe cytological findings, HPV genotypes of each group (older age 

group/younger age group) were detected in 61.7%/83.1%, and high-risk 

HPV genotypes were detected in 56.4%/74.7% of women. In positive 

cervical smears, HPV 16 was the most frequently detected (28.5%) in the 

younger age group, while HPV 52 (31.3%) and 58 (27.2%) were detected 

more frequently than HPV 16 (18.4%) in the older age group. Conclusions: 

In Japan, although HPV infection as a cause of abnormal cervical cytology 

is more frequent among younger age groups than in older age groups, 

high-risk HPV infection was more highly associated with older individuals 

(older age group/younger age group: abnormal smear findings, 82.4%/ 

81.0%; HSIL or more severe cytological findings, 91.3%/89.9%). In older 

age groups, HPV 52 and 58 were more frequent than HPV 16. 


347s 


Prospective multicenter study evaluating the survival of patients with 

locally advanced cervical cancer (LACC) and negative positron emission 

tomography with computerized tomography (PET-CT) in the para-aortic 

area undergoing laparoscopic para-aortic (PA) lymphadenectomy before 

chemoradiation therapy. Presenting Author: Sebastien Gouy, Institut 


Background: In three comprehensive cancer centers, patients with LACC 

were systematically staged using conventional and PET-CT imaging before 

chemoradiotherapy. If patients had no uptake in the PA area, laparoscopic 

extraperitoneal PA surgery was then performed to define radiation field 

limits more accurately. The aim of this study was to evaluate the 

therapeutic impact of this management. Methods: A prospective multicenter 

series of 237 patients treated from 2004 to 2011 for LACC with a 

negative PET-CT of the PA area and undergoing laparoscopic PA lymphadenectomy. 

Radiation fields were extended to PA area when PA nodes were 

involved. Chemoradiotherapy modalities were homogeneous between Institutions. 

Patients with a poor prognosis histologic subtype, peritoneal 

carcinomatosis or ovarian metastasis were excluded. Results: Clinical 

stages were IB2 (n�79), IIA (n�10), IIB (n�120), III (n�23), IVA (n�5). 

The histologic types were squamous carcinoma (n�197), adenocarcinoma 

(n�34) and others (n�6). Twenty-nine (11%) patients had nodal involvement 

(false negative PET-CT results): 16 with PA nodal metastasis 

measuring � 5 mm and 13 � 5 mm. With a median follow-up of 18 (range, 

0-67) months, disease-free survival (DFS) at 2 years in patients without 

and with PA involvement was respectively 76% (68%-83%) and 61% 

(37%-80%)(p�.007). DFS at 2 years in patients without PA involvement 

or with PA metastasis measuring � or � 5 mm was respectively 76% 

(68%-83%), 89% (57%-98%) and 38% (14%-68%)(p�.0006). 

Conclusions: This is the largest series of patients reported undergoing such 

strategy. We obtained a similar survival rate for patients with PA nodal 

metastasis � 5 mm and patients without PA lymph node involvement 

suggesting that this strategy is highly efficient in such patients. Conversely, 

the survival of patients with PA nodal involvement � 5 mm remained poor, 

despite no extrapelvic disease at PET-CT imaging in this subgroup. Other 

treatment modalities should be evaluated for these patients. 


Nuclear Y-box binding protein-1 expression as a prognostic marker and 

correlation with epidermal growth factor receptor expression in cervical 

cancer. Presenting Author: Shin Nishio, Kurume University School of 

Medicine, Kurume, Japan 

Background: Y-box binding protein-1 (YB-1) is a member of the cold shock 

protein family and functions in transcription and translation. Many reports 

indicate that YB-1 is highly expressed in tumor cells and is a marker of 

tumor aggressiveness and clinical prognosis. Overexpression of epidermal 

growth factor receptor (EGFR) has been associated with poor outcomes in 

cervical cancer (CC). Clinical trials have shown that EGFR inhibitors are 

effective against CC (JCO 2011). Nuclear YB-1 expression correlates with 

EGFR expression in various types of cancer. Methods: Nuclear YB-1 

expression was immunohistochemically analyzed in tissue specimens 

obtained from 204 CC patients who underwent surgery. Associations of 

nuclear YB-1 expression with clinicopathological factors such as survival 

and EGFR (HER1 and HER2) expression were investigated. Results: 

Nuclear YB-1 expression was observed in 41 (20%) of 204 cases and 

correlated with stage, tumor diameter, stromal invasion, and lymph-node 

metastasis. Nuclear YB-1 expression also correlated with both HER1 

expression (p�0.0114) and HER2 expression (p�0.0053). Kaplan-Meier 

survival analysis showed that nuclear YB-1 expression was significantly 

associated with poor outcomes in terms of progression-free survival 

(p�0.0033) and overall survival (p�0.0003). On multivariate analysis, 

stromal invasion, parametrial invasion, and nuclear YB-1 expression were 

independent predictors of survival. Conclusions: Nuclear YB-1 expression is 

a prognostic marker and correlates with EGFR expression in CC. 




Concurrent chemoradiotherapy with paclitaxel and cisplatin for adenocarcinoma 

of the cervix. Presenting Author: Yutaka Nagai, University of the 

Ryukyus, Okinawa, Japan 

Background: Adenocarcinoma of the cervix has a worse prognosis than its 

squamous counterpart, particularly when cancer cells spread beyond the 

uterine cervix. This is derived from the observation that adenocarcinoma is 

less sensitive to radiotherapy (RT) and chemotherapy It is unclear whether 

cisplatin-based concurrent chemoradiotherapy (CCRT) has the same effect 

on adenocarcinoma as on squamous cell carcinoma. Methods: We retrospectively 

analyzed 32 patients with stage IIB–IVA cervical adenocarcinoma 

who were treated with RT or CCRT. Fourteen patients were treated with RT 

from 1983–1996, 8 with CCRT using cisplatin alone (CCRT-P) from 

1997–2002, and 10 with CCRT using cisplatin�paclitaxel (CCRT-TP) 

after 2003. The patients were treated with external beam radiotherapy, and 

low-dose or high-dose rate intracavitary brachytherapy. For CCRT-P, the 

patients received 20 mg/m2 cisplatin for 5 days every 3 weeks, and for 

CCRT-TP, the patients received 50 mg/m2 cisplatin every 3 weeks and 50 

mg/ m2 paclitaxel weekly. Results: A complete response was achieved in 

7/14 patients in the RT, 4/8 patients in the CCRT-P, and 9/10 patients in 

the CCRT-TP group. Ten of the 14 patients in the RT, 7/8 patients in the 

CCRT-P, and 2/10 patients in the CCRT-TP group experienced locoregional 

recurrence. The 5-year overall survival rate in the RT, CCRT-P, and 

CCRT-TP groups was 7.1%, 25.0%, and 74.1%, respectively (p � 

0.0094), and their central disease-free survival rate was 21.4%, 12.5%, 

and 78.8%, respectively (p�0.0119). The acute toxicities associated with 

CCRT-TP are manageable. Regarding late toxicity of CCRT-TP, no grade 3/4 

adverse effect was observed. Conclusions: The present study demonstrated 

that CCRT-TP achieved much better local control for adenocarcinoma of 

the cervix, leading to a decrease in locoregional recurrence. Prospective 

trials in larger series of patients are urgently needed. 


The impact of racial disparity on outcomes of patients with early-stage 

uterine endometrioid carcinoma in an equal-access environment. Presenting 

Author: Jared R. Robbins, Henry Ford Hospital, Detroit, MI 

Background: To determine if racial disparity exists between African American 

(AA) and non-African American (NAA) patients with early stage uterine 

endometrioid carcinoma who had similar multidisciplinary management. 

Methods: Our prospectively-maintained database of 1,450 uterine cancer 

patients was reviewed for this IRB-approved study. We identified 766 

consecutive patients with endometrioid carcinoma 1988 FIGO stages I-II 

who underwent hysterectomy between 1987-2009. Patients with nonendometrioid 

carcinoma, mixed histologies and those who received preoperative 

treatments were excluded. For the purpose of data analysis, patients 

were divided into two groups; AA and NAA. Recurrence-free survival (RFS), 

disease specific (DSS) and overall survival (OS) was calculated from the 

date of hysterectomy using the Kaplan-Meier method. Cox regression 

modeling was used to explore the risks of various factors on recurrence. 

Results: Median follow-up was 5.1 years. 27% were AA and 73% were NAA. 

All patients underwent hysterectomy and oophorectomy. 80% had peritoneal 

cytology and 69% underwent lymphadenectomy. AA patients were 

more likely to have higher grade tumors, and more lymphovascular space 

involvement (LVSI). Although the two groups were balanced in regards to 

surgical staging and adjuvant treatment received, the five-year RFS and 

DSS were significantly lower in AA compared to NAA patients (91% vs 

84%, p�0.030; 95% vs 88%, p�0.011, respectively). Between the two 

groups, OS was not significantly different. On multivariate analysis and 

after adjusting for other prognostic factors, race (AA vs NAA) was not a 

significant predictor of outcome. Grade 3 tumors and the presence of LVSI 

were the only two independent predictors of RFS and DSS with p��0.001 

and p��0.001, respectively. Conclusions: In this large hospital-based 

study, AA race was associated with a higher incidence of adverse pathological 

features and worse recurrence-free and disease-specific survival. 

However, on multivariate analysis race was not an independent prognostic 

factor. Further studies are needed to elucidate possible underlying molecular 

mechanisms for these poorer outcomes. 


How is the current clinical management of endometrial cancer worldwide? 

An international survey by the North-Eastern German Society of Gynaecological 

Oncology (NOGGO). Presenting Author: Robert W. Kraetschell, 

Charité University Department of Gynecology, Campus Virchow Clinic, 


Background: Indication, technique and extent of lymph-node-dissection 

(LND) in endometrial cancer (EC) remains controversial and is strongly 

debated in cancer community. We conducted a national- and at a second 

step an international-survey evaluating the current status-quo of the 

surgical and medical management of EC. Methods: A validated 15-itemquestionnaire 

regarding surgical and adjuvant procedures of EC was sent to 

all major gynaecological cancer societies and study groups worldwide. The 

questionnaire could also be answered online. Results: In a phase-I-national 

trial, the questionnaire was validated on basis of 316 German institutions. 

On the phase-II-international survey a total of 302 questionnaires were 

answered from 24 countries, mainly from Japan (38.7%), Spain (8.3%), 

Austria (7%), United-Kingdom (6.3%), Italy (6%), USA (4.3%) and 

Canada (4%). The vast majority of the participating clinics were academic 

(62.8%), while 75.2% of them belonged to gynaecology. Only 0.7% of the 

clinics internationally reported never performing LND in EC. 62.3% of the 

clinics perform both a pelvic and paraaortic lymph node dissection. 59.1% 

of the participants performed a systematic lymph node dissection with the 

intention of both adequate staging and for therapeutic value. 15.05% of 

the clinics perform LND up to the common-iliac-arteries, 9.03% up to the 

inferior-mesenteric-artery and 70.6% up to the renal-veins. The most 

common risk-factors to indicate LND were: high-grading (93%), nonendometrioid-histology 

(90.1%), lymphovascular-invasion (55.3%), bloodvessel 

invasion (45.4%) and tumor-diameter �2cm (38.4%). For advanced 

stage III&IV disease the vast majority (60% and 80%, respectively) of the 

physicians indicated systemic chemotherapy alone. Conclusions: This study 

presents the large variety in clinical management of EC worldwide, 

underlining so the high need of future prospective randomised trials which 

will establish standard and evidence based treatment guidelines for ECdisease. 


Association of smoking with pulmonary recurrences among women with 

intermediate- to high-risk early-stage endometrial adenocarcinoma. Presenting 

Author: Lori Elizabeth Weinberg, Case Comprehensive Cancer Center 

and Case Western Reserve University, Cleveland, OH 

Background: While a number of histologic risk factors have been identified 

in endometrial carcinoma, host factors are less well studied. Our aim was to 

examine the influence of smoking on the risk of pulmonary recurrences in 

women with early stage intermediate to high-risk endometrioid uterine 

cancer (EC). Methods: Women with surgically treated stage I or II EC from 

1994 to 2010 were included in this study if they had lymphovascular space 

invasion (LVSI), FIGO grade 2 or 3 histology (G2/3), or outer half 

myometrial invasion (OI). All demographic, medical and oncologic data 

were obtained from chart review. Patients were excluded if their follow-up 

period was less than six months or if they had a diagnosis of a second 

primary invasive cancer. We performed univariate and multivariate logistic 

regression analyses and Fisher’s Exact test for two-way analyses of 

categorical variables to identify prognostic factors of pulmonary recurrences. 

Significance was determined by two-sided tests with ��0.05. 

Results: 349 patients were identified to meet histologic criteria, 3% were 

excluded. The remaining 337 patients had a median follow-up of 60 

months (range 6 to 194). The median age of this cohort was 68 years and 

median BMI was 30.7 kg/m2. 81 patients (24%) had a past or present 

history of smoking. There were 14 pulmonary recurrences (4.1%), 36 

(10.7%) distant recurrences and 58 (17.2%) total recurrences in the 

cohort. Smoking (present or past) was significantly associated with pulmonary 

recurrences, with an odds ratio of 1.09 (95% CI 1.04-1.15; 

P�0.0002). In a multivariate analysis adjusting for age, BMI, grade, LVSI, 

OI, cervical invasion, and adjuvant therapy, smoking was still a predictor of 

pulmonary recurrences. Conclusions: Smoking is a significant and independent 

predictor of pulmonary recurrences among women with early stage EC. 

Refining our understanding of host factors that influence risk may further 

allow us to identify those who may benefit most from adjuvant therapies as 

well as intensive surveillance. 



External validation of a nomogram predicting overall survival (OS) of women 

with uterine leiomyosarcoma (ULMS). Presenting Author: Alexia Iasonos, 


Background: A nomogram for predicting OS of women with ULMS was 

developed , given the poor prognostic performance of FIGO and AJCC 

staging systems. We aimed to determine the validity of the ULMS 

nomogram using independent, external cohorts. Methods: The ULMS 

nomogram incorporates 7 clinical characteristics: age at diagnosis, tumor 

size, grade, involvement of cervix, locoregional metastases (direct extrauterine 

spread, locoregional lymph node), distant metastases, and mitotic 

index (per 10 HPF) to predict OS following primary surgery. Two independent 

cohorts from sarcoma centers (1 US, 1 Europe) were included. 

Eligible women were treated at the institutions (1994-2010) and had 

undergone hysterectomy. Women with locally advanced or metastatic 

disease who underwent more extensive surgery were included if the primary 

tumor (uterus) was resected. Women who previously underwent resection of 

the primary tumor or recurrences at other institutions were included if they 

received followup care at 1 of the centers. Women who presented with 

unresectable disease who never underwent surgery and those with insufficient 

information on any of the nomogram variables were excluded. Results: 

187 women with ULMS were identified who met the above criteria (median 

age 51 yrs, median tumor size 9 cm, median mitotic index 20). Tumors 

were generally high grade (88%), FIGO stage I-II (61%) without cervical 

involvement (93%) and without locoregional (77%) or distant metastases 

(83%). Median and 5-yr OS rates were 4.5 (95% CI 3.2-5.3) yrs and 46%, 

respectively; 65 women (35%) were alive at last follow up. The nomogram 

concordance index was 0.67(SE�0.02) which was as high as the concordance 

index from the initial cohort used for nomogram development. The 

concordance between actual OS and nomogram predictions suggests 

excellent calibration of the nomogram in the validation cohort. Predictions 

were within 1% of actual 5-yr OS rates, except for the patients with a 5-yr 

OS rate of greater than 0.68. Conclusions: The ULMS nomogram was 

externally validated and can be generalized to independent cohorts. The 

nomogram provides a more individualized and accurate estimation of OS of 

women diagnosed with ULMS following primary surgery. 


Prognosic value of lower uterine segment involvement in high-grade 

endometrial cancers. Presenting Author: Paola A. Gehrig, Lineberger 

Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 


Background: To determine the relationship of lower uterine segment (LUS) 

involvement and clinical-pathologic outcomes in high grade endometrial 

cancers (EC). Although LUS and prognosis has been previously reported in 

the literature, the results have been conflicting and limited to early stage 

cases without focus upon the highest risk histologies. Methods: A singleinstitution 

retrospective cohort analysis of all grade 3 EC from Jan 2005- 

Sept 2010 was performed. Clinical-pathologic data were abstracted. LUS 

status was determined based on permanent-section pathology. Statistical 

analyses were performed using univariate and bivariate analyses with 

t-tests, X2, and log-rank tests. Multivariate regressions were performed by 

cox modeling. Two sided p-values�0.05 were considered significant. 

Results: Of 329 cases, 52% were LUS�. Mean age was 66.1(SD 10.8) and 

BMI 31.7(SD 8.3). The majority were Caucasian (63.2%) and 30.1% were 

African-American (AA). Most women (80.2%) were overweight or obese, 

58.7% had hypertension, and 22.5% were diabetic. Most women had stage 

I disease (54.8%), but 8.6% had stage II disease, and 36.6% had stage 

III-IV disease. Histologic subtypes included 32.2% endometrioid, 47.4% 

serous/clear cell, and 17% carcinosarcoma. Thirty-nine percent had � 

50% myometrial invasion (MI) and 43.2% had LVSI. Most of the women 

(80.8%) underwent retroperitoneal node dissection (77.9% pelvic, 70.0% 

periaortic). Mean follow-up time was 24.5 months (range 0.13, 73.3). Age, 

HTN, and DM did not differ by LUS status. Statistically significant factors 

associated with LUS positivity included race AA (38.3 v 26.5%), obesity 

(57.5 v 46.7%), serous/clear cell (65.7 v 53.8%), LVSI (56.2 v 30.5%), 

deep MI (52.1 v 25.3%), and positive nodes (42.4 v 12.7%). LUS� was 

significantly associated with an increased rate of recurrence (HR 2.3, CI 

1.16-4.47, p �0.02) after adjusting for obesity, deep MI, LVSI, nodal 

status, stage, serous/clear cell histology, and adjuvant therapy. Conclusions: 

Lower uterine segment was independently associated with an increased 

rate of recurrence in high grade EC. This should be confirmed in 

prospective endometrial trials to see if this remains an independent 

predictor of recurrence. 


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Pair box (PAX8) protein to predict disease recurrence and its association 

with outcome in women with endometrial cancer: A retrospective study of 

229 patients. Presenting Author: Damanzoopinder Samrao, USC, Los 

Angeles, CA 

Background: Pax-8 is a member of the pair-box (PAX) family of transcription 

factor genes and it has been found to be overexpressed in numerous cancer 

cell lines including ovarian and endometrial. Possibly, inhibition of Pax8 

activity may even have an impact on cancer treatment. However the role of 

Pax8 in human endometrial cancer has not yet been explored. Thus, the 

aim of this study is to determine its predictive value in disease outcome of 

endometrial cancer. Methods: 229 patients with available clinical data and 

paraffin-embedded tissue were available for review and analysis. The 

clinical parameters used for modeling were age, histologic subtypes, 

myometrial depth of invasion, lympho-vascular invasion (LVI), FIGO grade, 

lymph nodes positive, recurrence, disease status, recurrence time and 

survival time. To test the association between Pax8 and the clinical 

parameters, Fisher’s exact test was performed. For survival analysis, 

Kaplan-Meier method was performed. Results: We found a strong association 

between PAX8� and high tumor grade (p�0.002), LVI � (p�0.018), 

and type II tumor subtype. Patients with tumor expressing Pax8 were more 

likely to present with shorter OS and DFS p� 0.00096 and p�0.018 

respectively. There was an association of PAX8 with OS (p�0.01486) with 

5-years OS probability of 80.04% for patients with Pax8- and 55.9% for 

patients with Pax8�. There was also an association of PAX8 and DFS 

probability (p�0.02028) with 5-years DFS probability was of 72.12% for 

patients with Pax8- versus 49.88% for patients with Pax8� expression. 

Conclusions: Pax8 is a reliable marker in endometrial cancer and its 

overexpression can predict poor outcome. 


Neoadjuvant chemotherapy plus radical surgery followed by chemotherapy 

in locally advanced cervical cancer. Presenting Author: Roberto Angioli, 

Department of Obstetrics and Gynecology, Campus Bio-Medico University 

of Rome, Rome, Italy 

Background: The aim of this study is to evaluate the efficacy, in terms of 

overall survival and progression free survival, and safety of adjuvant 

chemotherapy after neoadjuvant chemotherapy followed by radical surgery 

both in patients with and without node metastases. Methods: Between June 

2000 to May 2007, all patients with diagnosis of locally advanced cervical 

cancer referred to the Division of Gynecologic Oncology of the University 

Campus Bio-Medico of Rome were elegible for this protocol.All enrolled 

patients received 3 cycles of platinum-based chemotherapy every 3 weeks 

according to the scheme cisplatin 100 mg/mq and paclitaxel 175 mg/mq. 

After neoadjuvant chemotherapy all patients with stable or progression to 

treatment were excluded from the protocol, all other were submitted 

classical radical hysterectomy and bilateral systematic pelvic lymph node 

dissection, and after to adjuvant treatment with 6 cycles of platinum based 

chemotherapy with cisplatin 100 mg/mq and paclitaxel 175 mg/mq. 

Results: 110 patients with local advanced cervical cancer received the 

treatment with neoadjuvant chemotherapy followed by radical surgery and 

adjuvant chemotherapy.Our study focused on clinical and operative data , 

in terms of overall survival and disease free survival at 5 and 3 years. 5-year 

OS of our series was 78% at five years and 86% at 3-years, with 

encouraging results also in subgroup with and without node mestastases. 

Conclusions: The adjuvant chemotherapy regimen after neoadjuvant chemotherapy 

and radical surgery rappresents a valid treatment option for 

patients with locally advanced cervical cancer without lymph node involvement, 

both in terms of overall survival than in terms of disease-free interval, 

the results have also confirmed the validity of this approach in lymph node 

metastases, with a complication rate lower than the standard radiochemotherapy 

regime. 




The novel biomarker HE4 versus CA125 in detecting endometrial cancer: A 

case control prospective study. Presenting Author: Francesco Plotti, 

Campus Bio-Medico of Rome, Rome, Italy 

Background: In endometrial cancer, there are no markers routinely used in 

clinical practice. This study prospectively investigates the sensitivity and 

specificity of new marker HE4 in detection of endometrial cancer. Methods: 

Serum samples were prospectively obtained 24 hours before surgery from 

25 patients with endometrial cancer and from 25 patients with uterine 

benign pathology, operated from January 2011 to October 2011 at 

University Campus Bio-Medico of Rome. Preoperative CA125 levels were 

evaluated by a one-step “sandwich” radioimmunoassay. HE4 levels were 

determined using the HE4 enzymatic immune assay. The CA125 normal 

value is considered less than 35 U/mL. Two HE4 cut-off are considered: 

less than 70 pmol/L and less than 150 pmol/L. The specificity analysis was 

performed using the parametric T-Test for comparing the HE4 series and 

the Mann-Whitney test for the CA125 series. The level of statistical 

significance is set at p � 0.05. Results: The sensitivity of CA125 in 

detecting endometrial cancer is 16% whereas the sensitivity of HE4 is 48% 

and 28 % for 70 pmol/L and 150 pmol/L cut-off respectively. The 

specificity of HE4 is 100% (positive predictive value � 100%, negative 

predictive value � 65.79% and 58.14% considering the two HE4 cut-off, 

respectively), whereas the CA125 specificity is 72 % (positive predictive 

value � 36.36%, negative predictive value � 46.15%) in detection of 

endometrial cancer. Conclusions: HE4 has a good sensitivity and a 

specificity of 100% in detection of endometrial cancer and may be useful 

for detecting early stage endometrial cancer. In particular the HE4 at 

cut-off of 70 pmol/L yields the best sensitivity and specificity. 


Phase II trial on cisplatin-doxorubicin hydrochloride-paclitaxel (TAP) combination 

as neoadjuvant chemotherapy (NACT) for locally advanced cervical 

adenocarcinoma (LACA). Presenting Author: Francesco Raspagliesi, 

National Cancer Institute of Milan, Milan, Italy 

Background: NACT followed by surgery is a different therapeutic approach 

to locally advanced cervical cancer that seems to offer specific advantages 

over chemoradiation such as potential activity against distant micrometastases, 

a debulking effect improving subsequent surgical outcome, less 

toxicity, and an easier management of salvage therapy. This phase II trial 

was designed to evaluate the toxicity and activity of NACT with TAP in 

patients with LACA. Methods: Patients (pts) with FIGO stage IB2 (9 pts)- II 

(21 pts) uterine adenocarcinoma were treated with cisplatin 70 mg/mq, 

doxorubicin hydrochloride 45 mg/mq and paclitaxel 150 mg/mq day 1 

every 21 days for 3 cycles. Eight pts (26.6%) presented with positive 

lymphnodes ( �LY) at diagnosis (5 pelvic and 3 pelvic�paraortic). After the 

last cycle of chemotherapy patients underwent radical surgery with lymphnode 

dissection. Clinical responses to chemotherapy was evaluated 

according to Recist criteria. Pathological response was classified as no 

residual tumor (pCR), residual disease with �3 mm stromal invasion (pR1) 

or residual disease with �3 mm stromal invasion (pR2). Due to the slow 

accrual the trial was closed before the target population of 45 pts was 

reached. Results: Between 2003 to 2010, 30 women were enrolled. Two 

complete clinical responses (6.7%), 21 partial responses (70%) and 7 

stabilizations of disease (23.3%) were registered. All the patients underwent 

radical surgery and were assessable for pathologic responses. Five 

patients (16.6%) achieved a pCR , 8 (26.6 %) a pR1 response; 17 patients 

(56.7%) a pR2 response. At pathological assessment 10 pts (33.3%) 

presented with �LY (7 pelvic, 1 paraortic, 2 pelvic�paraortic). At a median 

follow up of 45 months progression free survival and overall survival were 

37 months (95% CI 1-98) and 45 months (95% CI 9-101�) respectively. 

Hematologic toxicity was the most relevant side effect with 13 pts (43 %) 

reporting grade 3-4 neutropenia. Conclusions: The TAP combination seems 

to be feasible with an acceptable toxicity profile and a promising response 

rate for the treatment of LACA. The effect of NACT on lymphnodes status 

warrant further investigation. 


Association of adjuvant therapy in early-stage low-risk endometrial cancer 

with increased mortality: A statewide cancer registry analysis. Presenting 

Author: Michael R. Milam, University of Louisville, Louisville, KY 

Background: National Comprehensive Cancer Network (NCCN) guidelines 

state that patients with early stage low risk endometrial cancer (defined 

with 2009 criteria as stage IA endometrioid endometrial cancer) may be 

managed with observation with consideration of adjuvant therapy.The 

premise of this study is to review the patterns of care of those patients who 

received adjuvant therapy and its impact on survival. Methods: This is a 

retrospective cohort analysis of 1044 women from 2004-2008 in the 

Kentucky Cancer Registry (KCR) one of the affiliates utilized in the 

Surveillance, Epidemiology and End Results (SEER) Program database. 

Inclusion criteria for the patients in this analysis were those women with 

2009 Stage IA uterine cancer of endometrioid histology, moderate and well 

differentiated tumor grade, who received definitive primary surgery. Adjuvant 

therapy was defined as any postoperative radiotherapy and/or chemotherapy 

after definitive surgical treatment. Patients with adjuvant therapy 

after surgery (AT) were compared to those patients who underwent surgery 

only (SO). Chi-square tests were used to identify associations between type 

of treatment and clinical/demographic factors. K-M plots and Cox regression 

models were used to examine survival between the two treatment 

groups. Results: 5.3% (55/1044) of patients with early stage low risk 

endometrial cancer were treated with AT compared to 94.7% (989/1044) 

of SO patients.No statistical differences in mean age, race, tumor size, 

smoking status, insurance status, lymph node dissection and gynecologic 

oncology care were found among the AT or SO groups. Five year survival was 

significantly better in the SO cohort compared to the AT cohort (92% alive 

at 5 years for SO vs. 66% alive at 5 years; p�0.0001). Controlling for other 

confounders in the multivariate Cox regression analysis, SO patients had 

substantially less risk for death compared to the AT groups (HR: 0.21; 

95%CI 0.12-0.38; p�0.0001). Conclusions: In this statewide cancer 

registry analysis, adjuvant therapy after surgery in early stage low risk 

endometrial cancer patients is uncommon and is associated with an 

increased risk of mortality. 


Analysis of somatic mutation in miRNAs and miRNA regulation-related 

genes in gynecological cancers: New frameshift mutation of TNRC6A found 

in endometrial cancer. Presenting Author: Qi Mei, Department of Oncology, 

Tongji Hospital, Tongji Medical College, Huazhong University of Science 

and Technology, Wuhan, China 

Background: Micro RNAs (miRNAs) are small non-coding RNAs which plays 

an important role in tumorigenesis and mutation of a miRNA gene or 

miRNA regulation-related gene may cause butterfly effect on alteration of 

global gene expression.In order to investigate this hypothesis,high resolution 

melting analysis (HRM) and denaturing high-performance liquid 

chromatography (DHPLC) were used to screen 20 miRNA genes and 6 

miRNA regulation-related genes for mutations in gynecologic cancers. 

Methods: In this study,182 DNA samples from breast cancer tumors,42 

from ovrian cancers and 28 from endometrial cancers were obtained.18 

human cancer cell lines were also included.We used HRM and/or DHPLC to 

screen mutations of these genes in human cancer cell lines and tumor 

tissues. All samples with curves that differed in shape compared to 

wild-type were directly sequenced for confirmation.Secondary structures 

for the wild-type and variant primary precursor of miRNA sequences 

obtained from sequencing were predicted using RNAfold software.Western 

blot and immunohistochemistry were used to evaluate the related protein 

change in cancer cell line and tumor tissues. Results: Polymorphisms of 

these genes were very frequently observed in gynecologic cancers.Two rare 

variants were found in the primary precursor sequences of mir-200c and 

mir-142 gene.Moreover,a novel frameshift mutation( c.3547_3548insA) 

in TNRC6A gene was found in two endometrial cacner cell lines (RL95-2 

and Hec-1A) and endometrial cancers (1/28).Western blot and immunohistochemistry 

showed loss of expression of TNRC6A protein in the endometrial 

cacner cell lines and endometrial cancers with this mutation. 

Conclusions: Two rare novel variants in 20 miRNA genes and a novel 

frameshift mutation in TNRC6A gene were identified in gynecologic 

cancers.Oue data indicate that mutations in TNRC6A gene may contribute 

to the cancer development and might be a potential new therapeutic target 

in endometrial cacner. 



Clinicopathologic characteristics of endometrial cancer in Lynch syndrome. 

Presenting Author: Fabrice Lecuru, European Hospital George 

Pompidou, Paris, France 

Background: Poor data exist on clinico-pathological description of endometrial 

cancer (EC) in Lynch syndrome (LS) compared with sporadic ones. To 

evaluate the clinico-pathological findings of Lynch-related EC to establish 

histological criteria to discriminate familial and sporadic EC and to decide 

the optimal management of patients. Methods: Retrospective study of 

prospective cohort of patients with LS in our institution from 1999 to 

2011. We identified and described all cases of endometrial cancers. 

Management and follow-up were detailed. Results: Of a cohort of 126 

patients with LS, 10 women developed endometrial carcinoma. The 

median age at diagnosis was 51 years (41-58). Five patients had an 

identified mutation (2 hMLH1, 2 hMSH2 and 1 hMSH6). In 9 cases, EC 

was the first Lynch-related tumor to occur. No patient developed ovarian 

cancer. All, except 2 patients (1 serous carcinoma and 1 clear cell 

carcinoma), had endometrioid adenocarcinoma (80%). Tumor grade was 

grade 1 in 3 patients, grade 2 in 5 and grade 3 in 2 patients. Forty per cent 

of patients had lymphovascular space involvement (LVSI). The FIGO stages 

were as follows: stage IA (n�7), stage IB (n�2) and stage IIIC (n�1). Four 

in ten patients had tumor located in the lower uterine segment. With a 

median follow-up of 14 months (range9–40months), recurrence occurred 

in one patient with a stage IB grade 2 endometrioid adenocarcinoma with 

LVSI. Conclusions: EC in LS is characterized by early age at onset, 

localization in lower uterine segment, and high rate of LVSI. Other data on 

histology and survival do not differ from sporadic cancers. These results 

suggest that we can consider conservative treatment in patients with good 

prognosis tumors. Further studies are required. 


The effects of age on treatment and outcomes in women with stage IB-IIB 

cervical cancer. Presenting Author: Dario R. Roque, Women and Infants 

Hospital, Providence, RI 

Background: Advanced age may affect the treatment choice and subsequent 

outcome in elderly patients with cervical cancer. Given the potential 

for cure with either surgery or chemoradiation in early stage disease, we 

aimed to determine whether a patient’s age influenced the treatment 

received and the outcome. Methods: Our retrospective cohort identified a 

total of 303 patients diagnosed with Stage IB1 through IIB cervical 

carcinoma who were treated at our institution between 2000 and 2010. 

The eligible patients were divided into two groups based on age at the time 

of diagnosis: �65 and � 65 years. Adjusted odd ratios were calculated to 

determine variables associated with treatment received (chemoradiation or 

surgery). Single and multivariate Cox proportional hazards modeling were 

used to estimate hazard ratios for variables associated with disease specific 

survival. Results: Of the patients meeting inclusion criteria, 253 were �65 

years and 50 were � 65 years. The distribution of tumor histology, stage 

and grade was not different between the two groups. After adjusting for 

histology, stage and a validated comorbidity score, the odds ratio of 

receiving chemoradiation vs. surgery for the cohort � 65 years was 1.69 

(OR 95% CI: 0.68-4.17). There was no significant difference in the type of 

primary treatment received between the two groups (P � 0.16). Persistent 

disease was seen in 46 (18%) of the younger patients and in 19 (38%) of 

the older patients (P � 0.02). In the elderly cohort the treatment received 

did not influence disease-specific or all-cause mortality. However, compared 

to women under 65, older women treated surgically had increased 

disease specific (HR 3.18, 95% CI: 0.98-10.3) and all-cause mortality 

(HR 6.53, 95% CI: 2.57-16.6). Conclusions: Age does not appear to be a 

factor influencing the treatment received by patients with Stage IB1-IIB 

cervical cancer. The type of treatment received does not seem to affect 

disease-specific mortality among older versus younger women. However, 

surgery was associated with a 6.5-fold increased risk of all cause mortality 

among older women when compared to women under 65 years. 


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Prognostic factors and treatment-related outcomes in patients with uterine 

serous cancer (USC). Presenting Author: Maria deLeon, Yale University, 

New Haven, CT 

Background: USC an uncommon (10%) but aggressive form of uterine 

cancer, causes 50% of uterine cancer deaths. The purpose of this study is 

to report a large single-institution experience with USC investigating the 

effects of clinicopathological parameters and treatment on overall (OS) and 

disease-free survival (DFS). Methods: Records from our institution were 

reviewed from 1987-2009. All 334 USC patients (pts) identified were 

surgically staged. Postoperative treatments used were: (1) observation 

(OBS, n�33); (2) platinum-based chemotherapy (PCH, n�78); (3) whole 

pelvis radiation therapy (WPRT, n�16); (4) PCH and vaginal apex brachytherapy 

(PCHR, n�165); (5) vaginal apex brachytherapy (VAB, n�35). The 

cancer stages were 121 pts IA (36.2%), 36 IB (10.8%), 27 II (8.1%), 39 

IIIA (11.7%), 2 IIIB (0.6%), 32 IIIC1 (9.6%), 9 IIIC2 (2.7%), 28 IVA 

(8.4%) and 40 IVB (12%). Results: The 5-year OS for stage IA/IB, II, 

IIIA/IIIB, IIIC1/IIIC2, IVA/IVB were 82%, 70%, 64%, 36%, and 9%, 

respectively. The 5-year DFS for stage IA/IB, II, IIIA/IIIB, IIIC1/IIIC2, 

IVA/IVB were 82%, 68%, 56%, 24%, 6%, respectively. Advanced stage 

was associated with significantly shorter OS and DFS (p �0.01). The 5-year 

OS for stage IA/IB disease was 94% for pts who received PCHR, 90% for 

OBS, 75% for PCH, 65% for VAB and 0% for WPRT. The 5-year DFS for 

PCHR, OBS, PCH, VAB and WPRT for Stage IA/IB were 89%, 82%, 86%, 

72% and 0% respectively. For stage II-IVB pts, the 5-year OS was 51% for 

PCHR, 0% for OBS, 23% for PCH and 20% for WPRT. The 5-year DFS for 

stage II-IVB with PCHR, OBS, PCH and WPRT were 42%, 0%, 17% and 

13% respectively. Older age pts had worse survival, (p�0.01). Race and 

BMI did not impact survival. Incomplete surgical debulking (p�0.01), 

depth of myometrial invasion �50% (p�0.01) and lymph node metastasis 

(p�0.01) were all associated with worse prognosis. Conclusions: PCHR 

overall exhibited better OS and DFS regardless of disease stage. Age, 

incomplete surgical debulking, depth of myometrial invasion and lymph 

node involvement were independent prognostic factors in USC patients in 

this study. 


Phase II trial of topotecan, cisplatin, and bevacizumab for recurrent or 

persistent cervical cancer. Presenting Author: Israel Zighelboim, Washington 

University School of Medicine and Siteman Cancer Center, St. Louis, 

MO 

Background: The prognosis associated with recurrent or persistent cervical 

cancer is exceedingly poor. GOG-179 demonstrated a survival benefit with 

the combination of cisplatin and topotecan compared to single-agent 

cisplatin, with the former showing median PFS of 4.6 months, median OS 

of 9.4 months, and a 27% objective response rate. The role of angiogenesis 

in cervical carcinogenesis and progression has been well documented. We 

evaluated the activity and safety of the combination of topotecan, cisplatin 

and bevacizumab in patients with incurable carcinoma of the cervix. 

Methods: Patients with histologically proven measurable recurrent or 

persistent cervical carcinoma not amenable to curative intent treatment 

were eligible. No prior chemotherapy for recurrence was allowed. Cisplatin 

50 mg/m2 day 1, topotecan 0.75 mg/m2 days 1, 2 and 3 and bevacizumab 

15 mg/kg day 1 were prescribed in a 21-day cycle. Cytokine support was 

allowed at physician discretion. The primary endpoint was 6-month PFS. 

Additionally, objective clinical response and toxicity were evaluated. 

Accrual goal (N�27) was based on a 50% improvement goal in 6-month 

PFS in relation to GOG-179 (40% to 60%), with a one-sided 0.10 

significance and 80% power. Results: 27 eligible patients received a 

median of 3 treatment cycles (range, 1-19). All patients received radiotherapy 

as part of their first line treatment. Median follow-up was 8.5 

months (1.2-32.9). The 6-month PFS was 59% (95%CI: 38.0-74.7). 

Among 26 RECIST-evaluable patients, objective response rates were (%; 

95%CI): 1 CR (4%; 1-19.6), 7 PR (27%; 11.6-47.8), 11 SD (42%; 

23.4-63.1) and 7 PD (27%; 11.6-47.8). Median OS was 9.8 months 

(95%CI: 7.7-20.6) and median PFS was 7.1 months (95%CI: 2.0-12.1). 

Grade 3-4 hematologic toxicity occurred in 96% of patients (thrombocytopenia 

93% leukopenia 70%, anemia 70%, neutropenia 59%). Other grade 

3-4 toxicities were also common (metabolic 48%, pain 37%, genitourinary 

30%, constitutional 22% and gastrointestinal 19%). Conclusions: The 

addition of bevacizumab totopotecan and cisplatin results in a highly active 

but toxic regimen. Future efforts should focus on identification of predictive 

biomarkers and treatment modifications to minimize toxicity. 




Phase II trial of robotic stereotactic radiosurgery (SBRT) in patients with 

recurrent gynecologic malignancies. Presenting Author: Charles Kunos, 

Case Comprehensive Cancer Center and Case Western Reserve University, 

Cleveland, OH 

Background: Ablative radiation dose delivered by a robotic SBRT platform 

has shown progression-free survival benefit in two limited case series 

among patients with recurrent gynecological malignancies. The therapeutic 

impact of SBRT on disease progression (PD) was evaluated in the recurrent 

setting in this phase II trial. Methods: Fifty patients with recurrent and 

measurable gynecologic malignancy were treated with SBRT. The cohort 

included patients with recurrent ovarian (n �25), endometrial (n �14), 

cervical (n �9), or vulvar (n �2) cancer, 1 prior chemotherapy or radiation 

regimen, and GOG performance status 0, 1, 2. Patients underwent 

image-guided SBRT in 3 daily doses of 800 cGy � 2400 cGy. SBRT 

planning target volumes were determined by both the radiation and 

gynecologic oncologist using non-contrasted CT and 18F-FDG PET/CT 

overlays. The primary endpoints were 6-month clinical benefit rate (# 

complete response � # partial response � # stable disease without PD [by 

RECIST v1.0] / 50), and less than 30-day posttherapy toxicity. Results: 

Between July 2009 and September 2011, 50 patients were enrolled and 

have a median posttherapy follow-up of 9 months. At 3 months, 50% 

(n�25) had complete response, 46% (n�23) had partial response, and 

4% (n�2) had stable disease in SBRT-targeted lesions. Twenty-six patients 

(52%) have had non-SBRT target PD and 18 (36%) have died of PD. Of the 

50 patients, 33 had a PD-free interval of at least 6 months, for an overall 

clinical benefit rate of 66%. Less than 30-day posttherapy SBRT-related 

toxicities were grade 2 fatigue (n �9 [18%]), grade 2 nausea (n �3[6%], 

grade 3 nephropathy (n �2[4%]), and grade 4 hyperbilirubinemia (n 

�1[2%]). Conclusions: This is the first phase II clinical trial of SBRT 

showing a clinically relevant benefit of ablative radiation in the setting of 

recurrent gynecological disease. Despite excellent control of targeted 

lesions with minimal toxicity, non-SBRT target PD rates are high, spurring 

interest for future SBRT-chemotherapy clinical trials. 


A phase II study of dose-dense neoadjuvant chemotherapy with weekly 

paclitaxel and carboplatin followed by chemoradiation in locally advanced 

cervical carcinoma. Presenting Author: Rajkumar Bikramjit Singh, All India 

Institute of Institute, New Delhi, India 

Background: We prospectively studied dose dense neoadjuvant chemotherapy 

(NACT) designed for an enhanced cell kill, better local control and 

eradication of micrometastases prior to standard concurrent chemoradiation 

(CRT) in locally advanced cervical cancer. Methods: Between June 

2010 and December 2011, 21 patients (median age - 51 years, range 35 - 

67) of cervical cancer with locally advanced disease received NACT using 

paclitaxel (60mg/m2 ) and carboplatin (AUC-2) weekly for 6 doses. Patients 

(pts) then received concurrent CRT (external and brachytherapy) with 

weekly cisplatin (40mg/m2 for 6 doses) at a mean interval of 15 days (range 

7–20 days). The primary end-point was response rate i.e. complete 

response (CR) and partial response (PR) 12 weeks post CRT. Results: 

Baseline stages were: stage 2A - 19%, 3B - 71.4%, 4A - 9.5%. Squamous 

cell carcinoma and adenocarcinoma constituted 95.2% and 4.7% pts 

respectively. Following NACT, 66.6% pts responded (CR -9.5% %; PR – 

57.1 %), 23.8% had stable disease (SD) and 4.7% had progressive disease 

(PD). A total of 18 pts completed NACT and CRT of which 17 were in CR 

and 1 in PR. One patient with stage 4A disease developed vesicovaginal 

fistula at end of NACT for which she underwent pelvic exenteration and was 

in pathological CR. After NACT, one patient developed choroid metastases 

and was taken off study protocol while another patient was lost to follow up. 

At a mean follow up 5.8 months (range 1 - 14), 90% pts were in CR, 5% in 

PR and 5% had PD. During NACT, Grade 3/4 neutropenia, thrombocytopenia 

and anemia were seen in 33.3%, 4.7% & 9.5% of pts, respectively and 

grade 3/4 non-hematological toxicities in 9.5% pts. Following CRT, Grade 

3/4 neutropenia, thrombocytopenia and anemia were seen in 25%, 5% and 

10% of pts, respectively while 20% pts had grade 3/4 non-hematological 

toxicities. G-CSF was used in 30% pts during NACT and 25% pts during 

CRT, respectively. Conclusions: NACT with weekly paclitaxel and carboplatin 

followed by radical CRT is feasible and is associated with a high 

response rate in locally advanced cervical cancer. This approach needs to 

be studied in a phase III trial. 


Neoadjuvant chemotherapy of docetaxel and carboplatin in patients with 

stage Ib2 to IIb nonsquamous cervix cancer of the uterus. Presenting 

Author: Shoji Nagao, Saitama Medical University International Medical 

Center, Hidaka, Japan 

Background: Non-squamous carcinoma of the uterine cervix has a resistance 

to radiation therapy and chemotherapy, and this is associated with 

worse prognosis compared with squamous carcinoma. This is a phase II 

study to assess an efficacy and safety of neoadjuvant chemotherapy of 

docetaxel and carboplatin (DC therapy) in patients with stage Ib2 to II 

non-squamous cervix cancer of the uterus. Methods: Patients with histologically 

confirmed, stage Ib2-II non-squamous uterine cervix cancer were 

received DC therapy prior to type III radical hysterectomy. IV doceaxel was 

administered at 60 mg/m2 followed by IV carboplatin administration based 

on AUC�6. The treatment was repeated every 21 days for a total of 1 to 3 

cycles. Surgery was performed as soon as sufficient response was obtained. 

Results: Fifty-three women with non-squamous cervical carcinoma (FIGO 

stage Ib2,15; IIa, 7; IIb, 31) received DC therapy. Median age and tumor 

size were 49 years old (range: 27-71) and 52mm (range: 10-92), 

respectively. Fourty of 47 patients (74%) received 2 cycles of chemotherapy. 

Clinical response occurred in 69.8% of patients (complete 

response, 5; partial response, 32; stable disease, 15; disease progression, 

1), and 96% (52/54) of patients completed the surgery. Incidences of 

grade 3/4 hematological toxicities were 98% (53/54) for neutrocytopenia, 

4% (2/54) for thrombocytopenia, and 9% (5/54) for anemia. Febrile 

neutropenia was observed in three patients. Observed grade 3/4 nonhematological 

toxicities included were 5 for nausea, 2 for vomiting, 3 for 

constipation, 4 for allergic reaction. Median follow-up duration was 860 

days with a range of 147- 1635 days. The 2-years progression-free survival 

rate and 2-years overall survival rate were 63% and 79% in stage IB2, 71% 

and 86% in stage IIA2, and 67% and 86% in stage IIB, respectively.Twenty 

patients recurred and twelve patients died. Conclusions: Neoadjuvant 

chemotherapy using DC therapy was well tolerated and had good response. 

It seems to be benefical in patients with satge Ib2 to II nonsquamous 

cervical cancer. 


Prognostic significance of high-risk human papilloma virus (HPV), p16, 

and p53 status in women with vulvar squamous cell carcinoma (VSCC). 

Presenting Author: Ghassan Allo, University of Toronto, Toronto, ON, 

Canada 

Background: The incidence of VSCC is increasing. Studies suggest the 

presence of two histologically and molecularly distinct subsets of VSCC; 

one contingent on and another independent of HPV infection. However, it is 

uncertain if HPV status has prognostic significance. HPV oncoproteins can 

result in degradation of the tumor suppressor p53, cell cycle deregulation 

and abnormal expression of cyclin dependant kinase inhibitor p16. The aim 

of this study was to investigate HPV infection, p16 and p53 in relation to 

clinical parameters in women with VSCC. Methods: Sequential cases of 

VSCC from patients (pts) treated at Princess Margaret Hospital (PMH) from 

2000 to 2008 were reviewed. HPV infection was evaluated by Roche Linear 

array. A tissue microarray was constructed. p16 and p53 immunohistochemistry 

was performed. Clinical data was abstracted from medical records and 

PMH Cancer Database. Survival analysis was performed using Kaplan- 

Meier curves and log rank test. Results: We identified124 pts with VSCC. 

HPV was detected in 43/123 (35%) pts (median age 71 � 16 yrs). HPV16 

was the most common serotype (38/43; 88.4%). p16 was expressed in 

30/115 (26%) pts and p53 in 59/117 (50.4%) pts. Median age of pts was 

not different in relation to HPV, p16 and p53 status. Expression of p16 

(p�0.0001) and loss of p53 (p�0.007) were associated with HPV 

infection. Pts with HPV positive tumors were less likely to recur (recurrence 

rate at 5 years (RR) 12.5% vs 50.3%, p�0.009). HPV positive VSCC were 

not associated with better 5 yr disease free survival (DFS), 58% vs 31%; 

p�0.15, or overall survival (OS), 61% vs 61% ; p�0.94. p16 positive 

tumors had a lower RR at 5 yrs, 23.8% vs 59%, p�0.006 and better 5yr 

DFS (61% vs 27% ; p�0.009) but not significant for OS (65% vs 59%; 

p�0.94). Among pts with HPV positive VSCC, OS and DFS were not 

different between p16 positive and negative VSCC. In the 46 pts treated 

with radiotherapy, HPV and p16 positive tumors were associated with a 

lower RR (p�0.004 and 0.005). p53 expression was not prognostic in any 

pt group. Conclusions: Women with HPV-positiveVSCC have a lower risk of 

disease recurrence. p16-expressing VSCC are associated with reduced 

disease recurrence and improved DFS. 



ADXS11-001 immunotherapy targeting HPV-E7: Preliminary survival data 

from a phase II study in Indian women with recurrent/refractory cervical 

cancer. Presenting Author: Partha Basu, Chittaranjan National Cancer 

Institute, Kolkata, India 

Background: ADXS11-001 immunotherapy is a live attenuated Listeria 

monocytogenes (Lm) bioengineered to secrete a HPV-16-E7 fusion protein 

targeting HPV transformed cells. The Lm vector serves as its own adjuvant 

and infects APC where it naturally cross presents, stimulating both MHC 

class 1 and 2 pathways resulting in specific T-cell immunity to tumors. 

Here we describe the preliminary survival data associated with ADXS11- 

001 administration in Lm-LLO-E7-015, a randomized phase II study being 

conducted in India in 110 patients with recurrent/refractory cervical cancer 

who have been treated previously with chemotherapy, radiotherapy or both. 

Methods: Patients are randomized to either 3 doses of ADXS11-001 at 1 x 

109 CFU or 4 doses of ADXS11-001 at 1 x 109CFU with cisplatin 

chemotherapy. Naprosyn and oral promethazine are given as premedications 

and a course of ampicillin is given 72h after infusion thereby clearing 

any residual vector. Patients receive CT scans at baseline and Days 84, 

184, 273, 365 and 545. The primary endpoint is 12 month survival. 

Results: As of January 26, 2012, 88 patients have received 200 doses of 

ADXS11-001; with the percentage of patients alive at 6 months at 62% 

(34/55); at 9 months at 41% (15/37) and at 12 months at 40% (6/15). 

Tumor responses have been observed in both treatment arms with 3 

complete responses (elimination of tumor burden) and 4 partial responses 

(�30% reduction in tumor burden) by RECIST. One serious (Gr3) adverse 

event and 77 mild-moderate (Gr 1-2) adverse events possibly related to 

study treatment have been reported in 35% (31/88) of patients. The 

non-serious adverse events consisted predominately of transient, noncumulative 

flu-like symptoms associated with infusion that responded to 

symptomatic treatment, or resolved on their own within hours of treatment. 

Conclusions: This immunotherapy can be safely administered to patients 

with advanced cancer alone and in combination with chemotherapy. 

ADXS11-001 is well tolerated and presents a predictable and manageable 

safety profile. Early signs of clinical benefit merit further investigation. 

Updated findings will be presented at the meeting. 


Preoperative geriatric assessment (GA) and surgical outcomes in older 

women with gynecological (gyn) cancer. Presenting Author: Daneng Li, 


Background: GA can predict surgical outcomes in older patients (pts); 

however, pre-surgical evaluation for older pts with gyn malignancies has not 

been well-described. This study will determine the association between GA 

variables with post-operative morbidity and mortality. Methods: Women 

75yrs or older who had geriatric evaluation before any gyn surgery at 

Memorial Sloan Kettering Cancer Center (MSKCC) between 1/2010-6/ 

2011 were identified. Pre-operative GA included: Mini-Cog Test (cognition), 

fall history, medication list, nutritional status (weight loss �10lbs, 

albumin), functional status (activities of daily living (ADL), instrumental 

I-ADL), and Charlson comorbidity index. Outcomes included: delirium, 

length of hospital stay (LOS), 30-day surgical adverse events (AE, grade 

1-5, via prospective-MSKCC surgical database), 30-day hospital readmission 

and 6-month mortality. Utilizing bivariate analyses, associations 

between GA measures and post-operative outcomes were evaluated. 

Results: 72 pts (median age 79yrs, range 75-92) with gyn cancer (54% 

uterine, 36% ovarian/peritoneal/tubal, 10% cervical/vaginal/vulvar) had 

gyn surgery. 34 pts (47%) had stage III/IV disease. 21pts (30%) had 

secondary cancer history. Pt’s baseline GA measures: ADL-dependent 

(13%), IADL-dependent (19%), weight loss (18%), fall history (18%), mini 

cog score (median 4, range 0-5), Charlson score (median 2, range 0-9). 

24pts (33%) had surgical AE; no significant association with age or GA. 

Median LOS was 2 days (range 0-20); 11pts (15%) required 30-day 

readmission. Delirium (p�0.01), nutrition (weight loss p�0.04, albumin 

p�0.04), anemia (p�0.003) and high comorbidity index (p�0.013) were 

associated with longer LOS. Six-month mortality was 8%; older age 

(p�0.02), poor functional status (lower ADL and IADL, p�0.001 and 

p�0.007), number of medications (p�0.05) and poor cognition (p�0.001) 

were associated with shorter survival. Conclusions: Surgical morbidity is 

common in older pts. Although AE’s were not associated with GA variables, 

GA can detect high-risk features for longer LOS and shorter survival. 

Further prospective studies with pre-operative GA and interventions are 

warranted. 


353s 


Cervical cancer treatment for operable lesions in a low-resource contemporary 

setting. Presenting Author: Caroline Dorothy Lynch, Indiana University, 


Background: To compare HIV� and HIV- women with operable cervical 

cancer in a low resource contemporary setting. Methods: A retrospective 

study using well-matched controls from a Kenyan teaching and referral 

hospital. Results: 183 women were treated for cervical cancer between 

October 2007 and June 2011. The histologic subtype was squamous cell in 

all but one case. At presentation, 28 had operable lesions (Stage IA1– 

IIB1); 7 more received neoadjuvant chemotherapy prior to surgery. HIV 

seroprevalence was 54% (18/33) among initial operative cases and 57% 

among the neoadjuvant group (p�ns). Mean age was 42 (HIV�), and 43 

(HIV-), (range 25-64). HIV- vs. HIV� cervical cancer patients (mean CD4 

count 373, 50%�200) were detected by visual inspection with acetic acid 

(VIA) (18% (2/11)vs 68% (15/22) p�.099), symptoms (27%(3/11) vs 

14%(3/22) p�.43), or Pap smear (45% (5/11) vs .09% (2/22) p�.06), 

respectively.HIV� patients (two Stage IB1, two Stage IB2) did not require 

more downstaging than HIV- patients (two stage IIB, one stage IIIA) before 

surgery (18% (4/22) vs 27% (3/11) p�.63). Surgical treatments were not 

statistically different in either group and included radical hysterectomy(25), 

total abdominal hysterectomy(2), cesarean hysterectomy(1), 

and total vaginal hysterectomy(5). Postoperative complications included 

fever, dehiscence, DVT, ileus, fistula, and infectious complications (chest, 

urinary tract, wound). One HIV- patient suffered postoperative fever, 

vesicovaginal fistula, and wound dehiscence (overall complications 

.06%).Lymph node involvement was noted in 7 HIV� and 3 HIV- patients 

who underwent full staging procedures (p�.004). Conclusions: In patients 

with operable cervical cancer, HIV serostatus does not affect complication 

rate or influence need for downstaging prior to surgery compared to a 

well-matched control group. HIV� patients were not more likely to receive 

neoadjuvant chemotherapy but were more likely to have positive lymph 

nodes. VIA detected the majority of cervical cancers HIV� patients. 


Genome-wide association analysis in host characteristics of progression to 

high-grade cervical intraepithelial neoplasia for women with human papilloma 

virus infection and normal cytology. Presenting Author: Chyong-Huey 

Lai, Gynecologic Cancer Research Center, Chang Gung Memorial Hospital 

and Department of Obstetrics and Gynecology, Chang Gung University 

College of Medicine, Taoyuan, Taiwan 

Background: Although it is well accepted that persistent human papillomavirus 

(HPV) is necessary for carcinogenesis of cervical neoplasms, the 

molecular mechanism for progression is unclear. HPV testing is widely used 

for cervical cancer screening. The hazard ratio of developing cervical 

intraepithelial neoplasia grade 2 or more severe (CIN2�) in baseline 

HPV-positive/normal cytology women is 30-50 fold as compared with 

HPV-negative/normal cytoloy women. HPV positivity would cause substantial 

anxiety. It is important to identify a prognostic profile for predicting 

progression. Methods: We collected blood samples from women aged � 30 

years in a population-based nested cohort study enrolling women with HPV 

infection (n � 871) or HPV-negative (n � 902) with normal cytology in 

2004-2009 for prospective follow-up. To identify the host genetic characteristics 

associated with cervical carcinogenesis, a genome-wide association 

study (analyzing 530,194 SNPs) was conducted in 23 cases who 

developed CIN2� and 62 viral type- and age-matched controls who were 

HPV-positive at baseline without developing CIN throughout the follow-up 

period. Results: One SNP with significant P values (rs16969682; P�4.58 x 

10-5 ,OR�5.9, 95% CI�2.52-13.96) located in SEC14-like 1 (SEC14L1) 

gene localized to chromosome 17 was identified with association between 

progression to CIN2� and controls without CIN throughout follow-up. 

SEC14L1 belongs to the widely-expressed SEC14-superfamily. This superfamily 

consists of � 500 members that are involved in biological functions 

including membrane trafficking and phospolipid metabolism. Furthermore, 

using T-cell based cDNA screening, SEC14L-1a is identified as a regulator 

of HIV-1 replication. Conclusions: The potential role of SEC14L1 in 

host-viral interaction will be further elucidated. Additional statistically 

significant SNPs including rs16969682 will be validated on cases with 

CIN2� (n � 250) and normal controls (normal cytology/HPV-negative at 

baseline without acquisition of HPV or abnormal cytology/histology during 

follow-up, n � 500). 




Validation of the predictive value of modeled HCG residual production “P” 

in low-risk gestational trophoblastic neoplasia (GTN) patients treated in 

GOG-174 phase III trial. Presenting Author: Benoit You, Centre Hospitalier 

Lyon Sud; Hospices Civils de Lyon; EMR UCBL/HCL 3738, Faculté de 

Médecine Lyon-Sud, Université Claude Bernard Lyon1, Lyon, France 

Background: In low-risk GTN, chemotherapy is changed according to serum 

hCG levels. We previously showed mathematical modeling of hCG kinetics 

provides a parameter production “P”, a useful early predictor of methotrexate 

(MTX) resistance (You et al; Ann Oncol 2010; ASCO and ISSTD 2011). 

We applied this approach to patient cohort of GOG-174 trial, in which 

weekly MTX (Arm 1) was compared to dactinomycin (Arm 2). Methods: 

Database (210 patients, including 78 with resistance) was split into 2 sets. 

A 126 patient Model Set was initially used to adjust model parameters. 

Patient hCG kinetics from day7 to day50 were fit with NONMEM program 

to: “[hCG(time)] � hCG0i * exp(–k*time) � P”; where P is residual hCG 

tumor production, hCG0i is the initial hCG level, and k is the rate constant. 

Three putative P-based classifiers of resistance were assessed using ROC 

analyses. Then an 84 patient Test Set with blinded-resistance status was 

used to assess the validity of predictions. The primary endpoint was 

treatment resistance defined as relapse and/or lack of hCG normalization. 

Results: Due to initial surge in 14% patients, hCG kinetic modeling was 

started on day7. Individual hCG decline profiles of Model Set patients were 

modeled. There was no impact of treatment arm on variability of kinetic 

parameter estimates. The best P cut-offs to discriminate resistant vs. 

sensitive patients were 7.7 in Arm 1 and 74.0 in Arm 2. They were 

combined to define 2 predictive groups with low vs. high risks of resistance 

(ROC AUC � 0.82; Se � 93.8%; Sp � 70.5%). The model was then 

applied to Test Set patient cohort. The predictive value of P-based 

predictive groups regarding resistance was reproducible (ROC AUC � 0.81; 

Se � 88.9% (95% CI: 70.8%-97.7%); Sp � 73.1% (95% CI: 60.0%- 

84.4%)). Both P and treatment arm were associated with resistance using 

multivariate logistic regression tests. Predictive value of P was less 

accurate in dactinomycin arm. Conclusions: The early predictive value of 

the modeled kinetic parameter P regarding resistance appears promising in 

GOG-174 study, especially in MTX arm. This is the second positive 

evaluation of this procedure study. Prospective validation is warranted. 


OPSALIN: A phase II placebo-controlled randomized study of ombrabulin 

in patients with platinum-sensitive recurrent ovarian cancer treated with 

carboplatin (Cb) and paclitaxel (P). Presenting Author: Eric Pujade- 

Lauraine, Université Paris Descartes, AP-HP, Hôpitaux Universitaires Paris 

Centre, Site Hôtel-Dieu, Paris, France 

Background: Most women with ovarian cancer have disease recurrence after 

responding to their first treatment with platinum-based chemotherapy and 

are considered to have platinum-sensitive disease if the relapse-free period 

is more than 6 months. Although CbP is standard first-line chemotherapy 

for ovarian cancer, patients with platinum-sensitive recurrent disease are 

often retreated with CbP. Ombrabulin (AVE8062) is a vascular disrupting 

agent and analogue of combretastatin A4 that damages established tumor 

vasculature causing tumor necrosis and has synergistic antitumor activity 

with platinum agents in tumor models in vivo (Cancer Sci. 2003;94:200). 

A phase I study showed that treatment with vivo ombrabulin plus CbP is 

feasible in patients with advanced solid tumors (NCI-AACR-EORTC 2010; 

Abs 386). We initiated OPSALIN, a phase II randomized trial, to evaluate 

whether the addition of ombrabulin to CbP improves outcomes in patients 

with platinum-sensitive recurrent ovarian cancer (NCT01332656; 

EFC10260). Methods: Eligibility criteria include age of at least 18 years, 

ECOG PS 0–2, measurable carcinoma of the ovarian epithelium, fallopian 

tube, or primary peritoneum that is platinum sensitive, and completion of 

only one previous line of platinum-based chemotherapy. Exclusion criteria 

include uncontrolled brain metastases, peripheral neuropathy �grade 1, 

and a prior history of cardiovascular disease. Patients are being randomized 

(1:1) to receive either ombrabulin 35mg/m2 or placebo plus CbP every 3 

weeks. Assigned treatment will continue until disease progression or death, 

unacceptable toxicity, or consent withdrawal. The primary endpoint is 

progression-free survival stratified by the time of first disease recurrence 

(6–12 months or �12 months). Secondary endpoints include safety, 

response rate, overall survival, pharmacokinetics, and analysis of predictive/ 

prognostic biomarkers. Planned randomization is a total of 150 patients at 

approximately 45 sites globally. Sixty-five patients have been randomized 

as of January 2012. 


Nomogram prediction for overall survival of patients diagnosed with 

cervical cancer. Presenting Author: Christoph Grimm, Department of 

General Gynecology and Gynecologic Oncology, Comprehensive Cancer 

Center, Medical University of Vienna, Vienna, Austria 

Background: Cervical cancer is clinically staged based upon the International 

Federation of Gynecologists and Obstetricians (FIGO) system. FIGO 

stage is well established as prognostic parameter. It is well known that 

other additional parameters are useful to estimate overall survival (OS) in 

patients with cervical cancer. The aim of this multi-center was to create a 

nomogram to predict OS in patients diagnosed with cervical cancer. 

Methods: Cervical cancer databases of two large Austrian institutions were 

analysed. Characteristics known to predict OS were collected. For each 

patient association between each prognostic parameter and OS was 

assessed by multivariable modeling. The corresponding 3-year and 5-year 

OS probabilities were then determined using the nomogram. The constructed 

nomogram was then validated using the bootstrap correction 

technique. Results: Mean 5-year OS rates for patients with FIGO stage IA, 

IB, II, III, and IV were 99.0% (1.0), 88.6% (3.0), 65.8% (5.2), 58.7% 

(11.0), and 41.5% (14.7), respectively (p�0.001). Mean five-year OS 

time was 44.2 (30.9) months. Based on the multivariable model FIGO 

stage, tumor size, age, histologic subtype, lymph node ratio, and parametrial 

involvement were identified as nomogram parameters. The bootstrap 

sample corrections provided an estimated concordance probability (interquartile 

range) of 0.794 (0.779-0.805). Conclusions: Based on 6 easily 

available parameters a novel nomogram to predict 3-year and 5-year OS of 

patients diagnosed with cervical cancer was constructed and internally 

validated. Application of this nomogram allows more accurate and individual 

prediction of patients’ prognosis. 


A study of autologous dendritic cell therapy targeting mucin-1 for treatment 

of patients with epithelial ovarian cancer in first remission. Presenting 

Author: Jonathan S. Berek, Stanford Cancer Center, Stanford, CA 

Background: Cvac (Cvac) is an autologous dendritic cell immune stimulant 

targeting mucin-1 positive tumors. A phase IIa study demonstrated 

potential for treating mucin-1 positive epithelial ovarian carcinoma (EOC). 

A phase IIb study was designed to determine on a pilot basis if Cvac could 

demonstrate an effect on progression free and overall survival in patients 

with EOC in first or second remission. The current study, CANVAS (CANcer 

VAccine Study) is evaluating Cvac treatment of EOC patients in first 

remission after surgery and standard chemotherapy, with at least three 

cycles of platinum and taxane therapy. Endpoints include progression free 

survival, overall survival, safety evaluation and quality of life scores. 

Methods: Patients are eligible if they have stage III or IV mucin-1 positive 

EOC and have had optimal cytoreductive (�1cm residual disease) surgery. 

Apheresis to obtain immature dendritic cells occurs prior to chemotherapy. 

Cvac is manufactured during chemotherapy. Patients remain eligible for 

the study if they have a complete response to standard chemotherapy after 

surgery. Cvac or placebo is dosed every four weeks for three doses, and 

every twelve weeks for three additional doses. 1000 patients will be 

randomized to Cvac or placebo in 22 countries, with 800 expected to 

receive vaccine or placebo. CT or MRI imaging determines progression, and 

is centrally read prior to inclusion and at each timepoint. Recruitment 

commenced January 2012. Over 100 centers are participating in the study 

globally, with majority in Europe. Enrollment is expected to take 18-24 

months. An interim analysis is planned after 400 PFS events, and final 

analysis after 620 PFS events. Observation of 620 events would have 

approximately 90% power to detect a hazard ratio of 0.77 in PFS at a 

significance level of p�0.049 (approximately a 30% increase in median 

PFS in the Cvac group compared with the placebo group). 



ACRIN 6695 perfusion CT as prognostic imaging biomarker in ovarian 

cancer. Presenting Author: Chaan S. Ng, University of Texas M. D. 


Background: Tumor size and the cell surface glycoprotein CA125 levels 

have been traditional biomarkers for ovarian carcinoma, but remain 

suboptimal for assessing patients receiving chemotherapy. Current morphological 

criteria do not adequately evaluate lesion necrosis from antiangiogenic 

therapy when no tumor volume change is measured. The 

evaluation of functional biomarkers rather than tumor volume may better 

distinguish responders from non-responders early in treatment with antiangiogenic 

therapy. Perfusion CT can evaluate changes in tumor vascularity 

including blood flow (BF), blood volume (BV), mean transit time (MTT) and 

capillary permeability surface product (PS) before and after antiangiogenic 

therapy with/out decrease in tumor volume. Objectives: The 

aims of the study are to evaluate the relationship between changes in tumor 

perfusion parameters and clinical outcomes of progression free survival, 

overall survival, and standard RECIST anatomic response criteria. A 

test-retest perfusion CT scan will also be performed to evaluate reproducibility 

of perfusion parameters in a subset of participants. Methods: In this 

collaborative trial, participants will be co-enrolled in the GOG-262 treatment 

trial. Participants will receive doublet chemotherapy of paclitaxel and 

carboplatin, followed by anti-angiogenic monoclonal therapy at cycle two. 

Perfusion CT will be performed at three time points: at baseline prior to 

therapy (T0), between days 18 and 21 of cycle one chemotherapy (T1), and 

at 8-10 days (T2) in anti-angiogenic monoclonal therapy. Participants with 

primary epithelial ovarian, peritoneal or fallopian tube cancer with optimally 

or suboptimally debulked FIGO Stage II, III or IV disease are eligible 

for the trial. Lesion eligibility will be evaluated by size and attenuation 

criteria. Accrual: ACRIN 6695 is activated at 12 GOG sites; 4/78 

participants have accrued Discussion: Perfusion CT has been readily 

incorporated into the pre-existing clinical CT protocols and during scheduled 

RECIST scans. These perfusion CT functional maps of BF, BV, MTT 

and PS have been generated using vendor provided software without issue. 

Contact: Please contact Chaan Ng, MD cng@mdanderson.org for additional 

information. 


A phase III trial of adjuvant chemotherapy following chemoradiation as 

primary treatment for locally advanced cervical cancer compared to 

chemoradiation alone: The OUTBACK TRIAL. Presenting Author: Linda R. 

Mileshkin, Peter MacCallum Cancer Centre, Melbourne, Australia 

Background: Cervical cancer is a global health problem and the most 

common cause of cancer-related death among women in developing 

nations. Despite the recently developed cervical cancer vaccine, many 

women will continue to die from cervical cancer for many decades unless 

existing treatments can be improved. Unscreened women often present 

with locally-advanced disease that has a 5 year overall survival (OS) rate of 

60% or less following standard chemo-radiation. Although some evidence 

suggests that adjuvant chemotherapy following chemo-radiation may be of 

value, its role remains controversial. Methods: OUTBACK is a randomized 

phase III Gynecologic Cancer InterGroup (GCIG) trial designed and led by 

the Australia New Zealand Gynaecological Oncology Group (ANZGOG) in 

collaboration with the NHMRC Clinical Trials Centre. Participating countries 

(groups) include Australia and New Zealand (ANZGOG), India, the 

USA and Canada (GOG, RTOG). OUTBACK is suitable for women with 

locally advanced cervical cancer (FIGO stage IB1 and node positive, IB2, II, 

IIIB or IVA). The primary objective is to determine if the addition of 

adjuvant chemotherapy to standard cisplatin-based chemo-radiation improves 

OS. Women are randomized to either A) standard cisplatin-based 

chemo-radiation or B) standard cisplatin-based chemo-radiation followed 

by 4 cycles of carboplatin and paclitaxel chemotherapy. Secondary 

objectives are to compare progression-free survival, treatment-related 

toxicity, patterns of disease recurrence, quality of life and psycho-sexual 

health, and the association between radiation protocol compliance and 

outcomes. Blood and tumour samples are collected from consenting 

patients for future translational studies. 780 women will be enrolled to 

determine if the addition of adjuvant chemotherapy can improve the 5-year 

OS rate by � 10%. OUTBACK opened in Australia and New Zealand in 

2011. In early 2012 the trial opened in the USA and activation of GOG 

sites is ongoing. 15 patients have been randomized. It is expected that 

RTOG and India will open the trial later this year with recruitment 

increasing substantially once all sites are activated. 


355s 


A phase II study of live-attenuated listeria monocytogenes immunotherapy 

(ADXS11-001) in the treatment of persistent or recurrent cancer of the 

cervix (GOG-0265). Presenting Author: Warner King Huh, University of 

Alabama at Birmingham, Birmingham, AL 

Background: This is a GOG/NCI sponsored phase II study (NCT01266460, 

GOG 0265) of ADXS11-001 in patients with persistent or recurrent cancer 

of the cervix. ADXS11-001 is a live attenuated Listeria monocytogenes 

(Lm) immunotherapy bioengineered to secret a HPV E7 fusion protein 

targeting HPV-E7 transformed cells. A previous phase I dose escalation 

study determined the safety of ADXS11-001 in patients with late stage 

cervical cancer (Maciag PA. Vaccine. 2009 Jun 18;27(30):3975-83). The 

primary objectives of this study are: to evaluate the tolerability and safety of 

ADXS11-001; and to assess the activity of ADXS11-001 in patients with 

persistent or recurrent cancer of the cervix. Secondary objectives are 

progression-free survival, overall survival and objective tumor response. 

Methods: Patient eligibility criteria: Females age � 18 years with persistent 

or recurrent squamous or non-squamous cell carcinoma, adenosquamous 

carcinoma, or adenocarcinoma of the cervix with documented disease 

progression (disease not amenable to curative therapy). Patients must have 

measurable disease as defined by RECIST 1.1; at least one “target lesion” 

as defined by RECIST 1.1; have had one prior systemic chemotherapeutic 

regimen for management of their disease; have adequate organ function 

and must be free of active infection and not on antibiotics. This protocol is a 

Simon 2-stage design with a planned sample size of up to 67 patients. 

Patients will receive ADXS11-001 at a dose of 1x109 CFU on Day 1 and 

repeat every 28 days for 3 total doses in the absence of disease progression 

or unacceptable toxicity, with each dose followed at 72 hours by a7day 

course of ampicillin, 500 mg QID. Tumor tissue and serum samples may be 

collected periodically for translational research. After completion of study 

treatment, patients are followed every 3 months for 2 years and then every 

6 months for 3 years. This phase II study just began enrolling and as of 

January 27, 2012, 2 patients have been enrolled. 


356s Head and Neck Cancer 


DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 

5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with 

N2/N3 locally advanced squamous cell carcinoma of the head and neck 

(SCCHN). Presenting Author: Ezra E.W. Cohen, The University of Chicago, 

Chicago, IL 

Background: IC is associated with lower distant failure (DF) rates in SCCHN 

but an improvement in overall survival (OS) has not been validated. The 

goal of this trial was to determine whether IC prior to chemoradiotherapy 

(CRT) improves survival compared to CRT alone. Methods: In this phase 3, 

open-label trial, subjects with pathologically confirmed SCCHN; N2/N3 

disease without metastases; no prior therapy; KPS ³ 70%; and intact organ 

function were randomized to CRT alone (CRT arm) [5 days of D (25 mg/m 2 ), 

F (600 mg/m 2 ), hydroxyurea (500 mg BID), and RT (150 cGy BID) followed 

by a 9 day break] or to 2 cycles of IC [D (75 mg/m2 ), P (75 mg/m2 ), F (750 

mg/m2 day 1-5)] followed by the same CRT (IC arm). Primary endpoint was 

OS. Secondary endpoints included DF free survival, failure pattern, and 

recurrence-free survival (RFS). 280 subjects provided 80% power to detect 

a hazard ratio HR�0.5 for OS (a�0.05). Results: 280 subjects were 

accrued from 2004-09 with minimum follow-up 24 months. Of 142 

patients randomized to IC, 91% received 2 cycles and 87% continued to 

CRT. Treatment adherence during CRT was high for docetaxel and 

hydroxyurea, but fewer than 75% of the patients received target dose of 

5FU in both arms. RT was delivered without major deviations in 94% and 

95% of patients on IC and CRT arms, respectively. The most common grade 

3-4 toxicities during IC were febrile neutropenia (9%) and mucositis (8%), 

and during CRT (both arms combined) they were mucositis (45%), 

dermatitis (19%), and leukopenia (17%). Only grade 3-4 leukopenia and 

neutropenia rates were significantly higher in IC (p�0.002 and p�0.02, 

respectively). Table shows efficacy. Conclusions: High survival rates were 

observed in both arms. Further analysis and follow-up may provide insight 

into why the significant decrease in DF did not translate into improved OS. 

3-year outcomes. 

Endpoint 

IC arm 

(%) 

CRT arm 

(%) HR 95% CI p value 

OS 75 73 0.92 0.59-1.42 0.70 

DF-free survival 69 64 0.84 0.56-1.26 0.39 

RFS 67 59 0.76 0.52-1.13 0.18 

Cumulative incidence of DF 10 19 0.46 0.23-0.92 0.025 

Cumulative incidence of 

locoregional failure 

9 12 0.79 0.37-1.68 0.55 


A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) 

with or without panitumumab (pmab) in patients (pts) with unresected, 

locally advanced squamous cell carcinoma of the head and neck 

(LASCCHN). Presenting Author: Jordi Giralt, Hospital Vall d’Hebron, 


Background: Pmab is a fully human monoclonal antibody against the 

epidermal growth factor receptor. We evaluated the safety and efficacy in 

pts receiving CRT alone or CRT plus pmab (PCRT) as 1st-line treatment of 

LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage 

III, IVA, or IVB previously untreated LASCCHN of all sites excluding the 

nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT 

included cisplatin 100 mg/m2 for 3 cycles during standard fractionation 

radiotherapy (RT). PCRT included pmab 9.0 mg/kg � cisplatin 75 mg/m2 , 

both administered with RT as in the CRT arm. The primary endpoint was 

local regional control (LRC) rate at 2 years; key secondary endpoints 

included PFS, OS, and safety. Preplanned HPV subset analysis, as 

determined by p16 immunohistochemistry, was performed on available 

samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were 

men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 

pts with tumor evaluable for HPV, 42% were HPV�. Overall, the 2-year LRC 

rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for 

CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR 

[95% CI] 1.15 [0.68-1.96]; p�0.61). Death occurred in 36% of the PCRT 

arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; 

p�0.12). Disease progression was the cause of death in 22% of PCRT pts 

and 10% of CRT pts. There were no differences in outcome by tumor HPV 

status. No difference in fatal adverse events (AEs) was seen between arms. 

Grade 3� AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences 

in grade 3� toxicity between treatment arms (PCRT, CRT) were most 

pronounced for mucosal inflammation (55%, 24%), radiation skin injury 

(28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of 

�10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. 

Median cisplatin cumulative dose received was 223.1 mg/m2 in the PCRT 

arm and 296.9 mg/m2 in the CRT arm, reflective of differences in planned 

dose. Conclusions: The addition of pmab to CRT did not show an increase in 

efficacy and was associated with increased toxicity. Further results of HPV 

biomarker analysis will be presented. 


The PARADIGM trial: A phase III study comparing sequential therapy (ST) 

to concurrent chemoradiotherapy (CRT) in locally advanced head and neck 

cancer (LANHC). Presenting Author: Robert I. Haddad, Department of 

Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, 

Boston, MA 

Background: PARADIGM is a multicenter phase III study comparing TPF 

(docetaxel, cisplatin, and 5-fluorouracil)-based ST (Arm A) to upfront 

cisplatin CRT (Arm B) in patients (pts) with LAHNC. Pt accrual was 

terminated in 12/2008 due to slow enrollment with 145 of 300 planned 

analyzable patients accrued. Safety data was previously presented at the 

2010 ASCO annual meeting showing no unusual pattern of toxicities in 

either arm. Here we present the survival results. Methods: Pts were 

randomized to receive arm A-ST (as induction chemotherapy (ICT) with TPF 

x 3) followed by CRT with either weekly carboplatin and once daily 

radiotherapy, or weekly docetaxel and accelerated boost radiotherapy 

based on adequate response to ICT; or arm B - accelerated boost CRT with 

bolus cisplatin x 2. The primary endpoint was survival. With original accrual 

target of 300 analyzable patients, this study was powered at 80% to detect 

an improvement in 3-year survival from 55% (arm B) to 70% (arm A). 

Results: A total of 145 previously untreated pts were enrolled (Arm A: 70; 

Arm B: 75), of whom 127 were male and 127 were Caucasian. Median age 

was 55; patients had PS of 0 (97) or 1 (48). Sites of disease were 

oropharynx: 80, larynx: 24, hypopharynx: 15, and oral cavity: 26. Disease 

stages were II (1 pt), III (20 pts) and IV (124 pts). After a median follow-up 

of 49 months, 41 pts have died (20 in arm A and 21 in arm B). Three-year 

survival was 73% (arm A) and 78% (arm B) (HR1.09; 95% CI 0.59 to 2.03 

p�0.77). Three-year progression-free survival was 67% (arm A) and 73% 

(arm B) (HR 1.2; 95% CI 0.65 to 2.22; p�0.55). Patterns of failure will be 

presented at the meeting. Conclusions: Althoughthese results suggest no 

survival differences between CRT and ST for patients with LAHNC, the 

study was terminated before the planned accrual could be reached. HPV 

status for the oropharynx cases which represented the majority of patients 

was not available for stratification; and excellent survival was seen in both 

arms. 


Randomized phase II trial of cisplatin and radiotherapy with or without 

erlotinib in patients with locally advanced squamous cell carcinoma of the 

head and neck (SCCHN). Presenting Author: Renato Martins, University of 

Washington, Seattle, WA 

Background: The combination of cisplatin and radiotherapy is a standard 

treatment for patients with locally advanced SCCHN. Cetuximabradiotherapy 

is superior to radiotherapy alone in this population, validating 

EGFR as a target. Erlotinib, a small molecule inhibitor of EGFR, has activity 

in recurrent/metastatic disease. Adding EGFR inhibition to standard 

cisplatin-radiotherapy may improve efficacy. Methods: Patients with locally 

advanced SCCHN were randomized to receive cisplatin 100mg/m2 on days 

1,22 and 43 combined with 70Gy of radiotherapy (arm A) or the same 

chemoradiotherapy combined with erlotinib 150mg/day, starting one week 

prior to radiotherapy and continued to its completion (arm B). Randomizing 

204 patients had 80% power to compare a 60% complete response rate 

(CRR) to a 40% null rate. Available tumors were tested for p16, ERCC1 and 

EGFR FISH. Results: Between June 2006 and October 2011, 204 patients 

were randomized. Results presented are based on intention to treat. There 

were more females on arm A however no other differences in patient 

characteristics, including p16 positivity. Patients on arm B had more rash 

and gastrointestinal adverse events, but treatment arms did not differ for 

rates of other grade III/IV toxicities or serious adverse events (SAEs). Arm A 

had a CRR of 61% and arm B had a CRR of 68% (p�0.3). With a median 

follow-up of 23 months, there were only 29 events in the overall survival 

analysis and 46 in the progression-free survival (PFS) analysis. The 2 and 3 

year PFS were 71% and 63% for arm A and 78% and 73% for arm B 

(p�0.61). Conclusions: The addition of erlotinib did not increase the rate of 

SAEs but failed to significantly increase CRR. As seen in other recent trials, 

our results in both arms are superior to historical comparisons. Updated 

PFS data will be presented. Supported by a grant from the investigatorinitiated 

trial program of Genentech/OSI. 


5504^ Oral Abstract Session, Sun, 8:00 AM-11:00 AM 

Safety and efficacy of panitumumab (pmab) in HPV-positive (�) and HPVnegative 

(-) recurrent/metastatic squamous cell carcinoma of the head and neck 

(R/M SCCHN): Analysis of the global phase III SPECTRUM trial. Presenting 

Author: Jan Stoehlmacher-Williams, University Hospital Carl Gustav Carus, 

Dresden, Germany 

Background: SPECTRUM evaluated the safety and efficacy of pmab, a fully human 

monoclonal antibody against the epidermal growth factor receptor, with platinumbased 

chemotherapy (CT) vs CT alone in patients (pts) with R/M SCCHN. This 

predefined analysis presents outcomes by tumor HPV status. Methods: All tumor 

samples were centrally reviewed. HPV status was determined using a validated 

immunohistochemistry assay to p16INK4A by an independent lab blinded to 

treatment assignments. Tumor samples were scored positive or negative according 

to prespecified criteria. Results: Of 657 enrolled pts (ITT), 443 (67%) had samples 

evaluable for HPV testing. Ninety-nine (22%) tumors were HPV� and 344 (78%) 

were HPV- . HPV� rates varied by site (37% oropharynx, 19% larynx, 15% oral 

cavity, and 13% hypopharynx) and geographic region (44% N America, 22% W 

Europe, 21% Asia Pacific, 19% S America, and 18% E Europe). Demographics 

were generally balanced except pts with HPV� vs HPV- tumors were more often 

non-smokers (31% vs 14%), had oropharyngeal tumors (47% vs 23%), and had 

poorly differentiated tumors (30% vs 13%). Efficacy results are shown (Table). 

Adverse events were generally balanced between HPV� and HPV- pts. Conclusions: 

Pts with HPV- R/M SCCHN administered pmab � CT had improved overall survival 

(OS) and progression-free survival (PFS), whereas no improvement in OS or PFS was 

observed in pts with HPV� tumors. 

ITT 

(n�657) 

HPV � 

(n�99) 

HPV - 

(n�344) 

OS 

Events - % 

HR 

74 73 77 

a (95% CI) 

P value 

0.87 (0.73-1.05) 1.00 (0.61-1.64) 0.76 (0.59-0.97) 

b 

0.14 0.98 0.02 

Median OS (pmab � 

CT vs CT) - mos 

11.1 vs 9.0 11.0 vs 12.6 11.7 vs 8.6 

QITP 

PFS 

0.253 

Events - % 

HR 

86 91 90 

a (95% CI) 

p-value 

0.78 (0.66-0.92) 1.21 (0.76-1.92) 0.67 (0.53-0.84) 

b 

0.004 0.43 0.001 

Median PFS (pmab � 

CT vs CT) - mos 

5.8 vs 4.6 5.6 vs 5.5 6.0 vs 5.1 

QITP 

ORR ITT 

(n�566) 

0.068 

c 

HPV � 

(n�88) c 

HPV - 

(n�297) c 

ORR (pmab � 

CT vs CT) - % 

36 vs 25 44 vs 32 35 vs 27 

P value odds ratio 0.007 0.27 0.13 

Abbreviations: QITP, quantitative interaction test p-value; ORR, objective response rate. 

a b c 

Stratified hazard ratio. Stratified log-rank test p-value. Pts with baseline measurable 

disease per modified RECIST 1.0. 


PD-1:PD-L1(B7-H1) pathway in adaptive resistance: A novel mechanism 

for tumor immune escape in human papillomavirus-related head and neck 

cancers. Presenting Author: Sofia Lyford-Pike, Johns Hopkins Medical 

Institutions, Baltimore, MD 

Background: Human papillomavirus-associated head and neck squamous 

cell carcinomas (HPV-HNSCC) are associated with a strong host immune 

response. Despite ample tumor infiltrating lymphocytes (TILs), the cancer 

is able to persist and grow. Here, we provide evidence for an adaptive 

immune resistance mechanism mediated through the PD-1:PD-L1 pathway. 

Methods: We evaluated the peripheral blood and tumor infiltrating 

lymphocytes for PD-1 expression using flow cytometry in HPV-HNSCC 

patients. We evaluted PD-L1 expression within the tumors using immunohistochemistry. 

We performed functional assays evaluating IFN-gamma 

secretion of PD-1� and PD-1(-) CD8� T cells isolated from the tumor 

microenvironment of PD-L1� and PD-L1(-) HPV-related head and neck 

cancers. Results: We found the majority of CD8� TILs in HPV-HNSCC 

express the PD-1 co-inhibitory receptor. We report a striking association 

between expression of its ligand PD-L1 on tumor cells and tumor associated 

macrophages, and the presence of TILs. Interestingly, membranous 

PD-L1 staining on tumor cells and CD68� antigen presenting cells was 

geographically localized to the periphery of tumor nests and juxtaposed to 

fronts of infiltrating T cells. Functional assays demonstrated that PD-1dependent 

T cell inhibition required expression of PD-L1 in the tumor 

microenvironment. Finally, we report localized expression of PD-L1 in the 

deep crypts of normal tonsils, the site of HPV infection and origin of 

HPV-HNSCC. Conclusions: Our findings support the role of the PD-1:PD-L1 

interaction in creating an immune-privileged site for initial viral infection 

and subsequently adaptive immune resistance once tumors are established 

and suggest a rationale for therapeutic blockade of this pathway in patients 

with HPV-HNSCC. 


357s 


Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in 

patients with recurrent or metastatic (R/M) squamous cell carcinoma of the 

head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03. 

Presenting Author: Joel Guigay, Department of Medical Oncology, Institut 


Background: Cetuximab in combination with platinum and 5FU (PFEx) has 

become a standard in first-line treatment of patients (pts) with R/M 

SCCHN. Cetuximab and taxane combinations have shown promising 

activity. This multicenter phase II study evaluates the efficacy and safety of 

cetuximab, docetaxel and cisplatin combination (TPEx) as first-line treatment 

in pts with R/M SCCHN. Methods: Pts were required to have WHO PS 

0-1, no prior systemic therapy for R/M SCCHN, cumulative dose of cisplatin 

less than 300 mg/m² and no prior anti-EGFR therapy. Pts received 

docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and cetuximab (400 

mg/m² on day 1 of cycle 1 then 250 mg/m² weekly), repeated every 21 days 

x 4 cycles then followed by cetuximab 500 mg/m² every 2 weeks (wks) as 

maintenance therapy until disease progression or unacceptable toxicity. 

G-CSF support with lenograstim 150 �g/m²/day was delivered after each 

cycle of chemotherapy. Response was assessed every 6 wks, according to 

RECIST. The primary endpoint was objective response rate (ORR) at 12 

wks. Secondary endpoints were safety, best overall response, progressionfree 

survival (PFS), overall survival (OS) and biomarkers. Results: 54 pts 

have been enrolled: 52 males, median age 57.8years (28-69), 12 (22.2%) 

oropharynx, 55% metastatic.48 pts could be evaluated for ORR at 12 wks: 

partial response, stable disease and progression were respectively found in 

23 pts (PR 47.9%), 21 pts (SD 43.7%) and 4 pts (PD 8.3%). Best overall 

ORR was 54% (1 CR, 27 PR). The median PFS and OS were 7.1 and 15.3 

months, respectively. The 1-year OS was 58.6%. Median PFS after start of 

maintenance therapy was 4.2 months. Toxicity was manageable with 

G-CSF support. Treatment related toxicities included G4 neutropenia 

(n�3). Grade 3 events were skin rash (n�5), hypersensitivity reaction 

(n�3), mucositis (n�1), fatigue (n�1) and febrile neutropenia (n�1). 

Alopecia was common. 1 toxic death was related to sepsis on feeding tube. 

Conclusions: Efficacy analysis demonstrates that TPEx regimen is effective 

and might be a relevant substitute for PFEx as first-line treatment in fit pts 

with R/M SCCHN. 


Intra-arterial infusion of recombinant adenoviral human p53 gene combined 

chemotherapy for advanced oral cancer: A phase II double-blind 

randomized clinical trial. Presenting Author: Yi Li, Department of Head and 

Neck Oncology, West China Hospital of Stomatology, Sichuan University, 

Chengdu, China 

Background: The p53 tumor suppressor gene has been shown as having 

multiple anti-tumor functions and being capable of enhancing the efficacy 

of chemo-therapy. This study is to investigates clinical outcomes of 

intra-arterial infusion ofrecombinant adenoviral human p53 gene (rAdp53) 

combined with chemotherapy in treatment of advanced oral cancer. 

Methods: Ninety-nine patients with stage III or IV oral carcinoma, satisfying 

with the inclusion criteria, were randomly allocated to Group I (G1: n�35; 

rAd-p53 plus chemotherapy), Group II (G2: n�33; rAd-p53), or Group III 

(G3: n�31; chemotherapy). Intra-artery infusion of rAd-p53 were given 

through superficial temporal artery reverse intubation at a dose 1-4 �1012 viral particles (VP) , once every 3 days for 6 times. Chemotherapy regimen 

consisted of oxaplatin 200 mg/m2 on day1, bleomycin 8 mg/m2 on day 2, 

6, 8 and Methotrexate 30 mg/m2 on day1, 8, for squamous cell carcinoma 

(SCC), and oxaplatin 200 mg/m2 on day1, 5-Fu 200 mg/m2 on day1,3 and 

cyclophosphamide 400 mg/m2 on day2, 8 for adenoid cystic carcinoma 

(ACC). Results: The complete response rate (CR) in G1 (48.5%) was 

significantly higher than in G2 (16.7%) and G3 (17.2%). The overall 

response rates (RR) were 88.6%, 54.5%, and 51.6% for G1, G2 and G3, 

respectively. The 3-year overall survival (OS) of G1 (82.9%) was significantly 

higher than the patients in G2 (60.6%) and G3 (58.1%). All those 

patients receiving rAd-p53 had a self-limited fever. Positive Bax immunostaining 

was detected in all the patients receiving rAd-p53. Conclusions: 

Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent 

an alternative to the current standard treatment for the late stage oral 

carcinoma. 



5508 Clinical Science Symposium, Mon, 11:30 AM-1:00 PM 

An international, double-blind, randomized, placebo-controlled phase III 

trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma 

(MTC) patients (pts) with documented RECIST progression at baseline. 

Presenting Author: Patrick Schoffski, Department of General Medical 

Oncology, University Hospitals Leuven, Leuven, Belgium 

Background: MTC arises from parafollicular cells of the thyroid gland, 

accounts for 5-8% of thyroid cancers and represents an unmet medical 

need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. 

We conducted a phase III study of cabo vs placebo (P) in pts with 

progressive, unresectable, locally advanced or metastatic MTC. Methods: 

Eligible pts were required to have documented RECIST progression within 

14 months of screening. The primary efficacy measure was progression-free 

survival (PFS) as assessed by an independent review facility (IRF) using 

RECIST. Secondary efficacy measures included objective response rate 

(ORR) and overall survival (OS). The study has 90% power to detect a 75% 

increase in PFS and 80% power to detect a 50% increase in OS. Tumor 

assessments occurred every 12 weeks. Crossover between treatment arms 

was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts 

(median age 55 yrs; 67% male; 96% measureable disease; RET mutation 

status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, 

no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base 

[175 mg salt form] qd; n�219) or P (n�111). The planned primary PFS 

analysis included events through the date of the 138th event. As of 

15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving 

study treatment. Statistically significant PFS prolongation of 7.2 mo was 

observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 

95% CI 0.19-0.40, p�0.0001). PFS results favored the cabo group across 

subset analyses including RET status and prior TKI use. ORR was 28% for 

cabo vs 0% for P (p�0.0001). An interim analysis of OS (44% of the 217 

required events) did not show a difference between cabo and P. The most 

frequent grade �3 adverse events (cabo vs P) were diarrhea (15.9 vs 

1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 

2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). 

Conclusions: This phase III study met its primary objective of demonstrating 

substantial PFS prolongation with cabo vs. P in a patient population with 

MTC and documented progressive disease in need of therapeutic intervention. 


A molecular diagnostic panel for thyroid cancer disease management. 

Presenting Author: Shih-min Cheng, Quest Diagnostics Nichols Institute, 

San Juan Capistrano, CA 

Background: In 2009, the American Thyroid Association revised its guidelines 

for patients with thyroid nodules and differentiated thyroid cancers, 

recommending BRAF, RAS, RET/PTC, and PAX8-PPAR� molecular testing 

in patients with indeterminate fine-needle aspirate (FNA) cytology. Alterations 

in any of these markers in thyroid nodules are strongly associated with 

malignancy. We studied the prevalence of these alterations in thyroid FNA 

specimens in order to establish a strategy to improve disease management. 

Methods: DNA and RNA were extracted from thyroid FNA specimens 

(N�149) and tested for BRAF mutations using allele-specific PCR (V600E 

and K601E); for RAS (H-, K-, N-) mutations using pyrosequencing (codons 

12, 13, and 61); and for RET/PTC1 and RET/PTC3 rearrangements and 

PAX8-PPAR� translocations using RT-PCR. Results: Overall, 90 (60.4%) of 

the specimens had alterations in �1 of the 4 molecular markers (Table). 

BRAF V600E mutations (54.4%) were the most prevalent mutations in 

papillary thyroid cancer (PTC); no K601E mutations were found. RAS 

mutations were found in PTC, follicular adenoma (FA), and follicular 

thyroid cancer (FTC) specimens; half of these mutations involved N-RAS 

Q61. RET/PTC rearrangements were detected in 3.5% of PTC specimens 

and were evenly distributed between the 2 major subtypes, RET/PTC1 and 

RET/PTC3. PAX8/PPAR� translocations were detected in 18.8% of FTC 

but not in FA, probably due to small sample size. Out of 7 indeterminate 

thyroid nodules, 2 had BRAF mutations and 2 had RAS mutations. The 

presence of the 4 markers was generally mutually exclusive; only 1 PTC 

specimen had concurrent RAS and RET/PTC1 alterations. Conclusions: The 

prevalence of BRAF, RAS, RET/PTC, and PAX8/PPAR� alterations in 

thyroid cancer specimens highlights the potential for targeted therapeutic 

strategies. The mutually exclusive pattern of alterations also suggests a 

hierarchical screening strategy for samples with limited availability. 

Prevalence of marker alterations in thyroid FNA specimens (NT � not 

tested). 

Diagnosis # 

BRAF 

(%) 

RAS 

(%) 

RET/PTC 

(%) 

PAX8/PPAR� 

(%) 

Total 

(%) 

PTC 114 62 (54.4) 11 (9.6) 4 (3.5) NT 77 (67.5) 

FA 12 NT 2 (16.7) NT 0 2 (16.7) 

FTC 16 NT 5 (31.3) NT 3 (18.8) 8 (50%) 

Indeterminate 7 2 (28.6) 2 (28.6) 0 0 4 (57.1) 

5509^ Clinical Science Symposium, Mon, 11:30 AM-1:00 PM 

Reacquisition of RAI uptake in RAI-refractory metastatic thyroid cancers by 

pretreatment with the MEK inhibitor selumetinib. Presenting Author: Alan 

Loh Ho, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Therapies for radioactive iodine (RAI)-refractory thyroid cancers 

of follicular origin (TC-FCO) are desperately needed. TC-FCO mouse 

models show that blocking mitogen-activated protein kinase (MAPK) 

signaling with a MAP kinase kinase 1/2 (MEK1/2) inhibitor increases 

sodium iodide symporter expression and iodine incorporation. This 20 

patient (pt) pilot study aimed to evaluate if the MEK1/2 inhibitor selumetinib 

(AZD6244, ARRY-142866) can reverse RAI-refractoriness in 

TC-FCO pts (NCT00970359). Methods: RAI-refractory TC-FCO disease was 

defined as: 1) non-RAI-avid lesion/s on a diagnostic or post-therapy RAI 

scan, 2) RAI-avid lesion/s that was stable or increased in size after RAI 

therapy, or 3) fluorodeoxyglucose (FDG)-avid lesion/s by positron emission 

tomography (PET) scan. rhTSH-stimulated lesional dosimetry with 124I PET 

was performed prior to and after 4 weeks of treatment with selumetinib (75 

mg orally bid). If the second 124I PET scan predicted a lesional RAI dose of 

� 2000 cGy, therapeutic RAI was administered while on the drug. Primary 

endpoints were to evaluate changes in tumor iodine uptake and RECIST 

response after RAI therapy; changes in serum thyroglobulin (TG) after RAI 

was a secondary endpoint. Results: 24 pts were enrolled, 22 eligible, and 

20 evaluable. For the 20 evaluable pts, median age was 61 (range 44-77 

yrs), 11 were men. 19 pts had tumors analyzed for BRAF and N-,K- RAS 

mutations. 8 pts had BRAF mutant (MUT), 11 BRAF wild-type (WT) 

tumors; 1 pt to be analyzed. Selumetinib increased 124I uptake in 12 of the 

20 pts (4 of 8 BRAF MUT; 8 of the 12 other pts). The 8 of those 12 pts 

achieving sufficient iodine avidity to warrant RAI therapy included all 5 pts 

known to be NRAS MUT to date and 1 BRAF MUT pt. Of the 7 pts who have 

received RAI, 5 had partial responses (PRs); 2 stable disease (SD). Mean 

percent reduction in TG in this group (pre- vs 2 months post- RAI) was 

91%. No � grade 2 CTCAE toxicities attributable to selumetinib were 

observed. 1 pt was diagnosed with myelodysplastic syndrome � 51 weeks 

after RAI (unrelated to selumetinib). Conclusions: Selumetinib can enhance 

iodine uptake in a subset of RAI-refractory TC-FCO and may be 

particularly effective for RAS MUT tumors. 


12:00 PM-1:00 PM 

A multicenter randomized controlled trial (RCT) of adjuvant chemotherapy (CT) 

in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA (EBV DNA) 

following primary radiotherapy (RT) or chemoradiotherapy (CRT). Presenting 

Author: Anthony T. C. Chan, Department of Clinical Oncology, Prince of Wales 

Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong 

Background: The benefit of adjuvant CT in NPC is unclear. Administering CT after 

full-dose CRT presents challenges in treatment compliance and toxicity. Post-RT 

EBV DNA predicts poor survival and may be a biomarker of subclinical residual 

disease. We conducted a biomarker driven RCT using EBV DNA to select high 

risk NPC patients (pts) for adjuvant CT while sparing low risk pts from 

unnecessary toxicity. Methods: Biopsy proven NPC, AJCC stage IIB-IVB, detectable 

EBV DNA at 6-8 wks post-RT, no persistent locoregional disease or distant 

metastasis, ECOG 0 or 1, adequate organ function. Randomised with stratification 

for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A 

(adjuvant cisplatin 40 mg/m2 and gemcitabine 1000mg/m2, both given on 

D1�8 q3w x 6 cycles) or arm B (clinical follow-up). EBV DNA and PET scan were 

performed before and 6 months after randomization. Primary endpoint was 

relapse free survival and secondary endpoints included toxicity of adjuvant CT. 

With a hazard ratio of 2, 100 pts were required with a power of 0.8 and an alpha 

at 0.05. This safety analysis was approved by DMSC. Results: From 9/2006 to 

12/2011, 514 pts consented for EBV DNA screening, 95 with detectable EBV 

DNA consented for adjuvant study. After work-up, 74 were eligible for randomization 

(37 to arm A; 37 to arm B). The two arms were well balanced in baseline 

characteristics. 80% received prior neoadjuvant and/or concurrent CT. Staging: 

IIB (36.5%), III (29.7%), IVA (18.9%), IVB (14.8%). Five pts refused adjuvant 

CT after randomization. Overall 65% and 57% completed 5 and 6 cycles 

respectively. Mean dose intensity (DI): 84% for cisplatin (22.5 mg/m2/wk, range 

0.0-26.7), 92% for gemcitabine (612.8 mg/m2/wk, range 333.3-777.8). 

Treatment related adverse events above CTC G2 were summarized in Table. 

Conclusions: Delivery of 6 cycles of adjuvant CT is feasible with acceptable 

toxicity after full dose RT or CRT. 

Events (No) G3 G4 G5 

Non-hematological 

Bleeding 1 1 

Electrolytes 2 1 

Fatigue 1 

Hearing 3 

Infection 1 

Mucositis 1 

syncope 2 

Weight loss 1 

Hematological 

Febrile neutropenia 1 

Hemoglobin 10 

Neutrophils 14 10 

Platelets 2 



12:00 PM-1:00 PM 

Five years’ results of the German ARO 04-01 trial of concurrent 72 Gy 

hyperfractionated accelerated radiation therapy (HART) plus once weekly 

cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck 

cancer. Presenting Author: Volker Budach, Department of Radiooncology 

CCM/CVK, Charite University Medicine, Berlin, Germany 

Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with 

concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in 

terms of overall survival (OS) and metastases-free survival (MFS)? Methods: 

Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of �80% 

stratified for sites, N-status, grading, hemoglobin and center. The HART 

schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was 

applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or 

MMC/5-FU at 10mg/m2 day 1�36 and for both arms with 600mg/m² 5-FU 

days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using 

3D-conformal or IMRT-TP. 364 patients were analysed using an ITT 

principle for OS, MFS, progression-free survival (PFS) and loco-regional 

control (LRC). Hazard ratio (HR) calculations were adjusted for competing 

risk factors. Results: Median follow-up was 48 mos. for both arms. Mean 

age was 55.4 years, 83/17% were male/female and 100% stage IV patients 

(UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP 

cancer, respectively. The OS and MFS at 4 years for the DDP- versus 

MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p�.05), 

respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs. 

57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute 

toxicity and 9 for late morbidity showed no significant differences between 

the treatment arms except for creatinine for the DDP-arm (p � 0.001) 

using nonparametric analyses of variances for repeated measurements. The 

overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC: 

86%, respectively. Conclusions: This phase III trial first establishes level 

IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4 

yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of 

acute and late radiation sequelae for both treatment arms. No significant 

differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly 

DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily 

compete with other concurrent chemo- or bio-radiation schedules including 

induction TPF followed by radiation. 


12:00 PM-1:00 PM 

A phase II study of temsirolimus/sorafenib in patients with radioactive 

iodine (RAI)-refractory thyroid carcinoma. Presenting Author: Eric Jeffrey 

Sherman, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple 

targets, including RAF, VEGFR1, and VEGFR2. Published response rates 

with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%. 

Temsirolimus is an intravenous inhibitor of mTOR; mutations in the 

PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be 

associated with aggressive disease. Methods: The study was a single 

institution, phase II design. Primary objective was response rate. Eligible 

patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)avid, 

recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable 

disease; and adequate organ/marrow function. Sorafenib was given at 

200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly. 

38 patients were enrolled; 37 were eligible and 36 patients started 

treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12. 

Fourteen pts are still actively on study. Results: Of the 37 eligible pts, 

demographics: female-46%; median age-64 years (30-81); histologypapillary 

(23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic 

(2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse 

events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt): 

grade 4 – colonic perforation (1 pt). Evaluation of best response: partial 

(PR) (8, including 3 with anaplastic/poorly differentiated); stable disease 

(SD) (21); progression (1); inevaluable (7). The partial response rate was 

38% in the cohort that previously did not receive any systemic treatment. 

There was no correlation of response to either BRAF (10) or RAS (5) 

mutational status. Median time on treatment is 203 days (range 14-638 

days) at the cutoff date. For the 21 pts with SD, the maximum percentage 

shrinkage by RECIST criteria ranged from -2% to -35% (one patient with 

unconfirmed PR) with a median time on treatment of 203 days (range 

39-503 days). Conclusions: The combination of sorafenib and temsirolimus 

shows promising results in a heavily pretreated population. This study was 

approved and funded by the National Comprehensive Cancer Network 

(NCCN) from general research support from Pfizer, Inc. 


359s 


12:00 PM-1:00 PM 

Cetuximab/radiotherapy (CET�RT) versus concomitant chemoradiotherapy 

(cCHT�RT) with or without induction docetaxel/cisplatin/5-fluorouracil 

(TPF) in locally advanced head and neck squamous cell carcinoma 

(LASCCHN): Preliminary results on toxicity of a randomized, 2x2 factorial, 

phase II-III study (NCT01086826). Presenting Author: Maria Grazia Ghi, 

Medical Oncology Department, Venezia, Italy 

Background: The standard treatment options for LASCCHN are cCHT�RT or 

CET�RT. Strategies to improve the efficacy with the integration of 

induction chemotherapy are being investigated. Primary endpoints of this 

study were to compare: 1) the overall survival (OS) of induction vs. no 

induction arms; 2) the Grade(G)3-4 in-field toxicity of cCHT�RT vs. 

CET�RT. Methods: Patients (pts) with unresectable LASCCHN, stage 

III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: 

cCHT�RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET�RTX; Arm B1: 

3 cycles of TPF followed by the same cCHT�RT; Arm B2: 3 cycles of TPF 

followed by CET�RT. A total of 204 deaths over 420 pts ( including the 

101 randomized in the phase II part of the study comparing cCHT�RT with 

or w/o induction TPF) were required to detect a HR of death of 0.675 

(A1�A2 vs. B1�B2; 2-sided a�0.05; b�0.20) and a 10% difference in 

G3-4 in-field mucosal toxicity (A1�B1 vs. A2�B2). Results: By February 

2012, 387 pts over 413 pts were evaluable for toxicity. 82% of pts were 

male; median age was 60y; PS: 0�77.8% and 1�22.2%. Disease stage 

was III (31%) or IV (69%). Sites of disease were oral cavity (21.7%), 

oropharynx (54.8%), hypopharynx (23.5%). At a median follow-up of 21 

months, 126 deaths occurred. Data on G3-4 in-field toxicity (primary 

endpoint) and compliance to cCHT�RT vs CET�RT are shown in the table. 

Conclusions: No advantage for CET�RT over cCHT�RT was observed 

regarding G3-4 in-field toxicities and feasibility. Pts are still being 

followed-up to assess OS. 

cCHT�RTX CET�RTX p 

In-field mucositis G3-4 29.4% 23% 0.15 

In-field skin reaction G3-4 11.1% 13.7% 0.43 

RT median dose, Gy (range) 66 (18-70.2) 70 (35-70.4) �0.01 

RT median duration, weeks (range) 7.2 (0.6-13.3) 8.4 (1-12.7) �0.01 

RT interruption > 3days 32.8% 38.7% 0.28 

Pts receiving 2 CHT cy or 7 weekly CET 91.3% 78.2% �0.01 

RT modification due to acute toxicity 18.5% 27.7% 0.08 


12:00 PM-1:00 PM 

Expression of p16, ERCC1, and EGFR amplification as predictors of 

responsiveness of locally advanced squamous cell carcinomas of head and 

neck (SCCHN) to cisplatin, radiotherapy, and erlotinib: A phase II randomized 

trial. Presenting Author: Melissa Austin, University of Washington, 

Seattle, WA 

Background: This study evaluated the expression of p16 and ERCC1 and 

EGFR amplification as predictive and prognostic factors in a recently 

completed phase II randomized trial comparing cisplatin (100 mg/m2 on d 

1, 22, 43) with radiotherapy (70Gy) �/- erlotinib (150 mg/d during 

radiotherapy) in locally advanced SCCHN. p16 (HPV surrogate) is a known 

prognostic factor in oropharyngeal SCCHN, and high ERCC1 expression has 

been correlated with resistance to cisplatin. EGFR gene copy number may 

be prognostic in SCCHN and alter response to erlotinib. Methods: Pretreatment 

formalin-fixed, paraffin-embedded tumor tissue was available for 

84/204 patients. EGFR copy number was assessed using Vysis LSI DNA 

probes, and immunohistochemistry was performed on Leica Bond III 

machines using Lab Vision ERCC-1 (8F1) and CINtec p16 antibodies. All 

assays were performed in accordance with manufacturer instructions; all 

studies were reviewed by a single Pathologist (MA) who was blinded to 

patient outcome. Logistic regression and Cox regression models fit a 

treatment arm by marker interaction and tested selected linear contrasts. 

Results: Efficacy analysis showed no difference in complete response rate 

(CRR) and progression-free survival (PFS) between treatment arms. However, 

PFS in both arms was better than historical comparisons, with only 46 

events over a median follow-up of 23 months. Positivity in p16 was 

associated with greater CRR (OR 3.5, p�0.03) and longer PFS (HR�0.38; 

p� 0.07). The CRR effect was greater for the erlotinib arm (OR 8.1, 

p�0.01) than for Arm A (OR 1.5, p�0.56). The ERCC1 (�) rate was 46% 

(39/84).ERCC1 expression above the median was not associated with 

worse CRR (OR 0.69; p�0.46) or PFS (HR 0.99; p�0.98). Only 4 tumors 

showed EGFR amplification precluding further analysis. Conclusions: p16(�) 

tumors had a better outcome, similar to other recent trials, and erlotinib 

seemed to increase the CRR among p16(�) tumors. ERCC1 expression did 

not predict chemoradioresistance in this study. EGFR amplification was too 

rare in the tested population to assess predictive or prognostic value. 




12:00 PM-1:00 PM 

Cilengitide with cetuximab, cisplatin, and 5-FU in recurrent and/or metastatic 

squamous cell cancer of the head and neck: The ADVANTAGE phase 

II trial. Presenting Author: Jan Baptist Vermorken, Department of Medical 

Oncology, Antwerp University Hospital, Edegem, Belgium 

Background: Prognosis for patients with recurrent and/or metastatic squamous 

cell cancer of the head and neck (R/M-SCCHN) is very poor. �v�5 

integrin is overexpressed in SCCHN and selective integrin blockade is being 

investigated as a treatment strategy. Methods: ADVANTAGE was a phase I/II 

study evaluating cilengitide with cetuximab and platinum-based chemotherapy. 

Eligible patients were �18 years with �1 measurable lesion, 

Karnofski performance status �70%, and confirmed R/M-SCCHN. The 

phase II part reported herein was an open-label, randomized, controlled 

trial investigating progression-free survival (PFS) in patients treated with 2 

cilengitide 2000 mg regimens: once weekly (CIL1W) and twice weekly 

(CIL2W) administration combined with cisplatin, 5-FU, and cetuximab 

(PFE) as compared with PFE alone (control). Secondary objectives included 

overall survival (OS) and objective response (OR). Treatment-emergent 

adverse events (TEAEs) were monitored. Results: 184 eligible patients were 

enrolled. Overall, patient characteristics were similar across arms. Median 

duration of treatments was shorter in the CIL2W arm compared with the 

CIL1W arm (cilengitide: 16.1 vs 23.4 wk, cetuximab: 16.0 vs 22.6 wk, 

platinum: 16.0 vs 18.0 wk, and 5-FU: 14.6 vs 18.0 wk). Median PFS was 

6.4 months in the CIL1W group, 5.6 months in the CIL2W group and 5.7 

months in the control group, with CIL1W and CIL2W having HRs of 1.03 

(95% CI: 0.67–1.59) and 1.55 (95% CI: 0.99–2.43) vs control. The latter 

HR was possibly due to less compliance in the CIL2W arm. Median OS was 

12.4, 10.6, and 11.6 months in the CIL1W, CIL2W, and control groups, 

respectively. ORs were observed in 46.8%, 26.7%, and 35.5% of patients 

in the CIL1W, CIL2W, and control arms, respectively. Most common 

(�15%) grade 3/4 TEAEs were neutropenia, hypokalemia, leukopenia, 

stomatitis, and fatigue. No safety differences were noted between treatment 

arms. Overall, there were 7 drug-related TEAEs (2 in CIL1W, 2 in 

CIL2W, and 3 in control) leading to death. Conclusions: In this population, 

neither of the cilengitide-containing regimens was able to demonstrate a 

PFS benefit over PFE alone. 


12:00 PM-1:00 PM 

Lenvatinib treatment of advanced RAI-refractory differentiated thyroid 

cancer (DTC): Cytokine and angiogenic factor (CAF) profiling in combination 

with tumor genetic analysis to identify markers associated with 

response. Presenting Author: Douglas Wilmot Ball, The Johns Hopkins 

University School of Medicine, Baltimore, MD 

Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting 

VEGFR1-3, FGFR1-4, RET, KIT and PDGFR�. In a phase II study of 

lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of 

50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib 

at a starting dose of 24 mg oral once daily in 28-day cycles. Serum 

was collected at baseline (BL), on day 8 and on day 36 and concentrations 

of 47 CAFs were measured using multiplex bead arrays and enzyme-linked 

immunosorbent assay (ELISA). 33 genes (443 mutations) were examined 

in archival tumor tissues (n�25). Association of baseline CAF, changes in 

CAF levels upon treatment and gene mutation status with treatment 

outcomes was investigated. Results: Combination of low baseline VEGF and 

ANG-2 (p�0.02 and HR�0.386) correlated with longer PFS. Both 

baseline and changes in CAF levels demonstrated an association with gene 

mutation status. High baseline levels of VEGF were observed in pts with 

wild type RAS and BRAF (p�0.035) whereas high baseline sTIE-2 levels 

associated with RAS mutation (p�0.023). Supporting pre-clinical mouse 

xenograft tumor model developed using ANG2-overexpressing human 

thyroid cancer cell line FTC-286 demonstrated reduced sensitivity to 

lenvatinib treatment. Increased levels of IL-10 and FGF-2 8-day posttreatment 

(8d post-tx) significantly associated with RAS (N- or K-) and 

BRAF mutation. Combination of gene mutation status with baseline CAF 

levels provided better prediction of longer PFS compared to gene mutation 

alone. Hierarchical clustering modeling using changes in CAF levels 8d 

post-tx with tumor shrinkage identified a set of CAFs that could predict two 

categories of lenvatinib response: longer PFS and greater tumor shrinkage 

or longer PFS in the absence of significant tumor shrinkage. Conclusions: 

CAF profiling identified potential predictive biomarkers of lenvatinib 

treatment outcomes in DTC. Combination of RAS and BRAF mutation with 

baseline VEGF and ANG-2 or treatment-associated changes in FGF-2 and 

IL-10 level correlated with lenvatinib treatment response. 


12:00 PM-1:00 PM 

Genomic profiling of a clinically annotated cohort of locoregionally advanced 

head and neck cancers (HNC) treated with definitive chemoradiotherapy. 

Presenting Author: Tanguy Y. Seiwert, The University of Chicago 


Background: Recent advances in genomic technology and sequencing have 

allowed the near comprehensive characterization of genetic abnormalities 

in HNC, but their correlation with clinical outcome remains to be determined. 

We analysed a clinically annotated cohort of locoregionally advanced 

HNC for copy number changes and mutations and correlated with 

outcome in an exploratory fashion. Methods: 120 head and neck cancers 

(frozen tissue) and matching normal tissues/blood from patients with 

locoregionally advanced HNC treated with definitive chemoradiation �/induction 

at the University of Chicago were obtained from our tissue bank. 

DNA, RNA, protein were extracted. Barcoded, multiplexed sequencing 

libraries for 500 head and neck cancer associated genes (Agilent capture) 

were built and sequenced on Illumina HiSeq next generation sequencers. 

150 commonly copy number altered and HNC relevant genes were analysed 

for copy number alterations (CNA) using the Nanostring nCounter platform. 

Respective genetic aberrations in curated pathways were allocated to tumor 

subgroups. Exploratory analysis correlated data with induction response 

and progression free survival. Confirmatory HPV testing was performed 

using an E6, nested, multiplex PCR. Results: �80% of targeted sequences 

were successfully captured and sequenced. Commonly mutated genes 

included: TP53, CDKN2A, PIK3CA, NOTCH1. Of note PIK3CA mutations 

were enriched in HPV(�) tumors. Commonly copy number altered genes 

included amplifications of VEGF1, CCND1, MYC, EGFR, MDM4, CTTN, as 

well as PIK3CA, and deletions of CDKN2A, SUCLG2, FHIT, TGFBR2, 

PTPRD, IKBKG, TRAF6, and RASSF1. CCND1, and MYC were commonly 

co-amplified and correlated with poor progression free survival, representing 

a distinct HNC phenotype. Analysis for additional genes and influence 

on induction response will be presented. Conclusions: Targeted, medium 

throughput genomic profiling is feasible, and provides the majority of HNC 

specific genetic aberrations at a comparably low cost. Impact on outcome 

(CCND1/MYC amplification) and potential treatment targets (PIK3CA 

mutations in HPV(�) tumors) were identified. 


12:00 PM-1:00 PM 

Safety, molecular, and imaging responses to cetuximab administered in a 

window pre-operative study in squamous cell carcinoma of the head and 

neck (SCCHN). Presenting Author: Sandra Schmitz, Department of Head 

and Neck Surgery, St-Luc Hospital, Catholic University of Louvain, Brussels, 

Belgium 

Background: Only a minority of SCCHN pts benefits from anti-EGFR mAbs. 

Trials with pre- and post-therapy tumor biopsies are crucial to better 

characterize the molecular pathways involved in treatment response or 

resistance. Targeted agents (TA) are often investigated in unselected 

end-stage cancer pts, making difficult optimal translational research. One 

way to resolve this issue is to perform “window” studies where a TA is given 

during the incompressible period between the diagnosis and surgery. 

Methods: We conducted a phase I/II study: cetuximab (C) was given 

pre-operatively to treatment-naïve SCCHN pts selected for primary curative 

surgery. C (400mg/m2 first wk followed by 250mg/m2/wk) was given 

during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 0). 

Tumour biopsies, FDG/PET, and CT were performed at diagnosis and 

surgery. In the phase I, we investigated the safety of preoperative C by 

progressively reducing the delay between the last dose of C and surgery 

(minimum delay : 24 hrs ; 3�3 phase 1 design). The aims of the phase II 

were (i) safety, (ii) C activity by FDG-PET (Po�0.10, P1�0.35, a�0.05 and 

b� 0.10). As controls, 5 additional pts were included without C treatment 

but with the same requirements regarding biopsies and imaging. Results: 

The phase 1 study (n�18) demonstrated that C infusion given 24 hrs 

before surgery was safe. Safety was confirmed in the phase II (n�20). 90 % 

had a FDG-PET partial response (PR) (EORTC guideline) in the C group and 

0% in the controls. 52% had a �SUVmax decrease of �50%. 2 pts 

evaluable by CT/MRI had a PR (RECIST). Then, we compared the pre-and 

post treatment biopsies by immunochemistry. For the whole group, C did 

not reduce Ki67 (p�0.1) and did not seem to induce apoptosis (caspase). 

However, for pts with �SUVmax decrease � 25% or � 50%, Ki67 was 

decreased (p�0.04 and 0.006). C induced downregulation of pEGFR 

(p�0.0004) and pERK (p�0.007) but not pAKT/AKT (Histoscore). 

Conclusions: Pre-operative study with C is safe. Our findings suggest that 

the main downstream molecular pathway blocked by C in SCCHN is the 

RAS/RAF/ERK. Further analyses are ongoing to better characterize molecular 

response and escape mechanisms. 



12:00 PM-1:00 PM 

Role of c-MET pathway in the outcome prediction of cetuximab-based 

therapy in patients with recurrent or metastatic squamous cell carcinoma of 

the head and neck. Presenting Author: Victoria Casado, Oncology Department. 

Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, 

Spain 

Background: Activation of the c-MET oncogene promotes tumor growth, 

invasion and metastasis in several tumor types. In addition, c-MET has 

been reported in consort with EGFR and/or be activated as a compensatory 

pathway in the presence of EGFR blockade resulting a mechanism of 

acquired resistance to EGFR inhibitors in lung and colorectal carcinoma. 

We investigated the impact on cetuximab sensitivity of HGF, c-MET, c-MET 

activation and c-MET gene status in recurrent or metastatic squamous cell 

carcinoma of the head and neck (HNSCC) patients. Methods: A singleinstitution 

retrospective analysis including 50 HNSCC patients was carried 

out. For each case, formalin-fixed tumor specimens were assayed for HGF, 

total and phosphorylated Y1234/35 c-MET (p-c-MET) by immunohistochemistry 

and c-MET gene by FISH. Overexpression criteria were defined by ROC 

curves for each protein and amplification was defined by �2 copies in at 

least two of the three studied tumor areas. Results were analyzed for 

association with clinico-pathological features and survival outcomes for 

cetuximab-treated patients (median follow-up 75 months). Results: c-MET 

overexpression was detected in 26 (52%) of patients, c-MET amplification 

in 15 (30%) and p-c-MET in 12 (24%). Amplification was associated with 

c-MET overexpression (p�0.004). HGF overexpression was observed in 8 

(12%) associated with c-MET phosphorylation (p�0.001), suggesting a 

paracrine activation of receptor. No significant association with clinicopathological 

parameters was detected. Log-rank test showed significantly 

worse outcome in c-MET overexpressing patients for progression-free (PFS) 

(p�0.002) and overall survival (OS) (p�0.045); p-c-MET was correlated 

with worse PFS (p�0.014) and OS (p�0.001). In multivariate logistic 

regression analysis, p-c-MET was an independent prognostic factor for PFS 

(HR 6.5; 95% CI 1.5-8.9). Conclusions: HGF/c-MET pathway correlated 

with worse outcome in cetuximab-based regimen treated HNSCC patients, 

acting as a resistance mechanism for EGFR inhibitors and supporting a 

dual blocking HGF/c-MET and EGFR pathways for treatment of these 

patients. 


12:00 PM-1:00 PM 

Exploratory pharmacodynamics (PD) trial to investigate the mechanism of 

action of RG7160 (GA201), a novel dual-acting, monoclonal antibody 

(mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), 

compared with cetuximab (C) in neoadjuvant head and neck squamous cell 

carcinoma (HNSCC). Presenting Author: Stéphane Temam, Institut Gustave 


Background: GA201 efficacy was superior to C in orthotopic xenograft 

models in terms of activity and PD. In a phase I study, objective responses 

and long lasting stable disease were observed in heavily pre-treated 

patients (pts). Methods: HNSCC pts (T2-4, any N, M0) received i.v. 

neo-adjuvant 700/1400 mg GA201 or C (as per SPC), on D1 and 8. Tumor 

biopsies were taken at baseline (BL) and pre-surgery. The primary objective 

was determination of changes in tumor immune cell infiltration after 

treatment. Peripheral CD3�, CD16�, CD56� cells, plasma cytokines, 

tumor EGFR and 18F-FDG-PET avidity were also studied. Results: To date, 

39 pts (15/10 vs 14 pts for 700/1400 GA201 vs C, respectively) were 

evaluable for the primary objective and 4 pts are on-going. Patient 

characteristics at BL were as follows: median age, 57/62 vs 62 years; 

gender, 11/10 vs 12 male; tumor size � 4 cm, 7/3 vs 3 pts. A greater 

proportion of pts receiving GA201 compared to C had metabolic tumor 

reduction (� 25% of SUVmax) (10/15 at 700 mg [1 pathological CR], 7/10 

at 1400 mg GA201 vs 7/14 C pts) and symptomatic relief (6/12 at 700 mg, 

6/7 at 1,400 mg GA201 vs 2/10 C pts). Table shows changes in PD 

markers. Conclusions: GA201 treatment, compared to C, exhibited more 

extensive tumor immune cell infiltration and a greater metabolic response. 

Consistent with the proposed mechanism of action of GA201, peripheral 

NK cells dropped and a unique cytokine profile was observed. The data 

support the immunomodulatory superiority of GA201 - a mAb designed to 

enhance ADCC compared to C. 

Median change from BL (range) 

GA201 

C ‡ 

700 mg* 1,400 mg † 

Tumor biopsy 1 

CD3� (cells/mm 2 ) 396 (–987, 2336) 205 134 (–45, 722) 

EGFR (intensity 3; %) –14 (–83, 25) – –5.5 (–65, 43) 

Peripheral blood 

CD16� and/or CD56�/CD3– % –97 (–100, –92) –98 (–100, –97) –1 (–71, 59) 

CD3� % –89 (–98, –73) –93 (–96, –78) –59 (–86, 178) 

IL-15 % 946 (0, 2113) 695 (649, 742) 0 (–53, 7) 

IL-1RA % 6,950 (706, 21,933) 1,201 (873, 1,529) –16 (–70, 19) 

*n� 14-15; † n � 1-2; ‡ n � 8-12 for paired samples. 

1 

Correlations with SUVmax are being investigated. 


361s 


12:00 PM-1:00 PM 

Differential expression of EGFR, HER2, P16, and high-risk (hr) HPV status 

in oropharyngeal (Or) and oral cavity (OC) squamous cell carcinoma (SCC). 

Presenting Author: Anne Sudaka, Centre Antoine Lacassagne, Nice, France 

Background: We aimed to better characterize the expression of epidermal 

growth factor receptors family in Or and OC SCC and correlate it to hr HPV 

status and anatomoclinical features. Methods: In formalin fixed paraffin 

embedded tumor tissues, chromogenic in situ hybridization (CISH) was 

performed to detect hr HPV and immunohistochemistry to evaluate EGFR 

(positive score: 4 to 6), HER2 (0�negative, 1�positive) and P16 (positive 

score:�70% labeled cells) expression. Baseline data were collected and 

analyze will be used. Results: Among 128 pts, 69 were tobacco users and 

58 male. Median age at diagnosis was 61 y [23-95]. EGFR, Her2, P16 

expression and hrHPV positivity were seen in 84 (65%), 12 (9%), 47 

(37%) and 47 (37%) respectively. P16 signal was linked with absence of 

tobacco (31% vs. 72%, Pearson chi2 test: p�10-3 ), absence of alcohol 

(48% vs. 83%, p�10-3 ), Or site (53% vs. 76%, p�0.005), T1 (34% vs. 

19%, p�0.06), N0 (52% vs. 23%, p�0.003), absence of nodal capsular 

rupture (85% vs. 68%, p�0.02), WHO grade 3 (37% vs. 68%, p�0.001), 

hr HPV detection (17% vs. 70%, p�10-3 ). Multivariate analysis confirmed 

the link between P16 expression and hr HPV CISH positivity (OR�0.05, CI 

95% [0.01-0.21], p�10-3 ) , absence of tobacco (OR�9.2, CI 95% 

[2.1-40.7], p�0.03) and N0 (OR�0.2, CI 95% [0.04- 0.75], p�0.02). 

EGFR signal was linked with tobacco (31% vs 78%,p�10-3 ), alcohol (57% 

vs 81%, p�0.02), OC localization (77% vs 58%, p�0.03), well differentiated 

SCC (73% WHO grade 1-2 vs 56% grade 3, p�0.04), absence of hr 

HPV detection (74% vs 52%, p�0.01) and absence of P16 labeling (78% 

vs 44%, p�10-3 ). Multivariate analysis confirmed the link between EGFR 

positivity and tobacco (OR�0.32, CI 95% [0.1-0.9], p�0.03), alcohol 

(OR�9.5, CI 95% [1.2- 72.8], p�0.03) and OC localization (OR�0.3, CI 

95% [0.1-1], p�0.05). HER2 signal was linked with alcohol (5% vs 18%, 

p�0.04), history of tobacco associated neoplasia (10% vs 0%, p�0.02), 

Or site (14% vs 2%, p�0.03) and who grade 3 (5% vs 14%, p�0.06). 

Her2 labeling was not associated with tobacco, sex, hr HPV detection, P16 

positivity or EGFR one. Conclusions: Hr HPV associated SCC have a low 

expression of EGFR and are not associated with HER2 labeling. 


12:00 PM-1:00 PM 

Differences in biomarker expression in HNSCC according to p53 status. 

Presenting Author: Rebecca Anne Feldman-Moreno, Caris Life Sciences, 

Phoenix, AZ 

Background: Patients with p53 wildtype head and neck squamous cell 

carcinoma (HNSCC) tend to be HPV-positive, which associates with better 

prognosis. The purpose of this study was to explore biomarker expression 

profiles for insight into molecular differences in HNSCC patients based on 

p53 status. Methods: TP53 gene sequencing using the AmpliChip p53 

microarray (Roche Molecular Systems, Inc.) was attempted on 61 HNSCC 

patients previously tested with Caris Target Now tumor profiling service. 

DNA was extracted from a FFPE sample, amplified and processed on the 

AmpliChip p53 microarray to detect single base pair substitution and 

deletion mutations in exons 2-11andtheir flanking splice sites in the 

TP53 gene (GenBank X54156). EGFR FISH , HER2 IHC and 22 other 

predictive biomarkers, e.g. TS, TOPO2A, MGMT, etc., were assayed and 

retrospectively analyzed. All tests were performed in a CLIA-certified lab 

and interpreted by board-certified pathologists or cytogeneticists. Statistical 

analysis was performed using SPSS (PASW statistics17) for parametric 

and non-parametric tests of independence. Results: 52 cases provided 

sufficient quality DNA for p53 analysis and results revealed a mutation rate 

of 25% in HNSCC patients. Interestingly, only EGFR FISH and HER2 IHC 

(p�.002 and p�.004, respectively) were differentially expressed in 

wildtype vs. mutated p53. Matched-pair analysis in the p53 mutated 

subgroup (n�13) showed no significant trend regarding EGFR status 

(p�.763) but a slight trend towards HER-2 negativity (p�.020). In the p53 

wildtype subgroup (n�39), a strong association with EGFR FISH nonamplification 

(n�28, 71.8%, p�.001) as well as HER-2 negativity (n�38, 

97.4%, p�.001) was shown. Conclusions: To our knowledge, this is the first 

analysis of differential biomarker expression profiles in HNSCC based on 

p53 status. We hypothesize that the absence of EGFR amplification in the 

p53 wildtype cancers may be a contributing factor to the improved 

prognosis observed in HPV-positive HNSCC. Additionally, the strong 

association between p53 wildtype HNSCC patients and EGFR nonamplification 

suggests EGFR-targeted therapies like cetuximab would 

likely fail in p53 wildtype patients. 




12:00 PM-1:00 PM 

New DNA methylation markers associated with oral cancer (OC) development 

(dvlpt). Presenting Author: Pierre Saintigny, University of Texas M. D. 


Background: We have reported that DNA methyltransferase-3B (DNMT3B) 

gene expression is a strong predictor of OC dvlpt. Using high-throughput 

DNA methylation profiles of oral preneoplastic lesions (OPL), we identified 

86 candidate genes that were hypermethylated in patients (pts) developing 

OC and suggested that a CpG island methylation phenotype may occur early 

during OC dvlpt. Our aim was to validate some of the candidate genes and 

to study the value of LINE1 repetitive element methylation, a surrogate of 

global DNA methylation, as biomarkers of risk to develop OC. Methods: 

Validation cohort included 40 pts with a median follow-up of 4.2 years, 

including 14 pts who developed OC. None of them were used in the 

discovery phase. Frozen OPL were collected prospectively and subject to 

DNA extraction. We performed a quantitative analysis of the degree of 

methylation of LINE1, and AGTR1, FOXI2, PENK, and HOXA9 promoters 

CpG sites using pyrosequencing. Results: The degree of methylation of 

AGTR1 (Mann-Whitney P�0.0001), FOXI2 (P�0.0002), PENK 

(P�0.0001), but not HOXA9 (P�0.0714) was significantly higher in pts 

who developed OC. On the contrary, LINE1 methylation was significantly 

lower in pts who developed OC (P�0.0001). The median percent of 

methylation was used to dichotomize the pts into high versus low methylation 

levels. Oral cancer-free survival (OCFS) was significantly worse in pts 

with high levels of AGTR1 (Log-rank P�0.0229), FOXI2 (P�0.0170), and 

PENK (P�0.0142) promoter methylation. No significant difference was 

found with HOXA9. A Methylation Index (MI) was developed by averaging 

the percent of methylation of AGTR1, FOXI2, and PENK promoters; pts 

with a high MI had a worse OCFS (P�0.0031). On the other hand, pts with 

low levels of LINE1 methylation had a significantly worse OCFS (P�0.0118). 

Finally, in 26 pts, a positive correlation was observed between DNMT3B 

gene expression levels and the MI (rho�0.65, P�0.0003); surprisingly, 

there was a negative correlation with LINE1 methylation (rho�-0.74, 

P�0.0001). Conclusions: AGTR1, FOXI2 and PENK promoter methylation 

may be associated with increased OC risk in pts with OPL and correlate with 

DNMT3B expression. Global DNA hypomethylation is an early event in OC 

dvlpt. 


12:00 PM-1:00 PM 

Effects of low-level laser therapy in the prevention and treatment of 

concurrent chemoradiotherapy induced oral mucositis: A triple-blind randomized 

controlled trial. Presenting Author: P.U. Prakash Saxena, Department 

of Radiotherapy & Oncology, Kasturba Medical College, Udupi, India 

Background: Oral mucositis (OM) is the most cumbersome acute side effect 

of concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC). 

OM associated pain affects oral function also may lead to CCRT break. 

Several modalities have been tried to prevent and treat this complication 

but none has been proved successful till date. We used prophylactic Low 

Level Laser Therapy (LLLT) for the prevention and treatment of CCRT 

induced OM. Methods: In this triple blind study, 221 HNC patients 

scheduled to undergo CCRT were randomized into laser (n�111) and 

placebo (n�110) group. Laser group received LLLT (Helium Neon laser, 

��632.8nm, P�24m, W�3.0J/cm2 ) while placebo received sham treatment 

daily prior to radiation for 45days. Oral Mucositis (OM) (RTOG/EORTC 

Scale), oral pain (Visual Analog Scale - VAS), dysphagia (Functional 

Impairment Scale - FIS), weight loss, duration of analgesic use were 

assessed. Data was analyzed using frequencies and percentage, generalized 

estimating equations (GEE) and Odds ratio. Results: There was 

significant reduction in incidence of severe OM (F�16.64, degree of 

freedom df�8,876, p�0.0001) and its associated pain (F�25.06, 

df�8,876, p�0.0001) and dysphagia (F�20.17, df�8,876, p�0.0001) 

and loss of weight (F�87.56, df�8,876, p�0.0001) when compared 

between the Laser and placebo group. The duration of step III analgesia 

required was also significantly lower (p�0.001) in laser (3.2 �1.4days) 

than placebo (6.7 �2.6days) group. Conclusions: LLLT was able to 

decrease the incidence of CCRT induced severe OM its associated pain, 

dysphagia, weight loss and the duration of analgesic use. 

Statistical analysis of OM and FIS scores between laser and placebo group. 

Week 

Laser group 

OR (95% CI) 

Oral mucositis Functional Impairment Scale 

Placebo group 

OR (95% CI) 

Laser group 

OR (95% CI) 

Placebo group 

OR (95% CI) 

7 19.05 (9.78-37.12) 8.18 (3.03-22.05) 12 (6.77-21.2) 5.24 (3.15-8.72) 

6 12.72 (6.73-24.04) 5.17 (1.83-14.58) 9.5 (5.45-16.53) 4.7 (2.85-7.74) 

5 7.06 (3.88-12.83) 3.86 (1.37-10.84) 6.1 (3.62-10.28) 3.89 (2.35-6.45) 

4 3.65 (2.05-6.49) 3.24 (1.27-8.27) 2.7 (1.74-4.2) 2.48 (1.57-3.91) 

3 Ref Ref Ref Ref 


12:00 PM-1:00 PM 

Hearing evaluation of head and neck cancer patients (HNCP): Comparison 

of adverse event (AE) criteria. Presenting Author: A. Dimitrios Colevas, 

Stanford University School of Medicine, Stanford, CA 

Background: The incidence and severity of baseline hearing abnormality in 

HNCP is poorly characterized, as is the subsequent CDDP associated 

hearing loss. While formal behavioral audiograms can characterize CDDP 

associated hearing loss in great detail, most oncologists either rely on 

subjective evaluation of hearing loss or grade hearing impairment using the 

CTCAE. Two new grading systems for grading cisplatin ototoxicity have 

been developed for use in pediatrics, the Brock and Chang systems. This 

report is the first evaluation of these 3 hearing loss criteria in an adult 

cancer patient population. Methods: We conducted an electronic medical 

records (EMR) search for all HNCP between 2004 and 2010 treated at the 

Stanford Cancer Institute (SCI) and identified which patients had audiograms 

in the EMR, and who had received CDDP. Three investigators (RL, 

ADC, KC) independently graded these audiograms using the CTCAE v3 and 

v4, Brock and Chang criteria. Baseline distributions, changes following 

CDDP dosing, and inter-observer variability were calculated for hearing 

impairment grading using all four criteria. Results: We evaluated 460 

audiograms in 111 patients. Because 282/460 of the audiograms did not 

have threshold shifts measured at 1,2,3,4,6 and 8 kHz, CTCAE v4 could 

not be applied to them . We therefore limited all further comparisons to 

CTCv3, Brock and Chang criteria. The table below summarizes the analysis. 

Conclusions: The Brock and Chang ototoxity criteria scales deliver a 

distribution of hearing AE grades at baseline more compatible than the 

CTCAE v3 with respect to the expectation that most HNCP do not have 

severe baseline hearing loss. Both the Brock and Chang scales are more 

sensitive than the CTCv3 to CDDP associated hearing changes. The Brock 

scale, followed by the Chang scale, demonstrated highest inter-rater 

agreement. Additional data concerning performance characteristics and 

utility of these three grading systems will be presented. Replacement of the 

present hearing impairment criteria in the CTCAE with either the Brock or 

Chang scales should be considered. 

Ototoxicity scale CTCAE v3 Brock Chang 

Baseline median grade 2 0 0 

% inter-rater agreement 69 91 80 

% with grade changes following CDDP 33 44 47 


12:00 PM-1:00 PM 

ARIX: A randomized trial of acupuncture versus oral care sessions in 

patients with chronic radiation-induced xerostomia following treatment for 

head and neck cancer. Presenting Author: Richard Simcock, Sussex Cancer 

Centre, Brighton, United Kingdom 

Background: Radiation induced xerostomia impairs quality of life of in head 

and neck cancer survivors. Prior small non-randomised studies suggest that 

acupuncture may alleviate symptoms. We report the first large randomised 

trial comparing 8 weeks of group acupuncture with oral care sessions as a 

control. Methods: 145 patients with radiation induced xerostomia�18 

months were recruited from 7 UK Cancer centres. Subjects received 

standardised group sessions of oral care (OC) education and 8 sessions of 

weekly group acupuncture (A) in a randomised crossover design with a 4 

week washout (Group One OC/A and Group Two A/OC). Acupuncture was 

standardised to a technique previously piloted (3 auricular points and two 

distal points bilaterally). Patients completed the EORTC QLQ H&N questionnaire 

at baseline and weeks 5, 9, 13, 17 and 21 in addition to rating 4 key 

dry mouth symptoms. The primary outcome was patient reported improvement 

in dry mouth symptoms. The statistical analysis was longitudinal 

based on logistic regression models and adjustment for potential carry over. 

Stimulated and unstimulated saliva was measured. Results: An improvement 

for 5/7 symptoms was noted following acupuncture. In Group One 

24% showed improvement 8 weeks following A (19% after OC). In Group 

Two 26% reported improvement in severe dry mouth after A (14% after 

OC). The estimated OR of improved dry mouth 5 weeks after A compared to 

OC was 2.0 (p�0.031), after adjusting for effects of time, potential 

carry-over, centre and patient characteristics. The estimated odds ratios of 

improvement in severity of symptoms for A compared to OC were (OR�1.67, 

p�0.048) for sticky saliva, (OR�2.08, p�0.011) for needing to sip to 

swallow food and (OR�1.71, p�0.013) for waking up at night needing to 

drink. Mean attendance rate for A was 89% and 80% for OC. There was no 

significant change in saliva production over time or by intervention. Mean 

global QoL score did not change significantly over time either within or 

between groups. No adverse events were seen. Conclusions: Eight sessions 

of weekly group acupuncture provides significantly better relief of radiation 

induced xerostomia than group oral care education. 



12:00 PM-1:00 PM 

A phase II trial of cetuximab in high-risk premalignant lesions of the upper 

aerodigestive tract. Presenting Author: Joseph A Califano, Johns Hopkins 

University School of Medicine, Baltimore, MD 

Background: High risk head and neck premalignancy includes patients with 

prior HNSCC and loss of heterozygosity (LOH). These patients demonstrate 

30-60% rates of progression to malignancy despite conventional surgical 

excision. We performed a phase II trial using short term therapy with 

cetuximab, a humanized monoclonal antibody directed against EGFR, in 

the treatment of high risk premalignant lesions of the UADT. Methods: 

Inclusion criteria required; 1) presence of 3p, 9p21, or 17p LOH, and/or 2) 

surgically unresectable high grade premalignant lesions, and/or 3) high 

grade premalignancy after curative therapy for HNSCC. Patients received 

cetuximab 400 mg/m2 on week one followed by 250 mg/m2 on week 2-8 or 

observation, with the option for crossover to cetuximab for patients 

originally randomized to the observation arm. Histologic grade (1�benign, 

2�mild dysplasia, 3�moderate dysplasia, 4�severe dysplasia/carcinoma 

in situ, 5�invasive cancer) and change in grade of dysplasia was evaluated. 

Results: 19 patients were enrolled. Two patients discontinued therapy due 

to toxicity. We noted a decrease in grade of dysplasia in the cetuximab 

treated group (-1.0) vs. the observation group (-0.2), (Wilcoxon test p value 

� 0.18). In the observation group, 0/5 patients (0%) underwent complete 

resolution of dysplasia; while 4/12 (33.3%) treated patients had no 

remaining dysplasia after therapy (p � 0.26), three of these patients had 

complete resolution of dysplastic changes after cetuximab therapy alone. 

Of these three patients, two have had no recurrence of leukoplakia or 

dysplasia at 1.5 and 2 years. One patient treated with oral cavity dysplasia 

has had no recurrence of dysplasia or lesions within the oral cavity, but 

developed a hypopharyngeal cancer at 1.5 years after trial completion. Of 5 

patients randomized to observation, three underwent crossover to cetuximab 

therapy, and two of these three patients had complete resolution of 

dysplasia. Conclusions: EGFR blockade with cetuximab alone can result in 

significant, durable, and complete clinical and histological resolution of 

moderate to severe dysplasia in at least a subset of high risk patients. 


12:00 PM-1:00 PM 

The influence of institutional head and neck cancer (HNC) clinical trial 

accrual on overall survival (OS): An analysis of RTOG 0129. Presenting 

Author: Evan John Wuthrick, Ohio State University Medical Center-James 

Cancer Hospital, Columbus, OH 

Background: NCCN recommends HNC patients (pts) be treated by providers 

with experience in HNC management. Whether treatment by experienced 

providers (measured by no. of pts treated) is associated with HNC survival 

outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 

with stage III-IVa HNC with known tumor HPV and smoking status 

randomized to cisplatin concurrent with standard or accelerated fractionation 

radiotherapy (RT). Participating centers were stratified into pt accrual 

tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for 

experience, we investigated the independent effect of AT on OS and 

progression-free survival (PFS) in multivariable cox proportional hazards 

models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In 

Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT 

(low accruing centers [LAC]) were similar and compared to the upper AT 

(high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 

pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N 

stage, comorbidities and study arm assignment (SAA), but pts at LAC had 

better performance status (PS)(Zubrod 0; 62% vs 52%; p�0.04), fewer T4 

tumors (27% vs. 35%; p�0.05) and were more likely uninsured (12% vs 

4%; p�0.009). Compared to HAC, LAC pts had significantly worse OS, (5 

yr 51.0% vs 69.1%; p � 0.002), and PFS (5 yr 42.7% vs 61.8%; p � 

0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p �0.001). 

Treatment at LAC was associated with ~90% increase in risk of death (OS 

HR 1.91, 95%CI 1.37-2.65) and progression (PFS HR 1.89, 95%CI 

1.39-2.56) when compared to pts treated at HAC, after adjustment for age, 

PS, pack-years, T and N stage, SAA and HPV status. Acute and chronic 

toxicities, RT dose, fractions, and treatment duration did not differ for pts 

at LAC vs HAC. RT at LAC was more likely than HAC to differ from protocol 

(18% [16.8% acceptable variation {AV}, 1.2% unacceptable deviation 

{UD}] vs 6% [4.7% AV, 1.3% UD]; p�0.001). Conclusions: Pts with HNC 

treated at LAC in RTOG trials were associated with significantly worse 

survival outcomes compared to pts treated at HAC. 


363s 


12:00 PM-1:00 PM 

Prognostic significance of the AJCC staging in patients with squamous cell 

carcinoma of the oropharynx. Presenting Author: Carlos Rodrigo Acevedo- 

Gadea, Yale University School of Medicine, New Haven, CT 

Background: There have been significant changes in the epidemiology of 

head and neck squamous cell carcinomas (HNSCC), with an increase in the 

incidence of oropharyngeal (OP) cancer and opposite effect in other sites. 

Since the rise in OP cancer incidence is attributed to human papillomavirus 

(HPV), which is associated with a different biology and clinical behavior, we 

evaluated whether the current AJCC system retained its prognostic impact 

in this patient population. Methods: The Surveillance Epidemiology and 

End Results (SEER) registry was queried for patients with HNSCC diagnosed 

between 2004 and 2007. Overall survival (OS) was estimated by the 

Kaplan-Meier method and the Cox model was used to compare the survival 

curves for each AJCC stage. Patients were grouped into three anatomical 

locations: oral cavity (OC), larynx (L) and OP. Results: There were 26,520 

patients meeting eligibility criteria, including 8622 OP, 7332 OC, and 

10566 L. The AJCC staging retained its prognostic significance across all 

stages for patients with HNSCC of the OC and L. Patients with OP cancer, 

however, had similar 4-year survival for stages I through IVA, whereas stage 

IVB and IVC had a significantly decrease survival compared to IVA and IVB 

respectively (Table). Conclusions: The OS for stages III and IVA OP cancer is 

similar to those with stages I and II, in an effect that may be attributed to 

the increased frequency of HPV in this population, rendering the tumors 

more sensitive to chemotherapy and radiation. Therefore, the AJCC stage in 

OP cancer may be more useful in guiding the therapy than as a prognostic 

factor. 

4-year OS according to tumor site and stage. 

Oral cavity Larynx Oropharynx 

I 72.9% 71.6% 62.4% 

II 59.3% Vs I (HR 1.91, 64.0% Vs I (HR 1.51, 57.7% Vs I (HR 1.14, 

p � 0.001) 

p � 0.001) 

p � 0.22) 

III 44.5% Vs II (HR 1.51, 48.9% Vs II (HR 1.68, 67.2% Vs II (HR 0.81, 

p � 0.001) 

p � 0.001) 

p � 0.017) 

IVA 33.9% Vs III (HR 1.49, 39.3% Vs III (HR 1.29, 63.9% Vs III (HR 1.16, 

p � 0.001) 

p � 0.001) 

p � 0.014) 

IVB 27.2% Vs IVA (HR 1.46, 23.1% Vs IVA (HR 1.85, 42.6% Vs IVA (HR 1.99, 

p � 0.001) 

p � 0.001) 

p � 0.001) 

IVC 12.0% Vs IVB (HR 1.74, 16.6% Vs IVB (HR 1.28, 22.2% Vs IVB (HR 2.14, 

p � 0.001) 

p � 0.027) 

p � 0.001) 


12:00 PM-1:00 PM 

Outcomes of HIV patients treated with chemoradiotherapy (CRT) for 

squamous cell carcinoma of the head and neck (SCCHN). Presenting 

Author: Waleed F Mourad, Beth Israel Medical Center, New York, NY 

Background: SCCHN with HIV is a challenging clinical situation in the 

medical arena due to limited data. We report our outcomes and the impact 

of chemotherapy (CT) and HPV on this patient (pt) population Methods: This 

is a single institution retrospective study of 71 HIV pts with SCCHN treated 

from 1998-2011. The median age at RT and HIV diagnosis was 51 (32-72) 

and 34 (25-50) respectively. HIV duration was 11 yrs (6-20). Stage I-II, III 

and IV were 22, 27 and 51% respectively. Pts treated with RT alone were 

37% and CRT 63% {CDDP 91%}. Fifty pts were on HAART during 

treatment and 50% of pts with SCC of the oropharynx were HPV�. Median 

dose of 70, 63 and 54 Gy were delivered at 1.8-2 Gy/fraction to gross 

disease, high and low risk neck respectively. Twelve pts (17%) underwent 

neck dissection for N3 Results: With a median follow up of 50 months 

(12-140) the median weight loss was 20 lbs (6-40). Acute skin desquamation 

and mucositis grades � 2 and 3 were 76 and 24% respectively. 

Treatment breaks � 10 and 5 days were 7 and 21% respectively. One pt 

died from induction CT, 1 was hospitalized for grade 4 mucositis and 1 

developed osteoradionecrosis during CRT. Late dysphagia grades � 2, 3 

and 4 were 74, 15 and 11%. Late xerostomia grades � 2 and 3 were 77 

and 23% respectively. The median CD4 count and viral load before, during 

and after treatment were 370, 135, 100 and 0, 160, 260 respectively. 

Seven pts (10%) developed second primary malignancy. The 4 yr locoregional 

control (LRC) and overall survival (OS) were 69% and 55% 

respectively. Chi-square test shows significant relationship between LRC 

and RT duration, as well as between CT and lower CD4 counts and higher 

viral load (P�0.001). Positive trends were observed between (weight loss 

�10% and LRC) and (absence of second malignancy and OS) (P�0.271). 

There was no significant relationship between HPV �ve or CT on either LRC 

or OS. Conclusions: The addition of CT to RT yielded higher morbidity and 

mortality without clear benefit on LRC or OS. HIV per se seems to have a -ve 

impact on HPV �ve pts outcomes. Comparing observed rates of LRC and 

OS, our data show that RT�CT administered for HIV �ve pts with SCCHN 

appears to be less effective than HIV-ve pts. Larger size studies are 

warranted to optimize the management of this growing patient population. 




12:00 PM-1:00 PM 

Influence of extracapsular extension on lymph node staging for patients 

with squamous cell carcinoma of the head and neck. Presenting Author: 

Megan Ann Baumgart, Yale University School of Medicine, New Haven, CT 

Background: Although extracapsular extension (ECE) is a known poor 

prognostic factor in head and neck squamous cell carcinoma (HNSCC) and 

recommended to be collected by the current AJCC manual, it currently does 

not influence the final stage. We evaluated the prognostic impact of ECE in 

4 primary sites. Methods: The Surveillance Epidemiology and End Results 

(SEER) was queried for patients with squamous cell cancers of the oral 

cavity (OC), oropharynx (OP), hypopharynx (H) and larynx (L), known ECE 

status, M0, and diagnosed between 2004 and 2007. Survival curves were 

estimated by the Kaplan-Meier and compared by Cox proportional hazards 

models. Results: There were 23,384 patients meeting eligibility criteria, 

including 14,664 (62.7%) N0, 6483 (27.7%) N� without ECE (NECE), 

and 2237 (9.6%) with ECE. ECE was associated with decreased 3-year 

overall survival (OS), compared to NECE, for all lymph node stages 

including N1 (52% vs 61%, HR 1.32, p � 0.001), N2a (60% vs 76%, HR 

1.82, p�0.001), N2b (44% vs 62%, HR 1.62, p�0.001), N2c (34% vs 

47%, HR 1.43, p�0.001), N3 (31% vs 44%, HR 1.38, p�0.012). ECE 

was also an independent poor prognostic factor for cancer in the OC (HR 

1.43, p � 0.001), OP (HR 1.44, p � 0.001), H (HR 1.58, p � 0.01), and 

L (HR 1.28, p � 0.01). The comparison between ECE and NECE with one 

additional N degree showed no significant OS difference, except OP N1 and 

H N2a ECE, where survival was inferior to OP N2a and H N2b NECE 

respectively (Table). Conclusions: ECE is a significant predictor for poor 

outcomes in HNSCC, with survival equivalent to one additional degree of N 

involvement. 

N2a NECE vs 

N1 ECE 

N2b NECE vs 

N2a ECE 

N2c NECE vs 

N2b ECE 

N3 NECE vs 

N2c ECE 

Oral cavity 

(n�1,886) 

HR 1.19 (0.78-1.8; 

p�0.423) 

HR 0.77 (0.45-1.31; 

p�0.337) 

HR 0.96 (0.71-1.29; 

p�0.765) 

HR 0.98 (0.60- 1.62; 

p�0.950) 

Oropharynx 

(n�4,821) 

0.42 (0.30- 0.60; 

p��0.0001) 

0.85 (0.58-1.23; 

p�0.392) 

1.22 (0.95-1.56; 

p�0.124) 

0.72 (0.50-1.03; 

p�0.073) 

Hypopharynx 

(n�687) 

0.69 (0.38-1.23; 

p�0.208) 

0.57 (0.34-0.98; 

p�0.040) 

1.35 (0.83-2.20; 

p�0.222) 

0.96 (0.47-1.98; 

p�0.920) 

Larynx 

(n�1,346) 

1.30 (0.73-32; 

p�0.364) 

0.63 (0.35-1.12; 

p�0.113) 

0.81 (0.57-1.15; 

p�0.232) 

1.09 (0.66, 1.78; 

p�0.738) 


Phase II study of biweekly dose-intense docetaxel plus gemcitabine 

(GEM/DOC) in patients with recurrent locoregional or metastatic head and 

neck squamous cell carcinoma. Presenting Author: Ammar Sukari, Karmanos 

Cancer Institute, Detroit, MI 

Background: Patients with metastatic head and neck squamous cell 

carcinoma (HNSCC) have a poor prognosis, limited treatment options, and 

median survival of 6 to 9 months. Docetaxel and gemcitabine have both 

shown activity in HNSCC. The optimal combination, dosing, and scheduling 

of both drugs is, however, unknown. Thus, we investigated the efficacy 

and safety of biweekly dose intense GEM/DOC in patients with recurrent 

locoregional or metastatic HNSCC. Methods: An open-label, singleinstitution, 

single-arm, phase II study was conducted for patients who were 

previously treated with no more than two cytotoxic regimens. The patients 

received docetaxel (60 mg/m2IV) and gemcitabine (3000 mg/m2 IV) on day 

1. The treatments were repeated every 14 days (one cycle), until disease 

progression or unacceptable toxicity. The primary end point was response 

rate. RECIST-defined response was evaluated every 4 cycles and toxicities 

were evaluated at each cycle. Results: A total of 36 patients were enrolled 

(M:F 26:10; median age (range), 60 years (46-79); performance status 

0-1) , 29 of whom were response-evaluable. The patients received a 

median of 4 cycles (range 0-24). Of these 29 patients, none achieved 

complete response (CR) and 6 demonstrated a partial response (PR). Thus, 

the overall response rate was 21% (95% confidence interval [CI], 0.10 – 

0.38). Ten patients had stable disease (SD), resulting in tumor control (CR 

or PR or SD) in 16 of 29 patients (55%), whereas 13 patients (45%) had 

disease progression. The median response duration was 3.2 months (80% 

CI: 2.0 – 6.1 months). For all 36 patients, the median overall survival was 

4.2 months (95% CI: 2.4 – 7.0 months). Myelosuppression was the most 

common adverse event. Grade 3-4 neutropenia and anemia were observed 

in 10 (30%) and 13 (39%) patients, respectively. None of these patients, 

however, had febrile neutropenia or bleeding events, and there were no 

treatment-related deaths. Conclusions: The combination of biweekly dose 

intense GEM/DOC was tolerable and active regimen in patients with 

recurrent locoregional or metastatic HNSCC. Our findings warrant further 

investigation in a larger patient population. 


Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): 

Analysis of African American patients. Presenting Author: David N. Hayes, 

UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 

Background: Previous retrospective analyses show poor outcomes for 

African American (AA) patients with head and neck carcinoma (HNC). Such 

racial disparities are not well understood, but patient (pt) demographics, 

comorbidities, tumor site, and human papillomavirus (HPV) status are 

suggested to play a role. Methods: The LORHAN registry was used to 

identify pts �18 yrs of age with de novo, non-metastatic HNC, and a record 

of survival time. This study evaluated pt and treatment characteristics by 

race, and conducted adjusted Cox regression analyses of overall survival 

(OS) and progression-free survival (PFS) to identify prognostic factors and 

interactions, and estimate hazard ratios (HRs) of AA vs. non-Hispanic white 

(NHW). Results: Baseline pt characteristics (see table below). The median 

OS/3-yr rate was 41.7 mo/51% in AA vs. 52.9 mo/70% in NHW, 

(age-adjusted HR: 1.73 [95% CI: 1.45, 2.08]). The median PFS/3-yr rate 

was 29.6 mo/43% in AA and 49.9 mo/62% in NHW, (age-adjusted HR: 

1.64 [95%CI: 1.40, 1.93]). Multivariate analysis of OS and PFS showed 

that AA race, stage III and IV, PS 2, and smoking were significantly 

associated with a worse HR, while OP demonstrated a favorable HR over 

other sites. Significant interaction tests led to subgroup analyses for OS 

showing an elevated risk in AA with OP (HR: 2.62 [95%CI: 1.95, 3.52]) 

and similar risk elevations in male AA as well as in AA with PS 0-1 when 

compared to NHW in the corresponding subgroups. Conclusions: Controlling 

for other factors like PS and smoking, a worse prognosis was seen in AA 

males with OP localized SCCHN. Further investigation to improve the 

outcomes in this population is warranted. 

AA 

n�385 

NHW 

n�2,733 p value 

Age Yrs, mean (SD) 58.9 (10.1) 59.8 (10.8) 0.13 

Sex Male 295 (76.6%) 2,143 (78.4%) 0.43 

Smoking Yes 341 (88.6%) 2,133 (78.1%) �0.0001 

Alcohol Yes 331 (86.0%) 2,278 (83.4%) 0.19 

Site Hypopharynx 32 (8.3%) 102 (3.7%) �0.0001 

Larynx 134 (34.8%) 549 (20.1%) 

Oral cavity 43 (11.7%) 439 (16.1%) 

Oropharynx (OP) 143 (37.1%) 1,290 (47.2%) 

Stage I, II 155 (41.5%) 1,399 (52.1%) �0.0001 

III, IV 218 (59.3%) 1,284 (47.8%) 

PS 0, 1 308 (80.4%) 2,496 (91.7%) �0.0001 

HPV test in OP 

patients only 

Completed 21 (25.3%) 194 (24.1%) 

HPV result in OP 

patients only 

Pos 8 (38.1%) 159 (82.4%) �0.0001 


An open-labeled, multicentric clinical study of cetuximab combined with 

intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy in 

locoregionally advanced (LA) nasopharyngeal carcinoma (NPC): A 2-year 

follow-up report. Presenting Author: Chun-yan Chen, Cancer Center, Sun 

Yat-sen University, Guangzhou, China 

Background: To evaluate the safety and efficacy outcomes of concurrent 

cetuximab plus IMRT and cisplatin in Chinese patients with LA NPC. 

Methods: Patients with primary stage III-IVb (UICC/AJCC 2002 staging 

system) and non-keratinizing NPC were enrolled in this prospective, 

multicentric, phase II study. Cisplatin (80mg/m2 ,q3week) and cetuximab 

(400mg/m2 one w before radiation, and then 250mg/m2 /w) were given 

concurrently. The prescription dose of IMRT to GTVnx (primary tumor in 

nasopharynx) was 66 Gy - 75.9 Gy, GTVnd (positive cervical lymph nodes) 

was 60 Gy - 70Gy, The response rate was evaluated according to RECIST 

1.0 criteria, and adverse events (AEs) were graded according to NCI CTCAE 

V3.0 criteria. Results: From July 2008 to April 2009, 100 patients were 

enrolled (74 male), with median age of 43 years. The proportion of stage 

III, IVa and IVb patients were 71%, 22% and 7% respectively. 99% of 

enrolled patients completed the planned treatment. AEs were within the 

expected range and manageable. No toxic death occurred during the 

treatment. Acneiform skin eruptions, mucositis, in-field dermatitis, xerostomia 

and neucopenia were the most common seen AEs, with 64% grade 2/3 

acneiform eruptions, 26% grade 2/3 in-field dermatitis, 90% � grade 2 

mucositis (2 cases of grade 4 mucositis with spontaneous bleeding), 40% 

� grade 2 xerostomia and 8% grade 2/3 neucopenia. With a median 

follow-up time of 23.5 months, the 2 year overall survival (OS), disease-free 

survival (DFS), local recurrence-free survival, regional (cervical lymph 

node) recurrence free survival and distant metastasis-free survival rates for 

the ITT population were 91%, 89%, 90%, 90% and 89%, respectively 

Multivariate analysis showed that N stage was the only prognostic factor for 

OS (p�0.0392, HR�2.946) and DFS (p�0.0062, HR�4.246) in these 

patients. Conclusions: Cetuximab combined with IMRT plus concurrent 

cisplatin in patients with LA NPC shows satisfactory 2-year locoregional 

control rate and 2-year overall survival. The combination seems to be well 

tolerated with a manageable side-effect profile. 



Gingival cancer: 11 year follow-up at Karolinska University Hospital (2000- 

2010). Presenting Author: Rusana Simonoska, Department of ENT, Karolinska 

Institutet/Karolinska University Hospital, Stockholm, Sweden 

Background: In Sweden, approximately 500-600 cases of oral cancer are 

diagnosed every year. These include cancer of the gingiva, retromolar 

trigonum, bucca, hard palate, tongue and floor of the mouth. Each year, 

around 15 cases of gingival cancer (GC) are diagnosed in the Stockholm 

region. The goal of this study was to study the onset of symptoms, 

treatment, prognosis, and sequelae of GC in order to optimize the 

treatment. Methods: The study consists of a retrospective review of medical 

records of all diagnosed cases of GC in Stockholm region between 

2000-2010, identified through the ENT-clinic Karolinska Hospital patient 

database. Results: Our retrospective study comprised 156 patients diagnosed 

with GC. The average age was 72 years sharing equally between the 

sexes, 50% were smokers. 98% had a squamous cell carcinoma (scc). 

Presenting symptoms were often lump or ulceration in the gums, pain, 

bleeding or discomfort/misfit of dentures. Around 30% had premalignant 

lessons in the oral cavity before diagnosis. 3/4-th of all GC was localized in 

the lower jaw. 66% of the GC-patients presented as aT4 cancer. At 

presentation, 26% had a regional metastasis and of those 90% had their 

primary tumor in the lower jaw. Six cases had bilateral neck disease. 81% 

of the patients with regional metastasis had low to medium grade of scc 

differentiation of the primary tumor. 84% of all patients with regional 

metastasis had a T4 primary tumor. Neck dissection was performed in 38% 

(n�59). Of these 35 cases where staging neck, i.e. N0 at presentation and 

in 7 cases (20%) a positive neck disease was found. The risk for second 

primary was 15%. The overall 5-year survival was 24%. Conclusions: 

Advanced age and high number of T4 cancer at diagnosis partly explains 

the poor survival statistics. Almost 30% of the patients in our material have 

had premalignant lessons in the oral cavity before the cancer diagnosis and 

are at high risk for new tumors (second primary); therefore patients with GC 

should be followed up for at least 5 years, possibly longer in the presence of 

premalignant lessons. GC of the lower jaw is more likely to metastasize than 

GC of the upper jaw. Due to 20% occult metastasis occurrence in the 

staging neck cases, we recommend staging neck dissection for patients 

with GC. 


A phase II study of sorafenib in combination with cisplatin and 5-fluorouracil 

in the treatment of recurrent or metastatic nasopharyngeal carcinoma. 

Presenting Author: Cong Xue, Sun Yat-sen University Cancer Center, 

Guangzhou, China 

Background: Nasopharyngeal carcinoma (NPC) is a disease with distinctive 

epidemiology and clinical behavior compared with Head and neck cancer 

(HNC) and more common in South-East Asia. Sorafenib monotherapy has 

been shown modest anticancer activity in HNC and NPC (C Elser et al; JCO 

2007). This study was to evaluate the efficacy and tolerability of sorafenib 

combined with cisplatin and 5-fluorouracil (5-FU) for patients with recurrent 

or metastatic NPC. Methods: A phase II, single arm clinical trial was 

conducted in three centers in China. Chemotherapy-naive histologically 

confirmed NPC patients with recurrent or metastatic disease were enrolled. 

Patients received oral sorafenib 400mg bid continuously until disease 

progression or unacceptable toxicity, cisplatin 80mg/m2 intravenously (iv) 

on day 1-5, and 5-FU 400mg/m2 iv infusion for 96 hours on day 1. 

Treatment was repeated every 21 days for a maximum of 6 cycles. Results: 

54 patients were enrolled. Most patients were with bone metastases 

(70.0%), followed by liver (56%) and lung metastases (56%). The median 

chemotherapy administrated was 4.0 cycles (range, 2-6cycles). The 

disease control rate (DCR) reached 90.7%, including one complete 

response (CR), 41 partial responses (PR) and 7 stable diseases (SD). 

Median PFS was 7.2 months (95% CI 6.8-8.4 months) and median OS was 

11.8 months (95% CI 10.6-18.7 months). Tumor cavitation after treatment 

was observed in 32.1% of patients with lung metastases. Decreased 

percentage of contrast update in responder patients (PR and CR) with liver 

metastases was also observed by Contrast-Enhanced Doppler ultrasound. 

The major toxicities include hand foot syndrome (HFS), myelo-suppression 

and gastrointestinal reaction.Dose reduction of sorafenib was required in 

22 patients (40.7%) and dose interruption in 14 patients (25.9%) because 

of toxicity. Conclusions: Sorafenib combined with cisplatin and 5-FU has an 

encouraging efficacy profile with tolerable toxicity. Further randomized 

studies are needed to confirm the clinical benefit of sorafenib combined 

with chemotherapy in recurrent or metastatic NPC. 


365s 


Efficacy of concurrent cetuximab (C225) versus 5-fluorouracil/carboplatin 

(5FU/CBDCA) or cisplatin (CDDP) with intensity-modulated radiation 

therapy (IMRT) for locally advanced head and neck cancer (LAHNSCC). 

Presenting Author: Lauren Quinn Shapiro, Memorial Sloan-Kettering Cancer 


Background: We reported inferior outcomes for LAHNSCC patients (pts) 

that received concurrent C225 vs. high-dose CDDP with IMRT (IJROBP 

2011; 81:915). Prior to FDA approval of C225 for LAHNSCC, non-CDDP 

candidates at our institution were treated with 5FU/CBDCA (JNCI 1999; 

91:2081). The purpose of this study was to compare the outcomes of 

concurrent C225 vs. 5FU/CBDCA vs. CDDP with IMRT for LAHNSCC. 

Methods: Retrospective review of records was performed for pts treated at 

MSKCC with concurrent C225 (n�49) vs. 5FU/CBDCA (n�52) vs. highdose 

CDDP (n�259) and IMRT from 11/02 to 04/08. Overall survival (OS), 

locoregional failure-free survival (LRFS), and late toxicity for all pts and 

oropharyngeal subset were obtained. Outcomes were analyzed using 

univariate/multivariate Cox proportional hazards model or competing-risks 

analysis. Multivariate OS analysis was confirmed by propensity score 

adjustment. Results: Pts were similar with regard to site, overall stage, and 

alcohol/tobacco history. Compared to pts treated with CDDP, those who 

received C225 or 5FU/CBDCA were older, with lower performance status, 

higher Charlson score, higher T stage, and worse renal function. With 

median follow-up of 53.1 months for survivors, the 4-year OS was 40.9% 

(95% CI 26.0-55.2%) for C225 vs. 70.2% (95% CI 55.5-80.9%) for 

5FU/CBDCA vs. 86.9% (95% CI 82.0-90.6%) for CDDP. Compared with 

CDDP, C225 (hazard ratio [HR] 4.01, p�0.0001) but not 5FU/CBDCA (HR 

1.54, p�0.15) was associated with worse OS on multivariate analysis. 

Propensity score analysis yielded a HR of 2.76 (p�0.01) for treatment with 

C225 vs. platinum-based chemotherapy. 4-year actuarial LRF for 5FU/ 

CBDCA was similar to CDDP (9.7% vs. 6.3%, HR 1.51, p�0.42 by Gray’s 

method) and significantly lower than C225 (40.2%, HR 4.95, p�0.002). 

Late toxicity was as follows: C225 (6.1%) vs. CDDP (7.7%) vs. 5FU/CBDCA 

(21.2%). Conclusions: After adjusting for independent risk factors, there 

was no significant difference in OS or LRFS between 5FU/CBDCA and 

high-dose CDDP, but C225/RT resulted in significantly inferior OS and 

LRFS. Late toxicity was worst with 5FU/CBDCA. 


Patterns of care in elderly patients with squamous cell carcinoma of the 

head and neck: A SEER-Medicare analysis. Presenting Author: Noam 

Avraham Vanderwalde, Department of Radiation Oncology, University of 


Background: Head and neck squamous cell carcinoma (HNSCC) is predominantly 

a disease of the elderly, however age and co-morbidity may affect 

therapy decisions. The purpose of this study was to assess the patterns of 

care of elderly HNSCC patients and identify factors associated with 

non-receipt of surgery and chemoradiation (CRT). Methods: Using the 

Surveillance, Epidemiology, and End Results (SEER)-Medicare linked 

database (1992-2007) we identified a retrospective cohort of nonmetastatic 

HNSCC patients and categorized them into treatment cohorts. 

Comparisons were made between surgery vs. non-surgery, and CRT vs. 

non-CRT cohorts. Multivariate logistic regression models examined factors 

associated with non-receipt of treatment. Variables included tumor location, 

stage, year of diagnosis, age, gender, marital status, race, comorbidity, 

race-comorbidity interaction, SEER region, socioeconomic variables, 

and hospital affiliations. Results: The final cohort of 11,336 were 63% 

male and 83% white. 52% had no co-morbidities, 44% had oral cavity 

HNSCC, 52% were diagnosed between 2002 and 2007, 58% had surgery, 

and 21% received CRT. For the CRT vs. non-CRT model, increasing age 

(OR � 0.93; 95% CI 0.92 -0.94) and non-whites with co-morbidity (OR � 

0.71; 95% CI 0.55 – 0.92) were associated with decreased likelihood of 

receiving CRT. More advanced staged disease, oropharyngeal tumor location, 

and diagnosis after 2002 were associated with increased likelihood of 

receiving CRT. For the surgery versus non-surgery model, age was not 

associated with receipt of surgery (OR 0.99; 95% CI 0.99-1.00), nor was 

existence of comorbidity in white patients (OR 0.97; 95% CI 0.88-1.05). 

However, recent year of diagnosis, non-oral cavity tumor location, and 

advanced stage were all associated with reduced likelihood of receiving 

surgery. During the 15 year surveillance period, patients were less likely to 

receive surgery, and CRT was used more often. Conclusions: Age may 

influence the non-receipt of CRT in this elderly cohort but does not appear 

to be significantly associated with the non-receipt of surgery. There has 

been an increasing trend in the receipt of CRT with a decrease in surgery 

over the past 15 years. 




Prevalence, trends, and survival impact of human papillomavirus on 

oropharyngeal cancer in Indian population. Presenting Author: Ankur Bahl, 

Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of 

Medical Sciences, New Delhi, India 

Background: Among oropharyngeal squamous cell carcinoma (OSCC), the 

true prevalence of HPV remains variable and studies have estimated that up 

to 60% may be HPV positive. Patients with HPV positive tumor are 

usuallyyounger in age, less likely to have history of tobacco or alcohol 

consumption and associated with a better prognosis but this information for 

Indian patients is largely unknown. Methods: 105 newly diagnosed patients 

of OSCC were enrolled. HPV genotyping was done on the biopsy specimen 

by consensus polymerase chain reaction and reverse line-blot hybridization 

assay. HPV prevalence was studied according to gender, age, tobacco and 

alcohol use and high risk sexual behavior. Results: Overall HPV prevalence 

was 22.8%. HPV positive patients were younger by 8 years as compared to 

negative patients (P�0.003). No significant correlation between tobacco 

consumption, alcoholic habits, and HPV status was observed. The mean 

number of life time sexual partners in HPV positive patients was 1.66 

while, it was 1.33 in HPV negative patients (P�0.049). Incidence of high 

risk sexual behaviors was more in HPV positive patients (P�0.001). There 

were no significant associations between the two groups with respect to 

tumor size, nodal stage and the overall stage of the tumor. 16% of the base 

of tongue cancers and 40% of tonsillar carcinoma were positive (P � 0.02). 

Among positive samples, HPV 16 was the commonest (79%) followed by 

HPV 18 (12%). 96% of patients received treatment. At 18.8 months there 

was no significant difference in OS, EFS between HPV positive and negative 

OSCC (P � 0.97 and P� 0.51 respectively). Conclusions: The current study 

reconfirms that HPV positive OSCC patients are younger with high risk 

sexual behavior. Impact of smoking and alcohol consumption on HPV 

status was not found in this study. HPV positive rates were significantly 

higher for tonsillar cancer. Contrary to literature, we did not find any 

differences in OS or EFS between two groups. Small numbers of patients in 

the study group, short follow up period and significant tobacco smoking in 

HPV group may be the one of the reason for this. 


Phase II trial of chemoradiotherapy concurrent with S-1 plus cisplatin in 

patients with unresectable, locally advanced squamous cell carcinoma of 

the head and neck (SCCHN): Results of the Japan Clinical Oncology Group 

study, JCOG 0706. Presenting Author: Makoto Tahara, National Cancer 


Background: To evaluate the efficacy and safety of chemoradiotherapy 

(CRT) concurrent with S-1 plus cisplatin in patients with unresectable 

locally advanced SCCHN. Methods: Eligibility criteria included histologically 

proven SCCHN with unresectable locally advanced lesions, PS 0-1, 

aged 20 to 75 years old, adequate organ function, and no prior treatment. 

Chemotherapy consisted of administration of S-1 twice daily on days 1-14 

at 60 mg/m2 /day, and cisplatin at 20 mg/m2 /day on days 8-11, repeated 

twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions 

was given concurrently startingon day 1. For patients achieving an objective 

response after CRT, two additional cycles of chemotherapy wereadministered. 

The primary endpoint was clinical complete response rate (%CR), 

which was the proportion of complete response (CR) and good partial 

response (good PR). Good PR was defined as remaining tissue with tumor 

shrinkage, which was not regarded as residual tumor but rather as scar 

material.The planned sample size was 45 patients, which was calculated 

by SWOG’s two-stage attained design based on an expected %CR of 60% 

and a threshold of 45%, with a one-sided alpha of 0.1 and a power of 0.9. 

Results: From July 2008 to July 2010, 45 eligible subjects were accrued, 

including 43 males, with median age 63 years, ECOG PS 0/1 (36/9), 

oropharynx/ hypopharynx/larynx (26/15/4), T1/T2/T3/T4a/T4b (1/11/7/ 

17/9) and N0/N2a/N2b/N2c/N3 (2/3/10/24/6). %CR was 64.4% (8 CR, 

21 good PR) on central review. After a median follow-up of 1.56 years, 

1-year local progression-free survival was 77.8%, with 1-year progressionfree 

survival of 70.9%, 1-year overall survival of 93.3% and 1-year time to 

treatment failure of 57.6%. Grade 3 or 4 toxicity included mucositis 

(46.7%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis 

(26.7%), neutropenia (26.7%) and febrile neutropenia (4.4%). No treatment-related 

deaths were observed. Conclusions: This combination showed 

promising efficacy with acceptable toxicities. Further investigation in a 

phase III trial is planned. 


Phase II trial of everolimus in patients with previously treated recurrent or 

metastatic squamous cell carcinoma of the head and neck (SCCHN). 

Presenting Author: Prakash Varadarajan, University of Texas Health Science 

Center at San Antonio, San Antonio, TX 

Background: The PI3K/Akt/mTOR pathway plays an important role in 

SCCHN pathogenesis and resistance to treatment. We conducted a phase II 

study of everolimus, an oral inhibitor of mTOR, in patients with refractory 

SCCHN. Methods: Patients with recurrent or metastatic SCCHN treated 

with at least 1 prior regimen, performance status (PS) 0-2, and adequate 

organ function, received everolimus 10 mg once daily orally. The primary 

endpoint was the disease control rate (DCR) defined as the proportion of 

patients with a complete response, a partial response, or stable disease. A 

two-stage design was followed. Cytokines were measured in plasma and 

serum at baseline and post treatment. Results: 9 patients were enrolled. 

Median age 63 years (range 51 - 82), Male/Female, 6/3, performance 

status 0/1/2, 2/5/1. Primary site: oropharynx (2), oral cavity (4), larynx (1), 

others (2). Median number of palliative therapies in the recurrent/ 

metastatic setting prior to study was 1 (range 1- 4). Median number of 

cycles of everolimus delivered was 1 (range 1-5). No objective responses 

were seen. One patient had stable disease that lasted 6 months but all 

other patients had progression as best response. DCR was 11%. Median 

progression-free survival was 40 days. Four patients have died due to 

disease progression. Grade 3 adverse events were infrequent: pain (2 

patients), anemia (2 patients), and 1 patient each with pruritus, hypertransaminasemia, 

hyponatremia, lymphopenia, and fatigue. No Grade 4 

toxicities were reported. Biomarker analysis in 2 patients with available 

post treatment samples showed reduced plasma levels of VEGF-A, Gro-�, 

and IL-17, after everolimus treatment, but no reduction was observed in 

the plasma levels of IL-6 and IL-8, two cytokines often associated with 

SCCHN disease progression. Conclusions: Everolimus as monotherapy was 

well tolerated but did not have sufficient activity in this setting. This phase 

II study did not meet the predefined primary endpoint in the first stage of 

accrual. 


Validation for a novel diagnostic standard in HPV-positive oropharyngeal 

squamous cell carcinoma. Presenting Author: Xiao-Jun Ma, Advanced Cell 

Diagnostics Inc, Hayward, CA 

Background: HPV testing is now widely advocated in the work up of 

oropharyngeal squamous cell carcinoma (OPSCC). The �gold standard� for 

oncogenic HPV detection is the demonstration of transcriptionally active 

high-risk HPV in fresh tumour tissue. For clinical utility, testing strategies 

have necessarily focused on formalin-fixed paraffin-embedded (FFPE) 

tissue, but this has been at the expense of reduced sensitivity and 

specificity for oncogenic HPV. This study evaluates a novel RNA-based in 

situ hybridisation test against the analytical gold standard; detection of 

high-risk HPV mRNA, derived from fresh frozen tissue samples, by 

quantitative reverse transcriptase polymerase chain reaction (qPCR). 

Methods: A tissue-microarray comprising FFPE cores from 79 OPSCC was 

tested using High Risk HPV RNAscope (Advanced Cell Diagnostics, USA) 

for HPV16, 18, 31, 33, 35, 52, and 58. Analytical accuracy and capacity 

for prognostic discrimination was determined by comparison with HPV RNA 

qPCR for HPV16, 18 and 33. Demographic and tumour parameters were 

compared by Chi-squared and Kruskal-Wallis tests. Test sensitivity and 

specificity were calculated against the standard. Kaplan–Meier survival 

estimates were constructed to assess prognostication. Results: High risk 

HPV RNAscope had sensitivity and specificity of 97% and 93% respectively 

(PPV 91%, NPV 98%) by comparison to the gold standard. Kaplan- 

Meier estimates of disease specific survival (DSS, p�0.002) and overall 

survival (OS, p�0.001) by RNAscope were similar to the gold standard 

(DSS, p�0.006, OS, p�0.002) and superior to p16 immunohistochemistry 

(IHC) or the combination of p16 IHC and DNA qPCR. Conclusions: We 

demonstrated that High Risk HPV RNAscope can be used to detect 

oncogenic HPV in FFPE OPSCC samples and has both excellent analytical 

and prognostic performance against the gold standard test for oncogenic 

HPV. These results raise the possibility that High Risk HPV RNAscope 

could be adopted as an ‘international standard’ test for OPSCC in clinical 

practice. As the oncology community approaches therapeutic de-escalation 

based on HPV status, such a reliable and efficacious test may have 

immediate application. 



A multi-institutional phase II trial of pazopanib monotherapy in advanced 

anaplastic thyroid cancer. Presenting Author: Keith Christopher Bible, 


Background: Pazopanib, an orally bioavailable multitargeted inhibitor of 

kinases including VEGF-R, demonstrated impressive activity in metastatic 

differentiated thyroid cancer (49% durable RECIST PRs) and promising 

preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its 

evaluation also as a candidate therapeutic in advanced ATC. Methods: A 

multicenter single arm phase II trial of 800 mg pazopanib daily was 

undertaken with the primary endpoint of RECIST response rate. The trial 

was designed such that there would be a 90% chance of detecting a 

response rate of �20% at the 0.10 significance level when the true tumor 

response rate is �5%. A pre-specified stopping rule designated that 

enrollment would cease unless 1 or more RECIST PRs�CRs were observed 

in the first 14 of 33 potential patients. Eligibility required informed 

consent, �18 years of age, performance status ECOG 0-2, systolic blood 

pressure (BP) �140 mm Hg and diastolic BP �90 mm Hg at entry, QTc 

interval �480 msecs, and measurable disease by RECIST criteria. Anatomical 

imaging and toxicity evaluations were required every 4 weeks. Results: 

Sixteen patients were enrolled. One patient withdrew prior to therapy, 

leaving 15 evaluable patients – 33.3% were male, with a median age of 66 

years (range 45-77); 11 of 15 patients had progressed through prior 

systemic therapy. Four patients required 1-2 dose reductions, with the 

most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension 

(13%) and pharyngolaryngeal pain (13%). Reasons for treatment 

discontinuation included: disease progression (12 pts), death on study due 

to a vascular event possibly related to treatment (1 pt.), and intolerability 

(radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). 

Although transient disease regression was observed in several patients, 

there were no confirmed RECIST tumor responses, triggering study closure 

at time of interim analysis. Two patients are alive with disease 9.9 months 

and 2.9 years post-registration; the remaining 13 died of disease. The 

median time to progression was 62 days and the median survival time was 

111 days. Conclusions: Pazopanib has poor single agent activity in 

advanced anaplastic thyroid cancer. 


The role of family caregiver in the head and neck cancer: Psychological 

distress and quality of life evaluation. Presenting Author: Mario Airoldi, San 

Giovanni Antica Sede Hospital, Turin, Italy 

Background: The family caregiver (FCG) has become a hot topic. This figure 

among head and neck cancer patients is still largely un-investigated; aim of 

our study was: 1) to describe in a more detailed way the role of FCG, 2) to 

evaluate quality of life (QoL) and psychological distress of FCGs and 

patients 3) to investigate relationships between FCG’s wellbeing and 

patient’s QoL and emotional pattern. Methods: Sixty couples of patients and 

their caregivers were enrolled in this observational cross-sectional study 

between April 2007 and May 2011 at 1st ENT Division, 2th Medical 

Oncology Division and 2th Radiotherapy Division of San Giovanni Battista 

Hospital of Turin. Inclusion criteria were: diagnosis of SCC, advanced stage 

(III-IV), completion of curative treatment and no evidence of disease at the 

enrolment. Psycho-oncological assessment was performed using: Distress 

Thermometer (DT), Stay-Trait Anxiety Inventory Manual in Y1 and Y2 form 

(STAI Y1-Y2), Beck Depression Inventory (BDI) and Montgomery-Asberg 

Depression Rating Scale (MDRS), EORTC-QLQ-C30 and Head and Neck-35 

module and Caregiver Quality of Life Index-Cancer (CQOLC). Results: 

Patients: state and trait anxiety are 46,7% (STAI Y1 mean value 40,2�10,2; 

cut-off 40) and 36,7% (STAI Y2 mean value 36,7�8,2; cut off 40) 

respectively; self reported and clinician rated depression are 31,6% (BDI 

mean value 8,2�5,3; cut-off 9) and 48,3% (MDRS mean value 7,9�5,9; 

cut-off 6) respectively.CGs: state and trait anxiety are 50% (STAI Y1 mean 

value 42,5�9,9; cut-off 40) and 41,7% (STAI Y2 mean value 39,1�8,7; 

cut off 40) respectively; self reported and clinician rated depression are 

28.3% (BDI mean value 7,3�4,7; cut-off 9) and 41.7% (MDRS mean 

value 7,6�5,8; cut-off 6) respectively.Data analysis underlined a positive 

association among emotional scales of patients and caregivers. Patients’ 

psychological aspects are negatively associated with caregivers’ QoL and 

vice versa. Conclusions: Anxiety and depression are often present in FCGs 

and cured HNC patients. Long term patient’s QoL is the result of a frail 

balance between FCG and patiet emotional and psychological distress. A 

psychological support for FCG could improve patient well-being. 


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A phase I study of everolimus (E) plus weekly cisplatin (CDDP) plus 

intensity-modulated radiation therapy (IMRT) in head and neck (HN) 

cancer. Presenting Author: Matthew G. Fury, Memorial Sloan-Kettering 


Background: The PI3K/mTOR/eIF4E pathway is upregulated in many HN 

cancers, and expression of eIF4E in surgical margins has been associated 

with increased risk of recurrence (Cancer Res 2007; 67:2160. Clin Cancer 

Res 2004; 10:5820. JCO 1999; 17:2909). Daily E � weekly CDDP was 

well tolerated in a phase I study for patients with advanced solid tumors 

(Cancer Chemother Pharmacol 2011 Sep 13; Epub ahead of print]. E 

achieves radiosensitization in pre-clinical models. This study evaluated 

weekly CDDP � daily E given concurrently with IMRT in HN cancer. 

Methods: This was a single institution phase I study with a standard 3 � 3 

dose escalation plan. Patients (pts) received standard definitive IMRT (66 

Gy resected tumors, 70 Gy unresected tumors) concurrent with CDDP 30 

mg/m2 weekly X 6 and daily oral E according to the dose escalation plan. 

Four dose levels (DLs) of daily oral E were planned: 2.5 mg, 5 mg, 7.5 mg, 

and 10 mg. Toxicities were recorded according to NCI CTCAE v.3. Results: 

Thirteen (9M, 4F) pts enrolled, with median age 52y (range, 37 – 65y) and 

median KPS 90 (range, 80-100). Primary sites: oral cavity (4), salivary 

gland (4), oropharynx (2), nasopharynx (1), scalp (1), unknown primary (1). 

Stage: IVA (11), IVB (1), II (1). Prior treatment: surgery (10), chemotherapy 

(2). The most common � G.3 treatment related AEs were mucositis 

(functional 62%, clinical 31%), oral pain (31%), and lymphopenia (31%). 

There were no DLTs among 3 patients at DL1 or the first 3 patients at DL2. 

Among 4 pts at DL3, there were 2 DLTs: grade 3 mucositis with failure to 

thrive, and grade 3 mucositis with hypoxia. Among 3 additional patients 

enrolled at DL2, there was one 1 DLT: grade 3 mucositis with inability to 

tolerate E. There were no treatment-related deaths. With a median 

follow-up of 8.9 months, 3 patients have experienced recurrent disease, 

one of whom has died of disease. Median PFS has not been reached. Tissue 

correlates in process. Conclusions: When administered with weekly CDDP 

(30 mg/m2 ) and definitive IMRT for HN cancer, the phase II recommended 

dose of E is 5 mg/day. 


Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with 

differentiated thyroid cancer (DTC). Presenting Author: Maria E. Cabanillas, 


Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET, 

VEGFR2, and RET that is currently undergoing evaluation in several 

oncology indications. Differentiated thyroid cancer (DTC) pts were included 

in this study based on involvement of the MET, VEGFR, and RET signaling 

pathways in this disease. The primary objective of this study is to determine 

the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone 

(rosi). Anti-tumor activity and safety were also evaluated. Methods: Metastatic 

DTC pts who were enrolled to this study were required to be 

RAI-refractory, have progressed on standard therapies and have measurable 

disease. Cabo was given daily at a dose of 140 mg free base 

(equivalent to 175mg salt form) starting at Day 2. Rosi (4mg) was given Day 

1 and Day 22 to complete PK assessment for drug-drug interaction (DDI). 

Cabo was continued until PD. On Day 57 and every 8 weeks thereafter 

subjects underwent tumor assessments by mRECIST. Results: 15 DTC pts 

were enrolled. Median number of prior regimens was 2 (11/15 pts had at 

least 1 prior VEGFR inhibitor). 8/15 pts (53%) had confirmed PRs 

including 1 pt with marked improvement of a bone infiltrating lesion; 6 

(40%) had best response of SD; all 14 pts with �1 post-baseline scan 

experienced tumor regression (range: -9 to -55%). Disease control rate (PR 

� SD): 80% at 16 weeks; 10/15 (67%) remain on cabo with a median 

follow-up of 7.3 months. Median PFS and OS have not been reached. Most 

common Gr 3/4 AEs were: diarrhea (20%), lipase increased (20%), 

hypertension (13%) and palmar-plantar erythrodyesthesia (13%); one 

related Gr 5 event reported: hemoptysis due to aorto-trachael fistula in a pt 

with history of prior mediastinal XRT and extensive neck surgeries. PK data 

suggest that clinically relevant doses of cabo do not alter the Cmax or 

AUC of rosi, consistent with no inhibition of CYP2C8. Conclusions: In 

0-24h 

pts with DTC, cabo treatment resulted in substantial anti-tumor activity. 

The safety profile of cabo was comparable to that seen with other VEGFR 

TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate). 




Recurrent/metastatic salivary gland malignancies (RMSGM): Final report of 

60 cases treated with cisplatin plus vinorelbine (DDP�VNB). Presenting 

Author: Fulvia Pedani, Department of Medical Oncology, San Giovanni 

Antica Sede Hospital, Turin, Italy 

Background: RMSGM are not amenable to the usual treatment with surgery 

and post-operative radiotherapy. The role of chemotherapy (CT) for RMSGM 

is palliative only. VNB showed moderate activity in our experience (Bull 

Cancer 85:892;1998) and in a randomized phase II trial we had demonstrated 

that the DDP�VNB combination had a better outcome than VNB 

alone (Cancer 91:541; 2001). In this abstract we report the final results of 

this combination in 60 cases. Methods: From April 2001 to February 2009 

, 60 cases with RMSGM were enrolled. All patients received the following 

regimen: DDP 80 mg/sm d.1 � VNB 25 mg/sm d. 1,8 every 3 weeks. The 

study foresees a maximum of 6 cycles. Results: Patients characteristics 

were as follows: 35 males (58%) and 25 females (42%).; median age: 56 

yrs (range 20-68); median ECOG PS: 1 (0-2); histology: adenocarcinoma 

15 (25%), adenoid cystic ca. 34 (57%), others 11 (18%); site of disease: 

local 30 (50%) , mts �/- local 30 (50%). Forty-two pts received DDP�VNB 

as first line CT (70%) while 18 pts (30%) had the combination as 

second-line CT (30%). After a median of 5 cycles of first line DDP�VNB 

responses were: 3 CR (7%), 10 PR (24%), 14 NC (33%) and 15 PD (36%). 

After a median of 4 cycles of second line CT responses were: 0 CR; 1 PR 

(5%), 6 NC (33%) 11 PD (62%). Median survival: 10 months (3-29) for 

first line CT ; 4 months (1-12) for second line CT. G3-4 toxicity: 

neutropenia (20%), anemia (12%), nausea/vomiting (12%) , peripheral 

toxicity (3%). Conclusions: DDP�VNB is an effective first line CT in 

RMSGM ; second line CT has a low palliative activity. Toxicity seems 

acceptable. This regimen could be suitable for an integration with new 

biologic target agents. 


Preoperative recombinant adenoviral human p53 gene combined with 

intensity-modulated radiation therapy in treatment of stage IV papillary 

thyroid carcinoma: A randomized clinical study. Presenting Author: Jingqiang 

Zhu, West China Hospital in Sichuan University, Chengdu, China 

Background: Most of stage IV papillary thyroid carcinoma (PTC) is initially 

unresectable due to invading surrounding structures, and is also commonly 

resistant to standard radio- or chemo-therapy. P53 gene therapy could 

increase tumor radiosensitivity and inhibit tumor angiogenesis. This study 

is to evaluate the benefits of pre-operative recombinant adenoviral human 

p53 gene (rAd-p53) combined with intensity-modulated radiation therapy 

(IMRT) in treatment of stage IV PTC. Methods: Forty-six patients with 

historically-diagnosed stage IV PTC, satisfying the inclusion criteria, were 

randomly assigned into two groups: experimental group (EG) control group 

(CG). EG received intratumoral injection of 2-4�1012 rAd-p53 viral 

particles (VP) per 3 days for 10 times and IMRT once per day for 28 days at 

a total dose of 65 Gy. CG received the same IMRT therapy. Once month 

after the combined treatment, patients were assessed for resectability. A 

radical surgery was performed on the patients with a resectable tumor. All 

the patients received standard I131 therapy 1-1.5 months after surgery or 

after the last IMRT. Results: EG including 25 cases, 19 females and 6 

males, had a radical surgery rate of 76% (19/25), one-year survival rate of 

96%, and no local recurrence and distant metastases for patients having a 

surgery. The tumors in six patients of EG were still unresectable. But all 

these six patients had a local partial response. The tissue sample analyses 

showed increased fibrous tissues, apoptotic cells, and increased Bax and 

p21 protein and mRNA levels. CG including 21 cases, 15 females and 6 

males, had a radical surgery rate of 47.6% (10/21), one-year survival rate 

of 81.0%, and distant metastatic rate of 20% (2/10) for patients having a 

surgery. The local partial response rate of unresectable patients in CG was 

72.7% (8/11). There were no changes in Bax and p21 protein and mRNA 

levels. The main side effects of rAd-p53 were self-limited fever, occurring 

in 24 of EG patients. Conclusions: Pre-perative rAd-p53 combinedwith 

IMRT in treatment of the stage IV PTC increases radical surgical rate and 

response rate, and improves long-term efficacy. 


Phase II study of temsirolimus and erlotinib in patients (pts) with 

recurrent/metastatic (R/M), platinum-refractory head and neck squamous 

cell carcinoma (HNSCC). Presenting Author: Julie E. Bauman, University of 

New Mexico, Albuquerque, NM 

Background: The Epidermal Growth Factor Receptor (EGFR) is a validated 

target in HNSCC. In R/M disease, primary or acquired resistance to 

anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/ 

Akt/mTOR pathway is an established resistance mechanism. We hypothesized 

that concurrent mTOR blockade may improve efficacy of anti-EGFR 

therapy and conducted this phase II study. Methods: We evaluated the 

combination of erlotinib 150 mg po daily and temsirolimus 15 mg IV 

weekly in pts with platinum-refractory R/M HNSCC and ECOG PS 0-2. The 

exact, single-stage phase II design had 80% power (5% significance level) 

to detect improvement in progression-free survival (PFS) from 2.3 to 4.4 

mos with 35 evaluable pts. Correlatives included determination of PIK3CA 

mutation (mut) status; p16, EGFR and PTEN expression; and immunomodulatory 

cytokine levels. Results: From Dec 2009 – Mar 2011, 12 pts 

enrolled. Six pts withdrew prior to first planned response assessment, due 

to toxicity (5) or death (1), prompting referral to the Data Safety and 

Monitoring Committee and early closure. Grade � 3 toxicities included 

fatigue (5), diarrhea (2), GI infection/peritonitis (2), dyspnea (2), HN 

edema (2), and neutropenia (1). Among 8 progression-evaluable pt, 

median PFS was 1.9 mos. Median OS was 4.1 mos. 4/12 tumors were 

p16(�); 4/10 were EGFR(�); 11/11 showed no PTEN expression. PIK3CA 

mut was present in 1/11; the mut(�) pt withdrew after 3 wk for 

diarrhea/peritonitis with minor response. There were no associations 

between tumor p16, EGFR or PTEN status and oncologic outcomes. Five of 

6 toxicity-related withdrawals occurred in p16(-) pts. Immunomodulatory 

cytokine levels in pre- and post-temsirolimus plasma did not significantly 

differ or associate with toxicity. Two pts with � 4.4 mos PFS were p16(-) 

and PIK3CA mut(-). Conclusions: The combination of erlotinib and temsirolimus 

was poorly tolerated in this population, with toxicities predominant in 

p16(-) pts. Although the sample size was small, this R/M cohort demonstrated 

lack of PTEN expression and 9% PIK3CA mut, justifying further 

investigation of PI3K/Akt/mTOR pathway inhibitors in selected HNSCC pts. 


Association of smoking status with p16 and cyclin D1 (CCND1) expression 

with clinical characteristics and overall survival (OS) in oropharyngeal 

squamous cell carcinoma (OSC). Presenting Author: Mei-Kim Ang, National 

Cancer Centre, Singapore, Singapore 

Background: Smoking-related head and neck cancer (HNC) is genetically 

different, with higher mutation rates compared with non-smokers (NS). 

Human papillomavirus (HPV)-positive (�) OSC has a superior prognosis 

independent of treatment. Among HPV� patients (pt), current or prior 

smokers (CS) have poor OS compared with NS. Expression of p16, a known 

HPV surrogate, and CYD1, a cell cycle marker often dysregulated in HNC, 

was evaluated with respect to smoking status and OS. Methods: Expression 

of p16 and CYD1 was assessed by immunohistochemistry in 108 OSC pt 

treated between 1999-2009, using cutoffs of �70% (p16�) and �10% 

(CYD1�) stained tumor cells. Associations between expression, clinical 

characteristics and OS were evaluated by Kaplan-Meier method and 

compared by log rank test. Hazard ratio (HR) for death was estimated using 

Cox models. Results: 31 pt (28.7%) were p16� and 80 pt (75.5%) were 

CYD1 negative(-). p16� pt were younger (median age 57 v 66 yrs, 

p�0.002), more likely female (35.5% v 15.2%, p�0.035), NS (51.6% v 

13.9%, p�0.001) with lower combined age-comorbidity score (ageCS) 

(p�0.003). CYD1� pt were older (median 66 v 57 yrs, p�0.015), more 

likely CS (81.5% v 48.1%, p�0.002) with higher ageCS (p�0.018). At a 

median f/u of 65.7 months, median OS was 57.3 months. p16� pt had 

better OS than p16- pt (median OS not reached (NR) v 22.3 mths, 

p�0.001). CYD1� pt had poorer OS than CYD1- pt (median OS NR v 17.7 

mths, p�0.001). On multivariable analysis p16 and CYD1 status were 

independently associated with OS (HR 0.412, p�0.045 and HR 4.06, 

p�0.011 respectively), independent of smoking status (HR 5.01, 

p�0.008), ageCS (HR 1.32 per 1 point increase, p�0.001) and stage. 

Strikingly, among NS, 5-year OS in p16� compared with p16- pt was 

100% vs 67% (p�0.001). In contrast, among CS, p16 status had no 

association with OS (HR 0.97, p�0.943), while CYD1 status and ageCS 

were independent predictors of death (HR 4.70, p�0.025 and HR 1.28, 

p�0.001 respectively). Conclusions: In OSC, NS with high p16 expression 

have excellent prognosis. Among CS, pt with fewer comorbidities and low 

CYD1 expression have better OS. p16 status was not prognostic in the latter 

group of patients. 



Response of chemoradiation therapy after induction chemotherapy failure 

in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). 

Presenting Author: Yoojoo Lim, Department of Internal Medicine, Seoul 

National University Hospital, Seoul, South Korea 

Background: Although induction chemotherapy (IC) for LA-HNSCC has 

shown high response rates, some patients do not respond to IC. Surgery has 

been the usual choice for the non-responding patients, but practically, not 

all of these patients are eligible for operation. The purpose of this study was 

to evaluate the efficacy of definitive radiation therapy (RT) for the HNSCC 

patients who failed IC. Methods: We have retrospectively analyzed the 

outcome of patients with LA-HNSCC who were initially treated with IC at 

Seoul National University Hospital between Jan. 2006 and Dec. 2010. 

Chemotherapeutic regimens used were 5-FU/cisplatin, docetaxel/5-FU/ 

cisplatin, and docetaxel/cisplatin with or without cetuximab. After IC, 

patients were treated with RT, concurrent chemoradiation (CCRT), or 

surgery, either alone or with postoperative RT. Treatment modality was 

chosen on multi-disciplinary basis of our institution. Response was 

evaluated using RECIST criteria. Results: A total of 225 LA-HNSCC 

patients treated with IC were analyzed. Median age was 54 (range 24-77). 

Primary tumor locations were oral cavity (39.5%), nasal cavity/paranasal 

sinus (13.1%), oropharynx (13.1%), nasopharynx (13.1%), larynx (7.9%) 

and hypopharynx (13.1%). Among the 225 patients, 38 (16.9%) patients 

did not respond to IC [stable diseases (SD) � 23 (10.2%), progressive 

disease (PD) � 15 (6.7%)], and their median overall survival was 14.5 

months. Among the 38 non-responders, 14 (36.8%) patients were undertaken 

surgery and 22 (57.8%) unresectable or inoperable patients were 

treated with either definitive RT or CCRT. Responses to subsequent 

definitive RT or CCRT for 20 evaluable patients were as follows: complete 

response � 6 (30.0%), partial response � 7 (35.0%), SD � 3 (15.0%), PD 

� 4 (20.0%) Overall response rate to definitive RT or CCRT in nonresponder 

to IC was 65.0% (95%CI: 44.1%- 85.9%). Nine out of 15 

patients who showed PD to IC received definitive RT or CCRT and 

interestingly, 3 (33.3%) patients responded to definitive RT or CCRT. 

Conclusions: A significant portion of HNSCC patients who failed to IC can 

benefit from subsequent definitive RT or CCRT. Further prospective study is 

warranted. 


Expression and prognostic significance of directed therapy targets and 

mutational analysis of the EGFR pathway in malignant salivary gland 

tumors. Presenting Author: Jerome F. Cros, Georges Pompidou European 

Hospital, Paris, France 

Background: Malignant salivary gland tumors are rare and pleomorphic 

entities (24 sub types, WHO 2005). Curative treatment relies on surgery 

sometimes completed by radiotherapy. Management of non-surgical, locally 

advanced or metastatic tumors is difficult as conventional chemotherapies 

are ineffective. Directed therapies may provide important benefits for 

these patients. The aim of this work was to assess the expression and 

prognostic value of directed therapy targets on salivary gland tumors and 

search for mutations within the key players of the EGFR pathway. Methods: 

Immunochemistry on formalin fixed paraffin embedded (FFPE) samples 

from 124 patients for c-KIT, EGFR, c-ERBB2, MUC1, phospho-mTOR, 

androgen/estrogens/progesterone receptors and Ki67 was performed and 

related to progression free interval and survival. DNA was extracted from 

FFPE samples and conditional for treatment mutations of EGFR/KRAS/ 

BRAF were assessed. An additional high throughput screening for mutations 

of key oncogenic genes was performed. Results: EGFR was the most 

expressed marker, found across almost all histotypes. Expression of the 

other markers was heterogeneous but some potential therapy leads were 

suggested by high levels of C-ERBB2 and androgen receptors in salivary 

duct carcinomas or C-KIT over expression in myoepithetial carcinomas. 

Tumor grade and a high proliferation index (Ki67�20%) were associated 

with progression free interval and survival. None of the other marker was. 

No mutation was found in EGFR/KRAS/BRAF. 7% (7/104) of the tumors 

harbored a mutation at the codon 61 of HRAS. In epithelial and epithelialmyoépithélial 

carcinoma, the mutation rate reached 33%. Mutations of 

PI3K and p53 were the most frequently found in the broader screen. 

Conclusions: Several tumor subtypes expressed frequently some targets of 

directed therapies suggesting potential therapy leads. The EGFR/MAPK 

pathway seems intact suggesting a low efficacy of small kinase inhibitors 

such as erlotinib or gefitinib. The mutation of H-RAS, known to be 

important but not sufficient to trigger urothelial carcinoma, could be a key 

oncogenic event in tumors with a myoepithelial component. 


369s 


The accuracy of 18F-fluorodeoxyglucose-positron emission tomography/ 

computed tomography (FDG-PET/CT) in the staging of newly diagnosed 

nasopharyngeal carcinoma: A systematic review and meta-analysis. Presenting 

Author: Balamurugan A. Vellayappan, National University Cancer 

Institute, Singapore, Singapore, Singapore 

Background: The specific role of FDG-PET/CT in pretreatment staging of 

nasopharyngeal carcinoma (NPC) remains to be validated. We performed a 

systematic review and meta-analysis to assess the diagnostic accuracy of 

staging FDG-PET/CT for newly diagnosed NPC with reference to conventional 

staging modalities and/or clinical follow up. Methods: We searched 

MEDLINE, Cochrane central register of controlled trials, proceedings of 

ASTRO and ASCO as well as Chinese databases (Chinese National 

Knowledge Infrastructure and CBMdisc) from the date of inception to 

September 2011 for relevant studies. Study quality was assessed using the 

Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. 

We determined the sensitivities and specificities across studies, pooled 

diagnostic odds ratios (DOR) and constructed summary receiver operating 

characteristic curves using hierarchical regression model. Results: We 

found 15 relevant studies (of which seven were in English) including 851 

patients. Of the 15 studies: five addressed primary tumor (T), nine 

addressed regional lymph nodes (N) and seven addressed distant metastasis 

(M). The combined sensitivity estimate for FDG-PET/CT in T classification 

was 0.77(95% confidence interval (CI) 0.59-0.95). The combined 

sensitivity estimate for N classification was 0.88 (95% CI 0.86-0.90), 

specificity 0.85(95% CI 0.83-0.88), DOR 82.4 (23.2 to 292.6) and 

Q-index was 0.90. For M classification, the combined sensitivity estimate 

was 0.82(95% CI 0.65-0.93), specificity 0.98 (95% CI 0.96 – 0.99), DOR 

120.9 (43.0 to 340.0) and Q-index was 0.89. Conclusions: FDG-PET/CT 

showed good accuracy in N and M but not T classification for newly 

diagnosed pre-treated NPC. FDG-PET/CT, together with Magnetic resonance 

imaging (MRI) of the nasopharynx, should be part of the routine 

staging investigations for NPC. Future research should evaluate the 

accuracy of FDG-PET/MRI fusion as a single staging modality for NPC. 


Association between salivary cytokine levels and chemoradiotherapyinduced 

toxicities in head and neck cancer patients. Presenting Author: 

Paolo Bossi, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 

Background: Mucositis is a common complication of chemoradiotherapy 

(CTRT) for head and neck cancer (HNC), linked to a balance between proand 

anti-inflammation serum cytokines. No study has yet addressed the 

role of salivary cytokines in influencing toxicity severity. Methods: Twenty 

consecutive stage III (15%) and IV (85%) HNC patients (pts) were treated 

with radiotherapy (64-70 Gy) plus cisplatin (n�15), carboplatin (n�4) or 

cetuximab (n�1). Primary tumor site was oral cavity (15%), oropharynx 

(55%), nasopharynx (15%), larynx or hypopharynx (15%). Unstimulated 

saliva samples were collected according to standardized protocols before 

CTRT, during (3rd ,5th and 7th weeks) and two weeks after; concomitantly, 

mucositis grade (WHO classification), weight loss and need for feeding tube 

were evaluated. The salivary levels of 11 different cytokines (IFN�, IL1�, 

IL2, IL4, IL5, IL6, IL8, IL10, IL12p70, TNF� and TNF�) were analysed 

both in pts and in healthy donors (HD, n�10) by optimized bead-based 

multiplex immunoassay. The cytokine change during treatment was calculated 

as the difference between the mean of individual values and the 

baseline value. The Wilcoxon rank sum test was used for between-groups 

comparisons. Results: At baseline, no difference in cytokine levels was 

observed in pts as compared with HD, except IL8. A significant and 

progressive increase of IL1�, IL6, IL8, TNF� and IL10 levels was observed 

during treatment, with high levels persisting two weeks after treatment for 

all cytokines but IL1�. Significant association was shown between IL6 

increase and G3/4 mucositis (p�0.009) or feeding tube need (p�0.04). 

The same trend was observed for TNF�. Interestingly, IL8 increase 

appeared to be specifically linked to weight loss (�10%, p�0.003). In 

contrast, baseline cytokine salivary levels were not predictive of treatmentinduced 

toxicities. Conclusions: The increase of IL6, IL8 and TNF� salivary 

levels occurring in HNC patients with CTRT seems to be directly associated 

with mucositis severity, feeding tube prevalence and weight loss. Cytokines 

may represent a potential new target for preventive and/or therapeutic 

intervention. 




Organ preservation with daily concurrent chemoradiotherapy using a new 

superselective intra-arterial infusion for stage III, IV tongue cancer. 

Presenting Author: Iwai Tohnai, Department of Oral and Maxillofacial 

Surgery, Yokohama City University School of Medicine, Yokohama, Japan 

Background: Combined radiotherapy and intra-arterial chemotherapy, which 

delivers a very high concentration of anticancer agent to the tumor, is 

currently used to treat advanced head and neck cancer. However, chemotherapy 

and radiotherapy cannot be performed simultaneously on a daily 

basis under conventional methods because long-term catheterization is not 

possible. Therefore, we developed a new method using superselective 

intra-arterial infusions via the superficial temporal artery and the occipital 

artery, and used it to perform daily concurrent chemoradiotherapy for the 

treatment of advanced tongue cancer. Methods: Seventy-two patients with 

advanced tongue cancer underwent chemoradiotherapy using this superselctive 

intra-arterial infusion method. Catheters were inserted superselectively 

to the feeding arteries of the tumor via the superficial temporal artery 

and the occipital artery. Long-term catheterization is possible in this 

method. Daily concurrent combined therapy with radiotherapy (total dose: 

60 Gy), superselective intra-arterial chemotherapy using DOC (total dose: 

60 mg/m2 ) and CDDP (total dose: 150 mg/m2 ) was performed. The 

anticancer agent was injected in a bolus through the intra-arterial catheter 

simultaneously with radiotherapy. Results: No major complications were 

observed. Clinical efficacy was CR in 64 (88.9 %) patients and PR in 8 

(11.1 %). With a median follow-up period of 31 months (range 6 to 72 

months), the overall survive rate was 74.8 % and the local control rate was 

93.7%. Conclusions: This superselective intra-arterial infusion allows for 

long-term catheterization, unlike the conventional method, so that chemotherapy 

can be performed simultaneously with radiotherapy on a daily 

basis. This treatment method promises to be the strategy of choice for the 

treatment of advanced tongue cancer. 


Recombinant adenoviral human p53 gene combined with radio- and 

chemotherapy in treatment of advanced nasopharyngeal carcinoma: A 

randomized clinical study. Presenting Author: Guiping Lan, The People’s 

Hospital of Guangxi Zhuang Autonomous Region, Nanning, China 

Background: Studies showed p53 gene therapy could enhance the antitumor 

effect of both chemo- and radiotherapy. The anti-tumor function of 

p53 gene is associated with up-regulated expression of p21 and Bax. Here, 

we investigate the beneficial role of recombinant adenoviral human p53 

gene (rAd-p53) combined with chemoradiotherapy in treatment of advanced 

nasopharyngeal carcinoma (NPC), and p21 and Bax protein 

expression in pre- and post-treatment tumor tissues. Methods: Sixty-three 

patients with historically-diagnosed advanced NPC, with ECOG performance 

status less than 2, life expectancy greater than 3 months and 

adequate organ function tests, were randomly assigned into two groups: 32 

in experimental group (EG) and 31 in control group (CG). EG received 

intratumoral injection of 1�1012 rAd-p53 viral particles (VP) per 3 days for 

6-8 times, carboplatin 300 mg/m2 on day1 and continuous infusion of a 

total dose of 2000 mg/m2 of 5-Fu on day1-5 for 3 cycles, and radiotherapy 

at a dose of 2Gy/fraction for a total dose of 70-76 Gy/35-38f. CG received 

the same chemo- and radiotherapy. Pre- and post-treatment tissue samples 

were analyzed for Bax and p21 protein levels. Results: The median 

follow-up time was 28 months. EG achieved a complete response rate (CR) 

of 62.5% and overall response rate (RR) of 90.6%, both rates being 

statistically significantly higher than that of CG (CR�35.5%, RR�74.2%). 

One-year of overall survival (OS) was 100.0% for EG and 90.3% for CG, 

and one year of progress free survival (PFS) was 96.7% and 77.4% for EG 

and CG, respectively. Two-year OS was 95.7% and 86.4% for EG and CG, 

respectively, and two-year of PFS was 79.6% and 73.5% for EG and CG, 

respectively. After treatment, both Bax and p21 protein levels in EG 

increased significantly. In CG, both proteins levels also increased after 

treatment but not significantly. The main side effects of rAd-p53 were 

self-limited fever, occurring in all of EG patients. Conclusions: RAd-p53 as 

a component of the comprehensive therapy for advanced NPC contributes 

significant beneficial effects. Increased levels of Bax and p21proteins after 

treatment represent two mechanisms of p53 anti-tumor activities. 


Gemcitabine versus cisplatin concurrent with radiation therapy in locally 

advanced head and neck squamous cell carcinoma. Presenting Author: 

Magda Mostafa, Kasr Al Aini Center of Clinical Oncology and Radiation 

Therapy (NEMROCK), Cairo, Egypt 

Background: In locally advanced head and neck squamous cell carcinoma 

(HNSCC) weekly cisplatin concurrent with radiation therapy is the standared 

treatment. However some patients cannot tolerate cisplatin. So we 

conduct a prospective randomized trial comparing cisplatin versus gemcitabine. 

Methods: This trial was done in Kasr El-Ainy Center of Clinical 

Oncology and Radiation therapy (NEMROCK), during the period from 

March 2010 till June 2011. Sixty patients with locally advanced HNSCC 

were randomized to receive Cisplatin (30 mg/m2 ) weekly for 6 consecutive 

weeks (30 patients) or Gemcitabine (50 mg/m2 ) weekly for 6 consecutive 

weeks (30 patients) both concomitant with radiation therapy reaching a 

dose of 70 Gy over 7 weeks. Primary end points include response rate, 

progression free survival and toxicity. Toxicities were graded according to 

NCI-CTCAE v3.0. Results: Thewhole study group included 48 (80%) males 

and 12 (20%) females. Mean age was 47.9 (� 6.5) years (range 26-61). 

Both arms were comparable regarding their age, gender, performance 

status and stage. There were 9 (30%) CR, 7 (23.3%) PR, 2 (6.7%) SD and 

12 (40%) PD in cisplatin arm versus 12 (40%) CR, 4 (13.3%) PR, 1 

(3.3%) SD and 11 (36.7%) PD in gemcitabine arm. Median progression 

free survival (PFS) in cisplatin arm was 9 months versus 11months in 

gemcitabine arm with a hazard ratio of 0.08 (95% CI 0.005 – 1.47). We 

did not reach median overall survival. Radiotherapy induced skin toxicity 

(slight or patchy atrophy), nausea, vomiting, mucositis, salivary gland 

affection and weight loss were equally distributed in both arms. Dysphagia 

and fatigue were markedly higher in gemcitabine arm. While infection and 

neutropenia were slightly higher in cisplatin arm. Conclusions: Weekly 

gemcitabine 50mg/m2 concomitant with radiotherapy was found to be of 

equal efficacy and toxicity comparable with weekly cisplatin in the 

treatment of locally advanced HNSCC. 


Outcomes of occult primary (OP) of the head and neck squamous cell 

carcinoma (HNSCC) treated with oropharynx (OPX)-targeted radiotherapy 

(RT) and concurrent chemotherapy (CCRT). Presenting Author: Kenneth 

Hu, Beth Israel Medical Center, New York, NY 

Background: OP of HNSCC is commonly treated with comprehensive 

mucosal RT including nasopharynx, OPX, hypopharynx and larynx and 

bilateral neck. We are reporting the long term outcomes of a conservative 

mucosal sparing technique consisting of targeting only the OPX mucosa 

and bilateral necks. Methods: This is a single-institution retrospective 

study. From January 1998-2010, a total of 68 patients with OP of HNSCC 

were treated with CCRT (90%) or RT alone (10%), 40% with IMRT. RT 

fields comprehended OPX mucosa only and bilateral necks. Gross disease 

in the neck received 70Gy, involved neck 63 Gy, OPX 60 Gy, uninvolved 

neck and ipsilateral retropharyngeal nodes 54 Gy. All fractions were given 

at the rate of 1.8-2 Gy/fraction. The median age was 58 (21-87), 80% 

Caucasian, and 75% males. Stage IVa (N2) was 75% of the population, 

while stages III (N1), and IVb (N3) were 9, and 16% respectively. 16 

patients (9N3�7 bulky N2) underwent neck dissection (ND). The median 

time interval from diagnosis to RT and RT duration were 60 (13-70) and 50 

days (49-63) respectively. The Median number of Chemotherapy cycles 

was 2 (1-3). Cisplatin was given to 70% of pts, while Carboplatin and 

Cetuximab were 10 and 20% respectively. Results: With a median follow-up 

of 5.3 years (1– 13.6), the loco-regional control, (LRC) for all stages is 95.6 

%. The median time to LRF is 18 months (12 - 63). Chronic CCRT toxicity 

was; grade (1) xerostomia (67%), dysphagia (35%), altered taste (28%), 

neck stiffness (15%), skin toxicity (12%), dysphonia (9%), and trismus 

(6%). One HIV patient developed grade 4 dysphagia. No patients experienced 

distant metastases. The emergence of primary was (1.5%) 1 patient 

developed subglottic SCC 2 years after CCRT, 2 patients failed in the neck 

(originally N3) all the 3 patients were salvaged successfully by surgery. 

Kaplan-Meier curve shows the 5-year cause-specific survival to be 100. 

Conclusions: Our data show that CCRT or definitive RT alone to the OPX and 

bilateral neck provides excellent oncologic and functional outcomes. 

Sparing the mucosal surfaces of the nasopharynx, hypopharynx, and larynx 

seems reasonable and likely reduces toxicity. 



Acetylated tubulin and risk of nodal metastases in squamous cell carcinoma 

of the head and neck (SCCHN). Presenting Author: Nabil F. Saba, 

Winship Cancer Institute, Emory University, Atlanta, GA 

Background: We previously established that AT expression predicts for 

response to chemotherapy in SCCHN (Saba et al, AACR 2010 meeting 

abstr 3744). We wanted to further examine the relation of AT expression 

and nodal metastases in SCCHN. Methods: We assessed AT expression in 

archival tissue specimens from primary SCCHN cases with (50 cases) and 

without (53 cases) lymph node metastases (NM) using standard immunohistochemistry 

(IHC). Clinical characteristics of patients were retrieved 

from the department of pathology under the guidelines of the institutional 

review board (IRB). IHC staining for AT was scored based on intensity and 

percentage of tumor cells stained: 0 � no staining, 1� �weak, 2� � 

moderate, 3� �moderate to high, 4� �high and a weighted index (WI) 

was calculated as percent stain x stain intensity. Wilcoxon two-sample test 

and Kruskal-Wallis test were used to estimate the relationships of the WI 

with nodal metastasis, node status, primary tumor location, grade, and 

stage. Log-rank test was used to examine the difference in OS and DFS 

among four groups based on quartiles of the WI. A Cox proportional hazard 

model was employed to estimate the adjusted effect of WI on OS and DFS. 

Results: A higher AT expression was associated with nodal metastasis 

(p�0.0155) and higher stage (p�0.0311). A lower AT expression was 

associated with oral cavity primary (p�0.0107). After adjusting for age, 

gender, race, and smoking status, a lower AT expression was significantly 

associated with better DFS in the subset of patients with NM by multivariate 

analysis (HR�1.008; 95% CI�1.002- 1.014; p�0.0123). Among 

patients with no NM there was a marginally significant difference in OS 

among four different groups based on quartiles of AT expression 

(p�0.0765). Conclusions: High AT expression is associated with nodal 

metastases in SCCHN and may be a marker of poor prognosis in patients 

with node positive disease. The value of AT as a prognostic marker in 

SCCHN needs to be better defined. This work is supported by a SPORE CDP 

Grant P50 CA128613-03 to NFS. 


Nomogram for prediction of prognosis in patients treated for oral cavity 

squamous cell carcinoma. Presenting Author: Pablo H. Montero, Head and 

Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer 


Background: TNM staging is an effective tool for prognostic prediction in 

patients with oral cavity cancer, but it disregards variables such as the 

anatomic subsite, medical comorbidity, lifestyle, etc. A nomogram has the 

ability to take into account many factors predictive of outcome for an 

individual patient, beyond the traditional TNM. We have developed a 

nomogram to accurately predict overall mortality (OM) and disease specific 

mortality (DSM) in individual patients treated for oral cancer. Methods: 

Demographic, host, and tumor characteristics of 1,617 oral cancer 

patients treated with surgery and adjuvant treatment between 1985 and 

2009 were available from a preexisting database. Recurrent disease was 

recorded in 509 patients, 328 died of cancer-related causes and 542 died 

of other causes. The median follow-up was 42 months (range 1-300 

months). Cox proportional hazards regression model was used for OM and 

competing risk regression was used for DSM. Death from other causes was 

treated as competing risk for DSM. Missing values in the predictors were 

multiply imputed before analysis. Variables analyzed as prognosis predictors 

included age, gender, race, alcohol/tobacco use, anatomic subsite, 

comorbidity, tumor size/thickness, bone/deep muscle invasion, nodal 

status/level, grade, vascular/perineural invasion, margin status and adjuvant 

therapy. Step-down method was used to select the statistically most 

powerful predictors for inclusion in the final nomogram for each outcome. 

Results: Age, severe comorbidity, subsite, tumor size, bone/deep muscle 

invasion, margin status, vascular and perineural invasion, nodal status and 

level, and adjuvant therapy were the variables with highest predictive value 

for OM. The most influential predictors of DSM were gender, tumor size, 

nodal status and location, subsite, margin status, grade and vascular 

invasion. Nomograms were generated for prediction of OM and DSM. The 

nomograms were internally validated with correction for over-fitting; biascorrected 

concordance index for OM was 75% and DSM 76%. Conclusions: 

We have developed nomograms that can accurately estimate OM and DSM 

based on tumor and host characteristics of an individual patient treated for 

oral cancer. 


371s 


Patient-reported symptoms following IMRT alone for oropharynx cancer: A 

survivorship study. Presenting Author: Gary Brandon Gunn, University of 


Background: Patients (pts) with favorable oropharynx cancer (OPC) are 

often treated with single modality RT with excellent disease control. We 

present the pattern of pt-reported symptoms in OPC survivors treated with 

IMRT alone. This will represent a benchmark for later comparison to pts 

treated with other modalities (e.g., proton therapy, transoral surgery). 

Methods: Pts eligible for this cross-sectional questionnaire-based study had 

OPC treated with IMRT (no systemic therapy), in remission �18 mos, 

completed the MD Anderson Symptom Inventory – Head and Neck Module 

(MDASI-HN). Clinical data were tabulated and analyzed using nonparametric 

statistics. Results: 89 pts participated. OPC sub-site was tonsil 

in 58, base of tongue (BOT) in 30, and soft palate in 1 pt. 65% were TX/1, 

28% T2, and 7% T3/4, while 53% were NX/1 with 47% N2. Mean RT dose 

was 66 Gy (SD�2.5). Median age was 54 years (SD�11). Mean follow-up 

at MDASI-HN was 74 months (SD�15). Mean MDASI-HN symptom rating 

(0 to 10 scale) was 1.3 (95% CI 0.97-1.6), with no significant difference 

by OPC sub-site. No single MDASI-HN items showed significant difference 

in the percentage of pts with moderate to severe (M/S) reports by OPC site, 

thou dry mouth approached significance (p�0.054), 53% in BOT vs. 32% 

for tonsil. Overall, 14% of pts were entirely symptom free (i.e. “0” across all 

22 symptom items), 33% reported only mild symptoms, 23% only 

moderate symptoms, and 31% reported any symptom as severe . The top 7 

symptoms were dry mouth, swallowing, sleep, taste, fatigue, distress, and 

teeth and these were reported at M/S levels by 39%, 24%, 19%, 17%, 

16%, 14%, and 10% of pts, respectively. For those with any M/S symptom, 

the median number of symptoms reported at M/S levels was 3. 1/89 pts had 

a feeding tube at the time of MDASI-HN completion. Conclusions: The late 

symptom burden for long-term OPC survivors following IMRT alone was low, 

with nearly half of pts with only minimal symptoms across all items. 

Considering other endpoints (e.g. disease control, acute toxicity, second 

malignancies, and functional measures), future treatment strategies should 

seek to match or exceed these results. Future RT symptom prevention/ 

reduction strategies should focus on the top symptoms identified here. 


Head and neck cancer in Fanconi anemia and dyskeratosis congenita. 

Presenting Author: Blanche P. Alter, National Cancer Institute , Bethesda, 

MD 

Background: Fanconi Anemia (FA) and dyskeratosis congenita (DC) are 

inherited bone marrow failure syndromes (IBMFS) with extraordinarily high 

risks of cancer, particularly head and neck squamous cell carcinoma 

(HNSCC). The standardized incidence ratios (SIR) for solid tumors are 40 

in FA and 10 in DC, and for HNSCC 700 and 900 respectively. In the 

general population, cancers of the oropharynx may be associated with 

human papilloma virus (HPV) more than the oral cavity. The specific 

locations of HNSCC in FA and DC have not been reviewed, and thus the 

hypothetical role of HPV in these cancers is unknown. Methods: Literature 

cases were reviewed through PubMed searches using the terms “Fanconi 

anemia” and “dyskeratosis congenita”. All papers were reviewed, and 

details of the specific cancers recorded. FA literature included reports from 

1927 through 2011, and DC literature from 1910 through 2011. Participants 

in the National Cancer Institute (NCI) IBMFS retrospective/ 

prospective protocol (NCI 02-C-0052, opened in 2002) were also analyzed 

for cancer. The HPV vaccine was not available during most of the time 

frame of this study. Results: There were 411 cases of cancer among 2190 

(19%) cases of FA described individually in the literature, and 21 cancer 

cases out of 116 (18%) FA patients in the NCI cohort. HNSCC were 

reported in 112 FA literature cases (5%), and 9 (8%) in the cohort. The 

oropharynx was the initial site for HNSCC in 31/112 literature cases (28%) 

and 3/9 NCI cases (33%). With regard to DC, 51/647 (8%) cases in the 

literature had cancer, as did 9 of 94 (10%) NCI participants. HNSCC were 

reported in 21/647 (3%) DC literature cases, and in 5/94 (5%) from the 

NCI cohort. Four of the 21 HNSCC (19%) in the literature were oropharyngeal, 

and 2/5 (40%) in the NCI cohort. The cumulative incidences of any 

HNSCC in the NCI FA and DC cohorts were 50% and 21% by 40 years of 

age (censored at death from other causes). Conclusions: Patients with FA 

and DC have extremely high risks of HNSCC at substantially younger ages 

than the general population. Approximately 30% of these cancers occur in 

the oropharynx. The HPV vaccine could be important in prevention of these 

cancers. Future studies of the HPV status of oral cavity and oropharynx 

HNSCC tumors from patients with FA and DC will be informative. 




Should age affect our treatment decisions for head and neck cancer? 

Presenting Author: Estrella M Carballido, H. Lee Moffitt Cancer Center & 

Research Institute, Tampa, FL 

Background: Current opinion suggests elderly patients (pts) with head and 

neck cancer, those 65 or older, do not tolerate surgery, chemotherapy, or 

radiation as well as their younger counterparts. If this holds true, elderly pts 

may not be offered standard treatments to prevent assumed complications. 

Methods: A retrospective cohort study at our comprehensive cancer center 

was conducted of newly diagnosed pts with head and neck squamous cell 

carcinoma to explore differences in treatment-related complications between 

older and younger groups. We included data from the first 199 

eligible pts (99 younger than 65 year old and 100 older than 65) evaluated 

between April 2009 and June 2010. Results: 79% of pts receiving 

treatment were male with a mean age of 54.9 and 71.6 years for the 

younger and older groups respectively. The older group had significantly 

more comorbidities (p � 0.001). The majority of older pts presented with 

oral cavity tumors (46%) while the oropharynx was the predominant site in 

the younger group (45%). 55% of younger and 49% of older pts presented 

with stage 4 disease across all sites. A total of 51 pts were p16 positive with 

no statistical differences between the groups. Surgery was the initial 

treatment for 57% of older pts (p � 0.008) while 46% of younger pts 

received concurrent chemotherapy and radiation as the primary treatment 

(p � 0.008). There was no statistically significant difference in surgical or 

radiation complications between the groups. Although most pts receiving 

chemotherapy experienced complications, older pts had slightly more 

(93% vs. 78%; p�0.031). The mean survival was 24.8 months with no 

statistical difference between groups. Significantly more pts in the older 

group, at last follow-up, were disease free (p � 0.012). Conclusions: The 

treatment of elderly pts with head and neck squamous cell carcinoma in our 

experience was congruent with that of younger pts. Elderly pts did not 

suffer more complications with surgery or radiation, however chemotherapy 

produced somewhat more complications in the elderly pts. Elderly pts did 

display less evidence of disease on follow-up. Age is always a consideration 

when treating individuals, but should not preclude the curative standard. 


ECOG 1308: A phase II trial of induction chemotherapy followed by 

cetuximab with low dose versus standard dose IMRT in patients with 

HPV-associated resectable squamous cell carcinoma of the oropharynx 

(OP). Presenting Author: Shanthi Marur, The Johns Hopkins University 


Background: Human papillomavirus (HPV) infection is now recognized as a 

risk factor of oropharyngeal squamous cell carcinoma (OPSCC) and 

approximately 60% of OPSCC are HPV positive (�). ECOG 2399 using 

induction chemotherapy (IC) followed by chemoradiation demonstrated 

significantly improved 2-yr progression-free survival (PFS; 85% vs. 50%, 

p�0.05) and overall survival (OS; 94% vs. 58%p�0.004). These results 

have generated interest in development of less toxic regimens for HPV(�) 

patients with lower dose radiation. Methods: Design: This is a phase II 

clinical trial .The primary objective is the estimation of the 2-year PFS in 

the reduced dose RT arm. Secondary objectives include toxicity, OS, 

objective response, quality of life (QOL) and correlative studies of biomarkers. 

Eligibility Criteria: Patients with Stage III or IV resectable HPV(�) 

OPSCC. HPV(�) disease is defined as p16 IHC strongly (�) on at least 70% 

of cells, and/or HPV-16 ISH (�).Treatment : Patients received IC with a 

combination of paclitaxel 90mg/m2 on days 1,8, and 15, cisplatin 

75mg/m2 on day 1, and cetuximab loading dose of 400 mg/m2 on day 1, 

cycle 1 followed by cetuximab 250 mg/m2 weekly, thereafter. Each cycle 

was 21 days for a total of 3 cycles. After completion of IC, patients were 

assessed clinically with a complete head and neck exam and imaging 

studies. Those with clinical CR at primary site received radiation to 54Gy 

plus cetuximab. Patients with clinical PR or SD at primary site received 

standard dose RT with cetuximab. Correlative Studies: The expression of 

biomarkers on tumor and blood samples and QOL parameters will be 

correlated with the clinical outcomes. Results: Current enrollment: Target 

accrual was 83 patients. The study accrued 90 patients from March 17, 

2010 to accrual on October 19, 2011. Baseline characteristics reveal; 

median age 57 years, 94% male, 95% white, 47% never smokers, 10% 

�10 pack year (pyr) smoking, 38% �10 pyr smoking, 84% not current 

smokers, 39% node (N) stage N2b and 29% N2c, 22% tumor (T) stage T1, 

52% T2, 16% T3, and 10% T4. Conclusions: Enrollment has just 

completed with no data analysis available. 


EGFR-KRAS genotyping and EGFR-CDX2 expression in sinonasal intestinal 

type adenocarcinomas: Toward a new targeted therapy? Presenting Author: 

Olivier Choussy, CHU Rouen-Service ORL, Rouen, France 

Background: Sinonasal carcinomas are very rare tumors which are sometimes 

not eligible for curative surgery. Alternative therapies (i.e. conventional 

chemotherapies/radiotherapy) are used but with poor results. 

Therefore, the need for a more efficient treatment is mandatory. Aims of our 

study: Comparing EGFR and KRAS genetic profiles, EGFR and CDX2 

phenotypes of sinonasal intestinal type adenocarcinomas (ITAC) with 

colorectal adenocarcinomas (CRC). Methods: 41 patients were treated in 

our institution between 1983 and 2007. All pathological specimens were 

reclassified according to the 2005 WHO classification. An immunohistochemical 

(IHC) study was carried out for EGFR and CDX2 expression. We 

were able to analyze 38 of the 41 specimens for KRAS and EGFR 

mutations. SNaPshot multiplex system was used to determine the presence 

of the most common mutations which are located in exon 18, 20 and 21 for 

EGFR and in exon 2 (codon 12 and13) for KRAS. Fragment analysis 

method was used for EGFR exon 19 deletions. Results: Thirty five of the 38 

patients were classified as ITAC (33 men and 2 women). The mean age was 

64.5 years. Exposure to wood work was found in 29 cases (85%). CDX2 

expression was present in 31 (89%) cases of ITAC and absent in all non 

intestinal adenocarcinomas (3 cases). EGFR was expressed in 29 ITACs 

(83%) with various degrees of IHC expression: 19 (56 %) 1�, 7 (21%) 2�, 

and 3 with 3� immunopositivity. No EGFR mutation was found in the 

whole population; 5 ITAC patients (14%) disclosed KRAS mutations. 

Conclusions: Histological, phenotype and genetic profiles of ITAC are very 

similar to those of colorectal adenocarcinoma. These results suggest that 

ITACs with wt KRAS could respond to anti MoAb anti-EGFR therapy in the 

same way as metastatic CRC. We propose that all sinonasal tumors should 

undergo: firstly, CDX2 IHC in order to confirm the ITAC histological subtype 

and then KRAS genotyping to select the wt population which could benefit 

from such anti EGFR targeted therapy. 


Young adults with squamous cell head and neck cancer: Ten years of a 

single institution’s experience (1999-2008). Presenting Author: Marcos 

Pantarotto Alves, Instituto Portugues Oncologia Francisco Gentil, Oporto, 

Porto, Portugal 

Background: Head and neck cancer of squamous cell type (SCHNC) is 

characterised by its aggressiveness and strong relationship with smoking 

and drinking habits. It is generally diagnosed in locally advanced stages, 

mainly in middle-aged men. People younger than 35yo are rarely affected 

by this disease, and little is known about its behaviour among young 

Portuguese adults. Our aim was to describe the clinical and epidemiological 

features of young adults with diagnosis of SCHNC in a single 

oncological centre in Portugal. Methods: Retrospective cohort including 

clinical registries’ databases for patients (pts) with diagnosis of SCHNC, 

with 3391 eligible pts from 1999 to 2008. Pts aged �18yo and �35yo at 

diagnosis with histopathological diagnosis in our Institution were included. 

Pts admitted to radiation therapy with no follow-up information were 

excluded. 39 pts fulfilled the criteria described, comprising the study 

population. Statistical analysis was carried out using SPSS v19.0 for Mac 

(IBM, 2010, EUA), with values of p�0,05 considered significant. Results: 

Male sex predominance (82%) was observed. The median age of presentation 

was 33 yo [22; 35], with 90% smokers with a median of 18,5 

package-years [1; 48]. Alcohol consumption was mild to moderate (n�9; 

23%) or heavy (n�15; 38%). The median of follow-up time was of 24 

months [1;151]. Locally advanced diseased was present at diagnosis in 24 

pts, where localised disease was commonest among women (57%) than in 

men (29%). Median overall survival (OS) was not reached on this 

population, although K-M graphs seems to show a significant difference in 

survival between sexes. Alcohol consumption was the most significant 

variable to influence the survival (p�0,01). Conclusions: SCHNC in young 

people is a rare condition, with distinct epidemiological and clinical 

features. Women seems to have greater survival rates, which may be 

explained by other risk factors already reported for this gender, namely HPV 

infection. The finding of an apparent relationship between alcohol consumption 

and OS, and the high prevalence of alcoholic intake habits on this 

parcel of the population, urge the need of development of public health 

programs addressed to this specific age group. 



Feasibility and short-term efficacy of four facio-cervical fields’ conformal 

radiotherapy for nasopharyngeal carcinoma. Presenting Author: Wang fang 

Zheng, Zhejiang Cancer Hospital, Hangzhou, China 

Background: Conventional bilateral facio-cervical fields increased the local 

control and overall rates for nasopharyngeal carcinoma, and generated 

severe late complications, while intensity-modulated radiation therapy 

(IMRT) may take up a lot of labor power and material resources.This study 

was to explore feasibility and short-term efficacy of four facio-cervical 

fields’ conformal radiotherapy (4F-CRT) for nasopharyngeal carcinoma. 

Methods: Between November 2007 and June 2009, 101 patients with 

histology-proven nonmetastatic NPC were rolled into this study and 

received 4F-CRT. 90 of all patients received four cycles chemotherapy. 

Results: The treatment was completed for all patients within 7 weeks. The 

complete response (CR) rate was 95.0% (96/101) and the partial response 

(PR) rate 5.0% (5/101). Overall response was 100% for nasopharyngeal 

lesions. The CR rate was 90.0% (91/101) and the PR rate 7.0% (7/101) in 

lymph node lesions. One year local control, regional control, overall survival 

(OS) rate, metastasis-free survival (MFS) and disease-free survival (DFS) 

rate are 100%, 100%, 100%, 97%, 97%, respectively. The major 

toxicities observed were grades 1-2 leukocytopenia. Conclusions: 4F-CRT 

can generate desirable dose distribution of tumor volume for nasopharyngeal 

carcinoma. The short-term efficacy of 4F-CRT is satisfactory and its 

acute toxicities are tolerable. 


Paranasal sinus squamous cell carcinomas (PNSSCC) incidence and 

survival trends. Presenting Author: Benjamin Ansa, Morehouse School of 

Medicine , Atlanta , GA 

Background: PNSSCC are rare, accounting for 3 percent of all head and 

neck malignancies. They generally present with local invasion and have a 

high rate of local recurrence. There has been little information on the trends 

in incidence and survival of PNSSCC and no randomized trials to guide 

therapy. We analyzed the incidence rates and survival outcomes for 

patients diagnosed with PNSSCC in the SEER database. Methods: Data 

were obtained from the U.S. National Cancer Institute’s Surveillance, 

Epidemiology, and End Results (SEER) Program. Newly diagnosed PNS- 

SCC reported to SEER from 1973 through 2008 were categorized according 

to the patient’s sex, age, year of diagnosis, and stage. The incidence 

and survival were then examined and compared across different demographic 

and disease-related categories. Results: A total of2,323 patients 

were identified. The mean age was 62 years, range: 14-85 yrs; malesaccounted 

for 62.7%. Whites accounted for 75.8%, blacks for 12.2 % and 

12.0% were of asian or pacific islanders and other groups. Maxillary sinus 

primary accounted for 76.3%, ethmoid (10.2%), sphenoid (4.3%). The 

disease was localized in 9.5%, had regional spread in 72.0% and distant 

disease in 12.2%, at diagnosis. A statistically significant decrease (Annual 

Percent Change of -1.6%, 95%CI� [-2.0, -1.1]) in the overall incidence 

was observed by Joinpoint analysis (p�0.01). The decrease in incidence 

was significant in patients with maxillary sinus (p�0.01) and was more 

pronounced in the white population compared to other groups. Both the 

observed and relative 5-year survival significantly increased over time and 

this was more notable in the white population compared to other groups. 

The observed 5-year survival rate increased from 24.9% (95% CI � 

[20.3-29.6]) during the 1975-1983 time-period to 40.8% (95% CI � 

[33.4-48.0]) during the most recent period of 2002-2008. Conclusions: 

There has been a decline in the overall incidence of PNSSCC more notably 

in the white population and for patients with maxillary sinus tumors. The 

5-year observed and relative survival has significantly increased. Our 

findings should incite more efforts to understand the factors behind the 

change in incidence and survival. 


373s 


Effects of vandetanib on body composition in patients with advanced 

medullary thyroid carcinomas: Results from a placebo-controlled study. 

Presenting Author: Marie-Helene Massicotte, Institut Gustave Roussy, 

Nuclear Medicine and Endocrine Oncology Service, Villejuif, France 

Background: Muscle (MT) and adipose tissue (AT) share common intra 

cellular pathways with tumor, thus it is not surprising to observe metabolic 

consequences with targeted therapies. The aim of the study was to assess 

the effects of vandetanib, a tyrosine kinase inhibitor (TKI) which demonstrated 

efficacy for the treatment of advanced medullary thyroid carcinoma 

(MTC), on MT and AT. Methods: 33 patients (25 men and 8 women, mean 

age of 54 years) with metastatic MTC received vandetanib 300 mg/d 

(n�23) or placebo (n�10) in the setting of the ZETA study. Cross-sectional 

areas (cm2 ) of visceral adipose tissue (VAT), subcutaneous adipose tissue 

(SAT) and MT were assessed by computed tomography imaging at 3rd 

lumbar vertebra and were indexed for height (cm2 /m2 ). Comparisons 

between treatment and placebo were made at 3 months, and long-term 

evolution was evaluated over 12 months. Results: At 3 months, compared to 

baseline, patients treated with vandetanib gained 1.5 kg, 1.3 cm2 /m2 of 

MT, 5.1 cm2 /m2 of VAT and 4.5 cm2 /m2 of SAT. In contrast, patients under 

placebo lost 1.5 kg (p�0.02), 1.0 cm2 /m2 of MT (p�0.009), 5.5 cm2 /m2 of SAT (p�0.004) and gained significantly less VAT (0.6 cm2 /m2 ) 

(p�0.02). At 12 months, compared to baseline, patients treated with 

vandetanib gained 2 kg (NS), lost 0.3 cm2 /m2 MT (NS), gained 3.4 cm2 /m2 of VAT (NS) and 8.7 cm2 /m2 of SAT (95% CI, 1.1 to 16.2). A significant 

decrease of calcitonin (defined as �50% compared to baseline) was 

associated with higher weight (p�0.01), VAT (p�0.01), and total adipose 

tissue (p�0.02). Conclusions: Beyond its proved efficacy in MTC treatment, 

and despite common intracellular pathways, vandetanib is the only studied 

TKI to preserve MT and to restore AT. Further research is needed to explore 

whether the relationship between changes of VAT and vandetanib treatment 

results from a direct metabolic action of vandetanib or is a 

consequence of biochemical tumor control. 


Impact of p16 status on the QOL effects of chemoradiation for locally 

advanced oropharynx cancer: Results of TROG 02.02. Presenting Author: 

Jolie Ringash, Princess Margaret Hospital and University of Toronto, 


Background: We report the impact of p16 status on quality of life (QOL) for 

patients with stage III or IV (excluding T1-2N1 and M1) squamous cell 

carcinoma of the oropharynx (OPC) treated with concurrent chemoradiotherapy 

in a large international phase III trial (TROG 02.02/HeadSTART). 

Methods: The 861 patients accrued received definitive radiotherapy (RT) 

(70 Gy/7 weeks) concurrently with 3 cycles of either cisplatin (100mg/m2 ) 

or cisplatin (75 mg/m2 ) plus tirapazamine (290 mg/m2 /day) by random 

assignment, as previously described. QOL was measured with the FACT- 

H&N at baseline, 2,6,12, 23 and 38 months. No significant difference in 

overall or subscale QOL score change from baseline was observed between 

arms at any subsequent time point; results for the oropharynx subgroup by 

p16 status are reported for both treatment arms combined. Results: Of 853 

eligible participants, 465 had OPC, for whom p16 status could be 

determined in 206. Of 179 who received adequate RT (� 60 Gy, no major 

deviations) and completed baseline QOL, 104 were p16� and 79 were 

p16-. p16� patients had better baseline ECOG PS, lower T-category, 

higher N-category, were younger and were less likely to be current smokers. 

Baseline mean FACT-H&N score was statistically and clinically significantly 

better in p16� patients (111 vs. 102, p�0.001). The drop in QOL 

from baseline to 2 months was more severe in p16� cases (-20.4 vs -9.1, 

p�0.001), resulting in an equalization of 2 month scores (p16�: 90.6, 

p16-: 93.6, p�0.16). At 6 and 12 months post-treatment, no difference in 

score changes from baseline by p16 status was seen (6 mo, p16�: -6.2, 

p16 -:-1.2, p�0.22; 12 mo, p16 �: -0.3, p16 -: �2.0, p�0.82). 

Conclusions: p16 associated oropharyngeal cancer has been shown to be a 

distinct entity with different demographic features. In our study, such 

patients exhibited better baseline QOL and a more severe drop immediately 

after treatment, but did not differ in long-term QOL response to the effects 

of aggressive concurrent chemoradiation. Given the favorable prognosis of 

p16-associated oropharyngeal cancer, efforts to reduce the QOL burden of 

treatment are warranted. 




Correlation between PI3K/PTEN/AKT/mTOR pathway genetic variations 

and clinical outcome in patients with squamous cell carcinoma of the head 

and neck receiving cetuximab-docetaxel treatment. Presenting Author: 

Alberto Fusi, Department of Hematology and Medical Oncology, Charité, 

CBF, Berlin, Germany 

Background: The PI3K/PTEN/AKT/mTOR pathway is one of the most 

targeted in human cancers and alterations in the axis are frequent events in 

squamous cell carcinoma of the head and neck (HNSCC). Specific genetic 

variations in this pathway have been associated with variation in recurrence, 

survival and response in lung cancer and esophageal cancer. The 

aim of this study was to determine whether single nucleotide nucleotide 

polymorphisms (SNPs) in AKT1, AKT2, FRAP1, PI3KCA and PTEN 

identified in other cancers were associated with treatment response and 

clinical outcome in patients with HNSCC. Methods: Genomic DNA was 

extracted from FFPE tissue specimens of 45 patients with recurrent or 

initially metastatic HNSCC who received a combined treatment with 

docetaxel and cetuximab in a phase II study. Eleven single SNPs in the 

genes AKT1, AKT2, FRAP1 (mTOR), PIK3CA and PTEN were genotyped by 

means of Real Time PCR system or by direct sequencing and analysed for 

association with response to therapy and survival. Results: None of the 

SNPs was related to treatment response. Two SNPs (AKT2:rs8100018 and 

PTEN:rs12569998) were associated with variation in progression risk. The 

AKT2:rs8100018 homozygous variant resulted in increased risk, with a HR 

of 4.83 (95% CI, 1.11-21.03) and the PTEN:rs12569998 homozygous 

variant in an increased risk, with a HR of 2.36 (95% CI, 1.24-4.50). 

AKT2:rs8100018 and PTEN:rs12569998 genetic variation had an additive 

effect on risk of tumor progression. The AKT2:rs8100018 homozygous 

variant was significantly associated with overall survival (OS) with HR of 

3.57 (95% CI, 1.06-12.00) while presence of one of the two variant alleles 

of AKT1:rs3803304 with a lower risk of death (HR: 0.51; 95% CI, 

0.27-0.97). Conclusions: We found significant associations between common 

genetic variants in the PI3K/PTEN/AKT/mTOR pathway and outcome 

in patients with HNSCC. Despite the small sample size, patient cohort and 

treatment were homogeneous. As a consequence, evaluation of SNPs as a 

host factor may be considered in addition to tumor-specific mutations for 

personalized treatment development. 


Genetic alterations in HRAS gene in relation to outcome and response to 

cetuximab in head and neck squamous cell carcinoma. Presenting Author: 

Theodoros Rampias, Yale University School of Medicine, New Haven, CT 

Background: Aberrant signaling through RAS/MAPK pathway is implicated 

in resistance to EGFR-targeted agents in cancer. Genetic alterations in 

Hras gene such as mutations and specific polymorphisms are associated 

with aggressive phenotype in several smoking-related malignancies. We 

sought to determine the impact of Hras genetic alterations on response to 

cetuximab and prognosis in HNSCC. Methods: Clinical outcome according 

to Hras status was investigated in a retrospective cohort of 140 HNSCC 

specimens. Primary endpoints were overall survival (OS) and disease-free 

survival (DFS) and secondary endpoint was treatment response. For 

statistical analysis, T-test was used for continuous data and x2 –test for 

categorical data. Cetuximab-resistant cell lines harboring mutant Hras 

(BB49, T24) were infected with lentivirus expressing shRNA targeting the 

Hras or a scrambled- shRNA. MTT assay was used to determine the effect of 

cetuximab on growth of lentivirus infected cells. Biochemical analysis 

involved immunoblotting for pERK1/2. Results: Mutationanalysis of tumor 

samples showed that 5.7% participants harbored Hras mutations and 

16.42% harbored Hras polymorphisms (rs12628, rs41258054) that are 

associated with tumorigenesis. Patients bearing tumors with mutated Hras 

had inferior mean OS ( 22.13vs 35.20, p�0.02) and a non-significant 

trend for inferior mean DFS. Patients with tumors containing Hras genetic 

alterations (mutation or polymorphism) had significantly inferior mean OS 

(p�0.02) compared to those harboring wt Hras and trended towards 

inferior DFS (p�0.07). Patients had received various treatments such as 

surgery plus/minus RT and various chemotherapy regimens. A subgroup 

analysis of 38 patients treated with cetuximab-based regimens showed that 

wt Hras was associated with higher likelihood of attaining CR or PR to 

treatment of borderline significance (p�0.06) due to small sample size. 

Silencing of Hras in Hras-mutant cell lines restored sensitivity to cetuximab 

and caused a direct downregulation of pERK1/2 levels. Conclusions: Hras 

genetic alterations are associated with aggressive clinical course and may 

affect response to cetuximab in HNSCC. 


Correlation of microbiomic profiles with disease status and MDR1 methylation 

in head and neck squamous cell carcinoma (HNSCC). Presenting 

Author: Pauline Funchain, Cleveland Clinic, Cleveland, OH 

Background: Recent studies of the aerodigestive tract have uncovered the 

functional importance of the microbiome, the total collection of microorganisms 

that reside within the human host. Furthermore, specific bacterial 

species have been shown to be etiologic agents or show potential as a 

screening biomarker in cancers including gastric, colon and pancreas. 

Here, we hypothesize that specific microbial populations may contribute to 

HNSCC pathogenesis via epigenetic modifications in inflammatory- and 

HNSCC-associated genes. Methods: Matched tumor and adjacent normal 

fresh frozen tissue specimens were collected from 55 prospectively 

enrolled HNSCC patients. Microbiomic profiles were obtained using Sanger 

sequencing of 16S rDNA PCR products. Methylation status of four genes 

previously linked to HNSCC or inflammation (MDR1, IL8, RARB, TGFBR2) 

was assessed in 49 samples by combined bisulfite restriction analysis and 

by Illumina HumanMethylation27 chip. Principle component analysis and 

multivariate analysis of covariance (MANCOVA) were used to identify 

bacterial subpopulations significantly associated with HNSCC and relevant 

clinical variables. Results: In this cohort, median age is 62, male:female 

ratio is 3:2, 16% are HPV�. Specific bacterial subpopulations associate 

with HNSCC over normal tissue and correlate with larger tumor size and 

higher nodal stage (p�0.05). Furthermore, microbial populations can 

separate tumors by tobacco (p�0.005) but not alcohol (p�0.7) status. 

Bacterial profiles are independent of HPV status. MDR1 promoter methylation 

is seen in tumor samples but not in normal oral mucosa (22/49 vs 

0/49), and associates with specific microbiomic subpopulations in the 

order Enterobacteriales and phylum Tenericutes (p�0.001). Additionally, 

MDR1 methylation correlates with regional nodal metastases. Conclusions: 

Specific bacterial subpopulations differ between normal and tumor tissue 

and show association to specific clinicopathologic features, suggesting a 

role for microbial profiling in HNSCC as a novel area of investigation for 

diagnosis, prognostication, and therapeutic targeting. 


Identification of head and neck cancers (SCCHN) that may respond to dual 

inhibition of EGFR and HER3 signaling. Presenting Author: David S. 

Shames, Genentech, South San Francisco, CA 

Background: Oncogenic signaling through the epidermal growth factor 

receptor family is one of the most frequent alterations found in human 

epithelial cancers. These receptor tyrosine kinases mediate their effects via 

high-level co-expression and homo- and heterodimerization events that 

drive tumor growth, metastasis, and survival. Extensive preclinical studies 

suggested that some cell lines depend on oncogenic autocrine signaling 

through HER3 (Wilson et al.). This phenotype was particularly prominent in 

cell lines derived from SCCHN and was strongly correlated with high HRG 

expression. Interestingly, two patients with SCCHN tumors that expressed 

high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A, 

a dual-action human IgG1 antibody that blocks ligand binding to EGFR and 

HER3 (Schaefer et al.) had partial responses. To further explore the 

hypothesis that high-level HRG expression defines a sub-population of 

SCCHN that may be sensitive to agents targeting HER3, and to identify 

other potential target indications for the development of MEHD7954A, we 

evaluated the expression of HRG in large cohorts of multiple solid tumor 

indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR 

in 648 formalin-fixed paraffin embedded primary tumor samples from 

patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast 

cancer. Results: SCCHN-derived tumor samples had the highest levels of 

HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern 

that is clearly distinct when compared to other tumor types. These data 

suggest that high HRG levels and potentially HER3-dependent autocrine 

signaling occur more frequently in SCCHN than in other tumors. Further we 

investigated whether overexpression of HRG in SCCHN correlated with 

stage and disease outcome. Updated results from these extended studies 

will be presented. Conclusions: SCCHN tumors exhibit bimodal expression 

of HRG, suggesting that HRG expression levels may be useful in identifying 

a subset of patients most likely to benefit from inhibition of HER3 activity. 

Antitumor activity in such patients has been observed in a phase I study of 

MEHD7954A (abstract #95245). 



Predictors for response to cetuximab in a prospective clinical trial (E2303) 

of patients with head and neck squamous cell carcinoma (HNSCC). 

Presenting Author: Amanda Psyrri, University of Athens, Athens, Greece 

Background: Theidentification of resistance mechanisms to Epidermal 

Growth Factor Receptor (EGFR) inhibitors remains critical lack in the 

management of HNSCC. We sought to determine predictors for response to 

cetuximab in a phase II clinical trial. Methods: 63 patients (pts) with 

operable stage III/IV HNSCC participated in E2303, an Eastern Cooperative 

Oncology Group (ECOG) phase II trial of induction chemotherapy with 

weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy 

with the same regimen. A tissue microarray was constructed and 

EGFR, ERK1/2, Met, pAkt and STAT protein expression levels were 

assessed using AQUA. The objectives of analysis were to determine 

association of biomarkers with E2303 efficacy outcomes (best objective 

response (OR), overall survival (OS), progression-free survival (PFS), and 

event-free survival (EFS)). The logistic regression model was used to 

examine relationship between marker measurements (on a continuous 

scale) and OR. The univariate and multivariate Cox proportional hazards 

models were used to evaluate the relationship between markers and 

event-time distributions. Fisher’s exact test was used to evaluate differences 

in response rate between groups (high vs. low AQUA scores). 

Event-time distributions were estimated by the Kaplan-Meier method and 

compared by the log-rank test. Results: Cytoplasmic ERK1/2 levels weresignificantly 

associated with PFS and OS (p�0.03 and 0.01, respectively). 

Nuclear ERK1/2 levels were significantly associated with OS (p�0.02) and 

tended towards significance for PFS (p�0.09). The multivariate Cox 

regression analysis shows that cytoplasmic and nuclear ERK1/2 are 

significantly associated with OS and PFS after controlling for primary site 

and disease stage, respectively There was no significant association 

between cytoplasmic or nuclear ERK1/2 status and OR (p-values 0.98 and 

0.41, respectively).No association was found between expression of any of 

other biomarkers and outcome measures. Our data analysis was based on 

35 pts with marker data available. Conclusions: Ras/MAPK/ERKpathway 

may be associated with resistance to cetuximab in HNSCC. 


A combined evaluation strategy of FDG PET/CT and contrast-enhanced diagnostic 

CT (ceCT) for lymph nodes in the neck. Presenting Author: Neetha Gandikota, 

Department of Nuclear Medicine, Mount Sinai Medical Center, New York, NY 

Background: Accurate assessment of cervical lymph nodes (LNs) for determination 

of metastatic involvement is of prime importance for management. Our 

objective was to determine the incremental value of combining metabolic and 

morphologic information in the differentiation between benign and malignant 

LNs. Methods: A total of101 pts with head and neck squamous cell (n�91) or 

thyroid cancer (n�6) or lymphoma (n�4) were included in the study. PET/CT 

and neck ceCT were acquired simultaneously or sequentially at staging (n�48) 

or restaging (n�53). In 131 LNs, variables evaluated includes SUVmax, size, 

shape (elliptical vs non-elliptical), presence of extracapsular extension (Ecextirregular 

margins), necrosis, and fatty hilum. Histopathology (n�96) and 12 mo 

follow-up (n�35) were used for confirmation of the findings. ROC analyses 

determined the SUVmax cut-off. Results: Of131 LNs, malignancy wasconfirmed 

in 49 (37%).Results are shown in table. In the detection of malignancy, SUVmax 

of 4.5 yielded the best balance between the sensitivity and specificity, 

performing better than all CT variables alone. Combination analysis improved 

results only when SUVmax (4.5) was added to Ecext. However, best combination 

results were obtained at a SUV cut-off of 3.7. Higher SUV cut-off did not 

significantly improve overall performance of SUVmax alone (Table). Conclusions: 

In the differentiation of malignant from benign LNs, SUVmax (4.5) yields better 

results than CT variables alone. However combining a lower SUVmax (3.7) with 

Ecext produced the best results. Increasing SUVmax cut-off only produced a gain 

in specificity at a significant cost of sensitivity. 

Univariate variables Sen Spec Odds ratio 95% CI P value 

SUVmax 82% 79% 16 5 – 54.6 � 0.01 

�/- ecext 41% 93% 10 3.4 – 28.8 � 0.01 

�/- necrosis 44% 88% 5.9 2.4 – 14.5 � 0.01 

Shape 54% 83% 5.8 2.5 - 13 � 0.01 

�/- fatty hilum 90% 15% 0.6 0.2 - 2 0.4 

Size (1.2 cm) 70% 58% - - 0.11 

Combined analyses SUV max 

and ecext 

SUV max 

and necrosis 

SUV max 

and elliptical 

shape 

Sen Spec Sen Spec Sen Spec 

SUVmax cut 3.7 95% 80% 100% 22% 100% 23% 

SUVmax cut 4.5 86% 80% 91% 44% 89% 23% 

SUVmax cut 5.3 76% 100% 82% 78% 73% 62% 

P value 0.005 0.007 0.03 


375s 


The impact of advanced age on outcomes in squamous cell carcinoma of 

the head and neck. Presenting Author: Virginia Ann Moye, University of 

North Carolina School of Medicine, Chapel Hill, NC 

Background: Limited data are available regarding outcomes in elderly head 

and neck cancer patients. This retrospective study was designed to 

characterize head and neck cancer in geriatric patients in the UNC Tumor 

Registry. Methods: Of 1,598 patients identified from the registry, 1,291 

patients were �70 years old (young group, YG) and 307 patients were � 70 

(elderly group, EG) at diagnosis. Both overall survival (OS), calculated from 

diagnosis to death or the last follow up, and relapse free survival (RFS) were 

censored at 60 months. Log-rank test was used to compare survival 

difference. Cox proportional hazard model was used to estimate hazard 

ratio, adjusting for potential confounding factors. All tests were performed 

in R 2.13.1. Results: EG patients were more likely to present at an early 

stage with 25% presenting at stage I and 37% presenting at stage IV 

compared to 17% and 51% respectively in YG. EG had a median OS of 35 

months (95% CI: 28-41 months) compared to approximately 60 months in 

YG (p � 0.0001 log rank test). The median RFS for EG and YG are 25 (95% 

CI: 20-32 months) and 44 (95% CI: 38-52 months) months respectively (p 

� 0.0001 log rank test). When controlling for possible confounders, EG 

patients were nearly twice as likely to die (HR 1.94, 95% CI 1.635-2.302, 

p�0.0001) and 70% more likely to relapse in 5 years compared to YG (HR 

1.704, 95% CI 1.449-2.004, p�0.05). The median life expectancy for 

elderly patients in our study was nearly 5 years for stage I/II and �2 years 

for stage III/IV. Conclusions: Poor OS and RFS in elderly patients compared 

to younger patients in this study indicate a need for further investigation 

considering comorbidities and aggressiveness of treatment. Significant 

differences in life expectancy in elderly patients with early versus late 

disease may help guide patients and clinicians in determining how 

aggressively to treat. 


A phase I/II study of concurrent nab-paclitaxel, carboplatin, and IMRT for 

locally advanced squamous cancer of the head and neck (LASCCHN). 

Presenting Author: Roy B. Tishler, Department of Radiation Oncology, 

Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA 

Background: We studied escalating doses of weekly nab-paclitaxel (Abraxane, 

AB) combined with weekly carboplatin (CP) and daily IMRT in patients 

with LASCCHN to determine the safety and optimal dosing of AB. The 

favorable biodistribution of AB, an albumin bound formulation of paclitaxel, 

may allow for intensified locoregional treatment without increasing 

normal tissue toxicity. Methods: An AB dose escalation was performed, 

initially using concurrent weekly CP (AUC � 1.5), Erbitux (ER) and daily 

IMRT to 70 Gy. After ER was dropped, dose escalation of AB from 20 

mg/m2 to 50 mg/m2 was performed in 10 mg/m2 increments using a 3 � 3 

study design. Results: A total of 28 patients have enrolled and all have 

completed treatment. Patients ranged in age from 42 to 72 years old 

(median � 59), with follow up from 3 to 48 months (median � 25). Most 

patient had oropharyngeal primaries (n�22) and stage III (n�8) or IV 

(n�20) disease; 18 were HPV�, 6 HPV- and 4 unknown. Initially 6 

patients received weekly AB (20 mg/m2 ), ER and CP, but ER was dropped 

due to greater than anticipated mucositis and dysphagia. Subsequently, 3 

patients each received CP with AB at 20, 30 and 40 mg/m2 weekly and a 

total of 13 received CP with AB at 50 mg/m2 . The median radiation dose is 

70 Gy and the median number of weekly chemotherapy cycles is 7. The 

primary toxicities were Grade 3 dysphagia, mucositis and dermatitis in 24 

of 28 patients. Only 3 (of 28) PEG tubes remain at 4, 6 and 14 months. No 

DLTs were observed at any dose level. There have been 5 recurrences, with 

4 being local-regional. Two patients have died of disease and 26 are alive. 

Conclusions: Concurrent AB, CP, and IMRT is a safe chemoradiotherapy 

combination in LASCCHN with early data demonstrating feasibility and 

efficacy. 




P16 and cyclin D1 (CYD1) as prognostic markers in hypopharyngeal (HSC) 

and oropharyngeal squamous cell carcinoma (OSC). Presenting Author: 

Siok Hoon Ang, Duke-NUS Graduate Medical School Singapore, Singapore, 

Singapore 

Background: In head and neck cancer (HNC), dysregulation of cell cycle 

proteins p16 and CYD1 are common. Variable associations of p16 over- and 

underexpression and CYD1 overexpression with overall survival (OS) have 

been described in different HNC sites. We evaluated the relationship of 

p16 and CYD1 expression with clinical characteristics and OS in OSC and 

HSC. Methods: p16 and CYD1 expression was evaluated by immunohistochemistry 

in 77 HSC and 103 OSC patients (pts) and recorded as p16N 

(0% tumor cells stained), p16L (5-69%) and p16H (�70%), CYD1- 

(�10%) and CYD1� (�10%). OS between groups was evaluated by 

Kaplan-Meier method and compared by log rank test. Hazard ratio (HR) for 

death was estimated using multivariable Cox models. Results: Pts were 

predominantly Chinese (83.6% v 85.4%) with locally advanced HNC 

(91.4% v 92.2%). Compared to OSC, HSC pts were older (median age 67 v 

61 yrs), more likely male (89.3% v 74.0%), current or ex-smokers (83.3% 

v 63.6%) with higher comorbidity-age combined risk score (ageCCI), less 

likely p16H (6.5% v 30.1%)(all p�0.001) and had similar CYD�. p16H 

pts were younger (median age 58 (p16H) v 65 (p16L) v 66 (p16N) yrs, 

p�0.002), more likely non-smoker (51.4% v 23.4% v 13% p�0.001) with 

lowest ageCCI (p�0.001). Clinical characteristics did not differ by CYD1 

status. At median f/u of 50mths, median OS was 33 mths. Median OS was 

poor in HSC compared to OSC (23.9 v 72.1, p�0.001). Multivariate 

analysis showed associations of N2/N3 disease (HR 1.57, p�0.036), 

ageCCI (HR 1.22 per 1 pt increase, p�0.001), p16 (p16H: ref; p16L: HR 

2.34, p�0.045; p16N: HR 2.74, p�0.013) and CYD1� (HR 1.94, 

p�0.015) with death, independent of gender, smoking and site. Association 

of p16 with OS was seen mainly in OSC (median OS p16H: not reached 

(NR), p16L: 62, p16N: 22 mths, p�0.001) compared with median OS 

(HSC) (27 v 28 v 21, p�0.609). Similarly the association of CYD1 with OS 

was mainly in OSC (median OS CYD1-: NR v 23 mths, p�0.001 v HSC: 25 

v 25 mths, p�0.19). Conclusions: In OSC, p16 expression correlates with 

OS, with p16N associated with worst OS. CYD1 has an independent 

association with OS. Poorer OS in HSC may be due to adverse clinical 

characteristics. Assessment of p16 and CYD1 status in HSC did not predict 

for OS. 


HPV and survival in patients with oropharyngeal squamous cell cancer of 

the head and neck (OPC) treated with induction chemotherapy followed by 

chemoradiotherapy (ST) versus chemoradiotherapy alone (CRT): The Dana- 

Farber experience. Presenting Author: Jochen H. Lorch, Department of 

Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, 

Boston, MA 

Background: HPV status is a major prognostic marker for survival in patients 

with OPC. We examined overall survival (OS) and progression free survival 

(PFS) in patients with OPC and known HPV status treated at Dana-Farber 

Cancer Institute with ST and CRT between 2002 and 2011. Methods: 280 

patients with OPC and known HPV status were identified retrospectively 

and clinical information was recorded. Results: 174 patients were treated 

with CRT (124 HPV positive, 50 HPV negative) and 106 patients were 

treated with ST (77 HPV positive, 29 HPV negative). For all 280 patients, 

OS and PFS were significantly better for patients who were HPV positive 

compared to those who were HPV negative. 3 year OS was 89.1% for HPV 

positive (95% CI, 83.8-94.7) and 70.5% for HPV negative patients 

(95%CI, 59.9-83%, HR 0.37, p�0.0007). Among HPV positive patients 

treated with CRT, 13/124 had died at 3 years (OS 88.5%, 95%CI 

81.7-95.9) while 13 deaths were recorded among 50 HPV negative 

patients (OS 72.2%, 95% CI 59.1-88.2, HR 0.38, p�0.011). PFS at 3 

years was also significantly better for HPV positive versus HPV negative 

patients(81.7% vs 58.8%, HR 0.42, p�0.006). In the group treated with 

ST, outcomes were similar despite a higher rate of stage IV versus stage III 

disease compared to the group treated with CRT (100% stage IV in ST 

versus 77% stage IV and 23% stage III disease in CRT group). Three year 

OS was 89.7% for HPV positive and 68.2% in the HPV negative group 

(8/77 HPV pos vs 10/29 HPV neg, HR 0.33, p�0.015). PFS was borderline 

better for HPV positive patients (81% vs 61.7%, HR 0.48, p� 0.058). 

Conclusions: We present the DFCI experience treating OPC with ST and CRT 

for patients with known HPV status over one decade.OS and PFS were 

superior for HPV positive versus HPV negative patients. Outcomes were 

virtually identical for patients treated with CRT versus ST despite a higher 

rate of stage IV disease in the ST group. Outcomes for the HPV negative 

patients in particular were superior compared to the published literature. 


The role of postoperative radiotherapy (PORT) in the management of 

parotid gland malignancy (PGM). Presenting Author: Louis Harrison, Beth 

Israel Medical Center, New York, NY 

Background: To report the role of PORT in the management of PGM and to 

analyze the prognostic factors for optimal locoregional (LRC) and distant 

control (DC) Methods: This is a single institution retrospective study. From 

March 2001-2011, a total of 118 patients with PGM were treated with 

surgery and PORT (100%) of which 75% were treated with IMRT, 20 and 

10% received concurrent carboplatin and CDDP respectively. Indications 

for PORT were: recurrent or gross residual disease, �ve or close margins, 

nerve invasion and �ve lymph nodes (LN). PORT fields comprehended 

parotid bed and ipsilateral neck. Median PORT doses delivered were 70, 

63, 54 Gy (at 1.8-2 Gy/fraction) for gross, microscopic disease, and 

ipsilateral neck respectively. All PORT was delivered via 4-6 MV photons 

with daily 3-5 mm bolus. The median age was 52 (18-89). Females and 

Caucasian made up 56% and 64% of the population, respectively. 

Histologic findings were adenoid cystic carcinoma 20%, mucoepidermoid 

carcinoma 19%, adenocarcinoma 18%, pleomorphic carcinoma 16%, 

salivary duct carcinoma 9%, acinic cell carcinoma 8%, ex-pleomorphic 

carcinoma 7%, and sarcoma 3%. Pathological stages I, II, III, IV were 10, 

30, 20 and 40% respectively Results: With a median follow up of 56 

months (12-124), the LRC and DC for the whole cohort were 96% (5/118) 

and 93% (8/118) respectively. The median duration of PORT was 45 days 

(40-60). The median time to LR failure (LRF) and distant metastases were 

16 (12 - 30) and 28 months (24-48) respectively. Late RT toxicity was; 

grade I xerostomia 30%, altered taste 15%, trismus 6%, dysphagia and 

neck stiffness 2%. Kaplan-Meier curve shows the 5-year cause-specific 

survival to be 100%. Chi square and regression analysis tests show 

significant relationship (P�0.001) between salivary duct ca (70%) and 

distant metastases (DM), also males are at higher risk (17%) to develop 

LRF and DM, compared to females (6%). Poor prognostic features for DM 

and LRF were salivary duct ca, stage IV, PNI, and multiple LN involvement. 

Conclusions: Our data show that surgery followed by PORT to the tumor bed 

and ipsilateral neck provide excellent long standing oncologic and functional 

outcomes. Further studies are warranted to optimize the management 

of patients at higher risk of DM despite LRC and RT � chemotherapy 

administered. 


Phase II study of low-dose paclitaxel and cisplatin in combination with 

split-course concomitant twice-daily reirradiation (XRT) in recurrent squamous 

cell carcinoma of the head and neck (SCCHN): Long-term follow-up 

of Radiation Therapy Oncology Group (RTOG) protocol 9911. Presenting 

Author: Corey J. Langer, Abramson Cancer Center at the University of 


Background: Loco-regionally recurrent SCCHN or new second primary tumor 

(SPT) in a previous radiation field, if not curable by surgery, is virtually 

always fatal. Chemotherapy alone yields a median survival time (MST) of no 

more than 10 to 11 months, 1- and 2- year overall survival (OS) rates of 

35% and 10-15% at best. Concurrent re-irradiation and chemotherapy is 

an alternative strategy. Methods: Eligibility for RTOG protocol 9911 stipulated 

measurable, recurrent SCCHN or SPT in a previous radiation field, PS 

0-1, and adequate end-organ indices. Patients (pts) received twice-daily 

XRT (1.5 Gy per fraction BID x5devery 2 weeks x4), plus cisplatin 15 

mg/m2 IV QD x 5 and paclitaxel 20 mg/m2 IV QD x 5 every 2 weeks x 4. 

G-CSF was administered days 6 - 13 of each 2-week cycle. Primary 

endpoints were OS and progression-free survival PFS at 1 and 2 yrs. 

Secondary endpoints included acute/late toxicities and patterns of failure. 

Results: 105 patients were enrolled from March 2000 through June 2003. 

100 patients were analyzable (76% male, med age 60 yrs). Oropharynx 

(41%) and oral cavity (27%) were the predominant primary sites. 23% had 

SPT. Median prior XRT dose was 65.7 Gy. 73% of pts completed all 

chemotherapy. Grade � 4 acute toxicity occurred in 28%, grade � 4 acute 

hematologic toxicity in 21%. 9 treatment-related deaths (9%) occurred: 

five in the acute setting, four late (including three carotid hemorrhages at 

116, 427 and 2772 days). 1-, 2-, and 5-year OS rates were 50%, 27%, 

and 15% respectively. PFS at 1, 2, and 5 yrs were 35%, 18%, and 7%. 

64.9% died from the incident cancer, 3.2% from SPT, and 21.2% from 

other, non-cancer causes. Estimated 10 yr survival is 5% with 6 pts still 

alive, including 2 free from relapse. Conclusions: Despite a high incidence 

of grade 5 toxicity, 1-, 2-, and 5- yr OS rates for split-course bid XRT and 

concurrent cisplatin/paclitaxel exceed results usually seen with chemotherapy 

alone. At 5-10 yrs, we have observed longterm survivors free of 

recurrence. 



Sentinel lymph node biopsy for clinically N0 oral squamous cell carcinoma. 

Presenting Author: Hiroyuki Goda, Ehime University Graduate of Medicine, 

Department of Oral and Maxillofacial Surgery, Ehime, Toon, Japan 

Background: Regionallymph node metastasis is an important prognostic 

factor in oral squamous cell carcinoma (OSCC). Sentinel lymph node 

biopsy (SLNB) is a widely accepted procedure in various human malignancies. 

In clinically N0 (cN0) OSCC cases, SLNB has received considerable 

attention for its role in deciding whether to perform neck dissection. In this 

study, we assessed the efficiency of SLNB for cN0 OSCC case in a 

single-institution experience. Methods: 100 patients with cN0 OSCC 

underwent SLNB between 2001 and 2011, of which 95 were clinically T1 

and T2. The primary site was tongue, gingiva, oral floor, buccal mucosa, 

and lip in 50%, 36%, 8%, 5%, and 1%, respectively. The location of 

sentinel lymph node (SLN) was determined by radioisotope (RI) method 

with preoperative lymphoscintigraphy and intraoperative use of a handheld 

gamma probe and/or dye method, and evaluated by histopathological 

examination and genetic analysis. Results: SLNB was performed with RI 

and dye method (79%), only dye method (14%), or only RI method (7%). 

SLN was successfully identified with RI method (100%) and dye method 

(71%). The average number of SLN was 2.5 with dye method and 1.9 with 

RI method. The rate of SLN identified side was 84% in ipsilateral, 10% in 

bilateral, and 6% in contralateral. Fifteen of 100 patients (15%) had 

metastasis-positive SLN, and 3 patients was up-grade to stage III and 

others to stage IVA. Eight patients with negative SLN developed latent neck 

lymph node metastasis. The sensitivity, specificity, accuracy, and negative 

predictive value was 65% (15/23), 100% (77/77), 92% (92/100) and 

91% (77/85). Disease specific survival rate for SLNB-negative patients 

were 98% (79/81), and for SLNB-positive patients were 73% (11/15), 

respectively. Conclusions: SLNB is a minimally invasive and highly reliable 

means of staging the cN0 neck for patients with OSCC. Patients with 

negative SLNB showed more excellent neck control rate and SLNB provides 

more accurate staging than elective neck dissection or wait and see. 


Importance of HPV involvement and FOXP3� T-cell status as prognostic 

factors in tonsilar squamous cell carcinoma. Presenting Author: Kwonoh 

Park, Department of Oncology, Asan Medical Center, University of Ulsan 

College of Medicine, Seoul, South Korea 

Background: Human papillomavirus (HPV) status is a strong and independent 

favorable prognostic factor for survival in tonsilar squamous cell 

cancer (TSCC). The reason for the improved survival in HPV associated 

TSCC is unclear. Recently, activation of immune surveillance mechanism 

against non-self Ag is postulated to one of reasonable causes as favorable 

prognosis of HPV associated with TSCC. Methods: We reviewed the medical 

records of histologically confirmed locally advanced TSCC patients, curatively 

treated in Asan Medical Center from January 2000 to December 

2008. The immunohistochemistry (IHC) assays for p16 and FOXP3 were 

done in TSCC pafaffin-embedded samples. Results: We identified 79 

patients who met the inclusion criteria. The median age was 54 years 

(range 32-76) and 16 (20%) patients were stage III and the others were all 

stage IV. With the median follow up of 62.9 months (95% CI, 59.2 - 66.7), 

sixty three (80%) were HPV-positive with p16 overexpression, and 38 

(48%) were Treg-positive with FOXP3. Treg involvement was significantly 

related to HPV positive status (P�0.011). The result was the same after 

adjustment of age, T&Nstage, smoking exposure and alcohol consumption. 

(Odd ratio � 6.54, 95% CI 1.58-27.1, P�0.01) Five-year overall 

survival (OS) rate in HPV-positive group was significantly higher than that of 

HPV-negative group (78% and 63%, Hazard Ratio (HR)�0.347, 95% CI 

0.14-0.87, P�0.025), and 5-year OS of Treg-positive group was also 

higher than that of Treg-negative group (89% and 61%, HR�0.158, 95% 

CI 0.05-0.53, P�0.003). In multivariate analysis, the Treg status was an 

independent prognostic factor (HR�0.11, 95% CI 0.03-0.40, P�0.001), 

as well as HPV status. (HR�0.28, 95% CI 0.10 - 0.78, P�0.016). 

Conclusions: HPV positivity was associated with Treg positivity in TSCC and 

both were found to be favourable prognostic factors for survival. 


377s 


Neoadjuvant chemotherapy followed by definitive local treatment in locally 

advanced carcinoma maxillary sinus. Presenting Author: Vijay Patil, TMH, 

Mumbai, India 

Background: Locally advanced carcinoma of maxillary sinus has been 

historically reported to have poor prognosis. We evaluated the role of 

neoadjuvant chemotherapy in improving the outcome in these patients. 

Methods: 41 patients with locally advanced borderline resectable (stage 

IVa) or unresectable maxillary carcinoma (stage IVb) were treated with 

induction chemotherapy between 2008 and 2011. The protocol included 2 

cycles of chemotherapy, response assessment and multidisciplinary clinic 

review for definitive local treatment. The demographic profile, response to 

induction therapy, toxicity of chemotherapy, definitive treatment received, 

time to treatment failure (TTF) and overall survival (OS) were analysed. 

Univariate and multivariate analysis was performed to determine factors 

associated with response, TTF and OS. Results: The cohort of 41 patients 

had a median age of 48 years (22-71) with male preponderance (80.5%). 

The chemotherapy included two drugs (platinum and taxane) in 34 patients 

(82.9%) and three drugs (platinum, taxane and 5 FU) in 7(17.1%) The 

taxane utilized was docetaxel in 22 patients (53.7%) and paclitaxel in 19 

patients (46.3%). There was no complete response, stable disease in 18 

(43.9%), partial response in 16 (39%), and progression in 7 (17.1%) 

patients. All patients competed two cycles of chemotherapy, adequate dose 

intensity was maintained in 33 patients (78%) and there were no deaths. 

Post-induction, the treatment planned included surgery in 12 (29.3%), 

CT-RT in 24 (58.5%), radical RT in 1 (2.4%), palliative RT in 1 (2.4%) and 

palliative chemotherapy in 3 ( 7.3%) patients. Overall, the median TTF was 

10.2 months. With 16 deaths, the median OS was not reached. Only 

response post-induction was significantly associated with better TTF 

(p�0.02). Grade 3 tumor (p�0.04) and baseline serum albumin more than 

4 mg/dl (p�0.02) were associated with better OS. Grade 3-4 neutropenia, 

febrile neutropenia and loose motions were seen in 21.1%, 23.8% and 

15.8% respectively. Conclusions: In unresectable maxillary carcinoma, 

induction chemotherapy has clinically significant benefit with acceptable 

toxicity. Response to induction was the only significant factor for improved 

TTF. 


Pretreatment neurocognitive function (NCF) status in head and neck 

cancer (HNC) patients (pts) with comparison to control cohort. Presenting 

Author: Albiruni Ryan Abdul Razak, Princess Margaret Hospital, Toronto, 

ON, Canada 

Background: There is increasing evidence that NCF abnormalities may 

occur in cancer pts. Data on pre-treatment NCF in HNC pts are lacking. 

This study reports NCF in pts with newly diagnosed, curable HNC compared 

to controls. Methods: HNC pts underwent a 2-hour battery of NCF tests prior 

to radio �/-chemo(bio)therapy. Domains tested were intelligence (IQ), 

memory, language, attention, processing speed, executive function and 

manual dexterity. Test performances were transformed into Z-scores using 

normative data (score � -1 signified deficit). Pts also had self-reported 

assessments for NCF, quality of life (QOL), fatigue and affect. Data 

obtained were compared to non-cancer controls who underwent the same 

tests. Results: Eighty HNC and 30 control subjects were assessed. Objective 

NCF testing demonstrated that HNC and control cohorts were similar 

across all domains, except for IQ, with pts having higher scores (mean 0.55 

vs 0.12, p�0.03). However, individual analysis showed that 39% of HNC 

and 43% of control subjects had abnormal Z-scores in � 2 domains. 

Multivariable analysis of factors associated with � 2 abnormal NCF 

domains included: low education level, significant smoking history (� 10 

pack year), previous mild brain injury, gender, and group (pt vs control). 

Amongst pts, HPV -ve status and non-oropharyngeal tumors were also 

associated with decreased NCF. Pts reported statistically worse subjective 

baseline symptoms compared to controls: NCF (mean FACT-COG 33.7 vs 

18.2, p�0.002), QOL (FACT H&N 33.8 vs 14.9), fatigue (FACT-F 35.1 vs 

15.1), anxiety (HADS 7.0 vs 3.1) and depression (HADS 3.9 vs 1.2), 

p�0.01 for all five parameters. Conclusions: Objectively assessed NCF was 

similar between HNC pts and controls, but a proportion of participants in 

both cohorts have multi-domain abnormal Z-scores. Several patient demographics 

and disease characteristics were associated with abnormal NCFs. 

Subjectively, pts reported worse NCF, QOL, fatigue and affect. These data 

suggest that participant and disease characteristics may play a larger role 

in determining NCF than previously shown. Whether such characteristics 

impact subsequent NCF is under investigation in a longitudinal study. 




Second primary tumors in head and neck squamous cell carcinoma 

patients: A cross-sectional study. Presenting Author: Luciana Garcia 

Landeiro, Clinical Oncology, Faculdade de Medicina do ABC, Santo Andre, 

Brazil 

Background: Head and neck squamous cell carcinoma (HNSCC) patients 

(pts) are at elevated risk of developing a second primary tumor (SPT). Here 

we aimed to study the frequency of SPTs and those characteristics related 

to an increased probability of SPT occurrence. Methods: It is a crosssectional 

study in pts diagnosed with SCC primary located in oral cavity, 

oropharynx, hypopharynx or larynx, treated in two Brazilian institutions, 

with an index tumor diagnosed from Jan/2000 to Jan/2009. All pts were 

followed according the current recommendations, including clinical visits, 

imaging and endoscopic procedures. A SPT was defined following the 

Warren and Gates criteria (Am J Cancer 51:1358,1932), and they were 

classified as synchronous or metachronous if detected less or more than six 

months after the diagnosis of the index tumor, respectively. Results: 38 out 

of 318 HNSCC pts (12%) were diagnosed with 41 SPTs in their follow-up, 

being 12 synchronous (29%) and 29 metachronous (71%), all classified as 

SCC. Regarding the index tumor, it was primary located in oral cavity (114 

pts, 36%), oropharynx (87 pts, 27%), larynx (83 pts, 26%) and hypopharynx 

(34 pts, 11%), and staged as I-II (30%) or III-IV (67%). The SPTs were 

located more frequently in oral cavity (27%), lungs (27%), oropharynx 

(15%) and esophagus (12%) and staged as I-II (44%) or III-IV (42%). 

Among the 29 metachronous SPTs, 12 (41%) were diagnosed in the first 

two years of follow-up, 11 (38%) between two and five years, and 6 (21%) 

after five years. Considering all the studied HNSCC pts and index tumor 

characteristics, including primary site, persistence of tabacco and alcohol 

habits, and treatment, none was identified as related to an increased 

probability of developing a SPT. In the median follow-up of 40 mo., the 

median overall survival was not reached in all 318 HNSCC pts. No 

difference in overall survival was observed between those pts diagnosed or 

not with a SPT (HR 0.35, p�0.555). Conclusions: We found a 12% 

incidence of SPTs in these HNSCC pts. At diagnosis, SPTs were located 

more frequently in oral cavity and lungs, in advanced stages, and may occur 

even after five years after the index tumor. More efficient primary and 

secondary preventive strategies of SPTs must be developed. 


Gene expression as a predictor of radiotherapy or chemoradiotherapy 

response in head and neck squamous cell carcinoma patients: A molecular 

approach. Presenting Author: Antonio Lopez-Pousa, Hospital De Sant Pau, 


Background: There are not validated markers of radioresistance in patients 

with a head and neck squamous cell carcinoma (HNSCC). The objective of 

our study was to explore the relationship between response to radiotherapy 

and the expression at transcriptional level of a panel of genes related with 

the HNSCC carcinogenic process. Methods: The study group was 76 

consecutive HNSCC patients treated with radiotherapy (n�51) or chemoradiotherapy 

(n�25) with curative intention, and a minimum follow-up of 

three years. Thirty-seven patients were T1-T2 tumors and 16 had an 

advanced tumor (T3-T4). Biopsy specimens were performed from the 

primary tumor before treatment and conveniently stored until processing. 

Expression of genes related with cell cycle (cyclin D1), apoptosis (Bcl-XL), 

angiogenesis (VEGF), inflammation (IL-8), and tissue invasiveness (MMP-2 

and MMP-9) were examined using a RT-PCR method. The continuous value 

of the mRNA expression level was evaluated with a classification and 

regression tree (CRT) method, considering the local control of the disease 

achieved with radiotherapy as the dependent variable. Results: During the 

follow-up 26 patients (33.8%) had a local failure. The CRT method found a 

significant relationship between VEGF and MMP-9 expression and local 

control of the disease. According the expression level of VEGF and MMP-9 

the patients were classified in three groups: the A group (n�19) defined by 

a low expression of VEGF, the B group (n�19) defined by a high expression 

of VEGF and a low expression of MMP-9 and the C group (n�38) defined by 

a high expression of both VEGF and MMP-9. The 5-year local recurrence 

free survival was: A group 94.7% (CI 95%: 84.7-100%), B group 83.3% 

(CI 95%: 66.1-100%), and C group 37.6% (CI 95%: 21.0-54.2%). There 

were significant differences in the local control of the disease according to 

the VEGF and MMP-9 expression values (test log rank, P�0.0001). 

Conclusions: Expression of VEGF and MMP-9 genes may be a radiosensitivity 

marker for patients with HNSCC treated with radical intention. We didn’t 

find prognostic significance for other genes explored. 


Pattern of symptoms in head and neck cancer (HNC) survivors treated with 

radiation therapy (RT): Association with systemic therapy. Presenting 

Author: David Ira Rosenthal, University of Texas M. D. Anderson Cancer 


Background: We sought, in a large, long-term follow-up cohort, to determine 

benchmark cross-sectional analysis of HNC patient (pt) symptom profiles 

as a function of chemotherapy (CT)/RT strategy. Methods: Pts treated with 

RT with or without CT in remission � 18 mos. were surveyed with the MD 

Anderson Symptom Inventory–Head and Neck Module (MDASI-HN). Clinical 

data were extracted. Data were tabulated, and group comparison 

performed using non-parametric analyses. Results: 250 pts participated; 

81% were male. Median age at RT was 54 years. 87% had oropharynx 

HNC. Most were T1/X (41%), 37% T2 and, 22% T3/4. For N-category, 

most were N2 (55%), �5% N3, and 40% NX-1. 18% had induction CT, 

26% concurrent, 5% both, and 50% had none. At a median follow-up time 

of 5.9 years (range 2-15), 11% of pts were entirely symptom free, 31% 

reported �mild symptom severity, 20% �moderate, and 38% reported �1 

symptom as severe. 16% of pts receiving RT alone and 11% sequential CT 

followed by RT were symptom free, vs. 1% of those receiving concurrent CT 

(chi-square p�0.01), and the symptom distribution profile was distinct 

(p�0.03). The proportion of pts who received concurrent CT reporting any 

severe symptom item was 44%, vs. 36% of those not receiving concurrent 

CT (p�n.s.). No difference was seen in the moderate to severe (M/S) 

symptom report by treatment group. For all MDASI-HN items, most pts 

rated “0” or “not present”, except dry mouth and difficulty swallowing 

items, where mild symptoms were most likely (36% and 33%). The most 

common symptoms rated M/S were dry mouth, swallowing, choking, 

fatigue, and mouth and throat mucus reported by 42%, 23%, 18%, 16%, 

and 16%. MVA demonstrated T-stage and primary site, but not CT cohort 

correlated with M/S symptom report. Conclusions: Cumulatively, most pts 

had no more that mild symptom severity, but a substantial group of pts 

experience M/S levels. The symptom severity profile was highest with 

concurrent CT, though this effect appears mediated by disease specific 

factors. The addition of sequential CT to RT did not to appear to alter M/S 

symptom report substantially; however, concurrent pts were almost never 

symptom free, in contrast to induction and no CT cohorts. 


A phase II trial of the multitargeted kinase inhibitor lenvatinib (E7080) in 

advanced medullary thyroid cancer (MTC). Presenting Author: Martin 

Schlumberger, Institut Gustave Roussy, Villejuif, France 


VEGFR1-3, FGFR1-4, RET, KIT and PDGFR�. In phase I studies of 

lenvatinib partial responses (PR) were observed in thyroid as well as 

melanoma, endometrial, and renal cancers. Methods: Patients (pts) with 

unresectable MTC and disease progression demonstrated by RECIST 

during the prior 12 months were enrolled. Pts may have received prior 

VEGFR targeted therapy. Pts were treated with a starting dose of lenvatinib 

24 mg once daily in 28 day cycles until disease progression or development 

of unmanageable toxicities. Primary end point was Response Rate (RR) by 

RECIST. Tumor genetic analysis and circulating cytokine and angiogenic 

factors (CAF) analysis were performed. Results: 59 pts were enrolled (med 

age: 52; Male: 63%;) and are evaluable for response. 54% of pts required 

dose reduction for management of toxicity, and 22% were withdrawn from 

therapy due to toxicity. The most common treatment-related adverse events 

were proteinuria 58% (Gr3: 2%), diarrhea 56% (Gr3: 5%), hypertension 

48% (Gr3: 7%), fatigue 44% (Gr3: 5%), decreased appetite 41% (Gr3: 

5%), nausea 34% (Gr3: 0), and weight decreased 32% (Gr3: 3%). No Gr4 

events were reported for these event categories. Confirmed PRs were 

observed in 21pts (RR: 36%, 95% CI: 24-49) based on independent 

imaging review (IIR) and 29 pts (RR: 49%, 95% CI: 36-62) based on 

investigator assessment. For pts who received prior VEGFR-directed treatment 

(n�26) RR�35% (IIR); with no prior VEGFR-directed treatment 

(n�33) RR�36 % (IIR). Median PFS by IRR is 9.0 mo (95% CI: 7.0-) 

(based on minimum 8 mo. f/u, 46% events observed). There was no clear 

difference in treatment response between RET-mutant (RET-mu) and 

RET-wild type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF 

and IL-8 were associated with greater tumor shrinkage and prolonged PFS 

whereas high baseline levels of VEGF and sVEGFR3 were associated with 

greater tumor shrinkage. Conclusions: Lenvatinib administered orally at a 

dose of 24 mg once daily to patients with MTC is associated with 

manageable toxicity and a RR of 36%, identifying lenvatinib as a promising 

new potential therapeutic agent for treating patients affected with this 

disease. 



Final results of a phase II study of sorafenib in combination with 

carboplatin and paclitaxel in patients with metastatic or recurrent squamous 

cell cancer of the head and neck (SCCHN). Presenting Author: 

George R. Blumenschein, University of Texas M. D. Anderson Cancer 


Background: Cytotoxic chemotherapy (CT) is the current standard treatment 

for metastatic/recurrent SCCHN. The prognosis for these patients (PTS) is 

poor with a median progression free survival (PFS) of 4 months with CT. 

Survival in PTS with SCCHN may correlate inversely with the number of 

angiogenic growth factors secreted. Sorafenib is a potent inhibitor of c-Raf, 

b-Raf, VEGFR-1/2/3 and PDGFR-�. To investigate the hypothesis that a 

multi-targeted TKI added to chemotherapy would improve outcomes in 

patients with metastatic/recurrent SCCHN, we performed a phase II trial of 

paclitaxel and carboplatin and sorafenib (PCS). Methods: PTS were 

required to have ECOG PS 0-1, measurable disease, controlled blood 

pressure, and may have received one regimen of induction, concomitant or 

adjuvant CT, but not CT for recurrent/metastatic disease. Sites of primary 

disease excluded nasopharynx and paranasal sinus. Treatment consisted P 

200mg/m2 and C AUC 6 intravenously on day 1 followed by S 400 mg orally 

bid (days 2-19) in every 3-week cycles. Primary endpoint was PFS, 

targeting median PFS of 6 months (M). Secondary endpoints include 

overall survival (OS), response rate (RR), exploratory biomarkers, and 

toxicity. Results: Forty-eight PTS with SCCHN were enrolled with 44 PTS 

evaluable for PFS and response using RECIST. Median age: 56 years 

(22-79 years), 89% male, median ECOG PS 1. Median follow-up was 24.1 

M. RR was 55% (n�24), disease control rate was 84% (n�37), median 

PFS was 8.51 M (95% CI: 5.98 ~ 13 months), and median OS was 22.6 M 

(95% CI: 13.1 - NA months). Grade ³3 treatment related toxicities included 

hand-foot syndrome (n�10), neutropenia (n�5), pain (n�6), elevated 

lipase (n�4), elevated amylase (n�3), anemia (n�3), fatigue (n�2), 

hypertension (n�2), neuropathy (n�2), febrile neutropenia (n�2), and 

thrombocytopenia (n�2). Conclusions: The combination of PCS was well 

tolerated and had encouraging activity in recurrent/metastatic SCCHN. 

Blood-based and tissue biomarkers are being analyzed. Final outcomes, 

toxicity, and correlative biomarker data will be reported. 


Long-term survival after distant metastasis in oropharyngeal carcinoma. 

Presenting Author: Sean M. McBride, Harvard Radiation Oncology Program, 

Boston, MA 

Background: The possibility of cure after distant metastases (DM) in 

oropharyngeal carcinoma (OPC) is uncertain. We conducted a retrospective 

cohort study to determine outcome and factors predictive of survival after 

metastasis in patients with OPC. Methods: From 2003-2010, 24 patients 

definitively treated (96% with concurrent chemo-radiation) at the Massachusetts 

General Hospital for OPC subsequently developed DM. At initial 

diagnosis, HPV status was available in 13 patients, 12 of whom were 

positive; six patients had T4 and 12 N2c-3 disease. Imaging studies 

pertinent to the diagnosis of DM were re-reviewed; 83% of patients had DM 

pathologically confirmed. Overall survival (OS) was defined from 1st 

radiographic evidence of DM to either death or last follow-up. Cox 

regression was used to evaluate factors predictive of OS after DM. Results: 

Median time to DM after initial treatment was 8.25 months (range, 

1.6-24). Twenty (83%) patients had isolated distant failure; of these, 6 

had limited (1 lesion or 2 adjacent lesions) single-organ disease. Eighteen 

(75%) had treatment after DM (83% had chemotherapy, 61% radiation, 

and 33% surgery). Median survival after distant metastasis was 19.2 

months. Median follow-up for survivors was 23.5 months (range, 7.9- 

60.3). In multivariate analysis, limited single-organ disease (HR�0.14, 

p�0.01, 95% CI 0.031, 0.67) was predictive of improved survival after 

DM; T4 disease at initial diagnosis predicted for decreased OS after DM 

(HR�3.9, p�0.01, 95% CI 1.31, 11.89). For patients with limited 

single-organ disease, the 2-year OS was 82% compared to 32% with 

extensive metastases (p � 0.006). Of the 6 patients with limited, 

single-organ metastatic disease, two remained alive at 59.4 and 60.5 

months without evidence of disease; both had HPV-positive tumors. One 

patient had a solitary hepatic failure and received neoadjuvant chemotherapy 

followed by partial hepatectomy; the other had a solitary lung 

metastasis and received wedge resection followed by radiation. Conclusions: 

Limited, single-organ metastatic disease predicts improved survival after 

DM in OPC. Cure is possible in this group. Patients with limited, 

single-organ distant disease should be considered for aggressive, local 

salvage treatment. 


379s 


TPF induction chemotherapy and pathologic response for patients with 

locally advanced and resectable oral squamous cell carcinoma. Presenting 

Author: Lai-ping Zhong, Department of Oral and Maxillofacial Surgery, 

Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 

Shanghai, China 

Background: The role of induction chemotherapy in locally advanced and 

resectable oral squamous cell carcinoma has not been well issued. 

Methods: A prospective, open label, parallel, and interventional randomized 

control trail has been performed to evaluate the induction chemotherapy of 

TPF protocol in resectable oral squamous cell carcinoma (OSCC) patients 

at clinical stage III and IVA. The patients received two cycles of TPF 

induction chemotherapy (75 mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, 

and 750mg/m2 5-fluorouracil d1-5) followed by radical surgery and 

post-operative radiotherapy with a dose from 54 to 66 Gy (the experimental 

group) or surgery and post-operative radiotherapy (the control group). 

Post-surgical pathologic examination was performed to determine a positive 

response or negative response. A positive response was defined as 

absence of any tumor cells (pathologic complete response) or presence of 

scattered foci of a few tumor cells (minimal residual disease with �10% 

viable tumor cells). The primary endpoint is the survival rate; the secondary 

endpoint is the local control and safety. This study has been approved by 

institutional ethics committee at Ninth People’s Hospital, School of 

Medicine, Shanghai Jiao Tong University. Survival analysis was conducted 

with the Kaplan-Meier method. Results: 256 patients were enrolled in this 

trail and 224 patients (111 in experiment group and 113 in control group) 

finished the whole treatment protocol. After a median follow-up of 21 

months (ranging 6-43 m). The pathologic positive response rate was 29.7% 

(33/111), and negative response rate was 70.3% (78/111). The patients 

with positive response had a better disease free survival (38.5�2.1m, 

95%CI 34.4-42.6m, P�0.003) compared with those with negative response 

(24.6�2.1m, 95%CI 20.6-28.7m) and control group (31.0�1.6m, 

95%CI 27.9-34.1m). The toxicity of induction chemotherapy could be 

tolerated. Conclusions: Pathologic positive response to TPF induction 

chemotherapy could benefit the patients with locally advanced and 

resectable OSCC. However, further long-term follow-up is needed to 

confirm the benefit on survival and local control. 


Progressive increasing in the risk of second and subsequent malignant 

tumors in patients with a head and neck cancer: A validation study with 

SEER data. Presenting Author: Xavier Leon, Hospital Sant Pau, Barcelona, 

Spain 

Background: Patients with a head and neck squamous cell carcinoma 

(HNSCC) index tumor have a increased risk (2-4% per year) for appearance 

of a second malignant neoplasms (SMN) and higher risk for successive 

malignant tumors during the follow-up. The objective of our study was to 

validate this concept with data of patients included in the Surveillance 

Epidemiology and End Results (SEER) program (1973-2008). Methods: 

We performed a population-based cohort study of 149.328 patients with a 

primary oral cavity, oropharynx, hypopharynx and larynx squamous cell 

carcinoma index tumor, included in the SEER program, to analize the 

actuarial survival-free of second and successive tumors. A total of 11.948 

(8%) patients had one or more malignant tumors before the diagnosis of 

HNSCC. Results: During the follow-up period, a total of 31.507 new SMN 

appeared. There was a progressive and significant increase in the risk of 

SMN. The annual hazard ratio for 2nd to 7th successive SMN was 2.3%, 

2.7%, 3.9%, 5.4%, 8.9% and 19.1% annual risk respectively. Additionally 

11 patients had 8th SMN. We observed a progressive increase in the 

risk of appearence of new malignant tumors located in and outside the 

aerodigestive tract. The increase in the risk of SMN was higher for tumors 

located in the aerodigestive tract than tumors located outside aerodigestive 

tract. It was a tendency towards the increase in the proportion of HNSCC 

with the appearance of new tumors, with a decrease in the proportion of the 

malignant tumors located in the lung and in locations outside the 

aerodigestive tract. There were significant differences inthe risk of SMN 

between second and third, third and fourth, fourth and fifth, and sist and 

seventh tumors (p�0.0001). Conclusions: In patients with HNSCC there is 

a progressive increase in the risk of appearance of successive tumors. 

Previous tobacco and alcohol consumption, persistence in the exposure to 

carcinogens and individual susceptibility (genetic) could play a role in the 

increased risk of SMN. We have validated this concept with data from the 

SEER program. 



5596^ General Poster Session (Board #32F), Sat, 1:15 PM-5:15 PM 

Contralateral parotid volume as an objective marker for adaptive radiotherapy 

in head and neck cancer. Presenting Author: Patrick James 

Gagnon, Southcoast Centers for Cancer Care, Fairhaven, MA 

Background: Deformable image registration simplifies the process of adaptive 

radiotherapy and allows for sophisticated dosimetric analyses of 

anatomic changes. Lacking is an objective measurement that could reliably 

predict for undesirable dosimetric changes during a course of radiotherapy. 

We analyzed daily changes in contralateral parotid volume and correlated 

these changes to mean dose delivered to the parotid gland over a course of 

radiotherapy in four patients. Methods: Daily cone-beam CT (CBCT) scans 

of four patients were imported into the MIM Maestro software. The 

simulation CT scan was registered to 35 daily CBCT’s per patient using a 

sequence of rigid and deformable registrations. Parotid contours were 

resampled and a deformed reconstruction of the planning CT was exported 

to the Eclipse treatment planning software. The CT reconstructions were 

extended superiorly and inferiorly and the original fluence map was 

re-computed on the reconstructions with the isocenter at daily treatment 

position. Mean dose percent change and mean volume percent change 

were calculated for all CBCT’s and averaged across all patients. Average 

mean dose percent change was plotted against average mean volume 

change and evaluated with simple regression analysis. Results: A mean of 

31 CBCT’s per patient were evaluated. Contralateral parotid volume 

percent changes for all patients were -31%, -40%, -40%, and -22% with a 

mean percent change of -33%. Mean dose percent changes were 25%, 

35%, 19%, and 25% with a mean percent change of 26% and a mean 

absolute dose increase to the parotids of 6.8 Gy. Simple regression analysis 

identified a coefficient of determination (R2 ) of 0.23 where the independent 

variable is volume percent change and the dependent variable is mean 

dose percent change. Conclusions: Daily or weekly volume assessment of 

critical volumes is feasible utilizing deformable image registration and 

CBCT. Our data suggests there may be a correlation between parotid 

volume changes and increases in mean parotid dose though no causality is 

inferred. This relationship could be useful as a simple objective volumetric 

threshold measurement to prompt adaptive re-planning and warrants 

further investigation. 

TPS5598 General Poster Session (Board #32H), Sat, 1:15 PM-5:15 PM 

LUX-H&N 1: A phase III, randomized trial of afatinib versus methotrexate 

(MTX) in patients (pts) with recurrent/metastatic (R/M) head and neck 

squamous cell carcinoma (HNSCC) who progressed after platinum-based 

therapy. Presenting Author: Jean-Pascal H. Machiels, Clinique Universitaires 

St-Luc, Brussels, Belgium 

Background: EGFR (ErbB1) is expressed in 90% of HNSCC and associated 

with poor prognosis. Despite clinical benefit (CB) of EGFR-targeted 

treatments such as cetuximab treatment resistance will occur resulting in a 

need for novel targeted treatments to improve prognosis. Afatinib is an 

ErbB Family Blocker that irreversibly blocks signaling from all relevant 

ErbB Family dimers and may overcome limitations of current EGFRtargeted 

treatments in HNSCC. In a randomized, proof-of-concept, Phase II 

trial, afatinib demonstrated comparable anti-tumor activity to cetuximab in 

pts with R/M HNSCC progressing after platinum-based therapy (Seiwert TY, 

et al; THNO, November 2011; Abs 40). Methods: LUX-H&N 1 is a phase III, 

randomized, open-label trial (NCT01345682) evaluating efficacy and 

safety of afatinib vs. MTX in pts with R/M HNSCC who have progressed after 

platinum-based therapy. Key eligibility criteria: confirmed R/M HNSCC not 

amenable to salvage surgery/radiotherapy; documented PD after cisplatin 

and/or carboplatin for R/M disease; any other than 1 previous platinumbased 

regimen for R/M disease; ECOG status 0 or 1; no PD �3 months of 

completion of curatively intended treatment for locoregionally advanced or 

metastatic HNSCC; and no prior EGFR-targeted small molecules treatment. 

Eligible pts are stratified into four strata: ECOG performance score (0 

vs. 1) and prior use of EGFR-targeted antibody therapy (Yes/No) given in the 

R/M setting. Pts are randomized 2:1 to: afatinib (40mg/d orally) or MTX 

(40mg/m2 IV weekly). Dose changes are permitted according to absence/ 

presence of drug-related AEs (afatinib: escalation to 50mg/d and/or 

reduction to 40, 30 then 20mg/d; MTX: escalation to 50mg/m2 and/or 

reduction to 40, 30 then 20mg/m2 ). Pts receive continuous treatment until 

PD or AEs requiring withdrawal. Randomized treatment may continue 

beyond PD in case of CB as judged by the investigator. The primary 

endpoint is PFS and secondary endpoints include OS, OR, health-related 

QOL and safety. Target enrolment is 474 pts and completion of pt 

recruitment and data analyses are awaited. 


Clinical outcomes and prognostic factors of 582 nasopharyngeal carcinoma 

patients treated with intensity-modulated radiotherapy. Presenting Author: 

Jin Yi Lang, Sichuan Cancer Hospital and Institute, Chengdu, China 

Background: To evaluate the 5-yrs clinical outcomes and prognostic factors 

of 582 nasopharyngeal carcinoma (NPC) patients treated with intensity 

modulated radiotherapy (IMRT). Methods: 582 NPC patients primarily 

treated with IMRT in Sichuan Cancer Hospital from Jan.2001 to Dec.2004 

were analyzed retrospectively, including 460 males and 122 females. The 

prescription dose was delivered as follows: gross target volume (GTVnx) 

67-76Gy in 30-33 fractions, positive neck lymph nodes (GTVln-R/L) 

60-70Gy in 30-33 fractions, The lower neck and the supraclavicular fossae 

were irradiated with the conventional 2D technique using an anterior field. 

The Kaplan-Meier method was used to calculate the local-regional control 

rate (LRC) and overall survival rate (OS). Acute and late toxicities were 

graded according to the Radiation Therapy Oncology Group (RTOG) 

radiation morbidity scoring criteria, meanwhile analyze the prognostic 

factors. Results: The median follow-up interval was 66.4 months. The 

5-year local control, regional control, distant metastasis-free survival, 

disease free survival, disease specific survival and overall survival rate was 

89.8%, 95.2%, 74.1%, 69.6%, 83.2% and 77.1%. 133 patients died 

during the follow-up. The 5-year DMFS of IMRT and IMRT combined with 

chemotherapy was 62.1% and 70.9%, the OS of them was 75.9% and 

79.1%. The incidence of grade 3 acute and late toxicity was 38.3% and 

4.2% respectively.Univariate analysis revealed that gender, T/N stage, 

clinical stage, radiotherapy interruption, anemia and weight loss was the 

significant prognostic factor for the OS. Multivariate analysis showed that N 

stage, radiotherapy interruption, chemotherapy, the volume of GTVnx, age, 

anemia and weight loss was the independent prognostic factors for the OS. 

Conclusions: The 5-year local control and overall survival rate of NPC 

treating with IMRT was 89.8% and 77.1%. The clinical stage, N stage , 

volume of GTVnx and chemotherapy was the main prognostic factor for the 

OS. The acute and late toxicities were mainly grade I and II. Distant 

metastasis was the main pattern of failure. 


LUX head and neck 2: A randomized, double-blind, placebo-controlled, 

phase III study of afatinib as adjuvant therapy after chemoradiation in 

primarily unresected, clinically high-risk, head and neck cancer patients. 

Presenting Author: Barbara Burtness, Fox Chase Cancer Center, Philadelphia, 

PA 

Background: Locally advanced squamous cell cancer of the head and neck 

(SCCHN) is treated with curative intent, but recurrence and death are 

common. SCCHN frequently over-expresses EGFR (ErbB1). Co-expression 

of other HER family members such as HER2 (ErbB2) may contribute to 

resistance to EGFR inhibition, which is the only validated targeted therapy 

in SCCHN. Methods: The trial investigates if adjuvant afatanib, an irreversible 

ErbB family blocker, which has shown preclinical activity against all 

ErbB dimers including EGFR and HER2, reduces the risk of recurrence in 

high-risk patients who have no evidence of disease following platinumbased 

chemoradiation with or without neck dissection. Patients are eligible 

who have received definitive chemoradiation to a minimum of 66 Gy, with 

concurrent cisplatin (�200 mg/m2 ) or carboplatin (�AUC 9), for SCC of 

the oral cavity, oropharynx, or hypopharynx or larynx. Patients with base of 

tongue or tonsil cancer and �10 pack years of tobacco use, as well as those 

with nasopharynx, sinus or salivary gland cancer, are excluded. Adequate 

bone marrow, liver and kidney function is required. Prior therapy with 

investigational agents or EGFR inhibitors is not permitted. Randomization 

must take place within 16 weeks of the completion of chemoradiation with 

or without subsequent neck dissection. Patients are randomized 2:1 to 

afatinib 40 mg po qd or placebo, and treatment continues for 18 months in 

the absence of disease recurrence, second primary tumors, or intolerance 

to the study medication. Dose escalation to 50 mg qd is undertaken in 

patients with no side effects, and stepwise dose reduction to 30 or 20 mg 

po qd for diarrhea, skin toxicity or other adverse events is permitted. The 

primary endpoint is disease-free survival (DFS). The study is planned to 

accrue approximately 669 patients worldwide, with a 90% power to detect 

a hazard ratio of 0.72. Secondary endpoints are DFS at 2 years, overall 

survival, health-related quality of life, and safety. 



A phase III study of standard fractionation radiotherapy with concurrent 

high-dose cisplatin versus accelerated fractionation radiotherapy (RT) with 

panitumumab in patients with locally advanced stage III and IV squamous 

cell carcinoma of the head and neck (SCCHN) (NCIC Clinical Trials Group 

HN.6). Presenting Author: John N. Waldron, Princess Margaret Hospital, 


Background: Standard treatment for locally advanced SCCHN, chemoradiotherapy 

(CRT), leads to significant acute and long-term morbidity. The 

demonstration that EGFR antibody (Ab) therapy improves outcome when 

added to standard RT (Bonner NEJM 2006) and that altered fractionation 

RT improves outcome compared to standard RT that is of similar magnitude 

as CRT (Bourhis Lancet 2006), led to the hypothesis that the combination 

of the two treatment strategies will improve efficacy compared to standard 

CRT with good tolerability. Methods: HN.6 is a Canadian phase III 

randomized study comparing standard RT 70Gy/35 over 7 weeks � 

cisplatin 100mg/m2 d 1, 22, 43 to accelerated RT 70Gy/35 over 6 weeks � 

panitumumab (anti EGFR Ab)) 9mg/kg 1 week prior to RT, d15, 36. Key 

eligibility criteria are: SCC of oral cavity, oropharynx, larynx or hypopharynx; 

TanyN�M0 or T3-4N0M0; adequate organ function and PS. Primary 

endpoint is progression free survival (PFS). Secondary endpoints include 

OS, local PFS, regional PFS, distant metastases, swallowing related QOL, 

functional swallowing outcomes, and economic evaluation (healthcare 

utilization, health utilities, indirect costs). Tissue and blood collection will 

allow biomarker evaluation including HPV status. Real time quality review 

of RT plans with plan data and radiology archiving will allow future analysis 

of RT parameters relative to toxicity and patterns of failure. Clinical 

epidemiological data will be prospectively collected and correlated with 

biomarkers and outcome. Planned sample size is 320 patients over 3.2 

years with 3 more years of follow-up and target hazard ratio � 0.7 (absolute 

difference in control arm 2 year PFS of 12%, power 80%, 2-tail type 1 error 

0.05). If superiority is not demonstrated, noninferiority will be tested. One 

interim analysis is planned. Conduct to Date: Study activation: Dec 2008 

and completed accrual in Nov 2011. In Oct 2011, the DSMC recommended 

trial continuation. Supported by CCSRI grant 021039 and Amgen 

Inc. ClinicalTrials.gov: NCT00820248. 


A pilot study of raltegravir and cisplatin in head and neck squamous cell 

carcinoma (HNSCC). Presenting Author: Julie E. Bauman, University of 

New Mexico, Albuquerque, NM 

Background: Metnase is a recently characterized DNA repair component 

present in anthropoid primates. Metnase, the fusion of a SET histone 

methylase domain and a Transposase nuclease (Tn) domain, enhances 

DNA double-stranded break (DSB) repair. The Tn domain trims free DNA 

ends for optimal end-joining, and is required to re-start stalled replication 

forks. The SET domain di-methylates H3K36 at the DSB, recruiting 

non-homologous end-joining repair components. Cisplatin (CDDP), the 

central chemotherapy in HNSCC, covalently binds DNA leading to intraand 

interstrand crosslinks (ICL). In addition to blocking strand transcription 

and segregation, the ICL stalls DNA replication fork progression 

leading to collapse and DSB. The role of Metnase in DNA repair, including 

overcoming the stalled replication fork, makes it a potential therapeutic 

target. We hypothesize that Metnase inhibition may be a useful adjunct to 

CDDP. 3D modeling of the Metnase Tn domain identified significant 

homology with human immunodeficiency virus 1 (HIV-1) integrase. A 

virtual screen of the Chem Div library identified the HIV-1 integrase 

inhibitor, raltegravir, as a lead compound for inhibiting the Metnase Tn 

domain. We designed a pilot study in HNSCC to evaluate potentiation of 

CDDP DNA damage by raltegravir. Methods: The primary objective of this 

window-of-opportunity study is to analyze biomarkers of DNA damage, fork 

arrest, and apoptosis in serial tumor biopsies from patients (pts) with 

HNSCC undergoing CDDP, with and without raltegravir. Eligible pts: 1) 

have HNSCC with tumor site amenable to repeat, awake biopsy; 2) are 

appropriate candidates for CDDP. Pts are treated with 2 doses of CDDP 30 

mg/m2 . One CDDP dose is administered with raltegravir 400 mg bid for 5 

days, starting the day before CDDP. Pts undergo 3 research biopsies, at 

baseline and 48-72 hours after each CDDP. Serial biopsies will be 

evaluated for expression changes in �H2AX, Annexin V, pChk1, pChk2, and 

p53BP1 by immunohistochemistry. Numerical increase in biomarker 

expression in tumors exposed to CDDP-raltegravir vs. CDDP will justify 

development of a phase I/II study. Four of 12 pts have enrolled and 

completed all biopsies. Supported by a grant from the American Cancer 

Society. 


381s 


Phase II trial of neoadjuvant chemotherapy for HPV-associated squamous 

cell carcinoma of the oropharynx followed by reduced-dose radiotherapy/ 

chemoradiotherapy for responders or standard dose chemoradiotherapy for 

nonresponders. Presenting Author: Bhoomi Mehrotra, Hofstra North Shore- 

LIJ School of Medicine, New Hyde Park, NY 

Background: Recent studies have established an improved outcome for HPV 

associated oropharyngeal squamous cell cancers with 3 year OS rates 

approaching 90%. Given that current aggressive treatment modalities for 

HNC include IMRT and chemotherapy (CT), they adversely affect the long 

term QOL of these patients who are considered highly curable. The primary 

objective of our study is to confirm the activity (CR � PR at 3 months post 

completion RT/CRT) of induction TPF followed by dose reduced IMRT �/concurrent 

CT, in nonsmokers with HPV associated, locally advanced SCC 

of H&N. Secondary objectives include: to define objective tumor RR to 

induction chemotherapy and to subsequent RT based treatment, per 

RECIST version 1.1 criteria, assess PFS and OS at 2 years,assess 

locoregional disease and distant disease control at 2 years, and monitoring 

of QOL instruments for HNC. Methods: Institutional IRB approval has been 

obtained for this study. Eligibility criteria include p16 expressing or ISH � 

SCC of the oropharynx, T1-3, N1-2, age � 17 years, adequate marrow and 

organ function and adequate PS. Exclusion criteria include T4 or N3 

disease, significant smoking history � 10 pack year lifetime exposure. 

Patients would be treated with standard TPF induction for 3 cycles followed 

by risk assessment. Pts. achieving locoregional CR or CR/PR at primary site 

would receive dose reduced RT (66 Gy) �/- CT, while those with SD/PD 

would receive standard CRT with full dose XRT. Post therapy assessments 

include serial evaluation of functional quality-of-life, including M. D. 

Anderson Dysphagia Inventory (MDADI) and Oropharyngeal swallowing 

efficiency (OPSE) measures of swallowing function, treatment related 

symptoms, dietary status assessments and formal sialometric measurement 

of parotid function. Interim analysis would include RR assessment at 

3 months post treatment in the first 12 patients who received dose reduced 

RT and compared with historical controls. Early stopping rules are built into 

the protocol. This study is currently open and patient accrual is ongoing. 


382s Health Services Research 


Racial disparities in breast cancer survival. Presenting Author: Jeffrey H. 

Silber, The Children’s Hospital of Philadelphia and The University of 

Pennsylvania Perelman School of Medicine, Philadelphia, PA 

Background: Reducing racial disparities in breast cancer survival has been a 

federal priority since the early 1990’s. We present a new method to assess 

disparities using sequential multivariate matching. We ask if racial disparities 

have increased or decreased over time and if so, what were potential 

reasons for such changes. Methods: We studied all women over 65 years of 

age in the Medicare fee for service system diagnosed with breast cancer 

between 1991 and 2005 who were treated in one of 12 SEER sites (the 

sites in SEER since 1991). There were 5,251 black patients (74% early 

stage (I-III), 9% late stage (IV) and 17% missing stage) and 72,695 white 

patients (81% early stage, 5% late stage and 14% missing stage). All black 

cases represented the focal group for all matches. Using multivariate 

matching and the propensity score, white controls were matched to blacks 

in steps: (1) White controls matched to black cases on age and year of 

diagnosis; (2) Age, year of diagnosis, and stage; (3): Age, year, stage, 

estrogen receptor status, grade, and 30 comorbidities. We then compare 

5-year survival in the Pre and Post-Taxane periods (1991-1998, 1999- 

2005). Results: When whites were matched to blacks on age and diagnosis 

year, 5-year Kaplan-Meier survival was 69.2% vs. 56.7%, P � 0.0001. 

Matching additionally on stage, differences � 64.1% vs. 56.7%, P � 

0.0001; Matching further on tumor characteristics and 30 comorbidities, 

the disparity reduced to 61.6% vs. 56.7%, P � 0.0001. Comparing trends 

over time, white-black differences in survival matched for age and year were 

67.6% vs. 55.2% (P � 0.0001) in the pre-Taxane era (difference � 

12.4%) and 71.2% vs. 58.7% (P � 0.0001) in the post Taxane era 

(difference � 12.5%); age and year matched paired racial differences were 

not different across eras (P � 0.389). Conclusions: While there may have 

been some improvements in overall survival, racial disparities in breast 

cancer survival have not improved, despite important policy initiatives and 

treatment advances. Adjusting for presentation at diagnosis does reduce 

differences in survival, but even these differences remain large and 

significant, suggesting that differences in both presentation and treatment 

given presentation are contributing to this disparity. 


An international study of multitrial data investigating quality of life and 

symptoms as prognostic factors for survival in different cancer sites. 

Presenting Author: Chantal Quinten, European Organisation for Research 

and Treatment of Cancer Headquarters, Brussels, Belgium 

Background: The prognostic value for survival of HRQOL data derived from 

self-report questionnaires, has been well documented in cancer research. 

The objective of this study was to examine the prognostic value of HRQOL 

parameters for different cancer sites using one standardized and validated 

patient self-assessment tool. Methods: A total of 11 different cancer sites, 

pooled from 30 European Organisation for Research and Treatment of 

Cancer (EORTC) Randomized Controlled Trials (RCTs), were selected for 

this study. For each cancer site, univariate and multivariate Cox proportional 

hazard modeling was used to assess the prognostic value (p�0.05) of 

15 HRQOL parameters, assessed with the EORTC QLQ-C30 at baseline 

before randomization, for overall survival. Models were adjusted for the 

parameters age, gender, distant metastasis, World Health Organization 

performance status and stratified by clinical study. Results: A total of 7,417 

patients completed the EORTC QLQ-C30 before randomization. For brain 

cancer cognitive functioning (CF) (hazard ratio (HR) �0.95; p�.0001) was 

prognostic. For breast cancer nausea and vomiting (NV) (HR�1.17; 

p�0.0011) was a prognostic indicator. For colorectal cancer physical 

functioning (PF) (HR�0.93; p�.0001), NV (HR�1.07; p�.0001), and 

appetite loss (AP) (HR�1.07; p�.0001) predicted survival. For esophageal 

cancer PF (HR�0.88; p�0.0072) and for head and neck cancer NV 

(HR�1.14; p�0.0097) were prognostic. For lung cancer PF (HR�0.94; 

p�0.0006) and pain (HR�1.08; p�0.0001), for melanoma dyspnea 

(HR�1.06; p�.0001), for ovarian cancer NV (HR�1.2; p�.0001), for 

pancreatic cancer global QOL (HR�0.83; p�0.0073), for prostate cancer 

role functioning (RF) (HR�0.96; p�0.006) and AP (HR�1.07; p�.0001), 

and for testis cancer RF (HR�0.81; p�0.0144) were predictors of 

survival. Conclusions: Our findings show that different HRQOL parameters 

provide prognostic information for survival for patients with different tumor 

sites and that no single HRQOL scale can predict survival in all cancer 

patients. Thus, each cancer site needs careful examination and no single 

QOL paramenter can predict survival in all cancer diseases. 


Competing causes of mortality in long-term survivors of head and neck 

cancer. Presenting Author: Shrujal S. Baxi, Memorial Sloan-Kettering 


Background: Most head and neck cancers (HNC) recur within the first 3 yrs 

of diagnosis. Patients who live beyond this time point continue to have an 

excess risk of mortality. We investigated the causes of mortality in 3-yr 

survivors of HNC. Methods: We completed a retrospective cohort study 

using the Surveillance Epidemiology and End Results (SEER) database. We 

identified patients with a diagnosis of non-metastatic HNC between 1992 

and 2005 who survived 3 yrs from diagnosis. The primary outcome was 

death from all-causes, HNC, non-HNC malignancy, cardiovascular disease 

(CVD), and pulmonary disease (PD). We estimated the age-adjusted 

standardized mortality ratio (SMR; observed-to-expected (O/E)) and the 

absolute excess risk (AER; O-E), for all-cause and cause-specific mortality 

compared to US population data. Results: 31,772 long-term survivors were 

identified with disease arising in the larynx (40%), oral cavity (29%), 

oropharynx (26%), nasopharynx (3%) and hypopharynx (1%). In this 

cohort, 8191 (26%) were female, 3021 (10%) were black and 15,321 

(48%) were younger than 60 yrs. In this cohort, 16,697 (53%) had 

locally-advanced disease and 8353 (26%), 8721(27%) and 13,919 

(44%) received radiation alone, surgery alone or both. With a median 

follow-up of 6.4 years (3-17 years), there were 10,757 deaths due to: HNC 

(24%), non-HNC malignancy (31%), CVD (21%), PD (6%), and other 

causes (19%). Compared to the US population, the all-cause SMR was 5.4 

(95% CI 5.3-5.6) with an AER of 336 deaths per 10,000 person-years (py). 

The greatest excess risk was attributable to non-HNC malignancies (956 

per 10,000 py), CVD (533 per 10,000 py) and pulmonary disease (136 per 

10,000 py). Conclusions: HNC survivors experience excess mortality 

compared to the general population. Competing causes of mortality 

challenge long-term survival. Additional analytic studies with detailed data 

on tobacco history, treatment characteristics and co-morbidities are 

required to further evaluate associations with specific causes of death and 

individualize risk in this heterogenous population of survivors. 


Regional variation in Medicare spending and survival among older adults 

with advanced cancer. Presenting Author: Gabriel Brooks, Dana-Farber 


Background: There is substantial regional variation in medical spending in 

the United States. Whether this variation extends to spending for cancer 

care and is associated with cancer survival outcomes is unknown. Methods: 

Patients aged 65 and older with incident advanced cancer were identified 

from the Surveillance, Epidemiology and End Results (SEER)-Medicare 

linked database. Advanced cancers included lung (stage IIIB/IV), pancreas 

(stage III/IV) colorectal, breast and prostate (stage IV). Medicare spending 

from 2 months pre-diagnosis until death or 12 months post-diagnosis was 

totaled in 2010 USD for Medicare-enrolled advanced cancer patients from 

80 hospital referral regions (HRR’s). HRRs were then ranked by mean 

composite 14-month spending and grouped into quintiles. The hazard ratio 

for death was assessed in each disease cohort for the comparison between 

the quintiles with lowest (Q1, referent) and highest (Q5) composite 

spending. Results: Mean composite 14-month spending ranged from 

$143,870 to $303,902 in HRR’s with the lowest and highest spending 

(Mason City, IA and Los Angeles, CA). As shown in the table, increased 

spending was associated with decreased risk of death for lung, colorectal 

and pancreas cancer but not for prostate or breast cancer. Conclusions: 

There is substantial regional variation in Medicare spending for patients 

with advanced cancer. This variation is associated with modest differences 

in risk of death between the lowest and highest quintiles of spending for 

lung, colorectal and pancreas cancer. 

Cohort Patients 

Mean spending 

Cohort Quintile 1 Quintile 5 Q1/Q5 

ratio 

HR for death, 

Q5 vs Q1 p 

Lung 36,312 $236,553 $192,477 $292,213 1.52 0.91 (0.87-0.94) �.0001 

Colorectal 9,912 $315,087 $261,545 $370,685 1.42 0.90 (0.83-0.97) 0.008 

Pancreas 6,993 $220,424 $169,396 $278,345 1.64 0.84 (0.78-0.91) �.0001 

Prostate 5,596 $153,376 $117,055 $195,460 1.67 1.09 (0.91-1.30) 0.363 

Breast 3,344 $222,661 $173,479 $270,266 1.56 1.01 (0.87-1.19) 0.859 

Composite 62,157 $229,058 $183,615 $281,740 1.53 NA NA 



Effect of early palliative care on health care costs in patients with 

metastatic NSCLC. Presenting Author: Joseph A. Greer, Massachusetts 


Background: Introducing palliative care soon after diagnosis for patients 

with metastatic non-small cell lung cancer (NSCLC) leads to improvements 

in quality of life, mood, end-of-life care, and possibly survival. We sought to 

investigate whether early palliative care is also associated with health care 

cost savings. Methods: This secondary analysis is based on a randomized 

controlled trial of 151 patients with newly-diagnosed, metastatic NSCLC 

presenting to an outpatient clinic at a tertiary cancer center between 

6/2006 and 7/2009. Participants received either early palliative care 

integrated with standard oncology care or standard oncology care alone. We 

queried participants’ electronic health records as well as our institution’s 

billing database to collect data on frequency and costs of outpatient clinic 

visits, inpatient hospitalizations, chemotherapy administration, and hospice 

services. The primary outcome was the difference in average resource 

use costs during the final month of life between groups. Results: By 

18-month follow up, 133 (88.1%) participants had died, and 125 (82.8%) 

had available data for this analysis. Participants in the early palliative care 

group had a mean cost savings of $2,282 (median�$2,432) per patient in 

total health care expenditures during the final month of life compared to 

the standard care group. The difference was primarily accounted for by 

lower costs for inpatient visits (mean saving per patient�$3,110) and 

chemotherapy administration (mean saving per patient�$640). Although 

expenditures for outpatient clinic visits were similar between groups, the 

costs for hospice services were greater for the early palliative care group 

because of the longer lengths of stay in hospice care (mean cost per 

patient�$1,125). Conclusions: Early palliative care for individuals diagnosed 

with metastatic NSCLC not only improves multiple patient outcomes 

but also may be associated with lower hospital resource use costs, primarily 

through decreased inpatient visits and chemotherapy administration at the 

end of life. 


A comparison of primary care providers’ and oncologists’ preferences for 

different models of cancer survivorship care. Presenting Author: Winson Y. 

Cheung, British Columbia Cancer Agency, Vancouver, BC, Canada 

Background: There is increasing interest in developing more efficient and 

effective strategies for coordinating and delivering cancer and non-cancer 

related follow-up care to survivors. The objectives of this nationwide survey 

were to describe and compare US physician preferences for different 

cancer survivorship care models. Methods: The Survey of Physician Attitudes 

Regarding the Care of Cancer Survivors (SPARCCS) was mailed to 

PCPs and oncologists in order to evaluate their views regarding physician 

responsibilities, knowledge levels about survivorship, and cancer follow-up 

testing. Using weighted univariate and multivariate models, we analyzed 

PCPs’ and oncologists’ preferences for different cancer survivorship care 

models (PCP/shared vs. oncologist vs. non-physician provider) and examined 

how physician attitudes towards and self-efficacy with their own skills 

during breast and colorectal cancer follow-up affected these preferences. 

Results: Of 3,434 physicians surveyed, 2,202 (64%) responded of whom 

2,026 (59%) provided eligible outcomes for this study: 938 (46%) PCPs 

and 1,088 (54%) oncologists. In unadjusted analyses, most PCPs (51%) 

supported a PCP/shared care system whereas the majority of specialists 

(59%) strongly endorsed an oncologist-based model (p�0.001). A number 

of PCPs and oncologists (23% for both) preferred to involve non-physician 

providers. A significant proportion of cancer specialists (87%) did not feel 

that PCPs can take on the primary role for cancer follow-up. Many PCPs 

believed that they have the skills to perform breast and colorectal cancer 

follow-up (57%), detect recurrent cancers (74%), and offer psychosocial 

support (50%), but only a minority (32%) were willing to assume exclusive 

responsibility. In adjusted analyses, PCPs already involved with cancer 

surveillance (43%) were more likely to prefer a PCP/shared care system 

than an oncologist-based survivorship care model (OR 2.08, 95%CI 

1.34-3.23, p�0.001). Conclusions: PCPs and oncologists have different 

preferences for models of cancer survivorship care. Prior involvement with 

cancer follow-up was one of the strongest predictors of PCPs’ willingness to 

assume this responsibility. 


383s 


Cancer patient acceptance, understanding, and willingness to pay for 

pharmacogenetic testing (PGT). Presenting Author: Henrique Hon, Ontario 

Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada 

Background: PGT offers the potential to improve cancer therapy through the 

use of specialized tests that can predict the level of efficacy and/or toxicity 

of specific treatments in an individual. However, there is currently little 

knowledge concerning cancer patient attitudes towards such testing in the 

clinical setting. Methods: We interviewed a broad cross-section of 278 

cancer patients (20% lung, 19% breast, 20% colorectal, 40% other) using 

hypothetical time, efficacy, toxicity and willingness-to-pay trade-off PGT 

scenarios. Results: 153 potentially curable patients and 125 incurable 

patients received a separate series of trade-off scenarios. For curative 

patients, 70% accepted chemo that had a 5% absolute improvement in 

cure rate and �5% of severe toxicity. Of these, 99% wanted PGT where the 

test identifies a subset of patients benefiting from chemo; the same 

individuals were willing to pay a median $2,000 (range: $0-25,000) for 

PGT and would accept a median wait time for PGT results of 21 days 

(0-90). Patient preferences were insensitive to variation of fractions of 

individuals carrying the genetics associated with lack of benefit. In the 

incurable scenario, 90% of patients accepted palliative chemo with an 

80% response rate and a severe side effect rate of 5%. Of these, 98% 

wanted PGT, where there test identifies individuals at highest risk of severe 

toxicity; the same individuals were willing to pay a median $1,000 

($0-15,000) for PGT, and would accept PGT turnaround times of 14 days 

(1-90). Patient preferences were insensitive to variation of fractions of 

individuals carrying the genetics associated with severe toxicity. The 

majority of patients (76% adjuvant; 87% metastatic) wanted to be involved 

in decision making regarding PGT; however, one in five patients (20% 

adjuvant; 22% metastatic) admitted that they lacked a basic understanding 

of what PGT means and its clinical implications. Conclusions: Among 

cancer patients willing to undergo chemo, almost all wanted PGT and were 

willing to pay for it, waiting several weeks for results. While patients had a 

strong desire to be involved in decision making for PGT, a considerable 

proportion lacked the necessary knowledge to make informed choices. 


Who gets a referral to oncologists and subsequent treatments for stages III 

and IV non-small cell lung cancer (NSCLC)? Presenting Author: Bernardo 

H.L. Goulart, Fred Hutchinson Cancer Research Center, Seattle, WA 

Background: We identified the physicians initially involved in the management 

of stages III and IV NSCLC, and explored associations of patient and 

their initial physician factors with referrals to oncologists and subsequent 

receipt of guideline-based therapies (GBTs) endorsed by the National 

Comprehensive Cancer Network. Methods: Using a retrospective cohort 

design, we identified patients with a new diagnosis of stages III and IV 

NSCLC from 01/01/2000 to 12/31/2005 included in the Surveillance, 

Epidemiology, and End Results-Medicare database. After collecting patient 

sociodemographic, tumor, and treatment data, we linked Unique 

Physician Identifier Numbers (UPINs) from Medicare claims to the American 

Medical Association Masterfile database to identify the initial physicians 

and subsequent referrals to cancer specialists, defined as surgeons, 

radiation oncologists and oncologists. We used logistic regression to 

explore associations between: 1) patient and initial physician independent 

variables with referrals to oncologists; 2) referrals to different combinations 

of cancer specialists with receipt of stage-specific GBTs, adjusted for 

confounders. The follow-up period was 12 months or up to 12/31/2006. 

Results: For 28,977 patients, mean age was 75 years, 53% were male, 

83% were white, 51% had stage IV, 37% initially saw an internal medicine 

doctor, 84% saw at least an oncologist, 31% saw all 3 types of cancer 

specialists, and 44% received GBTs. Younger age, white race, stage IV, 

higher income, lower co-morbidity index, initial physicians other than 

family practice doctors, and referral to pulmonologists were associated with 

higher likelihood of referral to oncologists (P�0.01 for all factors). 

Compared to those who saw only an oncologist, those who saw only a 

surgeon and/or a radiation specialist were less likely to receive GBTs 

(OR�0.3; 95%CI�0.3-0.4). Among patients who had no referrals or who 

saw specialties other than oncology, 14% received GBTs. Conclusions: 

Seeing an oncologist is a critical step in the standard treatment of 

advanced NSCLC. Yet, race, income, and the type of initial physician may 

constitute barriers of access to oncologists, which can result in substandard 

care. 




Oncologists’ and primary care providers’ awareness of late effects of cancer 

treatment: Implications for survivorship care. Presenting Author: Larissa 

Nekhlyudov, Harvard Medical School and Harvard Vanguard Medical 

Associates, Boston, MA 

Background: There is a growing population of cancer survivors, many of 

whom may experience late or long-term effects (LEs) of treatment. The goal 

of our study was to describe and compare primary care providers’ (PCP) and 

oncologists’ awareness of LEs. Methods: The Survey of Physician Attitudes 

Regarding the Care of Cancer Survivors was completed by a nationally 

representative sample of 1,072 PCPs and 1,130 oncologists (cooperation 

rate 65%). Respondents were asked to report for each of four standard 

chemotherapy drugs used to treat breast or colorectal cancer the five LEs 

they had observed and/or had seen reported in the literature. We described 

and compared the physicians’ responses and, using separate multinomial 

logistic regression models, determined predictors of their ability to identify 

the main LEs for all agents, adjusting for physician demographics and 

practice characteristics. Results: Almost all (95.3%) oncologists identified 

cardiac dysfunction as a LE of doxorubicin (Adriamycin), and peripheral 

neuropathy as LEs of both taxol (97.3%) and oxaliplatin (96.6%); while 

these LEs were identified by only 55.1%, 21.8% and 21.8% of PCPs, 

respectively. Most oncologists identified premature menopause (71.4%) 

and secondary malignancies (62.0%) as LEs of cytoxan, compared with 

only 14.8% and 17.2% of PCPs. Main LEs for all four chemotherapy drugs 

were identified by 65% (n�741) of oncologists and only 6% (n�60) of 

PCPs. In adjusted models, oncologists were more likely to identify the main 

LEs for all chemotherapy drugs if they spent 51-90% (OR 1.87, 95% CI 

1.21-2.88) or �90% (OR 1.82, 95% CI 1.08-3.08) of their time on 

patient care, and less likely if they were not board certified (OR 0.58, 95% 

CI 0.37-0.89). African American PCPs were less likely to identify the main 

LEs for all chemotherapy drugs (OR 0.19, 95% CI 0.08-0.45). Conclusions: 

Oncologists often identified the main LEs of cancer drugs while PCPs did 

not. While not surprising, these findings emphasize that in the transition of 

patients from oncology to primary care settings, PCPs should be informed 

about the LEs of cancer treatment so that they may be better prepared to 

recognize and address these among survivors in their post-treatment care. 

6010 Clinical Science Symposium, Sun, 8:00 AM-9:30 AM 

Do insurance status and neighborhood characteristics explain why minorities 

underutilize NCI cancer centers? Presenting Author: Lyen C. Huang, 

Department of Surgery, Stanford University, Stanford, CA 

Background: National Cancer-Institute (NCI) designated cancer centers 

provide some of the highest quality cancer care in the US, in part due to the 

availability of cutting edge technologies and access to cancer clinical trials. 

Racial/ethnic minorities suffer from persistent disparities in cancer outcomes, 

and these groups are typically under-represented in clinical trials. 

This may be due in part to under-utilization of NCI centers by these groups. 

Methods: A unique dataset linking the California Cancer Registry with 

California patient discharge abstracts was used to identify patients undergoing 

resection for a primary diagnosis of colorectal cancer (CRC) (1996- 

2006). Travel distance to treatment hospital was determined using GIS 

software. Chi-square analysis correlated patient demographics, clinical 

characteristics, insurance status, and neighborhood socioeconomics with 

NCI center use. Multivariable regression models were constructed to 

predict the likelihood of using an NCI center. Results: 95,994 CRC patients 

were identified. Median travel distance for care was �5 miles. Only 12,659 

(13%) lived within a 5 mile radius of an NCI center; and of those, fewer 

than 10% used the center for CRC care (n�1130). Black (OR 0.83 95%CI 

0.72-0.95) and Hispanic (OR 0.72 95%CI 0.65-0.81) patients were less 

likely than white patients to use NCI centers. Neighborhood socioeconomics, 

but not insurance status, were significantly correlated with NCI 

under-utilization. Asian populations were more likely to use NCI centers 

than white patients (OR 1.40 95%CI 1.28-1.54). Conclusions: Black and 

Hispanic patients are less likely to use nearby NCI hospitals for CRC care. 

Outreach efforts in communities with low socioeconomic status and 

educational attainment may increase use of NCI centers, improve CRC 

outcomes, and increase minority enrollment in clinical trials. 

CRA6009 Clinical Science Symposium, Sun, 8:00 AM-9:30 AM 

Patterns of decision making about cancer clinical trial participation among 

the online cancer treatment community: A collaboration between SWOG 

and NexCura. Presenting Author: Joseph M. Unger, SWOG Statistical 

Center, Seattle, WA 






be printed in the Sunday edition of ASCO Daily News 


Insurance status and cancer disparities in adolescents and young adults 

age 15 to 39: National Cancer Data Base, 1998-2003. Presenting Author: 

Anthony Robbins, American Cancer Society, Atlanta, GA 

Background: Since the mid-1970s there has been little progress in 

improving cancer survival for adolescents and young adults (AYAs, defined 

by the National Cancer Institute as individuals 15 to 39 years of age), in 

contrast to the substantial improvements for children and older adults. The 

association between insurance status and cancer disparities (stage at 

diagnosis, survival, and treatment) in AYA patients has not been examined 

in a national sample. Methods: The National Cancer Data Base, a national 

hospital-based cancer registry, was used to examine insurance status and 

cancer disparities in 177,359 AYA cancer patients. Cases were diagnosed 

during 1998�2003 and followed for vital status through 2008. We 

examined the association between insurance status and stage at diagnosis, 

stage-specific survival, and receipt of the most frequently used stagespecific 

treatments for common AYA sites (thyroid, female breast, non- 

Hodgkin lymphoma, and acute myeloid leukemia). Results: Insurance 

status was strongly related to cancer disparities in AYA patients. For 

example, compared to patients with private insurance, uninsured patients 

were 1.71 times more likely to be diagnosed at stage IV (95% confidence 

interval [CI], 1.63�1.79), had higher risk of death within every stage 

[stage I, hazard ratio (HR) (95% CI), 2.43 (2.13�2.76); stage II, 1.87 

(1.70�2.06); stage III, 1.55 (1.43�1.68); stage IV, 1.39 (1.31�1.48); 

and unstaged (leukemias, CNS tumors, etc.), 1.67 (1.58�1.76), and for 

the four sites listed above, were less likely to receive the most frequently 

used stage-specific treatments. Insurance status remained a strong independent 

predictor for each of these outcomes in multivariate models adjusting 

for patient, hospital, and tumor factors. Conclusions: In a large national 

sample, insurance status was a strong independent predictor of cancer 

disparities in AYA patients. The Affordable Care Act of 2010 should 

facilitate the acquisition of adequate health insurance by AYA, who are the 

most under- and uninsured age group in the US population, and should 

contribute to remediation of such disparities. 



Racial differences in the impact of financial hardship on the intensity of 

end-of-life cancer care. Presenting Author: Reginald D. Tucker-Seeley, 


Background: Research suggests that Black cancer patients have higher 

end-of-life (EOL) medical costs than White patients; and that Black, 

compared with White, families are more likely to use all or most of their 

savings to pay for EOL care. Although Black cancer patients receive more 

intense EOL care than Whites, research has yet to determine the effect of 

financial hardship on receipt of intensive EOL care, and whether the effect 

varies by the patient’s race. Methods: Coping with Cancer (CwC) is a 

longitudinal, multi-site cohort study of advanced cancer patients and their 

informal caregivers recruited from September 2002-February 2008. CwC 

was designed to investigate Black/White differences in EOL care. The 

purpose of this analysis was to determine the association between baseline 

financial hardship and receipt of intensive EOL care in the last week of life 

(CwC deceased cohort N�342), and to identify racial differences in this 

association. Financial hardship was defined as whether the household had 

to use all or most of their savings due to the family member’s illness 

(response �yes/no). Intensive EOL care was defined as the receipt of 

ventilation or resuscitation in the last week of life assessed by medical 

record review and patient’s caregiver. Results: Patients reporting financial 

hardship had higher odds of receiving intensive EOL care (OR � 2.83, CI: 

1.33, 6.05). After adjusting for socio-demographic characteristics the 

significant association remained (OR � 2.55, CI: 1.13, 5.81). Racestratified 

fully adjusted models revealed no statistically significant association 

between financial hardship and intensive EOL care for Whites; 

however, for Blacks, those reporting financial hardship had over five times 

higher odds of receiving intensive EOL care (OR � 5.21, CI: 1.51, 17.99) 

compared to those not reporting financial hardship. Conclusions: Financial 

hardship was associated with greater likelihood of receiving intensive EOL 

care. The intensity of EOL care received by White patients was insensitive 

to financial hardship; in contrast Black patients reporting depletion of life 

savings for cancer care were much more likely to die receiving intensive 

EOL care than their non-financially strained counterparts. 

6014 Poster Discussion Session (Board #2), Tue, 8:00 AM-12:00 PM and 

11:30 AM-12:30 PM 

Adjuvant chemotherapy (AC) initiation and early discontinuation in elderly 

patients (EPs) with stage III colon cancer (CC). Presenting Author: Jenny J. 

Ko, British Columbia Cancer Agency, Vancouver, BC, Canada 

Background: Research suggests that EPs with cancer are commonly 

undertreated, but the precise reasons for this observation are unclear. Our 

aims were to 1) evaluate the impact of advanced age on AC use (none vs 

capecitabine vs FOLFOX) for stage III CC, 2) determine the specific reasons 

for selecting and discontinuing a particular regimen, and 3) examine if the 

effect of AC on outcomes is modified by age. Methods: Patients diagnosed 

with stage III CC from 2006 to 2008 and referred to any 1 of 5 cancer 

centers in British Columbia, Canada were identified. Descriptive statistics 

were used to summarize treatment patterns in young patients (YPs) aged 

�70 vs EPs aged �/�70 years. Logistic regression was used to evaluate 

the association between AC and cancer-specific survival (CSS) in YPs and 

EPs. Results: We identified 810 patients: 51% men, 52% YPs and 48% 

EPs, and 74% received AC in the entire cohort. When compared to YPs, 

EPs had worse ECOG and more comorbidities (both p�0.01). EPs were less 

likely than YPs to receive AC (57 vs 91%, p�0.01). Frequent reasons for no 

treatment included age, comorbidities and perceived minimal benefit from 

AC. Among those treated with AC, EPs were less likely to receive FOLFOX 

(32 vs 74%, p�0.01) in favor of capecitabine due to patient preference, 

age and comorbidities. Once started on AC, EPs had similar rates of early 

treatment discontinuation as YPs (70 vs 62%, p�0.08). Reasons for early 

discontinuation were comparable between EPs and YPs (Table). Receipt of 

either FOLFOX or capecitabine was correlated with improved CSS, compared 

to surgery alone. Age did not modify CSS, irrespective of AC choice 

(interaction p for capecitabine and age�0.26; interaction p for FOLFOX 

and age�0.40). Conclusions: EPs with stage III CC frequently received 

either no adjuvant treatment or capecitabine monotherapy due to advanced 

age and comorbidities. The treatment effect of AC on CSS is similar across 

age groups, with comparable side effects and rates of discontinuation 

between EPs and YPs. AC should not be withheld from CC patients based 

on advanced age alone. 

Reasons for early discontinuation 

Side effects p Progressive disease p Patient choice p 

YPs 59% 0.99 21% 0.39 6% 0.27 

EPs 58% 16% 10% 


385s 


11:30 AM-12:30 PM 

Toxicity of chemotherapy dosing using actual body weight in obese versus 

normal-weight patients: A systematic review and meta-analysis. Presenting 

Author: Kathryn Cunningham Hourdequin, Dartmouth Hitchcock Medical 

Center, Lebanon, NH 

Background: Because weight-based chemotherapy calculations can be very 

large in obese patients, oncologists often empirically reduce doses due to 

fear of excess toxicity. The resulting underdosing may negatively impact 

survival. We performed a systematic review and meta-analysis to determine 

whether, among adults receiving chemotherapy dosed by actual body 

weight (ABW), obese patients experience differing toxicity or survival 

compared to normal-weight patients. Methods: We searched MEDLINE, 

Cochrane Library, Web of Science, and ClinicalTrials.gov through October 

2011 and reviewed reference lists. We included studies that compared 

outcomes of obese versus normal-weight adults receiving chemotherapy 

dosed according to ABW (�/- 5% variability). Studies followed subjects for 

at least one cycle of chemotherapy and reported at least one pre-specified 

outcome. Two authors independently abstracted data from eligible studies. 

We used random effects models to pool odds ratios (OR) for hematologic 

and non-hematologic toxicities. We summarized survival qualitatively. 

Results: Of 3,921 studies, five met inclusion criteria, for a total of 6,877 

subjects. Based on three studies, Grade 3/4 hematologic toxicity occurred 

less often in obese patients than normal-weight patients (OR 0.68, 95% CI 

0.51-0.89, I2�29%). A fourth study comparing leukocyte nadirs had 

variable results depending on the regimen, dosing, and patient comorbidities. 

Based on two studies, Grade 3/4 non-hematologic toxicity 

occurred less often in obese patients than normal-weight patients (OR 

0.74, 95% CI 0.63-0.87, I2�0%). A third study found rates of infection 

did not significantly differ. Three of four studies reported reduced overall 

survival in obese patients (statistical significance not reported). Conclusions: 

Contrary to common belief, obese patients receiving chemotherapy based 

on ABW appear to have lower rates of both hematologic and nonhematologic 

toxicities compared to normal-weight patients. These results 

do not support the practice of empiric dose reduction in obese patients. 

Further research should explore etiologies for the reduced survival in this 

group. 


11:30 AM-12:30 PM 

Comorbidity, chemotherapy toxicity, and outcomes among older women 

receiving adjuvant chemotherapy for breast cancer (BC). Presenting Author: 

Heidi D. Klepin, Wake Forest School of Medicine, Winston-Salem, NC 

Background: Comorbidity increases with age. We evaluated how comorbidity 

was associated with toxicity and clinical outcomes among older women 

with BC who received adjuvant chemotherapy. Methods: Cancer and 

Leukemia Group B (CALGB 49907) enrolled 633 women �65 years with 

early stage BC and randomized them to standard adjuvant chemotherapy 

(AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). 329 women 

on the Quality of Life companion study completed a pre-treatment health 

survey (Older American Resources and Services Questionnaire, physical 

health subscale). The survey evaluates 14 conditions and the degree to 

which each interferes with daily activities (rated from 1 “not at all” to 3 “a 

great deal”). Comorbidity was analyzed as follows: 1) total number 2) 

comorbidity burden score (summed conditions multiplied by interference 

rating); and 3) individual diseases. Primary outcomes were: 1) grade 3-5 

toxicity (incident and cumulative); 2) time to relapse (TTR), and 3) overall 

survival (OS). Contingency table methods were used to evaluate the 

association between comorbidity and toxicity. Cox proportional hazards 

models were used to evaluate TTR and survival outcomes. Results: Among 

329 women [median age 71 years (range 65-89), 86% white, 98% ECOG 

performance score 0-1, 75% stage 1-2] the median number of comorbidities 

was 2 (0-10), median comorbidity burden score was 3 (0-25), and 

most common conditions were arthritis (58%) and hypertension (54%). 

Few patients had diabetes (17%), heart disease (16%), and pulmonary 

disease (9%). No comorbidity measure was associated with toxicity or TTR. 

With a median follow-up of 5.4 years, increasing comorbidity was associated 

with shorter OS. For each additional comorbid condition the hazard of 

death increased by 18% (HR 1.18 [95% CI; 1.06-1.33]) after adjusting for 

age, tumor size, treatment, node status and receptor status. Comorbidity 

burden score was similarly associated with OS (HR 1.08 [95% CI; 

1.03-1.14]), while no specific condition was independently associated. 

Conclusions: Among older women with good functional status, comorbidity 

was not associated with toxicity or BC relapse. However, comorbidity 

burden was associated with shorter OS. 




11:30 AM-12:30 PM 

Refused versus recommended adjuvant chemotherapy in the United States: A 

reason for concern. Presenting Author: Elizabeth Butzer Habermann, Department 

of Surgery, University of Minnesota, Minneapolis, MN 

Background: We designed this study to identify factors driving treatment 

recommendations and refusal in surgically treated patients with gastrointestinal 

(GI) cancers eligible for adjuvant chemotherapy. Methods: Using the 2001-2008 

California Cancer Registry (CCR), we constructed a cohort of 22,469 patients 

surgically treated for three GI cancers and eligible for adjuvant chemotherapy 

(stage III colon cancer in patients � 80 years, Ib-IVM0 gastric cancer, or 

nonmetastatic resected pancreatic adenocarcinoma). Information on chemotherapy 

receipt, recommendation, and refusal was utilized to construct our 

outcome measures. Multivariate logistic regression models identified predictors 

of recommendation and refusal of adjuvant chemotherapy across three GI cancer 

sites, adjusting for potential confounders. Results: Of those eligible for adjuvant 

therapy, only 61.4% were recommended treatment and 54.3% received it. 

Refusal rate was 3.5%. Persons who were older, black, publicly insured or 

uninsured, or with gastric cancers were less likely to have adjuvant chemotherapy 

recommended. Yet, older, Medicaid-insured, and those treated for 

gastric cancer were more likely to refuse adjuvant therapies. Women were as 

likely as men to be recommended adjuvant therapies but more likely to refuse 

them (Table). Conclusions: Many patients eligible for adjuvant chemotherapy 

after GI cancer surgery have not been so advised. Striking variations exist 

between recipients of treatment recommendations versus those who refuse 

them. These results demonstrate a wide implementation gap between the 

recommendations arising from cancer clinical trials versus actual clinical 

practice. 

Age 

75-79 vs. 18-64 

Race 

Black vs. white 

Gender 

Female vs. male 

Insurance status 

Medicaid vs. private 

Medicare vs. private 

Disease site 

Colon vs. pancreas 

Gastric vs. pancreas 

Adjuvant chemotherapy 

recommended vs. other 

odds ratio (95% CI) 

0.38 

(0.34-0.41) 

0.80 

(0.72-0.89) 

1.06 

(1.00-1.12) 

0.85 

(0.76-0.96) 

0.86 

(0.80-0.92) 

1.56 

(1.43-1.70) 

0.68 

(0.62-0.75) 

Adjuvant chemotherapy 

refused vs. received 

odds ratio (95% CI) 

5.93 

(4.46-7.88) 

1.18 

(0.82-1.70) 

1.36 

(1.12-1.66) 

1.65 

(1.13-2.42) 

0.88 

(0.70-1.10) 

1.17 

(0.84-1.62) 

1.82 

(1.28-2.59) 


11:30 AM-12:30 PM 

Use of palliative chemotherapy and targeted agents in elderly patients with 

metastatic colorectal cancer (mCRC). Presenting Author: Matthew Chan, 

British Columbia Cancer Agency, Vancouver, BC, Canada 

Background: Elderly patients are increasingly diagnosed with advanced 

cancers, but they are consistently underrepresented in clinical trials, which 

may lead to undertreatment. Our aims were to 1) evaluate the impact of 

advanced age on patterns of first-line chemotherapy and bevacizumab use 

in mCRC, 2) examine the reasons for treatment choices and 3) compare 

adverse events and treatment discontinuations in elderly vs young patients. 

Methods: A random sample of mCRC patients diagnosed from 2006 to 

2007 and referred to any 1 of 5 regional cancer centers in British 

Columbia, Canada was reviewed. Summary statistics were used to describe 

treatment patterns between the elderly (�/�70 years) and young (�70 

years). Cox regression was used to determine the effect of systemic therapy 

on overall survival, controlling for age and confounders. Results: We 

identified 800 patients: 43% elderly and 57% young; 56% men; and 26 / 

36/38%ECOG0/1/2�, respectively. Fewer elderly patients were given 

chemotherapy (52% vs 79%, p�0.001). Among those treated, most 

common first-line palliative regimens for elderly vs young included: 

capecitabine (50 vs 15%), FOLFIRI (26 vs 38%), and FOLFOX (15 vs 

37%) (all p�0.001). Those aged �/�70 were also less likely to receive 

bevacizumab in their regimens (22 vs 50%, p�0.001). The most frequent 

reasons for no systemic therapy were similar between age groups: patient 

choice (31 vs 28%), poor ECOG (16 vs 17%), and significant co-morbidity 

(11 vs 13%). Risk of chemotherapy (p�0.30) and bevacizumab (p�0.39) 

adverse events were comparable between elderly and young as were rates of 

early chemotherapy (p�0.07) and bevacizumab (p�0.79) discontinuation. 

Receipt of systemic therapy �/- bevacizumab was associated with 

improved survival from mCRC (HR for death 0.50, 95% CI 0.31-0.62, 

p�0.001), regardless of advanced age (p interaction for age and treatment 

� 0.33). Conclusions: Elderly patients with mCRC are more likely to receive 

no chemotherapy, capecitabine monotherapy, or a regimen without bevacizumab. 

However, in carefully selected elderly patients, adverse events, 

treatment discontinuations, and overall survival benefit from treatment 

appear similar to those observed for younger patients. 


11:30 AM-12:30 PM 

Endocrine therapy use among Medicaid-insured breast cancer survivors 

with hormone receptor-positive tumors. Presenting Author: Racquel Elizabeth 

Kohler, University of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: Estrogen receptor positive (ER�) and progesterone receptor 

positive (PR�) cancers account for the majority of breast cancer diagnoses 

and deaths. Among women with ER� or PR� breast cancers, endocrine 

therapy (ET) is the cornerstone of adjuvant therapy and reduces 5-year risk 

of recurrence by as much as 40%. Observational studies in Medicare and 

privately-insured populations suggest that ET is underutilized. We sought 

to characterize ET use in a low-income Medicaid-insured population in 

North Carolina. Methods: We used Medicaid claims data matched to NC 

Central Cancer Registry records for women ages 18-64 diagnosed with in 

situ, stage I or II breast cancer from 2003-2007. We excluded dual 

eligibles and included only cases enrolled in Medicaid for at least 12 of the 

15 months following the index diagnosis. We defined our outcome as 

receipt of any ET medication (tamoxifen, letrozole, exemestane, or anastroxole) 

in prescription claims during the 15-month period post-diagnosis, 

among women with ER� or PR� disease. In multivariate logistic regressions, 

independent variables included age, race, tumor characteristics, 

receipt of other breast cancer treatments, co-morbidity, rural/urban residence, 

reason for Medicaid eligibility, involvement in the Breast and 

Cervical Cancer Control Program (BCCCP), patient-centered medical home 

enrollment, and diagnosis year. Results: Of the 269 women who met 

inclusion/exclusion criteria and were ER� or PR�, only 45% filled a 

prescription for ET during the study period. In multivariate analyses, being 

involved in the CDC-affiliated BCCCP was significantly associated with 

higher likelihood of receipt of guideline-recommended endocrine therapy 

(Marginal Effect: 0.299, p�0.01), but other independent variables were 

not significantly correlated with receipt of ET. Conclusions: Results suggest 

that ET is substantially underutilized in this low-income, vulnerable 

population and that intervention efforts to improve ET use may be 

important. Qualitative research is needed to understand the more nuanced, 

behavioral reasons for ET underuse, which may be related to symptom 

burden, cost, and patient-provider communication. 


11:30 AM-12:30 PM 

An assessment of the collective efforts of clinical trials to provide 

evidence-based practice guidelines in cancer care. Presenting Author: 

Shane Lloyd, Yale University School of Medicine, New Haven, CT 

Background: It is unclear how many of the recommendations in the National 

Comprehensive Cancer Network (NCCN) guidelines are based Category 1 

(C1: “high level evidence”), or whether current cancer research efforts are 

focusing on the knowledge gap between guidelines and supporting evidence. 

We defined the knowledge gap as the percent of NCCN recommendations 

based on lower levels of evidence, and assessed the relation 

between the knowledge gap and cancer research efforts in terms of clinical 

trial enrollment. Methods: We examined the active, phase 3 randomized 

controlled trials (RCTs) listed on clinicaltrials.gov for the 17 most prevalent 

solid tumors. We used the NCCN guidelines to tally the percentage of C1 

recommendations. We used the Pearson coefficient and linear regression to 

examine whether enrollment in active phase 3 RCTs is associated with 1) 

the knowledge gap and 2) measures of burden to society including 

prevalence, incidence, person years life lost (PYLL) and disability adjusted 

life years (DALY). Results: We identified 834 treatment recommendations 

for the 17 included cancer types. Overall, 15% of the NCCN recommendations 

were rated as C1, varying from 40% for hepatobiliary to 0% for 

endometrial cancer. There was no association between RCT enrollment and 

the proportion of C1 recommendations in univariate or multivariate 

analyses. RCT enrollment positively correlated with measures of burden to 

society including prevalence (p-value � 0.001), incidence (p-value 0.001), 

and DALY (p-value 0.038). Breast and prostate cancers have a large 

amount of RCT enrollment per PYLL and a relatively small knowledge gap. 

Melanoma, ovarian, and endometrial cancers have a moderate amount of 

RCT enrollment per PYLL and a relatively large knowledge gap. Lung, 

esophagus, bladder and CNS cancers have a low amount of RCT enrollment 

per PYLL and a moderate to large knowledge gap. Conclusions: RCT 

enrollment is not correlated to the knowledge gap. Current planned 

enrollment in RCTs is partially predicted by burden to society, with the 

strongest correlation to incidence and prevalence. Most recommendations 

in the NCCN guidelines are not based on C1 evidence. 



11:30 AM-12:30 PM 

A critical evaluation of oncology clinical practice guidelines. Presenting 

Author: Bradley Norman Reames, University of Michigan, Ann Arbor, MI 

Background: Clinical Practice Guidelines (CPGs) play an essential role in 

cancer care today, but there are significant concerns regarding their 

content and reliability. In 2011, the Institute of Medicine (IOM) report 

“Clinical Practice Guidelines We Can Trust” created standards for developing 

trustworthy CPGs. Using these standards as a benchmark, we sought to 

evaluate recent oncology guidelines. Methods: CPGs and consensus statements 

addressing the screening, evaluation or management of the four 

leading causes of cancer-related mortality in the US (non-small cell lung, 

breast, prostate and colorectal cancers) published between January 2005 

and December 2010 were identified using MEDLINE. A standardized 

scoring system based on the eight standards set forth by the IOM was 

devised, and the methodology, content and disclosure policies of CPGs 

were critically evaluated by four independent reviewers. All CPGs were 

given two scores; points were awarded out of a possible 8 major criteria and 

20 sub-criteria. Results: We identified 168 CPGs for inclusion in the study; 

45% were from US groups. None of the CPGs fully met all the IOM 

standards. On average, CPGs only met 2.8 of 8 standards set forth by the 

IOM (mean 2.8 points out of 8, SD 1.7; 8.3 out of 20, SD 4.3). Less than 

half of CPGs were based on a systematic review. Only half of CPG panels 

addressed conflicts of interest. Overall, the CPGs were most consistent with 

IOM standards for transparency regarding the development process, 

articulation of recommendations, and use of external review. Most did not 

comply with standards for inclusion of patient and public involvement in 

the development or review process, nor did they specify their process for 

updating. CPGs from the US had higher overall scores than CPGs from 

international groups. CPGs addressing non-small cell lung cancer had 

higher overall scores (mean 3.9) than those for other cancers. Conclusions: 

The vast majority of oncology CPGs fails to meet the IOM standards for 

trustworthy guidelines. Notably, most CPGs are not based on systematic 

reviews, lack full disclosure, and do not include all relevant stakeholders in 

the guideline process. This highlights the need for improved CPG development 

processes. 


11:30 AM-12:30 PM 

Trade-offs associated with axillary lymph node dissection: Implications of 

the eligibility versus enrollment in ACOSOG Z0011. Presenting Author: 

Monica Shalini Krishnan, Harvard Radiation Oncology Program, Boston, 

MA 

Background: Results from ACOSOG Z0011 suggest axillary lymph node 

dissection (ALND) may not be necessary for patients following positive 

sentinel lymph node biopsy (SLNB). Concerns have been raised regarding 

generalizability of this trial, given the low-risk patient population. It is 

uncertain whether a subgroup who would have been eligible for ACOSOG 

Z0011 but were not adequately represented in the study may still benefit 

from ALND. Methods: We constructed a decision analysis using a Monte 

Carlo model to simulate axillary recurrence risk, lymphedema, and quality 

of life of women aged 45, 55 and 75 y/o with Stage II cancers following 

breast conserving surgery (BCS) with positive SLNB who were then treated 

with ALND and whole-breast radiation (BRT) or BRT alone. Women were 

divided into two risk groups based on the Memorial Sloan-Kettering Cancer 

Center non-sentinel lymph node (NSLN) nomogram: those with risk of 

residual nodal involvement of 30-60% (high risk); and those with risk less 

than 30% (low risk, similar to the Z0011 patients). Probabilities and 

utilities for health states were derived from prior studies. Results: BRT alone 

resulted in improved quality-adjusted life expectancy (QALE) in the 

low-risk group, while ALND with BRT resulted in improved QALE in the 

high-risk group. Overall survival (OS) was similar at 5 years with both 

treatment strategies in both groups but was superior with ALND at 20 years 

in the high risk group (Table). Differences in outcomes decreased with 

increasing age. In the low-risk group, sensitivity analysis showed BRT alone 

is preferred unless the axillary recurrence risk with BRT is greater than 

1.6% or the lymphedema risk with ALND is less than 10%. In the high-risk 

group, ALND with BRT is the preferred strategy unless the axillary 

recurrence risk with BRT is less than 2.3%. Conclusions: Patients who 

would have been eligible for ACOSOG Z0011 but are at higher risk of having 

residual nodal disease following BCS and positive SLNB may benefit from 

ALND plus BRT rather than BRT alone. 

Overall survival and QALE in 55 y/o women. 

5 yr OS 20 yr OS QALE (yrs) 

BRT ALND BRT ALND BRT ALND 

Low risk (NSLN 0-30%) 88% 88% 47% 47% 15.53 15.46 

High risk (NSLN 31-60%) 86% 86% 38% 42% 13.55 14.36 



11:30 AM-12:30 PM 

Cancer patients’ trade-offs for efficacy, toxicity, and cost. Presenting 

Author: Yu-Ning Wong, Fox Chase Cancer Center, Philadelphia, PA 

Background: When making treatment decisions, cancer patients (pts) must 

make trade-offs between efficacy, toxicity (tox) and cost. However, little is 

known about how individual characteristics influence these decisions, 

particularly as many face high out of pocket costs. Methods: We presented 

cancer pts with hypothetical scenarios that asked them to choose between 

2 treatments of varying levels of efficacy, tox and cost. Each scenario 

included 9 choice pairs. Pts were given 2 of 3 scenarios described in the 

Table. Tox was also varied. Demographics, cost concerns and numeracy 

were assessed. Within each scenario, we used latent class methods to 

distinguish pt groups with discrete preferences. We then used regressions 

with group membership probabilities as covariates to identify associations. 

Results: We enrolled 400 pts. Median age was 61 years (range 27-90). 63% 

were female. 41% were college educated. 51% had an annual income 

�$60K. 25% were enrolled at a community hospital. 98% were insured. 

Within each of the 3 scenarios, we identified 3 pt classes with preferences 

for survival or aversion to high cost or toxicity. Across each of the scenarios, 

�6% of pts in the group averse to high cost chose the costlier treatment. 

�92% of pts in the group that favored survival chose the highest efficacy 

treatment. �65% of pts in the group with aversion to tox chose the lower 

tox treatment. Within each of the scenarios, pts in the group with 

preference for survival were more likely to have an income of �$60K 

(p�.05) and greater numeracy skills (p�.05). In scenarios 2 and 3, pts 

with concerns about treatment costs were more likely to be in the class that 

was averse to high cost (p�.05 for both). Conclusions: Even in hypothetical 

scenarios presented to insured pts, socioeconomic status was predictive of 

treatment choice. Higher income pts may be more likely to focus on survival 

when making decisions while those with greater cost concerns may be more 

likely to avoid costly treatment, regardless of survival or tox. This raises the 

possibility that health plans with greater cost-sharing may have the 

unintended consequence of increasing disparities in care. 

Efficacy Range of costs 

1 DFS 86% vs 73% $500-$10,000 over 6 m 

2 DFS 73% vs 67% $250- $6,000 over 6 m 

3 2 yr survival 23% vs 15% $60 - $800 every 3 wk 


11:30 AM-12:30 PM 

The involvement of partners in breast cancer treatment decision making. 

Presenting Author: Sarah T. Hawley, University of Michigan, Ann Arbor, MI 

Background: Incorporating partners into treatment decision making is an 

important element of patient-centered care, yet little is known about the 

role of partners in the decision process. Methods: We surveyed 503 partners 

of a population-based sample of breast cancer survivor 4 years after 

diagnosis (RR� 76%, N�382).The outcome was partners’ reports of 

decision regret. Independent variables included decision making process 

measures (partners’ reports of sufficient treatment information receipt and 

sufficient involvement in decision making), race/ethnicity, age, education 

and income. Multivariable logistic regression was used to assess associations 

between decision regret and race/ethnicity, controlling for other 

variables. Results: 49% of partners were white, 14% African American, 

15% more-acculturated Latino, and 18% less-acculturated Latino. One 

quarter (26%) of partners reported that they received insufficient information 

and one third (35%) desired more involvement in decision-making. 

Compared to whites, less-acculturated Latino partners more often reported 

that they received insufficient information (41% vs. 18%, p�0.05) and 

desired more involvement in decision-making (49% vs. 14%, p�0.001). 

Overall 30% of partners reported high decision regret. Multivariate analyses 

showed factors associated with high decision regret were lessacculturated 

Latinos, insufficient information receipt and desire for more 

involvement (Table). Conclusions: Most partners of breast cancer survivors 

reported low decision regret and positively appraised their involvement in 

the decision process. Less acculturated Latinos reported more dissatisfaction 

with the decision process. Findings suggest the need for culturally 

appropriate treatment decision support interventions that include partners. 

Factors associated with high decision regret 

Race/ethnicity 

White 

African American 

Latino–more acculturated 

Latino–less acculturated 

Sufficient information 

Yes 

No 

Sufficient involvement 

Yes 

No 

Controlled for age, education, and income. 

387s 

OR (95%CI) 

N�382 

1.00 

1.34 (0.58-3.12) 

1.82 (0.78-4.27) 

2.43 (1.00-5.89) 

1.00 

2.33 (1.25-4.31) 

1.00 

1.91 (1.04-3.48) 




11:30 AM-12:30 PM 

Improving the quality of breast cancer surgical treatment decisions. 

Presenting Author: Steven J. Katz, University of Michigan Medical School, 

Ann Arbor, MI 

Background: Ensuring breast cancer treatment decisions are high quality 

(i.e., informed and preference-concordant) is a key component of patient 

centered care. Methods: A web-based decision tool, including an interactive 

preference clarification exercise, was developed over a one-year period with 

input from health communication experts, clinicians, and women with 

breast cancer. Newly diagnosed early stage breast cancer patients from two 

cancer centers were recruited and randomized to view the tool before or 

after completing a survey. Mean scores for key outcome measures, 

including surgical treatment knowledge (4 true/false questions), decision 

satisfaction (12 questions each with a 5-point Likert scale from strongly 

agree to strongly disagree), and preference-concordant decisions, were 

compared between the groups using t-tests. Concordance between preferences 

and surgical choices was evaluated using the chi-square test. 

Results: 110 subjects were recruited and 105 completed the study. Their 

mean age was 57 years, 60% had a college degree or more, and 81% were 

white. Those viewing the website first had higher scores on several decision 

outcomes than those taking the survey first (Table). Knowledge scores were 

also higher among those viewing the website before the survey (3.0 vs. 

2.61, p�.23). The risk of recurrence was the most important treatment 

attribute, followed by retaining the natural breast, in both groups. Concordance 

between treatment choice and computer generated treatment was 

65% for website first and 61% for survey first groups. Conclusions: A tool 

focused on improving knowledge and preference-concordant decisions 

produced positive results on breast cancer surgical treatment decision 

making. Further work should assess the impact of the tool in larger and 

more diverse populations. 

Website first Survey first 

Response 1-5 

Decision outcomes 

(strongly agree – strongly disagree) 

I’m unsure what decision to make 4.12 3.35* 

The surgical treatment decision is hard 3.76 2.80 

for me 

I’m aware of the choices I have to treat 1.61 1.83* 

my breast cancer 

I am satisfied with my surgical treatment 1.44 1.65 

decision 

I feel the surgical treatment decision 

matches my values 

*P�0.05, ^P�0.10. 

1.32 1.77^ 


11:30 AM-12:30 PM 

Is care coordination associated with improved care quality for comorbid 

conditions in cancer survivors? Presenting Author: Claire Frances Snyder, 

The Johns Hopkins University School of Medicine and Sidney Kimmel 

Comprehensive Cancer Center, Baltimore, MD 

Background: Many cancer survivors have comorbid conditions, adding 

complexity to their already complicated care and requiring greater care 

coordination. We assessed the role of care coordination in comorbid 

condition care for cancer survivors. Methods: Using SEER-Medicare, we 

examined 7 published indicators of quality comorbid condition care in 

survivors of loco-regional breast, prostate, or colorectal cancer who were 

diagnosed in 2004, in fee-for-service Medicare, and survived �3 years. 

Comorbid condition care was evaluated during the transition from initial 

cancer treatment to survivorship (i.e. days 366-1095 post-diagnosis). 

Coordination risk was categorized as Likely, Possible, or Unlikely using an 

index developed and tested as part of the ACG case-mix adjustment and 

predictive modeling tool. The index factors in the number of unique 

providers, number of specialties, the percentage majority source of care, 

and generalist visits. We tested the hypothesis that lower coordination risk 

would be associated with better comorbid condition care using logistic 

regression, adjusting for socio-demographics, cancer type, and comorbidity. 

Results: The sample included 8661 survivors (53% prostate, 22% 

breast, 26% colorectal; mean age 75; 65% male, 85% white). Our 

hypothesis was not supported. Compared to patients with Unlikely coordination 

issues, patients with Likely coordination issues were more likely to 

receive appropriate care on 4 indicators and less likely on 1. Possible 

coordination issues were associated with better care on 1 indicator and 

worse care on 1 indicator. To explore this finding further, we conducted 

post-hoc analyses examining the role of each component of the coordination 

risk index. Having more unique providers was generally associated with 

better comorbid condition care, in contrast to the calculation of the index 

which considers more unique providers a greater risk for coordination 

issues. Conclusions: These findings suggest that traditional metrics of care 

coordination may not be valid for survivors of cancer. Understanding the 

role of care coordination in cancer survivorship care requires development 

and application of alternative coordination measures. 


11:30 AM-12:30 PM 

Does unblinding of treatment assignment impact participant perceptions in 

clinical trials? Presenting Author: Ann H. Partridge, Dana-Farber Cancer 


Background: Blinding patients to treatment regimen is an important 

component of high quality randomized clinical trials although concern 

exists about how receipt of a placebo will impact participants’ views. In 

ECOG5103, patients were randomized to receive adjuvant chemotherapy 

for breast cancer with either placebo (arm A) or bevacizumab (arms B and 

C) and treatment assignment was unblinded by 24 weeks. We sought to 

determine if unblinding was associated with differential changes in 

participants’ views. Methods: The Decision-Making/Quality of Life component 

(DM-QOL) included all patients enrolling on E5103 between 1/5- 

6/8/10. Women were surveyed pretreatment and after unblinding. Wilcoxon 

rank sum testing was used to examine differences. Results: 572 patients on 

DM-QOL started protocol therapy; 118 on arm A, 454 on arm B/C; the two 

groups (arm A vs. B/C) were well balanced. 516 patients participated in 

pretreatment, 514 in unblinding survey. Pretreatment, 32% reported 

�moderate chance of recurrence in 5 years, 27% �moderate chance of 

serious problem from treatment, 99% feeling at least somewhat informed, 

98% at least somewhat confident in study participation, most “extremely” 

confident. Overall, median response scores did not change over time, with 

no statistically significant differences between the groups in changes in 

perceptions of: recurrence risk (p�0.45); chances of a serious problem 

(p�0.12), feeling informed (p�0.99). However, they differed in confidence 

about study participation (p�0.04): after unblinding, a higher % of 

placebo-treated patients had increased confidence (38% vs. 25%), and a 

higher % of bevacizumab-treated patients had decreased confidence (29% 

vs. 22%), although 44% across all arms had no change. Conclusions: In a 

placebo-controlled, double-blinded RCT, unblinding did not significantly 

affect most participants’ views, regardless of receipt of placebo or experimental 

drug. However, confidence in study participation may have been 

affected by knowledge of receipt of bevacizumab; publicity surrounding 

this experimental therapy may have affected results. 


11:30 AM-12:30 PM 

Patterns of diagnostic imaging and cumulative radiation exposure among 

long-term young adult cancer survivors. Presenting Author: Corinne Daly, 

Clinical Decision Making & Healthcare, Toronto, ON, Canada 

Background: Young adults surviving a diagnosis of malignancy have a 

considerable life expectancy, however, little is known about radiation 

exposure from diagnostic imaging in these patients. This study aims to 

describe patterns of imaging and radiation exposure in young adult cancer 

survivors (YAS) and cancer-free controls in Ontario, Canada. Methods: We 

conducted a population-based retrospective study. Young adults aged 

20-44 diagnosed with an invasive malignancy between 1992 and 1999 

who lived at least 5 years without recurrent disease were identified in the 

Ontario Cancer Registry. YAS were matched 1:5 to randomly selected 

cancer-free controls on calendar year of birth, sex, and geographic location. 

Radiological procedures were identified through Ontario Health Insurance 

Plan administrative data. The rate at which individuals underwent diagnostic 

procedures after surviving 5-years was compared between survivors and 

controls using Poisson regression. Cumulative radiation exposure due to 

computed tomography (CT) and standard x-ray were calculated. Results: 

20,911 YAS and 104,524 controls had a median of 13.5 years observation 

time after cancer diagnosis/referent date. The rate of CT scanning after 5 

year survival was higher in YAS (rate ratio� 3.59, 95% CI: 3.46 – 3.73) 

and varied according to malignancy type (Table). Over the course of 

diagnosis, treatment and surveillance to 10 years, the average YAS was 

exposed to 33.8 mSv of radiation, 4.4 times the radiation exposure an 

individual in the general population received. 47% of YAS cumulative dose 

was attributed to exposure 5 years or more after diagnosis. Conclusions: YAS 

undergo imaging and are exposed to diagnostic irradiation at a significantly 

higher rate than controls even after 5 years of recurrence free survival. 

Alternative imaging techniques not associated with exposure to radiation 

should be considered for these patients. 

CT after 5 years 

n 

post-diagnosis 

YAS Rate ratio 95% CI 

All malignancy types 20,911 3.59 3.46 - 3.73 

Breast 4,581 3.21 2.96 - 3.48 

Gynecological 2,782 2.38 2.12 - 2.67 

Hodgkin’s lymphoma 1,071 6.69 5.82 - 7.69 

Melanoma 2,088 2.23 1.94 - 2.57 

Non-Hodgkin’s lymphoma 1,277 8.56 7.60 - 9.63 

Thyroid 2,388 1.74 1.55 - 1.96 



11:30 AM-12:30 PM 

How do elderly cancer survivors fare? A comparison of characteristics, 

health status, health behaviors, and spending between Medicare beneficiaries 

with and without a cancer history. Presenting Author: Xuehua Ke, 

University of Maryland School of Pharmacy, Batlimore, MD 

Background: Prior research on cancer (Ca) survivors has been limited to 

small cohorts or claims data with limited measures. In this study we used 

population-based survey data to characterize multiple dimensions of the 

survivor experience including socioceonomic status, health status and 

behaviors, and healthcare spending, comparing survivors to beneficiaries 

w/o a Ca history. Methods: Data were pooled from the 1997-2007 Medicare 

Current Beneficiary Survey (MCBS) including linked claims (3 yrs prior to 

MCBS enrollment to concurrent). Ca survivors were identified from ICD- 

9-CM codes on claims or self report of a prior Ca dx, survived 2� yrs from 

observed Ca dx, and had no active treatment, hospice enrollment or death 

in the selected survivorship yr. Beneficiary characteristics and healthcare 

use were based on self report augmented by claims-based measures. 

Bivariate and multivariate analyses were used to compare survivors’ 

characteristics and spending to controls. Results: The study included 

3,921 survivors and 7,056 subjects w/o Ca. Among survivors, breast 

(21%), prostate (21%), and colorectal (16%) were most common Ca sites. 

Compared to controls without (w/o) Ca, survivors had higher income and 

assets, were more likely to have supplemental medical and prescription 

drug coverage (74% vs. 70%), had more comorbid conditions as measured 

by Charlson Comorbidity Index score ��2 (18% vs. 15%), and a smoking 

history (60% vs. 53%); survivors were less likely to avoid visiting doctors 

(22% vs. 30%), and more satisfied with the quality of medical care 

received (96% vs. 92%). Survivors had higher annual healthcare spending 

(mean $12,095 vs. $8,928) and outpatient drug spending ($2,205 vs. 

$1,898). All differences in healthcare use and spending remained significant 

after adjusting for socioeconomic status, health conditions, and 

behaviors. Conclusions: Elderly Ca survivorshad more supplemental insurance 

coverage, stronger preferences for medical care, used more preventive 

services, and had higher spending compared to beneficiaries w/o Ca. These 

patterns may reflect the effects of survivorship on need for healthcare and 

care seeking behaviors. 


11:30 AM-12:30 PM 

Longitudinal changes in health care utilization by adult survivors of 

childhood cancer in the Childhood Cancer Survivor Study (CCSS). Presenting 

Author: Jacqueline N. Casillas, UCLA, Los Angeles, CA 

Background: The incidence of late effects increases as childhood cancer 

survivors age. Survivors require lifelong care focused on the risks arising 

from prior cancer therapy (survivor-focused care). Methods: We assessed 

longitudinal changes in health care utilization in adult survivors of 

childhood cancer participating in the CCSS. Utilization at baseline and 

most recent follow-up was classified into one of three mutually exclusive 

hierarchical categories: no health care, general medical care, or survivorfocused 

care. Relative risk (RR) and 95% confidence intervals (CI) were 

calculated for predictors of reduction in care over time from survivorfocused 

to general or no care. Multivariable models, adjusted for key 

treatment exposures, were created to assess the risk factors for reductions 

in level of care over time. Results: Among 8591 eligible survivors, mean age 

at last follow-up was 35.1 years (SD�7.8) with a mean of 11.6 years 

(SD�2.2) since baseline. Of 3993 (46%) survivors who reported survivorfocused 

care at baseline, 2383 (59.7%) reported a lower level of care at 

follow-up. Among 4598 (54%) not receiving survivor-focused care at 

baseline, 915 (20%) reported survivor-focused care at follow-up. Baseline 

predictors of a decreased level of care were no health insurance (RR�1.5, 

95% CI 1.2-1.9), male sex (RR�1.4, 95% CI 1.2-1.6), being 10-19 years 

from diagnosis compared with 20� years (RR�1.4, 95% CI 1.1-1.7). In 

contrast, factors associated with a maintenance in survivor-focused care 

were Canadian residency compared to U.S. residency with insurance 

(RR�0.7, 95% CI 0.6-0.9), unemployment (RR�0.8, 95% CI 0.7-0.9), 

physical limitations (RR�0.7, 95% CI 0.6-0.9), cancer-related pain 

(RR�0.7, 95% CI 0.5-0.8), poor emotional health (RR�0.7, 95% CI 

0.5-0.9), having mild-moderate (RR�0.5, 95% CI 0.4-0.6) or severedisabling 

chronic health condition (RR�0.6, 95% CI 0.5-0.7). Conclusions: 

Less than a third of adult survivors of childhood cancer report survivorfocused 

care. Rates decrease over time. Targeted interventions to maximize 

survivor-focused care in at-risk survivors should be tested so preventive and 

risk-reducing opportunities are not lost. 



11:30 AM-12:30 PM 

Patient-centered medical homes may improve breast cancer surveillance 

among survivors. Presenting Author: Stephanie B. Wheeler, University of 


Background: Community Care of North Carolina (CCNC) initiated a medical 

home (MH) program in the early 1990s focused on improving care in 

Medicaid-insured populations. CCNC has been successful in improving 

asthma, diabetes, and cardiovascular disease outcomes, but has not been 

examined in the context of cancer care. We sought to determine whether 

CCNC enrollment was associated with improved cancer surveillance among 

breast cancer survivors. Methods: Using state cancer registry records linked 

to Medicaid claims, we identified women ages 18-64 diagnosed with stage 

0, I, or II breast cancer from 2003-2007. We included only cases insured 

by Medicaid for at least 12 of 15 months following the index cancer 

diagnosis. Reflecting ASCO guidelines for breast cancer surveillance for 

survivors (2006), we defined outcomes as time to first surveillance 

mammogram post-diagnosis and overall receipt of mammogram by 15months 

post-diagnosis. Our primary independent variable was enrollment 

in CCNC, categorized as never enrolled, enrolled up to 6 months, and 

enrolled 7 months or more. We used multivariate Cox proportional hazards 

stratified by receipt of radiation therapy (RT) and logistic regressions. 

Results: 840 women were included in our sample. Approximately half were 

enrolled in CCNC for at least some time during the study period, 38% for 

more than 7 months post-diagnosis. Among women who received RT, being 

in a MH for at least 7 months corresponded to earlier follow-up mammogram 

(Hazard Ratio: 1.34; p�0.028), controlling for all other factors. 

Enrollment in a MH for at least 7 months post-diagnosis also was 

associated with overall receipt of mammogram by 15 months (p�0.01). 

Interaction terms indicated that women enrolled in MHs and living in a 

rural area had a statistically significant higher likelihood of receiving 

mammography. Conclusions: Results suggest that MH enrollment is associated 

with improved cancer surveillance among breast cancer survivors 

insured by Medicaid. Given the growing population of cancer survivors and 

increased emphasis on MHs in the Affordable Care Act, more research is 

needed to explore how patient-centered medical homes can be enhanced to 

improve the transition from cancer patient to cancer survivor. 


11:30 AM-12:30 PM 

How radiation oncologist accessibility influences treatment choice and 

quality in early-stage breast cancer: A SEER database analysis. Presenting 

Author: Thomas M. Churilla, The Commonwealth Medical College, Scranton, 

PA 

Background: Mastectomy and breast conserving therapy (BCT, partial 

mastectomy and adjuvant radiotherapy) are equivalent in survival for 

treatment of early stage breast cancer. This study evaluated the impact of 

radiation oncologist accessibility on choice of mastectomy versus BCT, and 

the receipt of radiotherapy after BCT. Methods: In the NCI SEER database, 

breast cancer cases from 2004-2008 were selected with the following 

criteria: T2N1M0 or less, lobular or ductal histology, and treatment with 

simple mastectomy or partial mastectomy (�/-) adjuvant radiation. The 

HRSA Area Resource File was combined to define average radiation 

oncologist density (ROD, number of radiation oncologists/100K people) by 

county over the same time period. Tumor characteristics, demographic 

information, and ROD were evaluated with respect to mastectomy rates and 

receipt of radiation therapy after BCT in univariate and multivariate 

analyses. Results: In the 118,961 cases analyzed, mastectomy was 

performed 33.3% of the time relative to BCT. After adjustment for 

demographic and tumor variables, the odds of having mastectomy versus 

BCT were inversely associated with ROD (OR [95% CI] � 0.94 [0.93- 

0.96]; p�0.001). Adjuvant radiation therapy was not administered in 

23.4% of BCT cases. Likewise, the odds of having BCT without adjuvant 

radiation were inversely associated with ROD (0.96 [0.95-0.98]; p�0.001, 

table). Conclusions: There was a significant, inverse and linear relationship 

between ROD and mastectomy rates independent of demographic and 

tumor variables. An inverse trend was also observed for the omission of 

radiotherapy after BCT. Access to radiation oncologists was a factor in 

surgical choice and receiving appropriate BCT in early stage breast cancer. 

Radiation 

oncologist 

density a 

(percentile) 

Mastectomy 

rate b (%) 

Odds of 

omission of 

radiotherapy 

after BCT c [95% CI] p value 

0-10 th d 45.4 1.30 1.22-1.39 �0.001 

10-25 th 40.6 0.92 0.85-0.99 0.020 

25-75 th 37.9 1.00 Referent -- 

75-90 th 40.0 0.85 0.79-0.92 �0.001 

90-100 th 36.4 0.89 0.83-0.95 �0.001 

a Number of radiation oncologists/100K. 

b Mastectomy/[Mastectomy � BCT w/ radiation]. 

c Multivariate. 

d 0-10 th represents 0 radiation oncologists/100K. 


389s



11:30 AM-12:30 PM 

Life expectancy (LE) and the receipt of conservative versus active treatment 

in men with prostate cancer (CaP): A population-based study. Presenting 

Author: Trevor Joseph Royce, UNC-CH School of Medicine, Chapel Hill, NC 

Background: Prostate-specific antigen (PSA) screening increases the diagnosis 

of low-risk and potentially clinically insignificant CaP, which raises 

concern for possible overtreatment. The National Comprehensive Cancer 

Network (NCCN) guidelines recommend surveillance (conservative management) 

for patients with less than 10 years LE diagnosed with low-risk 

cancer. In contrast, NCCN recommends active treatment for high-risk CaP, 

the most aggressive form of this disease, irrespective of LE. We examine 

patterns of care in CaP patients in the Surveillance, Epidemiology and End 

Results (SEER) registry by LE. Methods: 152,578 men with non-metastatic 

CaP diagnosed from 2004-8 were included. Gleason, PSA, and clinical 

stage were used for risk-categorization per D’Amico criteria. The sample 

was dichotomized into men 76 years and younger (who have an average LE 

of 10 years or more based on the US Social Security Administration 

actuarial period life tables) vs. 77 years and older (less than 10 years 

average LE). Logistic regression models examined factors associated with 

each treatment modality. Results: 56% of patients age 77 and older with 

low-risk CaP received conservative management, and 44% active treatment 

(Table). However, conservative management was just as common in 

older patients with high-risk cancer (62%); 21% of younger patients with 

high-risk CaP also received conservative management. Multivariable analysis 

showed decreased use of conservative management over time in older 

patients (OR 0.78 for 2008 vs. 2004, 95%CI 0.71-.86, p�.001). African 

American race, being unmarried, and older age were also significantly 

associated with conservative management. Conclusions: There may be 

overtreatment of low-risk CaP patients age 77 and older, which is worsening 

in recent years. Correspondingly, there appears to be undertreatment of 

elderly patients with high-risk CaP, the most aggressive form of this 

disease. 

Percent of patients receiving each treatment stratified by CaP risk and age. 

Low risk Intermediate risk High risk 

�77 �77 �77 

Conservative 22 56 13 47 21 62 

Radical prostatectomy 35 1 50 2 39 2 

Beam radiation 22 28 28 42 35 33 

Brachytherapy 21 15 8 9 6 3 


11:30 AM-12:30 PM 

Do patients with advanced-stage non-small cell lung cancer (AS NSCLC) 

live longer if managed within a clinical trial setting? Presenting Author: 

Taher Abu Hejleh, Division of Hematology, Oncology and Marrow Transplantation, 

Department of Internal Medicine, University of Iowa Hospitals and 

Clinics, Iowa City, IA 

Background: Treatment outcomes of AS NSCLC (stages IIIB and IV) are 

poor. There is an argument that participation in a clinical trial (CT) may 

confer survival benefit, probably, through enhancing quality of care. In this 

study, we explore the survival outcomes and perceived care quality for AS 

NSCLC patients (pts) treated within vs outside a CT. Methods: Data were 

obtained from surveys of newly diagnosed AS NSCLC pts studied by the 

Cancer Care Outcomes Research and Surveillance Consortium (CanCORS), 

a large cohort of pts across the United States. Pts who did not complete the 

baseline survey were excluded as this was associated with worse performance 

status (PS). Baseline characteristics according to CT participation 

were determined. Association between CT enrollment and survival was 

explored utilizing univariate and multivariate survival analysis after adjusting 

for age, comorbidities and self-reported PS. Results: Of 815 AS NSCLC 

pts, 56 (7%) were enrolled on a CT. Chemotherapy trials comprised 67% of 

all trials. Of the 815 pts, 697 (86%) died. Median survival for pts within vs 

outside a CT was 62 vs 64 months. Neither age, comorbidities nor recalled 

PS differed significantly between pts within vs outside a CT (P�0.2085, 

0.5818 and 0.1678 respectively). On the multivariate survival model, CT 

enrollment did not correlate with longer survival (P�0.8811) and only 

presence of comorbidities was associated with worse survival (P�0.0021). 

Comparing pts according to CT enrollment, there was no significant 

difference in symptom management, receiving hospice care (P�0.606), 

death location (P�0.2018), or following pts’ wishes (P�0.8321). However, 

perception of the overall cancer care quality was greater among CT 

enrollees (P�0.0171). Conclusions: Management of AS NSCLC pts within 

a CT setting conveyed a perception of superior care that did not translate 

into survival benefit after adjusting for differences in age, comorbidities, 

and self-reported PS. These findings suggest that providing cancer care 

within a CT should not imply a survival benefit when counseling AS NSCLC 

pts about entering CTs. 


11:30 AM-12:30 PM 

Timeliness of care and stage at diagnosis of non-small cell lung cancer 

(NSCLC) with the implementation of a cancer care coordination program 

(CCCP) at a VA medical center. Presenting Author: Susan Alsamarai, 

Yale-New Haven Hospital, New Haven, CT 

Background: Timeliness of care improves patient satisfaction and may 

improve outcomes. A CCCP was established in Nov 2007 to improve 

timeliness of care of NSCLC patients at the Veterans Affairs Connecticut 

(VACT) Healthcare System. Methods: We performed a retrospective cohort 

analysis of patients diagnosed with NSCLC at VACT between 2005-2010. 

We compared timeliness of care and stage at diagnosis before and after the 

implementation of the CCCP. Results: Data from 352 patients was 

analyzed: 163 with initial abnormal imaging between 1/1/2005 and 

10/31/2007, and 189 with imaging between 11/1/2007 and 12/31/2010. 

Variables associated with a longer interval between the initial abnormal 

image and the initiation of therapy were: (1) earlier stage (mean of 130 

days for stages I/II vs. 87 days for stages III/IV, p�0.001),(2) lack of 

cancer-related symptoms (145 vs 60 days, p�0.001), (3) presence of 

medical co-morbidities (111 vs 76 days, p�0.01), and (4) depression 

(127 vs 98 days, p�0.029). Substance abuse increased the interval from 

initial abnormal image to tissue diagnosis by 29 days (p�0.032) but did 

not affect the interval from image to treatment. The mean interval between 

diagnosis and initiation of treatment was 19 days longer in blacks vs. 

non-blacks (55 vs 36 days, p�0.0118) although the overall time from 

abnormal image to diagnosis and to treatment was not statistically 

different. In a multivariate model adjusting for stage, histology, reason for 

initial imaging, and presence of a primary care provider, implementation of 

a CCCP resulted in a mean reduction of 25 days in the time between the 

first abnormal image and initiation of cancer treatment (126 to 101 days, 

p�0.0154). The percent of patients diagnosed at stages I and II increased 

from 32% to 48% (p�0.0065) after the implementation of a CCCP. 

Conclusions: A centralized, multidisciplinary, hospital-based CCCP can 

improve timeliness of NSCLC care, and may also help ensure that 

incidental, early stage lung cancers are treated. 


11:30 AM-12:30 PM 

Results of a cluster randomized trial to evaluate a nursing lead supportive 

care intervention in newly diagnosed breast and colorectal cancer patients. 

Presenting Author: Jonathan Sussman, Juravinski Cancer Centre, Hamilton, 

ON, Canada 

Background: Patient transitions during the early phases of cancer care from 

initial diagnosis through oncology consultation are often poorly coordinated 

resulting in unmet need, poor continuity, and resultant distress. It has been 

proposed that better coordination of care during this period would improve 

the care experience from the patient’s perspective. We designed a 

randomized trial to test a community based nursing lead coordination of 

care intervention in newly diagnosed breast and colorectal cancer patients. 

Methods: Cluster randomized control trial in 193 newly diagnosed breast 

and colorectal cancer patients enrolled through surgical practices within 7 

days of cancer surgery in Toronto, Canada. Surgical practices were 

randomized between a standardized nursing intervention and a control 

group involving usual care practices. The intervention consisted of a 

standardized in person supportive care assessment with ongoing supportive 

care by telephone or in person that included linkage to community services 

using protocol specified guidelines according to identified needs. The 

primary outcomes measured at 8 weeks were validated patient reported 

outcomes (PROs) of 1) unmet need (SCNS) and 2) continuity of care 

(CCCQI). Secondary outcomes included 1) quality of life (EORTC QLQ- 

C30), 2) health resource utilization, and 3) level of uncertainty with care 

trajectory (MUIS) at 8 weeks. Results: 121 breast and 72 colorectal 

patients were randomized through 28 surgical practices. The intervention 

group had a median of 6 nursing contacts over the study period. There were 

no differences between groups on PROs of unmet need, continuity of care, 

quality of life, or uncertainty. Health service utilization did not differ 

between groups. Conclusions: A specialized oncology nursing intervention 

early in the care trajectory did not result in improved supportive care 

outcomes for patients. 

Intervention, n � 85 

Mean (SD) 

Control, n � 101 

Mean (SD) 

Difference 

[95% CI] 

SCNS Summary Score 2.0 (0.7) 1.9 (0.7) 0.1 [-0.3, 0.7] 

CCCQI Summary Score 4.0 (0.6) 4.0 (0.5) 0.0 [-0.2, 0.2] 

EORTC Global Health 66 (20) 67 (22) 1 [-5.6, 6.9] 

MUIS Summary Score 46 (15) 47 (14) 1 [-5.2, 2.8] 



11:30 AM-12:30 PM 

Which women with breast cancer do, and do not, undergo receptor status 

testing? A population-based study. Presenting Author: Linda Sharp, National 

Cancer Registry Ireland, Cork, Ireland 

Background: Receptor status is a determinant of breast cancer (BC) 

treatment and prognosis. Clinical practice guidelines advise that all women 

diagnosed with BC may undergo estrogen (ER), progesterone (ER) and 

human epidermal growth factor 2 (HER2) receptor tests. We conducted a 

population-based study to investigate what proportions of women undergo 

testing and predictors of test receipt. Methods: Incident BCs (ICD10 C50) 

diagnosed 2006-2008 were identified from the National Cancer Registry 

Ireland. Receptor tests were identified from registration records augmented 

by review of selected medical records. For each of the three receptors 

separately, logistic regression was used to identify which socio-demographic 

(age, marital status, smoking status, area of residence, and 

deprivation category) and clinical factors (grade, tumour size (T), nodal 

status (N), distant metastasis (M)) were associated with undergoing 

testing. Adjusted odds ratios (OR) and 95% confidence intervals were 

computed. Results: 7619 BCs were included. 7% were not tested for any of 

the receptors. 73% were tested for all three. Considering each receptor 

separately, 90% had an ER test, 86% a HER2 test and 80% a PR test. 

Women with T4 tumours were less likely to have ER and HER2 tests, and 

more likely to have a PR test, than women with T1 tumours. After 

adjustment for clinical variables, age was not a significant predictor for ER 

and HER2 testing, while older women (�70) were more likely than younger 

women to have a PR test. For all three tests, non-married women were 

significantly less likely to be tested (ER: OR�0.65, 95%CI 0.52-0.8; PR: 

OR�0.81, 95%CI 0.7-,0.93; HER2: OR�0.72, 95%CI 0.62-0.85) and 

current smokers more likely (ER: OR�1.55, 95%CI 1.14-2.1: PR: 

OR�1.38, 95%CI 1.15-1.66; HER2: OR�1.25, 95%CI 1.01-1.55). Area 

of residence at diagnosis was a significant predictor of having each test, 

although the geographical patterns varied. Conclusions: More than onequarter 

of women with BC do not have one or more of the receptor tests. 

After adjusting for clinical variables, socio-demographic factors were 

significant predictors of test receipt. In the interests of equity, the reasons 

underlying these associations should be further investigated. 

6038 General Poster Session (Board #1A), Mon, 1:15 PM-5:15 PM 

Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from 

African Americans (AAs). Presenting Author: Philip Edward Lammers, 

Vanderbilt-Ingram Cancer Center, Nashville, TN 

Background: In the AA population, previous studies have presented conflicting 

data on the frequency of EGFR mutations (Reinersman JTO 2011; 

Leidner JCO 2009), while frequencies of other gene mutations and 

translocations, including anaplastic lymphoma kinase (ALK), have not 

been described. Methods: 161 archival FFPE tumor specimens from self 

reported AA patients with any stage NSCLC from 1997-2010 were 

collected from 3 sites in Tennessee (132 samples) and one site in Michigan 

(29 samples). Samples were evaluated for known recurrent driver mutations 

in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 

by standard SNaPshot/sizing assays, and translocations in ALK by FISH. 

Clinical data was collected on 119 patients. Chi-square was used to 

compare the frequency of mutations in subgroups and Kaplan-Meier and 

log rank were used to calculate and compare PFS between groups. Results: 

5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% 

had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, 

or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had 

ALK translocations. PFS was the same in those with and without KRAS 

mutation (p�0.74) and showed a trend towards improvement in those with 

EGFR mutation (p�0.08). The frequency of EGFR mutations was higher in 

samples from Detroit versus those from Tennessee (17% vs 2.3%, 

p�0.01), as was the frequency of adenocarcinoma (62% vs 44%, 

p�0.05). The frequency of EGFR mutations in never smokers was higher in 

the samples from Detroit versus Tennessee (83% vs 7.1%, p�0.01). 

Conclusions: In the largest tumor mutational profiling study of NSCLC from 

AAs to date, EGFR mutations occurred less frequently than would be 

expected from a North American population. We noted a regional difference, 

with fewer EGFR mutations in Tennessee than in Michigan, a finding 

that may have been the result of more adenocarcinoma samples from 

Michigan. The rates of other mutations and translocations including ALK 

were low. While lung cancer tumors should continue to undergo routine 

molecular testing to prioritize therapy, future comprehensive genotyping 

efforts should focus on identifying novel driver mutations in this population. 

Funding: 5RC1CA162260 R01CA060691 R01CA87895. 


391s 


11:30 AM-12:30 PM 

Racial differences in delay of treatment for localized prostate cancer (CaP): 

A population-based study. Presenting Author: William Allen Stokes, University 

of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: African-Americans (AA) are diagnosed with more advanced 

CaP than Caucasians (CA) and are more likely to die from CaP. Treatment 

delay is a potentially modifiable obstacle to care and clinically may be more 

important in AA patients because of more aggressive cancer at diagnosis. 

We examined time from diagnosis to curative treatment (surgery or 

radiation) in AA and CA patients in the Surveillance, Epidemiologic and 

End Results (SEER)-Medicare linked database. Methods: 21,454 CA and 

2,506 AA patients who were diagnosed with non-metastatic CaP from 

2004-08 and received treatment within 12 months of diagnosis were 

included. Linear regression was used to examine factors associated with 

number of days from diagnosis to treatment initiation, and logistic 

regression to assess odds of treatment within 6 months of diagnosis. 

Results: AA patients were more likely to have high-risk CaP than CA patients 

(39 vs. 35%), and less likely to have low-risk CaP (27 vs. 31%) (p�.001). 

Time to treatment was significantly prolonged for AA patients in all risk 

groups of CaP, and the difference was most prominent for high-risk patients 

(median 105 days for AA vs. 96 days for CA, p�.002). Racial differences in 

time to treatment persisted in multivariable analysis (Table). Sensitivity 

analyses examining the proportion of AA and CA patients initiating 

treatment within 6 months of diagnosis revealed similar results. Conclusions: 

AA patients, especially those with high-risk CaP, experience longer treatment 

delays than CA patients. This is the first large-scale study to examine 

treatment delays in AA and CA patients with CaP. The differences found 

may contribute to our understanding of racial disparities in CaP treatment 

outcomes. 

Covariate Coefficient (days) P value 

Race (vs. CA) 

AA 6.7 �.001 

Risk group (vs. low-risk) 

Intermediate 1.2 .25 

High 4.2 �.001 

Age (vs. 65-69) 

70-74 -1.4 .15 

>75 -2.2 .05 

Modified Charlson comorbidity (vs. 0) 

>0 -0.1 .90 

Controls for SEER region, regional socioeconomic indicators, marital status, and 

treatment modality. 

6039 General Poster Session (Board #1B), Mon, 1:15 PM-5:15 PM 

Do patient-reported symptoms predict for emergency department visits? A 

population-based analysis. Presenting Author: Lisa Catherine Barbera, 

Odette Cancer Centre, Toronto, ON, Canada 

Background: Since 2007 in Ontario, Canada, the Edmonton Symptom 

Assessment System (ESAS) has been routinely used to assess symptoms in 

cancer patients in both ambulatory and home-care settings. The purpose of 

this study was to determine the relationship between individual patient 

symptoms, and their severity, with the likelihood of an emergency department 

(ED) visit. Methods: The cohort includes all cancer patients in Ontario 

who completed an ESAS assessment between January 2007 and March 

2009. We linked multiple provincial health databases to describe the 

cohort and determine if an ED visit occurred within 7 days of the patient’s 

first ESAS. Multivariate logistic regression was used to determine the 

association between symptom scores (absent: score 0; mild: 1-3; moderate: 

4-7; severe: 8-10) and the likelihood of an ED visit. Results: The cohort 

included 45,118 unique patients whose first assessment contributes to the 

study. 3.8% (n�1732) had an ED visit. The patients with ED visits were 

more likely to be men, to have lung or gastro-intestinal cancer, to have had 

recent radio or chemotherapy, and to have a shorter survival. The proportion 

of patients with ED visits increased from 2% to 10-12% as individual 

symptom scores increased from 0 to 10. Anxiety and depression were not 

associated with ED visits in the model, regardless of severity. Pain, nausea, 

drowsiness, appetite and shortness of breath with moderate or severe 

scores were associated with ED visits. Tiredness and wellbeing were the 

only symptoms to show a significant association for mild, moderate and 

severe scores. A well being score of 7-10 (reference score�0) had the 

highest odds ratio of 1.8 (95% CI 1.4-2.3). Conclusions: Worsening 

symptoms clearly contribute to ED visits. While specific symptoms like pain 

are obvious targets for management in the outpatient setting, constitutional 

symptoms like wellbeing or fatigue are associated with even higher odds. 

Though difficult to manage, such symptoms also warrant detailed assessment 

in order to optimize patient outcomes. 



6040 General Poster Session (Board #1C), Mon, 1:15 PM-5:15 PM 

Utilization of accelerated partial breast irradiation for ductal carcinoma in 

situ, 2002-2007: Report from the National Cancer Data Base. Presenting 

Author: Tomasz Czechura, North Shore University HealthSystem, Evanston, 

IL 

Background: The use of accelerated partial breast irradiation using brachytherapy 

(APBI-b) for patients with invasive cancer is increasing but data for 

ductal carcinoma in situ (DCIS) cases are limited. The American Society of 

Radiation Oncology (ASTRO) guidelines suggest that APBI-b should be 

used only on a �cautionary� or �on trial� basis for women with DCIS. The 

purpose of this study was to examine utilization trends and correlates of 

APBI-b use for patients with DCIS. Methods: A total of 70,043 postlumpectomy 

patients from the National Cancer Database diagnosed with DCIS 

between 2002 and 2007 were studied. Chi-square tests and logistic 

regression models were used to determine trends and factors related to 

APBI-b use. Results: The use of APBI-b increased from 0.7% in 2002 to 

10.0% in 2007 (p�0.001). Independent predictors APBI-b use were age, 

race, insurance status, comorbidity index, facility type, and facility location. 

Older patients were more likely to use APBI-b; relative to patients 

30-39 years old, the OR for patients 80-89 years old was 5.9 (95% CI: 

3.7-9.6). APBI-b use was higher in whites (4.9%), compared to blacks 

(4.4%), Hispanics (2.8%), and Asian pacific islanders (1.5%; p�0.001). 

Compared to noninsured, Medicare (OR�2.1, 95% CI: 1.3-3.3) and 

managed care patients (OR�2.0, 95% CI: 1.3-3.2) were more likely to 

undergo APBI-b. 2.3% of community cancer programs, 5.7% of comprehensive 

community programs and 4.1% of academic/research programs 

utilized APBI-b for treating DCIS (p�0.001). The use of APBI-b varied 

significantly by facility location; the West and South regions of the country 

were more likely to use APBI-b (OR�14, 95% CI: 10.1-19.6) than the 

Northeast region. 91% of the APBI-b patients fit the ASTRO �cautionary� 

guideline and 9% of patients fit the ASTRO �on trial� guidelines. In 2002, 

4% of ABPI-b patients fit the �on trial� guidelines which increased to 8.6% 

in 2007 (p�0.001). Conclusions: The use of APBI-b for DCIS increased 

from 2002-2007. APBI-b use varies by socioeconomic and facility factors 

with age being the most significant factor. Future studies are needed to 

determine the indications for APBI-b in patients with DCIS. 

6042 General Poster Session (Board #1E), Mon, 1:15 PM-5:15 PM 

Prospective evaluation of perceived barriers to medication adherence by 

patients on oral antineoplastics. Presenting Author: Benyam Muluneh, 

University of North Carolina Hospitals and Clinics Department of Pharmacy, 


Background: Appropriate use of oral antineoplastics (OA), especially those 

with a food-effect, is a challenge for patients and clinicians. Patient 

adherence is essential to optimize outcomes, minimize toxicity, minimize 

bias in clinical trials, and reduce health care costs. As the use of OA grows, 

due to the narrow therapeutic margin, it is critical to understand the 

barriers to patient adherence. The purpose of this study was to analyze 

cancer patients’ use of OAs and identify opportunities to improve patient 

adherence. Methods: We developed and tested a 30-question survey to 

address frequency and reasons for reducing/skipping doses; sources of 

information for OA use; perceived importance of food-drug effects, and 

ease of understanding directions on vial label. Surveys, consisting of Likert 

scale and multiple choice questions, were distributed to adult cancer 

patients on OAs at the UNC Cancer Hospital clinics. Results: Seventy-seven 

patients taking OAs with CML, RCC, breast cancer, and GI tumors 

completed the survey with a response rate of 97%. This was a welleducated 

population with 71% having completed some college; 54% 

female and 58% older than 50 years. Forty-three percent of patients taking 

drugs with a significant food-drug effect (sorafenib, pazopanib, lapatinib, 

imatinib, nilotinib, and capecitabine) did not think about the last time they 

ate before taking their OA and 23% did not know that their OA had a 

food-drug effect. In addition, 21% of patients indicated they intentionally 

skipped/cut back on their OAs and 38% of those did not inform their 

physician. Although 97% reported no difficulty reading instructions on 

drug vial, nearly 20% had some difficulty understanding the directions. 

Conclusions: There are three main barriers associated with appropriate use 

of OAs: confusion or misunderstanding about the timing of drug with food; 

reducing/stopping drug without informing MD; and difficulty understanding 

directions on the drug vial label. A multipronged integrated approach 

involving the pharmacist, physician and nurse is needed to optimize 

communication of directions for optimal OA use. 

6041 General Poster Session (Board #1D), Mon, 1:15 PM-5:15 PM 

Conflict of interest disclosure in off-label oncology clinical trials. Presenting 

Author: Blair Billings Irwin, Duke University Medical Center, Durham, 

NC 

Background: Off-label prescribing of anti-cancer targeted therapies is 

increasingly prevalent. Post-regulatory evidence and reporting requirements 

for reimbursement for off-label oncologic indications are less 

stringent than the threshold for United States Food and Drug Administration 

registration. What are the prevalence, reliability, and predictors of 

conflict of interest (COI) and funding disclosure statements in published 

reports of studies of cancer targeted therapies conducted in the postregulatory 

setting? Methods: As a part of a federally-funded systematic 

review, manuscripts were included in the analysis if they were used to 

support one of 19 indications for cancer targeted therapies that were 

off-label but reimbursable according to authoritative compendia in 2006 or 

before. Studies were categorized according to trial design, trial results, 

average impact factor of journals, and the presence of COI and funding 

disclosure statements. Results: Sixty-nine studies were included in the 

systematic review. Prevalence of COI and funding disclosures was low, at 

33% and 58%, respectively; time trends showed some improvement 

between 2002 to 2007, but only 60% of studies had disclosures by 2007. 

Predictors of COI disclosure were publication in high impact factor journals 

(p�0.001), large study sample size (p�0.001), enrollment exclusively in 

the US (p�0.04), and study of the targeted therapy in combination with 

other agents as opposed to the study drug alone (p�0.03). Studies with 

multiple sites were more likely to include a funding disclosure statement 

(p�0.01). Conclusions: There is need for more consistent disclosure of 

potential sources of bias in COI and funding statements in studies of 

off-label indications for anti-cancer targeted therapies. 

6043 General Poster Session (Board #1F), Mon, 1:15 PM-5:15 PM 

Bias in reporting of endpoints of efficacy and toxicity in randomized clinical 

trials (RCTs) for women with breast cancer (BC). Presenting Author: 

Francisco Emilio Vera Badillo, Princess Margaret Hospital, Toronto, ON, 

Canada 

Background: Phase III RCTs are designed to assess clinically important 

differences in endpoints that reflect benefit to patients. Accurate and 

unbiased reporting is essential to guide rational therapy. Here we evaluate 

the quality of reporting of the primary endpoint (PE) and of toxicity in RCTs 

for BC. Methods: PUBMED was searched from 1995-2011 to identify RCTs 

for BC. Scales for assessing bias in reporting of the PE and of toxicity were 

developed. For the PE, scales assessed whether the concluding statement 

of the abstract (CSAbs) was (a) based on the PE, (b) described appropriately 

a statistically positive or negative result for the PE, or (c) was based on 

secondary endpoints. Bias and completeness of reporting of toxicity was 

assessed using a hierarchy scale of whether reporting occurred in the 

CSAbs, elsewhere in the abstract, in the discussion of the article or only in 

the results. Association of bias with Journal Impact Factor (JIF); changes in 

the PE compared to protocol information in clinicaltrials.gov and funding 

source was also evaluated. Results: 164 trials were evaluated; 33% showed 

bias in reporting of the PE. The PE was more likely to be reported in the 

CSAbs if statistically significant [OR 5.2, 95% CI 1.9-14.3, p�0.001]. A 

statistically negative PE was not reported in the CSAbs in 27% of trials. Of 

the 30 trials where protocol information was available in clinicaltrials.gov, 

there were non-significant associations for the PE to show a positive result 

if had been changed, and for greater bias in reporting the PE if it was 

unchanged. 67% of studies showed bias in reporting of toxicity. Only 14% 

mentioned toxicity in CSAbs. When the PE was positive, bias in reporting of 

toxicity was more common [OR 2.0, 95% CI 1.0-3.9, p�0.04]. There was 

no apparent association between bias in reporting of either the PE or 

toxicity and JIF or funding source, but a non-significant association 

between change in the PE and industry funding. Conclusions: Bias in 

reporting of the PE is common especially for studies with a negative PE. 

Reporting of toxicity is poor especially for studies with a positive PE. 

Changing of the PE appears to be a strategy to increase the likelihood of 

observing a statistically significant result. 


6044 General Poster Session (Board #1G), Mon, 1:15 PM-5:15 PM 

Unintended consequences of health information technology: Evidence 

from Veterans Affairs Colorectal Cancer Oncology Watch Intervention. 

Presenting Author: John Bian, South Carolina College of Pharmacy, 

Columbia, SC 

Background: Although health information technology (HIT) has been hypothesized 

to help achieve greater adherence to recommended clinical guidelines 

and increase use of preventive care, well-conducted empirical studies 

evaluating this hypothesis are lacking. This study evaluated the ongoing 

Colorectal Cancer (CRC) Oncology Watch intervention, a clinical reminder 

system, implemented in 8 Veterans Affairs (VA) hospitals in 2008 for 

improving CRC (1) screening adherence among average- or higher-risk 

veterans, and (2) surveillance. Methods: VA administrative data were used 

to construct 4 cross-sectional groups of average-risk age 50-64 veterans, 

one for each of 2006, 2007, 2009, and 2010. We applied a linear 

probability model with hospital fixed-effects for estimation, using a natural 

experiment in which the 8 hospitals served as the intervention and other 

121 hospitals as a control and with 2006-2007 designated as the 

pre-intervention period and 2009-2010 as the post-intervention period. 

Results: The sample included 4,352,082 veteran-years in 4 years. The 

proportions adherent to screening were 37.6%, 31.6%, 34.4%, and 

33.2% in the intervention in 2006, 2007, 2009, and 2010, respectively, 

and the corresponding proportions in the control were 31.0%, 30.3%, 

32.3%, and 30.9%. Regression analysis showed that among those eligible 

for screening, the intervention was associated with a 2.2-percentage-point 

decrease in likelihood of adherence (P-value�0.0001). Additional analyses 

showed that the intervention was associated with a 5.6-percentagepoint 

decrease in likelihood of screening by colonoscopy among the 

adherent, but with increased total colonoscopies (any indication) of 3.6 per 

100 veterans age 50-64. Conclusions: The intervention may have slightly 

reduced CRC screening rates for the studied population. This consequence 

may have been caused by an unintentional shift of limited VA colonoscopy 

capacity from average-risk screening to higher-risk screening and to CRC 

surveillance, or by physicians’ fatigue due to the large number of clinical 

reminders implemented in the VA. 


Association of increases in quality of care with the NCI Community Cancer 

Center Program (NCCCP) pilot. Presenting Author: Michael T. Halpern, RTI 

International, Washington, DC 

Background: The NCCCP pilot is an initiative designed to enhance research 

and improve cancer care at community hospitals. As part of a multi-method 

evaluation of this pilot, we assessed changes in quality of care among the 

16 pilot NCCCP hospitals over time (before vs. after program initiation) and 

in comparison to a group of 25 similar hospitals that did not participate in 

the NCCCP. Methods: We compared changes in 5 NQF-approved quality of 

care measures (3 for breast cancer, 2 for colon cancer) from 2006/07 

(before NCCCP initiation) vs. 2008/09/10 (post-initiation) for NCCCP and 

comparison group hospitals. Data were collected from all study hospitals 

using the Commission on Cancer’s Rapid Quality Reporting System, which 

allowed near real-time tracking of quality of care process measures. Results: 

Analyses included 18,608 breast cancer and 7,031 colon cancer patients. 

Patient-level concordance rates for all 5 quality of care measures increased 

significantly among both NCCCP and comparison group hospitals. The 

change (from baseline to post-NCCCP) in quality of care among NCCCP 

hospitals was significantly greater than the change among comparison 

group hospitals for two measures: radiation therapy following breast 

conserving surgery (RT-BCS) and hormonal therapy for women with 

hormone receptor positive breast cancer (HT). For the RT-BCS measure, 

NCCCP patients from underserved populations also experienced significantly 

greater changes in concordance than did corresponding populations 

from comparison group hospitals. In multivariate regression analyses 

controlling for patient characteristics, the change for the HT measure 

among NCCCP hospitals was significantly greater than that among comparison 

group hospitals. Conclusions: While both NCCCP and comparison group 

hospitals showed improved quality of care, participation in the NCCCP was 

associated with significantly greater improvements for a subset of measures. 

Including a separate comparison hospital group was critical for 

assessing changes associated with NCCCP participation while controlling 

for broader U.S. trends in improved quality of care. Future work will 

examine how hospital networks may have facilitated improvements in 

quality of care. 


393s 


Osteoporosis screening among prostate cancer survivors treated with 

androgen deprivation therapy. Presenting Author: Alicia Katherine Morgans, 

Massachusetts General Hospital Cancer Center, Boston, MA 

Background: Androgen deprivation therapy (ADT), the standard systemic 

treatment for prostate cancer, has adverse effects including bone loss and 

fractures. Current national guidelines suggest that men receiving ADT 

undergo dual energy x-ray absorptiometry (DXA) before and during ADT to 

better characterize fracture risk. We assessed receipt of DXA testing in a 

population-based cohort of men treated continuously with ADT for at least 

1 year and identified factors associated with testing. Methods: Using 

Surveillance, Epidemiology, and End Results-Medicare data, we identified 

men aged �65 with local or regional prostate cancer diagnosed during 

2001-2007 and followed through 2009 who received at least 1 year of 

continuous ADT. We identified receipt of DXA testing in the 18-month 

period beginning 6 months before the first dose of ADT. We used logistic 

regression to identify factors associated with DXA testing, including patient 

and tumor characteristics and the physicians with whom they had outpatient 

visits. Results: Among 28,960 men treated with ADT for �1 year, 

6.5% had at least one DXA scan from 6 months before the first dose of ADT 

through 1 year after. DXA testing increased over time, with men initiating 

ADT in 2007-2009 more likely to be tested than those treated in 

2001-2002 (10.0% vs. 3.4%, OR 2.29, 95% CI 1.83-2.85). Men aged 

�85 were less likely than men aged 66-69 to undergo testing (OR 0.76, 

95% CI 0.65-0.89). Black men were less likely than white men to undergo 

testing (OR 0.92, 95% CI 0.61-0.86), as were men living in areas with 

lower educational attainment (P�.001). Compared with men seeing a 

urologist but no medical oncologist or primary care provider (PCP), men 

seeing a medical oncologist and a urologist (OR 2.11, 95% CI 1.39-3.21) 

and those seeing a medical oncologist, urologist and PCP (OR 2.59, 95% 

CI 2.01-3.34) had higher odds of testing. Conclusions: Few men receiving 

ADT for prostate cancer undergo DXA testing, with particularly low rates of 

testing among older men, black men, and those living in areas with low 

educational attainment. Visits with a medical oncologist were associated 

with increased odds of testing. Interventions are needed to increase bone 

density testing among men receiving long-term ADT. 


Geographic and network analysis of oncology trials: Portfolio assessment of 

ClinicalTrials.gov. Presenting Author: Steven Kunyuan Cheng, Oregon 

Health & Science University, Portland, OR 

Background: Increasing complexity and specificity of cancer trials (CT) 

necessitates collaboration across the CT network to optimize research 

efforts. The relationship among CT sites and networks provide unique 

insights into improving coordination and accrual. Methods: 5971 interventional 

CTs registered between 2007 and 2010 were aggregated by trial and 

location. CTs in the Aggregate Analysis dataset from ClinicalTrials.gov 

(AACT) were identified using MeSH terms. The distribution of mid-phase 

(MP)(phase I/II,II) and late-phase (LP)(PII/III,PIII) CTs for the ten most 

represented cancer types by number of sites was assessed using network 

graph theory and geographic analysis comparing distribution of trials across 

metropolitan statistical areas. Results: 66,566 CT sites were identified 

across the sample, 59.6% were in the United States (MP: 50.2%; LP: 

42.9%). Geographical availability of CTs and local cancer incidence rates 

were highly correlated (0.797, p� 0.001) but varied depending upon 

disease type. Network density (the degree of dyadic interconnections 

between sites studying similar cancer types) showed overall that MP trials 

were less dense with sparser interconnections among sites than LP trials. 

Network density of LP trials was higher for cancer types that had poorer 

correlation between geographic distribution of incidence and enrolling sites 

(-0.777, p�0.008). MP trials did not show a similar trend. Conclusions: 

The relationship between the distribution of CT and site location can be 

envisaged through geographic and network analysis of CT registry data. LP 

high-density networks should strive to diversify trial locations to better meet 

regional incidence rates. 

Incidence and trials MP (mid-phase) LP (late-phase) 

Pearson Corr. 

(all p



Electronic prompt to improve outpatient code status documentation for 

advanced lung cancer. Presenting Author: Jennifer S. Temel, Massachusetts 


Background: Rates of documentation of end-of-life care preferences in the 

medical record remain low, even among patients with incurable malignancies. 

The goal of this study was to assess the impact of electronic prompts 

to encourage oncology clinicians to document code status in the outpatient 

electronic health record (EHR) of patients with advanced lung cancers. 

Methods: We conducted two clinician focus groups (n�15) at an affiliated 

academic medical center to determine the appropriate content and timing 

of the electronic reminders. Based on the focus groups, we developed 

email reminders that were timed to the start of each new chemotherapy 

regimen. Between 6/09 and 1/11, 102 eligible patients with advanced 

lung cancer were approached, and 100 (98%) agreed to participate in the 

prospective study. Email reminders were sent to oncology clinicians at the 

patient’s next outpatient visit and with each new chemotherapy regimen. 

Using a pre-post design, we compared study participants to a retrospective 

cohort of 100 consecutive historical controls who began chemotherapy for 

advanced lung cancer at least one year prior to the start of this study. The 

primary outcome measure was the documentation of code status in the 

EHR. Results: Study participants were similar to historical controls, with no 

significant differences in age, gender, performance status, histology or 

initial cancer therapy received. At one year follow-up, 33/98 (34%) of 

participants had a code status documented in the outpatient EHR compared 

with 12/83 (15%) of historical controls, p�0.003. Mean time to 

code status documentation was significantly shorter in study participants 

(8.6 months [95% CI 7.6-9.5]) compared with controls (10.5 months 

[95% CI 9.8-11.3]), p�0.004. Conclusions: Email prompts triggered by 

changes in chemotherapy improved the rate and timing of code status 

documentation in the EHR. 


How do social factors explain outcomes in non-small cell lung cancer 

among Hispanics/Latinos in California? Presenting Author: Manali I. Patel, 

Stanford University Medical Center, Palo Alto, CA 

Background: Hispanics in the United States have a lower age-adjusted 

incidence and mortality rate from non-small cell lung cancer compared 

with non-Hispanic whites. Previous studies have demonstrated the influence 

of nativity on survival among Hispanic patients but no studies have 

evaluated the interplay of nativity, clinical factors, social factors, and 

neighborhood factors on survival among Hispanic patients with non-small 

cell lung cancer. Methods: All Hispanic patients with non-small cell lung 

cancer between the years of 1988-2008 were identified in the California 

Cancer Registry (CCR). Kaplan Meier curves depict survival by nativity 

status among Hispanics with non-small cell lung cancer. Cox proportional 

hazard models estimate the hazard of mortality by race with adjustment for 

individual covariates (age, gender, marital status), clinical factors (histologic 

grade, surgery, radiation, and chemotherapy), and social and neighborhood 

factors (neighborhood and ethnic enclave status). Results: A total of 

4,062 Hispanic patients with non small cell lung cancer were included. 

Overall, there was a 7% decreased risk of disease-specific mortality for 

foreign-born patients as compared with US-born patients (HR 0.93, 

p�0.08, 95% CI 0.87-1.00) although not-statistically significant. Adjustment 

for individual patient factors and clinical factors conferred a statistically 

significant 16% decreased risk of disease-specific mortality compared 

with US-born patients (HR 0.84, p�0.0001, 95% CI 0.78-0.91). Adjustment 

for socioeconomic status and neighborhood socioeconomic and 

ethnic enclave status did not explain the differences in survival (HR 0.84, p 

�0.001, 95% CI 0.78-0.91). Conclusions: Overall, foreign-born Hispanics 

with non-small cell lung cancer have a decreased risk of disease-specific 

mortality compared with US-born Hispanics with non-small cell lung 

cancer but social factors do not explain this survival advantage. Further 

investigation is needed to understand the drivers of the survival advantage 

outcomes in foreign-born populations. 


Positron emission tomography/computed tomography (PET/CT) for the 

diagnosis of recurrent cancer (PETREC): A multicenter, prospective cohort 

study. Presenting Author: John J. You, McMaster University, Hamilton, ON, 

Canada 

Background: The clinical utility of PET/CT in patients with suspected cancer 

recurrence remains unclear. The aim of this multi-center, prospective, 

comparative effectiveness study is to assess the impact of PET/CT on 

clinical management of patients with suspected cancer recurrence. Methods: 

Patients were eligible if cancer recurrence (non-small cell lung, breast, 

head and neck, ovarian, esophageal, Hodgkin’s or non-Hodgkin’s lymphoma) 

was clinically suspected, and if conventional imaging (e.g. X-ray, 

ultrasound, CT, or MRI) was non-diagnostic. As a pre-requisite to PET/CT 

booking, clinicians were asked at enrolment to indicate their planned 

management if PET/CT were not available. Patients then underwent 

18FDG-PET/CT. Clinicians were then asked to indicate their management 

plan based on PET/CT findings. Patients were followed up once at 3 

months. The primary outcome was change in planned management after 

PET/CT and was assessed independently and in duplicate by external 

outcome adjudicators using all available source documents. Results: 101 

patients (mean age 64 y, 45% male, median 1.3 y since last treatment) 

were enrolled from 4 centers in Ontario, Canada between April 2009 and 

June 2011. Distribution of tumor types was: non-small cell lung (55%), 

breast (19%), ovarian (10%), esophageal (6%), lymphoma (6%), head and 

neck (4%). 8 patients did not complete the study (non-adherence to 

protocol, 2; death, 5; disease progression prior to PET/CT, 1), of whom 2 

did not receive PET/CT. PET/CT changed planned management in 52 

(53%) patients (Table). At 3 months, planned management was carried out 

in 46/52 (88%) patients. Conclusions: In patients with suspected cancer 

recurrence, PET/CT changes planned management from non-treatment to 

treatment for approximately 1 in every 3 patients (“number needed to 

scan” � 3) and contributes importantly to clinical management. 

Impact on planned management 

PET/CT for suspected 

cancer recurrence (N�99) 

No change 47 (47) 

Major change* 

Minor change 

38 (38) 

Clinical/imaging follow-up to biopsy 9 (9) 

Imaging to clinical follow-up 2 (2) 

Biopsy to clinical/imaging follow-up 

Data are n (%). * No treatment to treatment. 

3 (3) 


Improving the impact of clinical research: A systematic analysis of kidney 

cancer trials. Presenting Author: Bradford Richard Hirsch, Duke Cancer 

Institute, Durham, NC 

Background: Clinical trials are essential to advancing cancer care, but the 

means to evaluate and improve the portfolio have been lacking. This study 

analyzes the renal cell carcinoma (RCC) trial portfolio using the database for 

the Aggregate Analysis of ClinicalTrials.gov. As RCC is an area of promise, what 

insights can an evaluation of the portfolio provide? Methods: 40,970 clinical 

studies registered with ClinicalTrials.gov between October 2007 and September 

2010 were aggregated by specialty using MeSH terms and submitted 

conditions. 8,942 oncology trials were identified and categorized by cancer 

type. 108 trials opening in October 2007 or later were identified as evaluating 

treatments for RCC. Descriptive statistics were used to characterize trial 

design, study agent(s), accrual and sponsorship. Results: 52 trials (48%) 

assessed agents already recommended as 1st or 2nd-line treatments in the 

National Comprehensive Cancer Network (NCCN) RCC Guidelines at the time 

of study initiation and 19 (18%) studied other FDA-approved treatments. 37 

trials (34%) included a novel (non-FDA approved) agent or vaccine. Total 

anticipated or actual accrual was 12,753, with 50% accrued/accruing to trials 

of only NCCN agents, 34% to novel agents and 16% to other FDA-approved 

agents. Industry was identified as a sponsor or collaborator in 48% of trials 

assessing only NCCN agents, 73% of novel agent trials and 53% of other 

FDA-approved agent trials. As shown in the table, a minority of trials were 

randomized, blinded or late-phase (Phase III or IV), regardless of approval 

status of study agent. Conclusions: The majority of new studies and accrual in 

RCC assess questions of treatment sequence and setting for established 

therapies, many of which lack rigorous design. Across the portfolio, studies are 

predominantly industry sponsored. Optimizing clinical research includes 

increasing studies of novel therapeutics and improving the comparative 

effectiveness research portfolio by increasing utilization of pragmatic designs, 

registries and late-phase programs. 

Trials Randomized Blinded Phase III or IV 

Agent 

n % n % n % n % 

NCCN-recommended 52 48% 17 33% 3 6% 7 13% 

Other FDA-approved 19 18% 3 16% 0 0% 1 5% 

Novel 37 34% 9 24% 3 8% 4 11% 



Influence of comorbidity on guideline concordant care for breast cancer: 

Findings from the Center for Disease Control and Prevention National 

Program of Cancer Registry (NPCR) patterns of care study. Presenting 

Author: Gretchen Genevieve Kimmick, Duke University Medical Center, 

Durham, NC 

Background: Comorbidity burden predicts cancer treatment and may 

influence outcome. We explore the relationship of specific comorbid 

illnesses with receipt of guideline concordant care for early stage breast 

cancer. Methods: The NPCR’s Patterns of Care study reabstracted the 

medical records of breast cancer cases diagnosed in 2004 from 7 cancer 

registries. We included women with nonmetastatic in situ and invasive 

breast cancer, known hormone receptor status, node status, and tumor 

size. Guideline-concordant management, including surgery, radiation, 

chemotherapy and endocrine components, was based on NCCN guidelines 

using tumor size, nodal and hormone receptor status. Comorbidity was 

measured according to the Adult Comorbidity Evaluation Index (ACE). 

Multivariate logistic regression models were used to determine factors 

associated with guideline-concordant care, and included overall ACE 

scores and 26 separate ACE comorbidity categories, as well as age, race, 

hormone receptor status, and HER2 status. Results: The study sample 

included 6904 women (mean age 58.7 and range 20-99 years, 76% white, 

45% with ACE comorbidity score of 0, 70% ER and/or PR�, 13% 

HER2�). Overall, 64% received guideline-concordant care. Receipt of 

guideline-concordant care varied by overall comorbidity burden (71% for 

none; 65% for minor; 63% for moderate; 50% for severe; p�0.05). The 

presence of hypertension (OR 1.26, 95% CI 1.08-1.48) predicted receipt 

of guideline concordant care, whereas, peripheral artery disease (OR 0.44, 

95% CI 0.21-0.93), diabetes (OR 0.78, 95% CI 0.63-0.97) and dementia 

(OR 0.31, 95% CI 0.13-0.74) predicted lack of guideline concordant care. 

Older age, black race, and hormone receptor positivity were associated with 

less, and HER2 positivity with receipt of more guideline-concordant care. 

Conclusions: Overall those with more comorbidity burden received less 

guideline-concordant care. However, the effects vary by specific conditions. 

The odds of receiving guideline-concordant care was greater in those 

with hypertension and less in those with peripheral arterial disease, 

diabetes, and dementia. 


A brief educational intervention to increase communication about complementary 

and alternative medicine (CAM) in community oncology settings. 

Presenting Author: Lorenzo Cohen, University of Texas M. D. Anderson 


Background: The widespread use of CAM in academic oncology settings has 

been well documented. However, there is a lack of communication between 

patients and health care professionals on CAM that may have negative 

health consequences. No comprehensive study of CAM use in community 

oncology settings exists. We examined the benefits of a brief educational 

intervention on nurse discussions of CAM with patients. Methods: A 

multi-site, randomized trial of an educational intervention (brief video, 

resource list) designed to encourage oncology nurses to discuss CAM use 

with their patients was conducted within the MD Anderson CCOP network. 

Nurses (N�175) and patients (baseline N�699 and different set of 

patients after intervention N�650) completed questions about CAM use, 

communication, and knowledge. Results: Nurses were 97% female, 96% 

non-Hispanic white. Two months after the intervention, nurses in the 

intervention group reported that they were more likely to ask about CAM use 

than those in the control group (OR�4.2; p�.005) and asked more of their 

last 5 patients about CAM use (p�.003). No significant intervention effect 

was found for the proportion of patients in the clinic who indicated they 

were asked about CAM use after the intervention (OR�1.6, p�.10). 

Approximately 40% of patients reported using CAM following their cancer 

diagnosis yet the majority of nurses estimated less than 25% of their 

patients used CAM. Conclusions: CAM use in community-based oncology 

patients is high and there is an underestimation of use by the oncology 

nurses. This very brief intervention significantly improved how often nurses 

reported asking patients about their CAM use. However, the patients of the 

nurses did not reflect this change in communication. Additional types of 

interventions are needed to increase communication between patients and 

nurses. 


395s 


Examining patient choices for metastatic breast cancer drugs. Presenting 

Author: Mary Lou Smith, Research Advocacy Network, Plano, TX 

Background: Patients with metastatic breast cancer face difficult drug 

decisions. Our previous research (ASCO Proc 2011, abstr 6044) focused 

on general benefit and toxicity showed that conjoint analysis (CA) allows 

patients to express preferences; our current research quantifies patient 

preference for specific drug profiles (capecitabine and paclitaxel). Methods: 

Research Advocacy Network and CBWhite conducted research using CA for 

DOD Center of Excellence for Individualization of Therapy in Breast Cancer. 

An online survey was sent by four breast cancer organizations (N�641). 

Questions elicited views on trade-offs between benefit and type/severity/ 

duration of toxicity. CA questions present pairs of hypothetical treatments 

and ask respondents their preferred alternative; a follow-up question asks 

whether the person would take the treatment if it were the only option 

available. Analysis of response patterns allows study of treatment preferences 

for combinations of benefit and described toxicity. Results: See table. 

Preferences show much greater attention to benefit than to toxicity. When 

CA is used to examine impact of biomarkers, focus on benefit continues. 

Paclitaxel profile (IV) set with moderate PN lasting 1 year post treatment: 

with 33% benefit LH, 6% of respondents change treatment decision if 

biomarker predicts 27% vs 60% toxicity likelihood; with 27% toxicity LH, 

22% of respondents change treatment decision if biomarker predicts 20% 

vs 50% benefit likelihood. Conclusions: For patients with metastatic 

disease, CA shows much greater attention to benefit than toxicity, and high 

likelihood to take treatment with at least 30% chance of benefit for any 

toxicity tested here. These results suggest biomarkers (for the profiled 

drugs) predicting benefit are more likely to be used to affect patient 

treatment decisions than biomarkers for toxicity. 

Prediction of % selecting treatment with benefit and toxicity likelihood (LH) 

under two scenarios (N�641). 

10% 

Toxicity LH 

20% 40% 60% 

IV drug profile—moderate peripheral neuropathy (PN) for 1 year 

Benefit LH 

20% N/A 77.4 72.3 65.3 

30% N/A 89.8 86.4 81.6 

50% N/A 97.1 96.1 94.3 

Oral drug profile—moderate Hand-Foot Syndrome during treatment 

10% 67.6 65.2 60.8 N/A 

30% 94.7 93.0 91.4 N/A 

50% 99.0 98.3 97.4 N/A 


Self-reported conflicts of interest (sfCOI) of authors and the interpretation 

of randomized phase III trials (RCT) and related editorials (REd) in cancer 

research. Presenting Author: Giovanni Mendonca Bariani, Instituto do 

Cancer do Estado de Sao Paulo, Sao Paulo, Brazil 

Background: Growing participation from industry in cancer research has 

resulted in increased reporting of COI. We aimed to test any association 

between author’s conclusion and sfCOI in cancer studies. Methods: All RCT 

and REd published in 6 major cancer journals in a 3.5 year period were 

selected. Two investigators blinded to COI disclosure independently 

analyzed each RCT and REd, classifying authors’ conclusions as highly 

positive, positive, neutral, negative, and highly negative with respect to 

author’s opinion on the experimental therapy. The agreement rate between 

investigators for conclusion classification was 90% (consensus was achieved 

for the remaining 10%). We also collected data on study results, COI and 

sponsorship. COI was defined as any self-reported financial tie between 

author and industry except for research funds. Predictors of positive/highly 

positive conclusions of RCT and of REd were tested separately in logistic 

regression multivariable models. Results: From Jan 2008 to Oct 2011, 

1,485 articles were retrieved: 150 RCT and 140 REd were eligible. Among 

the RCT, 82 (55%) were positive, and 78 (52%) were entirely or partially 

funded by industry. Any sfCOI was present in 103 (69%) RCT and in 71 

(47%) REd. Conclusions of REd and RCT were: 7.3% and 11.3% highly 

positive, 42.7% and 57.3% positive, 8.0% and 2.0% neutral, 29.3% and 

18.7% negative, and 12.7% and 10.7% highly negative, respectively. 

Multivariable analysis showed that RCT positive result was the only 

significant predictor for positive conclusion by RCT authors (OR�109, 

95% CI: 21-567; p�0.001). The only factor associated with positive 

conclusions of REd authors was a positive conclusion by RCT author 

(OR�42, 95% CI: 7-244; p�0.001). While 64 (43%) RCT reported 

negative results, 103 (68.7%) RCT authors interpreted studies positively. 

Logistic regression for discordance between RCT result and RCT conclusion 

did not find any association with COI. Conclusions: Theinterpretation of RCT 

results by authors was not influenced by sfCOI or trial sponsorship. Authors 

of REd were not influenced by study results or by their sfCOI when 

discussing cancer RCT. 




The cost-effectiveness of improving cancer screening compliance. Presenting 

Author: Michael S. Broder, Partnership for Health Analytic Research, 

LLC, Beverly Hills, CA 

Background: Expensive treatments and a growing number of cancer patients 

have resulted in increased spending on cancer care. Within a framework we 

developed for measuring the value of quality improvement (QI), we describe 

the cost-effectiveness of improving compliance with cancer screening 

measures compared to other quality measures. Methods: We used our 

framework to examine 18 Healthcare Effectiveness Data and Information 

Set (HEDIS) 2010 quality measures, synthesize related cost-effectiveness 

(CE) data and describe measure-specific QI-adjusted incremental costeffectiveness 

ratios (ICERs). For each measure we: 1) quantified current 

compliance; 2) reviewed literature for ICERs; 3) estimated per-person 

steady state cost and quality-adjusted life years (QALYs); 4) estimated 

affected population size; 5) estimated the cost of QI; and 6) calculated 

QI-adjusted ICERs at full compliance, defined as 95%. We assumed 

per-person QI costs did not change with compliance and varied this in 

sensitivity analyses. We compared QI-adjusted ICERs for 3 cancer screening 

measures to the remaining measures. Results: Published ICERs for the 

cancer screening measures were $43,180/QALY (breast), $5,102/QALY 

(cervix) and $15,173/QALY (colon) and for other measures from $195/ 

QALY (drug treatment) to $35,616/QALY (flu shots). Incorporating QI costs 

for cancer screening measures gave QI-adjusted ICERs of $64,549/QALY 

(breast), $15,463/QALY (cervix) and $22,991/QALY (colon), respectively. 

Incorporating QI costs for all 18 measures resulted in QI-adjusted ICERs 

from $195/QALY (drug treatment) to $9,075,868/QALY(antidepressant 

management), with a median of $15,463/QALY. Reaching 95% compliance 

with the 3 cancer measures would cost $5.1 billion and add 160,000 

QALYs ($32,640/QALY) and with all 18 measures would cost $13.4 billion 

and add 5.8 million QALYs ($2,313/QALY). Conclusions: Improving compliance 

with cancer screening may be cost-effective at a threshold of 

$50k/QALY, although improving care on all HEDIS measures may be even 

more cost-effective. Accurate assessment of the cost of increasing cancer 

screening requires integration of both the cost-effectiveness of the screening 

tests and the cost of the QI programs needed to change practice. 

6059 General Poster Session (Board #3H), Mon, 1:15 PM-5:15 PM 

Health care costs associated with venous thromboembolism in select 

high-risk ambulatory solid tumor patients in the United States. Presenting 

Author: Alok A. Khorana, University of Rochester, Rochester, NY 

Background: Venous thromboembolism (VTE) is an increasingly common 

complication of cancer and its treatment, including chemotherapy. VTE 

has significant clinical consequences, including mortality. However, contemporary 

data on the healthcare costs of cancer-associated VTE are 

limited. We examined the real-world economic burden of VTE in ambulatory 

patients initiating chemotherapy for select common high-risk solid tumors. 

Methods: Healthcare claims data (2004-2009) from the IMS/PharMetrics 

Patient-Centric database were collected for propensity score-matched 

adult cancer (lung, colorectal, pancreas, stomach, bladder and ovary) 

patients with VTE (n�912) and without VTE (n�2,736) after initiating 

chemotherapy. Healthcare resource utilization (inpatient, outpatient medical, 

and outpatient prescription drug claims) and costs were compared 

between the two cohorts during 12 months’ follow-up after the index VTE 

event. Incremental costs of VTE were adjusted for demographic and clinical 

covariates. Results: Cancer patients with VTE had ~3-times as many 

all-cause hospitalizations (mean 1.38 vs. 0.55 per patient) and days in 

hospital (10.2 vs. 3.4 per patient), and more outpatient claims (331 vs. 

206 per patient) than matched cancer patients without VTE (all P�0.0001). 

Cancer patients with VTE incurred significantly higher overall (all-cause) 

inpatient costs (mean $21,299 vs. $7,459 per patient), outpatient costs 

(mean $53,660 vs. $34,232 per patient) and total healthcare costs (mean 

$74,959 vs. $41,691 per patient) than cancer patients without VTE (all 

P�0.0001). Total VTE-related healthcare costs were (mean) $9,247 per 

VTE patient over 12 months. Adjusted incremental all-cause healthcare 

costs of VTE were (mean) $30,538 per patient across the selected tumors, 

ranging from $11,946 per patient for gastric cancer to $38,983 per 

patient for pancreatic cancer. Conclusions: VTE results in significant 

inpatient and outpatient resource utilization, and increased all-cause (in 

addition to VTE-related) healthcare costs. Measures to prevent outpatient 

cancer-associated VTE may reduce healthcare utilization and costs in 

high-risk cancer patients. 


Treatment and treatment outcomes of advanced NSCLC patients in routine 

clinical care: Results of the retrospective LUCEOR study. Presenting 

Author: Jason Scott Agulnik, Jewish General Hospital, Lady Davis Institute 

for Medical Research, McGill University, Montreal, QC, Canada 

Background: Although NSCLC is the most common type of lung cancer, 

published data on both treatment patterns and outcomes in routine clinical 

care are scarce. Collecting this data systematically across countries will 

help to understand, compare and improve patient care. Methods: 1,490 

patient charts were reviewed retrospectively from 40 sites in Australia, 

Belgium, Canada, France, Germany, Italy, Sweden, Turkey, the Netherlands 

and the UK, 1436 of those evaluable. Patients deceased before April 

2010 were eligible if �18 years, diagnosed with advanced stage IIIb/IV 

NSCLC and had received active 1st line anti-cancer treatment. Demographic 

data, disease and, treatment history and resource use were 

collected from start of first line treatment until death. Results: Mean age at 

NSCLC diagnosis was 64 years [SD�10.6], 67% of patients had stage IV 

disease at diagnosis and 66% were male. Confirmed tumor histology was 

adenocarcinoma in 50% of patients, squamous and large cell carcinoma in 

23% and 14%, respectively. Tumour histology was not available in 13% of 

patients. Mean number of treatment lines was 1.7 [range 1-8]. Biomarker 

analysis was performed in 19% of patients (of those 26% and 13% tested 

for EGFR and KRAS mutation, respectively) within less than one month of 

diagnosis. 1st line therapy included mainly platinum doublets (86%, 

mostly carboplatine/gemcitabine [23%]), 2nd line included erlotinib (35%) 

and pemetrexed (18%), and 3rd line included erlotinib (38%) and 

docetaxel (17%). Most treated patients had ECOG performance status of 1. 

Stable disease (based on RECIST) was highest during 1st line therapy with 

30%. Median PFS from start of 1st line treatment was 3.8 months 

[SD�7.1], with a median OS of 7.1 months [SD�11.6]. Conclusions: The 

majority of patients were diagnosed with an adenocarcinoma and a number 

of patients were tested for EGFR or KRAS mutation. Overall treatment 

outcomes observed in routine care seem lower than those observed in 

clinical trials. Also current therapeutic options for NSCLC seem to provide 

limited clinical benefit, underpinning the need for new treatment alternatives 

to prolong PFS and OS. 


Use and spending on antineoplastic therapy (AT) in the Medicare population 

and the role of supplemental coverage. Presenting Author: Amy J. 

Davidoff, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 

Background: Oral antineoplastic agents (OAA) represent a growing sector of 

cancer therapy. Prior studies of older adult cancer patients (pts) examined 

use of infused/ injected chemotherapy (IICT) covered by Medicare Part B. 

We examined trends in IICT and OAA use, and the effect of supplemental 

coverage on AT use and spending. Methods: We used Medicare Current 

Beneficiary Survey data (1997-2007). Newly diagnosed cancer pts were 

selected using ICD-9CM codes. IICT use was identified from Part B claims; 

OAAs were identified from self reported prescription medication events. 

Supplemental coverage and pt characteristics were assessed from administrative 

records and self-report. Total spending summed payments from all 

sources during the cancer diagnosis and subsequent year. Logistic regression 

examined factors associated with use of any and type of AT; 

Generalized Linear Models estimated factors associated with spending. 

Results: Of 1,836 newly diagnosed cancer pts 559 (31%) received AT; 395 

(21%) used IICT and 253 (15%) used OAAs. Spending per user was 

$7,544(AT), $9,892 (IICT), and $1,535 (OAA). Supplemental coverage 

was associated with increased odds of AT use compared to no supplemental 

coverage (see Table). Cancer site and age were key predictors of spending 

among users. OAA spending increased during 2006-7 relative to 2004-5. 

Conclusions: AT use in Medicare beneficiaries is sensitive to the presence 

but not type of supplemental coverage. OAAs were used by a relatively large 

proportion of cancer pts receiving AT, although spending was less than for 

IICT during this largely pre-Part D period. With the growing number of 

relatively new OAAs, and more in the pipeline, monitoring the role of 

supplemental coverage, and particularly the role of Part D on access and 

spending is a critical area for ongoing research. 

Adjusted effects of supplemental coverage on AT use. 

AT IICT OAA 

(OR) 

Supplemental coverage (ref�none) 

Employment related w/ Rx 1.92** 1.88** 2.25** 

Other private w/ Rx 1.93** 1.79* 2.20** 

Public w/ Rx 1.85** 1.86** 2.00* 

Medical only 1.92** 1.85** 2.33** 

OR signif @ **p�.05; * p�.10. Models controlled for site, demographics, health 

status, income, region, year, and months observed. 



Disparities in preoperative imaging for breast cancer: Not so black and 

white. Presenting Author: Richard J. Bleicher, Fox Chase Cancer Center, 


Background: Controversy exists about racial/ethnic differences in the care of 

breast cancer patients. Imaging plays a critical role in evaluation, but little 

national data exists on breast imaging by race. This study was performed to 

determine if imaging disparities exist in Medicare patients, when adjusting 

for socioeconomic (SE) factors. Methods: Surveillance Epidemiology and 

End Results (SEER) data linked to Medicare claims were reviewed for 

patients diagnosed with invasive nonmetastatic breast cancer between 

2000 and 2005, undergoing surgery as their 1st treatment modality. 

Diagnostic imaging was reviewed during the interval between the 1st physician visit and surgery (“preoperative interval”[POI]) and imaging use 

was defined as �1 imaging-specific claim. SE factors included rural/urban 

setting, and education, poverty, and median income per census tract. 

Results: Among 39,790 patients, there were 34,774 White (87%), 2,341 

Black (5.9%), 1,459 Hispanic (3.7%), and 1,216 Asian/Pacific Islander 

(3.1%) patients. Univariate racial differences were noted for all imaging 

types (p’s �0.0001 to 0.007). During the POI, when adjusting for 

demographics, tumor characteristics, and SE factors in multivariable 

analysis, use of mammogram, ultrasound (US), breast MRI, CT, and bone 

scan were not different between Blacks and Whites. Education level was a 

predictor for US (p�0.007), breast MRI (p�0.0001), CT (p�0.006) and 

bone scan use (p�0.002), but not mammography (p�0.90). There were 

varying correlations between Hispanics or Asians vs Whites for all imaging 

types. Stage, histology, U.S. region, and comorbidity index were most 

consistently predictive of imaging use of all types. When evaluating 6 mos 

prior to the 1st physician visit along with the POI, 96.4% of all patients had 

�1 mammogram, with 94.1% of Blacks having mammograms vs 96.5% of 

Whites (OR 0.7, 95% CI 0.6-0.9; p�0.001). Conclusions: There is little 

racial difference in imaging performed during the POI for Medicare patients 

having breast cancer, and efforts to determine causes of survival disparities 

in such patients should be focused elsewhere. Whether these findings 

apply to the privately insured or the uninsured requires additional exploration. 


Rural versus urban differences among patients (pts) with hormone-receptor 

positive (HR�) breast cancer (BC) and a 21-gene assay recurrence score (RS). 

Presenting Author: Molly Andreason, University of Wisconsin, Madison, WI 

Background: Differences in BC outcomes have been noted between rural and urban 

women. The influence of tumor biology vs treatment factors as the driver of these 

differences remains unclear. The Oncotype Dx 21-gene assay RS predicts distant 

recurrence risk for HR�BC;aRS�18 indicates possible chemotherapy benefit. We 

assessed rural vs urban differences in RS and therapies received (endocrine therapy; 

chemotherapy for RS�18). Methods: Retrospective chart review was conducted on 

BC pts diagnosed 2005–2010 with a 21-gene assay RS. Stage, grade, medications 

and receptor status were abstracted; RS information was obtained from Genomic 

Health. Rural-Urban Commuting Area (RUCA) codes defined rural vs urban status. 

Comparisons between rural vs urban pts were made using two-sample tests, 

chi-square or Fisher’s exact test for discrete data such as RS (� 18 vs � 18), stage 

and ER status. T- or Wilcoxon rank sum test were used for continuous data (RS 

0-100 and age.) All tests were at a two-sided significance level of 0.05. Results: Of 

495pts with RS, 488 had RUCA codes (91% white, 61% postmenopausal). For 

rural vs urban pts, mean RS was 18 vs 19, p�0.15. The table shows univariate 

analysis for other predictors. For treatment, 321/354 (97%) rural vs 118/134 

(94%) urban pts started endocrine therapy (p�0.2). For RS�18, 17/55 (31%) rural 

vs 83/165 (50%) urban pts received chemotherapy (p�0.02, Chi-square test). 

Conclusions: Rural pts did not have significantly different RS compared with urban 

pts, but received significantly less chemotherapy for RS�18. This suggests that for 

HR� BC, rural vs urban discrepancies may be explained in part by treatment factors. 

We suggest prospective comparison or confirmation in another cohort. 

BC in rural vs urban women. 

Rural 

N�134 (%) 

Urban 

N�354 (%) p value 

RS # 

Age 

18 (8.8) 19 (9.0) 0.15* 

# 

BMI 

58 (10.3) 56 (10.1) 0.08* 

# 

30.0 (7.3) 28.8 (7.5) 0.12* 

Hormone use at diagnosis 

Yes 17 (13) 60 (17) 0.28 ^ 

No 113 (84) 279 (79) 

Unknown 4 (3) 15 (4) 

Stage 

I 92 (69) 247 (70) 1 ^ 

II 36 (27) 95 (27) 

Unknown 6 (5) 12 (4) 

Grade 

1 36 (27) 116 (33) 0.13 ^ 

2 71 (53) 191 (54) 

3 24 (18) 41 (12) 

Unknown 3 (2) 6 (2) 

# Mean (SD); *t-test; ^ Chi-square test (excludes unknown). 


397s 


Patient-related predictors of poor-quality pain care in advanced lung 

cancer patients. Presenting Author: Inga Tolin Lennes, Massachusetts 


Background: Unrelieved pain remains a major problem for all patients, 

including those with cancer, despite national standards for pain management. 

Screening and addressing pain is an integral part of oncology visits 

and an ASCO QOPI indicator of quality oncology care. The goal of this study 

was to assess associations between patient-related factors, particularly 

patient distress, and meeting ASCO quality metrics for appropriate management 

of pain in patients with advanced lung cancers. Identification of 

patient related factors could lead to targeted quality improvement efforts. 

Methods: From 8/07 to 9/10, we recruited consecutive new patients in a 

multidisciplinary thoracic oncology clinic to participate in a research 

database for which patients completed self-report instruments for distress, 

depression (PHQ-9) and anxiety (GAD-7), at their first oncology visit. We 

then performed a QOPI chart audit for patients with advanced lung cancer 

who received care at our institution. A composite measure of appropriate 

pain management was calculated. Components of the composite measure 

included 1) documentation of pain assessment, and 2) for patients with 

moderate-severe pain (�4 on 10 point scale) plan of care documentation. 

Results: 253 patients completed baseline assessments and had follow up. 

Pain was assessed in 252 (99%) patients. Over a third (88/253) of newly 

diagnosed advanced lung cancer patients had at least moderate pain on 

their first visit to the medical oncologist. Almost half of patients with 

moderate-severe pain were depressed (40/88). Of the patients with 

moderate-severe pain, 54/88 (63%) had a plan of care related to pain 

documented in the oncologist’s note. In total, 219 (87%) patients received 

appropriate pain assessment and care. In a multivariate model including 

age, sex, histology, ECOG PS, provider, depression, and anxiety, only 

depression independently predicted inadequate pain care. Depressed 

patients were 3 times more likely to receive poor quality pain care (OR 

2.75, 95% CI 1.04-7.25, p�0.04). Conclusions: At initial oncology visit, 

pain is present in over a third of patients with advanced lung cancer. 

Depression is highly co-morbid with pain and appears to be a risk factor for 

inadequate pain care. 


Impact of county-level surgical specialist density on breast (BrCa) and lung 

cancer (LuCa) mortality. Presenting Author: Andrei Karpov, British Columbia 

Cancer Agency, Vancouver, BC, Canada 

Background: Variations in distribution of the surgical workforce may result 

in differential access to cancer screening and treatment. Our aim was to 

explore the relationship between county-level surgical specialist density 

and BrCa and LuCa mortality. Methods: Using data from Area Resource File, 

US Census and National Cancer Institute, regression models that controlled 

for cancer incidence, county demographics and socioeconomic 

factors were constructed to examine the association among a) general 

surgeon (GS) and radiation oncologist (RO) density with BrCa mortality and 

b) thoracic surgeon (ThS) and RO density with LuCa mortality. Plastic (PS) 

and transplant surgeons (TrS) were used as surgical controls as they were 

not expected to correlate significantly with BrCa or LuCa mortality. Results: 

A total of 1,557 and 2,044 US counties were analyzed for BrCa and LuCa, 

respectively: mean incidences were 119 and 75 and death rates were 25 

and 59 per 100,000 people, respectively, for BrCa and LuCa. Mean 

specialist densities were 7.72 (GS), 0.80 (RO), and 0.97 (PS) [for BrCa 

counties] and 0.55 (ThS), 0.55 (RO), and 0.01 (TrS) [for LuCa counties] 

per 100,000. When compared to counties with no surgical specialist, those 

with at least one GS and RO for BrCa and at least one ThS and RO for LuCa 

were associated with decreased mortality (Table). Increasing the density of 

GS and RO beyond 9 and 1 per 100,000 did not result in significant 

reductions in BrCa mortality. Likewise, increasing the density of ThS and 

RO to above 1 each per 100,000 failed to yield further improvements in 

LuCa mortality. Counties with more elderly residents also correlated with 

worse BrCa and LuCa outcomes. Conclusions: The presence of specific 

surgical specialists is associated with lower BrCa and LuCa mortality. There 

appears to be a threshold at which point further increase in their density do 

not contribute to continued improvements in outcomes. Distributing the 

surgical workforce across all counties will offer population-based improvements 

in BrCa and LuCa mortality. 

BrCa LuCa 

Specialist Effect on mortality* p Effect on mortality* p 

GS -0.21 0.001 n/a n/a 

RO -0.10 0.003 -0.03 0.032 

ThS n/a n/a -0.04 0.009 

PS -0.04 0.29 n/a n/a 

TrS n/a n/a -0.01 0.84 

*Beta estimates 




Prevalence and characteristics of patients with stage IV solid tumors who 

receive no anticancer therapy. Presenting Author: Alexander C. Small, 

Division of Hematology and Medical Oncology, The Tisch Cancer Institute, 

Mount Sinai School of Medicine, New York, NY 

Background: Clinicians caring for patients with cancer are well aware that a 

subset of patients who present with metastatic solid tumors never receive 

anticancer therapy for reasons including poor functional status, comorbidities, 

and patient preference. The prevalence and characteristics of this population 

have not previously been described. Methods: The National Cancer Database 

was queried for patients diagnosed with metastatic (stage IV) solid tumors 

including breast, cervix, colon, kidney, small-cell and non-small cell lung 

[NSCLC and SCLC], prostate, rectum and uterus. Patients who received 

neither radiation therapy nor systemic therapy were identified. Other factors 

such as age, race, income, insurance status, and diagnosis year were assessed. 

In an exploratory analysis, log-binomial regression was used to estimate 

prevalence ratios (PR) for the proportion of untreated stage IV to treated stage 

IV cancer cases according to these factors. Results: From 2000-2008, 

773,233 patients with stage IV cancer were identified of whom 159,284 

(21%) received no anticancer therapy (Table). Patients with NSCLC accounted 

for 55% of untreated patients. Across all cancer types, older age (PR range 

1.37-1.49, all p�0.001), black race (PR range 1.05-1.32, all p�0.001), 

lack of medical insurance (PR range 1.47-2.46, all p�0.001), and lower 

income (except uterus) (PR range 0.91-0.98 for every $10,000 income, all 

p�0.001) were associated with increased prevalence of not receiving treatment. 

Conclusions: Approximately 20% of patients who present with stage IV 

solid tumors never receive anticancer therapy. These findings have potential 

implications with regards to healthcare policy and access to care. 

Prevalence of patients with metastatic cancer who receive no anticancer 

therapy (2000-2008). 

Cancer Type 

Untreated 

stage IV 

Total 

stage IV % untreated 

Cancer-specific 

% of total 

untreated cases 

Kidney 12,079 47,417 25.5% 7.6% 

NSCLC 87,400 353,748 24.7% 54.9% 

Uterus 297 1,217 24.4% 0.2% 

SCLC 21,085 99,206 21.3% 13.2% 

Rectum 4,305 26,140 16.5% 2.7% 

Colon 18,816 119,748 15.7% 11.8% 

Cervix 1,407 9,535 14.8% 0.9% 

Breast 7,313 57,148 12.8% 4.6% 

Prostate 6,582 59,074 11.1% 4.1% 

Total 159,284 773,233 20.6% 100.0% 


The use of the word “cure” in oncology. Presenting Author: Kenneth David 

Miller, Sinai Hospital of Baltimore, Baltimore, MD 

Background: Use of the word “cure” in cancer care reflects a balance of 

physician and patient optimism, realism, medico-legal concerns, and even 

superstition. The purpose of this study was to survey a group of clinicians 

regarding the frequency and determinants of using the word “cure” in their 

practice. Methods: In 2011, 180 oncology clinicians at the Dana-Farber 

Cancer Institute were invited to complete a survey regarding the word 

“cure” in cancer care. Participants completed a 19 question survey 

regarding how commonly their patients are cured, how often they use the 

word cure, in what circumstances they would tell a patient that they are 

cured, the timing of telling a patient that they are cured, and hesitancy in 

using the word cure. Three patient case scenarios were presented to elicit 

participants’ views regarding whether patients were cured and whether they 

need continued follow-up. Results: The 117 participants who provided 

answers to the cure questions (65% of the original 180 invitees), were 

evenly divided between males and females,73% were medical doctors, and 

56% had 10 or more years of experience since their training. Eighty-one 

percent of respondents were hesitant to tell a patient that they are cured 

and 63% would never tell a patient that they are cured. Only 7% feel that 

greater than 75% of their patients are, or will be, cured. This varied 

significantly by subspecialty (p�0.001). The participating clinicians reported 

that only 34% (sd: 30%) of patients ask if they are cured. In 

considering 20-year survivors of seminoma, large cell lymphoma, and 

estrogen positive breast cancer, 81%, 73%, and 47% of clinicians, 

respectively, believed that the patients were cured and 33%, 38%, and 

52% recommended annual oncology follow-up of the patients. Twentythree 

percent of clinicians believed that patients should never be discharged 

from the cancer center. Conclusions: Oncologists report that 

patients are hesitant to ask whether they are cured, and the clinicians are 

hesitant to tell, although this varied by cancer subspecialty. Annual 

oncology follow-up was frequently endorsed, even after 20 years in 

remission. 


Utility of positron emission tomography (PET) scans on the management of 

cancers of unknown primary. Presenting Author: Hao Chen, British Columbia 

Cancer Agency, Vancouver, BC, Canada 

Background: PET scans can be potentially useful in the diagnostic and 

staging workup of certain cancers. Although frequently ordered, its precise 

role in the investigation and management of cancers of unknown primary 

(CUP) remains poorly defined. Our main study aims were to 1) compare the 

utility of PET vs. CT scans in determining the primary site, lymph node 

status, and metastases for patients with CUP, and 2) describe the overall 

survival of patients for whom the primary site was determined by PET vs. 

those who were not. Methods: Patients diagnosed with CUP in British 

Columbia, Canada from 2006 to 2009, evaluated at 1 of 5 regional cancer 

centers in the province, and underwent a PET scan were reviewed. We 

measured concordance rates between PET and CT scans and constructed 

regression models to characterize the effect of PET scans on treatment and 

survival. Results: A total of 175 patients were included: median age was 60 

years and 76% were men. PET scans were most commonly performed for 

the following indications: locating primary (45%); staging (42%); and 

others (13%). Among those in whom CT did not detect the primary site, 

PET revealed the location of the primary in 9% of cases. CTs and PETs were 

concordant in demonstrating nodal status and metastases in 91% and 95% 

of patients, respectively. PET scans were able to show additional nodal 

involvement and uncover metastatic disease in 9% and 5%, respectively, 

when compared to CT scans. Identification of the site of primary cancer by 

PET did not substantially modify subsequent therapy (p�0.37) and it also 

failed to significantly improve the median overall survival (10.1 vs. 7.3 

months, p�0.57) when compared to those in whom the location of the 

primary was unconfirmed. Conclusions: In this retrospective cohort of CUP 

patients, CT and PET scans appear to provide a similar level of diagnostic 

and staging information. For a small proportion of CUP patients, PETs were 

superior in clarifying the primary site, nodal status, and metastases, but 

these did not alter therapy or increase overall survival. Based on these 

findings and considering the cost implications of intensive imaging studies, 

the diagnostic value of PET scans over CT scans appears limited to a small 

subset of patients with CUP. 


Sown the seeds: An analysis of published trials in clinical oncology. 

Presenting Author: Natalie M. Spradlin, Vanderbilt University Medical 

Center, Nashville, TN 

Background: Competition in the pharmaceutical marketplace has resulted 

in “seeding trials” which appear to serve little scientific purpose other than 

to gain a financial hold in the marketplace. Hallmarks of “seeding” clinical 

trials [Kessler, et al N Eng J Med 1994] include trial design that does not 

support stated research goals, industry sponsorship without novel findings 

or poor scientific rationale, and drugs introduced into an already crowded 

therapeutic class, i.e. “me too” drugs. We evaluated clinical trials published 

in high impact oncology journals to ascertain the prevalence of trials 

bearing the characteristics of a seeding trial. Methods: We conducted a 

PubMed search using “clinical trial”, “oncology”, published 2/2005 – 

2/2010, in Ann Oncol, J Clin Oncol, Lancet, Lancet Oncol, ortheN Engl J 

Med. All phase I/II, II and III studies were included. Phase I, hematology, 

radiation oncology, and pediatric studies were excluded. Data collected 

included disease site, phase, funding source, journal, and whether the trial 

fit criteria for “seeding” as previously defined. Results: 1781 articles have 

been evaluated to date. 528 met criteria for analysis. 130 were considered 

seed studies. Seed studies per journal were Ann Oncol 26 of 128, J Clin 

Oncol 88 of 340, Lancet 8of22,Lancet Oncol 5 of 16, and N Engl J Med 3 

of 22. Studies published per disease site and percent seed studies were 

melanoma 19 and 31.6%, breast 106 and 30.2%, GI 126 and 20.6%, 

lung 101 and 29.7%, GU 65 and 24.6%, gynecology 40 and 30%, head 

and neck 24 and 12.5%, CNS 24 and 12.5%, sarcoma 11 and 18.2%, and 

advanced cancer 12 with zero seeds. Overall phase totals were phase I/II 

16, phase II 272, and phase III 240. Seed studies per phase were phase II 

28.7%, phase III 21.7% and zero for phase I/II. 210 studies were solely 

industry sponsored, and of these, 37.1% were seed studies. Funding was 

not listed for 73 studies. Conclusions: The integrity of clinical trials is 

challenged in the race to claim major market share. Our analysis of clinical 

trials published in high impact oncology journals found seeding trials 

account for 24.6% of publications. 37.1% of industry sponsored trials are 

seed studies. Seed studies are more common among the major disease 

sites or sites for which targeted therapies exist. 



Effectiveness of a screening intervention to identify clinical-trial-eligible 

patients. Presenting Author: Leo Chen, University of British Columbia, 


Background: Advancements in cancer therapy require clinical trials, but 

only 3% of all cancer patients (CP) participate in trials causing many 

studies to be delayed or fail to complete. Literature indicates that accrual to 

clinical trials is primarily driven by MD related factors. The objective of this 

study was to evaluate whether the screening and identification of potentially 

eligible patients (PEP) for specific clinical trials would lead to an 

increased rate of accrual (RA). Methods: During a 4 month period, the 

charts of CP attending the outpatient clinics of 12 MDs were reviewed to 

determine eligibility for 21 phase II-IV trials for CP with BR, GI, GU, GY, or 

LG cancer. Trials were included if they had been open for � 4 months and 

would remain open � 8 months from the start of the intervention. A 

screening coordinator with minimal clinical background reviewed the 

electronic record of new and followup CP to determine eligibility according 

to protocol specified criteria. PEP were identified for medical oncologist by 

attaching notices to CP charts. Participating MDs were surveyed regarding 

the helpfulness and accuracy of the forms. A negative-binomial regression 

model was used to compare RA and find 95% CI for relative rates. Results: 

Between May 1 to August 31, 2011 a total of 2,098 charts were screened 

for eligibility for 21 trials, and 120 PEP were identified. Of these, 15 were 

randomized to the referred study, 4 to a different study, and 4 CP were 

offered but declined the referred study. Four month RA for included trials 

were 61 before, 73 during and 51 after the intervention. Relative rates 

adjusted for MD bookings were 0.85 (95% CI: 0.67, 1.06, p � 0.15) 

before and 0.70 (95% CI: 0.54, 0.90, p � 0.005) after, relative to during 

the intervention. 33 completed questionnaires were received: 22 (67%) 

were helpful and 23 (70%) were accurate. Screening required a 1.0 Full 

Time Equivalent position during the period of the intervention. Conclusions: 

Manual screening of patient records to determine clinical trial eligibility is 

labor intensive and increases enrolment to specific clinical trials. Notifications 

were deemed mostly helpful and accurate by oncologists. Screening 

interventions should be considered to improve clinical trial accrual. 


Burnout prevalence in medical and radiation oncologists at British Columbia 

Cancer Agency (BCCA). Presenting Author: Catherine A. Fitzgerald, BC 

Cancer Agency, Vancouver Island Centre, Victoria, BC, Canada 

Background: Burnout, reported to affect 30-60% of oncology workers, is a 

syndrome of psychological distress typically manifesting in three dimensions: 

Emotional Exhaustion (EE), Depersonalization (DP) and Low Personal 

Accomplishment (PA). Causal factors include workload, dealing with 

terminally ill patients and difficulties maintaining a balance between 

professional and personal life. As workload rises due to increased complexity 

of therapy and increasing prevalence of cancer patients, burnout may 

increase, especially in times of financial constraint. We sought to determine 

the prevalence of burnout in medical and radiation oncologists 

working at BCCA, which provides all radiation and the majority of medical 

oncology services to BC’s 4.5 million people. Methods: In March 2011, 

BCCA oncologists were invited to participate in a confidential online survey 

consisting of basic demographics and the 22 item MasLach Burnout 

Inventory (MBI) instrument, the latter a validated tool measuring distress in 

the three main dimensions of burnout. Normative data for physicians were 

used to interpret the results. Results: Response rate was 59%, female:male 

40:60% with similar response rates for medical and radiation oncology (60 

v 59%). Of the 73 who indicated their age range, 34 (47%) were between 

35 and 44 years old. Respondents indicated that they had considered 

reducing their Full Time Equivalent (FTE) (67%) or leaving BC (46%). In 

those with at least 2 scores at a severe level, these rates were 76% and 

71% respectively. Conclusions: Over 60% of responding BCCA oncologists 

report burnout in at least one domain of the MBI tool. Many have 

considered leaving the province or reducing their hours. These data are 

consistent with Grunfeld’s survey of Ontario oncologists (CMAJ 2000), 

although the rate of burnout is higher in this survey. Further research into 

ways to lessen burnout in oncology is urgently needed. 

Percentage of responding BCCA oncologists (n�78) with “severe” score on 

burnout (MBI) survey. 

Burnout factor 

Emotional 

exhaustion Depersonalization 

% scores at 

“severe” 

level 

Low personal 

achievement 

At least 

1 factor 

More 

than 

1 factor 

All 3 

factors 

51% 44% 28% 64% 44% 14% 


399s 


Disparities in the treatment and outcomes of lung cancer among HIVinfected 

people in Texas. Presenting Author: Gita Suneja, Department of 

Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, 

PA 

Background: HIV-infected (HIV�) people are at elevated risk for lung cancer 

and have higher mortality following lung cancer diagnosis than uninfected 

(HIV-) individuals. The disparity in survival is partly due to advanced stage 

at diagnosis, but it is unclear whether HIV� people with lung cancer are 

less likely to receive cancer treatment, which could worsen survival. 

Methods: We included adults � 18 years of age with lung cancer reported to 

the Texas cancer registry (N�156,930). HIV status was determined by 

linkage with the enhanced Texas HIV/AIDS Reporting System. We compared 

HIV� and HIV- lung cancer cases with respect to demographic and 

clinical characteristics. For non-small cell lung cancer (NSCLC) cases, we 

identified predictors of cancer treatment (surgery, radiation, and chemotherapy) 

using logistic regression. We used Cox regression to evaluate the 

effects of HIV and treatment on lung cancer-specific mortality. Results: 

Compared with HIV- lung cancer cases (N�156,593), HIV� lung cancer 

cases (N�337) were more likely to be young, non-Hispanic black, male, 

and to have distant stage disease (53.7% vs. 44.4%). HIV� cases were 

less likely to receive cancer treatment than HIV- cases (60.3% vs. 77.5%; 

odds ratio 0.39, 95%CI 0.30-0.52 after adjustment for diagnosis year, 

age, sex, race, stage, and histologic subtype). In Cox models adjusted for 

these variables, both HIV infection (hazard ratio [HR] 1.34, 95%CI 

1.15-1.56) and lack of cancer treatment (HR 1.69, 95%CI 1.66-1.72) 

were associated with higher lung cancer-specific mortality. After adjustment 

for cancer treatment, the association between HIV and lung cancer 

mortality was attenuated (HR 1.25, 95%CI 1.06-1.47). The association 

between HIV and lung cancer-specific mortality was stronger among 

untreated lung cancer cases (HR 1.32, 95%CI 1.01-1.72) than treated 

cases (adjusted HR 1.16, 95%CI 0.94-1.43; p-interaction�0.34). 

Conclusions: In this population-based study, HIV� people with NSCLC were 

less likely to be treated for lung cancer than their HIV- counterparts. This 

lack of treatment may be partly responsible for higher cancer-related 

mortality in HIV� cases. Further investigation is needed to understand 

disparities in cancer treatment for HIV� people. 


Clinical and cost impact of diagnostic slide review. Presenting Author: 

Justin Cuff, Aegis Review, San Francisco, CA 

Background: Diagnostic error is postulated to represent a significant source 

of preventable mortality, morbidity, and cost. A primary pathologic diagnosis 

of cancer has a relatively high error rate necessitating cost effective 

solutions to mitigate diagnostic related harm. Methods: A review of 773 

consecutive inbound transfers to Stanford, with review of prior pathology 

material, was performed to measure diagnostic discrepancy. Information 

was collected about the originating practice size and type, subspecialty 

area, additional testing, and a description of the disagreement. For a subset 

of cases, itemized payment data was collected to explore the financial 

impact of slide review. Results: We found that 9% of cases have diagnostic 

discrepancies when comparing the incoming working diagnosis with the 

result of the pathology slide review. Major diagnostic discrepancies, likely 

to alter treatment, were identified in 3% of cases. Discrepancy rates 

differed significantly between subspecialty areas (p�0.01) although few 

areas were spared major error. Disagreements about classification were 

common as were over/under calling malignancy, grading errors, and 

incorrect ordering or interpretation of ancillary testing. The subset of cases 

(n�107) with billing information demonstrated ~42,800 unique charge 

events associated with these episodes of care. The mean charge for patients 

was $292,813 (median $130,467). Typical of charge data the dollar 

amounts exhibited strong right-skew. Average reimbursement was $76,017 

(median $23,999) and the median charge:reimbursement ratio was 3.3. 

When analyzing cases by service line, only 1.4% of charges related to the 

diagnostic review of the prior pathology material, demonstrating a remarkably 

small impact on the overall cost. While additional testing was 

performed on 10% of cases, there was no evidence that cases with a 

discrepancy were associated with increased overall costs. Conclusions: 

Diagnostic slide review on prior material is relatively inexpensive in terms of 

the cost of overall care and permits the detection of significant errors that 

may affect treatment planning. Pathology slide review represents a clinically 

impactful and low cost way to prevent errors in diagnosis from 

becoming errors in management. 




Colorectal cancer survivors’ needs and preferences for survivorship information. 

Presenting Author: Talya Salz, Memorial Sloan-Kettering Cancer 


Background: We assessed colorectal cancer (CRC) survivors’ needs and 

preferences for information to guide development of a survivorship care 

plan. Methods: We conducted a survey of survivors treated for stage I-III 

CRC at two hospitals in New York City. Participants completed treatment 

6-24 months before the interview and had not received a survivorship care 

plan. We evaluated whether survivors knew their basic treatment history, 

whether they understood ongoing risks, and their preferences for receiving 

survivorship information. Results: 175 CRC survivors completed the survey 

between June 2010 and November 2011. Survivors generally remembered 

basic information about their diagnosis and treatment: 88% accurately 

reported the location of their cancer; 95-100% accurately reported 

whether they had surgery, chemotherapy, or radiation; and 90-95% 

correctly reported the completion date (within 6 months) for each treatment. 

Survivors knew less about the risks of local and distant recurrences 

(69% and 77% correct, respectively) and of getting another CRC compared 

to unaffected individuals (40% correct). More than three quarters of 

participants received information about their cancer, their treatment 

history, ongoing oncology visits, and testing to be done by the oncologist 

(77-86% across categories). Across these categories of information, 

93-99% of those who received information found it useful. Most survivors 

did not receive information about symptoms to report to their doctors, 

returning to work, financial issues, or legal issues (59-95% across 

categories); but those who received this information found it useful 

(67%-100% across categories). Conclusions: Even without receiving survivorship 

care plans, CRC survivors generally understood their cancer 

diagnosis and treatment. However, many lacked knowledge of ongoing 

risks, prevention, and nonmedical survivorship issues. Most survivors found 

the survivorship information they received useful. The greatest benefit of 

survivorship care plans to survivors may not be summarizing past care as 

much as helping survivors understand their risks and plan for the future. 


Out-of-pocket (OOP) health care expenditure burden for Medicare beneficiaries 

with cancer. Presenting Author: Ilene H. Zuckerman, University of 

Maryland School of Pharmacy, Baltimore, MD 

Background: Concern is increasing about the OOP burden faced by cancer 

patients (pts). Medicare beneficiaries have multiple comorbidities, have 

limited financial resources, and may face substantial cost sharing under 

traditional Medicare if they do not have generous supplemental coverage. 

We examined OOP spending and burden relative to income for Medicare 

beneficiaries with cancer, compared to a non-cancer comparison group. 

Methods: We used Medicare Current Beneficiary Survey data (1997-2007). 

Newly diagnosed cancer pts were selected using ICD-9CM codes on claims 

after a 12 mos washout period. OOP spending was assessed using self 

report for the index(diagnosis) and subsequent year. Pt characteristics were 

self reported. Generalized Linear Models estimated effects of pt characteristics 

on OOP spending; logistic regression identified pt characteristics 

associated with high burden, defined as OOP spending �20% of income. 

Results: The cohort included 1,869 beneficiaries with, and 10,057 

beneficiaries without cancer. Relative to the non-cancer cohort, cancer pts 

were older, had greater comorbidities, and were more likely to lack 

supplemental coverage (22 vs 16%) (all at p�0.01).OOP spending was 

$4,727 or 11.4% of total spending for cancer pts. The unadjusted 

difference between cancer and non-cancer pts in OOP spending was 

$1,518 (p�.001); with adjustment for patient characteristics, cancer 

patients faced an incremental $956 (p�.01) in OOP spending. Median- 

[mean] OOP/income was 10%[24%] for beneficiaries with, compared to 

6%[14%] without cancer (p�.001). Over ¼ (28%) of beneficiaries with 

cancer spent 20% of their income OOP, compared to 16% of beneficiaries 

without cancer (p�.001). Supplemental insurance and higher income were 

protective against high OOP burden, whereas assets, comorbidity, and 

receipt of cancer-directed radiation and antineoplastic therapy were 

associated with higher OOP burden. Conclusions: Medicare beneficiaries 

with cancer face higher OOP burden than their counterparts without 

cancer; some of the higher burden was explained by higher comorbidity 

burden and lack of supplemental insurance. Financial pressures may 

discourage some elderly patients from pursuing treatment. 


Speed of accrual into published phase III oncology trials: A comparison 

across geographic locations. Presenting Author: Nancy R. Ruther, Gundersen 

Lutheran Health System, La Crosse, WI 

Background: There is a perception that patient accrual may be slower in the 

US than it is in Europe (Wang-Gillam A et al, J Clin Oncol 2010;28:3803- 

3807). However, a systematic study has not been performed. We seek to 

determine the speed at which patients are accrued into published phase III 

oncology trials across geographic locations and to identify factors that may 

influence this process. Methods: We searched MEDLINE and identified all 

original phase III oncology therapeutic trials published in 2006-2010 (N � 

567). Trials with no reported activation and completion dates were 

excluded (n � 20). Accrual speed per trial was expressed as patients per 

month and was calculated by dividing the number of patients enrolled by 

number of months a trial was open. Results: The 547 trials included in our 

study enrolled 281,340 patients. Most trials were for adults only (95.6%), 

late stage cancers (77.5%), and involved multinational participation 

(44.1%). Funding sources were cooperative groups (45.5%), industry 

(33.8%) and academic centers (20.5%). The top 5 cancers studied were 

hematologic (19.2%), gastrointestinal (16.5%), lung (16.3%), breast 

(15.4%), and gynecologic (8.4%). Trial results were negative (57.4%), 

positive (38.2%), or equivalent (4.4%). The mean (�SD) accrual speeds 

varied according to trial location (multinational [25.0�25.4], US 

[13.3�16.5], other countries [11.4�15.7], Europe [8.7�11.8]; [P� 

.001]), funding source (industry [28.3�24.7], cooperative groups 

[13.3�19.0], academic [6.8�6.5]; [P� .001]), and cancer type (breast 

[24.0�29.4], gastrointestinal [20.2�24.2], lung [19.3�22.7], gynecologic 

[15.3�19.2], hematologic [11.2�10.7]; [P� .001]). After adjusting 

for funding source, accrual speeds were significantly different across trial 

locations only in 2 cancers: gastrointestinal (multinational [25.2�3.7], US 

[24.1�8.2], Europe [11.5�3.7], other [7.5�8.5]; P� .046) and gynecologic 

(multinational [28.9�5.4], other [10.5�7.8], US [6.6�5.3], Europe 

[4.2�5.9]; P� .004) studies. Conclusions: Among published phase III 

oncology trials, multinational studies accrued patients faster in gastrointestinal 

and gynecologic cancers and at a similar speed in other cancers. 


Racial disparities in depressive symptom prevalence and selective serotonin 

reuptake inhibitor (SSRI) utilization in cancer patients: An analysis 

from ECOG E2Z02: Symptom Outcomes and Practice Patterns (SOAPP). 

Presenting Author: Fengmin Zhao, Dana-Farber Cancer Institute, Boston, 

MA 

Background: Rates of diagnosis and treatment of depression in primary care 

vary widely by race. It is unclear whether such disparity exists in oncology. 

Methods: 3106 patients with cancer of the breast, prostate, colon/rectum, 

or lung were enrolled from multiple sites in a longitudinal study of 

symptoms. Patient-reported depressed mood (PRD) on a 0-10 numerical 

rating scale and clinician-reported psychological distress (CRD) were used 

to identify depressive patients at baseline. Patients also rated depressed 

mood 4-5 weeks after baseline. A 2-point change was considered clinically 

significant for change in PRD. Logistic regression models were used to 

examine the effect of race on prevalence of depression and antidepressant 

use. Ordinal logistic regression models examined the effect of race on 

changes in depression. Results: Of the 3106 patients, 2648 were white, 

364 were black, and 94 were other race. At baseline, 20% had moderate/ 

severe PRD; CRD was 28%. Black patients had higher rates of depression 

than whites, but the difference was not significant after adjusting for other 

covariates (PRD: 24% vs. 20%, adjusted OR�1.1, P�0.6; CRD: 30% vs. 

27%, adjusted OR�1.06, P�0.8). Improvement in depressed mood varied 

by baseline PRD score (57% with severe depression, 51% with moderate, 

and 14% with mild). In patients with moderate/severe depression at 

baseline, blacks were less likely to have depression improvement than 

whites (adjusted OR�0.41, P�0.008 for moderate depression, adjusted 

OR�0.35, P�0.01 for severe depression). Among patients with depression 

defined by CRD, 29% were taking an SSRI (blacks: 14%, whites: 31%), 

Blacks were less likely to take an SSRI than whites (adjusted OR�0.38, 

P�0.01). Conclusions: Less than one third of patients with depressive 

symptoms are taking SSRI antidepressants. Black race is not only associated 

with less improvement in depressive symptoms over time but also 

lower probability of SSRI utilization. 



Cost-effectiveness of biomarker-directed bevacizumab for first-line therapy 

of persons with metastatic colorectal cancer. Presenting Author: Kristin 

Berry, Fred Hutchinson Cancer Research Center, Seattle, WA 

Background: When added to first-line chemotherapy for metastatic colorectal 

cancer, bevacizumab provides a moderate survival increase, but is 

associated with significant adverse events and high cost. As only a minority 

of patients respond to antiangiogenic therapy, a diagnostic that identifies 

potential responders ex ante could potentially change the benefit to risk 

profile of bevacizumab and likely improve cost-effectiveness. Since efforts 

to identify a predictive test have so far been unsuccessful, a novel strategy 

may be to measure tumor response after bevacizumab treatment initiation 

using an in vivo biomarker test to guide decisions on whether patients 

should continue treatment. The objective is to estimate the costeffectiveness 

of biomarker-directed use of bevacizumab in first-line treatment 

of metastatic colorectal cancer compared to standard care. Methods: 

The analysis takes the perspective of the US healthcare system. A decision 

model was built to estimate the incremental effect of adding bevacizumab 

to IFL, FOLFIRI, 5FU/LV and FOLOFOX/XELOX regimens. Survival data, 

estimated through a meta-analysis of four clinical trials, combined with 

utilities from the literature were used to calculate quality-adjusted life 

years (QALYs). Costs were based on Medicare reimbursement and expert 

opinion. Assumed performance characteristics of the biomarker technology 

(sensitivity, specificity – provided by our industry partner) were 75% and 

95% 10 days after commencement of bevacizumab. Results: The biomarkerdirected 

bevacizumab strategy dominated usual care, providing both an 

average per patient gain of 0.015 QALYs and a cost-savings of $21,038. 

The cost-effectiveness of the biomarker technology was most influenced by 

the cost of the test and colorectal cancer utilities. Variations in biomarker 

specificity and sensitivity changed the magnitude of cost-savings and 

benefit gain but did not change the overall result of dominance. Conclusions: 

Modeling predicts that a validated marker which could identify responders 

to bevacizumab will save money and improve quality-adjusted life years. 

The results support additional investment in identifying such a diagnostic. 


Surveillance after potentially curative breast cancer treatment: The impact 

of HMOs. Presenting Author: Robert J. Avino, Saint Louis University, St. 

Louis , MO 

Background: Over 230,000 new cases of breast cancer are diagnosed in the 

US annually. Most patients receive curative-intent treatment. Posttreatment 

surveillance is commonly done. We have previously documented 

dramatic variation in surveillance intensity among ASCO experts. The only 

surveillance modalities endorsed by ASCO for asymptomatic patients are 

office visit and mammogram. It is commonly believed that health maintenance 

organizations (HMOs) restrict test utilization. We sought to determine 

the effect of HMO penetration rate on the known variation in 

surveillance strategies. Methods: The 3245 ASCO members who indicated 

that breast cancer was a major clinical focus of their practice were surveyed 

regarding their surveillance practices. Members were asked to consider 4 

idealized clinical vignettes and indicate their surveillance plan for each. A 

menu of 12 testing modalities was offered. Practice patterns were stratified 

by HMO penetration rate (0-14%, 14-22%, 22-33%, 33-61%) in each 

physician’s practice location. Repeated-measures ANOVA was employed 

for analysis. Results: Of the ASCO members surveyed, 1012 responded; 

915 were evaluable. The modalities most frequently recommended were 

office visit, CBC, liver function tests (LFTs), and diagnostic mammogram. 

There was significant variation (p�0.05) in the recommended frequency of 

utilization of diagnostic mammogram, but in no other modalities. For 

example, in year 1, diagnostic mammogram was recommended 1.9 � 1.8 

(mean �SD) times for the 0-14% penetration rate cohort and 1.5 � 1.1 

times for the 14-22% cohort. Conclusions: We found little evidence that 

HMOs restrict test utilization. The HMO penetration rate in the clinician’s 

practice location cannot account for the overall variation we have documented 

previously. 


401s 


Deviations from guideline-based therapy for febrile neutropenia in cancer 

patients. Presenting Author: Jason D. Wright, Columbia University College 

of Physicians and Surgeons, New York, NY 

Background: Febrile neutropenia (FN) is a common cause of morbidity in 

cancer patients. We examined guideline and non-guideline based care for 

cancer patients hospitalized with FN and examined how treatment influenced 

outcomes. Methods: The Perspective database was used to examine 

the treatment of solid tumor patients with FN from 2000-2010. To capture 

initial decision-making, we examined treatment within 48 hrs of admission. 

Based on evidence-based guidelines we determined the appropriate 

use of guideline-based antibiotics as well as use of treatments not routinely 

recommended, vancomycin and granulocyte-colony stimulating factors 

(GCSF). Hierarchical mixed effects models were developed to examine the 

influence of patient, physician, and hospital characteristics on the quality 

of treatment. Patients were stratified into low and high-risk groups and the 

effect of initial treatment on outcome (nursing home discharge and death) 

examined. Results: Among 25,231 patients with FN, within 48 hours of 

admission blood cultures were obtained in 90%, guideline-based antibiotic 

administered to 79%, vancomycin to 37%, and GCSF to 63%. Patients 

treated at high-volume hospitals, by high-volume physicians and patients 

managed by hospitalists were more likely to receive guideline-based 

antibiotics (p�0.05). Vancomycin use increased with time from 17% in 

2000 to 55% in 2010 while GCSF use only decreased from 73% to 55%. 

Patients treated by internists and hospitalists were more likely to receive 

vancomycin; high-volume physicians were less likely to treat with both 

vancomycin and GCSF (p�0.05). Among patients who received GCSF, 

15% received only one dose and 22% received 2 doses of filgrastim. 

Among low-risk patients prompt initiation of guideline-based antibiotics 

decreased the risk of discharge to a nursing facility (OR�0.78; 95% CI, 

0.66-0.91) and death (OR�0.65; 95% CI, 0.50-0.85). Conclusions: There 

is substantial variability in the initial treatment for FN in cancer patients. 

While use of appropriate empiric antibiotics is high, use of non guidelinebased 

treatments such as vancomycin and GCSF are common. Physician 

and hospital factors are the most important predictors of both guideline and 

non guideline-based treatment. 


The relationship between symptom burden and perceived comorbidity in 

outpatients with common solid tumors. Presenting Author: Christine 

Ritchie, Unviersity of California, San Francisco, San Francisco, CA 

Background: Cancer patients have high symptom burden, but it is unclear 

whether comorbid conditions are associated with patient-reported symptom 

burden (the number and severity of symptoms). Methods: The Eastern 

Cooperative Oncology Group (ECOG) enrolled 3106 patients with invasive 

cancer of the breast, colon/rectum, prostate and lung, regardless of phase 

of care or stage of disease. At baseline, patients completed the M.D. 

Anderson Symptom Inventory (MDASI) and were also asked how bothered 

they were by difficulties related to health problems other than cancer. 

Symptom burden (SB) was defined as the number of symptoms scored 7 or 

higher on the 13-item MDASI physical scale. Variance-weighted least 

squares regression was used to identify factors associated with increasing 

levels of being bothered by comorbid conditions. Results: About 65% of 

patients were at least a little bothered by symptoms associated with 

comorbidities. There was a strong association between increased bother by 

comorbidities and increased SB (p�0.0001). Among those not bothered 

by difficulties related to comorbidities, �1 symptom was rated 7 or worse 

by 29% of patients, compared to 51% in patients bothered by difficulties 

related to comorbidities (Fisher’s exact p�0.0001). Except for hair loss, 

the severity of all symptoms was higher in those patients reporting bother 

due to other perceived comorbidities. Factors associated with increased 

bother include SB (p�0.0001), taking medications for diabetes 

(p�0.0001), impaired ECOG performance status (p�0.03), older age 

(p�0.004), and being perceived by the clinician as having higher degree of 

difficulty for providing care (p�0.0001). Conclusions: Symptom burden 

varies significantly according to the degree to which cancer patients 

perceive bother that they attribute to comorbid health problems. Perception 

of comorbidity is worth exploring as a stratification factor in symptom 

research and as an indicator for complexity in patient care. 




Physician age and surveillance intensity following curative-intent treatment 

for breast cancer patients. Presenting Author: Steven F. Abboud, 

Saint Louis University , St. Louis, MO 

Background: Breast carcinoma is a large health care concern for patients, 

physicians, and society. 2.5 million women have been treated for breast 

cancer and are candidates for surveillance in the US. We have documented 

dramatic variation in post-treatment surveillance strategies utilized by 

ASCO experts caring for such patients. Since it is often asserted that 

younger physicians order more tests than older physicians, we sought to 

measure the effect of clinician age on post-treatment surveillance intensity 

for breast cancer patients by analyzing a recent survey of ASCO members. 

Methods: We surveyed the 3245 ASCO members who indicated that breast 

cancer treatment was a major focus of their practice. 4 succinct clinical 

vignettes describing generally healthy women with breast cancer of varying 

prognoses and a menu of 12 surveillance modalities were offered. The 

menu was chosen after a literature search indicated that no other 

surveillance tests were commonly used. We analyzed data from one of the 4 

idealized vignettes only (the patient with TNM IIA carcinoma) and stratified 

responses by clinician age. Practice patterns were compared by years after 

completion of training (0-10, 11-20, 21-30, 30-40, �40 years), a 

surrogate measure of physician age. Statistical analysis employed ANOVA. 

Results: There were 1012 responses; 915 were evaluable. Statistically 

significant differences were observed across age strata for CBC, liver 

function tests (LFTs), and serum CEA level only. For example, ASCO 

clinicians in practice for 0-10 years after completion of training recommended 

CBCs 1.3 � 1.4 (mean � SD) times in year 1. Those � 40 years 

after completion of training recommended CBCs 2.4 � 1.3 times in year 1 

(p�0.001). Conclusions: Younger physicians recommend statistically significantly 

fewer CBCs, LFTs, and serum CEA levels during post-treatment 

surveillance than older physicians. However, the magnitude of the difference 

is clinically small for all 3 modalities and does not explain the known 

overall variation in surveillance practice among clinically active experts. 


Chemotherapy in the oldest old: The feasibility of cytotoxic therapy in the 

80� population. Presenting Author: Shelly Sud, Division of Medical 

Oncology, The Ottawa Hospital Cancer Centre, Department of Medicine, 

University of Ottawa, Ottawa, ON, Canada 

Background: The incidence of most common malignancies increases with 

age. As life expectancy improves globally, more elderly cancer patients will 

be candidates for systemic therapy. There is little data investigating 

chemotherapy (CT) in those over 80 – the “oldest old”. Our hypothesis is 

that CT in the 80� population may be associated with significant toxicities 

and is therefore not feasible for many patients. Methods: A retrospective 

chart review was undertaken to report outcomes of patients �80 years old 

who initiated CT for solid tumors at the Ottawa Hospital Cancer Center 

between Nov. 2005 and Jan. 2010. Baseline data on patient demographics, 

cancer type and CT were collected. Primary endpoints included: rates 

of CT dose reduction, omission, delay and discontinuation due to toxicity, 

hospitalization and blood transfusion rates. Results: CT was initiated on 

212 occasions (32% lung, 31% GU, 24% GI, 13% other cancer). Median 

age was 83 (range 80-92) and 60% of patients were male. Where data were 

available, 60% had a good performance score (ECOG 0-1) and 63% were 

current or ex-smokers. 82% had Charlson risk index scores of �5, 37% had 

�6 baseline medications, 18% lived alone independently. At baseline, 

11% were anemic, 12% had leukocytosis, and 45% had impaired renal 

function (eGFR�60). Most patients had stage 4 disease (76%), were 

treated with palliative intent (75%) and were receiving first line CT (77%). 

Initial dose was adjusted in 34% of cases. Therapy was discontinued due to 

toxicity in 30% of cases, and 53% of patients required dose reduction, 

omission or delay. In 38% of cases, patients were hospitalized during their 

course of therapy or within 30 days thereof. Blood transfusions were 

required in 24%. Factors associated with risk of hospitalization included 

baseline number of medications �6 (OR 1.96, 95% CI 1.1-3.5) and 

baseline anemia (OR 2.55, 95% CI 1.07-6.05). Initial dose reduction at 

cycle 1 did not significantly affect rates of hospitalization, transfusion or CT 

discontinuation. Conclusions: CT in the 80� population is associated with a 

significant risk of hospitalization, transfusion and discontinuation due to 

toxicity, even when doses are adjusted from the outset. We plan to 

prospectively validate these findings. 


Comparison of drug approval between health Canada (HC) and the U.S. 

Food and Drug Administration (FDA). Presenting Author: Doreen Ezeife, 

University of Calgary, Calgary, AB, Canada 

Background: Differences in drug approval processes between countries can 

impact patient access to new therapies. In Canada, patients can freely 

access a new treatment after regulatory approval by Health Canada (HC) 

followed by funding approval from the provincial government. The aims of 

this study were to delineate the Canadian drug approval timeline and to 

compare the time to drug approval between HC and the US FDA. Methods: 

Cancer drugs approved by the FDA from 1989 to 2011 were reviewed. For 

each drug, the following endpoints were determined: publication date of 

phase I and pivotal phase III trial, date of FDA and HC approval, HC 

submission date, and funding approval in Alberta (AB). Time intervals 

between the aforementioned endpoints were calculated. Results: Of 55 

FDA-approved drugs, 51 drugs are approved by HC with 40 of these drugs 

funded in AB. HC approval occurs an average of 14.4 months post FDA 

approval (95% CI -36.9 to 66.1, sign rank test p�0.0001). However, there 

was no significant difference between the mean time from Phase I to FDA 

approval (48.5 months; 95% CI 21.2 to 75.8) and Phase I to HC approval 

(61.5 months; 95% CI 32.4 to 90.5). Most drugs (74%) were approved by 

the FDA prior to publication of the phase III trial. There was a trend towards 

faster drug approval from Phase III to FDA approval compared to HC 

(-14.97 versus 0.1 months, p � 0.05). HC submission occurs before FDA 

drug approval 77% of the time (mean 3.0 months prior; 95%CI: -59.1 to 

43.4, p � 0.0206). HC approval occurs on average 17 months post HC 

submission. AB funding approval occurs on average 22 months after HC 

approval. The time interval from Phase I to AB funding approval was 

significantly shorter for targeted compared to cytotoxic agents (mean time 

58 vs. 120 months; p � 0.039). Conclusions: HC drug approval lags behind 

FDA approval by about 14 months. Time from Phase III to drug approval 

tends to be shorter for the FDA compared to HC. This is the first 

documentation, to our knowledge, of the time required to bring a drug from 

phase I trial to provincial funding approval. 


Does drug cost drive drug adherence? The designer drug phenomenon. 

Presenting Author: Jalal Ebrahim, St. Michael’s Hospital, University of 


Background: Cancer patients (pts) are on many medications, both for 

malignancy and supportive therapies. The cost of oral medications are 

funded by either the pt, public, or private mechanisms. Low adherence 

rates are observed in oral treatments, and non-adherence is the primary 

cause of treatment failures. To our knowledge, cost-related adherence to 

oral therapy in the context of malignancy has not been studied extensively 

in the existing literature. We assessed the relationships between oral 

medication costs and adherence rates. Methods: This cohort study enrolled 

453 pts at 3 outpatient heme/onc clinics in the Greater Toronto Area. A 

7-item survey was designed to assess pt demographics, self-reported 

adherence to oral medication, type of drug coverage (private payer, public 

payer, self payer) and patients’ perceived cost of oral drugs. Oral medications 

were recorded and actual monthly costs were calculated. Descriptive 

statistics were used to describe frequencies. Spearman Rank Order 

Correlations and Chi-Square Analyses were used to examine relationships 

between variables. Results: Of 453 pts, 50% had a private drug plan, 24% 

paid out of pocket, 44% had government funding and 4% reported their 

physician had arranged funding. 51% of pts had oral drug costs of � 

$100/month. Self reported adherence to prescribed oral medications was 

80%. As the cost of prescribed medications increased, so did self reported 

adherence (r�0.144, p�0.002). There was also a significant relationship 

between drug coverage and oral drug costs (c²�23.78, df�12, p�0.02). 

Pts paying out of pocket were significantly less likely than all other pts to 

have oral drug costs of �$500/month (11% vs 19%) Conclusions: As oral 

drug costs increase, so does likelihood of adhering to prescribed regimen. 

This implies that further pt education about the efficacy and importance of 

medications may help with adherence, regardless of cost. It is possible that 

pts are provided with more education regarding newer and more expensive 

agents than they are regarding older and cheaper agents, regardless of 

efficacy. Disparities observed in medication costs between those with 

private drug plans vs. those without suggests financial restrictions may 

affect prescription patterns in this group. 



Physical activity (PA) and physical function (PF) in adult cancer survivors 

(CS). Presenting Author: Peter Crawford Birks, British Columbia Cancer 


Background: The longevity of CS is increasing, underscoring the importance 

of lifestyle modifications and preventive care, consisting of regular PA and 

maintenance of PF. Our aims were to 1) compare PA and PF among 

short-term CS, long-term CS and non-cancer controls (NCC) and 2) identify 

other clinical factors associated with decreased PA and PF. Methods: We 

identified CS and NCC from the US National Health and Nutrition 

Examination Survey (NHANES). CS were categorized into �/�5 (shortterm) 

and �5 years (long-term) based on date of diagnosis. Multivariate 

weighted regression models were constructed to examine for differences in 

28 and 26 measures of PA and PF, respectively, while controlling for age, 

gender, ethnicity, education, income, and other confounders. We explored 

specific and general PA domains such as aerobic activity and decline from 

past activity level as well as PF areas including ADLs, IADLs and mobility. 

Results: In total, 26,185 subjects were identified: 968 short-term CS, 

1,367 long-term CS, and 23,832 NCC. For the entire cohort, the mean age 

was 50 years, 52% were men, and 50% were white. Comparing across the 

3 patient groups, CS were generally older than NCC (60 vs 45 years, 

p�0.01). In terms of PA, short-term CS reported less general activity 

compared to 1 year ago (OR 0.58, 95%, CI 0.46-0.73, p�0.01) than 

long-term CS and NCC. In comparison to NCC, both groups of CS also 

described less current activity than their baseline from 10 years ago (OR 

0.63, 95% CI 0.48-0.82, P�0.001 and OR 0.67, 95% CI 0.55-0.83, 

P��0.01). There were significant differences among patient groups in 

several areas of PF (Table). Other factors that were associated with lower PA 

and PF included advanced age, low education, and low income. Conclusions: 

PA between CS and NCC were similar, although current activity as 

compared to that of the preceding year or past decade appears lower in CS, 

which may reflect their older age. Impairments in several measures of PF 

were observed among CS, which could impact their quality and quantity of 

life. 

Limited work 

OR (95%CI) p 

Limited 

mobility OR 

(95%CI) p 

Limited 

leisure 

activities OR 

(95%CI) p 

NCC 1.00 0.01 1.00 0.02 1.00 0.05 

CS 5y 1.61 (1.3-1.9) 1.44 (1.1-1.9) 1.02 (0.6-1.7) 


Involvement of low- and middle-income countries (LMCs) in oncology 

randomized controlled trials (RCTs). Presenting Author: Janice C. Wong, 

Princess Margaret Hospital, Toronto, ON, Canada 

Background: Lower costs and fewer regulatory barriers make clinical trials in 

LMCs attractive, but little is known about characteristics of such trials and 

roles of investigators from LMCs. We describe trends in participation of 

investigators from LMCs in oncology RCTs over a decade. Methods: We used 

Medline to identify all RCTs published in English between January 1 1998 

and December 31 2008 evaluating treatment in five solid tumours (lung, 

breast, colorectal, stomach, liver) with high mortality in LMCs as per 

GLOBOCAN 2002. Data on author affiliations and roles (first, middle or 

corresponding author), trial characteristics, funding and study interventions 

were abstracted using an electronic form. Countries were stratified 

into low-, middle- and high-income using World Bank data. Interventions 

were categorized as requiring basic, limited, enhanced or maximal resources 

as per the Breast Health Global Initiative classification. Logistic 

regression identified factors associated with investigator participation from 

LMCs. Results: 454 trials were identified: lung (n�177), breast (n�165), 

colorectal (n�82), stomach (n�29), liver (n�7). The annual number of 

trials published increased from 10 trials in 1998 to 86 in 2008. The 

proportion of trials with at least one LMC author also increased over time 

from 20% in 1998 to 29% in 2008 (p�0.01), but almost all LMC authors 

were from middle-income countries. In 17% of trials involving LMC 

authors, they were first or corresponding authors. 67% of trials involving 

LMC investigators evaluated interventions requiring enhanced or maximal 

resources for implementation. Factors associated with LMC participation 

included industry funding (OR�3.57, p�0.0001), use of placebo arm 

(OR�2.59, p�0.02) and metastatic setting (OR�3.87, p�0.0003). 

Conclusions: An increasing number of oncology RCTs involve LMC investigators 

primarily in non-leadership roles. These trials are commonly industryfunded 

and often test interventions that require at least enhanced resources 

for implementation. To minimize concerns of exploitation and facilitate 

future collaboration it is crucial that interventions are locally feasible and 

investigators receive appropriate authorship. 


403s 


The NCI Community Cancer Centers Program (NCCCP): A model for 

reducing cancer health care disparities. Presenting Author: Donna M. 

O’Brien, NCI NCCCP Program, Bethesda, MD 

Background: In 2007, NCI launched the NCCCP, a public-private partnership 

with 16 community hospital cancer centers in 14 states, to explore 

methods to improve patient access to advanced cancer care in the 

community. With 40% of its NCI funding directed to reduce disparities 

across the cancer continuum, the NCCCP aims to: 1) Enhance access to 

care; 2) Improve quality of care; and 3) Increase clinical trials accrual. This 

approach supports priorities in the 2009 ASCO Policy Statement: Disparities 

in Cancer Care. Methods: A disparities workplan was developed to 

support the three aims. NCI and the sites worked as a learning collaborative 

to develop strategies and metrics for: race and ethnicity data tracking; near 

real-time reporting of adherence to Commission on Cancer (CoC) treatment 

quality measures; community outreach and patient navigation to increase 

cancer screening; and improved clinical trial underserved accrual. The 

tools and resources supporting these efforts will be discussed. 

(http://ncccp.cancer.gov/About/Progress.htm). Results: Evaluation of the 3 

year pilot shows improvement for underserved populations: Concordance 

with CoC treatment quality measures for radiation therapy for breast 

conserving surgery among Medicaid patients improved from 59.5 percent 

to 84.8 percent (p�.05). Increased community screening events (from 

992 to 1,585) and community partnerships focused on underserved 

populations (from 78 to 195). Increased accrual to NCI trials (minority 

accrual from 82 to 151 and elderly from 200 to 641). Conclusions: To be 

effective in reducing healthcare disparities, a multi-level approach is 

needed. This includes having: organizations which demonstrate a strong 

community-oriented mission; commitment by hospital management; engagement 

of private practice physicians; targeted training of staff; use of 

standardized data collection and metrics; involvement of strategic partners 

with aligned goals at the national and local level; support by relevant NCI 

experts; and sharing best practices across a learning collaborative. The 

NCCCP disparities model was used in a variety of community settings 

targeting different underserved populations and has demonstrated effect in 

care in the respective communities. 


Beyond the performance rate: Understanding differences in treatment 

status using the Rapid Quality Reporting System (RQRS). Presenting 

Author: Erica J. McNamara, Commission on Cancer, American College of 

Surgeons, Chicago, IL 

Background: RQRS is a cancer registry based tool for rapid case ascertainment 

and real-time care tracking using 5 National Quality Forum approved 

quality measures for breast (BC) and colon cancer (CC) and 1 American 

Society of Clinical Oncology, National Comprehensive Cancer Network and 

Commission on Cancer (CoC) endorsed rectal cancer (RC) measure. RQRS 

was introduced in 2009 for testing at selected CoC accredited programs. 

The purpose of this study was to evaluate the proportion of cases with 

treatment administered for 4 measures where care is concordant with 

treatment either “administered” or “considered but not administered” 

(CNA). Methods: Case information on 19,631 breast, colon and rectal 

cancer patients diagnosed from 2009 – 2010 submitted by 64 RQRS 

participating sites were reviewed for 4 measures: (1) hormone therapy 

within 1 year of diagnosis (dx) for AJCC T1c, N0M0, or stage II or II; 

hormone receptor positive BC (HT), (2) multi-agent chemotherapy within 4 

months of dx; age � 70; hormone receptor negative BC (MAC), (3) adjuvant 

chemotherapy within 4 months of dx; age �80; AJCC Stage III CC (ACT), 

and (4) radiation therapy within 6 months of dx; age �80; AJCC T4N0M0 

or stage III patients receiving surgical resection for RC (AdjRT). Treatment 

status was defined as concordant (administered or CNA) or non-concordant 

(NC – not part of planned first course therapy or received after required time 

frame). Patient demographics and Charlson-Deyo (CD) co-morbidity scores 

were compared by concordance status using Chi-square tests. Results: The 

aggregate concordance rate was 83.3%. Among these 889 (5.4%) were 

CNA. Co-morbidity score was � 0 for 15% of cases. Patients age � 70, with 

Medicare insurance, CD score � 0 were significantly more likely to be CNA 

compared to completed or NC. Patient choice was the most common reason 

for CNA (64%). Conclusions: Among patients treated at RQRS test sites for 

which RQRS measures applied and care was concordant, only 5% were 

CNA. Patients over age 70 or with CD � 0 were more likely to have 

treatment CNA. Inclusion of CNA as concordant care has a minor impact on 

concordance rates and provides cancer programs with important information 

for targeting care review and quality improvement programs. 




Use and duration of chemotherapy (CT) in patients (pts) with metastatic breast 

cancer (MBC) according to tumor subtype (TS) and line of therapy (tx). 

Presenting Author: Davinia Shien Seah, Dana-Farber Cancer Institute, Boston, 

MA 

Background: Benefits of CT vary widely in MBC pts. We aimed to describe the impact 

of breast cancer TS and line of tx on the duration of CT. Methods: In a retrospective 

analysis, we identified 205 pts treated with CT for MBC at the Dana-Farber Cancer 

Institute between 2005-8. TS were classified as hormone receptor (HR)� (ER�/PR�/ 

HER2-), triple negative (TN) (ER-/PR-/HER2-) or HER2� (HER2�, any HR). CT 

duration was defined as �time from start of one CT line to the start of the next CT.� 

Chi-square, Kruskal-Wallis, and Kaplan-Meier methods were used. Results: Median 

follow-up was 54 months (m). Most pts had received adjuvant tx, though 23% had 

MBC at diagnosis. Almost all HER2� pts had concurrent anti-HER2 tx. CT duration 

was longest in 1st line with consecutive stepwise decrease. The proportion of pts 

who received CT beyond the 3rd line varied by TS: 52% of HER2� pts received � 4 

CT lines, compared with 37% of HR� and 29% of TN pts. Duration in later CT lines 

also differed by TS. Median CT duration in HER2� pts was � 4 m in all 6 lines, but 

HR� and TN pts had a median CT duration of �4m from the 4th line onwards. 

Quartile estimates suggested a substantial fraction of HER2� and HR� pts 

receiving �6m of CT in 5th and 6th line; by contrast, CT duration for TN pts were 

consistently brief in later CT lines. Conclusions: TS determines the likely duration 

and number of lines of CT for MBC. Among HR� and HER2� pts who receive CT 

beyond 3rd line, there are substantial rates of prolonged tx suggesting clinical 

benefit. For TN pts, the opportunity for additional lines and the CT duration declined 

more dramatically. The true role of advanced (� 3rd) CT lines for all MBC in 

improving quality of life, survival, and the predictors of such benefit, warrant further 

study. 

CT characteristics. 

HR� TN HER2� 

No. of pts, N (%) 102 49 45 22 58 28 

No. of CT lines 

median, min, xax 

Pts receiving nth CT line 

N, % 

3 1 9 3 1 8 4 1 9 

1 102 100 45 100 58 100 

2 79 77 36 80 44 76 

3 56 55 26 58 40 69 

4 38 37 13 29 30 52 

5 24 24 8 18 24 40 

6 

CT duration 

Median, 1st, 3rd quartile 

9 9 6 13 19 33 

1 6.5 2.9 12.0 5.8 2.8 10.7 9.0 4.3 13.1 

2 4.4 2.6 7.9 3.3 2.0 6.3 5.1 2.8 11.3 

3 3.6 1.9 6.0 2.8 2.1 6.8 6.3 2.9 8.3 

4 4.0 2.1 7.3 3.4 1.8 8.1 4.7 2.7 8.9 

5 3.5 1.9 6.5 2.6 1.9 3.2 4.0 2.3 7.0 

6 3.3 2.1 7.4 2.0 1.8 2.3 4.2 1.9 6.1 


Recruitment of cancer patients to National Institute for Health research 

cancer research network portfolio studies between 2001 and 2011. 

Presenting Author: Matthew Cooper, National Institute for Health Research 

Cancer Research Network, Leeds, United Kingdom 

Background: The National Institute for Health Research Cancer Research 

Network (NCRN) was established in 2001 in England, United Kingdom to 

improve cancer patient outcomes by improving the coordination, integration 

and speed of cancer research. Methods: Baseline recruitment of cancer 

patients in England to clinical studies was around 4% of incident 

population. Research Networks were established initially in England 

(NCRN) and then across the UK, co-terminus with clinical cancer service 

networks, and a per capita based funding model used to provide a research 

infrastructure to support recruitment to a nationally defined research 

portfolio. Results: Within 3 years, as the networks were established, 

recruitment of patients to studies doubled from 10,000 to 20,000 cancer 

patients per year. Recruitment has continued to increase year on year, 

supported initially by underspend that had accrued from earlier years in the 

life of NCRN, and more recently from additional resources invested via the 

NIHR comprehensive networks. Data for 2010/11 show that over 45,000 

cancer patients are now recruited into portfolio studies in England each 

year, with over 50,000 across the whole of the UK. Conclusions: Dedicated, 

targeted, clinician-led National Health Service investment into supporting 

national portfolio studies, has delivered an unprecedented five-fold increase 

in recruitment of cancer patients into clinical trials across the 

United Kingdom. This required coordinated research infrastructure, close 

cooperation with research funders, particularly Cancer Research UK and 

the National Cancer Research Institute, and the enthusiasm and hard work 

of many clinicians, patients and others working to deliver clinical cancer 

care in the National Health Service in the United Kingdom. 


Health-related quality of life assessment in EORTC cancer clinical trials. 

Presenting Author: Efstathios Zikos, European Organisation for Research 

and Treatment of Cancer Headquarters, Brussels, Belgium 

Background: Over the last three decades health-related quality of life 

(HRQOL) has become an important part of the randomised controlled trials 

(RCTs) conducted by the European Organisation for Research and Treatment 

of Cancer (EORTC). This review aims to undertake a descriptive 

database evaluation of all the HRQOL studies conducted in EORTC since 

1980. Methods: The EORTC protocol database (n�785) was reviewed, 

restricting the search to between 1980 and 2011 (n�735). We investigated 

the number of HRQOL studies conducted in EORTC trials, the RCTs’ 

status and the use of HRQOL tools since 1980. Results: 157 protocols with 

HRQOL assessment were identified involving 70,903 patients. 73 studies 

ended as defined in the protocol; 27 studies closed early due to poor 

accrual; 17 are at the final analysis of the primary end point stage; 14 

studies are still open to recruitment; 11 are closed to patient entry; and 15 

new RCTs are pending activation with HRQOL. The majority of phase III 

(n�135) and phase II/III (n�9) RCTs have HRQOL as secondary endpoint. 

EORTC also conducted a number of large scale field studies (n�11), where 

HRQOL was the primary endpoint. During the early period of 1980 to 1989 

HRQOL was assessed in 12 EORTC RCTs by using a small number of 

HRQOL items, but from 1990 to 2000, HRQOL was assessed in 97 RCTs 

using more comprehensive HRQOL tools. Between 2001 and 2011 the 

number of RCTs with HRQOL was 48. The EORTC clinical groups with the 

most RCTs containing HRQOL were Radiation Oncology (n�22), Genito- 

Urinary (n�20), Gynaecological (n�16), Breast Cancer (n�16), Lung 

(n�13), Gastrointestinal, (n�13) and Brain (n�10). The EORTC HRQOL 

tools were used in 90% of the trials, with other validated tools being used 

when required. Conclusions: Our review of EORTC RCTs has shown how 

patient perspective has been constantly considered of major importance in 

oncology during the last three decades. The inclusion of patient perspective 

in drug development shows that a more comprehensive HRQOL assessment 

has taken place over time as better instruments have become available. As 

the positive value of patient perspective grows to clinicians, regulatory 

bodies and industry, we expect that EORTC will continue its support by 

including HRQOL endpoints where appropriate. 


Characterizing fatigue associated with sunitinib (SU) in patients (pts) with 

metastatic renal cell carcinoma (mRCC). Presenting Author: David Cella, 

Department of Medical Social Sciences, Northwestern University Feinberg 

School of Medicine, Chicago, IL 

Background: Fatigue is common in cancer pts and associated with use of 

tyrosine kinase inhibitors (TKIs) such as SU. Limited data exist on the time 

pattern of fatigue with TKI therapy. Methods: Data from treatment-naïve 

mRCC pts in SU arms of two clinical trials were analyzed retrospectively. 

Study 1; 375 pts were randomized to SU 50 mg/d on a 4 weeks-on-2-weeksoff 

schedule (Schedule 4/2), for up to 30 cycles. Study 2; pts were 

randomized to SU 50 mg/d Schedule 4/2 (Group 1; n�146) or 37.5 mg/d 

continuous daily dosing (CDD; Group 2; n�146). In both trials, fatigue was 

measured with the question to pts: “I feel fatigued” over the past week 

(5-point rating scale, not at all-very much), and with the provider-rated 

Common Terminology Criteria for Adverse Events (CTCAE). In addition to 

descriptive profiles, Study 1 used two modeling approaches; repeated 

measures model (M1), with time as a categorical predictor; and random 

intercept-slope model (M2), with time as a continuous predictor. Study 2 

calculated mean absolute values of within-cycle rate of change (from one 

assessment to the next) through the first 6 treatment cycles. Results: In 

Study 1, representing fatigue across cycles, M1 showed that the initial 

increase in patient-reported fatigue was worst during Cycle 1; mean values 

at all subsequent cycles were numerically better. For CTCAE fatigue, M1 

showed that all but one of the pair-wise comparisons of the cycle means 

were not significantly different. M2 showed that the overall trend for 

patient-reported fatigue and CTCAE fatigue was not statistically different 

from zero. In Study 2, the mean absolute rate of change for fatigue during 6 

treatment cycles was greater for Group 1 (4/2) compared to Group 2 (CDD): 

0.042 vs. 0.032, respectively; P�0.003, t-test. Conclusions: In Study 1, 

pts reported notable fatigue in Cycle 1, which improved or stabilized, 

thereafter. In Study 2, Schedule 4/2 was associated with more within-cycle 

fluctuation in fatigue. These findings illustrate how SU-associated fatigue 

occurs early in therapy and continues with more within-cycle fluctuation 

associated with 4/2 dosing. This may help patient-clinician communications 

and interventions that support maintaining effective therapy. 



Unanticipated hospital admissions in patients undergoing radiotherapy 

with or without concurrent chemotherapy: Incidence and predictive factors. 

Presenting Author: Nabeel H. Arastu, University of North Carolina at Chapel 

Hill and Brody School of Medicine at East Carolina University, Greenville, 

NC 

Background: Unanticipated admissions are burdensome for patients and 

the healthcare system. An improved understanding of their frequency and 

predictive factors can inform initiatives to prevent such admissions and 

mitigate their associated human and financial costs. Methods: Electronic 

medical records of 500 patients undergoing external beam radiotherapy 

(RT) at our center in 2010 were reviewed. Unanticipated admission within 

90 days of initiating RT, and associated clinical factors, were recorded. 

Chi-squared and uni- and multivariate logistic regression was used to 

examine factors associated with admission. Results: Unanticipated admissions 

occurred in 20% (101/500) of patients, mean length of stay was 4 

days (range 1-16), and the mean interval between the start of RT and 

admission was 32 days (0-86 days). The most common indications for 

admissions were pain (19% of admissions), respiratory distress (15%), and 

neurologic symptoms (13%). On univariable analysis, 33% of patients 

treated for palliative intent were admitted (vs. 16% of curative intent 

patients, p�0.001), as were 26% of patients receiving concurrent chemotherapy 

(vs. 17% receiving RT alone, p�0.02). Multivariable analysis 

showed treatment intent, chemotherapy, and marital status to be associated 

with unplanned admissions (Table). A highly variable rate of unanticipated 

admission per diagnosis was observed (e.g. 4% for breast, 19% for 

GI/GU/GYN/ENT, and 37% for metastatic sites). Conclusions: Rates of 

unanticipated admissions are �20% in patients undergoing RT. Approximately 

1/3 of patients receiving palliative RT, and more than 1/4 receiving 

concurrent chemoradiation, experienced an unplanned admission. Prophylactic 

measures should be studied in these high-risk patients to reduce 

admission rates, as unplanned admission may be an important quality of 

care indicator in oncology. 

Odds of an unanticipated admission: Multivariate analysis. 

Covariate OR P value 

Concurrent chemotherapy (vs. RT alone) 3.4 �0.001 

Palliative intent (vs. curative) 2.7 �0.001 

Not married (vs. married) 2.3 �0.001 


Cost-effectiveness of adjuvant radiotherapy for older women with early 

hormone-receptor positive breast cancer. Presenting Author: Katherine 

Elizabeth Reeder-Hayes, University of North Carolina Hospital, Chapel Hill, 

NC 

Background: Radiation therapy (XRT) following breast conserving surgery 

decreases local recurrence at the expense of additional morbidity and 

treatment costs. However, its utility in elderly women at low risk of 

recurrence has been questioned. This study assessed the cost-effectiveness 

of adding XRT to hormonal therapy (HT) in women over 70 with stage I, 

hormone-receptor positive (HR�) breast cancer after breast conserving 

surgery. Methods: A decision tree model was used to assess the costs and 

benefits of XRT � HT versus HT alone in 10,000 women age 70� with 

stage I HR� breast cancer. Using a societal perspective, we considered 

medical costs and quality of life effects of initial treatment, recurrences, 

and metastatic disease as well as long-term XRT-associated complications 

including breast fibrosis, chronic pneumonitis and cardiac disease. Probabilities 

of recurrence and death were modeled on recent clinical trial 

results, while toxicity probabilities were taken from literature review. The 

primary health outcome was incremental quality-adjusted life years (QALYs) 

gained. One-way and probabilistic sensitivity analyses (PSA) were performed 

to assess the sensitivity of model results and conclusions to various 

parameter estimates. Results: In the base-case scenario, the incremental 

cost-effectiveness ratio (ICER) for the addition of XRT was $923,017/ 

QALY. The ICER was highly sensitive to variations in utility weights, 

particularly those reflecting patient preferences for initial treatment with or 

without XRT and those reflecting the decrement in quality of life resulting 

from breast fibrosis. In PSA, XRT was associated with lower qualityadjusted 

life expectancy at higher cost in 58% of simulations. Conclusions: 

In women over 70 with stage I HR� breast cancer, the addition of XRT to 

HT is not cost-effective at a willingness-to-pay threshold of $100,000/ 

QALY, and is associated with little or no improvement in quality-adjusted 

life expectancy. Providers should be aware that the cost-effectiveness of 

XRT in this population is strongly influenced by patient preferences 

surrounding recurrence and toxicity risks, and should weigh these factors 

when making shared decisions with patients. 


405s 


Association between financial relationships with commercial interests and 

research merit at the ASCO Annual Meeting (AM). Presenting Author: 

Beverly Moy, Massachusetts General Hospital, Boston, MA 

Background: Financial relationships with commercial interests (COI) are 

common in cancer research. There are few data examining the correlation 

between COI and research merit. Meeting placement prominence (MP) and 

peer review score (PRS) are indicators of research merit. We examined the 

association between ASCO AM abstracts whose authors disclose COI and 

both MP and PRS. Methods: We reviewed abstracts presented at the ASCO 

AM in 2006 and 2008-2011. We evaluated associations between COI 

disclosed by any author and PRS and MP (order of prominence: plenary 

session (PS), clinical science symposium (CSS), oral presentation (OP), 

poster discussion session (PDS), vs. general poster session (GPS)). Chisquare 

tests, T-tests, and logistic regressions of COI were used to assess 

associations with MP, PRS, and year. Results: Of 12,446 total abstracts 

accepted for presentation, 78% of PS, 59% of CSS, 54% of OP, 52% of 

PDS, and 39% of GPS report at least one COI. Abstracts selected for PS, 

CSS, OP, and PDS had more COI compared to those selected for GPS (p � 

0.05). Stock ownership COI were more frequently disclosed in PS (30%), 

CSS (30%), OP (22%), and PDS (22%) compared to GPS (16%) (p � 

0.05). Employment COI were more frequently reported among abstracts 

presented at PS (39%), CSS (37%), OP (27%), and PDS (27%) compared 

to GPS (21%) (p � 0.05). Consultant COI were more likely to have higher 

MP than GPS placement (OR for PS�5.5; CSS�2.4; OP�2.2; PDS�1.9). 

Similarly, honoraria COI were more likely to have higher MP than GPS 

placement (OR for PS�3.9; CSS�1.8; OP�2.1; PDS�1.7). Better PRS 

was associated with COI (OR 0.17; p � 0.05). The relationship of better 

PRS with any COI strengthened over time from 2006, 2008-2011 (PRS 

times year interaction OR�0.65, p�0.001). Conclusions: ASCO abstracts 

whose authors report COI have higher merit as measured by MP and PRS. 

This suggests a dependence on industry relationships for access to 

important data that will lead to prominent cancer research. These relationships 

will require further investigation and ongoing management. To our 

knowledge, this is the first study examining the scientific merit of research 

with relation to COI. 


The impact of race/ethnicity concordance between patients and their 

navigators in time to diagnostic resolution of breast and cervical cancer 

screening abnormalities. Presenting Author: Marjory Charlot, Boston University 

Medical Center, Boston, MA 

Background: Patient navigators have been shown to reduce cancer disparities 

among racial/ethnic minorities by improving timely diagnosis and 

treatment of cancer. For a group of navigators who received cultural 

competency training, we sought to determine if racial/ ethnic concordance 

of the navigator and patient improved time to diagnostic resolution of 

cancer screening abnormalities. Methods: Demographic data on 1466 

patients and their 23 navigators from the Boston Patient Navigation 

Research Program were used to assess concordance by race and ethnicity. 

All participants with either breast (n�751) or cervical (n�715) screening 

abnormalities were followed up to one year. Kaplan-Meier survival curves 

and proportional hazards regression models examined the effect of race/ 

ethnicity concordance on time to definitive diagnosis, adjusting for age, 

race, language, economic status, insurance status, and severity of screening 

abnormality. Analyses were performed separately for the breast and 

cervical groups. Results: Of the 1466 patients, 32% were White, 27% 

Black, 31% Hispanic, and 10% Asian. Navigators were 61% White, 17% 

Black, 13% Hispanic and 9% Asian. Fifty eight percent of patientnavigator 

pairs were concordant by race/ethnicity. Overall rate of diagnostic 

resolution of cancer screening abnormalities within 365 days was high at 

90%. In both the breast and cervical cancer screening groups, racial/ethnic 

concordance was not associated with time to diagnostic resolution, with an 

aHR 1.03 (95% CI: 0.85, 1.25) for breast patients and HR 1.02 (95% CI: 

0.85, 1.21) for cervical patients. Conclusions: Patient-navigator racial/ 

ethnic concordance is not associated with time to diagnostic resolution of 

cancer screening abnormalities, in part because overall rates of diagnostic 

resolution were high. Our data suggest that with cultural competency 

training, navigators can be equally effective with patients from different 

ethnic and cultural backgrounds. 




Relationship between Oncotype DX testing and the use of chemotherapy in 

high-risk patients (pts). Presenting Author: Winston Wong, CareFirst 

BlueCross BlueShield, Baltimore, MD 

Background: CareFirst BlueCross BlueShield (CFBCBS) insurance network 

partnered with Cardinal Health Specialty Solutions (CHSS) to develop a 

cancer care pathway for network physicians in 2008. The program included 

a recommendation for molecular diagnostic testing with the Oncotype DX 

assay for pts with early-stage estrogen receptor-positive breast cancer. 

Based on NCCN guidelines, the pathway suggested adjuvant chemotherapy 

for all pts with Oncotype DX Recurrence Scores (RS) in the high-risk 

category. We aimed to determine the RS risk distribution among pts who 

received Oncotype DX testing and assess the patterns of care that followed. 

Methods: Using data from CFBCBS, CHSS proprietary claims software, and 

Genomic Health, we retrospectively identified a cohort of women with 

breast cancer who were treated on the CFBCBS clinical care pathways 

program from 8/2008 to 6/2011 and received Oncotype DX testing. We 

determined the number of pts with a RS value in the low- (RS �18), 

intermediate- (RS 18-30), and high-risk (RS �31) groups along with the 

number of pts who subsequently received chemotherapy in each category. 

Results: Of 1174 women who received Oncotype DX testing, 53% of pts 

were in the low-, 35% in intermediate-, and 12% in the high-risk groups. 

Five percent of low-, 41% of intermediate-, and 74% percent of pts in the 

high-risk category were treated with chemotherapy. Twenty-six percent of 

pts in the high-risk group did not receive chemotherapy. Conclusions: The 

proportionate use of chemotherapy in the low and intermediate risk groups 

was as expected based on adjuvant chemotherapy guidelines; however, the 

underuse of chemotherapy in 26% of high-risk pts was an unexpected 

finding. Further study is needed to determine: (1) why physicians avoided 

chemotherapy in 26% of high-risk pts; (2) the overall number of appropriate 

pts who underwent Oncotype DX testing; and, (3) the tumor characteristics 

that may have driven the underutilization of chemotherapy in the 

high-risk population. 


Quality of life of elderly patients undergoing concomitant chemoradiation 

therapy for head and neck cancers, including assessment of geriatric 

parameters. Presenting Author: Martine Extermann, H. Lee Moffitt Cancer 

Canter & Research Institute, Tampa, FL 

Background: Data on the quality of life of older patients undergoing 

concomitant chemoradiation therapy (CCRT) for head and neck (H&N) 

cancer are very scarce and no study has focused specifically on them. 

Furthermore, no study has assessed the contribution of geriatric symptoms 

to their quality of life. Methods: We prospectively assessed patients aged 65 

and older undergoing curative intent CCRT for H&N cancers, either alone or 

adjuvantly after surgery. We used the Quality of life-Radiation Therapy 

Instrument (QOL-RTI), with its H&N module (Trotti et al., 1998). In 

addition we created a 12-items senior adult questionnaire (SAQ). Patients 

were assessed at baseline, at 4 weeks, at the end of treatment (EOT), and 2 

months after EOT (recovery). Results: Fifty patients were enrolled. Median 

age was 69 years (range 65-87). Eighty-two percent of patients had locally 

advanced stage IV disease. Twenty-eight percent had prior surgery. All 

patients were treated with IMRT, 92% at 70 Gy. The most frequent 

chemotherapy regimen was cisplatin q3wks (58%), followed by weekly 

carboplatin (24%). Patients had on average 4 comorbidities (CIRS-G), 

54% of them a grade 3 or 4 disease. Forty-four percent were independent 

in IADL, and 98% were ECOG PS 0 or 1. The baseline scores were QOL-RTI: 

7.72 (SD 1.36), H&N module 7.7 (SD 2.16), SAQ 8.21 (SD 1.54). At EOT, 

the scores were 6.22 (1.26), 4.59 (1.82), 7.38 (1.38) respectively, and at 

recovery 7.17 (1.25), 6.06 (1.66), 7.96 (1.16). The scores paralleled 

functional evolution, as 24% of patients had an ECOG PS 2 and 76% were 

IADL dependent at EOT; 16% ECOG 2-3 and 55% IADL dependent at 

recovery. Cronbach alphas for the 3 QOL measures were 0.88, 0.89, and 

0.81, suggesting adequate internal consistency reliability. The SAQ was 

low-to-moderately correlated with the other two QOL measures (r�0.22 to 

0.59) at different points of assessment. Conclusions: Older H&N cancer 

patients experience significant impact of CCRT on their function, and on 

their quality of life on all three measures. Most recover after two months, 

although some may take longer. A geriatric module adds significant 

information to the general QOL-RTI and H&N questionnaires. 


Utilization of bone densitometry and administration of bisphosphonates to 

prevent osteoporosis in patients with nonmetastatic prostate cancer receiving 

anti-androgen therapy. Presenting Author: Muhammad Atif Khan, 

University of Arkansas for Medical Sciences Hospital, Little Rock, AR 

Background: Prostate cancer subjects with PSA relapse who are treated with 

androgen deprivation therapy (ADT) are recommended to have baseline and 

serial bone densitometry (BD) and receive intravenous bisphsphonates 

(BP). Utilization of BD and BP therapy was evaluated in a retrospective 

SEER Medicare database analysis. Methods: A cohort study of men aged 

aged � 65 years with a nonmetastatic incident diagnosis of prostate cancer 

between 2004 and 2008 was conducted. Data were obtained from the 

Surveillance, Epidemiology and End Results (SEER) linked Medicare 

claims. Medicare claims were used to select prostate cancer cases who had 

ever received ADT and intravenous BP as part of their treatment. ADT was 

defined as an orchiectomy, goserelin, leuprolide, leuprolide implant, or 

triptorelin. BD and treatment with pamidronate or zoledronic acid were 

identified using Medicare HCPCS codes. One-sided exact binomial test of 

proportion was used to determine if the physician compliance rate is 

consistent with 80%; meaning equal to or higher than 80%. Results: 

157,974 newly diagnosed prostate cancer cases were identified. Of those, 

100,865 were age 65 and above and had no bone metastases. Subjects 

who did not have ADT claims were excluded. 30,846 patients were eligible 

for analysis. Cases were further stratified by use of BD and BP therapy. 

Results revealed 86.8% (N�26,774) on ADT did not receive either a BD or 

intravenous BP therapy. Approximately 2.9% (N�885) of the cases on ADT 

received BP treatment without ever receiving a BD. 9.3% (N�2,863) of the 

cases on ADT received a BD without receiving intravenous BP, while only 

1.05% (N�324) of the cases on ADT received both a BD and BP. A 

compliance rate of 1.05%, those patients receiving both bone densitometries 

to screen for bone loss and preventive therapy, was well below the 

expected rate of 80%. Conclusions: Contrary to the recommendations, BD 

assessment and BP use is under utilized in men receiving ADT for non 

metastatic prostate cancer. Education of practicing physicians regarding 

better screening and preventative measures for osteoporosis in this population 

is warranted. 


Long-term central venous catheter use among cancer patients in administrative 

claims data. Presenting Author: Allison Nicole Lipitz Snyderman, 


Background: This study’s objective was to examine administrative claims 

data’s capacity to serve as a surveillance tool for long-term catheter use and 

related bloodstream infections among cancer patients. Population-based 

estimates and efforts to track catheter use and infections for this group are 

limited. As such, we sought to explore catheter use documentation using a 

cohort of colorectal cancer patients. Methods: We performed a retrospective 

analysis using the population-based SEER-Medicare dataset for patients 

66 years or older diagnosed with colorectal cancer in 2005-2007 (n � 

54,870). Insertions and removals of long-term central venous catheters 

(i.e., tunneled, ports/pumps, peripherally inserted central catheter [PICCs]) 

were identified by billing codes within 2 years of diagnosis. Factors 

associated with catheter use were identified in multivariable logistic 

regression analysis. Results: Findings were consistent with clinical expectations. 

A total of 11,775 patients (21%) had at least one documented 

long-term catheter insertion within 2 years of diagnosis, 19% within 6 

months. Of those with catheters, approximately 25% had more than one 

insertion. Sixty-eight percent had at least one port/pump, 8% at least one 

tunneled catheter, and 33% at least one PICC. Seventy-four percent of 

catheterized patients had IV chemotherapy. Of patients stages I, II, III, and 

IV, 10%, 18%, 37%, and 39% had catheters, respectively. Adjusted for 

other factors, patients with catheters were significantly more likely to be 

younger, female, black (vs. white), and have comorbidities (vs. none 

documented in year prior to diagnosis), compared to patients without 

catheters. By the end of the study, 34% of patients with ports/pumps had 

documented removal and 42% died (for patients with tunneled catheters, 

28% and 52%, respectively). Conclusions: Findings support the use of 

claims data to capture long-term catheter use in cancer patients, providing 

a foundation for exploration of its capacity to capture infections. Given 

extensive documented catheter use (21%), infections may be a significant 

problem. Claims data may offer a low-burden method for surveillance and 

study, aiding the development of targeted initiatives. 



Assessment of cancer registries (CR) in low- and middle-income countries 

(LMCs). Presenting Author: Leah L. Zullig, Department of Health Policy and 

Management, University of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: CRs are crucial for cancer control, yet few global standards 

exist. This study identifies characteristics of quality CRs in LMCs and 

globally. Methods: A Medline search was conducted in PubMed to identify 

peer-reviewed articles describing: 1) CR development and functionality 2) 

types of CRs and 3) implementation, development and utility of CRs in 

LMCs. We examined articles describing CRs and assessed benchmarking 

data that could be used to define quality characteristics. Full-text, 

English-language articles were reviewed. References cited were searched 

for additional articles. We categorized characteristics into 4 domains: 

comparability, completeness, validity and timeliness. Results: The literature 

search yielded 16 key characteristics within 4 domains that may define 

high quality CRs. In the “comparability” domain, the key characteristic was 

use of standard definitions. CRs in the US, Europe and China generally 

adhere to the International Classification of Diseases for Oncology and 

histological verification of disease; in 2007 only 40% of African registries 

did so. In the “completeness” domain the key characteristic was population 

coverage. African CRs monitor 8% of the population, the Costa Rican 

registry covers 90%, US and Madras cancer registries reach 96%. In the 

“validity” domain the key criterion was pathologic diagnosis confirmation. 

Most LMC CRs are not pathology-based. CRs in wealthier settings like Hong 

Kong report histologic confirmation in �85% of cases. In the “timeliness” 

domain standards for timely data reporting are largely undocumented. 

Conclusions: No consensus exists on characteristics of quality CRs in a 

global context. The current study provides an initial set of metrics. A Delphi 

panel of international experts is planned to further address this. Based on 

this literature review, CRs in LMCs have limited reporting, validation and 

regional population coverage. 


Differential receipt of sentinel lymph node biopsy within practice-based 

research networks. Presenting Author: Anne-Marie Meyer, University of 


Background: Sentinel lymph node biopsy (SLNB) for breast cancer was 

introduced into clinical practice in the late 1990s as an alternative to 

axillary lymph node dissection (ALND). Provider-based research networks 

(PBRNs) are believed to promote diffusion of innovations like SLNB into 

clinical practice; however, evidence of this association is limited. This 

study examines the diffusion of SLNB for early-stage breast cancer through 

the Community Clinical Oncology Program (CCOP), a community-based 

PBRN. Methods: We identified women undergoing breast conserving 

surgery with axillary staging for stage I or II breast cancer between January 

2000 and December 2003 using Surveillance Epidemiology and End 

Results-Medicare data (n�6,226). The primary outcome was receipt of 

SLNB vs. ALND, and exposure was care received from CCOP physicians or 

institutions between diagnosis and surgery. Exposure was quantified as 

both a binary measure of ever seeing a CCOP, and as a proportion of all their 

claims associated with a CCOP. Covariates included race, age, marital 

status, education, Medicaid eligibility, comorbidity, tumor grade, stage, 

estrogen receptor status, year of diagnosis, SEER region, and other 

institutional characteristics such as NCI center designation, cooperative 

group, and medical school affiliation. Multivariable generalized linear 

modeling with generalized estimating equations was used to measure 

association between CCOP exposure and receipt of SLNB. Results: Women 

who received a higher proportion of their care from a CCOP-affiliated 

physician or hospital were more likely to receive SLNB. A 10% increase in 

the proportion of CCOP-affiliated claims was associated with a greater odds 

of receiving SLNB (OR 1.14; 95% CI 1.08, 1.20), after controlling for 

covariates. Similarly, sensitivity analysis of the binary indicator of CCOP 

exposure also showed greater odds of receiving SLNB (OR 1.32; 95%CI 

1.01, 1.74). Conclusions: The quality of cancer care delivered in community 

settings can be influenced by provider-based research networks. Our 

findings contribute to the growing body of evidence that community-based 

PBRNs can facilitate adoption of cancer innovations outside of academic 

medical centers. 


407s 


Development of a disease-specific measure of quality of life in myelodysplastic 

syndromes (MDS): The “QUALMS-1”. Presenting Author: Gregory Alan Abel, 


Background: Studies assessing the quality of life (QoL) experienced by patients 

with MDS have almost universally relied upon generic measures; however, 

disease-specific QoL tools can allow for more sensitive assessments of the 

impact of changes in disease status. Methods: Using a clinical impact method of 

instrument development, individual and combined focus groups were conducted 

with 32 members of our institution’s MDS community (patients, their caregivers, 

and health care providers) to identify MDS-relevant QoL domains and associated 

question topics. Participants’ rankings of the importance of the domains and 

question topics were compared, collapsing patients/caregivers into one group 

and physicians/other providers into another. A draft scale was constructed taking 

a greater number of questions from the more highly-ranked domains. Results: 

“Fatigue” was ranked as the most important domain (see table). None of the 12 

domains were ranked significantly differently by patients/caregivers versus 

providers. The two groups ranked 5 of 60 question topics differently: “Too tired 

for routine tasks” (providers higher; p� .05); “limited availability of support 

beyond the family” (providers higher; p� .02); “organizing life around transfusion/MD 

appointments” (providers higher, p� .03); “bruising” (patients/ 

caregivers higher, p� .05) and “anger over diagnosis” (providers higher, p� 

.03). Conclusions: A high level of agreement in the rankings of domains and 

question topics between MDS patients/caregivers and providers suggests that 

the QoL experience of MDS patients is consistently compromised. The resulting 

38-item draft QUALMS-1 tool is now being piloted (cognitive debriefing and 

behavioral coding) in a new cohort of MDS patients, with the ultimate goal of 

validation in a multi-institutional setting. 

Domain 

Mean ranking 

(n�32; 1� most important, 

12� least important) 

Fatigue 1.4 

Emotional health 3.3 

Uncertainty/sense of control 4.6 

Disease information 5.5 

Disruption of life/logistics of care 5.7 

Family relationships 6.6 

Symptoms other than fatigue 6.6 

Financial concerns 7.0 

Awareness of positives/hope 7.1 

Social/role functioning 7.9 

Sexual health 11.0 

Appearance/self-image 11.0 


Comparative effectiveness of erlotinib versus no treatment for advanced 

non-small cell lung cancer patients in the Veterans Administration. 

Presenting Author: Benjamin Kim, UCSF School of Medicine, San Francisco, 

CA 

Background: Erlotinib (E) is FDA-approved for second-line treatment of 

unselected advanced non-small cell lung cancer (aNSCLC) patients. 

Clinical trials have shown increased response rates with E in aNSCLC 

patients having East Asian ethnicity, female gender, never-smoking history, 

or adenocarcinoma histology. The objective of this study was to compare 

the real-world effectiveness of E versus no treatment (NT) for first- and 

second-line treatment of aNSCLC patients in the Veterans Administration 

(VA). Methods: All incident aNSCLC cases diagnosed in the VA during 2007 

were identified through the VA Central Cancer Registry, a subset of which 

underwent medical record abstraction through the VA External Peer Review 

Program. Abstracted records were then merged with national VA Decision 

Support System pharmacy and Corporate Data Warehouse encounters data 

through 2010. Treatment lines were determined through adaptation of a 

published algorithm. The impact of E versus NT on overall survival for each 

treatment line was then evaluated using 1:N greedy propensity score 

matching (PSM) and 2-stage residual inclusion (2SRI) estimation. Results: 

Among 1965 aNSCLC patients assessed for first-line treatment, 78 (4%) 

received E and 782 (40%) received NT; among 1124 assessed for 

second-line treatment, 128 received E (7%) and 638 (33%) received NT. 

1:3 PSM of E cases to NT controls showed no difference in overall survival 

by Kaplan-Meier estimation in the first- (median 2.6 vs. 2.9 mos., 

p-value�0.86) and second-line (3.4 vs. 3.2 mos., p�0.85) settings. 

Chemotherapy use by Veterans Integrated Service Network was selected as 

the instrumental variable for 2SRI. Expected mean survival of E versus NT 

was similarly not statistically prolonged in the first- (E:NT survival time ratio 

2.55, p�0.35) and second-line (2.49, p�0.32) settings. Conclusions: For 

a population with few aNSCLC patients having 3 out of the 4 clinicopathologic 

characteristics associated with improved response, E did not appear 

to confer a survival advantage over NT. Linking mutation results to 

observational datasets may improve comparative effectiveness research of 

personalized medicine in oncology. 




Advanced gastrointestinal cancer patients’ perceptions of prognosis and 

goals of treatment. Presenting Author: Areej Raed El-Jawahri, Massachusetts 


Background: Patients with advanced cancer require accurate perception of 

their illness in order to make informed decisions regarding their care. 

However, little is known about the accuracy of these patients’ illness and 

prognostic understanding. The objectives of this study are to 1) examine 

prognostic understanding in patients with advanced gastrointestinal (GI) 

cancers, 2) assess patient preferences for prognostic information, and 3) 

explore associations of perceptions with quality of life (QOL) and mood. 

Methods: Cross-sectional study of 50 patients within 6-12 weeks post 

diagnosis of advanced GI cancers (gastric, esophageal, pancreatic, and 

hepatobiliary). We assessed patients’ perceptions of prognosis with a 

15-item questionnaire, the Perception of Treatment and Prognosis Questionnaire. 

QOL and mood were assessed using the Functional Assessment 

of Cancer Therapy-General (FACT-G) and hospital anxiety and depression 

scales (HADS), respectively. Results: We enrolled 50/62 (80%) consecutive 

eligible patients within an 11-month period. 50% (25/50) of participants 

responded that the primary goal of their cancer treatment was to “cure their 

cancer.” Similarly, 54% (27/50) reported that they were “somewhat” to 

“extremely likely” to be cured from their cancer. Only 22% (10/49) 

reported having a discussion about their end-of-life care preferences with 

their oncologist. 76% (38/50) reported wanting to know as many details as 

possible about their cancer diagnosis and treatment and 64% (32/50) 

rated this information as “extremely important.” Patients who perceived 

knowing about their prognosis as “extremely helpful” reported a better QOL 

(p � 0.009), lower symptoms of anxiety (p � 0.02) and depression (p � 

0.02). Conclusions: Although the majority of patients report that they desire 

detailed information about their prognosis, half incorrectly perceived their 

cancer as curable and the majority did not discuss their end-of-life care 

preferences with their oncologist. Patients who found learning about their 

prognosis to be extremely helpful reported better QOL and mood. Studies of 

interventions to increase advanced cancer patients’ knowledge of their 

prognosis and to encourage end-of-life discussions are warranted. 


Assessing the clinical significance of real-time quality of life data in cancer 

patients treated with radiation therapy. Presenting Author: Michele Y. 

Halyard, Mayo Clinic, Scottsdale, AZ 

Background: This pilot study evaluated whether providing clinicians with 

patient(pt) QOL results and symptom management pathways linked to QOL 

domains at the time of clinical appointment would result in improvement in 

QOL and treatment (tx) satisfaction. The objective was to obtain preliminary 

effect size estimates and logistical evidence for design of a larger, 

definitive trial. Methods: Oncology pts receiving 5-7 weeks of radiotherapy 

(RT) electronically completed QOL assessments (LASA) at baseline and 

biweekly prior to seeing clinicians. Was It Worth It (WIWI) and Interpersonal 

Patient-Provider Relationship (IPPRS) were measured at tx end. Pt endpoints 

(pro-rated primary endpoint LASA area under the curve (AUC), LASA 

changes from baseline, and WIWI responses) and clinician endpoints 

(IPPRS) were compared between the control group (Phase 1: no QOL 

feedback) and the intervention group (Phase 2: QOL feedback) via 

Wilcoxon, Chi-square and Fisher Exact tests. There was 80% power to 

detect a 10 point difference in average AUC. Results: 148 pts enrolled (79 

Phase 1, 69 Phase 2) from 11/28/2008 to 09/20/2011 (sites GI (27%), 

Lung (22%) and Head and Neck (52%)). 68% received RT and chemo. 

There were consistently moderate effect sizes observed but no statistically 

significant differences in any AUC nor end of tx change from baseline 

scores. 20% fewer pts in phase 2 reported clinical deficits in overall QOL 

(pain). In pts receiving 7 weeks of RT, end of tx average overall QOL, mental 

well-being (WB), physical WB and pain severity were significantly better in 

Phase 2 pts. WIWI results showed 76% found participation worthwhile, 

95% would participate again, and 92% would recommend the study to 

others. No differences between groups were found in communication 

between clinicians and pts (IPPRS). Conclusions: Preliminary estimates 

indicate potentially clinically significant improvements of moderate effect 

size in mental and physical WB and pain severity when clinicians received 

QOL real time with symptom management pathways. Further study is 

warranted in larger trial setting. 


Association between baseline physical function and comorbidity status 

with patient-reported quality of life after prostate cancer treatments: 

Combined analysis of two prospective cohort studies. Presenting Author: 

Ronald C. Chen, University of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: Treatment-related bowel, urinary, and sexual dysfunction in 

prostate cancer patients varies by treatment type, baseline function and 

other patient factors. To better predict patient outcomes after treatment, 

we examined the impact of comorbidity on these quality of life (QOL) 

outcomes in a secondary data analysis of two pooled, prospective cohort 

studies. Methods: A total of 697 patients from 3 academic hospitals who 

received radical prostatectomy, external beam radiation, or brachytherapy 

were included. Using a validated instrument, patients reported bowel, 

urinary, and sexual symptoms pretreatment, and at 3, 12, 24, and 36 

months after treatment. Baseline physical function was measured by the 

physical component summary score (PCS) of the SF-12 using patient 

report. Comorbidity as measured by the Index of Co-Existent Disease 

(ICED) was obtained from medical record review. Repeated QOL measurements 

were analyzed using a mixed modeling method, by random coefficient 

modeling. Separate models were built for each outcome using bowel, 

urinary, and sexual scale scores at each time point.Covariates in all models 

included baseline age, education, ICED, and PCS. Results: Approximately 

70% of patients had one or more comorbid conditions at baseline. After 

adjusting for age and education in mixed-models, we found baseline 

comorbidity was independently associated with more sexual dysfunction 

(p�.001) and urinary incontinence (p�.03). Worse baseline physical 

functioning was independently associated with more bowel problems 

(p�.001) and sexual dysfunction (p�.001). There were no treatment by 

comorbidity or physical functioning interactions. Conclusions: Comorbidity 

and worse physical functioning at baseline are significantly associated with 

poorer bowel, urinary, and sexual function after treatment for prostate 

cancer, but the associations do not appear to differ by treatment. Patients 

with comorbidity recovered more slowly. This information may help patients 

and their physicians anticipate outcomes after surgical and radiation 

treatments. 


Changes in adjuvant breast cancer chemotherapy regimen selection over 

time in the community. Presenting Author: Debra A. Patt, Texas Oncology, 

US Oncology, Austin, TX 

Background: Adjuvant breast cancer (BC) chemotherapy (CT) treatment has 

evolved over time due to improved understanding of risk conveyed by 

pathology and patient (pt) characteristics, as well as emergence of new and 

mature data for survival and toxicity. We aimed to evaluate how CT regimen 

selection has changed in recent years in various subgroups. Methods: Using 

iKnowMed EHR data from The US Oncology Network, we retrospectively 

identified female pts diagnosed with stage I-III BC between 1/2007 and 

12/2010 at practices with EHR data available at time of diagnosis. Pts with 

�5 office visits, those with a second primary or previous cancer diagnoses 

were excluded. Age, ER, HER2, nodal status, stage and year of diagnosis 

were captured. CT utilization was determined by the number of pts who 

received CT within 6 months of their diagnosis. Clinical trial pts were 

included. Regimens were categorized by the initial CT title and drugs 

assigned. Pts with metastatic regimens were excluded. CT regimens were 

analyzed by subgroups and trended over time. Results: During the time 

period, 26,095 stage I-III BC pts were identified. A CT regimen within 6 

months of diagnosis was documented in 56% of pts. CT utilization was 

83% in HER2� pts, 85% in ER-/HER2- pts, and 45% in ER�/HER2- pts. 

CT utilization decreased overall with increasing pt age (71%, 64%, 51%, 

33%, and 13% for pts in their 4th ,5th ,6th ,7th and �8th decade of life). In 

HER2� pts, use of non-anthracycline containing regimens increased from 

26 to 62%, and anthracyline-taxane combination regimens decreased from 

33 to 15%. In HER2-/ER� pts, the most used non-anthracycline regimen 

was docetaxel � cyclophosphamide (TC) at 41%. Anthracycline-taxane 

combinations were used more often in the HER2-/ER- group (32%). 

Conclusions: In the 4 year study period, this data suggests that ER and 

HER2 status may drive chemotherapy choice more than nodal status. 

Anthracycline containing regimens are being used less often possibly due 

to similar efficacy but less cardiac toxicity, particularly when combined 

with trastuzumab. These results suggest a change away from anthracyclines 

in specific subgroups with the controversy over the benefits of that 

change unsettled, and cost implications yet unquantitated. 



Frequency of cognitive impairment (CI) in elderly patients (pts) suffering 

from malignancies and impact on therapeutic decision. Presenting Author: 

Thibault De La Motte Rouge, Medical Oncology Department, AP-HP, 

Salpetriere Hospital, University Paris VI, Paris, France 

Background: Therapeutic decision remains complex when a cancer is 

diagnosed in elderly pts. Our aim was to evaluate the frequency of CI in this 

population and its impact on therapeutic decision. Methods: An oncogeriatric 

evaluation including Comprehensive Geriatric Assessment (CGA) is 

systematically performed for all elderly cancer pts referred in our unit. We 

reviewed data of all pts assessed by geriatric oncologist at our institution 

from January 2009 to June 2011. Results: 378 pts were identified, among 

them a CI was noted in 87. Median age was 84 years (range 71 –94), 70 % 

� 80 years. Most of the pts (78/87) were referred at the time of diagnosis. 

Metastatic disease was diagnosed in 32 pts (52%) and Diffuse Large B Cell 

Lymphoma stage III or IV in 21 pts (81 %). In 41 pts, CI was already 

diagnosed: Alzheimer disease (AD) (n�38) and Vascular Dementia (n�3). 

CGA help to identify CI in 46 additional pts: AD (n�36); Vascular Dementia 

(n�2) and Mild Cognitive Impairment (n�8). 45/87 pts (52 %) were 

dependant for at least one activity of daily living (ADL). As a result of CGA 

and benefit/risk oncologic assessment, best supportive care was recommended 

in 12 pts. Among them, only 4 pts presented with advanced 

metastatic disease (main reason for palliative care). Pts in whom “best 

supportive care” decision (n�12) was recommended were more dependants 

than those who received specific anticancer therapy (n�75): 

dependence for at least 2 ADL: 10/12 pts (83%) versus 16/75 (21%); and 

presented more AD already diagnosed (11/12 versus 30/75). In the 

remaining 75 pts, specific cancer therapy was proposed, including chemotherapy 

(n�67), surgery (n�5), radiotherapy (n�3) and hormonotherapy 

(n�9). Treatment was initiated as recommended in all but 4 pts (best 

supportive care decision taken following discussion with pts and relatives). 

During the follow-up, only 11/75 pts needed to be placed in nursing home 

because of loss of autonomy. A survival � 1 year was observed in 27/75 

(36%) pts. An update of cognitive performance will be presented. 

Conclusions: Our data support that even if CI is frequent in elderly pts with 

malignancies, specific anticancer therapy remains feasible and should be 

considered in most elderly pts with CI. 


An integrated analysis of comprehensive geriatric assessment (CGA) in elderly 

patients with non-small cell lung cancer (NSCLC) (JCOG1115-A). Presenting 

Author: Hiroshi Katayama, JCOG Operations Office, National Cancer Center, 

Tokyo, Japan 

Background: The number of elderly NSCLC patients is increasing all over the 

world. Actual age and ECOG PS is not always efficient to select �fit-elderly� for 

chemotherapy. We integrated the data from two phase III trial (JCOG0207, 

JCOG0803/WJOG4307L) and evaluated 4 CGA items as well as age and PS to 

determine whether they would predict survival, response and toxicities. Methods: 

Eligibility criteria of both trials included histologically or cytologically proven 

NSCLC; stage III/IV; age 70 or more; ECOG PS of 0-1; unfit for bolus cisplatin; no 

prior treatment; adequate organ function. Patients were randomized to receive 

either weekly docetaxel (D) or D plus cisplatin (DP) in J0207, and either 

3-weekly D or DP in J0803/W4307L. This study included all eligible pts for 

whom all of 4 CGA items (Activity of Daily Living [ADL], Instrumental Activity of 

Daily Living [IADL], Mini-Mental State Examination [MMSE], Geriatric Depression 

Scale [GDS-15]) were assessed before treatment. Primary endpoint was 

overall survival (OS). Survival curves are estimated by Kaplan-Meier method and 

multivariate analysis for OS adjusting baseline factors were performed by using 

stratified Cox regression model. Results: This analysis included 331 pts (J0207/ 

J0803-W4307L: 105/226) in total. The result of multivariate analysis for OS 

was shown in the table. After adjusting baseline factors, MMSE as well as sex and 

PS was significantly associated with OS. None of the CGA items were associated 

with response and toxicities. Conclusions: It is not actual age but MMSE and PS 

that is useful for predicting prognosis of elderly pts. MMSE should be taken into 

consideration to determine the indication of chemotherapy for elderly pts. 

mOS Multivariate analysis 

n 

(months) HR 95%CI p 

Sex 

Male 243 12.8 1 

Female 

Stage 

88 24.1 0.44 0.30-0.66 �.001 

III 102 15.4 1 

IV 

PS 

229 14.5 1.25 0.89-1.75 0.194 

0 119 21.2 1 

1 

Age 

212 11.7 1.66 1.18-2.32 0.0033 

70-74 96 17.1 1 

75-79 181 15.0 0.96 0.67-1.37 0.810 

80- 

ADL 

54 11.3 1.45 0.91-2.29 0.119 

20 300 15.0 1 

-19 

IADL 

31 11.3 1.15 0.68-1.95 0.591 

5 267 15.0 1 

-4 

MMSE 

64 14.1 1.01 0.69-1.49 0.956 

30 133 21.2 1 

-29 

GDS-15 

198 13.5 1.46 1.05-2.03 0.025 

-4 207 14.8 1 

5- 124 15.0 0.84 0.61-1.15 0.268 


409s 


Cancer survivorship outcomes in immigrants. Presenting Author: Phyllis 

Noemi Butow, University of Sydney, Sydney, Australia 

Background: Immigration is increasing world-wide. Cancer survivorship is 

now recognised as a period of difficult adjustment for all patients, and 

possibly more so for immigrants. We explored disparities in quality of life 

outcomes for immigrant (IM) versus Anglo-Australian (AA) cancer survivors. 

Methods: In a cross-sectional design, cancer survivors were recruited 

through the New South Wales, Queensland and Victorian Cancer Registries 

in Australia. IM participants, their parents and grandparents were born in a 

country where Chinese, Greek, or Arabic is spoken and spoke one of those 

languages. AAs were born in Australia and spoke English. All were 

diagnosed with cancer 1-3 years previously. Questionnaires (completed in 

preferred language) included the Hospital Anxiety and Depression Scale 

(anxiety/ depression), FACT-G (quality of life) and Supportive Care Needs 

Survey (unmet needs). Outcomes were compared between AA and IM 

groups in adjusted regression models that included age, gender, socioeconomic 

status, education, marital status, religion, time since diagnosis 

and cancer type (prostate, colorectal, breast and other). Results: There were 

599 participants (response rate 41%). Consent was unrelated to demographic 

and disease variables. AA and IM groups were similar except that 

immigrants had higher proportions in the low and highly educated groups (p 

� 0.0001), and higher socioeconomic status (p � 0.0003). In adjusted 

analyses (see table), IMs had clinically significant higher depression 

(possible range 0-21), greater unmet information and physical needs, and 

lower quality of life than AAs. The possible range for the latter three is 

0-100. Conclusions: Immigrants experience poorer outcomes in cancer 

survivorship, even after adjusting for socio-economic, demographic and 

disease differences. Interventions are required to improve their adjustment 

after cancer. Results highlight areas of unmet need that might be better 

addressed by the health system (particularly with regard to provision of 

information and support. 

Outcome 

(possible range) Immigrant Anglo-Australian P 

Depression 

4.6 2.7 �.0001 

(0-21) 

Unmet information needs 19.2 10.7 �.0001 

(0-100) 

Unmet physical needs 

14.8 10.2 .0006 

(0-100) 

Quality of life 

76.6 82.7 �.0001 

(0-100) 


Implications of smoking for quality of life and illness perceptions of lung 

cancer patients. Presenting Author: Sarah Danson, Academic Unit of 

Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom 

Background: Adverse publicity about smoking may lead to feelings of guilt 

among lung cancer patients or pessimism about their future, potentially 

compromising health-related quality of life (QoL) and adherence with 

medical advice. QoL is an important outcome in clinical trials, particularly 

where survival rates are low. We aim to compare QoL and illness perceptions 

of lung cancer patients depending on smoking history. Methods: 

Clinical data, measures of QoL (EORTC-QLQ-C30�LC13) and illness 

perceptions (Brief IPQ – includes items to assess perceived severity, 

causality, timeline, understanding, emotional impact, and control over 

illness) were completed by 190 newly diagnosed lung cancer patients 

(Non-small cell: 75%; Mean age: 68 years, range: 48-85 years; 58% 

males). Of these, 24% were current smokers, 69% former smokers, and 

7% never smoked. Results: Although overall QoL was similar between the 

three smoker groups, there was a significant effect of smoking status on 

QoL subscale emotional function (EF)(F(2,168)�4.08,p�.019). Those 

who never smoked had significantly higher EF than current smokers 

(p�.03). There was also a significant effect of smoking history on cough 

(F(2,166);�5.40 ,p�.005) with smokers reporting significantly greater 

levels than former smokers (p�.004). Smokers were more likely than 

former smokers (p�.015) to attribute their lung cancer to smoking 

(F(2,161)�16.49,p�.000). Furthermore, there was a significant effect of 

smoking on the perceived timeline of illness (F(2,144)�3.33,p�.039), 

with smokers being more pessimistic about this than former smokers 

(p�.043). Conclusions: These findings have implications for planning the 

care of lung cancer patients. In addition to the different treatment needs of 

smokers and former smokers, smokers may need greater support to cope 

with the emotional effects of their illness. Our findings suggest that 

smokers blame their illness on their own behaviour, and have a more 

pessimistic view of likely survival time, so they may need more encouragement 

to accept life-prolonging treatments. These results may also inform 

tailored smoking-cessation advice. 




Impact of oncology drug shortages on patient treatment. Presenting Author: 

Daniel Jacob Becker, St. Luke’s-Roosevelt and Beth Israel Medical Center, 

Continuum Cancer Centers of New York, New York, NY 

Background: Cancer drug shortages increased considerably over the past 5 

years, but quantitative analyses of the scope and effects are limited. We 

assessed the effects of drug shortages on outpatient medication use in a 

single New York City university hospital. Methods: We examined pharmacy 

records for drug shortages, defined by the ASHP as supply issues that affect 

“how the pharmacy prepares or dispenses a drug product or influences 

patient care when prescribers must use an alternative agent.” We examined 

outpatient records for all cancer patients treated with infusional antineoplastic 

and/or supportive medications from 4/2010-9/2010 and from 4/2011- 

9/2011, and performed subgroup analysis on Aug/Sept 2011, the peak of 

medication availability problems at our hospital. We compared proportions 

of patients treated with specific medications in 2010 and 2011 with 

Pearson’s chi-square test. Results: Twelve medications were in shortage 

during the study period in 2010 and 22 in 2011. Between 4/1/10 and 

9/30/10, 335 cancer patients were treated, and 379 patients were treated 

between 4/1/11 and 9/30/11. Median patient age was 60 years. Cancer 

site of origin was comparable between years: breast (40%), GI (15%), 

lymphoma (10%), GU (8%), and lung (7%). Drugs considered in shortage 

were used for 170 (50.8%) patients in 2010 and 241 (63.6%) patients in 

2011 (p�0.0005). Of 235 patients treated in Aug/Sept 2011, there were 

23 (9.8%) documented therapy changes due to shortages, compared with 

0 changes among 211 patients treated in Aug/Sept 2010 (p�0.0001). 

Among patients treated in Aug/Sept 2010 24 (11.4%) patients received 

paclitaxel and 19 (9.0%) received docetaxel. Among patients treated in 

Aug/Sept 2011, 11 (4.7%) received paclitaxel and 38 received docetaxel 

(16.2%), a 69% decrease for paclitaxel and 80% increase for docetaxel 

from 1 year prior (p�0.009, and p�0.024, respectively). The estimated 

cost of a single treatment with paclitaxel for 1 patient with BSA 1.75 was 

$47.59 versus $858.39 for docetaxel, a 1704% increase. Conclusions: 

Oncology drug shortages affected the majority of patients in our center and 

increased at an alarming rate. Drug shortages have substantial economic 

costs and mandate treatment changes that may affect efficacy and toxicity. 


Pregnancy outcomes in women with cancer. Presenting Author: Andrea 

Milbourne, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Parenthood after cancer is a critical concern for many cancer 

patients (pts). Pregnancy (prg) during cancer is an emotional time for about 

1/1000 pregnant women. No randomized controlled studies exist examining 

the impact of cancer treatment (tx) on the developing fetus nor on the 

woman with cancer. Methods: From 2002-2011, women presenting for 

cancer tx during prg were approached for this IRB-approved prospective 

database study. All pts provided written consent. Results: To date 143 pts 

are evaluable. The median age at diagnosis was 32.1 years and median 

gestational age (GA) at enrollment was 18.2 weeks. 95/143 (66.4%) are 

White, 19 (13.3%) are African American, 17 (11.9%) are Hispanic and 12 

(8.4%) are Asian/Other. Primary cancers included breast (n�59, 41.3%), 

hematologic (n�29, 20.3%), melanoma (n�13, 9%), GYN (n�11, 8%), 

GI (n�8, 5.6%), head/neck (n�7, 6%) and other (n�16, 11%) (brain�4, 

GU�1, thyroid�3, head/neck�7, thoracic�1, sarcoma�6, unknown primary�1). 

111/143 (77.6%) of prgs resulted in live births. Median birth 

weight was 6.5 lbs. Median follow-up time for pts was 32.3 months. To 

date, 3/19 pts who terminated prgs have died (1.6%). Most terminations 

occurred in the 1st trimester. To date, 79 pts (55.2%) are NED and 23 pts 

have died; of these 19 (1.7%) had live births. No major malformations were 

observed in the 74/143 (52%) of pts who received chemotherapy (CTx) 

during pregnancy. 57% received FAC/FEC; other regimens included ABVD 

(n�5), cytarabine (n�5), CHOP/R-CHOP, and platinum-based regimens. 

Median GA at the start of CTx was 19.7 wks. Median number of CTx cycles 

during prg was 4. Other pts underwent surgery (n�32), no tx (n�14), 

deferred tx until after delivery (n�17), radiation (2), transplant (3), other 

(1). Conclusions: Cancer diagnosis during prg is compatible with successful 

tx and prg outcome. Cancer tx during the 2nd and 3rd trimester can be 

safely given and in our pts did not result in adverse prg outcomes. Tx during 

the 1st trimester is usually not recommended. Thus cancer pts in their 1st 

trimester need to be extensively counseled about their disease as well as 

about the risks to the prg. In our pts continuation or termination of prg were 

not associated with an increased risk of death. 


Participation of teenagers and young adults (TYA) in cancer clinical trials 

(CCT): What can we learn from six years of accrual data in England? 

Presenting Author: Lorna Anne Fern, University College Hospitals London, 


Background: We reported underrepresentation of TYA in CTT in England, 

2005-06. Since 2005 national healthcare policies and research initiatives 

aimed at increasing participation of TYA in CCT have been implemented. 

We aimed to determine if this has improved accrual rates (AR). Methods: We 

analyzed accrual by age during 2005-2010 to UK Cancer Research 

Network interventional trials recruiting newly diagnosed patients (pts) with 

leukaemia, lymphoma, bone/soft tissue sarcoma, central nervous system 

and germ cell tumours. AR were expressed as the ratio of pts entered onto 

trial compared to population incidence cases for 2005-08; for 2009-10, 

mean incidence of 2005-08 was used. Results: 2005-10 showed an AR 

increase of 10.3% for pts 10-14 yrs, 17.9% for pts 15-19 yrs but only 

4.6% for pts 20-24 yrs (Table). In 2010 AR was 54.4% for pts 10-14 yrs, 

43.3% for 15-19 yr olds and 20.6% for pts 20-24. Annual increases of AR 

were observed for pts 15-19 yrs, but in no other age groups, 0-59 yrs. We 

looked at AR for children and younger teenagers , 5-14 yrs, vs older TYA, 

15-24 yrs. Overall, AR for 5-14 yr olds was greater, 53.7% vs 23.0% for pts 

15-24 yrs; however, during 2005-10 AR increased by 9.7% for pts aged 

15-24 compared to 7.8% for pts aged 5-14. Conclusions: AR for TYA has 

improved in between 2005-10. Most benefit is evident for older teenagers; 

AR for young adults remain disappointing. Changes relate to increased trial 

availability and access, centralisation of care for TYA, amendments to age 

eligibility criteria to reflect tumour biology and increased collaboration 

between adult and paediatric clinical research groups. Strategies to 

improve AR for young adults require further development. 

Number recruited (R), incidence (I), and AR for pts 0-24 yrs. 

0-4 5-9 10-14 15-19 20-24 

R I AR R I AR R I AR R I AR R I AR 

2005 203 350 58.0 129 249 51.8 107 243 44.0 99 388 25.5 84 524 16.0 

2006 207 352 58.8 132 245 53.9 120 276 43.5 110 361 30.5 67 519 12.9 

2007 225 356 63.2 115 212 54.2 111 237 46.8 110 358 30.7 58 565 10.3 

2008 243 317 76.7 149 204 73.0 131 242 54.1 121 341 35.5 76 558 13.6 

2009 200 345 58.0 129 230 56.1 115 252 45.6 144 364 39.6 104 543 19.2 

2010 232 345 67.2 132 230 57.4 137 252 54.4 158 364 43.4 112 543 20.6 

%D 9.2 5.6 10.3 17.9 4.6 


Financial burdens (FB), quality of life, and psychological distress among 

advanced cancer patients (ACP) in phase I trials and their spousal 

caregivers (SC). Presenting Author: Fay J. Hlubocky, University of Chicago 

Pritzker School of Medicine, Chicago, IL 

Background: FBs have been identified as a significant predictor of stress for 

cancer patients and their caregivers/partners. FBs may indirectly affect the 

quality of life and psychological distress of clinical trial subjects, particularly 

those with advanced disease on Phase I trials. Methods: A convenience 

sample of ACP enrolling in phase I trials was assessed at baseline (T1) and 

one month (T2) using several measures including: depression (CES-D), 

state-trait anxiety (STAI-S/T), quality of life/qol (FACIT-Pal), and global 

health (SF-36). Data on FB were obtained via the questions of Ell (2008), 

querying subjects on: employment status, unexpected medical costs, 

concerns regarding wages (e.g. termination, use of sick time), and financial 

stress. Results: 104 subjects (52 Phase I ACPs and 52 SC) were separately 

interviewed at T1 and T2. For the total population: median age 61 

(28-78y); 50% male; 100% married; 87% Ca; 67%� HS educ; 55% GI 

dx; 53% income �$65,000 yr, with45% ACPs employed full/part-time; 

55% retired; 66% SC employed full/part-time with 34% retired. At T1, 

82% of ACP reported medical cost concerns and 79% reported financial 

stress. For SC at T1, 69% reported medical costs concerns; 83% employed 

SC reported wage concerns; and 81% reported financial stress. For both 

ACP and SC, rates remained consistent with the exception of increased 

self-report re medical cost concerns at 85% and 72% respectively at T2. At 

T2, ACP who reported unexpected medical costs had higher STAI-S (31 � 

10v29�12, p�0.02) and CES-D scores (12 � 11v10� 9, p�0.04). SC 

with self-reported financial stress had higher STAI-S anxiety (39 � 17v35 

� 13, p�0.03) at T2. In regression analyses, ACP with medical costs 

concerns had poorer FACIT-Pal QOL over time. Also, SC with medical cost 

concerns at T2 was negatively associated with SF-36 scores. ACP and SC 

qualitative responses re FBs revealed salient themes: insurance coverage, 

unexpected costs associated with research study participation, Medicare, 

bankruptcy, and worry re financial stability after ACP death. Conclusions: 

FBs are negatively associated with quality of life among clinical trial 

subjects and SC in phase I trials. 



Influence of hospital characteristics on immediate breast reconstruction 

following mastectomy. Presenting Author: Catherine A. Richards, Mailman 

School of Public Health, Columbia University, New York, NY 

Background: Immediate breast reconstruction (IBR) following mastectomy 

is underutilized in the U.S. Racial, economic and geographic factors are 

associated with lower rates of IBR. Prior research has explored the 

association of individual and surgeon-level factors with the use of IBR, with 

little attention paid to hospital characteristics. Methods: We analyzed data 

from the 2008 Nationwide Inpatient Sample (NIS), a 20% random sample 

of academic, public and private U.S. hospitals. We used ICD-9 codes to 

identify women diagnosed with invasive breast cancer or DCIS who 

underwent mastectomy, and IBR (natural or expander/implant). If a 

hospital performed at least one IBR during 2008, they were classified as 

performing reconstruction. Relative risk regression was used to assess the 

hospital factors associated with a hospital performing IBR. Results: Of the 

3,518 hospitals that performed mastectomy in 2008 only 50.4% performed 

at least one IBR. For hospitals that did not perform IBR, the average 

number of mastectomies was 5, compared to 35 at hospitals that did 

perform IBR (p�0.01). Among hospitals that did perform IBR, the mean 

proportion of mastectomy patients that had IBR was 34% (SD�20). In a 

multivariable adjusted model, urban/teaching (RR�3.47) and urban/nonteaching 

(RR�2.86) hospitals were significantly more likely to perform IBR 

compared to rural hospitals. Hospitals with a high proportion of privately 

insured patients (RR�1.10) were significantly more likely to perform IBR 

compared to hospitals with a low proportion of privately insured patients. In 

contrast, hospitals with a high proportion of publically insured patients 

(RR�0.24) and hospitals with a high proportion of female patients � 70 

years old (RR�0.75) were significantly less likely to perform IBR. Hospital 

region, hospital ownership status and the proportion of nonwhite patients 

were not significantly associated with IBR. Conclusions: Almost half of all 

U.S. hospitals where mastectomies are performed do not have any patients 

who have undergone IBR. The likelihood a hospital will perform IBR varies 

significantly by hospital characteristics. 


Do patient tracking, follow-up, and referral practices contribute to breast 

cancer disparities in a large urban area? Presenting Author: Christine B. 

Weldon, Center for Business Models in Healthcare, Chicago, IL 

Background: Chicago Black women are 62% more likely to die from breast 

(BC) cancer than White women. Previous data from 39 Chicago hospitals 

suggested significant quality deficits in breast cancer screening and 

treatment (Chicago Breast Cancer Quality Consortium, 2010). Patient 

tracking, follow up and referral practices may influence quality of care for 

minority women (Mojica et al, Cancer Control, 2007). Our goal is to 

evaluate tracking, follow up and referral practices during screening, 

diagnosis and treatment of BC at Chicago hospitals servicing Black women. 

Methods: Using the framework approach of qualitative research, we 

conducted interviews with providers of BC screening and care from 20 

Chicago institutions with Black patients averaging 50% of patient base (15 

community, 3 academic and 2 public hospitals). Informants included 

surgeons, medical oncologists, radiologists, mammography technicians, 

internists, nurses, administrators, and patient navigators. Interviews were 

transcribed, and thematic and statistical analyses were performed (simple 

frequencies and Fisher’s exact test). Results: Six of the 20 sites (30%) 

follow up with patients who did not show for a scheduled mammography 

visit. Five of these sites (83%, 5/6) have a low “no-show” rate (below 20%), 

compared to 4 sites (29%, 4/14) with low “no-show” rates among the 14 

sites without follow-up (p�0.05). Seven of the 20 sites (25%) direct 

diagnosed patients to their next step in care by providing referrals and 

guidance, while other 13 sites rely on a primary care physician or leave the 

patient without a clear care plan. BC patients at 6 of the 7 sites directing 

care (83%, 5/6) are referred to a mid- or high-volume surgeon (3� BC 

surgeries / month), compared to patients from only 1 of the 13 sites not 

directing care (p�0.001). Nine of the 20 sites track diagnosed BC patients 

through their care. Five of them (56%, 5/9) also track survivors, compared 

to none (0%, 0/11) of the 11 sites who do not track patients (p�0.008). 

Conclusions: Poor tracking, follow up and referral practices for breast 

cancer screening and treatment are associated with suboptimal care and 

may contribute to outcome disparities for Black women in Chicago. 


411s 


Why do cancer patients die in the emergency department (ED)? Analysis of 

283 deaths in North Carolina EDs in 2008. Presenting Author: Ashley 

Nicole Leak, UNC Gillings School of Global Public Health, Department of 

Health Policy and Management, Chapel Hill, NC 

Background: Emergency departments (ED) in the US are utilized by cancer 

patients for symptom management, treatment side effects, oncologic 

emergencies, and/or end of life care. EDs have become a place where acute 

care needs are addressed and there are discussions about end of life care. 

The purpose of this study was to describe characteristics of cancer patients 

who died in the ED, highlighting lung cancer patients and their ED visit 

characteristics. Methods: A secondary data analysis of ED visit data fromthe 

North Carolina Disease Event Tracking and Epidemiologic Collection Tool 

(NC DETECT), a population database of 110 of the 112 EDs in NC in 2008. 

This was a descriptive, retrospective analysis providing descriptive statistics 

of patient demographics including: sex, age at death, insurance, 

cancer type, and visit categories (hour, day, month). Free text chief 

complaints, as recorded by the health care provider, were cleaned and 

categorized. Results: There were37,760 ED visits by 27,644 patients 

associated with cancer; 283 (1%) of these visits resulted in death in the 

ED. The most common chief complaints of those who died were respiratory 

distress (17.3%), neurological changes (13.4%), and pain (5.7%). Of all 

cancer deaths, 63% were male with a mean age of 66 (SD 14.2). Over a 

third (N� 104, 36.7%) of cancer ED visits resulting in death had a code for 

lung cancer listed. Medicare was the insurance provided for almost half 

(47.3%) of these patients. Majority of deaths occurred on a patient’s first 

ED visit (70.9%). Although a third (34.7%) of deaths occurred during 

weekends, over a third (37.5%) occurred during weekday clinic hours. 

Conclusions: Even though deaths in the ED were infrequent, this study 

provides insight into reasons patients visit the ED. Some patients were 

enrolled in Hospice and/or had a DNR documented. This study can inform 

future research associated with precipitating factors leading up to the ED 

visit (e.g. worsening shortness of breath, location of care prior to ED visit). 

This study illustrates the importance of research on discussion of end of life 

care needs (advanced directives, code status, use of Hospice services) with 

cancer patients and their family before they reach the final stage of their 

disease. 


Competing event risk stratification may improve the design and efficiency 

of clinical trials: Secondary analysis of SWOG 8794. Presenting Author: 

Brent Shane Rose, Harvard University, Boston, MA 

Background: Efficiency of clinical trials may be improved by stratifying 

according to competing event risk. We aimed to test whether effect and 

sample size estimates would be altered when adjusting for competing event 

risk, using data from the SWOG 8794 trial of adjuvant radiation therapy 

(RT) for high-risk post-operative prostate cancer. Methods: The primary 

outcome was metastasis-free survival (MFS), defined as time to first 

occurrence of metastasis or death from any cause (i.e., competing mortality 

(CM)). We developed separate risk scores for time to metastasis and CM 

using backward stepwise competing risks regression. Risk factors for 

metastasis were PSA, Gleason score, and seminal vesicle invasion, and for 

CM were age, performance status, and Charlson comorbidity index. 

Treatment effects were estimated using Cox models adjusted for risk 

scores. We identified an enriched subgroup of 75 patients at high risk of 

metastasis and low risk of CM, based on risk score cutoffs. Sample size 

estimates assumed type I and II error of 0.10 and 0.20, and accrual and 

follow-up times of 6 and 6 years. Results: The mean CM risk score was 

significantly lower in the RT vs. control arm (p�0.001). The effect of RT on 

MFS (HR 0.70; 95% CI, 0.53-0.92; p�0.010) was attenuated when 

controlling for metastasis and CM risk (HR 0.76; 95% CI, 0.58-1.00; 

p�0.049). The hazard for CM was reduced by RT (HR 0.82; 95% CI, 

0.59-1.14; p�0.24), but this effect was attenuated when controlling for 

CM risk (HR 0.94; 95% CI, 0.67-1.31; p�0.71). In contrast, there was no 

difference in the adjusted and unadjusted HRs for metastasis (0.50; 95% 

CI, 0.31-0.81; p�0.005 and 0.49; 95% CI, 0.30-0.81; p�0.005). 

Compared to the whole cohort, the enriched subgroup had the same 

baseline 10-year incidence of MFS (40%; 95% CI 22-57%), but a higher 

incidence of metastasis (30% (95% CI, 15-47%) vs. 20% (95% CI, 

15-26%)). A randomized trial in an enriched population could have 

achieved 80% power with 44% less patients (313 vs. 709 patients, 

respectively), due to the differing event composition. Conclusions: Stratification 

based on competing event risk may improve the design and 

efficiency of clinical trials. These findings should be externally validated. 




Variation in health-related quality of life (HRQOL) by ECOG performance 

status (PS) and fatigue among patients with chronic lymphocytic leukemia 

(CLL). Presenting Author: Christopher Flowers, Emory University, Atlanta, 

GA 

Background: Clinicians and investigators commonly use ECOG PS and 

clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multifaceted 

construct that comprehensively looks at the pt perspective on 

disease and well-being. Because limited data exist on the relationships 

between PS, fatigue, and HRQOL for CLL pts, we examined the associations 

between these measures, and 3 validated HRQOL instruments: the 

Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, 

and Brief Fatigue Inventory (BFI). Methods: Data were collected in 

CONNECT CLL, a prospective US observational registry initiated in 2010. 

Patient demographics and clinical characteristics were provided by clinicians. 

Patient HRQOL was self-reported at enrollment using the FACT-Leu, 

EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and 

clinician-reported fatigue (yes, no). Differences in HRQOL scores were 

assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 

148 community, 10 academic, and 3 government centers. ECOG PS was 

available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, 

FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS 

severity and was worse in pts with fatigue (all p�0.0001). All FACT-Leu 

domains except social/family were worse in pts with fatigue and those with 

higher ECOG PS. Mean EQ-5D pain/discomfort, mobility, self care and 

usual activities domain scores worsened in severity as ECOG worsened and 

for pts with fatigue (all p�0.011). BFI data indicated that global fatigue, 

fatigue severity and fatigue-related interference worsened by ECOG severity 

and were associated with clinician-reported fatigue (all p�0.0001). 

Conclusions: Initial CONNECT CLL results confirm that HRQOL worsens 

with worsening ECOG PS and was worse among pts with fatigue, especially 

in physical/functioning domains, pain/discomfort, and mobility. These 

results indicate that baseline ECOG PS and physician-rated fatigue are 

rapid assessments that predict robust measures of HRQOL. Future analyses 

are planned to examine how HRQOL, ECOG PS and fatigue change over 

time with changes in treatment and CLL disease status. 


Prevalence and predictors of adherence to antiemesis prophylaxis in lung 

cancer: A population-based study. Presenting Author: Daniel Richard 

Gomez, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Nausea/vomiting is a significant toxicity in the treatment of 

lung cancer, but barriers exist to the delivery of prophylaxis. We studied 

compliance and predictors of prophylactic antiemetics with chemotherapy 

in this setting. Methods: We used a Texas state registry of clinical data 

linked with Medicare claims from 2001-2007. Our study population was 

incident lung cancers treated with platinum agents within 12 months of 

diagnosis. To define guideline-adherent care, we assessed compliance to 

the American Society of Clinical Oncology recommended prophylactic 

agents dexamethasone and a 5-HT3 antagonist. Adherence was scored as a 

binary variable and defined as administration within 24 hours of the first 

day of the first cycle of chemotherapy. We utilized a logistic regression 

model to evaluate the role of the following factors in predicting adherence: 

concurrent radiation therapy (RT), race (black vs. white), histology (small 

cell vs. non-small cell), rural location, Charlson Comorbidity Index (CCI), 

household income (by quartiles [Q]), education, and treatment year 

(binary). Results: Of 31,762 patients in the database, 5155 patients met 

the above criteria. The adherence rate to dexamethasone and 5-HT3 

antagonists increased over time, from 51.5% in 2001 to 71.6% in 2007. 

Patients treated in the years 2005-2007 were 1.739 times more likely to 

be adherent to prophylaxis than were those from 2001-2004. Variables 

that predicted adherence (adjusted odds ratio [OR], 95% confidence 

interval [CI]) were: age (OR�1.013, CI [1.001, 1.026]), treatment year 

(OR�1.756, CI [1.548, 1.991]), race (black vs. white OR�0.684, CI 

[0.548,0.853]), median income (higher vs. lower OR�1.83 [Q2 vs. Q1]; 

OR�1.296 [Q3 vs. Q1]; OR�1.496 [Q4 vs. Q1]), CCI (1� vs. 0, 

OR�0.613, CI [0.530,0.709]), and concurrent RT [yes vs. no OR�1.358, 

CI [1.197,1.541]). Conclusions: Compliance with guidelines for prophylactic 

antiemetics is suboptimal, but increasing over time. Several characteristics 

predict for improved adherence, including white race, median income, 

advanced age, and the receipt of concurrent RT. These findings highlight 

substantial economic disparities in supportive care of lung cancer in the 

state of Texas. 


Loss to follow-up of cancer patients in the poorest district of the United 

States. Presenting Author: Antranik Mangardich, Lincoln Medical and 

Mental Health Center, Bronx, NY 

Background: Loss to follow-up (LFU) of cancer patients is a serious 

dilemma, and has only been narrowly studied. Lincoln Medical and Mental 

Health Center (LMMHC) serves South Bronx (SB), the poorest district in the 

nation. The purpose of this study was to assess rates of LFU and correlate it 

with age, sex, ethnicity, race, cancer types, and stage at diagnosis. 

Methods: We collected data from 1,552 patients diagnosed with invasive 

cancer in LMMHC between 2006-2010. The data collected were age, sex, 

ethnicity, race, type of cancer, stage, LFU, treatment, and vital status. 

Results: From the 1,552 patients, roughly 25 % were LFU, with 50% 

receiving some initial form of treatment. The remaining percentages are 

shown below (Table). A higher rate of LFU was with patients younger than 

65 (OR: 1.38, 95% CI: 1.08-1.76). There was no correlation between sex 

and LFU. Non-Hispanics were more likely to be LFU compared to Hispanics 

(OR: 1.39, 95% CI: 1.07 – 1.8). Blacks were more likely to be LFU 

compared to non-Blacks (OR: 1.43, 95% CI: 1.12–1.82). There was no 

significance between LFU and stage at diagnosis. Looking at cancer 

specific data, colon cancer (C) and head and neck cancers (HN) had the 

highest percentage of LFU (30% each). There was higher LFU rate for C 

compared to breast cancer (B) (OR: 1.7, 95% CI: 1.03-2.8), prostate 

cancer (P) (OR: 1.88, 95% CI: 1.18-3.02), and lung cancer (L) (OR: 1.64 

95% CI: 0.94- 2.8). HN patients were more likely LFU compared to B (OR: 

2.4, 95% CI: 1.13-5.2), P (OR: 2.69, 95 % CI: 1.28-5.68), and L (OR: 

2.3, 95% CI: 1.05-5.19) patients. There was no significant difference 

between C and HN patients in respect to LFU. Conclusions: In the SB, LFU 

rates are related to age, ethnicity, race, and type of cancer. Younger 

patients, blacks, non-Hispanics, and those with C and HN cancers were 

most likely to be LFU, the latter likely due to the lack of a HN surgeon at 

LMMHC. We hope that with focus on race, ethnicity, and cancer-specific 

disparities in LFU rates, we will improve the retention rate of our cancer 

patients in the future. 

Continued to 

Sent to nursing 

Transferred 

LFU 

follow up 

home/hospice 

to other facility 

371 (24%) 863 (55%) 167 (11%) 151 (10%) 

No Rx Rx No Rx Rx No Rx Rx No Rx Rx 

190 (51%) 

Rx�treatment 

180 (49%) 190 (22%) 672 (78%) 105 (63%) 67 (37%) 93 (62%) 58 (38%) 


In-hospital mortality of patients admitted through the emergency department 

of a comprehensive cancer center. Presenting Author: Ahmed F. 

Elsayem, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Cancer is a common presenting condition for emergency 

departments (EDs); however, there is limited information on outcomes of 

ED cancer patients subsequently admitted to the hospital. The purpose of 

this study is to describe outcomes of patients with hematologic malignancies 

versus those with solid tumors admitted through the ED of a 

comprehensive cancer center. Methods: We queried the ED database of The 

University of Texas MD Anderson Cancer Center for calendar year 2010 and 

linked it to our institutional data warehouse, including tumor registry data. 

We classified all leukemia and related disorders, lymphoma, multiple 

myeloma, and bone marrow transplant patients as hematologic malignancies, 

and remaining cancers as solid tumors. Descriptive statistics, including 

chi-square, and t-tests were used in two-sided comparisons. All 

statistical analyses were performed using SPSS version 15. Results: 

20,732 total ED visits were made by 9,320 unique cancer patients. Of 

these, 5,364 (58%) were admitted to the hospital at least once (range 1-13 

admits). ED admissions constituted 39% of total unique patients admitted 

(N�13,753). The main admission indications for solid tumor patients were 

infectious complications (particularly pneumonia), intractable pain, or 

dehydration. For hematologic malignancies, the main indication was 

neutropenic fever. 211/1656 (13%) of liquid tumor patients were admitted 

to the Intensive Care Unit (ICU) compared to 484/3708 (13%) of solid 

tumor patients (P�NS). Of all patients admitted through the ED, 587/ 

5364 (10.9%) died during hospitalization. The hematologic hospital 

mortality rate was 225/1653 (13.6%) versus 362/3708 (9.8%) for solid 

tumors (P�0.001). Only 242/8389 (3%) of patients admitted directly 

from outpatient clinics died during the hospitalization (p�0.001). 

Conclusions: Patients admitted through the ED, particularly those with 

hematologic malignancies, have a high hospital mortality rate. ED-based 

palliative care interventions may be justified to improve quality of life and 

prevent unnecessary costly interventions and ICU admission. Further 

research should define predictors of poor outcomes in cancer patients 

admitted through the ED. 



Caring for Alaska native prostate cancer survivors in primary care: A survey 

of Alaska Tribal Health System providers. Presenting Author: Jon C. Tilburt, 


Background: Little is known about the actual constraints of doing so in the 

distinctive geographic context of Alaska. We performed a survey of primary 

care providers (PCPs) within the Alaska Tribal Health System (ATHS) to 

learn more about their attitudes and practices surrounding prostate cancer 

(PC) survivorship care. Methods: We surveyed primary care physicians, 

nurse practitioners, and physician assistants practicing in the ATHS. We 

administered surveys to assess attitudes about PSA monitoring, responsibility 

for long-term surveillance, supporting emotional health and medical 

needs, their degree of confidence in managing patients on androgen 

deprivation therapy (ADT), as well as their comfort level in managing 

common side effects of treatment. Results: Of the 221 providers surveyed, 

114 responded (52%). Most PCPs indicated a preference for annual PSA 

monitoring (69%), but several (27%) indicated monitoring every 6 months, 

and a few (4%) indicated monitoring every 24 months. Most (60%) thought 

PCPs should manage cancer surveillance, but many (40%) thought a 

specialist (urologist or medical oncologist) should perform that function. 

When asked about supporting patients’ emotional needs, PCPs indicated 

that support groups (63%) followed by survivorship clinics (16%) or on-site 

specialist visits (14%) were the most appropriate venues to address these 

concerns. Most respondents thought that medical needs of PC survivors 

could be addressed locally with appropriate specialty input (71%) or 

potentially through dedicated survivorship clinics (14%). Only 46% indicated 

being �moderately� or �very� confident managing ADT. Most PCPs 

indicated being moderately or very comfortable monitoring for recurrence 

(59%), managing erectile dysfunction (66%), addressing urinary incontinence 

(63%), and addressing emotional needs (61%). Conclusions: PCPs 

practicing in the ATHS express comfort with monitoring for PC recurrence, 

but express some concerns about the full range of issues in PC survivorship. 

Constructing cancer survivor care models in geographically dispersed and 

resource-limited contexts for Alaska Natives is an ongoing clinical and 

policy challenge. 


Financial relationships with commercial interests (COI) among abstracts at 

the ASCO Annual Meeting. Presenting Author: Angela R. Bradbury, Clinical 

Genetics, Fox Chase Cancer Center, Philadelphia, PA 

Background: ASCO has a formal policy that requires disclosure of COI with 

entities having a commercial interest in research. There are limited data 

describing the frequency and type of COI reported in cancer research and 

how these have changed over time. Methods: We reviewed author-reported 

COI for abstracts submitted for the ASCO Annual Meeting in 2006 and 

2008–2011. COI are classified as employment, stock, consultant, honoraria, 

research, expert witness, and other. Logistic regression models were 

used to evaluate the association between COI and acceptance at the annual 

meeting and change over time. Results: 37% of all abstracts reported at 

least one author with a COI. Any COI increased significantly from 33% in 

2006 to 39% in 2011 (p�0.001). Any COI and all categories of COI were 

significantly more prevalent among abstracts accepted for presentation 

compared to those accepted for publication only (Table). Among abstracts 

accepted for presentation, any COI increased from 39% in 2006 to 48% in 

2011 (p�0.001) Increases by year were statistically significant for overall 

(p�0.001), honoraria (p�0.045), and research (p�0.002) COI. 

Conclusions: Many authors submitting abstracts accepted for presentation 

at the ASCO Annual Meeting disclose COI. Reported COI have increased 

over time and are significantly more frequent among abstracts accepted for 

presentation than for publication only. These data suggest either that 

cancer research increasingly involves relationships with industry or that 

COI reporting has become more common. Policies to manage and foster 

these relationships will continue to be required and revised. 

COI among abstracts submitted for the ASCO Annual Meeting (n�21,108). 

COI 

Accepted for 

presentation 

(n�12,448) 

Publication 

only 

(n�8,660) 

OR (CI) 

in 2006 

Multiplicative 

increase in OR (CI) 

for each year 

post-2006 

Any COI 45% 25% 2.0 (1.8-2.3) * 1.06 (1.03-1.10)* 

Employment 24% 13% 2.1 (1.8-2.5)* 1.01 (0.97-1.06) 

Stock 19% 9% 2.2 (1.8-2.6)* 1.03 (0.98-1.08) 

Consultant 27% 12% 2.5 (2.1-2.9)* 1.09 (0.99-1.09) 

Honoraria 23% 10% 2.4 (2.0-2.8)* 1.05 (1.001-1.10)*** 

Research 29% 13% 2.2 (1.9-2.5)* 1.07 (1.03-1.12)** 

Expert witness 1.7% 0.5% 3.1 (1.6-5.8)* 1.0 (0.9-1.3) 

*p�0.001, **p� 0.02, ***p�0.002. 


413s 


Geographic and socioeconomic determinants of participation by elderly 

patients in surgical oncology trials. Presenting Author: John H. Stewart, 

Wake Forest School of Medicine, Winston-Salem, NC 

Background: A recent report by our group demonstrated that �0.5% of 

elderly patients with breast, prostate and lung cancer participate in surgical 

oncology trials. However, little work to date has evaluated the roles of 

regional healthcare infrastructure and socioeconomic factors on clinical 

trial participation in this cohort. Methods: The NCI Cooperative Group 

Surgical Oncology Trial (CGSOT) database was queried for patients treated 

for breast, prostate and lung cancer cancer between 2000 and 2008 

(n�13,541). Geographical Information Systems data were used to evaluate 

proximity to healthcare facilities while regional socioeconomic characteristics 

were obtained from the 2000 US Census and Area Resource file. 

Counts were used to create a proportion of respondents with the corresponding 

95% confidence interval calculated using the central limit theorem. 

Independent t-tests were used to assess differences in outcome measures 

between the two age groups. Results: We found that 4136 participants in 

the NCI CGSOT database were 65 years of age or older. Interestingly, 

92.7% of this cohort was white and 85.7% was female. Socioeconomic 

determinants of participation are shown in the table. Conclusions: The work 

presented herein suggests that elderly minority patients are less likely to 

participate in surgical oncology trials than their white counterparts. 

Furthermore, elderly participants tend to reside in less affluent areas. 

Future work will utilize interventions that improve the recruitment of elderly 

patients to these trials. 

Geographic 



Multidisciplinary assessment and reporting of fitness to drive in brain tumor 

patients: A gray matter. Presenting Author: Alexander V. Louie, London 

Regional Cancer Program, London, ON, Canada 

Background: In some jurisdictions, there is a legal requirement for physicians 

to report medically unfit drivers. Objectives of this study are to 

determine physician knowledge and attitudes on reporting legislation and 

driving assessment, and review our institution’s experience in evaluating 

fitness to drive in brain tumour patients. Methods: Physicians caring for 

brain tumour patients in South-western Ontario were identified by public 

databases and surveyed by mail. Survey questions elicited demographics, 

opinions, and factors influencing the decision to report. Patients receiving 

brain radiotherapy at our institution between January and June 2009 were 

identified and details of driving assessment were extracted. Fisher’s exact 

test and a logistic regression model were used to determine differences in 

responses between specialists and family physicians and factors influencing 

reporting. Results: Surveys (n�467) were distributed with 198 (43%) 

responses. Most (76%) felt that reporting guidelines were unclear. Neurologists 

(43%) and Family Physicians (22%) were felt to be the most 

responsible to report unfit drivers. Compared to specialists, Family Physicians 

were less likely: to be comfortable with reporting (p�0.02), to 

consider reporting (p�0.001), or discuss the implications of driving 

(p�0.001). Perceived barriers in assessing fitness to drive included: lack 

of tools to assess (57%) and the impact on the patient-physician relationship 

(34%). 158 patients were retrospectively reviewed. Forty-eight patients 

(30%) were reported to the provincial licensing authority and 64 

(41%) were advised not to drive. 53 patients experienced seizures, of 

which 36 (68%) had a documented discussion on driving. Only 30 (56%) 

of these patients were reported to the licensing authority despite legal 

requirements. Age, primary disease, previous neurosurgery and seizures 

were predictive of reporting (p�0.05). On logistic regression modeling, 

seizures (OR 12.4) and primary CNS disease (OR 15.5) remained predictive 

of reporting. Conclusions: Despite guidelines and laws, the assessment 

of fitness to drive in patients with brain tumours is not routinely conducted 

or documented in a multidisciplinary setting. 


Predictors of retention in a cervical cancer survivorship study. Presenting 

Author: Lari B. Wenzel, University of California, Irvine, Irvine, CA 

Background: Women with cervical cancer experience numerous quality of 

life (QOL) disruptions. A completed pilot study indicated that QOL and key 

biomarkers could be improved with psychosocial telephone counseling 

(PTC). A confirmatory trial has recently completed accrual.The purpose of 

this study is to identify predictors of retention in this large biobehavioral 

trial, and examine retention differences between the pilot and confirmatory 

trial. Methods: Women with stage I – III cervical cancer diagnosed 9–30 

months earlier were randomized to either PTC or usual care. PROs and 

biological specimens were collected prior to randomization (N�204), and 

3 (T2) and 9 months post baseline. Sociodemographic, clinical and QOL 

variables were evaluated from baseline to T2 to identify predictors of study 

retention. Multiple measures, including the PROMIS Depression and 

Anxiety scales were entered into a multivariate stepwise logistic regression 

model to predict study retention. Results: In the multivariate model, being 

randomized to counseling (OR�4.4, 95% CI: 1.5-12.6), having clinically 

significant depression, defined as �1 SD above the 50th percentile 

(OR�4.2, 95% CI:1.7-10.5) and being single (OR�3.4, 95% CI: 1.3-9.2) 

were the most significant predictors of drop-out in the study overall. Among 

those in the counseling arm, depression is the strongest predictor of 

dropout, with a five times higher dropout rate (OR�5.2, 95% CI:1.9-15.6) 

than those with low to moderate levels of depression, or no depression. 

However, retention rates improved substantially overall from the pilot study 

(72%) to the confirmatory study (84%), in both study arms, and retention 

increased among Latinas from 60% in the pilot study to 83% in the current 

study, and from 52% to 81% among those with less than a high school 

education. Conclusions: Results from this analysis of predictors of retention 

indicate that enhanced attention to sociocultural disparities can improve 

study retention. Attending to baseline clinical depression may be a further 

consideration. 


Sociodemographic and patient disparities in use of first-line chemotherapy 

(CT) in older adult patients (pts) with advanced non-small cell lung cancer 

(AdvNSCLC): Analysis of Surveillance, Epidemiology, and End Results 

(SEER)-Medicare data. Presenting Author: Josephine Feliciano, University 

of Maryland Greenebaum Cancer Center, Baltimore, MD 

Background: Clinical trials have demonstrated that CT improves survival 

and quality of life in pts with AdvNSCLC. Our prior studies suggest that only 

26% of older pts diagnosed with AdvNSCLC received CT through 2002. In 

this study, we examined more recent patterns, and the effect of sociodemographics, 

race, and age on receipt of CT in older pts with AdvNSCLC. 

Methods: Medicare pts diagnosed with AdvNSCLC from 2001-2005 were 

identified in SEER registries. Medicare enrollment data provided demographic 

information (age, race, sex, marital status), augmented with census 

tract level data on median household income. Comorbid conditions at 

baseline were identified by ICD9-CM diagnoses on claims. Receipt of 1st 

line CT was identified based on agent-specific procedure codes in claims. 

Logistic regression examined predictors of 1st line CT. Results: Of 31,341 

pts with Adv NSCLC, 34% received 1st line CT. As reflected in the table, 

poor predicted PS (PredPS), multiple medical comorbidities, and black 

race were associated with lower likelihood of CT receipt. Being female, 

married, having higher income, and being diagnosed at a later year were 

associated with a higher likelihood of receiving CT. Conclusions: Even when 

controlling for factors such as PS, our results suggest the presence of age, 

race, and socio-economic disparities in the receipt of 1st line CT for older 

patients with AdvNSCLC. 

Multivariate association of pt characteristics with receipt of 1st line CT. 

Covariate Odds ratio 95% CI 

Dx age (yrs) 

-- 

-- 

70-74 

0.81 

0.76, 0.88 

75-79 

0.57 

0.53, 0.61 

80-84 

0.33 

0.30, 0.35 

>85 

0.13 

0.11, 0.15 

Race 

-- 

-- 

Non-Hispanic Black 

0.83 

0.76, 0.92 

Prior year Medicaid or MSP 0.86 0.79, 0.94 

Female 1.09 1.03, 1.15 

Married 1.54 1.46, 1.63 

Dx Yr 

-- 

-- 

2002 

1.12 

1.04, 1.22 

2003 

1.25 

1.15, 1.35 

2004 

1.27 

1.17, 1.38 

2005 

1.32 

1.22, 1.43 


Patient satisfaction with participation in phase II/III NCCTG clinical trials: 

Was it worth it? (N0392). Presenting Author: Cynthia Chauhan, North 

Central Cancer Treatment Group, Wichita, KS 

Background: Patient (pt) trial experience may give insight to quality of life 

(QOL) factors affecting accrual, retention and outcome. While pts are vital 

to clinical trial success, we know little about their post-trial opinions. This 

trial examined pt opinion of their trial and treatment decision making 

(TDM). Methods: Pts enrolled on designated North Central Cancer Treatment 

Group (NCCTG) phase II or III treatment trials completed the TDM 

Control Preferences Scale at baseline and the Was It Worth It (WIWI) 

satisfaction assessment at the ends of cycle 1 and active protocol 

treatment. The primary endpoint was the proportion of pts reporting 

worthwhile participation. Fisher Exact tests compared pt opinion across 

subgroups. Results: As of 01/15/2012, 264 pts were enrolled on 25 

protocols and treated at 79 sites. 86% of pts were in phase II studies and 

89% had stage IV disease. At the end of cycle 1, pts felt the trial was 

worthwhile (74%), would do it again (85%), and would recommend it to 

others (82%). 85% of pts reported undiminished QOL and only 7% rated 

the trial worse than expected. End of treatment responses were similar. 

Satisfaction rates varied by tumor site (p�0.04). 11% of pts having tumor 

response rated the trial as not worthwhile, and 66% of pts with progressive 

disease rated it worthwhile (see table). Pts with concordant preferred and 

actual TDM roles rated participation higher than pts with discordant TDM 

roles (see table). Conclusions: Most pts endorsed their clinical trial 

experience. Contrary to popular beliefs, treatment outcome did not have an 

overwhelming impact on pt satisfaction, and was just one of many factors 

such as TDM role discordance. Assessing pt satisfaction will inform future 

study design that can potentially improve pt accrual and retention. 

Answered yes to. .. 

Response by end of Tx WIWI scores CPS by 1-month WIWI scores 

CR/PR PD SD P value 

Concordant 

(N�230) 

Discordant 

(N�28) P value 

Worth it? 89% 66% 82% 0.01 75% 64% 0.13 

Do again? 92% 93% 81% 0.07 87% 68% 0.01 

QOL maintained? 83% 71% 84% 0.01 85% 75% 0.38 

Study expectations 

met or better? 

92% 81% 85% �0.01 94% 86% 0.11 

Recommend? 91% 90% 80% 0.15 83% 68% 0.04 



Relationship of MRI tests and referral of malignant adnexal masses to 

gynecologic oncologists for surgery. Presenting Author: Rachel Kupets, 

Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, 

Canada 

Background: To evaluate the patterns of radiologic imaging by family 

physicians and gynecologists in the work up of women found to have an 

adnexal mass on pelvic ultrasound. To evaluate whether advanced imaging 

tests are associated with improved referral of high risk adnexal masses to 

gynecologic oncologists. Methods: Centralized provincial databases of 

healthcare utilization were used to identify women aged 45 and older who 

received a pelvic ultrasound between 2006-2008. Subsequent imaging 

tests ordered by physician specialty were identified. Of those women who 

proceeded to laparotomy, logistic regression was performed to determine 

which imaging tests were associated with referral of high risk adnexal 

tumors to a gynecologic oncologist. Results: 193, 261 women had a pelvic 

ultrasound; 19, 949 (10.3%) had a laparotomy. 2223 and 627 women 

were categorized with benign and malignant adnexal masses respectively. 

Up to 12% of women had a pelvic MRI and 58% of women had a CT scan 

after a pelvic ultrasound.Family physicians referred 58% and gynecologists 

referred 47% of high risk ovarian masses to a gynecologic oncologist 

respectively after imaging.Gynecologic Oncologists operated on only 55% 

of women with malignant adnexal masses. On multivariate analysis factors 

significant for surgery by a gynecologic oncologist include a preoperative CT 

Scan OR 3.58 (p�.001) and CT Scan and MRI OR 7.78 (p�.001). 

Preoperative MRI alone had an OR of 1.86 (p�0.09) and was not 

significant. Mean time to surgery significantly increased when further 

imaging tests were performed after a pelvic ultrasound (100 days), CT (131 

days), MRI (170 days), CT and MRI (179 days),P 0.002. Conclusions: The 

addition of a pelvic MRI to a pelvic ultrasound does not improve the referral 

of high risk adnexal masses to a gynecologic oncologist. A consensus on 

appropriate imaging and triage is needed when an adnexal mass is 

identified on ultrasound. 


Relationship between whole-body tumor burden and quality of life in 

patients with neurofibromatosis. Presenting Author: Scott Randall Plotkin, 

Massachusetts General Hospital Cancer Center, Boston, MA 

Background: NF1, NF2, and schwannomatosis are a group of related 

genetic disorders in which affected individuals share the predisposition to 

develop multiple nerve sheath tumors. While previous studies have investigated 

the relationship between cutaneous tumor burden and quality of life, 

the relation between internal tumors and quality of life is unknown. 

Methods: As part of an IRB-approved research study, we performed 

whole-body MRI and administered the short form (SF)-36 to 245 adult 

subjects with NF. The number and location of internal nerve sheath tumors 

in each patient was identified by a board-certified radiologist and tumor 

volume was calculated using semi-automated volumetric analysis. One 

sample t-tests were used to compare subjects’ SF-36 scores to general 

population means. Independent linear regression analyses controlling for 

age and gender effects were used to relate whole-body tumor count, 

volume, and distribution (via Gini coefficient) to each domain of the SF-36. 

Results: 245 patients (142 with NF1, 53 with NF2, 50 with schwannomatosis) 

completed the study. On the SF-36, subjects with NF1 showed 

reduced quality of life in the physical role, emotional role, and mental 

health domains compared to the normal population (p�0.05). Subjects 

with NF2 showed reductions in the physical functioning, physical role, 

general health, and social functioning domains while subjects with schwannomatosis 

showed reductions in the physical role and bodily pain domains 

(p�0.05). In linear regression analysis, increased tumor number, increased 

tumor volume, and decreased Gini coefficient were correlated with 

decreased physical functioning in patients with NF2 (p�0.01). There was 

also a trend for increasing tumor volume to be correlated with decreased 

physical role and increased bodily pain in patients with NF1 and with 

increased bodily pain in patients with schwannomatosis (p�0.10). 

Conclusions: In our multi-institutional cohort, patients with all forms of 

neurofibromatosis show selected deficits in quality of life. Internal tumor 

burden does not correlate with these deficits, with the exception of physical 

function in NF2 patients. 


415s 


Patient-reported toxicity after treatment for cancers of the head and neck. 

Presenting Author: Christine E. Hill-Kayser, Hospital of the University of 


Background: Patients with cancers of the head and neck (HNC) may be at 

risk for significant late effects after treatment. Quality of life may be altered 

significantly as a result. This Internet based study evaluates patient 

perceptions of toxicity after treatment for HNC. Methods: Patient-reported 

data were gathered via a convenience sample frame from HNC survivors 

voluntarily utilizing a publically available, free, Internet-based tool for 

creation of survivorship care plans. Available at www.livestrongcareplan.com 

and through the OncoLinkwebsite, the tool allows survivors to enter data 

regarding diagnosis, demographics, and treatments, and provides customized 

guidelines for future care. During use of the tool, HNC survivors are 

queried regarding late effects associated with specific treatments. All data 

have been maintained with IRB approval. Results: Of 3866 survivors using 

this tool between 4/2010 and 10/2011, 140 (4%) had undergone primary 

treatment for HNC. Median diagnosis age was 52y and median current age 

56y. When queried regarding treatment received, 88% reported having 

undergone radiation, 73% surgery, and 67% chemotherapy. Many patientreported 

late effects were associated with local tumor control, and included 

difficulty swallowing/speaking (83%), decreased saliva production (88%), 

dental problems (49%), thyroid problems (33%), decreased neck mobility 

(60%), eye and vision deficits (9%), and tinnitus (40%). In addition, 53% 

noted concerns regarding cognitive function. Users of the tool reported that 

they would share it with their healthcare team in 55% of cases. The most 

common reasons for not sharing it were “I did not think they would care,” 

and “ I did not want to upset or anger them.” Conclusions: Survivors using 

this tool anonymously and voluntarily report significant toxicity after 

treatment for HNC. Not all survivors appear comfortable discussing these 

issues with healthcare providers, despite major potential impact on quality 

of life. The data reported here may be of significant impact in future study 

of outcomes after HNC, as well as patient counseling and survivor care. 


Predictive factors on the receipt and completion of adjuvant chemotherapy 

in a mixed sociodemographic cohort of patients. Presenting Author: Blase 

N. Polite, The University of Chicago , Chicago, IL 

Background: African Americans are more likely to die from breast, colon and 

lung cancer compared to whites. They are also less likely to receive and 

complete recommended therapy. The reasons for this are unknown. 

Methods: Breast, colon, and lung cancer patients eligible for adjuvant 

chemotherapy (stage IB-III breast, stage IIB-III colon, and Stage IB, II 

lung) and who received surgery at 2 urban medical centers, were approached 

between 2008 and 2010 and completed a self-administered 

survey focusing on sociodemographic factors, including social support, 

anxiety, depression, co-morbidities, trust and God Locus of Control (e.g., 

Whatever happens to my cancer is God’s will). These variables were related 

to receipt and completion of chemotherapy. 191 patients were approached, 

161 consented and 30 refused (16%); out of the 161, 23 were 

deemed ineligible because of previous cancers, non-curative stage or 

receipt of chemotherapy in the neoadjuvant setting. Results: Final sample 

consisted of 138 pts. Median age: 54; sex:81% F; Race/Ethnicity:47% AA, 

38% white, 9% Hispanic, 6% Asian/PI; Cancer Type: 73% Breast, 21% 

Colon, 6% Lung. Compared to whites, AA were more likely to have 

incomes�20K (35% vs. 10%, p�.0002), have any comorbidities (80% vs. 

57%, p�0.006), and have high levels of God Locus of Control (56% vs 

27%, p�0.003). There were no differences by race in chemotherapy 

receipt (89% vs. 88%) or relative dose intensity (RDI) of chemo��85% 

(58% vs. 67%). No factor in our model predicted chemotherapy receipt or 

RDI at a significant level. Pts with high God Locus of Control were 

somewhat more likely to start chemotherapy (OR 1.7, p�0.25) but were 

less likely to complete therapy (OR 0.55, p�0.19). The magnitude of these 

relationships held after controlling for age, race, comorbidities, cancer 

type, functional status, and social support. Conclusions: In a mixed 

sociodemographic cohort of patients, receipt and completion of adjuvant 

chemotherapy was similar by measured sociodemographic variables. Only 

high God Locus of Control was suggestive of being less likely to complete 

chemotherapy. Further attention and research on the role of religious 

beliefs in the cancer decision making process is warranted. 


416s Leukemia, Myelodysplasia, and Transplantation 

6500^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM 

Effect of anti-CD19 BiTE blinatumomab on complete remission rate and 

overall survival in adult patients with relapsed/refractory B-precursor ALL. 

Presenting Author: Max Topp, Department of Internal Medicine II, Division 

of Hematology and Medical Oncology, Wuerzburg, Germany 

Background: Blinatumomab is a bispecific T-cell engaging (BiTE) antibody 

that directs cytotoxic T-cells to CD19 expressing target cells. Methods: In 

adult patients with relapsed/refractory B-precursor ALL, a phase II dose 

ranging trial is being conducted to evaluate efficacy and safety of 

blinatumomab. The primary endpoint is the rate of hematological complete 

remission (CR) or CR with partial hematological recovery (CRh*) within 2 

cycles of blinatumomab treatment. Blinatumomab is administered by 

continuous intravenous infusion for 28-days followed by a 14-day treatmentfree 

interval. Responding patients can receive 3 additional cycles of 

treatment or proceed to bone marrow transplantation. Three dose levels 

were explored as shown in the table. Results: In total 36 patients have been 

enrolled, 25 are currently evaluable. Seventeen out of 25 treated patients 

(68%) reached a hematological CR/CRh* and a minimal residual disease 

(MRD) response (MRD level �10 -4 ) within the first 2 cycles. Five out of 17 

responders (29%) showed a CRh* due to partial recovery of platelets. For 

the first 18 patients, response duration is 7.1 months and the median 

follow-up time for overall survival (OS) is 9.7 months (median not reached). 

Six cases of relapses have been recorded of which 3 were CD19� , and 3 

CD19- . As final dose 5 �g/m²/day in week 1 and 15 �g/m²/day for the 

remaining treatment (cohort 2a and 3) was selected. In these cohorts 

(n�12), the most common treatment emergent adverse events (TEAEs, all 

grade 1-2) were pyrexia (67%), headache (33%) and tremor (33%). TEAEs 

of grade �3 (7 in 5 patients, no grade 4), irrespective of relationship, were 

infections, confusion, epilepsy, hypertension and thrombocytopenia. 

Conclusions: The final dose was well-tolerated and produced an exceptionally 

high complete remission rate. A global phase 2 study to confirm these 

data is underway. 

Summary of dose cohorts and outcomes (Oct 2011). 

Cohort 

Patients 

treated 

Week 1, cycle 1 

(�g/m 2 /day) 

Week 2, 

cycle 1 

(�g/m 2 /day) 

Weeks 3-4, 

cycle 1 and 

subsequent cycles 

(�g/m2 /day) CR/CRh* 

1 7 15 15 15 5 

2a (final dose) 5 5 15 15 4 

2b 6 5 15 30 3 

3 (final dose) 7 5 15 15 5 

Total 25 17 


A phase II trial of azacitidine (NSC-102816) and gemtuzumab ozogamicin 

(NSC-720568) as induction and post-remission therapy in patients of age 

60 and older with previously untreated non-M3 acute myeloid leukemia: 

SWOG S0703 protocol—Report on the good-risk patients. Presenting 

Author: Sucha Nand, Loyola University Medical Center, Maywood, IL 

Background: In pts with AML, response rates to standard chemotherapy 

decrease and early death rates increase with age. Whereas pts � 56 yrs of 

age have a complete remission (CR) rate of 65% and 30 day mortality risk 

of �3%, the respective figures are 33% and 31% in pts � 75 yrs. This trial 

was designed to improve safety and efficacy by using agents with low 

toxicity, different mechanisms of action and possible synergy. The treatment 

could be given in the outpatient setting. Methods: Newly diagnosed 

pts with non-M3 AML, 60 yrs or older, were treated as follows: Induction: 

Hydroxyurea 1500 mg b.i.d till WBC �10,000/mcL, followed by azacitidine 

75 mg/m2/day s/cu or iv days 1-7, gemtuzumab ozogamicin (GO) 

3mg/m2 on D8. Induction treatment was repeated for residual disease on 

D14. Pts achieving CR received a consolidation treatment identical to the 

induction treatment. This was followed by 4 cycles of azacitidine 75/m2/ 

day, D1-7, given q 4 weeks. Subsequent therapy was optional. Promoter 

and global methylation studies were performed at defined time points. 

Results: Pts were stratified into good risk (age 60-69 or Zubrod 0-1) and 

poor risk (age �70 and Zubrod 2 or 3) groups. The results presented here 

are from the good risk cohort. Eighty-three pts were entered of whom 79 are 

evaluable. Median age was 71 yrs (60-88) and 49 were males. Thirty-five 

achieved CR/CRi (44%: 95% CI 33%-56%). Median overall survival was 

11 months and median relapse-free survival with patients achieving a 

CR/CRi was 8 months. Six patients (8%), 3 with disease progression, died 

within 30 days of registration. The main non-hematologic toxicity was 

neutropenic fever (Grade 3 or higher), seen in 27 patients. Conclusions: The 

combination of hydroxyurea, azacitidine and GO is associated with a low 

induction mortality, can be given in the outpatient setting and produces 

results which compare favorably with standard chemotherapy regimens in 

elderly patients with AML. Our results are sufficiently encouraging to 

warrant further studies of this approach. Clinical Trials.govIdentifier: 

NCT00658814. 


Inotuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to 

calecheamicin, given weekly, for refractory-relapse acute lymphocytic 

leukemia (R-R ALL). Presenting Author: Elias Jabbour, University of Texas 


Background: Patients (pts) with R-R ALL have a poor prognosis. CD22 is 

highly expressed in ALL. We have previously reported on 49 pts with R-R 

ALL treated with IO at the dose of 1.8 mg/m2 every 3-4 weeks; the overall 

response rate was 57%. From preclinical studies, lower dose more frequent 

exposure schedules to IO may offer better anti-ALL activity. Methods: Pts 

with R-R ALL received IO 0.8 mg/m2 on Day 1, 0.5 mg/m2 on Day 8, and 

0.5 mg/m2 on Day 15. The total dose per course remained the same 1.8 

mg/m2. Courses were given every 3-4 weeks. Early stopping rules were 

implemented for an overall response rate � 40%. Results: 20 pts were 

treated so far. Median age was 57 yrs (range 22–84). Cytogenetics were: 

Ph� in 7 (35%), t(4:11) in 2 (10%) , diploid in 3 (15%), and other in 8 

(40%). CD22 was expressed in � 50% blasts in all pts and in � 90% in 14 

(70%). Median number of courses so far was 2 (1–4). 9 (45%) pts received 

IO as salvage 1 (S1), 5 (25%) as salvage 2 (S2), 6 (30%) as salvage 3 (S3). 

one pt had allo SCT before IO. Median follow-up is 22 weeks (range, 7-43). 

Overall, 2/20 pts (10%) achieved CR, 6 had CRp (30%), 2 had marrow CR 

(10%), 8 were resistant, 2 died within 4 wks. Overall, CR�CRp�mCR (OR) 

was 50%: S1 6/9 (67%); S2 2/5 (40%); S3 2/6 (33%). Of the 10 

responders, 7 pts (70%) became MRD negative. There were no clear 

correlations between OR and pts/ALL characteristics or with CD22 expression 

vs. � 90%. In 16 pts with evaluable pharmacokinetics studies, the 

median end of the infusion levels of IO were 117 ng/ml and 77 ng/ml in 

responders and non-responders, respectively. Median survival was 7� 

months. Median OR duration was 5� months. Median survival in 10 

responders has not been reached. Liver function abnormalities (LFA) were 

noted as IO related in 7 (35%) pts, severe and reversible in 2 (10%). 4 pts 

were able to proceed to allo SCT (1 in CR, 3 in CRp) after a median of 4 

weeks from the last infusion of IO; No cases of veno-occlusive disease were 

observed. Conclusions: IO given weekly is active in R-R ALL with an OR of 

50%. LFAs occur and are reversible. This study of IO weekly schedule is 

ongoing. IO and chemotherapy combinations are being pursued. 


PACE: A pivotal phase II trial of ponatinib in patients with CML and 

Ph�ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I 

mutation. Presenting Author: Jorge E. Cortes, University of Texas M. D. 


Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active 

against the native enzyme and all tested resistant mutants, including the 

uniformly resistant T315I mutation. Methods: The PACE (Ponatinib Ph�ALL 

and CML Evaluation) trial started Sept 2010. Pts with refractory CML (CP, 

AP or BP) or Ph�ALL resistant or intolerant (R/I) to dasatinib or nilotinib or 

with T315I received 45 mg ponatinib once daily. The trial is ongoing; 

enrollment completed Sept 2011. Data as of 17 Jan 2012 are reported. 

Results: 449 pts were enrolled, 5 of whom were ineligible (post-imatinib, 

non-T315I) but treated. Median age was 59 (18-94) yrs; 53% male. 

Diagnoses were: 271 CP-CML (R/I�207; T315I�64); 79 AP-CML (R/ 

I�60; T315I�19); 94 BP/ALL (R/I�48; T315I�46). Median time from 

diagnosis to ponatinib was 6 yrs. Prior TKIs included imatinib (96%), 

dasatinib (85%), nilotinib (66%), bosutinib (7%); 94% failed �2 prior 

TKIs, 59% failed �3 prior TKIs. 83% had a history of resistance to 

dasatinib or nilotinib; 12% were purely intolerant. In CP, best response to 

most recent dasatinib or nilotinib was MCyR 25%. Frequent mutations 

confirmed at entry: 29% T315I, 8% F317L, 4% E255K, 4 % F359V, 3% 

G250E. Median follow-up was 6.6 months. Response rates are presented 

in the table. Overall, 64% remained on therapy (77% CP). Most frequent 

reasons for discontinuation were progression (12%) and AE (10%). Most 

common drug-related AEs were thrombocytopenia (33%), rash (33%), dry 

skin (26%). Conclusions: Ponatinib has substantial activity in heavily 

pretreated pts and those with refractory T315I. Response rates continue to 

improve with longer follow-up. Multivariate analyses of predictors of 

outcome will be presented. 

n Response to ponatinib / N evaluable (%) 

Overall R/I T315I 

CP-CML 

MCyR* 126/258 (49) 88/197 (45) 38/61 (62) 

CCyR 105/258 (41) 70/197 (36) 35/61 (57) 

MMR 68/265 (26) 40/205 (20) 28/60 (47) 

AP-CML 

MHR* 38/57 (67) 31/43 (72) 7/14 (50) 

MCyR 27/72 (38) 18/55 (33) 9/17 (53) 

CCyR 12/72 (17) 8/55 (15) 4/17 (24) 

BP-CML/Ph�ALL 

MHR* 33/89 (37) 17/46 (37) 16/43 (37) 

MCyR 30/82 (37) 14/41 (34) 16/41 (39) 

CCyR 23/82 (28) 11/41 (27) 12/41 (29) 

*Primary endpoints: MCyR in CP; MHR in AP, BP/Ph�ALL (baseline MHR excluded). 



Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia 

in chronic phase (CML-CP): DASISION 3-year follow-up. Presenting 

Author: Andreas Hochhaus, Universitätsklinikum Jena, Jena, Germany 

Background: In the phase 3 DASISION trial of dasatinib v IM in patients 

(pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates 

of complete cytogenetic response (CCyR) and major molecular response 

(MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed 

CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P�0.001, 

meeting the primary endpoint. Methods: Pts were randomized to receive 

dasatinib 100 mg once daily (QD; n�259) or IM 400 mg QD (n�260). 

Results: Minimum 24-month follow-up (median 26.6 months) is reported 

here. 24-month molecular response rates were higher for dasatinib v IM: 

MMR (BCR-ABL �0.1%) 64% v 46%, P�0.0001; MR4 (BCR-ABL 

�0.01%) 29% v 19%, P�0.0053; MR4.5 (BCR-ABL �0.0032%) 17% v 

8%, P�0.0032. MMR rates were higher for dasatinib in all Hasford risk 

groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of 

pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had 

maintained their MMR at 24 months, respectively. Pts receiving dasatinib v 

IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 

15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts 

receiving dasatinib (n�9; 3.5%) transformed to accelerated/blast phase v 

IM (n�15; 5.8%) on study or during follow-up after discontinuation. 

24-month overall and progression-free survival were similar for dasatinib v 

IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few 

additional adverse events (AEs) were reported between 12 and 24 months 

in both arms, with grade 3/4 nonhematologic AE rates �1%. In each arm, 

10 pts had a BCR-ABL mutation detected at time of discontinuation. For 

dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs 

(7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v 

�1%), death (2% v �1%), and other (4% v 8%). Few pts discontinued 

between 12 and 24 months for dasatinib (n�19; 7%) and IM (n�16; 6%). 

Conclusions: Updated data with minimum 36-month follow-up will be 

presented, including mutation analyses in pts who discontinued, progressed, 

or had suboptimal response. Pts receiving dasatinib had a lower 

transformation rate and higher molecular responses v pts receiving IM, 

supporting the use of dasatinib in newly diagnosed CML-CP. 


Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant 

chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. 

Presenting Author: Neil P. Shah, University of California, San Francisco, 


Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 

1st- and 2nd-line therapy for CML pts with newly diagnosed disease or 

resistance/intolerance to imatinib. This ongoing study in pts with imatinibresistant/-intolerant 

CML provides the longest follow-up of a secondgeneration 

BCR-ABL inhibitor. Methods: Study design has been described 

(Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML 

(N�670) were randomized to dasatinib 100 mg once daily (QD), 50 mg 

twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are 

reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 

pts (74%) remain on QD dosing, 85 of whom (56%) are on �100 mg QD 

dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) 

originally randomized to BID dosing having switched to QD dosing. For pts 

randomized to the 100 mg QD arm (n�167), progression-free survival 

(PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate 

of transformation to advanced disease. In exploratory analyses, 42% and 

60% of pts had BCR-ABL levels �10% (International Scale) at 1 and 3 

months (mos), respectively. In a landmark analysis, BCR-ABL �10% at 1 

or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, 

nonhematologic adverse events (AEs; all grades) generally first occurred in 

�24 mos. Cumulative rates of AEs in the 100 mg QD arm were headache 

(33%), diarrhea (28%), fatigue (26%), and pleural effusion (24%). For 

dasatinib 100 mg QD, cytopenias (grades 3/4) generally first occurred in 

�12 mos. The most common hematologic AEs (grades 3/4) in the 100 mg 

QD arm were neutropenia (36%) and thrombocytopenia (24%). AEs were 

managed by dose/schedule modifications. Conclusions: Five-yr follow-up of 

pts who switched to dasatinib 100 mg QD after imatinib-resistance/ 

intolerance shows high rates of PFS, and OS with an overall low rate of 

transformation. Exploratory analyses suggest that achievement of a fast and 

deep response (�10% BCR-ABL) at 1 or 3 mos after initiation of dasatinib 

100 mg QD may be associated with a higher PFS. Dasatinib 100 mg QD 

was generally well tolerated over 5 yrs. Six-yr data will be presented. 



Switch to nilotinib versus continued imatinib in patients (pts) with chronic 

myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL 

after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up. 

Presenting Author: Jeffrey Howard Lipton, Princess Margaret Hospital, 


Background: Nilotinib induced significantly faster and deeper molecular 

responses vs imatinib in the ENESTnd trial. Achieving these deeper 

molecular responses may increase patient eligibility for future TKI discontinuation 

studies. Methods: CML-CP pts (N � 207) who achieved a 

complete cytogenetic response but were still BCR-ABL positive by RQ-PCR 

after � 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg 

BID (n � 104) or to continue their imatinib dose (400 or 600 mg QD [n � 

103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL 

by RQ-PCR with a sample sensitivity of � 4.5 logs in 2 consecutive 

samples). Other endpoints included molecular responses (MMR � 0.1% IS , 

MR4 � 0.01% IS , and MR4.5 � 0.0032% IS ) and BCR-ABL ratio over time. 

Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib 

by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL 

in at least 1 sample) by 12 mo was significantly higher on nilotinib vs 

imatinib (23.1% vs 10.7%; P � .02). Rates of MMR, MR4 ,MR4.5 , and 

CMR were also superior in pts switched to nilotinib, and these pts had 

significantly shorter times to achieve these responses. Imatinib-treated pts 

had minimal evidence of improvement in molecular response vs a median 

0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 

12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. 

The nilotinib safety profile was consistent with prior studies. Both drugs 

were well tolerated. Conclusions: Twice as many pts achieved deeper 

molecular responses after switching to nilotinib vs staying on imatinib. 

Nilotinib 

400 mg BID 

(n � 104) 

Molecular response by 12 mo (ITT population), % 

Confirmed CMR 12.5 

P � .108* 

CMR 23.1 

P � .02* 

Molecular response by 12 mo (in pts without the response at baseline), % 

MMR n � 24 

75.0 

MR 

P � .006** 

4 n � 74 

48.6 

MR 

P � .006** 

4.5 n � 94 

33.0 

P � .008** 

CMR 

*Stratified Cochran-Mantel-Haenszel test. **Stratified log-rank test. 

n � 101 

20.8 

P � .03** 

417s 

Imatinib 

400 or 600 mg QD 

(n � 103) 

5.8 

10.7 

n � 28 

35.7 

n � 78 

25.6 

n � 91 

16.5 

n � 100 

10.0 


The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatmentnaive 

(TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim 

results of a phase Ib/II study. Presenting Author: John C. Byrd, The Ohio 

State University Comprehensive Cancer Center and Arthur G. James Cancer 

Hospital and Solove Research Institute, Columbus, OH 

Background: Fludarabine based therapy, while effective, carries significant 

risk of morbidity and mortality in the elderly pts. As such, older CLL pts 

represent a high priority for new therapeutic approaches. PCI-32765 (P) an 

oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, 

migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses 

of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. 

Mature follow-up of the TN pts is reported. Methods: Pts �65 yrs old with 

active CLL requiring Tx by IWCLL guidelines were treated with oral P at 

doses of 420 mg or 840 mg administered daily for 28-day cycles until 

disease progression (PD). Response was evaluated according to 2008 

IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts 

(840 mg). The 840 mg cohort was terminated after comparable activity and 

safety between doses was shown in R/R pts. Median age 71 yrs (range 

65-84) with 74% of pts �70 yrs. 19/31 (61%) had baseline cytopenias 

(Hgb � 11g/dl or plts �100,000). Unmutated IgVH was present in 43% of 

pts. The majority of AEs have been Gr��2 in severity, most commonly 

diarrhea, nausea, and fatigue. Gr �3 non-heme AEs potentially related to P 

in 19% of pts. 10% of pts experienced Gr �3 infections or cytopenias. With 

a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a 

response by IWCLL criteria with 65% partial responses (PR) and 8% 

complete remissions with no morphologic evidence of CLL on marrow. An 

additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. 

Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle 

assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of 

high risk factors. 84% of pts remain on study, reasons for discontinuation 

� AE (3), investigator decision (1) and PD (1). There have been no deaths. 

Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: 

PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The 

high ORR, including marrow clearance and very low PD rate with the single 

agent suggests that P warrants further study as a first-line treatment 

approach in elderly pts. 




A phase Ib/II study evaluating activity and tolerability of BTK inhibitor 

PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/ 

small lymphocytic lymphoma (CLL/SLL) and related diseases. Presenting 

Author: Samantha Mary Jaglowski, The Ohio State University, Columbus, 

OH 

Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is 

critical for B-cell receptor (BCR) signaling in normal and malignant B 

lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor, 

antagonizes BCR signaling in CLL cells and abrogates protective 

features of the microenvironment. P is highly active as a single agent in 

CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent 

experience by combining P with ofatumumab (O), an anti-CD20 monoclonal 

antibody. We present initial safety and efficacy data from cohort 1. 

Methods: Pts with relapsed/refractory (R/R) CLL/SLL following �2 prior 

therapies (Tx), including a purine-nucleoside analog (PA), are treated with 

420 mg P daily, in 28-day cycles, until disease progression. O is added at a 

dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15, 

and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8. 

Results: As of November 2011, 27 patients with either CLL/SLL/PLL 

(n�24) or Richter’s transformation (RT, n�3) have been enrolled and have 

received at least 6 cycles of treatment. The median age is 66 (range 

51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range 

2-10), 15 pts had bulky disease (� 5 cm); 11 pts were PA refractory. 

Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9 

pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia 

have been observed. The majority of adverse events (AE) were G1/2. 

G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia 

(7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6 

cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range 

5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1 

CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions: 

PCI-32765 combined with ofatumumab is well tolerated and highly active 

(100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of 

response, low relapse rate, and favorable safety profile make this combination 

worthy of further study. Cohorts evaluating other Tx sequences are 

currently underway. 


4:30 PM-5:30 PM 

The prognostic significance of early molecular and cytogenetic response for 

long-term progression-free and overall survival in imatinib-treated chronic 

myeloid leukemia (CML). Presenting Author: Rudiger Hehlmann, Medizinische 

Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany 

Background: In the face of competing first line treatment options for CML 

early prediction of prognosis on imatinib is desirable to assure favorable 

survival or otherwise consider the use of an alternative therapy. We sought 

to evaluate the prognostic impact of early response landmarks. Methods: A 

total of 1,303 newly diagnosed imatinib-treated patients (pts) from the 

randomized CML Study IV were investigated to correlate molecular and 

cytogenetic response at 3 and 6 months with progression-free and overall 

survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The 

BCR-ABL expression was determined by quantitative RT-PCR and standardized 

according to the international scale (BCR-ABLIS ). The proportion of 

Philadelphia-chromosome positive metaphases (Ph�) was determined by 

conventional metaphase analysis. To confirm the prognostic significance of 

early molecular response, an independent validation sample of 174 pts 

treated with imatinib within the IRIS trial was analyzed. Results: The 

persistence of �10% BCR-ABLIS at 3 months separated a high-risk group 

(28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABLIS (41% 

of pts; 5-year OS: 94%; p�0.012), and from a group with �1% BCR-ABLIS (31% of pts; 5-year OS: 97%; p�0.004). By cytogenetics high-risk 

patients could be identified by the persistence of �35% Ph� (27% of pts; 

5-year OS: 87%) as compared to �35% Ph� (73% of pts; 5-year OS: 95%; 

p�0.036). At 6 months the �1% BCR-ABLIS group (37% of pts; 5-year 

OS: 89%) showed inferior survival compared to �1% (63% of pts; 5-year 

OS: 97%; p�0.001); survival of the �0% Ph� group (34% of pts; 5-year 

OS: 91%) was inferior to 0% Ph� (66% of pts; 5-year OS: 97%; 

p�0.015). Regarding the IRIS pts 3 month BCR-ABLIS �10% (25% of 

pts; 8-year OS: 81%) was associated with inferior survival compared to 

�10% (75% of pts; 8-year OS: 93%; p�0.011). Conclusions: Failure to 

achieve the response landmarks of 10% BCR-ABLIS or 35% Ph� at 3 

months of imatinib treatment and 1% BCR-ABLIS or 0% Ph� at 6 months 

identifies high-risk patients which might benefit from an early change of 

therapy. 


4:30 PM-5:30 PM 

Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid 

leukemia in chronic phase (CML-CP): ENESTnd 3-year (yr) follow-up (f/u). 

Presenting Author: Hagop Kantarjian, University of Texas M. D. Anderson Cancer 


Background: In ENESTnd, nilotinib significantly reduced progression to AP/BC 

and demonstrated superior rates of MMR, MR4 , and MR4.5 vs imatinib with f/u of 

2 yrs. Methods: 846 pts with Ph� CML-CP were randomized to nilotinib 300 mg 

BID (n � 282), nilotinib 400 mg BID (n � 281), or imatinib 400 mg QD (n � 

283). Here, we report 3-yr f/u data. Results: Both nilotinib doses continued to 

demonstrate significantly higher rates of MMR, MR4 , and MR4.5 vs imatinib. In a 

landmark analysis, pts with BCR-ABL transcript levels � 10% at 3 months (mo) 

had a higher probability of achieving MMR by 1 and 2 yrs vs pts with transcript 

levels � 10%. No new progressions occurred on treatment since the 2-yr 

analysis; rates of progression to AP/BC including events on treatment (n � 2, 3, 

12) and those occurring both on treatment and after discontinuation (n � 9, 6, 

19) were significantly lower for nilotinib 300 mg BID and nilotinib 400 mg BID 

vs imatinib, respectively. At 3 yrs, OS considering only CML-related deaths was 

significantly higher for nilotinib vs imatinib. The safety profiles of nilotinib and 

imatinib were similar to those at 2 yrs. Conclusions: 3-yr f/u confirms the 

superiority of nilotinib vs imatinib and an acceptable tolerability profile for the 

treatment of pts with newly diagnosed Ph� CML-CP. 

Nilotinib 

300 mg BID 

(n � 282) 

Response by 3 yrs, % 

MMR 73 

P � .0001 

MR4 50 

P � .0001 

MR4.5 32 

Nilotinib 

400 mg BID 

(n � 281) 

Imatinib 

400 mg QD 

(n � 283) 

70 

53 

P � .0001 

44 

26 

P � .0001 

28 

15 

3-mo landmark analysis: BCR-ABL transcript levels*, % 

< 1% (n � 120, 123, 41) 

> 1to< 10% (n � 89, 95, 133) 

> 10% (n � 24, 28, 88) 

Freedom from progression to AP/BC, % 

Estimated 3-yr rate on core treatment 

P � .0001 

76/89 

40/67 

4/29 

99.3 

P � .0003 

MMR by 1 yr/2 yrs, % 

72/91 

38/54 

14/29 

98.7 

71/78 

31/52 

2/20 

95.2 

Including events after discontinuation 

P � .0059 

96.7 

P � .0185 

98.1 

93.5 

OS, % 

Estimated 3-yr OS rate 

P � .0496 

95.1 

P � .0076 

97.0 

94.0 

Only CML-related deaths 

P � .4413 

98.1 

P � .0639 

98.5 

95.2 

Patients with BCR-ABL mutation, n 

Any mutation 

T315I 

P � .0356 

11 

3 

P � .0159 

11 

2 

21 

3 

* Patients with unevaluable/missing PCR assessments at 3 mo, atypical transcripts, or MMR by 3 mo were 

excluded. 


4:30 PM-5:30 PM 

Efficacy and safety of bosutinib (BOS) for Philadelphia chromosome– 

positive (Ph�) leukemia in older versus younger patients (pts). Presenting 

Author: Tim H. Brummendorf, Universitätsklinikum Aachen, Universitätsklinikum 

Hamburg-Eppendorf, Aachen and Hamburg, Germany 

Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity 

in Ph� leukemia. Methods: Efficacy and safety of BOS 500 mg/d was 

evaluated in older (�65 y; n � 119) and younger (�65 y; n � 451) pts in 3 

cohorts: chronic phase chronic myeloid leukemia (CP CML) after imatinib 

(IM; CP2L cohort; n � 287); CP CML after IM � dasatinib (DAS) and/or 

nilotinib (NIL; CP3L cohort; n � 119); and accelerated/blast phase 

(AP/BP) CML or acute lymphoblastic leukemia after IM � DAS and/or NIL 

(ADV cohort; n � 164). Results: Baseline events (�65yvs�65 y) included 

respiratory disorders (35% vs 13%), cardiac disorders (29% vs 9%), and 

diabetes (4% vs 4%). Median baseline medications were 3 (�65 y) and 5 

(�65 y). Median BOS duration was 11 mo and median follow-up was 31 

mo for all pts. 80% of ³65 y and 67% of �65 y pts discontinued BOS, 

including 32% and 18% due to an adverse event (AE; most commonly 

thrombocytopenia [6% vs 3%]). Rates of response were similar or lower in 

older versus younger pts (Table). On-treatment transformation to AP/BP 

CML was similar between groups. Incidences of nonhematologic treatmentemergent 

AEs were generally similar between older and younger pts, 

notably (all grades/grade �3 for �65yvs�65 y): diarrhea (85%/9% vs 

81%/8%), infection (56%/15% vs 49%/10%), and edema (8%/0% vs 

4%/�1%). Common grade �3 lab abnormalities (�65yvs�65 y) were 

thrombocytopenia (35% vs 35%), neutropenia (21% vs 25%), and anemia 

(19% vs 19%). Conclusions: BOS demonstrated similar efficacy and 

acceptable safety in both older and younger pts across Ph� leukemia 

cohorts. 

CP2L CP3L ADV 

>65 y 65 y 65 y


4:30 PM-5:30 PM 

BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts) 

with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) 

after 30 months of follow-up. Presenting Author: Carlo Gambacorti- 

Passerini, University of Milan-Bicocca, Monza, Italy 

Background: The BELA study compared the efficacy and safety of BOS (dual 

Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502 

pts with newly diagnosed CP CML were randomized to BOS 500 mg/d (n � 

250) or IM 400 mg/d (n � 252) and stratified by Sokal risk group and 

geographic region. Efficacy analyses included all randomized pts (ITT); 

safety analyses included all treated pts (BOS, n � 248; IM, n � 251). Data 

described below are for �24 mo of follow-up; updated data for �30 mo of 

follow-up will be presented. Results: Median treatment duration was 27.5 

mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving 

treatment. The primary reason for BOS discontinuation was a treatmentemergent 

adverse event (TEAE; 24% vs 7% with IM); the primary reason for 

IM discontinuation was disease progression (13% vs 4% with BOS). 

Cumulative complete cytogenetic response (CCyR) rates by 24 mo were 

79% for BOS and 80% for IM. Cumulative major molecular response 

(MMR) rates by 24 mo were 59% for BOS and 49% for IM (P � 0.019), 

including 16% and 12% of pts with complete molecular response (4.0-log 

sensitivity). On-treatment transformation to accelerated/blast phase occurred 

in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7 

BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML 

progression); 24-mo Kaplan-Meier overall survival estimates were 97% 

(BOS) and 95% (IM). BOS was associated with higher incidences of 

gastrointestinal events than IM (diarrhea [70% vs 25%], vomiting [32% vs 

16%]; primarily transient), but lower incidences of edema (13% vs 40%) 

and musculoskeletal events (cramps [4% vs 22%], bone pain [4% vs 

10%]). Grade �3 TEAEs in �2% of BOS or IM pts were diarrhea (12% vs 

1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade �3 lab 

abnormalities (�15% of pts) with BOS and IM were neutropenia (10% vs 

24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase 

(23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS 

was effective for newly diagnosed CP CML and had a distinct toxicity 

profile. With continued follow-up both on-treatment transformation to 

accelerated/blast phase and overall survival continue to favor BOS versus 

IM. 


4:30 PM-5:30 PM 

Reductions in JAK2V617F allele burden with ruxolitinib treatment in 

COMFORT-II, a phase III study comparing the safety and efficacy of 

ruxolitinib to best available therapy (BAT). Presenting Author: Alessandro 

M. Vannucchi, University of Florence, Florence, Italy 

Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved 

for the treatment of myelofibrosis (MF) based on results of the phase 3 

COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions 

in splenomegaly and improved MF-related symptoms and quality of life of 

patients (pts) with MF. Since one measure of efficacy is molecular 

response, this analysis correlates changes in mutant allele burden (%V617F) 

with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a 

randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg 

twice daily (BID) with BAT. The primary endpoint was a � 35% reduction in 

spleen volume from baseline (BL) at week 48. Change in %V617F was 

measured by allele specific qPCR. Pts were stratified by reduction in 

%V617F (� 10%, 10-20%, � 20%) and results were correlated with 

achievement of the primary endpoint. Results: More pts in the ruxolitinib 

arm had � 10% V617F reductions compared with BAT (41% vs 5%; P � 

.01; Table). The majority of reductions � 20% were gradual and progressive 

over the course of the study; 2 pts had rapid reductions from 48% to 

1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly 

more pts with a � 20% V617F reduction achieved the primary endpoint 

compared with pts with a � 10% reduction (79% vs 30%; P � .004); in 

each group, gender did not affect spleen response. For pts with � 10% 

reductions (15 mg BID, n � 16; 20 mg BID, n � 24), the average total daily 

dose (TDD) was ruxolitinib 29.6 mg; pts with � 20% reductions (15 mg 

BID, n � 3; 20 mg BID, n � 11) had a TDD of 35.3 mg. Conclusions: Pts 

who received ruxolitinib had larger reductions in JAK2V617F allele burden 

compared with BAT. %V617F reductions were gradual over the course of 

the 48-week study; longer follow-up is needed to determine the extent of 

allele burden reduction. 

Ruxolitinib 

(N � 145) a 

BAT 

(N � 69) a 

n(%) 

JAK2V617F � at BL 110 (76) 49 (71) b 

Median (range) %V617F 

JAK2V617F 

84.5 (5-96) 81 (1-95) 

� with week-48 data 

%V617F reduction 

68 (62) 22 (45) 

Median 

< 10% 

-7.0% 0% 

c 

40 (59) 21 (95) 

10-20% 14 (21) 1 (5) 

> 20% 14 (21) 0 

a b c 

Pts with %V617F data. Unknown JAK-mutation status, n � 4. Includes pts with increased 

%V617F (range, 0-7%). 


419s 


4:30 PM-5:30 PM 

Subcutaneous omacetaxine mepesuccinate in patients with chronic phase 

(CP) or accelerated phase (AP) chronic myeloid leukemia (CML) resistant/ 

intolerant to two or three approved tyrosine-kinase inhibitors (TKIs). 

Presenting Author: Franck E. Nicolini, Centre Hospitalier Lyon Sud, Pierre 

Bénite, France 

Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-inclass, 

reversible, transient inhibitor of protein elongation that facilitates 

tumor cell death without depending on BCR-ABL signaling. Clinical activity 

was shown in two phase 2, open-label, multicenter studies in treatmentresistant 

CML. Methods: A subset from the phase 2 studies included 

patients in CP or AP who were resistant/intolerant to �2 approved TKIs. 

Omacetaxine 1.25 mg/m2 was given SC twice daily: �14 consecutive 

days/28-day cycle for induction, �7 days/cycle as maintenance. Secondary 

results were calculated for responses by number of prior TKIs. Results: Of 

122 patients (median age, 60 years), 62 had received 2 TKIs (100% 

imatinib; 76% dasatinib; 24% nilotinib) and 60 had received all 3 

approved TKIs. Prior non-TKI therapies (eg, 52% hydroxyurea, 34% 

interferon) were common. Of 45 CP patients in the 2 TKI group, 12 (27%) 

had major cytogenetic response (MCyR; median duration of 17.7 mo), and 

of 36 in the 3 TKI group, 4 (11%) had MCyR (median duration not 

reached). Of 17 AP patients in the 2 TKI group, 6 (35%) had major 

hematologic response (MaHR; median duration, 13.4 mo), and of 24 in the 

3 TKI group, 5 (21%) had MaHR (median duration, 6.4 mo). Median 

months of survival in the 2 and 3 TKI groups were 30.1 and not reached for 

CP and 12.0 and 24.6 for AP. Treatment-related grade 3/4 adverse events 

(AEs) occurred in 52 (84%) patients in the 2 TKI group and 42 (70%) in 

the 3 TKI group (most common: thrombocytopenia [71%, 48%]). Fifteen 

(24%) and 16 (27%) had an AE leading to discontinuation, primarily 

disease progression. There were 20 deaths (primarily disease progression), 

11 in the 2 TKI group and 9 in the 3 TKI group; 4 were considered related to 

treatment (sepsis in 2, pancytopenia, febrile neutropenia). Conclusions: In 

patients with heavily pretreated CML, response to omacetaxine therapy 

occurred whether they had received 2 or 3 prior TKIs. The drug was well 

tolerated. Tolerability was similar across the TKI groups in both CP and AP 

patients. Support: Teva Pharmaceutical Industries Ltd. 


4:30 PM-5:30 PM 

Combination of the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 

with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/ 

refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a 

phase Ib/II study. Presenting Author: Susan Mary O’Brien, University of 


Background: BTK is an essential mediator of B cell receptor signaling and a 

critical kinase for lymphoma cell survival. PCI-32765 (P), an oral, 

selective, irreversible inhibitor of BTK, inhibits proliferation, migration and 

adhesion in CLL cells, and is highly active as a single agent for the 

treatment of R/R CLL pts. (O’Brien ASH 2011). BR produces an overall 

response rate (ORR) of 59% in R/R CLL (Fischer JCO 2011). We report 

interim data on P combined with BR. Methods: R/R CLL pts received P 420 

mg orally daily for 28-day (D) cycles (C) until disease progression (PD). B 

was administered 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on 

D0 for C1 and 500 mg/m2 on D1 for subsequent courses for a maximum of 

6 cycles. Response was evaluated according to IWCLL criteria. Results: 30 

pts were enrolled. Median age of pts was 62 yrs (range 41-82). 46% of pts 

were Rai stage III/IV and the median # of prior therapies was 2 (range 1-4). 

37% and 13% were considered refractory (treatment free interval �12 mo) 

to a purine analog containing regimen or BR, respectively. Bulky disease 

was present in 52%. Adverse events (AE) have been consistent with that 

expected with BR. Gr 3/4 neutropenia and thrombocytopenia have been 

noted in 47% and 10% of pts, respectively. Grade �3 non-hematologic 

AEs potentially related to P included rash (3 pts) and fatigue and tumor 

lysis reported in 2 pts each. There were no Gr 3/4 infusion reactions. There 

have been no discontinuations (D/C) due to AE and no deaths on study. At a 

median follow-up of 4.9 mos (range 2.7-8.3 mo) 16 pts have completed BR 

and 14 pts are still receiving BR. The ORR is 90% (27/30 pts) (CR 10%, 

PR 80%). 2 additional pts achieved a nodal response with residual 

lymphocytosis. Responses appear independent of high-risk clinical or 

genomic features. 90% of pts remain on study; reasons for D/C include PD 

(n�2) and 1 pt pursuing SCT. Conclusions: PCI-32765, in combination 

with BR, is highly active. The high ORR, low rate of PD, and good 

tolerability compares very favorably with historical controls, warranting 

additional investigation of this combination. 




4:30 PM-5:30 PM 

Phase II trial of the combination of ofatumumab and lenalidomide in 

patients with relapsed chronic lymphocytic leukemia (CLL). Presenting 

Author: Lorenzo Falchi, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: Based on the activity of ofatumumab and lenalidomide as 

monotherapy, we evaluated efficacy and tolerability of the combination in 

pts with relapsed CLL. Methods: Thirty-six pts entered this phase II study. 

All pts had an indication for therapy, adequate liver/renal function and 

received prior fludarabine. Ofatumumab IV was given weekly for 4 weeks 

(300mg w 1; 1,000 mg w 2-4), monthly during months 2-6, and every 

other month during months 7-24. Lenalidomide 10 mg PO/day started on 

day 9 and continued for 24 months. Responses were assessed (2008 IWG 

criteria) at month 3, 6 and every 6 months. Results: Thirty-four pts are 

evaluable. Median age was 64 yrs (34-82), 59 % of the pts had Rai stage 

III-IV disease, median �-2M level was 4.1 mg/dL (1.7-16), 62 % of the pts 

had unmutated IgHV, 26% del(17p) and 12% del(11q). Median number of 

prior treatments was 2 (1-8), all pts had been treated with FCR and 29% 

were fludarabine-refractory. The overall response (OR) rate is 65% (22 pts); 

7 pts (21%) achieved a complete response (CR) including 4 MRD-negative 

CR, and 15 pts (44%) achieved a partial response (PR). Twelve pts are still 

on therapy. Median duration of response has not been reached with a 

median follow up of 13 months. Seven pts discontinued therapy despite 

ongoing response: HSCT (3 pts), toxicity (2 pts) and physician choice (2 

pts); 3 pts discontinued therapy because of loss of response (at 12, 16 and 

16 months). Eighty-two % of the pts are alive. No deaths occurred on 

therapy, 6 deaths occurred after therapy discontinuation: CLL (4), HSCT 

(1) and CLL/lung cancer (1). Lenalidomide daily dose was 10 mg (9 pts), 

7.5 mg (4 pts), 5 mg (13 pts), �5 mg (8 pts). G3-4 toxicities included 

neutropenia (16 pts, 47%), thrombocytopenia (3 pts, 9%) and anemia (2 

pts, 6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs. 

One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3 

infections occurred: pneumonia (4), fever/bacteremia (5), parotitis (1), 

cellulitis (2), HZV (1), and CNS toxoplasmosis (1). G1-2 tumor flare 

reaction occurred in 8 pts (24%). Conclusions: The combination of 

ofatumumab and lenalidomide was well tolerated. It induced durable 

responses in 65% of FCR pre-treated pts with relapsed CLL. 


4:30 PM-5:30 PM 

A phase I/II study of the selective phosphatidylinositol 3-kinase-delta 

(PI3K�) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with 

previously treated chronic lymphocytic leukemia (CLL). Presenting Author: 

Richard R. Furman, Weill Cornell Medical College, New York, NY 

Background: PI3K� is expressed in cells of hematopoietic origin where it 

regulates the survival and proliferation of malignant B-cells. GS-1101 is an 

orally bioavailable, small-molecule inhibitor that selectively targets PI3K� 

and is highly active in patients with hematologic malignancies. Methods: 

This Phase 1/2 study evaluated repeated 28-day cycles of GS-1101 in 

combination with ofatumumab. GS-1101 (150mg BID) was co-administered 

with a total of 12 infusions of ofatumumab over 24 weeks (300mg 

initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101), 

followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks 

later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects 

received single-agent GS-1101 as long as the subject was benefitting. 

Results: Accrual is complete with 21 subjects enrolled and 11 evaluable. 

Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2. 

Median [range] age was 63 [54-76] years. The majority (9/11; 82%) of 

patients had bulky adenopathy. The median [range] number of prior 

therapies was 3 [1-6], including prior exposure to alkylating agents (10/11; 

90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab 

(3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the 

median [range] treatment duration was 5 [0-7] cycles. Almost all subjects 

(9/11;82%) experienced marked and rapid reductions in lymphadenopathy 

within the first 2 cycles. The lymphocyte mobilization that is expected with 

PI3K� inhibition was significantly reduced in magnitude and duration and 

persisted past Cycle 1 in only 1 patient. Early follow up data support a 

favorable safety profile and confirm a lack of clinically significant myelosuppression. 

Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were 

significantly reduced after 28 days of treatment. Conclusions: GS-1101/ 

ofatumumab offers a well-tolerated noncytotoxic combination regimen with 

substantial activity in previously treated patient with bulky adenopathy. 

Data on the complete cohort of 21 subjects will be presented. 


4:30 PM-5:30 PM 

Pretreatment prognostic factors associated with outcomes for first-line 

FCR-based treatments in previously untreated CLL. Presenting Author: 

William G. Wierda, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: First-line chemoimmunotherapy with fludarabine, cyclophosphamide, 

and rituximab (FCR) demonstrated improved outcomes, including 

survival, for fit patients (pts) with CLL. Modifications of this regimen, 

including intensified rituximab (FCR3), addition of mitoxantrone (FCMR) or 

addition of alemtuzumab fir high-risk CLL (CFAR), were evaluated but did 

not improve outcomes in historic comparisons. Methods: We correlated 

outcomes, including complete remission (CR), time-to-treatment failure 

(TTF) and overall survival (OS), with new and traditional pretreatment 

prognostic factors to identify high-risk pts. Results: All pts (N�473) had an 

NCI-WG indication for treatment and received a first-line FCR-based 

regimen on trial; the intended treatment was 6 courses. Patient characteristics 

correlated with outcomes are presented in the table. Factors not 

associated with outcomes included absolute lymphocyte count; platelet 

count; performance status; spleen size; liver size; and number of involved 

lymph node sites. Conclusions: We identified the following as high-risk 

pretreatment features for patients going on first-line FCR-based therapy: 

advanced age, presence of 17p del, high B2M (�4mg/l), and unmutated 

IGHV gene. Pts with these features should be pursued with new treatment 

modalities and novel agents in order to improve outcomes. 

Pretreatment 

characteristic Higher CR Longer TTF Longer OS 

Younger age UVA UVA UVA; MVA 

Female - UVA; MVA - 

Earlier Rai stage UVA; MVA - UVA 

Lower ß-2 microglobulin (


4:30 PM-5:30 PM 

A randomized phase II study of sapacitabine in MDS refractory to 

hypomethylating agents. Presenting Author: Guillermo Garcia-Manero, 


Background: Sapacitabine is an orally administered nucleoside analogue 

which causes single-strand DNA breaks and induces G2 cell cycle arrest. A 

multi-center, randomized phase 2 study was conducted to evaluate 3 dose 

regimens in older patients with MDS refractory to hypomethylating agents. 

The primary endpoint is 1-year survival. Secondary endpoints include the 

rate of CR, CRp, PR, major hematological improvement (HI) or stable 

disease and their corresponding durations. The study uses a selection 

design to identify a dose regimen which produces a better 1-year survival 

rate in the event that all three dose regimens are active. The planned 

sample size is 60 patients (20 patients in each arm). Methods: Eligible 

patients must be � 60 years with intermediate-2 or higher risk MDS 

previously treated with hypomethylating agents and 6 - � 20% blasts in 

bone marrow, ECOG 0-2, adequate renal and hepatic functions. Patients 

were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg 

b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5 

days per week x 2 weeks (Arm I). The number of cycles is not limited. 

Results: As of January 2012, 61 patients were enrolled and 56 had � 30 

days of follow-up. Mean follow-up was 173 days. Median age was 71. Two 

or 3 cytopenias were present in 42 patients and 14 have received both 

azacitidine and decitabine. Baseline bone marrow had 6-10% blasts in 31 

patients and 11-19% blasts in 25 patients. Median number of cycles was 2 

and 18 patients received � 4 cycles. To date, 8 patients have responded (2 

CRs, 2 CRp, and 4 major HIs): 15% (Arm G), 16% (Arm H) and 12% (Arm 

I). Time to response is 1-3 cycles. Additionally, 6 patients achieved stable 

disease lasting longer than 16 weeks. More than 50% of patients have lived 

16 weeks or longer. Three deaths occurred within 30 days of randomization 

and 1 death was considered to be related to sapacitabine. Common adverse 

events (all grades, regardless of causality) included fatigue, nausea, 

diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia, 

anemia, neutropenia and thrombocytopenia, most of which were 

mild to moderate. Conclusions: Sapacitabine appears to be safe and active 

across all 3 dose regimens. Updated data will be presented at the meeting. 


4:30 PM-5:30 PM 

Efficacy and tolerability of lenalidomide (LEN) in patients (pts) 75 and older 

versus those younger than 75 with RBC transfusion-dependent low/int-1-risk 

MDS and del 5q. Presenting Author: Pierre Fenaux, Hopital Avicenne, Bobigny, 

France 

Background: LEN is the approved treatment for pts with RBC transfusiondependent 

Low/Int-1-risk MDS and del 5q. In 2 multicenter trials (MDS-003/- 

004) LEN lead to RBC transfusion independence (TI) for � 26 wks in 35–58% of 

pts and cytogenetic response (CyR) in 25–73%. Most common grade (G) 3–4 

adverse events (AE) were neutropenia and thrombocytopenia, a safety concern in 

elderly pts. We evaluated efficacy and tolerability of LEN in pts � 75yvs�75 y 

in MDS-003/-004 trials. Methods: Pts received LEN 5 mg � 28 d, 10 mg � 21 d, 

or 10 mg � 28 d (all 28 d cycles). Dose reductions were required for G4 

neutropenia (both trials) and platelet counts � 30x109 /L (MDS-003) or � 25 x 

109 /L (MDS-004). Results: 32% of the 286 pts were � 75 y. Baseline (BL) 

characteristics, LEN treatment, and optional G-CSF use are shown in Table. In 

pts � 75yvs�75 y: RBC-TI � 26 wks was 39 vs 47% (P � NS); CyR was 64 vs 

54% (P � NS); 2-y AML progression rates were 10 vs 19% (P � NS); 2-y overall 

survival rates were 62 vs 73% (P � .001); G3–4 AE: neutropenia (63 vs 76%; P 

� .024), thrombocytopenia (56 vs 49%; P � NS), infection (36 vs 20%; P � 

.003); median time to recovery to ANC � 1x109 /L was 0.7 vs 0.7 mo (P � NS) 

and to platelet counts � 100x109 /L was 3.3 vs 1.7 mo (P � NS). 59% pts � 75 

y and 49% pts � 75 y discontinued LEN due to AE (33 vs 26%; P � NS), lack of 

effect (32 vs 49%; P � NS), or death (15 vs 6%; P � NS). Dose reduction and 

discontinuation rates are shown in Table. Conclusions: Pts � 75 y and � 75 y 

had comparable response and AML progression rates. In pts � 75 y, LEN 

appears to be well tolerated but the higher infection rate justifies close follow-up. 

< 75 y > 75 y P value 

BL characteristics 

Female, % 

Median time from diagnosis, y 

Median RBC transfusion burden, units/8 wks 

Neutropenia (< 1x10 

65 

3 

6 

79 

3 

6 

.019 

NS 

NS 

9 /L), % 

Thrombocytopenia (< 100x10 

11 8 NS 

9 /L), % 

del 5q, % 

Isolated 

Plus > 1 abnormality 

IPSS risk, % 

Low 

Int-1 

ECOG, % 

0 

1/2 

LEN treatment 

Median duration, mo 

Median total dose per cycle, mg 

Median % of assigned dose cycle 1–4 

Reason for dose reduction, % 

Neutropenia 


Reason for discontinuation, % 

Neutropenia 


Optional G-CSF use 

Pts treated, % 

14 

71 

24 

27 

45 

25 

26 

14 

126 

68 

33 

17 

2 

4 

37 

13 

67 

31 

40 

37 

12 

42 

9 

108 

56 

25 

30 

3 

3 

30 

NS 

NS 

NS 

.003 

.009 

NS 

NS 

NS 

.019 

NS 

NS 

NS 


421s 


4:30 PM-5:30 PM 

Use of single polymorphism arrays (SNP-A) to modify prognostic scoring 

systems for myelodysplastic syndromes. Presenting Author: Manojkumar 

Bupathi, Cleveland Clinic Foundation/MetroHealth Medical Center- 

Department of Translational Hematology and Oncology Research, Cleveland, 

OH 

Background: MDS are hematologic neoplasms characterized by dysplasia 

and cytopenias. Two commonly used risk stratifications, IPSS (Greenberg 

et al Blood 1997) and IPSS-R are based on clinical factors (marrow blasts, 

number of cytopenias and genetic abnormalities determined by conventional 

karyotyping), with the IPSS based on 4 cytogenetic risk groups and 

the IPSS-R based on 5 cytogenetic risk groups defined by Schanz et al JCO 

2012. A drawback to metaphase cytogenetics (MC) is its inability to detect 

small cryptic chromosomal defects and uniparental disomy (UPD). SNP-A 

can identify these small cytogenetic lesions/UPD and has been shown to be 

of prognostic value in MDS. The goal of this investigation was to determine 

if SNP-A detected defects could be used to refine the IPSS and IPSS-R. 

Methods: SNP-A karyotyping was performed as previously described (Tiu et 

al, Blood, 2011). We reviewed data from 327 patients idenfitying SNP-A 

results, MC, and the IPSS/IPSS-R-related clinical factors were identified. 

Overall survival (OS) measured from the date of sampling for SNP-A 

karyotyping was the primary endpoint. Data were analyzed using Cox 

proportional hazards models. Results: SNP-A lesions not detected by MC 

were grouped as 1) none or only gains/losses; 2) UPD only or gains�losses 

but no UPD; and 3) UPD�other defects. The frequencies/median os in 

months (mo) of the groups were: 66%/20.0, 23%/12.7 and 11%/5.8, 

respectively, p�.0001 for OS. Combining the SNP-A groups with MC resulted 

in revised definitions of cytogenetic risk that had better discrimination than 

the underlying models; and when combined with the relevant clinical 

factors resulted in refined IPSS (IPSSSNP-A ) and IPSS-R (IPSS-RSNP-A ) risk 

stratifications (Table). Conclusions: Detection of chromosomal gains, losses, 

and UPD by SNP-A has prognostic value in MDS and can be used to refine 

current risk stratifications. 

Median os in mo (% of pts) for each model. 

Risk groups 

Model 1 2 3 4 5 

IPSS 39.1 (21%) 20.0 (37%) 8.9 (21%) 4.6 (21%) --- 

IPSSSNP-A 47.0 (15%) 27.1 (30%) 15.3 (26%) 7.2 (18%) 2.5 (12%) 

IPSS-R 39.1 (9%) 30.4 (32%) 17.6 (12%) 16.7 (14%) 4.6 (28%) 

IPSS-R SNP-A 41.8 (23%) 27.7 (14%) 15.1 (34%) 6.6 (17%) 2.6 (12%) 


4:30 PM-5:30 PM 

Results of a phase II trial of azacitidine (AZA) with or without epoetin beta 

(EPO) in lower-risk MDS. Presenting Author: Claude Gardin, Hematology, 

Hopital Avicenne APHP, University of Paris 13, Bobigny, France 

Background: Although anemia of IPSS low and int-1 (LR) MDS initially 

responds to erythroid stimulating agents (ESA) in 40-50% of patients (pts), 

response is generally transient. Anemia recurrence with RBC cell transfusion 

dependency (RBC-TD) is an indicator of poor prognosis, even in 

absence of progression to higher risk MDS. AZA leads to RBC transfusion 

independence (RBC-TI) in 30–40% of LR-MDS (Lyons, JCO, 2009), but it 

has not been prospectively tested in LR-MDS patients resistant to ESA. It 

also remains unknown if the addition of ESA to AZA would be useful in such 

pts. Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, 

NCT01015352), the Groupe Francophone des Myélodysplasies (GFM) 

compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) 

to the same treatment plus EPO 60000U/week (AZA�EPO arm). Inclusion 

criteria were LR-MDS resistant to at least 12 weeks of ESA, with RBC-TD � 

4 RBC units in the previous 8 weeks. Responders in both arms were eligible 

for maintenance up to 12 monthly cycles, unless progression or loss of 

erythroid response occurred. The primary endpoint was RBC-TI (HI-E major 

using IWG 2000 criteria) after 6 courses. Results: Between 2009 and 

2010, the 98 planned pts were included: M/F 65/28; median age 71y 

(41-84); 5 pts were excluded (one consent withdrawal, 2 early unrelated 

events and 2 with exclusion criteria). In the remaining 93 pts, IPSS risk was 

low in 69 and int-1 in 23 pts, with no imbalance between arms. Five pts 

received � 4 cycles and 16 received only 4 or 5 cycles, mainly due to 

toxicity or progression. RBC-TI after 6 courses was observed in 16.7% 

(8/48) in the AZA arm and 18 % (8/45) in the AZA�EPO arm (P�1), and in 

19.5% (8/41) and 26 % (8/31) respectively, in the 72 pts who received � 

6 cycles (P�.57). Overall best response rate (at least HI-E minor using IWG 

2000 criteria) was 35 and 33% in the AZA and AZA�EPO arms, 

respectively (P�0.99). Of note, only 9 pts in the AZA�EPO arm required at 

least one hospitalization for a SAE, compared to 22 pts in the AZA arm 

(P�0.015). Conclusions: Erythroid response to AZA, in LR MDS with 

demonstrated ESA resistance, appears lower than expected, with no 

improved outcome when combined with an ESA. The latter may however 

improve tolerance of AZA in LR MDS. 




4:30 PM-5:30 PM 

Evaluation of the first-in-class antimitochondrial metabolism agent CPI- 

613 in hematologic malignancies. Presenting Author: Timothy S. Pardee, 

Wake Forest University Health Sciences, Winston-Salem, NC 

Background: Altered metabolism is a hallmark of cancer, including hematologic 

malignancies. Most tumor cells use glycolysis even under aerobic 

conditions (the Warburg effect). This altered metabolism is a possible 

therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class 

agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase 

complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in 

vitro and in vivo. It is also the subject of a phase I clinical trial for patients 

with hematologic malignancies. Results: CPI-613 was active against HL60, 

Jurkat, and K562 cells, with an average IC50 value of 14 �M (range 12.2 – 

16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index 

(CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown 

of p53 or MN1 expression, despite their increased resistance to 

standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABLexpressing 

cells and with sorafenib against Flt3 ITD-expressing cells. CI 

values for nilotinib � CPI was 0.059 (�/-0.002) and for sorafenib � CPI 

was 0.581 (�/-0.052). In vivo, CPI-613 synergized with doxorubicin; 

median survival improved from 12 days with doxorubicin to 16 days with 

CPI-613 plus doxorubicin (p�0.0001). In the phase I clinical trial, 7 of 13 

evaluable patients had a response of stable disease or better, for an overall 

response rate of 54% (see table). CPI-613 was well tolerated, with no 

evidence of marrow suppression and no dose limiting toxicity identified. 

Conclusions: The novel agent CPI-613 has activity against a variety of 

hematological malignancies, including acute leukemias. The therapeutic 

index appears high, with only minor toxicities observed. 

Patient # Diagnosis Dose CPI-613 mg/m 2 

Best response # of cycles 

1 NHL 420 NE 0 

2 AML 420 PD 1 

3 Myeloma 840 PD 1 

4 AML 840, 1386, 2100 CR 15 

5 Hodgkin’s 840 PD 1 

6 AML 1386 PD 0 

7 Myeloma 1386 SD 3 

8 Myeloma 1386 SD 4 

9 AML 1386 PD 1 

10 MDS 2100 SD 7 

11 MDS 2100 SD 6 

12 AML 2100 MLFS 2 

13 AML 2940 NE 0 

14 Burkitt’s 2940 SD 4 

15 AML 2940 PD 1 

SD� stable disease; CR�complete remission; MLFS�morphologically leukemia-free state; 

PD�progressive disease; NE�not evaluable. 


4:30 PM-5:30 PM 

A phase II study of bortezomib added to standard daunorubicin and 

cytarabine during induction therapy and to intermediate-dose cytarabine 

(Int-DAC) for consolidation in patients with previously untreated acute 

myeloid leukemia (AML) age 60-75 years: CALGB study 10502. Presenting 

Author: Eyal C. Attar, Massachusetts General Hospital, Boston, MA 

Background: We conducted a clinical trial to determine the complete 

remission (CR) rate in older AML patients treated with bortezomib (Bz) plus 

daunorubicin and cytarabine induction therapy and the maximal tolerated 

dose (MTD) of Bz when added to Int-DAC consolidation therapy. Methods: 

Ninety-five adults (60-75 yrs old; median, 67) with previously untreated 

AML (including therapy-related and prior MDS) received Bz 1.3 mg/m2 IV 

on days 1, 4, 8 and 11 with daunorubicin 60 mg/m2 on days 1-3 and 

cytarabine 100 mg/m2 by continuous IV infusion on days 1-7. Patients who 

achieved a CR received 2 courses of consolidation chemotherapy with 

cytarabine 2 gm/m2 over 3 hours on days 1-5 (Int-DAC) with Bz administered 

on days 1, 4, 8 and 11. Three cohorts with escalating dose levels of 

Bz were tested (0.7, 1.0, and 1.3 mg/m2 ). Dose limiting toxicities were 

assessed during the first cycle of consolidation. Predictors of response, 

including CD74 expression, were assessed. Results: The CR frequency was 

65% (62/95). An additional 4% (4/95) achieved CR with incomplete 

platelet recovery. The CR rate according to ELN Genetic Groups was 90% 

(9/10) for favorable, 71% (12/17) for Int-I, 52% (17/33) for Int-II, and 

46% (5/11) for adverse. Six patients had grade 3 sensory neuropathy. 

There were 6 treatment-related deaths during cycle 1 of induction and 2 

during cycle 2. Bz plus Int-DAC proved tolerable at the highest dose tested. 

The median disease-free (DFS) and overall survivals (OS) for patients on 

this study were 8.2 and 12.1 months, respectively. Lower CD74 expression 

was associated with CR/CRp (p�.04) but not with DFS or OS. Conclusions: 

The addition of Bz 1.3 mg/m2 IV on days 1, 4, 8, and 11 to standard “3 � 

7” daunorubicin and cytarabine induction chemotherapy for AML is well 

tolerated and results in a remission rate at least as high as would be 

expected with ”3�7” alone in older patients. The maximum tested dose of 

Bz given in combination with Int-DAC for remission consolidation was 1.3 

mg/m 2 

and proved to be tolerable. Further testing of this regimen in a phase 

III study is planned. 


4:30 PM-5:30 PM 

Initial salvage therapy in first relapse AML: A phase IIb study of CPX-351 

versus investigator’s choice—A subset analysis by prognostic group. 

Presenting Author: Stuart Goldberg, John Theurer Cancer Center, Hackensack, 

NJ 

Background: CPX-351 encapsulates cytarabine and daunorubicin within 

liposomes at a 5:1 molar ratio, shown in vitro to maximize synergy. 

Liposomal encapsulation enables preferential uptake of drug within leukemic 

blasts followed by intracellular release enhancing efficacy in AML. A 

randomized Phase 2b study in 1st relapse AML completed 1-year follow up 

with improvement in event free (EFS) and overall survival (OS). This report 

describes patient outcomes with a focus on the unfavorable subset per the 

European Prognostic Index (EPI) (Breems DA, et al. J Clin Oncol, 2005 Mar 

20;23:1969-1978). Methods: Patients (pts) �65yo in 1st relapse AML 

after an initial CR �1 month, ECOG PS� 0-2, serum creatinine� 2.0 

mg/dL, total bilirubin � 2.0 mg/dL, ALT/AST � 3 x ULN, and LVEF �50% 

were eligible. Pts with APL, daunorubicin exposure �368 mg/m2 (or other 

anthracycline equivalent), active CNS leukemia, uncontrolled infections 

were excluded. Pts were randomized 2:1 to receive up to 2 inductions and 2 

consolidation courses of CPX-351 (100 u/m2 ; D 1, 3, 5) or investigators 

choice of intensive salvage treatment. Post remission allo-transplantation 

was permitted. 126 pts were stratified by EPI into favorable, intermediate, 

and unfavorable groups (with projected 1-year OS of 70%, 49%, and 16%). 

The primary efficacy endpoint was % survival at 1-year. Results: CPX-351 

increased the rate of morphologic leukemia-free state (77% vs. 60%), the 

rate of CR � CRi (51% vs. 41%), and the median EFS (4.0 vs. 1.4 mo) and 

OS (8.5 vs. 6.3 mo) in the overall patient population. Significant survival 

improvement occurred amongst those with unfavorable EPI scores 

(HR�0.55, p-value�0.02) with improved 1-year survival (29% vs. 10%). 

CPX-351 treatment resulted in more prolonged cytopenias with increased 

febrile neutropenia and grade 3-4 infections, but not in the D 60 mortality 

(overall: 15% vs. 16%; unfavorable: 16% vs. 24%). Conclusions: CPX-351 

is highly active in AML and induces remission even in patients with prior 

cytarabine and anthracycline exposure. Efficacy was evident in every 

prognostic group, particularly in the unfavorable EPI group where a 

statistically significant improvement in 1-year survival was observed. 


4:30 PM-5:30 PM 

Stage I findings of a two-stage phase II study to assess the efficacy, safety, 

and tolerability of barasertib (AZD1152) compared with low-dose cytosine 

arabinoside (LDAC) in elderly patients (pts) with acute myeloid leukemia 

(AML). Presenting Author: Giovanni Martinelli, Department of Hematology/ 

Oncology Seràgnoli, Bologna, Italy 

Background: Barasertib is the pro-drug to barasertib-hQPA, a selective 

Aurora B kinase inhibitor with preliminary anti-AML activity in a Phase I/II 

study (Löwenberg et al. Blood 2011;118:6030). Methods: AML pts aged 

�60 y considered unsuitable for intensive chemotherapy were randomized 

2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg 

(sc twice daily for 10 days) in 28-day cycles (NCT00952588). The primary 

endpoint was improved objective complete response rate (OCRR: CR � CRi 

[Cheson criteria, but requiring CRi confirmation �21 days after first 

appearance, with partial recovery of platelets and neutrophils]). Secondary 

endpoints included duration of response (DoR), overall survival (OS) and 

safety. Results: 74 pts (barasertib, 48; LDAC, 26) received treatment and 

all completed �1 cycle. A significant improvement in OCRR was observed 

with barasertib (35.4% [17/48] vs 11.5% [3/26]; difference, 23.9% [95% 

CI, 2.7-39.9]; P�0.05); barasertib responses were seen in all cytogenetic 

risk groups and appeared to be durable (median DoR [range], 82 [28-321] 

days; vs LDAC 30-85 days). Although not formally sized to compare OS 

data, a trend favoring barasertib was observed (HR�0.88, 95% CI, 

0.49-1.58; P�0.663; median OS, 8.2 vs 4.5 mo). Stomatitis and febrile 

neutropenia were the most common adverse events (AEs) in the barasertib 

arm with higher incidences vs LDAC (71% vs 15%; 67% vs 19%, 

respectively). Grade �3 AEs with a greater incidence in the barasertib arm 

were febrile neutropenia (50% vs 19%), stomatitis (29% vs 0%) and 

pneumonia (25% vs 8%); grade �3 infection rates were also higher with 

barasertib (40% vs 23%). For both arms, there were similar discontinuation 

rates due to AEs (barasertib 8.3% vs LDAC 7.7%), deaths due to AEs 

(12.5% vs 11.5%) and 30-day mortality (12.5% vs 15.4%). Cumulative 

toxicities were not observed with barasertib treatment. Conclusions: In this 

population with poor prognosis using standard chemotherapy, barasertib 

showed a significant improvement in OCRR vs LDAC, and a safety profile 

that was manageable and consistent with previous studies. 



4:30 PM-5:30 PM 

Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin 

(FLAG-GO) on relapse-free survival in patients with newly diagnosed 

core-binding factor acute myelogenous leukemia. Presenting Author: Gautam 

Borthakur, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: Prior modulation with fludarabine increases cytarabinetriphosphate 

(ara-CTP) accumulation and granulocyte-colony-stimulating 

factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in 

leukemic blasts. Our front-line regimen of fludarabine, cytarabine and 

filgrastim (FLAG) based on this rationale showed improved event-free 

survival compared to anthracycline and cytarabine based regimens in 

patients (pts) with core-binding factor acute myelogenous leukemia (CBF- 

AML). Medical Research Council AML 15 trial reported survival benefit 

from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens 

in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial 

combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed 

CBF-AML, pts received GO on day 1 of induction and of post-remission 

cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised 

of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in 

induction and 3-4 days in post-remission cycles) with filgrastim started on 

day-1 and continued till neutrophil recovery. Pts who received one 

non-FLAG-GO induction could enroll irrespective of their remission status. 

Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 

of 50 (10%) were in remission at enrollment from prior induction]. Median 

age is 48 years (range, 19-76), median WBC count 12.3 x106 /L (range, 

1.3-97.2); 12 patients (24%) were �60 years of age and frequency of kit 

mutation is 8%. Complete remission with or without platelet recovery 

(CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. 

With 6 planned consolidations, the median number of consolidation 

treatments received is 5 (range, 0-6). Two-thirds of pts needed dose 

reduction during post-remission cycles. Seven (14%) pts [t(8;21)� 5, Inv 

16�2] relapsed and with a median follow-up of 34 months (range, 15-54 

months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a 

highly effective regimen and has resulted in high rate of relapse-free 

survival in pts with newly diagnosed CBF AML. 


4:30 PM-5:30 PM 

Clinical trial and compassionate use experience with glucarpidase for 

methotrexate toxicity. Presenting Author: Brigitte C. Widemann, Pediatric 

Oncology Branch, National Cancer Institute, National Institutes of Health, 

Bethesda, MD 

Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic 

leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma 

(NHL), and other cancers. MTX-associated renal impairment with delayed 

MTX elimination develops after 2 to 10% of treatment cycles, exposing 

patients to elevated MTX concentrations with potential for enhanced MTX 

toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of 

carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and 

provides an alternate way of clearance in patients with delayed MTX 

elimination. Methods: From November 1993 to June 2009, 492 patients 

experiencing renal toxicity and delayed elimination of MTX were treated 

with glucarpidase (50 U/kg intravenously) in compassionate use trials 

conducted in the US and EU. Their outcomes are presented here. Results: 

The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs). 

Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic 

sarcoma, 23% ALL, and 7% other malignancies. The median 

pre-glucarpidase MTX concentration was 17 �mol/L. Seventy-six percent of 

patients received 1 dose of glucarpidase, 22% received 2 doses, and 2% 

received 3 doses. The first dose of glucarpidase was given at a median of 3 

days after MTX administration. One-hundred and fifty-six patients had MTX 

concentrations determined by HPLC. At the first measurement (median 15 

minutes post-glucarpidase) MTX was reduced by a median of 99% relative 

to the pre-glucarpidase baseline. At the last measurement (median 40 hrs 

post-glucarpidase) median MTX reduction remained at 99% compared with 

baseline. In 410 patients with pre-glucarpidase renal impairment measured 

as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a 

median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated 

overall; adverse events included paresthesia (2.0%), flushing (1.8%) and 

headache (1.0%). Eight percent of patients died within 30 days of 

glucarpidase administration of causes unrelated to glucarpidase, as judged 

by the treating physician. Conclusions: Glucarpidase is well-tolerated and 

reduces MTX concentrations by 99% within 15 min of administration in 

patients with impaired renal clearance of MTX. 


423s 


4:30 PM-5:30 PM 

Allogeneic stem cell transplantation for patients over age 65 with acute 

myelogenous leukemia and myelodysplastic syndrome. Presenting Author: 

Henry Jacob Conter, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: ASCT represents a potentially curative approach for AML and 

MDS, diseases that primarily affects patients in 7th and 8th decade of life. 

Here, we report outcomes of patients older than 64 treated at the MD 

Anderson Cancer Center from 1996 until December 2011. Methods: 182 

patients older than 64 received an ASCT for AML (n�143) or MDS (n�39). 

Outcomes of interest were transplant-related mortality (TRM), incidence of 

acute and chronic graft-versus-host disease (GVHD), incidence of relapse, 

and overall survival (OS) - which were estimated from the date of 

transplant. Results: The median age of patients was 67 (range 65-79). Most 

patients were transplanted with active disease (table). Median follow-up for 

alive patients was 12.6 months (n�63; range 0-118). The cumulative 

incidence of 100-day, 1 year, and 3 year TRM was 14%, 18%, and 21%, 

respectively. 26% of patients developed grade II-IV acute GVHD and 35% 

suffered from chronic GVHD. The actuarial incidence of relapse was 46% at 

1 year and 53% at 3 and 5 years. Actuarial OS was estimated to be 45% at 

1 year, 28% at 3 years, and 21% at 5 years. 3 year OS for patients 

transplanted in CR and with active disease was 40% versus 23% (p�0.02). 

OS of patients age 65-69 or �69 was 30% vs. 20% (p�0.06) at 3 years for 

all patients; compared to 38% versus 27% (p�0.23) for patients in those 

age groups transplanted in CR. Conclusions: Although a significant minority 

of patients older than 64 years may achieve long-term disease control, new 

approaches are needed to reduce TRM and relapse in this cohort of 

patients. 

Category Parameter Number (%) 

Donor type Matched related donor 87 (48) 

Matched unrelated donor 73 (40) 

Mismatched unrelated donor 17 (9) 

Preparative regimens Fludarabine/melphalan 85 (47) 

Fludarabine/busulfan 61 (34) 

Fludarabine/idarubicin 13 (7) 

Immunosuppression Tacrolimus/mini-methotrexate 147 (81) 

Tacrolimus/mycophenolate 8 (4) 

Post-transplant cyclophosphamide 16 (9) 

Disease status at ASCT Primary induction failure 21 (12) 

Complete remission 1 38 (21) 

Complete remission 2 or 3 15 (8) 

Refractory/untreated disease 120 (66) 


4:30 PM-5:30 PM 

BCR-ABL kinase domain mutations and resistance in Ph� acute lymphoblastic 

leukemia from the imatinib to the second-generation TKI era. 

Presenting Author: Simona Soverini, Department of Hematology/Oncology 

Seràgnoli, Bologna, Italy 

Background: Advent of 2nd-generation TKIs has brought additional treatment 

options for Philadelphia-positive (Ph�) acute lymphoblastic leukemia 

(ALL) patients (pts). To analyze the changes they have determined in 

mutation frequency and type, we have reviewed the database recording the 

results of BCR-ABL mutation analyses done in our laboratory from 2004 

through 2011. Methods: 781 tests on 258 pts were performed by direct 

sequencing. Results: 143 pts were analyzed because of imatinib resistance; 

101 (71%) had one or more mutations (a single mutation in 91 pts; two 

mutations in 10 pts). Three mutation types were by far the most frequent: 

T315I (38 pts, 37%), E255K (19 pts, 18%) and Y253H (19 pts, 18%). Of 

84 pts who had developed resistance to 2nd- or 3rd-line therapy with 

dasatinib, nilotinib or bosutinib after imatinib failure, 65 (77%) were 

positive for Bcr-Abl mutations; 30 (46%) carried multiple mutations (up to 

four) and in 19 of them (63%) this was consequence of multiple lines of 

therapy. The most frequent newly acquired mutation in this setting was the 

T315I, detected in 35/57 (61%) cases acquiring mutations on dasatinib. 

Mutation analysis was also performed in 15 resistant pts enrolled in a study 

of dasatinib as 1st-line treatment of Ph� ALL; 12 pts were positive, 11 of 

them had a T315I. Taking advantage of a next-generation sequencer 

(Roche 454), allowing a high sensitive and quantitative mutation scanning 

of Bcr-Abl, serially collected samples from 24 selected cases who developed 

mutations and resistance to one or more TKIs were retrospectively 

analyzed to study the kinetics of expansion of mutant clones. Results will 

be presented. Conclusions: Although 2nd generation TKIs are more potent 

and have much fewer insensitive mutations, long-term disease control 

remains a problem and the T315I becomes an even tougher enemy. The 

high genetic instability fosters mutational events anytime during TKI 

treatment and some mutation types (T315I, Y253H) have been observed to 

emerge and take over very quickly (from �0.01% to 90% in one-two 

months). Supported by PRIN, AIL, AIRC, Fondazione CARISBO. 




4:30 PM-5:30 PM 

Outcomes of patients older than 60 years with acute lymphoblastic 

leukemia: Survey from the Surveillance, Epidemiology, and End Results 

(SEER) program. Presenting Author: Jae Hong Park, Leukemia Service, 


Background: The cure rate of pediatric acute lymphoblastic leukemia (ALL) 

has increased over the last 4 decades to above 80%, compared to a much 

smaller improvement in adults aged � 60 years. However, outcome 

information on older ALL patients (age � 60 years) is limited. Only a few 

clinical trials include the older patients, apply the same regimens developed 

for adults of all ages, and report a very poor outcome with no 

improvement over time. We therefore conducted a population-based survey 

of older ALL patients focusing on early death (ED) rates and changes in 

outcome over the last 30 years. Methods: Data from 9 population-based 

cancer registries that participate in the National Cancer Institute’s SEERprogram 

were used to identify patients aged 60 or older with a diagnosis of 

ALL. Survival rates at 1, 6, 12 and 24 months were estimated using 

actuarial methods for 4 calendar periods: 1980-1985, 1986-1992, 

1993-1999, and 2000-2006. ED was defined as death occurring within 

one month of ALL diagnosis. Results: A total of 1066 ALL patients were 

identified. The ED rate significantly improved over the four study time 

periods from 20.2% in 1980-1985 to 13.2% in 2000-2006 (p�0.03). 

The overall survival (OS) at 6 months improved from 32.8% in 1980-1985 

to 45.3% in 2000-2006, but at 24 months, only a modest difference in OS 

was noted across the time period (13.1% in 1980-85 vs. 17.5% in 

2000-06). The median survival increased from 3 months to 6 months from 

the period 1980-1999 to 2000-2006. Conclusions: Although the longterm 

OS for patients aged 60 and over remains poor, there has been a slight 

improvement in early mortality and median OS from 1980s to the early 21st century. While the progress in reducing ED and increasing survival at 6 

months is encouraging, and may be reflecting better supportive care 

measures, the limited improvement indicates poor tolerance and lack of 

efficacy of the toxic, long and complex chemotherapy regimens designed 

for younger adults. Therefore, future studies should be designed specifically 

for older ALL patients, focusing on novel, effective, but less toxic 

therapies, to further improve the short-term OS seen in the past decades 

and possibly a better overall outcome. 


Impact of treatment prior to allogeneic stem cell transplantation for 

myelodysplastic syndromes: A study on behalf of the SFGM-TC and the 

GFM groups. Presenting Author: Gandhi Laurent Damaj, Centre Hospitalier 

Universitaire Amiens Sud, Amiens, France 

Background: Until the early 2000s, treatment prior to SCT varied according 

to cytogenetics and % BM blasts and was mainly induction-type chemotherapy 

(ICT). The role of Azacitidine (AZA) prior to transplant remains 

uncertain. Methods: 163 consecutive pts (M/F�104/67; age � 18) 

underwent alloSCT between 2005 and 2009 from sibling (n�96) or HLAallele-MUD 

(10/10) (n�67). The SC source was blood (n�142) or marrow 

(n�21) and conditionings were myeloablative (n�33); nonmyeloablative 

(n�130). Pts who did not received neither prior ICT nor AZA were excluded 

since the main objective of this study was to investigate the impact of prior 

therapy on pts’ outcome. Results: At diagnosis, FAB/WHO was: 24 RA/RARS/ 

RCMD, 52 RAEB-1, 74 RAEB-2, 13 RAEB-t/AML; Cytogenetic: fav 

(n�93), int (n�32), unfav (n�37). 98 pts received prior ICT (ICT-group) 

and 65 had received AZA, either alone (AZA-group; n�48) or AZA preceded 

or followed by intensive CT (AZA-chemo-group; n�17). In AZA groups, the 

drug was started 38 to 941 days from transplant and discontinued 6 to 438 

days before transplant with a median number of 4 cycles (range 1-26). 

Overall, 119 pts were considered responders at SCT (CR, PR, mCR), 

including 33 (69%) treated with AZA-alone, 9 (53%) with AZA-chemo and 

77(78%) with ICT.While there were no differences between AZA-group and 

ICT-group in terms of OS, EFS, relapse and NRM, having a poor risk 

cytogenetic and receiving AZA-chemo prior to SCT were, in multivariate 

analyses, the most important factors that adversely influenced OS with 

[HR�3.03; 95% CI 1.84-4.96] (p�.0001) and [HR�2.72; 95% CI, 

1.38-5.35] (p�.004), respectively. Pts of AZA-chemo group had the same 

rate of relapse but significantly higher NRM rate (p�.059) than those who 

received either AZA or ICT alone. Conclusions: With the goal of downstaging 

underlying disease before allo-SCT, AZA treatment appears to be a 

valid therapeutic approach, but mainly in pts receiving AZA alone with an 

outcome at least equivalent to pts receiving ICT prior to SCT. Allo-SCT in 

pts who required both AZA and chemotherapy had less satisfactory 

outcomes, possibly reflecting additional toxicity and/or more resistant 

disease. 


4:30 PM-5:30 PM 

Impact of donor source on allogeneic stem cell transplantation for Philadelphia 

chromosome-negative acute lymphoblastic leukemia. Presenting Author: 

Satoshi Nishiwaki, Department of Hematology and Oncology, Nagoya 

University Graduate School of Medicine, Nagoya, Japan 

Background: Although allogeneic stem cell transplantation (allo-SCT) could 

improve the outcome of adult Philadelphia chromosome-negative acute 

lymphoblastic leukemia [Ph(-) ALL], the impact of the donor source, 

particularly the position of cord blood (CB) transplantation, is still uncertain. 

Methods: We retrospectively analyzed 1726 adult Ph(-) ALL patients 

transplanted at the first time between 1998 and 2009 with myeloablative 

preparative regimens who were registered in the Japan Society for Hematopoietic 

Cell Transplantation database. Two hundred and thirty-three 

received CB transplantation [first complete remission (CR1): 95, subsequent 

CR: 53, non-CR: 85], 809 received allo-SCT from unrelated donor 

(URD) (CR1: 434, subsequent CR: 158, non-CR: 217), and 684 received 

allo-SCT from related donor (RD) (CR1: 388, subsequent CR: 89, non-CR: 

207). Results: Overall survival (OS) in patients after CB transplantation in 

CR1 was comparable with that after allo-SCT from URD or RD [57% in CB, 

64% in URD, and 65% in RD at 4 years, respectively, P�0.11]. Donor 

source was not a significant risk factor for OS in multivariate analysis. 

Although URD was a favorable factor for relapse and an unfavorable factor 

for non-relapse mortality (NRM), CB was not a significant factor for them 

[Relapse: 22% in CB, 17% in URD, and 24% in RD at 3 years, respectively 

(P�0.02); NRM: 27% in CB, 23% in URD, and 13% in RD at 3 years, 

respectively (P�0.0001)]. Among CB recipients in CR1, age at allo-SCT 

(45 years or older) was solely a significant adverse prognostic factor in 

multivariate analysis. Among patients younger than 45 years who received 

allo-SCT in CR1, OS after CB transplantation was significantly better than 

that after allo-SCT from mismatched URD (4-year OS: 68% vs. 49%, 

P�0.04). Similarly, OS was not different by donor source in subsequent CR 

or non-CR [Subsequent CR: 48% in CB, 39% in URD and 48% in RD, 

P�0.33; non-CR: 18% in CB, 21% in URD, and 15% in RD, P�0.20 at 4 

years, respectively]. Conclusions: Allo-SCT using CB led to similar outcomes 

as either RD or URD in any disease status. CB transplantation is a 

good alternative for adult Ph(-) ALL patients without a suitable RD or URD. 

6535^ General Poster Session (Board #14B), Mon, 1:15 PM-5:15 PM 

Immune-reconstitution after combined haploidentical and umbilical cord 

blood transplantation. Presenting Author: Koen van Besien, Weill Cornell 

Medical College, New York, NY 

Background: Umbilical cord blood (UCB) stem cells are frequently employed 

for allogeneic stem cell transplantation. However, delayed myeloid 

and lymphoid immune-reconstitution with UCB transplantation leads to 

increased risk of infections. We recently reported a pilot study combining 

UCB with a HLA haploidentical donor (Liu et al. Blood. 2011). Here, we 

report the immune reconstitution after the haploidentical-cord blood 

transplantation. Methods: Pts received reduced-intensity conditioning with 

fludarabine/melphalan/rATG and were assessed for lymphocyte subsets, 

serological response to pneumococcal vaccination, Cylex Immuknow assay 

which measures amount of ATP secreted by CD4 lymphocytes on stimulation 

by PHA, and T-cell spectratyping. Results: 45 pts, enrolled between 

01/2007 and 04/2011, are included in this analysis. The median absolute 

lymphocyte subset counts at serial time-points are shown in the Table. The 

median absolute values of CD3, CD4 and CD8 counts remained below the 

normal range throughout the 1st year post-transplant. The NK-cells and 

B-cells reached normal range by day 30 and day 100, respectively. 

Serological response to pneumococcal vaccination was seen in 7/17 

(defined as seroconversion or �3 fold rise in titers of serotype 14, 19F and 

23F) evaluable pts at a median 74 days after vaccination. Immuknow assay 

showed that 6/6 pts tested within first 30 days of transplant had low values 

whereas 5/8 tested �1yr had normal/high values. Of the 9 pts who were 

assessed for T-cell receptor repertoire by T-cell spectratyping, 7 had a 

polyclonal, complex T cell repertoire similar to healthy controls. CMV 

viremia requiring treatment occurred in 14 patients. EBV reactivation 

occurred in 18 pts and 5 developed PTLD 68 to 314 days after transplant. 

Conclusions: Haploidentical cord blood transplantation leads to rapid 

myeloid recovery and recovery of B-cell and NK cell numbers. T-cell 

recovery is more delayed, but at 1-year most pts have a polyclonal T cell 

repertoire and robust T-cell responses. 

Absolute count, median 

Day 30 

N�28 

Day 100 

N�31 

Day 180 

N�23 

Day 365 

N�15 

Total lymphocyte 256 747 959 1,354* 

CD3 3.5 25 114 447 

CD4 2 6 70 194 

CD8 2.5 8 30 146 

CD19 1 297* 401 439 

CD56 (CD3-) 

* Within normal range. 

220* 228 267 150 



Impact of ATG on new HLA groups for unrelated donor allogeneic stem cell 

transplantation. Presenting Author: Soo Jung Lee, Department of Hematology/Oncology 

and Stem Cell Transplantation Unit, Kyungpook National 

University Hospital, Kyungpook National University School of Medicine, 

Daegu, South Korea 

Background: The outcomes of unrelated donor transplantation have improved 

with refinements in HLA testing. Recently, grouping of HLA 

matching for unrelated donor was suggested, defining by well-matched, 

partially-matched, and mismatched. In the current study, the role of ATG 

for each group was evaluated. Methods: A total of 92 patients diagnosed as 

hematologic diseases and received allogeneic stem cell transplantation 

(SCT) from unrelated donor were retrospectively analyzed. Results: Nineteen 

patients were classified as well-matched, 42 as partially-matched, 

and 31 as mismatched. Among them, 57 patients received anti-thymocyte 

globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis. The overall 

survival (OS) rate was higher for well-matched group (83%) compared to 

partially-matched (54%) and mismatched (34%, p�0.076). For partiallymatched 

group, the OS was significantly improved with ATG (83.3% vs. 

38.6%, p�0.018). But, the OS was not different between groups with or 

without ATG for well-matched (87.5% vs. 66.7%, p�0.487) and mismatched 

(32.4% vs. 41.7%, p�0.215). ATG decreased the cumulative 

incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p�0.068) and severe 

chronic GVHD (21.2% vs. 52.2%, p�0.037). The use of ATG (HR�0.248, 

p�0.029) was related with favorable OS for partially-matched group. 

However, the favorable effect of ATG was not observed in well-matched and 

mismatched groups. Conclusions: ATG effectively improved survival rate for 

partially-matched group in unrelated donor transplantation. However, the 

positive effect of ATG was not observed in well-matched and mismatched 

group. 


The outcomes of allogeneic stem cell transplantation in AML patients with 

monosomal karyotypes. Presenting Author: Sang Kyun Sohn, Department 

of Hematology/Oncology, Kyungpook National University Hospital, Kyungpook 

National University School of Medicine, Daegu, South Korea 

Background: The prognosis of acute myeloid leukemia (AML) with monosomal 

karyotype (MK) was reported extremely poor. We investigated the role 

of allogeneic stem cell transplantation (allo-SCT) for those with MK. 

Methods: A total of 114 patients who received allo-SCT for treatment of 

AML were retrospectively analyzed. All patients were treated with standard 

induction chemotherapy with anthracycline and cytarabine. Cytogenetic 

abnormalties were grouped according to recently published MRC criteria 

and MK was defined as at least two autosomal monosomies or one 

monosomy plus one or more structural abnormality. Results: Thirteen 

patients had favorable cytogenetic risk, 78 intermediate, 11 adverse 

without MK, and 12 adverse with MK at the time of diagnosis. Among 12 

patients with MK, 5 (41.7%) achieved CR after induction therapy, 1 

(8.3%) relapsed and 6 (50.0%) refractory at the time of allo-SCT. The 

2-year overall survival (OS) was significantly lower for patients with MK 

(17.5%) compared to favorable (76.9%), intermediate (61.0%), and 

adverse without MK (36.4%, p�0.017). In the multivariate analysis, those 

with MK was related with extremely poor outcomes (HR 6.02, p�0.008), 

which was independent risk factor for OS. Survival benefit was observed in 

MK group with chronic GVHD compared to those without chronic GVHD. 

The median survival was 272 days with chronic GVHD (95% CI 204-339 

days) compared to 159 days (95% CI 76-172 days) without chronic GVHD 

(p�0.010). Conclusions: The prognosis remained poor in patients with MK 

despite of allo-SCT. Innovative approaches to induce GLV effects are 

needed to improve SCT outcomes in patients with MK. 


425s 


Low day 100 transplant-related mortality (TRM) and relapse rate following 

clofarabine (CLO) in combination with cytarabine, total body irradiation 

(TBI), and allogeneic stem cell transplantation (AlloSCT) in children, 

adolescents, and young adults (CAYA) with poor-risk acute leukemia. 

Presenting Author: Kavita Radhakrishnan, New York Medical College, 

Valhalla, NY 

Background: CAYA with ALL or AML in third complete remission (CR3), 

refractory relapse (RR) or induction failure (IF) have an extremely poor 

prognosis, �20% EFS (Gaynon, BJH, 2005;Wells, JCO, 2003). CLO, an 

inhibitor of DNA polymerase and ribonucleotide reductase, has significant 

activity in CAYA with relapsed ALL/AML (Jeha, JCO 2006,2009) and 

synergy with cytarabine (Faderl, Blood, 2005). We sought to determine 

safety, day-100 TRM, and overall survival (OS) associated with CLO, 

cytarabine and TBI followed by AlloSCT in CAYA with poor-risk ALL/AML. 

Methods: This is a multi-center phase I/II trial of a novel conditioning 

regimen of CLO (dose escalation: 40mg/m2 [n�3], 46 mg/m2 [n�3], 52 

mg/m2 [n�19]) x5d, sequential (4 hrs later) cytarabine 1000 mg/m2 x6d 

and TBI (1200cGy) followed by AlloSCT from matched related or unrelated 

donors in CAYA with ALL/AML in CR3, RR or IF. Patients with unrelated 

donors received R-ATG. GVHD prophylaxis consisted of tacrolimus and 

MMF (Bhatia/Cairo, BBMT, 2009). Kaplan-Meier method was used to 

determine the probabilities of engraftment, GVHD, TRM and OS. Results: 

25 pts, median age: 11.3 yrs (1.5-20.7); M:F: 19:6, ALL/AML: 22:3 (10 

CR3, 3 RR, 12 IF), 10 related donors, 15 unrelated donors (9 BM/PBSCs, 

6 UCB). Median TNC and CD34 dose was 4.47x108 /kg and 4.84x106 /kg 

for BM/PBSCs and 4.0x107 /kg and 2.8x105 /kg for UCB, respectively. 

Probabilities of neutrophil, platelet engraftment and grade II-IV aGVHD 

were 100%, 92.9% and 47.5%, respectively. CLO dose was tolerable at 

52mg/m2 /d x5d without dose limiting toxicity. Probability of Day 100 TRM 

was only 4.3%. Probability of 1-yr PFS and OS were 51% (CI95: 28-71%), 

and 43% (CI95: 22-63%) respectively. Conclusions: Preliminary results 

suggest this novel regimen followed by AlloSCT is safe and well tolerated in 

CAYA with poor-risk ALL/ AML with CLO dose 52 mg/m2 . Results are 

encouraging with respect to low risk of day 100 TRM and leukemic relapse 

associated with this conditioning regimen in this poor-risk population. 


Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and 

GVL. Presenting Author: Alan M. Hanash, Memorial Sloan-Kettering Cancer 


Background: Intestinal graft vs. host disease (GVHD) is a major complication 

of allogeneic bone marrow transplantation (allo-BMT). Strategies to 

limit GVHD by selective promotion of epithelial regeneration in the absence 

of immunosuppression are largely unknown. Methods: We investigated the 

role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) 

mice as donors or recipients in allo-BMT. Results: We found that administration 

of an anti-IL-22 neutralizing antibody to allo-BMT recipients during 

the first month post-BMT led to increased GVHD mortality, indicating that 

IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of 

IL-22 KO donor T cells did not impair their ability to eliminate A20 

lymphoma cells upon tumor challenge, thus indicating that IL-22 was not 

essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. 

BMT with WT donors and recipients indicated that IL-22 levels in small and 

large intestine were increased after BMT and after radiation injury (RI) 

without BMT. IL-22 upregulation after RI was dependent on the presence 

of IL-23p40. Although intestinal IL-22 levels were increased after T 

cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 

production was mediated by host-derived innate lymphoid cells (ILC) that 

were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for 

reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in 

IL-22 KO mice led to increased apoptosis in epithelial crypts where the 

intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry 

and immunofluorescence demonstrated IL-22 receptor expression 

on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ 

reporter mice indicated that ISC were targeted by GVHD, and GVHD in 

IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical 

for protection of host epithelium during GVHD and critical for protection of 

ISC, and it does not contribute to donor T cell GVL responses. These 

findings may have broad relevance for protection of ISC and intestinal 

epithelium in clinical GVHD and other inflammatory intestinal diseases, 

and may be useful for clinical separation of pathologic GVH and therapeutic 

GVL responses. 




Outcomes of second allogeneic hematopoietic stem cell transplantation 

(SCT) for patients with acute lymphoblastic leukemia (ALL). Presenting 

Author: L. M. Poon, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: Disease relapse is the major cause of failure after allogeneic 

hematopoietic stem cell transplantation (SCT) for acute lymphoblastic 

leukemia (ALL). Treatment options for these patients (pts) are limited and 

only a second SCT provides a realistic chance for long term disease 

remission. Methods: We retrospectively analyzed the outcomes of 31 pts 

with ALL who relapsed following their first allogeneic SCT, and went on to 

receive a second allogeneic SCT. Univariate analysis was used to assess for 

risk factors which influenced treatment-related mortality (TRM), and 

progression free survival (PFS) following second SCT. Results: 31 pts were 

evaluable for response with 2 early deaths within 30 days of SCT. The 

median age of the pts was 26 years (range 7- 49), and the median duration 

between their first SCT (SCT1) to relapse was 9.5 months (range 2.2-32.6 

months). 39% of pts were transplanted in active disease (n�12). The 

complete remission (CR) rate post SCT was 89%; 83% of pts transplanted 

with active disease attained CR. With a median follow-up of 3 years among 

survivors, PFS, and OS rates at 1 year were estimated at 23%. The TRM 

rate was 41% at 12 months. We did not identify any factors that impacted 

TRM through univariate analysis. We found a significant relationship 

between the time to progression following SCT 1 and PFS following SCT 2 

(p�0.02, HR�0.93/month). Conclusions: In summary, a second transplant 

remains an effective method for achieving response in a highly refractory 

patient population. Pts with longer PFS following SCT1 have a better PFS 

following SCT2. While long-term survival is limited, a significant proportion 

of pts remain disease-free for up to one year following SCT2, providing a 

window of time to administer preventive interventions. Notably, our 4 

long-term survivors, received novel therapies in the form of a single 

umbilical cord blood unit in addition to the PBSC to augment the immune 

response (n�2), a change in the stem cell source for the SCT from cord to 

mismatched adult unrelated (n�1), and post SCT maintenance therapy 

with 5-azacytidine (n�1), underscoring the need for a fundamental change 

with the methods for the second transplant to improve outcome. 


Impact of antithymocyte globulin (ATG)-containing conditioning regimens 

on patients undergoing allogeneic stem cell transplantation (allo-CST) for 

poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report 

from the French Society of Stem Cell Transplantation and Cell Therapy 

(SFGM-TC). Presenting Author: Ibrahim Yakoub-Agha, University Hospital, 

Lille, France 

Background: Due to a risk of relapse of underlying disease in patients with 

PRC-MDS, the use of ATG, incorporated within the conditioning regimen 

prior to allo-SCT, is still controversial. Methods: Inclusion criteria included 

patients aged over 18 (n�101) who received allo-SCT transplanted 

between 1999 and 2009 from either a sibling (n�68) or HLA-allele-MUD 

(10/10) (n�33) for PRC-MDS. HLA matching was double-checked by the 

national Bone Marrow Donor Registry. Results: According to the FAB/WHO 

classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 

REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced 

disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or 

higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with 

progressive disease (relapsed/refractory, untreated or stable disease without 

hematological improvement). Median age at transplantation was 54 

years (range, 22-69). Pts received myeloablative conditioning (n�46) and 

nonmyeloablative (n�55). In this series, 48 patients received ATG as part 

of conditioning (’ATG’ group), whereas 53 did not (’no-ATG’ group). As of 

April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, 

overall and event-free survival rates were not significantly different between 

the two groups. In contrast, the cumulative incidence of grade 2-4 acute 

GVHD was 48% in the no-ATG group and 30% ATG group (P �.005). 

Although the cumulative incidence of chronic GVHD was similar in the 

no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG 

group (p�.06). In multivariate analysis, the absence of use of ATG was 

associated with an increased risk of acute grade 2-4 [HR � 1.92, p�.044]. 

Conclusions: The addition of ATG to the conditioning regimen resulted in a 

decreased incidence of acute GVHD without increasing relapse rates and 

compromising survival of patients undergoing allo-SCT for poor risk 

cytogenetic MDS. 


Randomized phase III trial of haploidentical HCT with or without an add 

back strategy of HSV-TK donor lymphocytes in patients with high-risk acute 

leukemia. Presenting Author: Claudio Bordignon, Università Vita-Salute, 

Istituto Scientifico San Raffaele; MolMed, Milan, Italy 

Background: Suicide gene therapy applied to allogeneic stem cell transplantation 

has been tested in several trials. When exposed to ganciclovir, donor 

lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK 

cells) are selectively eliminated. In a phase I-II trial (Ciceri, Bonini, Lancet 

Oncology 2009,489-500), TK cells were infused in patients after haploidentical 

transplantation. Of 50 patients enrolled, 28 received transduced-TK 

cells and 22 achieved rapid immune reconstitution, with a non-relapse 

mortality of 14%. GvHD after DLI-TK infusion was reported in 30% of 

patients and in all cases was fully controlled by ganciclovir treatment. 

Methods: High risk leukemia patients in first or subsequent complete 

remission are currently randomized in a 2-arm (3:1 ratio) phase III trial with 

or without the add-back strategy of HSV-TK donor lymphocytes in patients 

underwent T-depleted haploidentical stem cell transplant. Primary end 

point is disease-free survival (DFS), while secondary end points included 

overall survival, non-relapse mortality, immune reconstitution, acute and 

chronic GvHD incidence, and relapse incidence. For the primary analysis of 

DFS 170 patients (127 patients in the experimental group and 43 patients 

in the control) are required to detect an hazard ratio of 0.55 with at least 

80% power for 2-sided 0.05 level test. Patients are eligible for the study if 

they are older than 18 years-old, absence of timely and suitable HLA 

matched family or unrelated donor, and have a ECOG performance status � 

2. Patients are stratified by state of disease, ECOG PS and country before 

randomization. Results: Transduced lymphocytes are given to patients 

between day �21 and day �49 after haploidentical HCT in the absence of 

spontaneous immune reconstitution and/or development of GvHD. In 

absence of immune reconstitution and GvHD after the first TK-cells 

add-back further 3 infusions could be administered 30 days after the last 

infusion. TK lymphocytes dose is 1 x10^7 CD3/Kg. Conclusions: The study 

(TK008) is currently open to accrual in EU, US, Israel (clinicaltrials.gov: 

00914628). 


Minimum tolerable interval of 90yttrium ibritumomab-tiuxetan to autologous 

stem cell transplantation after high-dose chemotherapy with carmustin, 

etoposide, cytarabine, and melphalan for relapsed or refractory 

aggressive B-cell non-Hodgkin lymphoma. Presenting Author: Justin Hasenkamp, 

University Medicine Goettingen, Goettingen, Germany 

Background: High-dose therapy and autologous stem cell transplantation 

(ASCT) in patients (pts) with aggressive B-NHL failing from immunochemotherapy 

including rituximab show poor outcome with 3y PFS of 39% 

(Gisselbrecht et al. JCO 2010). Combining BEAM with 90yttrium ibritumomab 

tiuxetan is a promising option to enhance the efficacy of the 

high-dose regimen. Methods: Pts without disease progression during 

salvage therapy of relapsed or refractory CD20� aggressive B-NHL were 

included in this prospective, multicenter, phase I/II trial. Primary endpoint 

was the maximum tolerated dose of 90Yttrium ibritumomab tiuxetan given 

as close as possible to ASCT defined as �2 pts with dose limiting toxicity in 

a 6�6 pts cohort. First, we reduced the time interval of 90yttrium ibritumomab tiuxetan (0.4 mCi/kg body weight) to ASCT from 14 to 12 and 

then 10 days. Subsequently it was planned to increase the 90yttrium ibritumomab tiuxetan dose. Results: From 2006 to 2009 26 pts, median 

age 58y (34-66) were enrolled. Histology included 14 DLBCL, 6 FL III°, 5 

transformed FL and 1 aggressive B-NHL without further subtyping. 11/26 

pts had relapse/progression within 1y after diagnosis. Secondary IPI was 

�1 in 14 pts. Response to salvage therapy was CR in 6/26 pts and PR in 

12/26 pts. 20/26 pts achieved CR after ASCT. Engraftment showed no 

significant differences in pts of different cohorts with median recovery of 

leukocytes (�1/nl) and platelets (�25/nl) at d �10 and �13. Two early 

deaths (d �7, �18) occurred due to infections. 90Yttrium ibritumomab 

tiuxetan (0.4 mCi/kg body weight) at d -10 of ASCT was determined as 

minimum tolerated interval of radioimmunotherapy to ASCT after BEAM. 

Median follow-up of the survivors is 3.3 y. 3y PFS and OS is 67% (95% CI, 

49%-85%) and 75% (95% CI, 58%-92%), respectively. Main cause of 

death was relapse/progression with 27% (95% CI, 6%-38%) at 3y. 

Conclusions: Z-BEAM followed by ASCT was safe and feasible and results in 

a high response rate with durable remissions in rituximab pretreated 

patients with aggressive B-NHL. Extended studies at the maximum 

tolerated dose and confirmation of superiority compared to conventional 

ASCT are warranted. 



Allogenic stem cell transplant (ASCT) as initial salvage for patients (pts) 

with acute myeloid leukemia (AML) refractory to high-dose cytarabinebased 

induction chemotherapy. Presenting Author: Naval Guastad Daver, 


Background: Outcomes of pts with AML who are refractory to High-dose 

Cytarabine (HiDAC) based induction are dismal. ASCT as initial salvage 

may be effective and potentially superior to repeat induction with combination 

chemotherapies in such pts. Methods: 1597 AML pts were treated with 

HiDAC-based induction at MD Anderson Cancer Center between 1995 and 

2009. 285 primary refractory pts were identified. 28 (10%) of these 

underwent ASCT as initial salvage and were reviewed. Results: Median age 

was 56 years (36 to 77) and 50% were males. Median ECOG PS was 1 

(0-2). Antecedent hematological disorders were present in 14 pts (50%). 

Median white cell count, hemoglobin, platelet count and bone marrow (BM) 

blast percentage at diagnosis were 3.5 x 109 /l (0.6 to 73.6), 7.8 g/l (6.5 to 

11.4), 44 x 109 /l (9 to 615), and 43% (6-82), respectively. 9 pts (32%) 

had complex cytogenetics. FLT3 mutations were identified in 2 (15%) of 

13 evaluated pts. All pts were refractory to HiDAC-based induction. HiDAC 

was combined with an anthracycline in 16 pts (57%) and nonanthracycline 

in 12 pts (43%). Median time from induction to ASCT was 

76 days (28 to 184). Median BM blast and peripheral blast at ASCT were 

28% (3 to 82) and 4% (0 to 41). 21 pts (75%) had matched related donors 

(18 sibling and 3 haploidentical) and 7 (25%) had matched unrelated 

donors. Conditioning regimens were melphalan-based, busulfan-based, 

fludarabine-based or others in 7 (25%), 10 (36%), 8 (29%) and 3 pts 

(10%); respectively. Complete remission (CR) was achieved in 23 of 28 pts 

undergoing ASCT (CR � 82%) with median time to CR of 31 days (26 to 

134). 12 pts relapsed with median time to relapse of 5 months (2 to 19). 8 

pts remain alive with median follow up of 80 months (28 to 118). Median 

overall survival (OS) for the entire group is 20 months (5 to 118). In 

historical series of pts with AML refractory to HiDAC-based induction, 

salvage chemotherapies induced CR rates of 22% with median OS of 4 

months. Conclusions: Initial salvage with allogenic SCT is feasible and 

yields superior outcomes to salvage chemotherapy in primary HiDAC 

refractory AML pts. Randomized studies are warranted to further explore 

this treatment option. 


Neurotoxicity after high-dose melphalan. Presenting Author: Jose Eugenio 

Najera, M. D. Anderson Cancer Center Orlando, Orlando, FL 

Background: High dose melphalan (HDM) at 200 mg/m2 is the standard 

preparative regimen for patients with multiple myeloma (MM) and lightchain 

amyloidosis (AL) undergoing autologous hematopoietic stem cell 

transplantation (auto-HCT). Neurotoxicity has been seen with HDM. In this 

report we describe the incidence, clinical manifestations and outcome of 

HDM- associated neurotoxicity. Methods: We performed a chart review of all 

patients who received HDM and auto-HCT for MM or AL between January 

2007 to December 2009 at the University of Texas MD Anderson Cancer 

Center (MDACC). HDM- associated encephalopathy was defined as altered 

mental status, seizure or unexplained loss of consciousness within 30 days 

of auto-HCT. Patients with documented hemorrhagic or embolic stroke, or 

metabolic abnormalities were excluded. Results: 451 patients were included. 

Median age at auto-HCT was 59 years (range: 35-80). Thirty 

patients (6.6%) had AL and 61 patients (13.5%) had a pre-transplant 

serum creatinine of � 1.5 mg/dl. Nine patients (2.0%) developed HDMassociated 

encephalopathy with a median of 13 days (range 4-22) from 

auto-HCT. Among patients with encephalopathy, 8 (89%) developed 

changes in mental status ranging from drowsiness and confusion to loss of 

consciousness, while one patient had tonic-clonic seizures (11%). Of the 

affected patients there were 6 (66%) females, 8 patients (89%) � 59 years 

of age and only 2 patients (22%) had a creatinine clearance of � 60 

ml/min. One patient was dialysis-dependent. A CT scan or MRI was 

obtained in all 9 patients. Only one patient had imaging abnormalities 

reported as posterior reversible encephalopathy syndrome (PRES). Electroencephalogram 

(EEG) was performed on 6 patients. Epileptiform activity 

was seen in one patient with clinical seizures. Mild generalized slowing was 

noted in 2 other patients with mental status changes. Cerebrospinal fluid 

was obtained in 2 patients and did not show any abnormalities. Complete 

resolution of neurologic symptoms was seen in all patients prior to hospital 

discharge, and there were no deaths. Conclusions: HDM-induced encephalopathy 

was seen in only 2% patients, and it is associated with complete 

neurologic recovery without any increase in transplant-related mortality. 


427s 


A phase II trial 90y-ibritumomab tiuxetan in combination with reduced 

intensity regimen of fludarabine (flu) and melphalan (mel) followed by 

allo-HCT in patients with refractory B-cell lymphoma. Presenting Author: 

Auayporn Nademanee, City of Hope, Duarte, CA 

Background: RIC allo-HCT has reduced transplant-related mortality (TRM) 

in patients with relapsed NHL. However, relapses do occur despite 

potential graft vs. lymphoma (GVL) effect. We hypothesized that adding 

Zevalin to Flu/Mel may improve disease control and reduce relapse post 

allo-HCT. Methods: Patients received In- Zevalin on day -21 followed by 

90 2 Y- Zevalin 0.4mCi/kg on day -14, flu 25 mg/m daily on days -9 to -5 and 

mel 140 mg/m2 on day -4. Rituximab (R) level was measured on Day -22 

and -15 and if the level was � 10 �g/ml, R was not given prior to In-Zevalin 

or 90Y- Zevalin to enhance biodistribution. Tacrolimus and sirolimus was 

used for GVHD prophylaxis. Between 10/2007 and 11/2011, 31 were 

treated. Median age 55 (range 27-67), median regimen �3 (range 2-8). 

Median time from diagnosis to HCT was 20 mo (range 5-105). Histology: 

DLBCL (including transformed lymphoma)�14 (45%), MCL�7 (23%), 

FL�5 (16%) and SLL/CLL�5 (16%). Disease status at HCT: 1CR�7, 

Relapse�9, �2CR�5, primary refractory �10. Fifteen had chemoresistant 

and 19 had FDG PET� at HCT. Donors: sib�13, URD�18. Results: All 

patients engrafted with the median time to ANC �500 and platelet � 

20,000 was 14 (range 10-28) and 13.5 days (range 11-28), respectively. 

There were 10 deaths from disease progression (2) infection (5) GVHD (1) 

and multi-organ failure (2). TRM at day �100 and at 1 yr was 6.5% and 

17%, Five with DLBCL relapsed between 3-7 mos. Grade II-IV acute GVHD 

was 65%, Grade III-IV was 16%, chronic GVHD was 65%. Fifteen became 

PET- at day �100 while 4 remained PET� and relapsed. Twenty-one are 

alive at a median followup of 24 mos (range 2-46). The 2 yrs OS and PFS 

was 65% (95% CI, 51-75%) and 57% (95% CI, 46-67%), respectively. 

Univariate analysis identified disease status predict for OS and PFS while 

histology predict for PFS. Conclusions: This study demonstrates the 

feasibility of adding Zevalin to flu/mel in the allo-HCT setting for B-cell NHL 

and suggest that this approach could be used to provide early disease 

control before GVL effect takes place. Innovative approaches should be 

explored in DLBCL. 


Effect of radioimmunotherapy-based conditioning for autologous stem cell 

transplantation on poor-risk molecular profiling in diffuse large B-cell 

lymphoma. Presenting Author: Tanya Siddiqi, City of Hope, Duarte, CA 

Background: Gene expression profiling has improved risk stratification of 

diffuse large B-cell lymphoma (DLBCL) in the first line setting as shown by 

DNA microarray analysis and immunohistochemistry (IHC). 5-year overall 

survival (OS) for germinal center B-cell-like (GCB) DLBCL is significantly 

better than that for non-GCB DLBCL in newly diagnosed patients. However, 

in the relapsed/refractory setting, autologous stem cell transplant (ASCT) 

appeared to overcome the poor prognosis of cell of origin as defined by IHC 

using CD10, Bcl6 and MUM1 and there was no difference in survival 

between GCB and non-GCB groups. Ibritumomab tiuxetan (Z)-BEAM 

conditioning regimen for ASCT in DLBCL has produced promising response 

rates and progression free survival (PFS). The role of poor risk molecular 

markers in predicting outcome with the novel conditioning regimen 

Z-BEAM is unknown. Methods: We evaluated cell of origin (GCB, non-GCB) 

using IHC in 36 patients undergoing ASCT with Z-BEAM conditioning from 

2002 to 2010. Median age of the patients was 54.5 years. There were 12 

females and 24 males. 6 patients were in 1st CR/PR ( 17%), 12 had 

induction failure disease (33%), 9 were in 1st relapse (25%), 1 in 2nd relapse (3%) and 8 were in �2nd CR (22%). 27 patients had chemosensitive 

disease (75%) and all had prior rituximab exposure. Median number of 

prior treatments was 2. IPI at transplant was mainly low risk (78%). 22 

patients had GCB (61%) and 14 (39%) had non-GCB DLBCL. Results: 

Median follow up is 25.6 months. 12 patients relapsed (33%) and 9 died 

(25%). The major cause of death is relapse/disease progression. At 2 years, 

median OS is 79% and median PFS is 64%. No significant difference in 2 

year OS and PFS is noted between the GCB and non-GCB groups (p�0.07 

and 0.06 respectively). Conclusions: Z-BEAM conditioning for ASCT may 

overcome the poor prognostic effect of non-GCB DLBCL in relapsed/ 

refractory disease. Further evaluation of cell of origin using new markers 

like GCET1, LMO2 and FOXP1 could confirm these results as there seems 

to be better concordance of these markers with DNA microarray analysis. 




Dose-intensive cyclophosphamide, etoposide, cisplatin reinduction for 

relapsed/refractory aggressive non-Hodgkin lymphoma (r/r-aNHL). Presenting 

Author: Jan-Willem Henning, University of Calgary and Tom Baker 

Cancer Center, Calgary, AB, Canada 

Background: Approximately 2/3 r/r-aNHL patients (pts) respond to salvage 

R-ICE or R-DHAP, 1/2 proceed to autologous stem cell transplantation 

(ASCT), and 1/3 achieve 3 year (yr) progression-free survival (PFS); 

however, PFS is only 20% if prior Rituximab, time to progression (TTP)�1yr, 

or age-adjusted International Prognostic Index (aaIPI)�2-3 [JCO 2010;28: 

4184-90]. Since 1995, we re-induced poor prognosis r/r-aNHL with 

dose-intensive Cyclophosphamide 5.25g/m2 , Etoposide 1.05g/m2 and 

Cisplatin 105mg/m2 (DICEP), G-CSF days (d) 14-19, and apheresis 

d19,20, or 21. Rituximab was added d0,7 after 2006. Methods: We 

retrospectively analyzed 113 consecutive transplant eligible r/r-aNHL pts 

[diffuse large B-cell�95, transformed�9, peripheral T-cell�6, other�3] 

who received one cycle of DICEP (n�93) or R-DICEP (n�20) from 

1995-2009. Patient characteristics included: median age�49yr (22-69); 

primary refractory�68; TTP�1yr�85; elevated LDH�60; ECOG 2-4�42; 

aaIPI 2-3�59; bulk�10cm�26. Results: Of 113 pts, 77% responded to 

DICEP and 90% (102) proceeded to ASCT. The median CD34� cells 

collected was 19x106 /kg (0.3-142). Early treatment-related mortality 

(TRM) occurred in 3 pts (2.7%), and 4 others developed late second 

cancers (MDS/AML�2). With 94 months median follow-up (26-194), 5 

and 10yr OS rates for all 113pts are 48% and 41%, and PFS rates are 42% 

and 37%, respectively. 5 year PFS rates for ASCT vs no-ASCT are 46% vs 

9%, for relapse aaIPI�0-1 vs aaIPI�2-3 are 53.3% vs 32.1% (p�0.01), 

and for TTP�1yr vs �1yr are 63.9% vs 35.2% (p�0.009). Other 

predictors of inferior PFS in univariate analysis were elevated LDH, ECOG 

2-4, no response to DICEP; however, PFS for 27 pts who failed prior 

Rituximab-chemotherapy (56%) was similar to other 86 pts (38%) (logrank 

p�0.09). Predictors of PFS and OS in multivariate analysis include: 

TTP�1yr, elevated LDH, bulk, no response to DICEP. Conclusions: (R)DI- 

CEP is an effective re-induction regimen for r/r-aNHL, leading to excellent 

stem cell mobilization and a high chance of proceeding to ASCT. Long-term 

PFS and OS rates compare favourably to reports of other re-induction 

regimens, and a prospective multicentre trial is warranted. 


The comparison of up-front autologous peripheral stem cell transplantation 

in first remission and long-lasting intensive chemotherapy protocols in 

highly aggressive non-Hodgkin’s lymphomas: Results of a retrospective 

analysis. Presenting Author: Mustafa Ozturk, Gulhane Faculty of Medicine, 

Departments of Medical Oncology and Bone Marrow Transplantation Unit, 

Ankara, Turkey 

Background: Optimal therapy in adult patients with Burkitt’s and lymphoblastic 

lymphoma are still unknown. Despite long–lasting and intensive 

chemotherapy protocols, post-transplant relapse is common and the 

chemotherapy period is time consuming. Methods: In this retrospective 

study, the results of induction and consolidation chemotherapies followed-by 

high dose therapy (HDT) and autologous peripheral stem cell 

transplantation (APSCT) (n�21), which was given in a time period of 3 

months were compared to long–lasting and intensive chemotherapy protocols 

(LICP) (n�39) in patients with Burkitt’s and Lymphoblastic lymphoma, 

without bone marrow or central nervous system involvement at 

presentation. Cyclophosphamide, vincristine, prednisolone, doxorubicin 

(Adriamycin) with or without L–asparaginase were given as induction 

chemotherapy, followed-by a consolidation chemotherapy with DHAP and 

up-front HDT. Results: More than 60% of patients in both groups were in 

the intermediate and high risk group according to International Prognostic 

Index. There was no significantly difference according to age, gender, bulky 

disease, stage, Burkitt’s and Lymphoblastic lymphoma ratio in both groups 

(p�0,05). Median follow up was 32,3 months (min-max: 0-229 months). 

When HDT and LICP groups were compared: CR achieved in 76,3% and 

82,1% of patients (p�0,05); Median PFS was 10,4 months (min-max: 

6,1-20,3) and 10,1 months (min-max: 6,3- 69,0) (p�0,05); One year 

overall survival rate was 64,7% and 74,4% and five year overall survival 

rate was 50,1% and 56,7% (p�0,05) respectively. Conclusions: The 

current study suggests that induction and consolidation chemotherapies 

followed by HDT and APSCT have similar CR, PFS and OS rates when 

compared to more time consuming LICP therapies. This provides a short 

period of treatment with a high rate of survival in adult patients with highly 

aggressive lymphomas in first remission. 


Effect of lenalidomide induction therapy on peripheral blood stem cell 

collection in patients undergoing autologous stem cell transplant for 

multiple myeloma. Presenting Author: Divaya Bhutani, Karmanos Cancer 

Institute, Detroit, MI 

Background: Autologous stem cell transplant (ASCT) remains part of 

standard therapy for Multiple Myeloma (MM). Lenalidomide (LEN) is a 

newer, effective therapy for MM. It has been suggested that prior LEN 

therapy is associated with an increased risk of stem cell collection failure, 

particularly when only G-CSF is used for mobilization. Methods: We 

conducted a retrospective chart review of 310 consecutive MM pts who 

underwent pheresis to collect stem cells for first ASCT between July 1, 

2007 and June 30, 2011 at the Karmanos Cancer Institute. We compared 

differences in quantity of CD34 cells collected, days needed to collect the 

target number of cells (� 2.5 x 10*6 CD34� cells/kg), days to platelet and 

neutrophil engraftment. We also evaluated the association between CD34� 

cells collected and the number of cycles of LEN therapy. Results: Of 310 

patients, 90% were mobilized with only G-CSF initially. Patients were 

analyzed as two groups: LEN exposed (LEN(�); n � 128) and LEN 

naive(LEN(-); n � 182). Median age in both groups was 58 years. No 

differences in race, sex and MM stage distribution were observed between 

the two groups. The median number of stem cells collected in the LEN(�) 

group was significantly less than the LEN(-) group (6.46 vs. 7.56 x 10*6 

CD34 cells/kg; p� 0.0004). In addition, the median number of pheresis 

sessions required for adequate stem cell collection were significantly more 

in the LEN(�)group as compared to LEN(-) group (2 vs.1 sessions; 

p�0.002). In the LEN(�) group, there was a negative correlation between 

CD34� cells collected and the prior number of cycles of LEN (p�0.0001). 

There was no statistically significant excess in the number of stem cell 

collection failures with G-CSF in the LEN(�) group (7% vs. 4% p�0.31). 

All pts who failed collection after G-CSF were successfully collected with 

Cytoxan or Plerixafor priming. LEN exposure had no effect on post-ASCT 

neutrophil or platelet recovery. Conclusions: Although Lenalidomide exposure 

is associated with a slightly lower CD34� stem cell yield and on 

average an extra session of pheresis when G-CSF is used for mobilization, 

collection failure is uncommon and post-ASCT engraftment is normal. 


Validation of the M. D. Anderson Symptom Inventory multiple myeloma 

module. Presenting Author: Nina Shah, University of Texas M. D. Anderson 


Background: Validated scales exist for quality of life assessment in patients 

with multiple myeloma (MM); however, no existing tool comprehensively 

assesses disease- and treatment-related symptoms in these patients. The 

aim of this study was to validate a module of the M. D. Anderson Symptom 

Inventory developed for patients with MM (MDASI-MM). The MDASI-MM 

includes 13 core symptoms, 6 interference items, and 7 MM-specific 

items: constipation, muscle weakness, diarrhea, sore mouth/throat, rash, 

difficulty concentrating, and bone aches. Methods: The MDASI-MM was 

administered to 2 cohorts of patients with MM. The first cohort (N�86) 

consisted of cross-sectional symptom data from patients at the beginning 

of induction chemotherapy or autologous hematopoietic stem cell transplant 

(HSCT). This cohort was used to demonstrate i) known-group validity, 

by detecting differences in groups by performance status; ii) concurrent 

validity, by correlating selected items and subscales from the MDASI-MM 

with those from the Short Form Health Survey (SF-12) and the EORTC- 

QLQC30; and iii) reliability, by computing Cronbach alpha values. The 

second cohort (N�53) consisted of symptom data collected at 2 points: 

prior to transplant and 7 days post-HSCT. This cohort was used to 

demonstrate the sensitivity of the MDASI-MM to detect acute worsening of 

patients’ symptoms post-HSCT. Results: The MDASI-MM detected significant 

differences in symptoms and interference levels according to patients’ 

performance status (P � .001). MDASI-MM scores correlated with those 

from SF-12 subscales for physical, emotional, cognitive, and social 

functioning (all P �.001) and with comparable items from the EORTC- 

QLQC30 (such as pain, fatigue, difficulty concentrating, constipation, and 

diarrhea, all P � .001). Cronbach alphas were 0.85 for symptom severity 

and 0.87 for interference. The MDASI-MM’s overall mean scores worsened 

between pre- and post-HSCT (1.32 vs. 2.55 (range � 0-10), P � .001). 

Conclusions: The MDASI-MM is a valid, reliable, and concise tool that can 

be used to quantitatively assess symptom severity and interference in 

clinical trials and care of MM patients. 



Secondary neutropenia (SN) after autologous hematopoietic stem cell 

transplantation (AHSCT) in patients (pts) with lymphoma. Presenting 

Author: Sunita Nathan, Rush University Medical Center, Chicago, IL 

Background: Plerixafor for mobilization of autologous stem cells (ASC) has 

increased the yield of transplanted ASC and is evolving as an important 

option for mobilization. A prior study reported a 10% incidence of SN after 

AHSCT (BMT 2009 Aug; 44(3): 175-83). Incidence and outcome of SN in 

the setting of Plerixafor/G-CSF (P/G), is unknown. We report the incidence 

and possible etiology for the development of SN in pts undergoing AHSCT 

for lymphoma at our institution. Methods: Data from 80 consecutive AHSCT 

pts over a 2 year period were reviewed. All pts were mobilized using P/G. 

Demographics, AHSCT indication, prior therapies (Rx), conditioning regimen 

(CR), engraftment and post-transplant complications were identified 

and collected. SN was defined as ANC �1000 after initial engraftment. 

Results: 80 pts underwent an AHSCT for lymphoma from 2009-11. 70 pts 

had evaluable data. 37 (52.86%) pts (average age 55.4 yrs) were male and 

33 (47.14%) pts (average age 48.3 yrs) female. 25 (35.7%) pts had �2 

comorbidities. Indications included relapsed/ refractory B-NHL, T-NHL 

and HL. 47 (67%) pts had Stage IV ds, 48.9% with BM involvement. 17 

(24.3%) pts had �2 Rx, 18 (25.7%) with loco-regional XRT and 3 (4.3%) 

with RIT. CR included BEAM, BEC and Benda-EAM �/- Rituxan. # of 

CD34� cells given ranged; 1.77-19.99 x 10^6/kg. Neutrophil engraftment 

occurred at a median of 11 days. 26 (37.14%) pts developed SN 

possibly from PCP prophylactic antibiotics and infections. Prior BM 

involvement, Rx or XRT had no role. 5 (45.4%) pts with Benda-EAM CR had 

SN. Associated morbidity/mortality were not noted. Conclusions: We conclude 

that secondary neutropenia is common after autologous stem cell 

transplant using the Plerixafor/GCSF combination for mobilization and is 

higher than reported in the literature (37% vs 10%). Patients who received 

this combination for mobilization should be followed up closely in the 

post-transplant period for secondary neutropenia. About half the patients 

who received the Benda-EAM conditioning regimen developed secondary 

neutropenia warranting its use with caution outside of a clinical trial. 


An anthropometric study in children with chronic myeloid leukemia on 

imatinib. Presenting Author: Vamshi Krishna Reddy Goteke, Nizam’s 

Institute of Medical Sciences, Hyderabad, India 

Background: The long-term adverse effects, especially in children with 

chronic myeloid leukemia (CML) on imatinib are unknown. There is very 

little literature addressing the adverse effects on growth in children on 

imatinib. We analysed the effect of imatinib on anthropometry in children 

with CML. Methods: The records of children � 18 years with CML diagnosed 

at our institute between 2003 and 2011 were retrospectively analysed. 

Children who received imatinib for at least one year and on regular follow up 

were eligible for growth assessment. The data was analysed using WHO 

AnthroPlus v1.0.4 and SPSS.v19 software and the Height for age and BMI 

for age/sex “z” scores were computed. Results: A total of 61 children were 

started on imatinib. But, only 37 children were eligible for assessment of 

growth. Of them 3 were further excluded as the WHO AnthroPlus software 

supported data only till 19 completed years. Median age was 12 years 

(range: 5 – 17). 17 children were in the prepubertal age (5-11years) at 

commencement of imatinib. The mean duration of imatinib therapy was 

41.24 months (range: 12–91). The overall z- scores for height for age 

(HAZ) on follow up were significantly (p �0.029) lower, compared to 

baseline. However when analysed according to age groups, the HAZ was 

found significantly (p�0.005) lower among 5-11 year age group compared 

to age group of �12 years. No significant differences were observed in BMI 

for age/sex z scores by age groups, over the period. Conclusions: Imatinib 

appears to cause growth retardation in prepubertal children. Further follow 

up may shed more light on the degree of stunting and the deficit in the final 

adult height. 


429s 


Cost-effectiveness analysis of bendamustine plus rituximab versus CHOP-R 

in treatment-naive patients with mantle cell (MCL) and indolent lymphomas 

(IL). Presenting Author: Wayne Su, United BioSource Corporation, 

Bethesda, MD 

Background: To assess the cost-effectiveness of bendamustine plus rituximab 

(B-R) vs cyclophosphamide, doxorubicin, vincristine, prednisone, 

and rituximab (CHOP-R) for treatment-naive patients with MCL or IL from a 

US healthcare payer perspective. Methods: A discrete event simulation was 

developed for a mixed population of patients with MCL or IL. Two arms were 

simulated, each containing 1000 identical MCL or IL patients treated with 

B-R or CHOP-R. Input data for baseline characteristics, overall response, 

and risks for treatment-related adverse events (AEs) and infections were 

obtained from the NHL 1-2003 trial (n�549, primarily stage IV MCL and 

IL); gaps were filled by consultation with experts. Direct medical costs and 

utilities were estimated based on US databases and published literature. 

Costs and benefits were discounted at 3% per annum. Base case model 

predictions were performed by selecting regression models that had a best 

fit to progression free survival (PFS). Robustness of these models was 

evaluated by testing other models with reasonably good fit. Results: In the 

base case, model predicts longer PFS for B-R than for CHOP-R in MCL 

(average of 49.8 vs 28.6 months) and IL (67.9 vs 51.0). Quality-adjusted 

life-years (QALYs) per patient were higher for B-R than CHOP-R for MCL 

(3.51 vs 2.68) and IL (4.42 vs 3.58). For MCL, total per-patient costs were 

$115,191 for B-R and $100,261 for CHOP-R; for IL, respective costs were 

$134,814 and $110,065, resulting in incremental cost-effectiveness 

ratios (ICERs) for B-R vs CHOP-R of $18,161 per QALY for MCL and 

$29,549 for IL (ICER�$50,000 to be cost-effective). Higher complete 

and partial response rates for B-R than for CHOP-R impacted subsequent 

treatment costs, which were lower for B-R by $21,632 for MCL and 

$24,961 for IL, as well as AE costs, lower by $10,113 and $10,570, 

respectively. The model results were robust with respect to the use of 

alternative regression models for PFS estimation. Conclusions: In patients 

with MCL or IL, the model demonstrates that B-R is a cost-effective 

alternative to CHOP-R. Alternative regression models confirmed robustness 

of results. Support: Teva Pharmaceutical Industries Ltd. 


Prevalence of autoimmune manifestations in patients with large granular 

lymphocytic leukemia: Exploratory analysis of a series of consecutive 

patients. Presenting Author: Bruno Bockorny, Department of Medicine, 

University of Connecticut, Farmington, CT 

Background: Review of literature suggests certain autoimmune abnormalities 

to accompany LGL leukemia. The present study was set to identify the 

prevalence of autoimmune phenomena in LGL leukemia patients and 

compare it with same in general population. Methods: We conducted both 

retrospective and prospective analyses in a series of consecutive patients 

(n�11) with LGL leukemia that had been followed in outpatient setting. 

Median age was 71 years ( � 14 years). The presence of associated 

autoimmune disorders in our cohort was compared to the published 

prevalence of these conditions in general population. Statistical analysis: 

The obtained values were tested for statistical significance using Fisher’s 

exact test for small number of observations (95% confidence); a p value � 

0.05 was considered significant. Results: A total of 45% patients in our 

study were diagnosed with autoimmune conditions. Identified autoimmune 

disorders included rheumatoid arthritis [RA] (n�3), Hashimoto thyroiditis 

(n�3), Felty syndrome (n�1), aplastic anemia (n�1), pernicious anemia 

(n�1), and leukocytoclastic vasculitis (n�1). Statistical analysis showed 

the following significance: Hashimoto thyroiditis (p�0.044), RA (p�0.003), 

Felty syndrome (p�0.001), aplastic anemia (p�0.001), pernicious anemia 

(p�0.001), and leukocytoclastic vasculitis (p�0.001). Statistical 

difference was also noted for autoimmune serologic abnormalities, with 

ANA positivity present in 63.6% of the cases (p� 0.001) and RF present in 

50% of the patients (p�0.005). Conclusions: Nearly half of LGL leukemia 

patients in our cohort had autoimmune conditions, thus significantly 

exceeding the overall prevalence in general population. Statistically significant 

differences were recorded for RA, Hashimoto thyroiditis, Felty syndrome, 

aplastic anemia, pernicious anemia, leukocytoclastic vasculitis, 

ANA and RF positive serologies. The prevalence of Hashimoto thyroiditis 

and ANA positivity in our patient cohort was significantly higher than the 

one in existing literature. Given the relatively small size of the analyzed 

cohort, larger studies are expected to confirm our findings. 




Maintenance therapy with arsenic after induction in an alternative and 

long-term case for the prevention of recurrence of acute promyelocytic 

leukemia during the period between November 2005 and December 2011. 

Presenting Author: Mozaffar Aznab, Kermanshah University of Medicine, 

Kermanshah, Iran 

Background: Arsenic trioxide has been used in the first line treatment of 

acute promyelocytic leukemia and also for recurrence after ATRA and 

chemotherapy. In this study, it we used it in induction of remission and 

maintenance therapy Methods: Between November 2005 to December 

2011, 42 patients admitted in our department with APL diagnosis. There 

were 27 male and 15 women with a median age of 28 years. Arsenic 

trioxide started at 0.15 mg/kg intravenous infusion till patient’s bone 

marrows achieve to complete remission. Then, after 28 days rest, we did 

consolidation with Arsenic trioxide with the same dosage for 28 more days. 

We continued treatment with 14 days courses of Arsenic trioxide every 3-4 

months for 2 years, as maintenance therapy Results: Four patients died 

during the first 20 days of treatment. Thirty-eight patients achieved to 

remission. Two patients refused to continue treatment after achieving to 

remission and excluded from this study. Thirty-six patients finished whole 

treatment. After a median follow-up of 54 months, 4 patients died due to 

disease relapse and one patient relapsed and initiated treatment with 

Arsenic and ATRA. Five patients faced leukocytosis over 100,000/ml. In 

these cases we were obligated to discontinue Arsenic for 3-4 days and did 

chemotherapy by Danourobicin for 2 days. Totally 8 patients died during 

remission induction and long-term follow up. One year, 3 and 5 years RFS 

were 97%, 87.1% and 79.4 respectively and we didn’t observe any relapse 

for patients who remained in remission after 5 years. Finally, 31 patients 

are alive and free of disease. The overall survival was 79.5% for our cohort. 

Conclusions: Arsenic trioxide is an effective treatment as the first line 

therapy for new cases of APL and long term therapy with will reduce the risk 

of diseases recurrence without any major toxicity in long time. 


Response rates in patients with relapsed/refractory acute myeloid leukemia 

with FLT3-ITD mutation using 5-azacitadine plus sorafenib. Presenting 

Author: Mona Lisa Alattar, University of Texas at Houston Health Science 


Background: The outcome of patients with relapsed acute myeloid leukemia 

(AML) with FLT3-ITD mutation is poor. Sorafenib is an inhibitor of FLT-3 

kinase activity in nanomolar concentrations. We conducted this phase II 

study to evaluate the efficacy and tolerability of the combination of 

Sorafenib and 5-Aza for the treatment of patients with refractory or 

relapsed AML with the particular emphasis on those with FLT3-ITD 

mutation. Methods: Patients were eligible if they had relapsed or refractory 

AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 daily 

x 7 together with Sorafenib 200 mg BID X 28 days; cycles were repeated in 

approximately 1-month intervals. Responses were assessed after first cycle 

and then at the discretion of the treating physician at the time of the best 

peripheral blood response. Results: 32 patients with AML with a median age 

of 61 years (range, 24-87) were enrolled. They included 13 (41%) with 

diploid cytogenetics, 9 (28%) with complex cytogenetics, and 10 (31%) 

with miscellaneous chromosomal abnormalities. FLT-3-ITD was detected 

prior to the initiation of treatment in 30/32 patients. Patients had received 

a median of 2 prior treatments (range, 1-6). 12 (38%) patients had 

received �3 prior regimens and 11 had failed therapy with a FLT3 kinase 

inhibitor (6 with AC220, 1 with PKC412, and 5 with sorafenib, either as 

monotherapy or with plerixafor); 2 had failed 2 prior FLT3 inhibitors. 10 

patients were inevaluable as they never received therapy or discontinued it 

before response assessment at one month. The overall CR/CRi rate among 

the 22 evaluable patients is 50%, including 9 (41%) with CRi and 2 (9%) 

with CR; with a median of 3 (range, 1-9) treatment cycles. The median time 

to achieving CR/CRi was 3 months (range, 1-4) and the median duration of 

CR/CRi was 3 months (range, �1–5.5). Three patients proceeded to 

allogeneic stem cell transplant. The most common study drug-related 

adverse events were rash and fatigue with no deaths attributable to study 

medications. Conclusions: Combination of 5-Aza and Sorafenib is promising 

for the treatment of patients with relapsed and refractory AML with 

FLT-3-ITD mutation and may allow them to proceed to stem cell transplant. 


Effect of ROR1-targeting small molecules on chronic lymphocytic leukemia 

(CLL) cells. Presenting Author: Hakan Mellstedt, Karolinska University 

Hospital Solna, Stockholm, Sweden 

Background: There is a great interest to develop targeting drugs for CLL, 

both MAbs and small molecules, to improve the outcome for the disease. 

ROR1, a receptor tyrosine kinase, is overexpressed on CLL cells but not on 

normal cells. ROR1 is constitutively phosphorylated and siRNA transfection 

induces leukemic cell death. The aim of the study is to produce small 

molecules inhibiting the cytoplasmic tyrosine kinase activity of ROR1, 

which could induce specific killing of leukemic cells. Methods: A highthroughput 

screening assay in 384-format has been developed measuring 

phosphorylation of a substrate peptide by human recombinant intracellular 

ROR-1 kinase domain. A collection of 80.000 small molecules has been 

screened generating two chemical series. Novel leads have been synthesized 

and structure-activity-relationship has been developed using the 

assay. Results: Three compounds were selected (KAN0173631, 

KAN0438063, KAN0438175T). Freshly isolated leukemic CLL cells were 

used as targets in addition to PBMC from healthy donors to test cytotoxicity. 

The three compounds induced specific apoptosis of CLL cells (Annexin V/PI 

and MTT) both at 24 and 48h. Efficacy index (EI), i.e. killing of leukemic 

cells in relation to normal PBMC was favourable. The most promising drug 

KAN0438063 had an EI of 40 i.e. killed 40 times more CLL cells than 

PBMC at an IC50 of 10�M. The compounds induced PARP cleavage and 

cleavage of caspases 8 and 9 as well as down regulation of Mcl-1 and Bcl-xl 

(Western Blot). ROR1 was dephosphorylated (Western Blot). The selective 

apoptotic effect was compared to other small molecules targeting non- 

ROR1 structures in CLL (PCI-32765, CAL-101, R406, R788, STK- 

156485, STK-156133) and our compounds were significantly more 

effective (EI) (p�0.001). Conclusions: We have developed effective and 

selective series of compounds targeting ROR1 with promising ADMET 

properties. ROR1 targeting small molecules might also be effective for 

other tumor cells expressing ROR1 as has been noted for e.g. pancreatic 

carcinoma cells. Our model molecules will be further optimized and tested 

in animal tumor models. These molecules represent the first small 

molecules targeting ROR1 – a “survival factor” in CLL. 


Post hoc analysis of relationship between baseline white blood cell count 

and survival outcome in a randomized phase III trial of decitabine in older 

patients with newly diagnosed acute myeloid leukemia. Presenting Author: 

Chris Arthur, Royal North Shore Hospital, St. Leonards, Australia 

Background: In a large phase III trial (N�485), patients (pts) �65y with 

newly diagnosed acute myeloid leukemia (AML) received 1-h IV infusion of 

decitabine (DAC) 20 mg/m2 for 5 consecutive days every 4 wk or treatment 

choice (TC) with supportive care or cytarabine 20 mg/m2 subcutaneous 

injection for 10 consecutive days every 4 wk (NCT00260832; Kantarjian et 

al. JCO, in press). Enrolled pts had white blood cell (WBC) count �40 

x109 /L; baseline WBC counts were relatively low (median [range] DAC: 3.1 

x109 /L [0.3-127.0]; TC: 3.7 x109 /L [0.5-80.9]). This post hoc analysis 

assessed baseline WBC count and survival outcome. Methods: Overall 

survival (OS) and progression-free survival (PFS) were summarized by 

baseline WBC subgroups (�1, 1-5, �5 x109 /L). Results: Mature survival 

data (2010) were based on intent-to-treat (ITT) population (446 deaths: 

TC, n�227; DAC, n�219). OS was 5.0 mo for TC vs 7.7 mo for DAC 

(nominal P�.037). For each WBC subgroup, differences in OS for TC vs 

DAC were not significant (NS), but hazard ratios (HR) favored DAC for all 

subgroups (Table). There was a significant difference in PFS in favor of DAC 

for patients with baseline WBC 1–5 x109 /L (P�.005; HR�0.67) and �5 

x109 /L (P�.027; HR�0.71). Conclusions: These data are consistent with 

overall results, with a trend toward improved outcome with DAC regardless 

of baseline WBC count in older pts with newly diagnosed AML. Further 

analyses are warranted. 

Outcome WBC x10 9 /L 

TC 

Median, a mo 

Event/n 

OS All pts 5.0 

227/243 

�1 4.9 

20/22 

1-5 5.9 

106/115 

�5 4.3 

94/99 

PFS All pts 2.1 

221/243 

�1 2.2 

20/22 

1-5 2.9 

110/115 

�5 2.1 

98/99 

DAC 

Median, a mo 

Event/n 

7.7 

219/242 

8.6 

22/25 

9.5 

104/119 

6.3 

88/93 

3.7 

221/242 

5.5 

24/25 

3.8 

111/119 

3.4 

89/93 

Nominal P value b 

HR (95% CI) c 

P�.037 

HR�0.82 (0.68, 0.99) 

P�NS 

HR�0.85 (0.42, 1.70) 

P�NS 

HR�0.78 (0.58, 1.03) 

P�NS 

HR�0.82 (0.60, 1.10) 

P�.003 

HR�0.75 (0.62, 0.91) 

P�NS 

HR�1.05 (0.56, 1.97) 

P�.005 

HR�0.67 (0.51, 0.89) 

P�.027 

HR� 0.71 (0.53, 0.97) 

a Kaplan-Meier product limit estimates. b 2-sided log-rank test. c Stratified Cox regression 

model (age and cytogenetic risk as strata; treatment group as covariate). HR �1 means 

advantage for DAC. 



Increased risk of MDS/AML post radiation treatment for breast cancer: 

Analysis of SEER data 2001-2008. Presenting Author: Henry G. Kaplan, 

Swedish Cancer Institute, Seattle, WA 

Background: Ionizing radiation is a known cause of myeloid leukemia, but it 

is not known whether therapeutic doses for breast cancer (BC) pose risk. We 

hypothesized that BC radiation treatment is associated with increased risk 

of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)) 

as seen in a previously conducted institutional cohort study. Methods: We 

used 2001-2008 Surveillance, Epidemiology and End Results (SEER) 

database records to identify a cohort of first primary BC patients treated 

with radiation who were unlikely to be treated with chemotherapy (stage 0 

and estrogen receptor positive (ER�) stage I). We identified subsequent 

MDS/AML diagnoses in the BC cohort, using SEER to query appropriate 

ICD-O-3 codes. We compared observed MDS/AML rates in the BC cohort to 

expected rates, estimated for first primary MDS/AML in the entire population, 

and calculated observed/expected rate ratios with 95% confidence 

intervals (CI). Results: We estimated an increased overall risk of MDS/AML 

in the breast cancer cases treated with radiation compared to the general 

population (RR�4.23, 95% CI 3.41, 5.18). The relative risk was higher for 

stage I ER� breast cancer cases �65 years of age (RR�7.75, 95% CI 

5.18, 11.05) than for stage 0 cases �65 years of age (RR�3.65, 95% CI 

1.57, 7.05). Among women 65 years and older, there was a more modest 

increased risk, only seen for stage 1 ER� breast cancer cases (RR�1.52) 

(table). Conclusions: Our results suggest that radiation treatment for breast 

cancer is associated with increased risk of MDS/AML. The effect appears to 

be age-dependent. 

Expected and observed MDS/AML incidence rates in breast cancer cases 

with radiation treatment (per 100,000 person years). 

Expected 

rate 

Person 

years 

Observed rate 

(n�cases) 

Rate ratio 

(95% CI) 

Stage 0, age



Prognostic implication of monosomal karyotype in patients with acute 

myeloid leukemia who received allogeneic hematopoietic cell transplantation. 

Presenting Author: Yunsuk Choi, Department of Hematology, Asan 

Medical Center, University of Ulsan College of Medicine, Seoul, South 

Korea 

Background: Monosomal karyotype (MK), defined as at least two autosomal 

monosomies or one single autosomal monosomy with one or more structural 

cytogenetic abnormalities, has been associated with worse outcomes in 

acute myeloid leukemia (AML). We evaluated the prognostic impact of MK 

on outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) 

in AML. Methods: We retrospectively analyzed 169 adult patients with AML, 

who received allo-HCT in the first complete remission (CR) between 2000 

and 2009. All patients had cytogenetic results at the diagnosis of AML. 

Patients were classified as having good, intermediate, or poor risk cytogenetics 

according to the NCCN guideline, and MK status was also determined. 

Results: MK was observed in 12 patients (7.1%); of whom, 11 patients also 

had complex karyotype (CK). Compared to patients without MK, those with 

MK had significantly lower overall survival (OS) (62.2% vs. 0%) and event 

free survival (EFS) (58.9% vs. 0%), and higher relapse probability (RP) 

(22.9% vs. 66.7%) at 5 years (all, p�0.001). 22 patients with CK also 

showed inferior outcomes, but CK with MK was associated with more 

inferior outcomes than CK without MK. Multivariate analysis showed that 

MK had a significantly adverse impact on OS (hazard ratio [HR], 5.192; 

p�0.001), EFS (HR, 4.531; p�0.001), and RP (HR, 6.558; p�0.001) 

after allo-HCT (Table). Conclusions: MK is a major prognostic factor 

predicting extremely worse outcomes in AML patients who underwent 

allo-HCT in the first CR. 

Multivariate analysis. 

OS EFS RP 

HR (95% CI) p HR (95% CI) p HR (95% CI) p 

WBC count, >60 

(x103 /�L) 

1.990 (1.107-3.576) 0.021 1.885 (1.074-3.307) 0.027 - 

Time from diagnosis to 2.621 (1.216-5.650) 

HCT, >250, days 

Cytogenetics 

0.014 2.378 (1.115-5.071) 0.025 2.749 (1.140-6.629) 0.024 

Good 0.755 (0.231-2.463) 0.634 (0.196-2.054) 0.447 0.766 (0.180-3.248) 0.717 

Intermediate 1 1 1 

Poor, CK- 1.286 (0.576-2.872) 0.539 1.098 (0.496-2.435) 0.817 3.199 (1.338-7.648) 0.009 

Poor, CK�, MK- 1.686 (0.703-4.043) 0.242 2.171 (1.014-4.648) 0.046 3.525 (1.506-8.252) 0.004 

Poor, CK�,MK� 5.192 (2.552-10.561) �0.001 4.531 (2.255-9.108) �0.001 6.558 (2.739-15.703) �0.001 


Bendamustine retreatment of CLL in the outpatient setting. Presenting 

Author: Georg Guenther, Oncological Medical Practice, Potsdam, Germany 

Background: Several studies have proven that bendamustine is a highly 

active drug in the therapy of CLL (Knauf et al. J Clin Oncol. 2009;27:4378- 

84; Fischer et al. J Clin Oncol. 2011;29:3559-3556). Nevertheless, only 

few data exist about the real-life use and efficacy of bendamustinetherapies 

in the non-trial setting. The project group of internal oncology 

(p.i.o.) therefore implemented a registry for patients in the routine use of 

bendamustine in the therapy of CLL (Sauer et al. Onkologie 2010;33(suppl 

6):12). Since 2008 a total of 616 patients have been registered, out of 

which 473 have been thoroughly documented. To evaluate whether a 

retreatment with bendamustine in relapsed CLL is still active and well 

tolerable we present comparative data on therapies in patients with (group 

A) or without (group B) bendamustine pretreatment. Methods: 228 documented 

patients in relapsed situation were retrospectively appointed to one 

of two groups (see table below). Results: In Group A the ORR was 80 % and 

the median PFS lasted 15.6 month. In the patients without prior bendamustine 

treatment the ORR was 84% and the median PFS lasted 21.2 month. 

In both groups the median OS has not been reached yet. The grade 3/4 

toxicities were mostly hematologic and comparable in both groups. Similar 

grade 3/4 toxicities were observed for neutropenia (about 25% of the 

patients), thrombocytopenia (16%) and infections (5%). Conclusions: 

Bendamustine is broadly used in the routine treatment of CLL. Bendamustine-therapies 

show impressionable high activity and tolerability, even in an 

advanced-line context with prior exposition to bendamustine. The treatment 

results are comparable to results of clinical trials and underline the 

quality and feasibility of bendamustine in the outpatient treatment. 

Nevertheless, it is to note that this is a registry and that both groups 

therefore are not composed of randomized patient-populations (cf. ECOG, 

patients in lines and ratio of rituximab combinations). 

Group A Group B 

n 83 145 

Gender m/w 53/30 88 /57 

Median age (range) 51-84 (74) 45-93 (72) 

Ratio B/B�rituximab in % 57/43 51/49 

ECOG 0/1/2 in % 11/64/25 21/64/15 

Binet A/B/C in % 4/54/42 4/45/51 

Line 2./3./4./5./6.� in % 30/30/22/13/5 56/26/10/6/2 

Med. B-dose-intensity over 4 weeks 151,9 mg/m² 151,3 mg/m² 


Predicting outcome based on minimal residual disease (MRD) using 

multiparameter flow cytometry (FC) in acute myeloid leukemia (AML) 

patients (Pts). Presenting Author: Sagar D. Sardesai, Roswell Park Cancer 

Institute, Buffalo, NY 

Background: Most AML pts will experience relapse caused by persistent 

leukemic cells during complete remission (CR). The aim of our study was to 

predict outcome in AML pts in CR by assessing their MRD using standard 

4-colour FC panels available at our institute. Methods: We queried our AML 

database between 1/2004 to 10/2010 for newly diagnosed untreated AML 

pts �18 years of age who achieved CR after one induction regimen. 

Treatment included 7�3 or similar intensive approaches. The gating 

strategy used a series of Boolean regions that best defined the diagnostic 

abnormal population based on its expression patterns using three 4-colour 

FC panels (F7-CD38,CD10,CD19,CD34; F9-C11b,CD33,CD13,CD34; F38- 

CD15,CD56,CD7,CD34). The same regions were applied to post-induction 

samples, and the number of residual events was determined. Results: 140 

AML patients with a median age of 64 (range 24-93) years, including 74 

females (52.8%) were analyzed; 67 (47.8%) patients relapsed. Eightyeight 

(62.8%) pts were CD34-positive (CD34�) at diagnosis. Normal 

karyotype was detected in 27 (30.7%): FLT-3 ITD was detected in 4/23 

(17.4%) and NPM-1 mutation was detected in 1/15 (0.07%) samples. 

Median follow-up for CD34� pts was 17.9 months. Forty-two (30%) pts 

underwent stem cell transplantation (SCT) in first CR: 31 (22.1 %) were 

allogeneic and 11 (7.9%) autologous. In multivariate analysis, a detectable 

MRD in any of the 3 panels at or beyond week 16 among CD34� AML pts in 

CR was significantly associated with inferior relapse free survival (F7: 

P�0.035 , F9: P�0.027, F38: P�0.042). In addition, MRD � week 16 

using panel F9 was also significantly associated with inferior overall 

survival (P�0.0224). In pair-wise comparison, those who were MRDnegative 

� week 16 did not benefit from SCT compared to the non-SCT 

group. Similar analyses among CD34– AML pts did not achieve statistical 

significance. Conclusions: MRD� by FC in CD34� AML is an independent 

prognostic factor and can identify pts who may benefit from SCT/more 

intensive therapy to maintain remission. However, the value of studying 

MRD in CD34– AML requires further consideration. More effort is needed 

to identify stem cells in CD34– AML. 


Effect of epitopes derived from the mutated region of cytoplasmatic 

nucleophosmine 1 (NPM1) on CD4� and CD8� T-cell responses in 

patients with acute myeloid leukemia. Presenting Author: Jochen Greiner, 

Department of Internal Medicine III, University of Ulm, Ulm, Germany 

Background: Mutations of the nucleophosmin gene (NPM1mut) are one of 

the most frequent molecular alterations in AML and constitute an important 

prognostic marker. The impact of NPM1mut on leukemogenesis and 

progression remains to be elucidated. Immune responses against NPM1mut 

might contribute to the favourable prognosis of AML patients with 

NPM1mut. Therefore, we examined T cell responses against NPM1mut. 

Methods: NPM1 wildtype as well as NPM1mut were screened for HLA- 

A*0201 binding T cell epitopes with the help of different algorithm 

programs. Ten peptides with most favourable characteristics were tested 

with ELISpot analysis for interferon-� and granzyme B in 33 healthy 

volunteers and 30 AML patients. Tetramer assays against most interesting 

epitopes were performed and chromium release assays were used to show 

the cytotoxicity of peptide-specific CD8� T cells. Moreover, HLA-DRbinding 

epitopes were used to test the role of CD4� T cells in NPM1 

immunogenicity. Results: Two epitopes (#1 and #3) derived from NPM1mut 

induced CD8� T cell responses in a high frequency. In healthy volunteers, 

immune responses were detected in 39%/18% against #1 and #3, and in 

33%/44% of NPM1mut AML patients against #1 and #3. NPM1-peptide 

primed effector T cells showed specific lysis of pulsed T2 cells as well as 

leukemic blasts in chromium release assays. In tetramer assays a significant 

CD8� T cell population could be detected. To obtain a robust and 

continuous T cell reaction, the help of CD4� T cells is indispensable. 

Therefore, we investigated the increase of CD8� T cell responses by the 

activation of CD4� T cells stimulated with longer peptides called overlapping 

peptides (OL). Potent HLA-DR epitopes were predicted and several 

favourable peptides (OL 1 to 8) were synthesized. OL8 showed favourable 

results to activate both CD8� and CD4� T cells. Conclusions: Taken 

together, NPM1mut represents a candidate for immunotherapeutic approaches 

and we hypothesize that it is also potentially involved in 

immunogenic rejection of NPM1mut leukemic blasts. Therefore, NPM1mut 

is a promising target structure for specific immunotherapies in AML 

patients. 



Incidence of second and secondary malignancies in patients with CLL: A 

single institution experience. Presenting Author: Samir Dalia, H. Lee 

Moffitt Cancer Center & Research Institute, Tampa, FL 

Background: Patients with chronic lymphocytic leukemia (CLL) have a 

higher incidence of second malignancies than the general population with 

one study showing the risk at 2.2 times the general popualtion. The 

increased incidence is thought to be due to immunosupression which 

results in decreased cell surveillance and proliferation of malignant cells. 

Our study aims to present the rate of second malignancies by cancer type in 

patients with CLL at our institution. Methods: The Moffitt Cancer Center 

Total Cancer Care (TCC) database was used to identify patients who had a 

diagnosis of CLL between January 1993-December 2009. Individual 

charts were reviewed to confirm the diagnosis of CLL, collect demographic 

data, and to assess for the presence of a second malignancy under an IRB 

approved protocol. A second malignancy was defined as another malignancy 

or transformation of CLL reported in the medical record. Second 

malignancy data was placed in three categories; skin cancers, solid tumor 

malignancy, and hematologic malignancy. Results: 546 CLL patients were 

included in the study. Median age was 62.5 years. 84 (43%) were Stage 0 

and 62 (32%) were Stage 1 RAI at diagnosis indicating earlier disease. 266 

(49%) patients had a second or secondary malignancy. A total of 304 

cancers were identified. 14% of patients had more than one malignancy. 

Melanoma was identified in 44 (16.5%) patients and non-melanoma skin 

cancer was identified in 54 (20%). Lung cancer was identified as the most 

frequent solid tumor malignancy with 36 (13.5%) cases, followed by 

prostate (35), breast (21), colorectal (15), and bladder (14). 10 patients 

had a Richter’s transformation of their CLL. 26 patients developed either 

myelodysplastic syndrome or acute myelogenous leukemia. Conclusions: 

Second malignancies are frequent in CLL patients. Immunosupression, 

increased UV light exposure, longer life expectancy in low risk CLL, and 

tertiary cancer center referral bias are likely reasons for these increased 

rates. Further research is needed to identify the precise mechanism which 

cause patients with CLL to have higher rates of second malignancies and to 

identify if there is an increased risk of a specific type of malignancy in 

patients with CLL. 


Phase II study of AZD2171 for the treatment of patients with myelodysplastic 

syndromes. Presenting Author: Shannon Eileen O’Mahar, University of 

Wisconsin, Madison, WI 

Background: Inhibition of vascular endothelial growth factor receptors 

(VEGFR) can block growth and trigger apoptosis in neoplastic cells. 

AZD2171 (cediranib) is a highly potent, orally bioavailable, VEGFR-1/2 

inhibitor. We conducted a phase II study of the efficacy of AZD2171 for the 

treatment of MDS. Methods: Adults with MDS (IPSS Int-2 or High) were 

eligible if they exhibited adequate organ function and ECOG 0-2. The 

primary endpoint was proportion of responses according to the IWG criteria 

assessed at one and every 3 months. Prior investigation of cediranib at 45 

mg daily in patients with acute leukemia demonstrated toxicity concerns 

and therefore, the starting dose of this study was lowered to 30 mg daily. 

Results: A total of 16 pts with MDS (median age 73 years) were enrolled at a 

30 mg starting dose, and all were evaluable. Median baseline marrow blasts 

were 12.0 % (range 2-18); 3 pts (18.8 %) had low, 6 (37.5 %) 

intermediate, and 7 (43.8 %) had high risk cytogenetics. Prior therapy 

included azacitidine (n�7), decitabine (n�2), cytarabine (n�2), erythropoietin-stimulating 

agents (ESAs) (n�2), lenalidomide (n�1), or none 

(n�6). Patients were treated for a median of two 28-day cycles (range 1 to 

11). There were no confirmed responses. Patients with baseline blasts � 

5% showed no significant reduction in the blast count at 4 and 12 weeks. 

Median OS was 4.7 mo (95% CI: 2.6 – 11.6). Median TTP was 3.8 mo 

(95% CI: 1.7 – 10.8). Grade 4 hematological adverse events at least 

possibly related to cediranib were neutropenia (n�2) and thrombocytopenia 

(n�4). Grade 3 hematological adverse events at least possibly related to 

study treatment included: neutropenia (n�3), thrombocytopenia (n�2), 

and anemia (n�2). Grade 3 non-hematological adverse events included 

fatigue (n�4), dyspnea (n�3), dehydration (n�2), diarrhea (n�2), nausea 

(n�2), asthenia (n�1), and hypertension (n�1). Hypertension and proteinuria 

was uncommon with the 30 mg/day dose. Conclusions: With no 

confirmed response from 16 patients, cediranib was determined to be 

ineffective at a dose of 30 mg daily in our patient population. Supported by 

NCI N01-CM62205, NCI P30-CA014520 and the UW Carbone Comprehensive 

Cancer Center. 


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Induction chemotherapy with high-dose cytarabine and mitoxantrone in 

elderly acute myeloid leukemia (AML) patients. Presenting Author: Muthalagu 

Ramanathan, UMass Memorial Medical Center and UMass Medical 

School, Worcester, MA 

Background: Induction chemotherapy is often not used in elderly patients 

with AML due to poor prognosis and inferior outcomes. We present here our 

experience in treating 20 patients age�70yrs with an induction regimen 

consisting of high dose cytarabine and mitoxantrone (HiDAC/MITO). 

Methods: We analyzed all patients age � 70 years who underwent induction 

with HiDAC/MITO at our institution from January 2009 to December 2011. 

20 patients received HiDAC at 3 g/m2 daily on days 1-5 and mitoxantrone 

80mg/m2* once on day 2(*one patient received 60mg/m2). The end points 

analyzed were complete remission (CR) and induction mortality at day 30, 

overall survival and progression free survival. Results: Median age was 75 

years (70-83). 11 (55%) patients were male and 9 (45%) patients were 

female. Median duration of follow up of 10 (50%) patients who are still 

alive at the time of this analysis is 439 days (38-1095). High risk 

cytogenetics was noted in 11 (55%) patients including two patients with 

FLT3 mutated cytogenetics. Intermediate risk cytogenetics was noted in 9 

(45%) patients including 2 patients with NPM1 mutated FLT 3 WT AML. 

12 (60%) patients had secondary AML. The age unadjusted charlson 

comorbidity index (CCI) was 3 (2-9). 15 (75%) patients attained CR and 3 

(15%) patients attained a CR with incomplete platelet recovery (CRp). CR 

�CRp rate was 90%. Two (10%) patients were refractory to induction and 

5 (25%) patients relapsed at a later time point after induction. Median 

duration of hospital stay was 28 days (22-60). Median time to ANC �1K 

was 23.5 days (18-29), excluding 2 patients who had refractory disease. 

Median time to platelet recovery �100K was 25 days (20-44), excluding 2 

patients with refractory disease and 3 patients with CRp. Regimen related 

toxicity included cardiac toxicity in 4 patients and bacteremia in 11 

patients. Five (25%) patients were consolidated with stem cell transplant. 

Median overall survival (OS) was 151 days (38-1095) and progression free 

survival (PFS) was 131 days (38-1049). Conclusions: HiDAC/MITO induction 

is well tolerated by elderly patients with AML and demonstrates an 

overall response (CR�CRp) rate of 90% coupled with no induction deaths. 


Overall and cancer-specific survival of breast, colon, and lung cancer in 

patients with and without chronic lymphocytic leukemia: A SEER populationbased 

study of over 1 million patients. Presenting Author: Benjamin M. 

Solomon, Mayo Clinic, Rochester, MN 

Background: Chronic lymphocytic leukemia (CLL) is associated with an 

increased risk of developing second cancers. However, it is unknown 

whether CLL alters the natural history of these cancers once they occur. 

Methods: All patients with breast (n�583,838), colon (n�412,932), 

prostate (n�632,922), lung (n�489,290), kidney (n�95,902), pancreas 

(n�82,121) and ovarian (n�61,958) cancer reported to the Surveillance, 

Epidemiology, and End Results (SEER) Program from 1990 to 2007 were 

identified. Overall survival (OS; death due to any cause) and cancer-specific 

survival (death due to cancer site of interest) were examined, comparing 

patients with or without pre-existing CLL. Age- and sex-adjusted hazard 

ratios (HRs) were calculated. Results: OS for patients with pre-existing CLL 

was inferior for patients with breast (HR�1.61; p�0.001), colon 

(HR�1.65; p�0.001), kidney (HR�1.41; p�0.001), prostate (HR�1.75; 

p�0.001), and lung (HR�1.22; p�0.001) cancer after adjusting for age 

and sex. After excluding CLL-related deaths, OS remained shorter among 

patients with breast (p�0.001), colon (p�0.001), kidney (p�0.03), 

prostate (p�0.001), and lung (p�0.001) cancer. Cancer-specific survival 

was inferior for patients with breast (HR�1.29; p�0.03), colon (HR�1.75; 

p�0.001), and lung cancer (HR�1.17; p�0.001) who had pre-existing 

CLL after adjusting for age and sex. Conclusions: Several common cancers, 

including breast, colon, and lung, have inferior overall and cancer-specific 

survival when there is coexistent CLL. 

HRs for OS by cancer type. 

OS, including CLL deaths OS, excluding CLL deaths 

Cancer HR 95% C.I. p value HR 95% C.I. p value 

Breast 1.61 1.44-1.80 �0.001 1.38 1.21-1.57 �0.001 

Colon 1.65 1.52-1.78 �0.001 1.59 1.46-1.74 �0.001 

Kidney 1.41 1.19-1.68 �0.001 1.25 1.02-1.52 0.03 

Lung 1.22 1.15-1.29 �0.001 1.20 1.12-1.28 �0.001 

Ovary 1.13 0.86-1.49 0.38 0.98 0.73-1.33 0.91 

Pancreas 1.00 0.84-1.19 1.00 0.98 0.82-1.17 0.83 

Prostate 1.75 1.62-1.90 �0.001 1.35 1.22-1.50 �0.001 




Treatment outcomes in patients older than age 60 with acute myeloid 

leukemia (AML) in the nonclinical trial setting. Presenting Author: Steven 

Duffy, SUNY Upstate Medical University, Syracuse, NY 

Background: Optimal treatment of older adults with AML remains challenging. 

While AML tends to be a disease of older adults, this population 

experiences greater treatment-related toxicity and worse overall survival 

than younger patients. Only fit older adults enter clinical trials and thus the 

results may not apply to the entire population. Methods: We conducted a 

retrospective analysis of patients � 60 years with AML (APL excluded) 

diagnosed prior to 2008 with IRB approval. The association of clinical 

factors (age, sex, comorbidities, prior chemotherapy), leukemia (prior 

myelodysplastic syndrome or myeloproliferative neoplasm, cytogenetics, 

WBC count), and therapy (induction chemotherapy, palliative chemotherapy, 

and best supportive care) as they relate to overall survival was 

evaluated using bivariate and multivariate regression analyses. Results: Of 

87 patients (median age 73), 45% were male, 58% had high risk 

cytogenetics, 38% had prior MDS/MPD, 92% were chemotherapy naive, 

and 21% were in the high/very high Charlson risk class. The majority (67%) 

received standard dose induction chemotherapy (IC), 9% received (palliative 

intent) low-dose chemotherapy (LDC), and 24% received best supportive 

care (BSC). The median overall survival (OS) of the entire cohort was 2.5 

months. On bivariate analysis high WBC (�50,000 at presentation) was 

negatively associated (1.0 vs 2.7 months p �0.01) with survival. OS for IC, 

LDC, and BSC were 3.1, 2.8, and 0.7 months, respectively (p�0.001). On 

multivariable analysis, IC conferred longer survival when compared to LDC 

and BSC combined (OR 0.33 CI 0.2-0.6, p�0.001). High WBC was 

associated with a decreased survival time (OR 2.96 CI 1.6-5.5, p�0.02). 

Mortality during induction or consolidation chemotherapy was 38%. At 

5-year follow-up, only 4 patients were alive. Conclusions: In a non-clinical 

trial setting, OS of older adults with AML remains dismal. While IC offers a 

chance of longer survival, mortality with IC is unacceptably high. Further 

studies are required to identify and validate tools for risk stratification in 

older adults with AML as well as to utilize therapies with an improved 

toxicity profile. 


Evaluation of combination therapies with MOR00208, an Fc-enhanced 

humanized CD19 antibody, in models of lymphoma. Presenting Author: 

Mark Winderlich, MorphoSys AG, Martinsried/Planegg, Germany 

Background: MOR00208 (formerly XmAb5574) is a Fc-engineered humanized 

anti-CD19 antibody with superior cytotoxicity in a number of in vitro 

and in vivo models of lymphoma and leukemia, currently being evaluated in 

patients with relapsed/refractory CLL. Bendamustine (BEN), an alkylating 

agent, fludarabine (FLU), a purine analogue, and the CD20 antibodies 

rituximab (RTX) and ofatumumab (OFA) were evaluated for their ability to 

enhance the cytotoxicity of MOR00208. Methods: Utilizing CD19/CD20� 

MEC-1 CLL cells, cytotoxicity was assessed in vitro by flow cytometry. 

MOR00208 was tested alone and in combination with BEN, FLU, RTX and 

OFA using peripheral blood mononuclear cells as effector cells. Median 

survival (MS) was evaluated in a murine model of disseminated lymphoma, 

using i.v.-administered RAMOS cells (CD19�) and treatment with 

MOR00208 alone and in combination with FLU. Combinatorial effects 

were classified according to Chou-Talalay (Pharmacol Rev. 2006 Sep;58(3): 

621-81). Results: MOR00208-mediated in vitro cytotoxicity was synergistically 

enhanced by BEN, FLU and the CD20 antibodies irrespective of their 

different modes of action (Combination Index � 1). In vivo, FLU alone at 

doses up to the maximum tolerated dose (MTD) did not prolong MS, 

whereas MOR00208 at 3 mg/kg increased MS by 26% compared to the 

isotype control. Co-administration of MOR00208 with 125 mg/kg FLU 

significantly enhanced MS by 65%. Despite its lack of single agent activity, 

FLU thus significantly enhanced the cytotoxicity of MOR00208. Conclusions: 

The cytotoxic in vitro activity of MOR00208 on CD19� B cells was 

synergistically enhanced by all studied drugs irrespective of their effector 

mechanisms. In vivo, the activity of MOR00208 in an aggressive lymphoma 

model was potentiated in combination with FLU. These results provide a 

mechanistic rationale for MOR00208 drug combinations which warrant 

further evaluation in clinical trials. 


A simple but effective model to decrease early deaths in acute promyelocytic 

leukemia (APL). Presenting Author: Anand P. Jillella, Department of 

Medicine, Division of Hematology/Oncology, Georgia Health Sciences 

University, Augusta, GA 

Background: Recent reports suggest that approximately 30% of patients 

with APL die during induction. This has been confirmed in large populationbased 

studies in Sweden and the US. A recent analysis of SEER data from 

13 population-based cancer registries with 1400 APL patients in the US 

showed that 17% of all patients and 24% of patients greater than 55 years 

of age die within one month of diagnosis. The most common causes of 

death are bleeding, infection, differentiation syndrome and multi-organ 

failure. Patients who survive induction have an excellent cure rate with few 

late relapses. Hence, decreasing early deaths is a high priority both at 

experienced as well as smaller centers with limited leukemia treatment 

experience in this highly curable disease. Methods: At Georgia Health 

Sciences University, between 7/2005 and 6/2009, 19 patients were 

diagnosed with APL. Seven patients (5 high-risk and 2 low-risk) died during 

induction resulting in an unusually high mortality rate of 37%. All patients 

who survived induction are still in remission at present. The high early 

death rate prompted us to develop a simple, 2 page treatment algorithm 

that focuses on quick diagnosis, prompt initiation of therapy, and proactive 

and aggressive management of all the major causes of death during 

induction. We also made our treatment protocol available to smaller 

treatment centers and helped the treating oncologists manage the patient 

during the first few days after diagnosis. Results: From 11/2010 to 

12/2011, we treated 4 patients at GHSU and helped manage 4 patients at 

2 outreach sites. The age range was 30 to 60; two patients were high-risk, 5 

intermediate- and one low-risk. There were no deaths during induction and 

all eight patients proceeded to consolidation treatment. Conclusions: While 

we recognize that this is a small cohort, our own experience and a similar 

approach pioneered by investigators in Brazil clearly shows this to be an 

effective intervention to decrease early deaths in APL. We believe our 

experience warrants large scale implementation of our protocol in an 

attempt to reduce early APL mortality. 


Cancer testicular antigens as a prognostic markers of chronic lymphocytic 

leukemia. Presenting Author: Julio C. Chavez, H. Lee Moffitt Cancer Center 

& Research Institute, Tampa, FL 

Background: CLL is the most common leukemia in adults and has a variable 

course and prognosis. Clinical staging systems and the use of biomarkers 

such as cytogenetics and the IGVH mutational status remain the gold 

standard for stratification. Cancer testis antigens (CTAs) expression analyses 

have shown prognostic impact in other hematological malignancies 

such as acute leukemias and multiple myeloma. With the analysis of CTAs 

we aim to discover additional molecular markers that can help us predict 

the clinical course and outcome in CLL patients. Methods: We analyzed the 

expression by RT-PCR of 39 known CTAs including members of the MAGE, 

GAGE, MAD-CT and SSX CTAs families in a group of 59 CLL patients seen 

at our institution. The Moffitt Cancer Center Total Cancer Care (TCC) 

database was used to correlated these findings with relevant clinical and 

molecular markers such as Rai stage, demographic data, initial WBC count, 

IGVH mutational status, CD38 expression, cytogenetics by FISH analysis 

and treatment outcomes. Overall survival (OS) and progression free survival 

(PFS) were calculated using Kaplan Meier curves with a SPSS statistical 

software Results: Deletion 13q was the most common gene abnormality in 

35/59 (59.3%). 29/59 (49.1%) required at least one line of treatment. 

MAGE family CTAs were present in 53/59 (83.9%), MAD-CT in 24/59 

(40.7%), SSX in 14/59 (23.7%) and GAGE in 12/59(20.3%). 35/59 

(59.3%) CLL patients expressed 2 or more MAGE family CTAs. No 

differences were noted in the Rai staging, initial white blood cell count, B 

symptoms, extranodal disease, presence of CD38, or unmutated IVGH. The 

OS was not significantly different among all CTAs families with a tendency 

towards a better OS those expressing the SSX family (p�0.63). Additionally, 

CLL patients with single expression of MAD-CT1 (p�0.05) and 

MAGE-B2 (p�0.038) antigens correlated with improved survival. 

Conclusions: Patients with SSX family have a trend towards improved 

survival. When analyzed by individual antigen, MAD-CT1 and MAGE-B2 

expression was associated with improved survival. Further studies with a 

larger number of patients are needed to assess the real value of the 

expression of CTAs in CLL. 



AML patients with IDH1 or IDH2 mutations treated with hypomethylating 

agents: A case series. Presenting Author: Christopher Brent Benton, 


Background: Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations play a 

significant role in acute myeloid leukemia (AML), yet optimal treatment for 

AML patients with IDH mutations remains unclear. IDH mutations have 

been associated with a globally hypermethylated genomic state, as the 

result of increased levels of 2-HG, a regulator of histone methylation. We 

sought to retrospectively determine responses of patients with IDHmutated 

AML to treatment with hypomethylating agents. Methods: We 

reviewed clinical data for AML patients treated at The University of Texas 

M. D. Anderson Cancer Center from June 2001 to December 2011 whose 

stored leukemia samples from bone marrow aspirateshad been tested 

retrospectively for IDH1 and IDH2 mutations. We searched three databases 

that contained records for 407 AML patients. We selected patients who had 

been treated with the hypomethylating agents 5-azacitidine or decitabine, 

alone or in conjunction with other therapeutics. We retrospectively reviewed 

the patients’ medical records to obtain demographic, laboratory, 

treatment, and clinical data. We evaluated response measured by remission 

status, reduction in bone marrow blasts and peripheral blood blasts, 

and time to relapse. Results: We identified 104 patients (25.6%) who had 

either an IDH1 or IDH2 mutation, and of these, 8 patients had also been 

treated with hypomethylating agents. A ninth AML patient, who is IDH2mutant, 

is currently undergoing treatment with decitabine alone. Of these 9 

patients, three had a durable complete remission without recovery of blood 

counts (CRp), three had a partial response (PR), with or without blood 

count recovery, and three had no response. All 9 patients did have an initial 

decrease in the percentage of bone marrow blasts, peripheral blood blasts, 

or both. Conclusions: This series of patients demonstrates the possibility 

that AML patients with IDH1 or IDH2 mutations benefit from the use of 

hypomethylating agents, and suggests it is worthwhile to prospectively 

investigate treatment of patients with IDH-mutated AML using hypomethylating 

agents. 


Analysis of outcomes of patients (pts) with blastic plasmacytoid dendritic 

cell neoplasm (BPDCN). Presenting Author: Naveen Pemmaraju, University 


Background: BPDCN, formerly known as CD4 � CD56 � hematodermic 

tumor or blastic NK cell lymphoma, is a rare and aggressive hematologic 

malignancy. Little is known about outcomes of pts with BPDCN. Methods: 

We conducted a retrospective review of pts meeting following criteria: 

pathological diagnosis of BPDCN confirmed by an experienced hematopathologist 

and age � 18. Results: 13 pts, diagnosed October 1998-July 

2011, were identified. Median (med) age: 62 years (range 20-86 years), 12 

(92%) were male. Bone marrow (BM) involved in 9 (69%), skin 8 (62%), 

lymph nodes 5 (38%), brain 1 and uterine/ovarian 1 pt. Immunophenotype 

by flow cytometry: CD4� (11/11 pts), CD56� (10/11 pts), TCL-1� (4/4 

pts). Karyotype (8 pts): del(12) (1pt), complex (2), and diploid (5). Med 

CBC: WBC 5.8 x 109 /L (1.7-76.5), Hb 12.3 g/dL (8.3-17.0), platelet 107 x 

109 /L (44-255). Med BM blasts: 22% (0-77). 10 pts received first-line 

therapy with Hyper-CVAD alternating with high-dose methotrexate(MTX) 

and cytarabine (HCVAD) (in 1 pt following one cycle of CHOP), CHOP (2), 

oral MTX (1). Med follow-up time: 9 months (mo) (2-14 mo). Med number 

chemotherapy regimens: 1 (1-5). Complete remission (CR) in 10 pts. Med 

CR1: 19 mo (4-39 mo). Med overall survival (OS) 29 mo (1-44 mo). 9 pts 

have died, unknown cause (3), multi-organ failure (6). 10 pts received 

HCVAD as part of first line therapy: med OS: 29 mo (1-44 mo), med CR1: 

21 mo (4-39 mo), 9/10 (90%) pts achieved CR1; 1 pt did not achieve CR1 

(died, pneumonia, day 15). 9 pts (69%) had BM involvement (7 with other 

organs involved besides BM). 4 (31%) pts had no BM involvement; all 4 of 

these pts had skin involvement only. Med OS, med CR1 of pts with BM 

involvement: 23 mo (1-44mo), 22 mo (4-39mo), respectively. Med OS, 

med CR1 of skin only pts: 29 mo (2-31 mo), 7 mo (6-19 mo), respectively, 

p�not significant. 4 pts received stem cell transplant (SCT) (2 allogeneic 

,2 autologous). Med OS for pts receiving SCT (n�4) was 31 mo(8-31 mo) 

versus med OS for non-SCT group (n�9) of 29 mo (1-44), p�not 

significant. Conclusions: Despite intensive multi-agent chemotherapy and 

SCT, response rates are low and survival is short. Better understanding of 

the biologic basis of this disease and novel treatment approaches for 

treatment of BPCDN are crucial. 


435s 


Phase I dose escalation study of TG02 in patients with advanced hematologic 

malignancies. Presenting Author: Gail J. Roboz, Weill Medical College 

of Cornell University, New York, NY 

Background: TG02 is a novel multikinase inhibitor with a unique spectrum 

of activity, targeting both the cell cycle regulatory cyclin-dependent kinases 

(CDKs) 1 and 2 and the transcriptional regulators CDKs 7 and 9. TG02 also 

inhibits the emerging oncogenic MAPK ERK5 and the DNA damage 

response mediator CDK5. TG02 kills primary blasts from a variety of 

hematologic cancers and is curative in the MV4-11 model of FLT3-mutant 

AML. Methods: This is a first-in-man,single arm, open label, phase I dose 

escalation trial. The primary endpoints are dose-limiting toxicity (DLT), 

maximally tolerated dose (MTD ) and recommended phase 2 dose (RP2D). 

Patients (pts) � 18 years with advanced hematological malignancies or 

newly diagnosed AML pts � 65 years unfit for intensive therapy were 

enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) 

schedules. Pts had acceptable organ function and ECOG PS 1-2. Definition 

of DLT was G3-4 AST or ALT �7 days, G4 AST or ALT, G4 hyperbilirubinemia, 

any other NCI CTC G3-4 events not due to underlying disease. 

Dose levels on arm A were 10mg to 70mg and 15mg-150 mg on arm B. 

Results: Forty-five pts have received at least one dose of study drug. Median 

age was 66 years (range, 37-87) and 80% were ECOG 0-1. Disease types 

enrolled included: AML (80%), high-risk MDS (22%), and CML-BC (3%). 

The median number of previous regimens was 3 (range, 1-12). The MTD on 

arm A was defined at 50 mg daily based on 2 DLTs at the 70mg dose level 

(G4 hyperbilirubinemia, G4 fatigue). Enrollment to arm B has competed 

dose levels 15 (N�3), 30 (N�3), 50 (N�3), 70 (N�3), 100mg (N�3), 

and enrollment at 150mg is ongoing without DLT to date. Common drug 

related adverse events were nausea (42%), vomiting (23%), fatigue (18%), 

decreased appetite (15%), constipation and diarrhea (13% each). Preliminary 

PK demonstrated dose proportional increases in exposure and a T1/2 , 

supporting once daily dosing. Conclusions: The MTD for TG02 has been 

determined for the daily schedule at 50mg. Enrollment continues on the 

intermittent schedule. Schedules of every other day and week on/week off 

dosing will also be evaluated. 


Outcome of acute myeloid leukemia in patients with a history of autoimmune 

disease. Presenting Author: Courtney Denton Dinardo, Hospital of 

the University of Pennsylvania, Philadelphia, PA 

Background: Increased risks of solid and lymphoid malignancies are 

described in patients with autoimmune (AI) disease. The association 

between AI disease, AI treatment (particularly anti-TNF therapy), and AML 

is less established. Moreover, the pathologic characteristics of AML in this 

population have not been evaluated. Here we describe our AML experience 

in patients with prior AI disease. Methods: Patients with AML from 1992 to 

2011 were identified from our database, and AI disorder was verified 

through chart review. Patients were included if they had an AI disorder that 

required systemic treatment, and diagnosed � 1 year prior to AML. 

Patients were excluded if details including the year of AI diagnosis or 

treatment(s) received were not documented. A total of 22 patients were 

included for analysis. Results: Median age at AML diagnosis was 59 years 

(range 32 – 78), 4 (18%) were men. 10 (48%) had received an anti-TNF 

agent, for a median duration of 30 months (range 2 – 120). Median latency 

from AI diagnosis to AML was 9.4 yrs. All FAB subtypes were represented 

except M0 and M6, 9 (41%) had M4 or M5 disease. 10/21 patients (45%) 

had normal cytogenetics, and 5 had favorable cytogenetics (2 with acute 

promyelocytic leukemia (APML)). Standard induction was given to 19 

patients, and APML-directed therapy for those with APML. One patient 

received an autologous transplant in CR1, and 5 an allogeneic transplant (1 

in CR1, 4 in CR2). 9 patients are alive in CR1. 13 relapsed, and 4 (31%) 

are alive in CR2 or CR3 (3 following allogeneic transplant in later CR). 

Median OS was 68.1 months. In univariate analysis, factors associated 

with OS were cytogenetics, FAB subtype, and gender. Anti-TNF therapy 

may be associated with poorer prognosis; this was not statistically significant. 

Median OS was 14.1 months for poor, 68.1 months for intermediate, 

and not reached for favorable risk cytogenetics. Conclusions: Median OS 

was higher (� 5 years) than expected. Younger age and an increased 

incidence of favorable risk AML may account for this finding: whether this 

is a meaningful biologic association or stochastic event can only be verified 

with larger studies. Our observations do not support a label of “secondary 

leukemia” or therapy-related neoplasm in this population. 




L-arginine depletion by PEG-arginase I, a new potential therapy for acute 

lymphoblastic leukemia. Presenting Author: Ofelia Crombet Ramos, Louisiana 

State University Health Sciences Center, New Orleans, LA 

Background: Advances in therapies have resulted in an overall complete 

remission rate of approximately 85% for childhood acute lymphoblastic 

leukemia (ALL). In contrast, the overall remission rate of adults with 

leukemia continues to be poor, only about 40% in cases of T cell-ALL 

(T-ALL). Therefore, it is imperative to generate new therapies that alone or 

in combination with other treatments could potentially increase the 

percentages of complete responders or be used to treat the refractory ALL 

population. Our published results show that a pegylated form of human 

arginase I (peg-Arg I) prevented T-ALL cell proliferation in vitro and in vivo 

through the induction of tumor cell apoptosis. Interestingly, the antileukemic 

effects induced by peg-Arg I did not affect the anti-tumor activity 

of normal T cells, suggesting an anti-tumor specific effect. Our hypothesis 

states that peg-Arg I has an anti-tumoral effect on B-ALL and T-ALL cells in 

vitro and that the sensitivity of ALL cells to peg-Arg I depends on their 

expression of argininosuccinate synthase (ASS) and their ability to produce 

L-arginine de novo from citrulline. Methods: Malignant T cell proliferation 

was tested using nonradioactive cell proliferation yellow tretrazolium salt 

kit. Apoptosis studies were based on the expression of annexin V. Western 

blot assays were conducted to determine enzymatic expression in different 

cell lines. Results: The results of our in vitro experiments showed that 

peg-Arg I had a pro-apoptotic and anti-proliferattive effect on B-ALL cells 

similar to the one previously seen on T-ALL cells. These effects can be 

overcome in cell lines able that express ASS and therefore to produce 

L-arginine de novo. Conclusions: Our results suggest the role of ASS in the 

ALL-apoptosis induced by peg-Arg-I. Our next steps include: _Understand 

why ASS-expressing ALL cells do not undergo apoptosis when cultured with 

peg-Arg-I_Determine the role of ASS in the anti-leukemic effect induced by 

peg-Arg-I in vivo. Completion of this research is expected to lead to a better 

understanding of how peg-Arg-I kills ALL cells and could provide the 

foundation for a novel therapy for ALL patients. 


Phase II study of the oral MEK inhibitor selumetinib (AZD6244) in 

advanced acute myeloid leukemia (AML). Presenting Author: Nitin Jain, 

The University of Chicago Medical Center, Chicago, IL 

Background: RAS-RAF-MEK-ERK pathway is activated in �75% of AML 

patients (pts). Selumetinib (AZD6244) is an orally bioavailable small 

molecule inhibitor of the MEK kinase. We report here the results of a phase 

II multicenter trial using selumetinib in advanced AML pts. Methods: Pts 

�18 years (yrs) with relapsed/refractory AML or �60 yrs old with untreated 

AML who were not candidates for standard chemotherapy were eligible. Pts 

received selumetinib 100mg twice daily. Pts were screened for KRAS, 

NRAS and FLT3 mutations. Analysis for p-ERK (downstream of MEK) was 

performed by flow-cytometry. Results: 47 pts (27 men) were enrolled. 

Median age was 69 yrs (range, 26-83). 85% were �60 yrs. Disease stage 

included previously untreated AML (13 pts, all were � 60 yrs; 11 had prior 

therapy for antecedent hematologic disease), primary refractory AML (14 

pts), 1st relapse (8 pts) and beyond first relapse (12 pts). Overall, 51% pts 

had secondary AML. Median number of prior therapies was 2 (range, 0-6). 

51% had poor-risk cytogenetics. 10 pts had a FLT3 ITD, 3 pts had an 

NRAS mutation and one pt had a KRAS mutation. Selumetinib was well 

tolerated. Median number of cycles administered was 1 (range, 1-21). 

49% received �2 cycles. Grade �3 adverse events possibly related to the 

drug included fatigue, dyspnea, and nausea occurring in 9%, 9% and 6% 

respectively. 1 pt has partial response, 3 pts had minor response (�50% 

decrease in blood and/or marrow blasts lasting �4 weeks), 2 pts had 

unconfirmed minor response (uMR: �50% decline in marrow blasts 

without a follow up confirmatory biopsy), 4 pts had stable disease (median: 

16.5 weeks, range: 9-85). No pt with FLT3 ITD or NRAS mutation 

responded. The sole pt with KRAS mutation had uMR with hematologic 

improvement in platelets. Analysis of p-ERK showed baseline activation in 

15/21 (71%) pts, but no difference in baseline levels in the responders vs 

non-responders (p�0.27). Conclusions: Administration of selumetinib in 

advanced AML is associated with modest antileukemic activity, which is 

independent of baseline p-ERK levels. Given its favorable toxicity profile, 

combination with drugs that target relevant signaling pathways in AML 

should be considered. (Sponsored by NCI grant NO1-CM-62201) 


Quantitative detection of ZAP-70 expression in chronic lymphocytic leukemia. 

Presenting Author: Peixuan Zhu, Creatv MicroTech, Inc., Potomac, 

MD 

Background: Intracellular ZAP-70 protein was recently recognized as 

prognostic marker in chronic lymphocytic leukemia (CLL). The specific 

objective of this study was to develop a simple and sensitive assay, for the 

quantitative detection of ZAP-70 protein in leukemic cells. Methods: 

Components of the assay system include sample preparation, immunomagnetic 

fluorescence assay, Signalyte-II spectrofluorometer. The leukemic 

cells were isolated from CLL patient blood samples and lysed to release the 

intracellular ZAP-70 protein. ZAP-70 protein was captured by magnetic 

beads coated with anti-ZAP70 capture antibody, and recognized by a 

fluorescent detector antibody, forming an immuno-sandwich complex. This 

complex was dissociated for measurement of the fluorescence signal, 

which was proportional to ZAP-70 concentration, using the spectrofluorometer. 

Results: The assay conditions were extensively optimized by selecting 

an optimal pair of capture/detector antibodies, conjugation of fluorescence 

dye, cell lysis condition and excitation/emission wavelengths. The protocol 

was further validated with two positive controls, Jurkat cell lysate and 

recombinant ZAP70 protein (rZAP70). The limit of detection was determined 

to be lower than 125 Jurkat cells and 39 pg of rZAP70 protein. The 

signal response was linear over a wide range of concentration, from 625 to 

40,000 Jurkat cells per test (R2�0.9987) and from 0 to 40,000 pg 

rZAP70 protein per test (R2�0.9928). The results from 20 CLL patients 

correlated strongly with flow cytometry analysis. The concordance between 

the two methods for positive and negative results was 100% (7/7) and 92% 

(12/13), respectively, while the overall concordance between the two 

methods was 95%. Conclusions: The assay is a simple, reliable, and 

reproducible method for quantitative detection of ZAP-70 in patient 

leukemic cells, without the need for cell fixation or permeabilization. The 

entire assay could be completed in 5.5 hours. The ZAP-70 signal was linear 

over a wide dynamic range, which we believe enables quantitative assessment 

of small changes in ZAP-70 expression over the course of the disease 

and in response to therapeutic intervention. 


Real-world response monitoring and tolerability of imatinib-treated chronic 

myeloid leukemia patients captured in a retrospective research registry. 

Presenting Author: David D. Stenehjem, Huntsman Cancer Institute, Salt 

Lake City, UT 

Background: Monitoring tolerability and response to imatinib (IM) is an 

important aspect of chronic myeloid leukemia (CML) management. The 

objective of this study is to assess real-world tolerability and response 

monitoring in IM treated CML patients (pts). Methods: A comprehensive 

retrospective outcomes research registry of CML pts was created from the 

University of Utah electronic health record system. Study inclusion was 

limited to pts diagnosed with CML in chronic phase in 2001 to 2010 and 

treated with IM as a first-line therapy. Utilization and outcome of cytogenetic 

and molecular testing within 18 months of IM initiation, rates of 

adverse drug events (ADEs), and therapy modifications were evaluated by 

chart review. Results: A total of 92 pts were treated with IM as first-line 

therapy. Within the first 18 months of treatment, cytogenetic testing was 

recorded in 45 pts (49%) and of these 33 pts (73%) achieved a complete 

cytogenetic response (CCyR) in a median of 241 days (range: 110-542); 

molecular testing was completed in 48 pts (52%) and of these 24 pts 

(50%) achieved at least a major molecular response (MMR) in a median of 

254 days (range: 99-546). Imatinib associated ADEs of any grade (n � 60) 

occurred in 42 (46%) pts resulting in dose reductions in 15 pts (36%) in a 

median of 77 days and discontinuation of IM occurred in 9 (21%) pts in a 

median of 130 days. The IM dose was increased to �400 mg in 21 (23%) 

pts in a median of 457 days (range: 21-2112). Of pts diagnosed between 

2006 to 2010 (n � 34; 37%), 8 (25%) pts transitioned to dasatinib or 

nilotinib in a median of 397 days (range: 147 to 1057). Reasons for 

therapy change included physician documented suboptimal response or 

treatment failure (n � 5) and ADEs to IM (n � 3). Conclusions: Utilization of 

cytogenetic and molecular testing within 18 months of IM initiation was 

lower than the National Comprehensive Cancer Network or European 

LeukemiaNet CML guidelines would suggest. Further research is warranted 

to understand limited response monitoring and outcomes in non-monitored 

pts. The ADE rate was similar to clinical trial data. The impact of ADEs on 

subsequent treatment and outcomes in CML pts deserves further study. 



Ofatumumab retreatment and maintenance in patients with fludarabinerefractory 

CLL. Presenting Author: Anders Österborg, Karolinska University 

Hospital, Stolkholm, Sweden 

Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab 

(ofa), given as monotherapy over 6 months, showed 47% overall response rate 

(ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to 

fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (�5cm) 

lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance 

(mt) are unknown. Methods: Pts who responded to ofa and then progressed 

or had stable disease (SD) in Study 406, were offered retx in Study 416 

(NCT00802737; GSK/Genmab) with ofa 1 x 300 mg � 7 x 2000 mg weekly 

followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better). 

Primary endpoint was ORR (1996 NCI-WG). Safety and time to event outcomes 

were also assessed. Results: Of 29 pts enrolled, 7 had SD and 22 had partial 

response (PR) and progressed in Study 406. Pts were defined per Study 406: 17 

FA-ref, 11 BF-ref, 1 “other”. Pretreatment characteristics were similar between 

groups. Pts received a median of 12 doses (range 3-32); 86% had 8 doses, 3% 

received all 32 doses. 72% of pts had infusion-related adverse events (AEs), 

41% at 1st infusion, mostly grade 1-2. The most common grade �3 AE 

occurring up to 60 days after last tx was infection (38%); the most common was 

pneumonia (17%). 3 pts (10%) had fatal infections, all bronchopneumonia. 

Clinical efficacy is shown in Table. Comparative analysis to Study 406 is 

ongoing. Conclusions: The response to ofatumumab (ofa) as induction retreatment 

and progression-free survival in this limited number of pts was similar to 

1st treatment (Study 406). Ofa maintenance had some clinical benefit for pts 

with advanced CLL. Ofa was well-tolerated with no unexpected toxicities. 

Efficacy of ofa retx. 

FA-ref (n�17) BF-ref (n�11) Total (n�29) 

Response % 

ORR (95% CI ) 

At 8 wks (end of weekly retx): 59 (33, 82) 18 (2, 52) 45 (26, 64) 

CR 6 0 3 

Nodular PR 6 0 3 

PR 47 18 38 

SD 29 55 38 

PD 6 0 3 

Not evaluable (NE) 6 27 14 

Through 24 wks (4 months mt) 24 (7, 50) 18 (2, 52) 21 (8,40) 

Through 52 wks (11 months mt) 24 (7, 50) 18 (2, 52) 24 (10,44) 

CR 12 0 7 

PR 12 18 17 

SD 47 64 52 

PD 18 10 

NE 12 18 14 

Time to event outcomes Median (95% CI), months 

Duration of response 11 (7, 11) 24 (NA) 24 (7, 24) 

PFS 8 (3, 13) 7 (2,12) 8 (5, 12) 

Overall survival 20 (11,28) 11 (5,NA) 18 (11, NA) 


Albumin as a prognostic factor for overall survival in newly diagnosed 

patients with acute myeloid leukemia (AML). Presenting Author: Awais M. 

Khan, University of Alabama at Birmingham Comprehensive Cancer Center, 

Birmingham, AL 

Background: Hypoalbuminemia (HA) is an adverse prognostic factor in 

multiple neoplastic diseases. Severe hypoalbuminemia (�3.0 g/dl) at day 

�90 post allogeneic hematopoietic cell transplant (AHCT) was reported as 

an independent predictive variable for non-relapse mortality and overall 

survival (Kharfan-Dabaja, et al Biol Blood Marrow Transplant 2009; 15). 

We examined the prognostic value of serum albumin level prior to induction 

chemotherapy in patients with newly diagnosed AML. Methods: Data were 

collected retrospectively in newly diagnosed AML patients receiving induction 

chemotherapy (3� 7 regimen). Primary objective was to examine the 

relationship between serum albumin at baseline and probability of achieving 

complete remission (CR) or incomplete remission (CRi) and overall 

survival (OS). The Kaplan–Meier method used to estimate median overall 

survival; chi-square test used for comparison of categorical variables and 

t-test for continuous variables. Log rank test used to compare Kaplan– 

Meier survival estimates between two groups. Results: Between November 

2004 to July 2007, 135 patients who received 3�7 induction chemotherapy 

were included. Patient baseline characteristics were similar between 

patients with serum albumin � 3.5 g/dl (HA) and those with serum 

albumin � 3.5 g/dl (no HA) with respect to age, sex, FAB subtype, history of 

antecedent MDS, karyotype, and chemotherapy . In patients with HA, mean 

age was 60 years compared to 56.5 years in non HA group. The median OS 

for patients with HA was 221 days (95%CI 149.5-292.5) compared to 421 

days (95%CI 236.7-605) with normal serum albumin (p�0.005). (Figure-1) 

The CR/CRi rate was 64%% for HA and 77.6% for those with normal 

albumin (p�0.09). In a multivariable Cox regression analysis including age 

� 60 years, history of MDS, karyotype, and serum albumin level at 

baseline; only age, karyotype and serum albumin were independent 

predictors of OS [Hazard ratio 0.47 (95%CI 0.31-0.71) (p�0.005) for 

normal serum albumin group]. Conclusions: In newly diagnosed AML, we 

demonstrate that hypoalbuminemia � 3.5 g/dl is an independent covariate 

for overall survival with conventional chemotherapy management. The 

prognostic value of low serum albumin should be validated in a prospective 

study. 


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Phase I study of TH-302, a hypoxia-activated cytotoxic prodrug, in subjects 

with advanced leukemias. Presenting Author: Marina Konopleva, University 


Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, 

bromo-isophosphoramide mustard designed to be selectively activated in 

hypoxic conditions. Preclinical data in mice with ALL have demonstrated 

marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito 

et al., PlosOne, in press). TH-302 also exhibited specific hypoxiadependent 

cytotoxicity when tested against primary ALL and AML samples 

in vitro. Based on these findings, a phase 1 study of TH-302 was designed 

for advanced leukemias. Methods: Eligibility: ECOG � 3, relapsed/ 

refractory leukemias for which no standard therapy options were available, 

and acceptable hepatorenal function. A standard 3�3 dose escalation 

design was used with 40% dose increments. TH-302 was administered IV 

over 30-60 minutes daily on Days 1-5 of a 21-day cycle. The objectives 

were to determine the MTD and PK profile of TH-302 with this schedule 

and to assess preliminary clinical activity of TH-302. Results: 34 subjects 

with previously treated AML (n�26), ALL (n�6) or CML in blast phase 

(n�1) received TH-302 at doses of 120 (n�4), 170 (n�4), 240 (n�3), 

330 (n�3), 460 (n�16) or 550 (n�4) mg/m². No skin or mucosal toxicity 

was noted in participants treated with TH-302 doses �240 mg/m2 .At330 

mg/m2 , grade 2 dermatological toxicities included skin ulcer (n�1) and 

hand/foot syndrome (n�1). Grade 2 mucositis (n�3) and grade 2 skin 

toxicity (e.g. skin rash, skin ulcers; n�3) were reported at 460 mg/m2 ; none 

were dose-limiting. Two of 3 evaluable subjects treated at the 550 mg/m2 cohort experienced DLTs of grade 3 esophagitis. Eight subjects had stable 

disease or better after 1 cycle. One ALL subject (at 120 mg/m2 ) cleared 

marrow blasts with persistent neutropenia. One AML subject (at 550 

mg/m2 ) achieved CRp after 1 cycle with resolution of leukemia cutis. 

Conclusions: TH-302 administered daily for 5 consecutive days every 3 

weeks is well-tolerated with increased incidence of skin and mucosal 

toxicity at higher dose levels. Clinical activity has been noted with a few 

objective responses, but majority of cytoreductions in the AML subset were 

transient. Clinical trials combining TH-302 with various chemotherapeutics 

with established efficacy in AML and ALL are planned. 


Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI) 

therapy in accelerated-phase CML (CML-AP). Presenting Author: Maro 

Ohanian, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: For patients (pts) presenting with CML-AP, TKIs are recommended. 

Although generally well tolerated, dose reductions and/or interruptions 

are often required. The impact of TKI dose intensity (DI) on CML-AP 

outcome has not been described. Aim: To determine impact of TKI dose 

interruptions and/or reductions on outcome in de novo CML-AP. Methods: 

Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or 

parallel clinical trials with TKIs as initial therapy: imatinib (n�36), 

dasatinib (n�5), or nilotinib (n�17). CML-AP features included: blasts 

�15% (n�8), basophils �20%, (n�22), platelets �100x109 /L (n�3), 

cytogenetic clonal evolution (n�22), or �1 feature (n�3). We examined 

the impact of dose reductions, treatment interruptions, and DI (ratio of the 

dose received vs. the intended dose for the entire treatment duration) on 

event-free (EFS), transformation-free (TFS), and overall survival (OS). 

Results: Among 58 pts, 37 required treatment interruptions and/or dose 

reductions (29 required dose reductions). 12 pts required dose reductions 

and/or interruptions due to hematologic toxicity and 23 for nonhematologic 

toxicities. Pts were divided into 3 DI tiers: 100% (n� 21), 

90-99%, (n�10), and �90% (n�27). Outcomes were analyzed based on 

DI tiers and presence or absence of dose reductions as shown in the table. 

Pts with dose reductions and/or interruptions for hematologic toxicities vs. 

non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100% 

(p�0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo 

or later were 100% and 91%, respectively (p �0.7). Conclusions: DI has no 

significant impact on de novo CML-AP outcome. However, dose interruptions 

and/or reductions for hematologic toxicities are associated with worse 

24-mo EFS, suggesting myelosuppression may in some patients be more a 

feature of the disease than toxicity from therapy. 

Outcome % Dose reduced Not reduced P value 100% 90-99%



Impact of ABL kinase domain mutations on the outcome of patients with 

chronic myeloid leukemia (CML). Presenting Author: Kendra Lynn Sweet, 

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 

Background: Patients with CML who develop resistance to imatinib commonly 

have mutations in the BCR-ABL kinase domain (KDM). Studies 

looking at outcomes in patients with P-loop versus non-P-loop mutations 

within the ABL-Kinase Domain have produced conflicting results. Methods: 

The Total Cancer Care (TCC) database was used to identify patients with 

CML treated at Moffitt Cancer Center (MCC). Descriptive data were 

reported, chi square test was used for categorical variables, and Kaplan 

Meier curves were used for OS and PFS. Log rank test was used to compare 

survival times between groups. Results: Between 1992 and 2011, 540 

CML patients were treated at MCC. Of those, 51% were male and 71% were 

under the age of 60. Sixty percent (n�322) were diagnosed after 2001. Of 

the 540 patients, 6.5% (n�35) were found to have mutations of which 26 

were detected in patients diagnosed after 2001. Of the 35 patients, 74% 

(n�26) had single mutations and 26% (n�9) had compound mutations. 

P-loop mutations were seen in 17% (n�6) and 43% (n�15) had T315I 

mutations. Patients with KDM progressed to accelerated or blast phase in 

46% (n�16) of cases compared to 27% (n�136) without mutations 

(p�0.03). Median OS was 126 months, 109 months, and not reached in 

patients with P-loop, T315I, and non-P-loop mutations respectively 

(p�0.17). The corresponding median PFS was 85 months, 89 months, and 

not reached (p�0.20). In patients with one mutation median OS was not 

reached compared to 105 months in patients with compound mutations 

(p�0.27). After 2001, patients with KDM had a median PFS of 75 months 

and OS of 126 months while neither was reached in the non-mutation 

cohort (p�0.007, p�0.26 respectively). Median PFS in patients with 

single mutations was 85 months versus 10 months in those with compound 

mutations (p�0.037). Patients with KDM had additional Ph� clones on 

cytogenetics in 49% of cases compared with 19% of cases in the 

non-mutation group (P � 0.005). Conclusions: T315I and P-loop KDM 

predict PFS and OS in CML patients, and convey a trend for worse 

prognosis. The presence of additional Ph� clones in patients with 

BCR-ABL KDM indicates a higher level of genetic instability and clonal 

evolution, which may be the contributing factor to poor outcomes. 


The large granular lymphocytic leukemia registry: A detailed analysis of 79 

patients with LGL leukemia and rheumatoid arthritis. Presenting Author: 

Kirsten Marie Boughan, Drexel University College of Medicine, Philadelphia, 

PA 

Background: The purpose of this study is to analyze patients enrolled in the 

LGL leukemia registry to distinguish the similarities between LGL leukemia 

and rheumatoid arthritis in order to access overlapping immune mechanisms 

that may be responsible for neutrophil mediated destruction. 

Methods: A retrospective chart review was performed on 79 patients 

enrolled in the LGL registry at Penn State Cancer Institute. All patients 

enrolled in the study had a diagnosis of both rheumatoid arthritis and 

potentially LGL leukemia. Data was collected for age, sex, RF factor 

positivity, family history, autoimmune disease, T-cell receptor gene rearrangement, 

and bone marrow invasion. Results: Of 79 patients the mean 

age of onset for LGL leukemia was 60 years old with no discrepancy noted 

between sexes, 37 M, 42 F. 49 patients were positive for rheumatoid 

factor. 27 patients had rheumatoid arthritis in a first degree relative with no 

discrimination between maternal or paternal inheritance. 22 patients were 

positive for any other autoimmune process. 60 patients were positive for 

T-cell receptor gene rearrangement. Of the remaining 19 patients that were 

negative for T-cell receptor rearrangement, 12 had evidence of bone 

marrow invasion (CD3/CD8� infiltrate in �20% bone marrow) and two 

showed bone marrow invasion of NK cell LGL (CD3/CD8-, CD57�) (Table). 

Conclusions: Patients with T cell LGL leukemia and rheumatoid arthritis 

appear to be clinically similar with regard to age, duration of disease, and 

other autoimmune disorders as patients with rheumatoid arthritis alone. 

Our patient population showed those with TLGL and RA also tends to have a 

positive family history of RA in up to 20% as opposed to 5-10% in RA 

patients. Given that RA and TLGL have a significantly higher expression of 

the HLA-DR4 haplotype than healthy patients, it is conceivable that with 

shared genetic alterations, and gene environment interactions that may 

promote posttranslational modification, there may be a loss of tolerance 

resulting in T cell activation, and eventual transformation into a T cell 

clone. 

LGL/RA No. (%) Bone marrow invasion No. (%) 

N 79 74 

TCR � 60 (75%) 72 (97%) 

TCR- 19 (24%) 12 (16%) 


A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the 

treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia 

(AML) and myelodysplastic syndrome (MDS). Presenting Author: Aziz Nazha, 


Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in 

acute myeloid leukemia (AML). Hypomethylating agents play an important role 

in the treatment of AML and MDS. We investigated the safety (phase I) and 

clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in 

pts with R/R AML and MDS. Method: Pts �18 years with MDS, CMML or AML, 

who failed prior therapies with performance status �2, adequate liver (bilirubin 

� 2x ULN, ALT � 2.5x ULN) and renal (creatinine � 2x ULN) functions were 

eligible. Pts received AZA 75 mg/m2 subcutaneously or intravenously for 7 days 

of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2; 

target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to 

12 cycles if benefit from treatment. Supportive care was standard. Results: 14 

pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before 

completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2 

received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and 

responses are summarized in the Table. The overall response rate (ORR) was 

3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles 

and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders 

received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were 

grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no 

difference between the 2 groups. No DLT was identified. Conclusions: 

PKC412�AZA is safe and well tolerated at the intended doses with good ORR in 

high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD. 

Updated result will be presented. 

Patients characteristics and responses. 

Parameter 

Number 14 

Age, years (range) 61 (38-86) 

Median N of prior therapies, N (range) 1 (1-7) 

Dose level, N 

Cohort 1 6 

Cohort 2 7 

Inevaluable (cohort 2) 1 

Median N of cycles (range) 2 (1-5) 

AML history, N (%) 

de novo 6 (43) 

MDS related 7 (50) 

Therapy-related AML 1(7) 

Cytogenetic risk group, N (%) 

Intermediate 5 (31) 

Unfavorable 9 (69) 

FLT3-ITD status, N (%) 

Positive 4 (29) 

Negative 9 (64) 

ND 1(7) 

Response rate, N (%) 

CRi 2 (14) 

PR 1(7) 

SD 3 (21) 


Pharmacokinetics (PK) and pharmacodynamics (PD) of rituximab administered 

by faster infusion in patients with previously untreated diffuse large 

B-cell (DLBCL) or follicular lymphoma (FL). Presenting Author: Michael 

Brewster, Roche Products Limited, Welwyn Garden City, United Kingdom 

Background: Faster infusion of rituximab (R) can improve patient (pt) 

convenience and reduce strain on oncology unit resources. To assess the 

safety, PK and PD of a 90-min infusion rate for R in NHL pts, a prospective, 

open-label, phase III, multicenter, single-arm trial (RATE) was conducted. 

Safety results have been previously presented (ASH 2011). Methods: Pts 

(�18 yrs old) with untreated DLBCL or FL, without clinically significant 

cardiovascular disease, received R-chemotherapy. R (375 mg/m2 ) was 

given at the standard infusion rate (4–6 h) in Cycle 1. Pts who did not 

experience Grade 3/4 infusion-related reactions (IRRs) and who had 

circulating lymphocyte counts � 5000/�l before Cycle 2, received subsequent 

R (375 mg/m2 ) infusions at a 90-min rate: 20% over 30 min then 

80% over the next 60 min. Pts (n�14) who completed all cycles at the 

90-min infusion rate gave further serum samples up to 16 wks after the last 

cycle for determination of PK parameters, including R terminal half-life 

(t½), maximum serum concentration (Cmax), systemic clearance (CL) and 

volume of distribution (V). Results: For pts (n�365) that received the 

90-min infusion rate at Cycle 2, serum R concentrations increased over the 

course of the study. Estimated median values were: CL, 107 ml/d; V at 

steady state, 3830 ml; t½, 24.6 d. At Cycle 2, 50.5% of pts had 

undetectable CD19� levels; this percentage increased during the study 

(68.3% Cycle 6, 87.5% Cycle 8). Conclusions: Peak R levels were higher 

than seen in published data of q3w R regimens but comparable with levels 

seen for q1w R regimens. The estimated median values for CL, V, t½ and B 

cell (CD19�) depletion with the 90-min infusion rate were similar to 

previously reported estimates for infusions at the standard rate. These 

results, in combination with the safety profile previously reported, show 

that a faster infusion of R can be an acceptable option for selected NHL pts 

who tolerated the standard infusion rate at Cycle 1 without a severe IRR. 

Serum R concentration (�g/ml) 

Cycle 2, Day 1 Cycle 6, Day 1 Cycle 8, Day 1 

Trough Peak Trough Peak Trough Peak 

N 329 335 241 238 34 36 

Mean (SD) 30 (26) 228 (64) 80 (35) 275 (72) 92 (51) 299 (91) 



Phase II study of omacetaxine (OM) and low-dose AraC (LDAC) in older 

patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic 

syndrome (MDS). Presenting Author: Tapan M. Kadia, University of 


Background: Treatment of AML in patients (pts) � 70 yrs of age with 

intensive chemotherapy is associated with high rates of early mortality and 

little benefit. Newer, lower-intensity approaches with novel mechanisms 

are needed. OM is a semisynthetic plant alkaloid which has demonstrated 

activity in AML as a single agent and with chemotherapy. Methods: We 

studied a low intensity program combining subcutaneous (SQ) OM with SQ 

LDAC in pts �/� 60 yrs, with AML or MDS, a performance status (PS) of 

�/�2, and adequate organ function. Initially, 6 pts were enrolled at the 

following doses: OM 1.25 mg/m2 SQ Q12 hrs x 3 days with AraC 20 mg SQ 

Q12 hrs x 7 days on a 4 week cycle. If safety is confirmed, the phase II 

portion would commence at the safe dose levels. Up to 12 courses can be 

given. The primary endpoint was to determine the complete remission (CR) 

rate. Secondary endpoints were: CR duration, DFS, OS, safety, and early 

mortality. Results: 17 pts were enrolled on study so far. The median age was 

74 yrs (range, 64-81); the median PS was 1 (0-1). The karyotypes in these 

pts were: diploid in 6 (35%), complex with chromosome (chr) 5 and/or 7 

abnormality (abnl) in 4 (24%), complex without chr 5 and/or 7 abnl in 2 

(12%), 11q abnl in 1 (6%), poor metaphases in 1 (6%), and other in 3 

(18%). Four pts with prior MDS were treated with a median of 2 prior 

therapies (1-3). Median bone marrow blast % at the start of therapy was 40 

(15-87). The median WBC, hemoglobin, and platelets were 2.1 (0.4– 

24.8), 8.9 (7.7–10.7), and 45 (14–104), respectively. These pts have 

received a median of 1 (1-3) cycle of therapy. Of the 11 pts evaluable for 

response, there were 2(18%) CR, 1(9%) CRp, 1(9%) PR for an ORR of 

4/11 (36%). Five pts had no response and were taken off study. Two pts 

died on study: 1 on day 6 and 1 on day 27. Both pts were 74 yrs with a 

complex karyotype. One died of pneumonia and multi-organ failure and the 

2nd died from cardiac arrest. Other than the deaths, serious adverse events 

included grade 3 transaminitis in 1 and grade 3 heart failure in 1. 

Conclusions: OM and LDAC appears to be tolerable in older pts with AML. 

The combination appears to have activity. Stopping boundaries for futility 

and safety have not been breached. Enrollment is ongoing. 


Monitoring and switching patterns in chronic myelogenous leukemia (CML) 

pts treated with imatinib (IM): A chart review analysis. Presenting Author: 

Lei L. Chen, Novartis Pharmaceuticals, East Hanover, NJ 

Background: The objective of this study is to evaluate compliance to 

National Comprehensive Cancer Network (NCCN) and European LeukemiaNet 

(ELN) guidelines regarding monitoring frequency and switching 

practices in CML patients (pts) treated with IM in community practices. 

Methods: Physicians treating CML pts were selected from 28 community 

practices throughout the USA. Each physician reviewed and extracted up to 

15 pt charts of CML pts in chronic phase not previously enrolled in clinical 

trials. Pts were required to have initiated 1st-line IM between 1/2006 - 

10/2010. Data on 1st-line IM treatment response monitoring frequency 

and outcomes, and corresponding therapy switching patterns were extracted. 

Results: Information was collected on treatment monitoring and 

response from a total of 297 pt charts. Median IM duration was 320 days. 

Percentages of pts monitored according to both guidelines are reported. In 

addition, the proportion of pts who missed milestones and the proportion of 

pts who did not switch to a 2nd-line tyrosine kinase inhibitor (TKI) when 

they missed milestones are reported. Conclusions: There is considerable 

undermonitoring of CML pts receiving IM, which is likely to result in a 

significant portion of pts with suboptimal response left undetected. The 

switching rate to 2nd-line TKI among pts with suboptimal response to IM is 

much lower than recommended by either NCCN or ELN guidelines. 

Milestone 

Mos Response % Monitored 

% Missed the 

milestone (among 

monitored pts) 

% Switched to 

2nd-line TKI 

(among pts who 

missed milestone) 

0-3 CHR †‡ 4-6 PCyR 

(N�297) 98.7 10.2 16.7 

†‡ 7-12 CCyR 

(N�285) 60.4 11.6 5.0 

†‡ 13-18 CCyR 

(N�284) 61.3 29.9 17.3 

† Pts previously achieved CCyR (N�145) 39.3 1.8 0.0 

Pts did not achieve CCyR* (N�119) 38.7 32.6 33.3 

19-24 Pts previously achieved CCyR (N�172) 36.6 3.2 0.0 





0-12 MMR 


‡ (N�297) 71.7 28.6 9.8 

13-18 (N�264) 72.7 13.0 12.0 

19-36 (N�245) 71.8 9.7 23.5 

† NCCN; ‡ ELN; * Did not achieve CCyR/not previously monitored. 


439s 


Prognostic and predictive significance of smudge cell percentage on 

routine blood smear in chronic lymphocytic leukemia patients: A single 

center study from northern India. Presenting Author: Ajay Gogia, AIIMS, 

New Delhi, India 

Background: Smudge cells are ruptured lymphocytes seen on routine blood 

smears of chronic lymphocytic leukemia (CLL) patients. We evaluated 

prognostic and predictive significance of smudge cells percentage on a 

blood smear in CLL patients. Methods: We calculated smudge cell percentages 

(ratio of smudged to intact cells plus smudged lymphocyte) on 

archived blood smears of 185 untreated CLL patients registered at I.R.C.H, 

AIIMS, New Delhi over a period of 11 years. Results: There were 135 males 

and 50 females. The median age was 60 years (28-89). Median absolute 

lymphocyte count was 42 X109 /L. Clinical Rai stage distribution was: stage 

0 - 10%, stage I - 15%, stage II - 40%, stage III -15 % and stage IV - 20%. 

The median smudge cells percentage was 27% (4% to 76%). There was no 

correlation of proportion of smudge cells with age, sex, lymphocyte count, 

organomegaly, ZAP 70 � or CD 38 � CLL patients, but there was 

significant correlation with stage of disease. Median smudge cell percentage 

in stage 0 & I -33% (12-76), stage II- 31% (12-61) and stage 

III&IV-21% (4-51) [ p��0.001]. One third of early stage (0, I &II) patients 

required treatment during follow up, at the end of 5 years of follow up 55% 

required treatment with smudge cell � 30%, against 24% patients 

requiring treatment with smudge cells � 30% [p�0.01]. The percentage of 

smudge cells as a continuous variable correlated with OS [HR 0.96, p� 

0.001]. The 5-year survival rate was 51% for patients with 30% or less 

smudge cells compared with 81% for patients with more than 30% of 

smudge cells. Thirty percent of patients died during follow up. Median OS 

was 5 years with median follow up period of 3.9 years. Smudge cells 

percentage (�30% vs. �30%) had significant association with OS [HR 

0.47, 95%CI (0.32-0.71), p�0.001)]. Conclusions: Simple and inexpensive 

detection of smudge cells on blood smears on routine diagnostic test 

useful in predicting progression free and OS in CLL patients and may be 

beneficial in countries with limited recourses. 


Treatment outcome of acute myeloid leukemia (AML) in HIV� patients. 

Presenting Author: Irene Ang Dy, Leukemia Program, Continuum Cancer 

Centers of New York, New York, NY 

Background: AML is diagnosed more frequently in HIV� patients than 

previously. The results with standard AML treatment in such patients have 

not been evaluated. We evaluated whether the results justify standard 

aggressive treatment of AML in HIV� patients. Methods: We identified 5 

HIV� patients at our institution who were subsequently diagnosed with 

AML and 68 previously reported HIV� patients with AML through PubMed 

from 1986-2011. The median age at the time of AML diagnosis was 40 

years (range 7-70 years). Of the 26 patients with known karyotype, 7 had 

favorable, 7 intermediate and 12 had unfavorable cytogenetics. The 

majority of treated patients received standard intensive induction therapy 

and complete responders (CR) received consolidation therapy. HIV was 

pre-, post-, and concurrently diagnosed in 47, 2 and 19 AML patients 

respectively. The Kaplan-Meier method examined whether CD4 count, AML 

treatment and CR attainment affected overall survival. Cox proportional 

hazard modeling, adjusted for age and CD4 count determined whether AML 

treatment and CR attainment were associated with death from AML. 

Results: The final analysis included pre- and concurrently HIV diagnosed 

AML patients (n�66). HIV infection occurred at a median of 5 years (range 

0.25-28 years) prior to the diagnosis of AML in 47 patients. The most 

common FAB types were M4 (22.6%) and M2 (22.6%). CR was achieved in 

71.7% (n�33/46) of treated patients and 51.5% (n�17/33) of them 

relapsed with a median CR duration of 9.2 months. Median survival of 

patients with CD4 count � 200 and � 200 was 7 vs. 13.4 months 

(p�0.03); median survival of untreated and treated patients was 1.0 

vs.13.2 months (p � 0.001) and median survival of treated patients who 

did and did not achieve CR was 2 vs. 21 months respectively (p � 0.001). 

All treated patients and those who achieved CR were less likely to die from 

AML than untreated patients and those who failed to respond (H.R�0.05; 

95% CI, 0.01-0.17 and H.R. � 0.11; 95% C.I, 0.04-0.35, respectively). 

Conclusions: Standard AML treatment and CR were associated with longer 

survival in HIV� patients regardless of CD4 count. More than half of 

patients studied achieved CR. HIV� AML patients should be offered 

standard AML therapy. 




Omacetaxine mepesuccinate in chronic-phase chronic myeloid leukemia 

(CML) in patients resistant, intolerant, or both to two or more tyrosinekinase 

inhibitors (TKIs). Presenting Author: Luke Paul Akard, Indiana 

Blood and Marrow Transplantation, Indianapolis, IN 

Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-inclass, 

reversible, transient inhibitor of protein elongation that facilitates 

tumor cell death without depending on BCR-ABL signaling. Clinical activity 

was shown in two phase 2, open-label, multicenter studies of patients with 

treatment-resistant CML who had failed at least prior imatinib, many of 

whom were also resistant to or intolerant of dasatinib and/or nilotinib. 

Methods: A subset of data from the phase 2 studies included patients in 

chronic phase who were resistant/intolerant to �2 approved TKIs. Omacetaxine 

1.25 mg/m2 was given subcutaneously twice daily: �14 consecutive 

days/28-day cycle for induction, �7 days/cycle as maintenance. 

Patients had never achieved or lost response to �2 TKIs (R group), were 

intolerant of �2 TKIs (I), or resistant to 1 and intolerant of another (R/I) 

were evaluated. Results: Of 81 patients (median age, 58 years), 69 were R, 

7 I, and 5 R/I. Major cytogenetic response occurred in 13 (19%) in the R 

group (median duration not reached), 2 (29%) I (median duration 7.4 

months), and 1 (20%) R/I (duration 17.7 months). For all patients, cycles 

of exposure and study duration were 7 cycles and 9.1 months (R); 4 cycles, 

7.3 months (I); and 2 cycles, 2.3 months (R/I). Median overall survival in 

months were 33.9 (R), not reached (I), and 25.0 (R/I). Of 66 (81%) 

patients with treatment-related grade 3/4 adverse events (AEs), the most 

common were thrombocytopenia in 44 R, 6 I, and 4 R/I patients and 

neutropenia in 32 R, 4 I, and 1 R/I. Fifteen patients had an AE leading to 

discontinuation (10 R, 2 I, 3 R/I), primarily disease progression. There were 

9 deaths (the most common were disease progression, sepsis), 8 I, 1 R/I; 2 

were considered related to treatment (both sepsis). Conclusions: This 

subset analysis of patients with chronic-phase CML and prior therapy with 

�2 TKIs shows that omacetaxine provides efficacy and tolerability across 

TKI-R, I, and R/I groups. Interpretation of the I and the R/I group data was 

limited by small sample sizes. Support: Teva Pharmaceutical Industries 

Ltd. 


Comparison of fludarabine (F), cyclophosphamide (C), and rituximab (R) 

versus FCR plus bevacizumab (B) in relapse chronic lymphocytic leukemia 

(CLL). Presenting Author: Hun Ju Lee, University of Texas M. D. Anderson 


Background: There is significant data to show that vascular endothelial 

growth factor (VEGF) is important in the development and progression of 

CLL. Bevacizumab (B) is an anti-VEGF monoclonal antibody associated 

with improvement in progression free survival (PFS) when combined with 

chemotherapy in pts with solid malignancies. FCR is the most active 

chemoimmunotherapy in treatment of CLL. We report data on a phase II 

trial combining FCR-B and comparing the results to those seen in a trial 

with FCR for pts with relapsed CLL (Badoux et al. Blood, March 2011). 

Methods: FCR consisted of F: 25 mg/m2 and C: 250 mg/m2 on D2-4; R: 375 

mg/m2 on D1 (for the first course) and 500 mg/m2 for courses 2-6, every 4 

weeks for 6 courses. FCR-B consisted as above for FCR and (B) 10 mg/kg 

was given on D3 of each cycle. Indications for treatment and response 

assessment were according to 1996 NCI-WG guidelines for both groups. 

Results: Baseline characteristics, complete remission (CR), overall response 

rate (ORR), PFS and OS of relapsed CLL pts are shown (Table). 

Conclusions: In relapsed pts with CLL, FCR-B showed a trend toward 

improved PFS compared to FCR. 

Characteristics FCR-B (%)[range] FCR (%)[range] P-value 

N 62 284 

Median age, yrs 64 [30-84] 60 [31-84] 

Median # of prior treatments 2 [1-5] 2 [1-10] 

Alkylating agent and (F) refractory 5 (8) 33 (11) 

Prior exposure to FCR 52 (84) 78 (27) 

Rai stage 

0-II 26 (42) 154 (54) 

III 9 (14) 34 (12) 

IV 27 (44) 96 (34) 

Karyotype/FISH 

Diploid/13q- 22 (36) 97 (34) 

11q- 25 (40) 16(6) 

� 12 3 (5) 13 (5) 

Complex 1 (2) 22 (8) 

Abn 17p 11 (18) 20 (7) 

Others 0 14 (5) 

Response 

CR 13 (21) 85 (30) 

ORR 44 (71) 210 (74) 

Overall Median (mo) [95% CI] 

PFS 34 [Not reached (NR)] 23 [18-27] Not significant (NS) 

OS NR 47 [40-53] NS 

Prior chemoimmunotherapy (FCR) 

PFS 34 [16-52] 20 [17-22] NS 

OS 38 [NR] 43 [36-49] NS 


FLT3 mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic 

leukemia (CMML). Presenting Author: Pavan Kumar Bhamidipati, 

Synergy Medical Education Alliance/Michigan State University, 

Saginaw, MI 

Background: FLT3 mutations occur in one third of acute myeloid leukemia 

(AML) patients (pts) and predict poor outcome. The incidence and impact 

of FLT3 in MDS/ CMML is unknown. Methods: We conducted a retrospective 

review at MDACC to identify FAB MDS/ CMML pts with FLT3 mutations at 

diagnosis. Results: From 1996 to 2010; 2052 MDS/ CMML pts had 

mutation analysis. 45 (2.2%) had FLT3 mutations (internal tandem 

duplication-ITD or D835) at diagnosis. 29 pts had MDS and 16 had CMML. 

Median (Med) age was 64 years (21 to 83) and 69% were males. FAB 

groups: 3 pts with refractory anemia (RA), 11 pts with refractory anemiaexcess 

blasts (RAEB), 18 pts with refractory anemia-excess blasts in 

transformation (RAEB-T) and 13 pts with CMML. IPSS: 3 in Low (7%), 16 

in Int-1 (36%), 11 in Int-2 (24%), and 15 in High (33%). Med white count, 

hemoglobin, platelet count and marrow blast percent at diagnosis were 5.2 

x109 /l (1.2 to 211), 10.0 g/l (6.8 to 14.9), 78 x 109 /l (8 to 429), and 14% 

(1 to 28), respectively. FLT3 ITD and FLT3 D835 mutations were present 

in 32 (71%) and 13 pts (29%), respectively. Karyotype was diploid in 30 

(66%); -5/-7 in 5 (11%), 11q in 1 (2%), and others in 9 pts (19%). All 5 

pts with -5/ -7 had the ITD mutation. Concurrent mutations were identified 

in RAS, NPM1 and C-Kit in 6 (13%), 3 (7%) and 1 (2%) pt, respectively. 

Med overall survival (OS) for FLT3 pts was 15 months compared to 17 

months for non FLT3 pts (P�0.9). 18 pts had RAEB-T: 13 (72%) received 

AraC-based therapy and 3 (17%) received hypomethylating therapy (HMT) 

with complete remission (CR) in 14 pts (78%). 14 pts had RA/ RAEB: 5 

(36%) received AraC-based therapy and 7 (50%) received HMT with CR in 

5 (37%) and hematological improvement (HI) in 4 (28%). 13 pts had 

CMML: 4 (31%) received AraC-based therapy and 6 (46%) received HMT 

with CR in 3 (23%) and HI in 3 (23%). Repeat FLT3 was available on 16 

pts achieving any response and was absent/ decreased in 14 (88%), stable 

in 1 (6%) and increased in 1 (6%). Notably, the 14 pts with absent/ 

decreased FLT3 had med OS of 27 months versus 12 months for remaining 

group (P�0.004). Conclusions: FLT3 occurs in MDS/ CMML at a lower 

frequency than AML and does not predict poor outcome. Pts who achieve 

absent/ decreased FLT3 seem to have significantly improved overall 

survival. 


Expression levels of nucleoside transporter hENT1 and dCK enzyme, as 

prognostic factors in patients with AML treated with cytarabine. Presenting 

Author: Carmen Corrales-Alfaro, Instituto Nacional de Cancerologia, Mexico 

City, Mexico 

Background: Cytarabine has been set as the main drug included in different 

schemas for the treatment of AML patients. This drug requires inflow to the 

cell by the nucleoside transporter hENT1 and its activation rate is limited 

by dCK enzyme. Therefore decreased expression levels of these genes may 

influence response rate to this drug. Methods: AML patients � 15 years, 

without previous treatment were included. After informed consent signature, 

peripheral blood was obtained and DNA was extracted by standard 

methodology. Amplification of hENT1 and dCK genes was done by RT-PCR. 

Clinical parameters were registered. All patients received cytarabine � 

doxorrubicine as induction regimen (7 � 3 schema). Descriptive statistics 

was used. Uni- and multivariate analysis was done to determine factors 

influencing on response and overall survival. This protocol was approved by 

local IRB. Results: From January till December 2011, 22 patients have 

been included. Median age was 36 years (15-72 y), 52.3 % were male. 

According with FAB classification, M2 subtype was the most frequent 

(28.5 %). All patients had an adequate performance status (ECOG 1 & 2 � 

34 & 66 %, respectively). Cytogenetic risk was considered as intermediate 

risk in 38 %, followed by unfavorable in 28 %. Complete response was 

achieved in 58 %. Higher hENT1 expression levels was the only factor 

influencing on response and survival by Spearmen correlation analysis. 

Conclusions: These are preliminary results but are highly suggestive that 

pharmacogenetic analysis regarding cytarabine inflow may be decisive in 

AML patients. Our results require to be confirmed with a larger sample, and 

a longer follow-up. 



Real-world study of imatinib treatment patterns and outcomes among 

veteran patients with chronic myeloid leukemia. Presenting Author: Lizheng 

Shi, Tulane University, New Orleans, LA 

Background: Imatinib (IM) is the most commonly used drug in the treatment 

of chronic myeloid leukemia-chronic phase (CML-CP) patients (pts). This 

study investigated the treatment patterns and outcomes for veteran 

CML-CP pts initiated on IM. Methods: Pts (age �18 yrs) with �1 CML 

diagnosis codes documented (ICD-9 CM: 205.1x) between 1/1/2000 and 

12/31/2010 were identified from the VISN 16 data warehouse. Pts were 

required to have initiated IM as the first-line therapy in CML-CP. Accelerated 

and blastic phases (A/BP) were identified based on WHO classification 

using CBC information. IM dose adjustments were assessed as dose 

increase from �400 mg to �600mg or from 400-600mg to �800 mg 

daily. Rates of IM discontinuation (no use of IM for �60 days) and 

switching to other drug therapy (dasatinib/nilotinib (DS/NL), hydroxyurea, 

and interferon-alpha) were estimated. Time to discontinuation, progression 

to A/BP, and survival were assessed using Kaplan-Meier analysis (K-M). 

Overall survival was measured from IM initiation while survival among pts 

with disease progression was measured from the date of progression. 

Results: Among the 137 pts selected, average age was 64.8 yrs and 

follow-up time was 4.0 yrs. 16.8% of pts had dose increase from �400mg 

to �600mg and 21.7% of these pts switched to other therapy after dose 

increase. 13.1% of pts had dose increase from 400-600mg to �800 mg 

with 22.2% of these pts switching to other therapy later. During the study, 

83.8% of the 74 pts who discontinued IM did not use other drug therapies; 

and 16.2% (12 pts) switched, among which 9 pts took DS/NL. K-M showed 

that 25.6% and 42.4% pts discontinued IM treatment by year 1 and 2 and 

8.1% and 16.0% pts experienced disease progression by year 1 and 2, 

respectively. Among the 28 patients who had disease progression, 32.1% 

continued IM use after progression and only 7.1% switched to other 

therapies (50% switching to DS/NL). The mortality rates were 3.0% and 

9.5% by year 1 and 2 after IM initiation, and 21.7% and 42.7% by year 1 

and 2 after disease progression, respectively. Conclusions: The majority of 

IM-treated patients, including patients with disease progression, discontinued 

IM use without switching to other effective therapies. 


A phase II study of clofarabine and daunorubicin in patients age 60 or older 

with newly diagnosed adult acute myeloid leukemia. Presenting Author: 

Carlos Enrique Vigil, Roswell Park Cancer Institute, Buffalo, NY 

Background: The outcome of acute myeloid leukemia (AML) patients (pts) 

�60 years (yrs) old remains poor, with a median overall survival of a few 

months. Neither the addition of other drugs during induction of the 

traditional 7�3 regimen nor an increase of cytarabine or daunorubicin 

doses has improved their overall survival. We have therefore designed a 

combination of clofarabine and daunorubicin. Aims: Determine the safety 

and efficacy of clofarabine and daunorubicin in pts � 60 yrs of age. 

Methods: Induction-clofarabine 20 mg/m2 /d in a 1-hour IV for 5 days 

followed 3 hrs later by daunorubicin 50 mg/m2 IV over 5 minutes on days 1, 

3, and 5. Pts who did not achieve complete remission (CR) or CR without 

platelet recovery (CRp) were eligible for a second round of induction as 

above. Consolidation - 2 cycles of clofarabine 20mg/m2 /d for 3 days and 

daunorubicin 50 mg/m2 /day on days 1 and 3. Results: Twenty-one pts were 

enrolled. The median age was 69 (range 60-85) yrs. Seven pts (34%) had 

secondary AML and 52% had complex karyotype. Twenty-one pts completed 

one induction cycle, one pt received a second induction due to 

residual disease and 6 pts underwent consolidation therapy. The principal 

toxicity was grade �3 infections and prolonged thrombocytopenia and 

neutropenia, which occurred in 18% and 21% of pts, respectively. Three 

deaths were documented from treatment complications (sepsis and fungal 

infections). Eight (38.1%) pts achieved either a CR or CRp. Responses 

were observed in 5/11 (45.5%) pts with high risk features (complex 

karyotype and/or presence of FLT3). The median disease free-survival was 

1.9 (range, 0.9-8) months and the median overall survival was 6.5 (range, 

4.2-14.2) months. The 1-yr overall survival was 35%. Conclusions: These 

preliminary results suggest that clofarabine in combination with daunorubicin 

is safe, well-tolerated with minimal toxicity, and active for the upfront 

treatment of �60 yrs old AML pts, including those with adverse features. 

Future trials will explore additional modifications to this regimen in order to 

optimize therapy for this group of pts with high risk features and frequent 

treatment failure. 


441s 


A comparison of CR versus CRi response following CPX-351 treatment of 

newly diagnosed AML in elderly patients (pts). Presenting Author: Jeffrey E. 

Lancet, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 

Background: A Phase 2b study randomized untreated elderly AML pts to 

CPX-351 or 7�3. CPX-351 improved leukemia clearance (88% v 71%, 

�5% marrow blasts), CR�CRi rate (67% v 51%), and was particularly 

effective in pts with adverse karyotype and antecedent hematologic 

disorders (sAML). Survival following CRi is usually inferior compared to CR. 

CPX-351 markedly prolongs plasma drug levels and maintains the 5:1 

molar ratio for optimal leukemic cell killing potentially delaying hematologic 

recovery among CRi patients. Consequently, we compared the 

characteristics and outcomes of pts achieving CR v CRi. Methods: Untreated 

AML pts, aged 60-75, PS� 0-2, SCr � 2.0 mg/dL, total bilirubin 

�2.0 mg/dL, ALT/AST �3 x ULN, and LVEF �50% were eligible. Pts were 

randomized 2:1 to receive up to 2 inductions and 2 consolidations with 

CPX-351 (100 u/m2 ; D 1, 3, 5; 90 min infusion) or 7�3 (cytarabine�100 

mg/m 2 

and daunorubicin�60 mg/m2 ). Consolidation with stem cell transplantation 

(SCT) was permitted. The 1o endpoint was CR�CRi rate. The 

7�3 control arm had only a single CRi among 21 responders. The CPX-351 

arm had 15 CRi (27%) and 41 CR (73%) allowing a CR v CRi comparison to 

be made. Results: CR and CRi pts were balanced by age, race, and PS. The 

CRi group had more males (87% v 51%), more baseline WBC�20K (27% v 

15%), and more adverse karyotype (40% v 27%) and sAML (47% v 29%). 

A smaller proportion of CRi pts received post-remission chemotherapy 

(47% v 73%) but had similar rates of SCT (13% v 20%). Most CRi pts had 

delayed platelet recovery (80%). By 1-year more CRi pts had relapsed 

(54% v 39%) and more had died (54% v 34%). Contributing causes 

included: relapsed AML (7 CRi v 10 CR pts), complications post SCT (1 CRi 

v 1 CR pt), chemotherapy complications (0 CRi v2CRpts) and unknown 

causes (0 CRiv1CRpt). The survival curves were not significantly different 

(p�0.39). Conclusions: More CRi patients had adverse karyotype and sAML 

and most (53%) received no post remission chemotherapy. Survival was 

not significantly different compared to CR patients but was markedly better 

than that of non-responders. These data suggest that CRi following 

CPX-351 provides clinically meaningful benefit, a finding that needs to be 

confirmed in a larger randomized study. 


Factors associated with outcome of secondary MDS and AML: Review of 

2,182 patients at MDACC. Presenting Author: Francesco Paolo Tambaro, 


Background: Secondary acute myeloid leukemia (sAML) and myelodysplastic 

syndromes (sMDS) have been associated with prior treatment for other 

malignancies, particularly chemotherapy, and associated with high-risk 

features and poor clinical outcomes. Methods: We identified 2,182 patients 

(pts) (57% male) diagnosed with AML (n�1,073; all FAB/WHO represented) 

or MDS (n�1,109; 984 MDS, 125 MDS/MPD, all WHO represented) 

and who had 1 (n�1,907), 2 (n�239), or 3 (n�36) prior 

malignancies (PM). Pt characteristics and outcomes were analyzed. Results: 

The median age was 67 yrs. Prior hematological neoplasms (25%), breast 

(16%), prostate (16%), skin (9%) were most common. The prior malignancy 

reflected prior treatment, 1,252 pts underwent surgery, 939 

received radiation, and 1,211 received chemotherapy alone or in combination; 

124 were untreated. Types of prior malignancy and prior treatment 

associated with AML and MDS will be presented. Median time to AML/MDS 

was 64 months (mo) and 46 mo (p�0.000) for pts with 1 or �1 PM, 

respectively, and correlated with type of PM (p�0.000) and previous 

monotherapy (surgery vs RT vs chemo) (p�0.020). For both AML and MDS, 

the incidence of poor-risk cytogenetics was nearly twice for pts who 

received prior chemotherapy compared to those who underwent surgery or 

radiation alone. Factors associated with survival in secondary AML and 

MDS are reported in the table. Conclusions: In conclusion, outcomes for pts 

with secondary AML and MDS are poor, especially for pts treated with prior 

chemotherapy. Type of prior malignancy and treatment are correlated with 

outcomes. Furthermore, greater number of prior malignancies correlates 

with inferior outcomes. 

AML MDS 

Variable 

Survival (mo) p Survival (mo) p 

#PM 1vs�1 8.6 vs 5 0.004 13.5 vs 10.3 .012 

Type prior malignancy Kidney vs lung 12 vs 4 0.00 19.2 vs 9.8 .000 

Prior treatment Surgery vs RT vs Chemo 11.7 vs 5 vs 3.5 0.000 19 vs 18 vs 12 .003 

Prior treatment Chemo vs No Chemo 10.1 vs 6.7 0.002 18.3 vs 11 .000 

Karyotype Bad vs Int vs Good 4.7 vs 12 vs 58.6 0.000 8.9 vs 21 vs 26 

Prior hematologic 

malignancy 

No vs Yes 8.6 vs 6.8 0.08 13.6 vs 11.1 .03 

FAB M3 vs M1 61 vs 4 0.000 NA 

IPSS High vs Int-1 vs Int-2 vs Low NA NA 7.6 vs 18 vs 9.7 vs 34.7 .000 

# cytopenias 0 vs 1 vs 2 vs 3 NA NA 15 vs 16.7 vs 9.6 vs 6.2 .000 




Pooled safety analysis of omacetaxine mepesuccinate in patients with 

chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors 

(TKIs). Presenting Author: Meir Wetzler, Roswell Park Cancer Institute, 

Buffalo, NY 

Background: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) 

is a reversible, transient inhibitor of protein elongation that does not 

depend on BCR-ABL signaling. It showed significant clinical activity in two 

phase 2, open-label, multicenter studies of patients with CML who were 

resistant/intolerant to prior TKI therapy. However, omacetaxine tolerability 

data across the 3 phases of CML are limited. Methods: Safety data were 

pooled from all patients in the 2 studies plus a small pilot study. 

Omacetaxine 1.25 mg/m2 was given subcutaneously twice daily: �14 

successive days per 28-day cycle for induction, �7 days/cycle as maintenance. 

Days of dosing could be adjusted and recombinant growth factors 

given, as clinically indicated. Results: Of 207 pooled patients (median age, 

57 years), 108 were in chronic (CP), 55 in accelerated (AP), and 44 in blast 

phase (BP). Median treatment was 4 cycles (range, 1–41). On study, 80% 

of patients had �1 hematologic adverse event (AE), 60% had a serious AE 

(SAE), 30% had a hematologic SAE, 34% had an SAE that resulted in 

hospitalization, and 15% discontinued treatment due to an SAE (most 

commonly disease progression). There were 49 (24%) deaths (15 CP, 11 

AP, and 23 BP). Of the 8 that were treatment related (5 CP, 2 AP, 1 BP), 

the most common cause was sepsis (3 patients). The most common AEs 

were thrombocytopenia (60%), anemia (51%), diarrhea (40%), neutropenia 

(37%), and nausea (30%). Injection site reactions (eg, injection site 

pain, erythema) occurred in 32%, with the majority being low grade. 

Infections (eg, pneumonia, bronchitis) occurred in 51%. Treatment-related 

grade 3/4 hematologic AEs included thrombocytopenia (52%), neutropenia 

(31%), anemia (30%), leukopenia (12%), and febrile neutropenia 

(11%). The most common treatment-related grade 3/4 nonhematologic AE 

was fatigue (4.3%). Overall, there were 34 (16%) grade 3/4 infections (12 

CP, 11 AP, 11 BP). Conclusions: In the largest safety analysis to date, 

subcutaneous omacetaxine 1.25 mg/m2 showed an acceptable safety 

profile in all phases of CML. AEs were primarily hematologic, and grade 3/4 

nonhematologic AEs were not common. Support: Teva Pharmaceutical 

Industries Ltd. 


Prospective evaluation of serial 2-hydroxyglutarate in acute myeloid leukemia 

(AML) to determine response to therapy and predict relapse. Presenting 

Author: Amir Tahmasb Fathi, Massachusetts General Hospital/Harvard 


Background: Mutations in isocitrate dehydrogenase (IDH1 and IDH2) occur 

in 10-20% of AML patients and result in production of 2-hydroxyglutarate 

(2-HG). We hypothesize that serial 2-HG quantification may be used to 

monitor response and predict relapse in patients with AML. Methods: We 

are conducting a prospective study at MGH and DFCI to (1) assess changes 

in serum and urine 2-HG levels during treatment in patients with newly 

diagnosed AML, (2) compare 2-HG levels in serum, urine, and bone marrow 

and, (3) serially compare 2-HG levels with IDH1/2mutant allele burden. In 

those with elevated serum 2-HG (�1000ng/ml), 2-HG is monitored serially 

or at relapse. Results: To date, 20 patients have been enrolled, 5 (25%) of 

whom had elevated baseline serum 2-HG. All 5 were found to have IDH1/2 

mutations. The serum 2-HG for these patients was significantly higher than 

for those who were IDH-wt (median 1933 vs 87ng/mL; p�0.001). Urine 

2-HG was also higher in IDH-mutant patients (median 30500 vs 4230ng/ 

mL; p�0.021), as was bone marrow 2-HG (median 9870 vs 309ng/mL; 

p�0.005). Serum 2-HG levels strongly correlated with that in urine (R2 0.987). Serum 2-HG decreased in all IDH mutant patients on therapy, but 

more rapidly in those receiving induction chemotherapy (Table), all of 

whom achieved remission, than those receiving hypomethylatingagents. 

Conclusions: Patients with IDH-mutant AML have markedly elevated serum 

and urine 2-HG. 2-HG levels decreased with therapy and there is a strong 

correlation between serum and urine 2-HG. Data on the sensitivity of serial 

2-HG monitoring as well as comparison with mutant IDH1/2allele burden 

will be presented. This data suggests that serial 2-HG quantification may be 

a valuable non-invasive biomarker in this genetically defined subset of 

AML. 

Serial analysis of serum 2HG (ng/mL) during therapy in IDH-mutant AML. 

Patient 1 (5-azacitidine) 

(IDH2 R140Q) 

Patient 2 (induction) 

(IDH1 R132H) 


(IDH1 R132H) 


(IDH2 R140Q) 

Patient 5 (5-azacitidine) 

(IDH2 R140Q) 

Day 0 Day 7 Day 14 Day 30 Day 60 Day 110 

1,933 2,125 2,006 1,599 2,077 60 

2,070 1,019 295 363 195 

66,207 1,477 1,043 407 154 

1,054 249 60 84 106 

1,296 786 935 503 


Analysis of imatinib (IM)-related, low-grade (LG), non-hematologic (heme) 

adverse events (AEs) in patients (pts) with chronic myeloid leukemia (CML) 

switched to nilotinib (NIL): ENRICH study update. Presenting Author: 

Michael J. Mauro, Knight Cancer Institute at Oregon Health & Science 

University, Portland, OR 

Background: This study update assesses change in chronic LG non-heme 

AEs in adult Ph� CML-CP pts switched from IM to NIL. Methods: Pts were 

eligible if treated with IM 400 mg/d for �3 mo, and had IM-related grade 

(G) 1/2 non-heme AEs persisting �2 mo or recurring �3 times and 

persisting despite best supportive care. Pts received NIL 300 mg BID. 

Primary endpoint is change in IM-related LG non-heme AEs at 3 mo. 

Disease response was monitored by RQ-PCR and pt-reported outcomes 

measured by 2 quality-of-life (QoL) questions and MD Anderson Symptom 

Inventory (MDASI)-CML. Results: 47 pts were enrolled as of data cut-off 

(11/14/2011). There were 168 baseline IM-related non-heme AEs: 121 

G1, 47 G2. 37 pts completed 3 mo NIL, by 3 mo 103 of 154 IM-related 

AEs (67%) improved (92 resolved, 11 improved from G2 to G1), 47 

unchanged, 4 increased in severity. 13 pts were dose reduced for 

NIL-related AEs; 8 pts re-escalated after AEs recovered to G1 or resolved. 

34 G3 AEs occurred in 15 pts; investigators reported 19 AEs as suspected 

NIL-related (increased bilirubin, lipase, or blood glucose; hypokalemia; 

hypophosphatemia; pruritus; bronchitis; dehydration; rash; arthralgia; 

pleural effusion). 8 pts discontinued NIL: 6 for AEs, 2 withdrew consent. 

No G4 AEs were reported. 32 pts had MMR (3-log reduction of Bcr-Abl; 

�0.1% IS) at entry; 16 additional pts achieved MMR on NIL. At entry, 18 

pts had 4-log reduction and 10 pts 4.5-log reduction in Bcr-Abl. 16 and 13 

additional pts achieved 4- and 4.5-log reduction, respectively, on NIL. At 3 

mo (n�34) 62% and 53% pts reported QoL improvement from baseline in 

the previous 24 h and 7 d, respectively. Reduction in MDASI-CML 

severity/interference scores indicates symptom improvement. Mean reductions 

in MDASI-CML from baseline at 3 mo: severity, 1.21 (n�34); 

interference, 1.55 (n�33). Conclusions: 3 mo after switching to NIL, 

~70% baseline chronic LG non-heme IM-related AEs improved and �53% 

of pts reported improvement in QoL. Molecular responses were maintained 

or improved in all patients. Switch from IM to NIL in majority of pts reduces 

IM-related toxicities and preserves/induces molecular response in CML-CP. 


Interim results of a phase I/II randomized study of clofarabine, idarubicin, 

and cytarabine (CIA) versus fludarabine, idarubicin, and cytarabine (FIA) 

for newly diagnosed or relapsed patients (pts) with acute myeloid leukemia 

(AML). Presenting Author: Michael Mathisen, University of Texas M. D. 


Background: Outcomes of pts with AML remain suboptimal. The addition of 

cladribine to 3�7 has been shown to improve complete remission (CR) 

rates and 3-year survival. The aim of this study was to assess the efficacy 

and safety of idarubicin � cytarabine (IA, idarubicin 10 mg/m2 on days 

1-3, cytarabine 1 g/m2 on days 1-5) combined with two other nucleoside 

analogs, clofarabine (C) or fludarabine (F), in pts with newly diagnosed and 

relapsed/refractory (RR) AML. Methods: Pts with newly diagnosed or RR 

non-M3 AML with normal organ function were eligible. Pts with RR disease 

were treated in the phase I portion defining the MTD of C. The starting dose 

of C was 15 mg/m2 with doses escalating to 25 mg/m2 on days 1-5 in 

subsequent cohorts. During phase II, patients were randomized in a 

Bayesian design to C at the MTD with IA or fludarabine (F) at 30 mg/m2 on 

days 1-5 with IA. Up to 6 consolidation cycles were planned according to an 

attenuated schedule using the same drugs. Dose adjustments were made 

for elderly pts or pts with poor PS. Results: 9 pts were enrolled in the phase I 

portion. The overall response rate (ORR) in this group was 44%. DLT were 

observed at C 20 mg/m2 and included hand/foot syndrome (HFS), elevated 

bilirubin, and prolonged myelosuppression. The MTD was 15 mg/m2 on 

days 1-5. 50 evaluable pts were enrolled (16 newly diagnosed, 34 RR) in 

the phase II. In the frontline cohort, median age was similar in both groups 

(C 56, F 55), as were the cytogenetic profiles. The CR rate was 100% in 

both groups (9 CIA, 7 FIA). Detailed efficacy information can be found in 

the Table. More than half of the RR cohort were receiving therapy as salvage 

2 or higher, and most had short first CR durations. Notable toxicities 

included elevated liver function tests for both groups, and HFS in the C 

group. There were 4 deaths on study, though most pts were receiving 

therapy as second salvage and were over the age of 60. Conclusions: CIA 

and FIA are effective regimens for newly diagnosed or RR AML with 

manageable toxicity profiles. The ORR were 100% and 32% for newly 

diagnosed and RR AML pts, respectively, with low early mortality rates. The 

study is ongoing. 



Impact of immunoglobulin heavy chain variable region mutational status on 

the outcome of patients with chronic lymphocytic leukemia harboring 

isolated 13q deletion. Presenting Author: Gelenis C. Domingo, H. Lee 

Moffitt Cancer Canter & Research Institute, Tampa, FL 

Background: Several prognostic factors can predict the course of chronic 

lymphocytic leukemia (CLL). Among them, the IGVH mutational status and 

the presence of cytogenetic abnormalities are the strongest predictors of 

outcome. Mutated IGVH and deletion 13q independently confer a survival 

advantage. CLL patients with mutated IGVH in combination with deletion 

13q have a better prognosis when compared to their unmutated IGVH 

counterparts. However, there is limited data on the outcome of patients 

harboring favorable deletion 13q and the unfavorable unmutated IGVH. 

This study aimed at identifying patients with these two indicators in order 

to obtain important prognostic information. Methods: We used the Moffitt 

Cancer Center Total Cancer Care (TCC) database to find patients with a 

diagnosis of CLL between January 1993 and December 2009. Individual 

charts were reviewed for demographic data and CLL cytogenetics, including 

IGVH mutation status and presence of deletion 13q. We analyzed the 

impact of having deletion 13q in combination with an unmutated IGVH on 

the overall survival (OS) for this subset of CLL patients using Kaplan Meier 

curves with SPSS statistical software. Results: 546 patients were identified 

during the aforementioned time period with a diagnosis of CLL. Median age 

was 62.5 years. 144 (26.4%) of these patients had IGVH and cytogenetic 

analysis available. 53 patients had 13q deletion as their sole genetic 

abnormality. Patients with unmutated IGVH and positive for deletion 13q 

were 19/53 (35.8%). Patients with mutated IGVH and positive for deletion 

13q were 34/53 (64.2%). Patients with mutated IGVH and positive for 

deletion 13q had an OS of 17 years. While patients with unmutated IGVH 

and positive deletion 13q had a lower median OS of 12 years (91.2% vs 

78.9%, p�0.05). Hazard ratio for patients with IGVH mutated and positive 

deletion 13q was 0.4, p�0.05. Conclusions: Mutated IGVH appears to be 

associated with improved OS in patients with isolated 13q deletion when 

compared to patients with unmutated IGVH and isolated 13q deletion. 

Further research is needed to assess these mutations in relation to other 

cytogenetic abnormalities in CLL. 


Assessment of age as its own risk factor in AML. Presenting Author: Thomas 

Buchner, University of Muenster, Muenster, Germany 

Background: Patients’ age is an important issue in treatment decisions for 

AML, while its role in this disease remains poorly explained. Methods: In the 

AMLCG 1999 trial 1223 patients (pts) were 16-59y and 1470 pts were 

60-85y of age. Their treatment was randomized between TAD-HAM vs 

HAM-HAM induction (TAD, standard dose thioguanine, cytarabine, daunorubicin 

60mg/m² x 3; HAM, high-dose cytarabine 3g/m² x 6, mitoxantrone 

10mg/m² x 3), TAD consolidation and monthly maintenance vs autologous 

SCT, any chemotherapy � vs - G-CSF priming. All randomization was done 

upfront. Pts of �60y received routine double induction and full dose HAM 

while pts of 60�y preferentially received only one course induction and 

HAM at 1g instead of 3g cytarabine /m² x6.Results: With little differences 

according randomizations, pts �60y and 60�y achieved a complete 

remission rate (CR) of 70.2% and 53.5% (p�.001), overall survival (OS) at 

5y of 41.3% and 12.9% (p�.001) and a relapse rate (RR) of 49.0 and 

72.0% (p�.001). We also focussed on pts around 60y of age and 

compared the 172 pts of 57-59y with the 261 pts of 60-62y excluding pts 

undergoing allogeneic stem cell transplantation. According to their similar 

age the two groups showed similar baseline characteristics. In contrast and 

due to the cut-off point for age adaption at 60y they differed considerably in 

treatment. Expressed by the cumulative dosage of cytarabine, the difference 

between the two groups was by factor 2.9. This difference, however, 

did not translate into a different outcome being 62% vs 60% CR, 28% vs 

21% 5y OS (p�0.25), and 73% vs 73% RR at 5y. A multivariable analysis 

in all pts between 16 and 85y of age identified cytogenetik/ molecular risk 

and age as a continuous variable, to be risk factors predicting CR, OS, as 

well as RR. In pts of 16-60y those below and above the median age of 47y 

differed in their CR rate by 75% vs 66% (p�.001), their OS by 49% vs 

35% (p�.001) and in their RR by 45% vs 53% (p�.007). In pts of 60-85y 

those below and above the median age of 67y differed in their CR rate by 

57% vs 51% (p�.023), and their OS by 16% vs 11% (p�.001), while their 

RR was similarly 71%. Conclusions: The outcome in pts with AML is 

substantially determined by patients’ age as its own risk factor, and not by 

treatment intensity. 


443s 


A new paradigm in CLL: Minimizing toxicity by using the minimum effective 

dose (MED) of lenalidomide for older patients with CLL. Presenting Author: 

Nicole Lamanna, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: While CIT has proven active for younger patients with CLL; 

studies from Germany and MDACC with fludarabine or fludarabine- based 

regimens did not benefit the patient over the age of 65 or 70. As the median 

age of diagnosis is 72, the development of safe, active therapies for older 

patients is an unmet need in CLL. Lenalidomide is an active drug in CLL. 

The current clinical trial was designed to assess whether low-dose continuous 

lenalidomide therapy can provide long-term disease control with 

minimum toxicity in patients older than 65. Methods: Patients initiate 

lenalidomide at 2.5mg daily (28-day cycle) and only dose escalate for 

progressive disease (POD). Results: 18 patients have been enrolled: 12 men 

and 6 women, med age 70 (range 65-84) with Rai-intermediate (7 pts) or 

high-risk (11 pts; 61%) disease; med WBC 50.5 (6.7-326.3), HGB 10.3 

(8.9-13.9), PLT 121 (44-215), �-2 microglobulin 4.9 (3.0-10.2). 16 

(89%) patients had chromosomal abnormalities: 3 with 13q, 6 with tris 12, 

3 with 11q, and 4 with 17p. 13 (72%) patients have unmutated IGHV. 5 

(28%) patients were previously untreated; 13 (72%) had prior therapy 

(range 1-5; med 2). Median dose of lenalidomide is 2.5mg (range 

2.5mg-10mg); median no. cycles is 7 (range 1-28). 11 patients (61%) are 

still on therapy (7 previously treated): 6 at 2.5mg; 4 at 5mg, and 1 at 

10mg. 7 have discontinued therapy: 1 for ITP; 3 for POD including one with 

Richter’s, 2 for desquamating rash; and 1 withdrew consent. Only 2 

patients had tumor lysis and 10 had tumor flare (8 given steroids briefly). In 

these older patients on long-term continuous treatment, therapy has been 

generally well tolerated. There have been no deaths on study. Pneumonia 

developed in 4 patients (3 of these had prior therapy). 1 patient with history 

of atrial fibrillation developed DVT/PE. Main hematologic toxicity is 

neutropenia seen in 11 patients but transient. Grade 3/4 thrombocytopenia 

and anemia was seen in 5 and 0 patients, respectively. Conclusions: 

Low-dose continuous lenalidomide therapy iappears to be well-tolerated 

and may offer long term disease control in some patients with CLL. 

Additional accrual and longer follow-up will be required to further assess 

the utility of this strategy. 


Disease response and survival outcomes in acute myeloid leukemia (AML) 

patients unfit for chemotherapy treated with 10-day decitabine as initial 

therapy. Presenting Author: Theodore Stewart Gourdin, University of 

Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 

Background: AML is primarily a disease of older adults, with a median age of 

67 years at diagnosis. Many patients are considered unfit for chemotherapy 

due to poor performance status and/or comorbidities, prompting investigation 

of less intensive approaches. A clinical trial in which 10-day courses of 

decitabine 20mg/m2 were given every 28 days as initial therapy demonstrated 

a promising complete remission (CR) rate and disease-free survival 

(DFS). We used this regimen to treat AML patients unfit for chemotherapy 

outside of a clinical trial. Methods: Charts of 32 newly diagnosed AML 

patients treated with 10-day courses of decitabine 20mg/m2 as initial 

therapy at the University of Maryland Greenebaum Cancer Center between 

September 2010 and November 2011 were retrospectively reviewed. If 

patients attained bone marrow blasts �5%, 5-day courses were administered 

subsequently and were continued until disease progression. Results: 

Median age at diagnosis was 74 years (range, 52-86). 18 patients were 

male and 14 female. 23 were Caucasian, 7 African-American and 1 

Hispanic. 10 patients (31%) had performance status � 2. All had 

significant cardiac, pulmonary and/or renal disease. Karyotype risk group 

was unfavorable in 17 patients, intermediate in 14 and unknown in one. 

There were 9 CRs and 1 partial remission, for an overall response rate of 

31%, following a median of 2 (range, 1 to 4) courses. 21 patients did not 

respond to treatment following 1 to 6 courses, and one died within 29 days 

of treatment initiation. 21 patients (65%) were hospitalized at least once 

for fever or infection during treatment. Of the 9 patients who achieved CR, 

5 had normal, 3 complex and 1 unknown karyotypes. Median DFS was 390 

days (range, 87�-468�) and median OS 180 days (range, 15-623�). 

Six-month OS was 37.5% and 1-year OS 16.5%. Conclusions: AML 

patients unfit for chemotherapy treated with 10-day decitabine 20mg/m2 

outside of a clinical trial had a higher response rate than reported for 5-day 

decitabine, but a lower response rate than in the reported clinical trial of 

the 10-day regimen. Additional novel treatment approaches are needed for 

these patients. 




High frequency of BCR-ABL oncogene in pediatric acute lymphoblastic 

leukemia (ALL) patients as revealed by RT-PCR and interphase FISH: 

Association with disease biology and treatment outcome. Presenting 

Author: Zafar Iqbal, Molecular Genetic Pathology Unit, Department of 

Pathology, College of Medicine and KKUH, King Saud University, Riyadh, 

Saudi Arabia; and Haematology, Oncology and Pharmacogenetic Engineering 

Sciences (HOPES) Group, HSRL, Zoology Department, University of the 

Punjab, Lahore, Pakistan 

Background: ALL is a complex genetic disease involving many fusion 

oncogenes (FGs) 1 frequency of which can vary in different ethnic groups2,3 thus having implication in differential diagnosis, prognosis and treatment. 

Methods: We studied FGs in 101 pediatric ALL patients using RT-PCR1 at 

Day 0, Day 15 and Day 29 and Interphase FISH, and their association with 

clinical features and treatment outcome. Results: Five most common FGs 

i.e. BCRABL (t 22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), 

MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 88.1% 

(89/101) patients. Frequency of BCR-ABL was 44.5% (45/101). Patients 

with BCR-ABL had significantly lower survival (43.733 weeks �4.241) as 

compared to others except MLL-AF4 and significantly higher TLC count. 

Overall survival was lower (52.2�3.75) than the patients with ETV6-RUN X 

1 (65.2� 9.9) which may be due to overall high frequency of poor 

prognostic FGs (71%) as compared to ETV6-RUNX 1 (17.1%) (p�0.01). 

Conclusions: This is the first study from Pakistan correlating molecular 

markers, disease biology and treatment response. It is the highest reported 

frequency of BCR-ABL in pediatric ALL and was associated with disease 

biology and survival. Some authors have reported BCR-ABL frequency 

higher than in West2,4,5 while others reported 45% frequency of ETV6- 

RUNX16 . These and our data reflect strong interplay of genetic and 

environmental factors in biology of pediatric ALL and its correlation with 

disease biology and treatment2,3 . Our data indicates immediate need for 

large clinical trials of imatinib, dasatinib and nilotinib in paediatric ALL 

treatment in our ethnic group. This study will lead to unravel the 

mechanisms of BCR-ABL Leukemogenesis and to find population-specific 

biomarkers and drug targets. References: 1) van Dongen JJ, et al., 

Leukemia. 1999 Dec; 13(12):1901-28. 2) Iqbal Z, et al. J Pediatr 

Hematol Oncol. 2007 Aug; 29(8):585. 3) Ariffin H, et al. J Pediatr Hematol 

Oncol. 2007 Jan; 29(1):27-31. 4) Ramos C, et al. 2011 Sep; 139(9):1135- 

42. 5) Artigas A CG, et al. Rev Med Chil. 2006 Nov; 134(11):1367-76. 6) 

Karrman K, et al. Br J Haematol. 2006 Nov; 135(3):352-4. 


CDKN2A-deletion to predict relapse in adult B-cell acute lymphoblastic 

leukemia (B-ALL). Presenting Author: Preet Paul Singh, Mayo Clinic, 

Rochester, MN 

Background: CDKN2A locus on chromosome 9p21 is implicated in altered 

molecular pathways leading to leukemogenesis as a tumor suppressor by 

inhibiting the proliferative kinases CDK4/CDK6 and blocking the cell-cycle 

division during G1/S phase. Deletion of CDKN2A locus is frequently seen in 

ALL, although prognostic significance remains unclear. Methods: Retrospective 

chart review at Mayo Clinic between 8/2005-11/2011 was performed 

on adult B-ALL patients (pts) who underwent fluorescent in situ hybridization 

(FISH) studies at diagnosis. Survival estimate was calculated using 

Kaplan-Meier statistics. Event-free survival (EFS) was defined as time 

between diagnosis and induction failure, relapse, or death, while overall 

survival (OS) as time between diagnosis and death Results: Out of 27 pts 

who had FISH studies for CDKN2A, 15 (56%) pts had CDKN2A deletions 

(8 homozygous/7 hemizygous), while 12 (44%) pts had diploid cytogenetics 

(none had abnormalities of MLL, bcr/abl fusion or CDKN2A deletion on 

FISH). There was no significant difference in median age, gender, WBC, 

hemoglobin, platelet count, LDH or complete remission (CR) rate (p�0.924) 

between the two groups. CDKN2A-deleted pts had higher circulating blasts 

(34% vs 16%, p�0.017). Of 13 CDKN2A-deleted pts, chromosome 9p 

was intact in 9 (69%) pts using routine cytogenetics. In the CDKN2Adeleted 

group, allogeneic stem cell transplant (ASCT) was performed in 7 

(47%) pts at first CR and 1 at second CR. Four of 15 (27%) CDKN2Adeleted 

pts also had bcr/abl fusion. Five-year EFS was poorer in CDKN2Adeleted 

pts compared to normal FISH group (22% vs 60%, p�0.042), 

while 5-year OS was 72% vs 60% (p�0.308), respectively. Excluding the 4 

bcr/abl fusion pts, 5-year EFS was still statistically significant (p�0.008). 

In the CDKN2A deleted group, both 5-yr EFS (80% vs 0%, p�0.006) and 

OS (100% vs 42%, p�0.016) were significantly superior in pts who 

received ASCT. Conclusions: CDKN2A deletions predict earlier relapse in 

pts with B-ALL. Majority of 9p abnormalities were only found by FISH 

testing and missed by conventional cytogenetics. In CDKN2A deleted pts, 

ASCT gave overall survival advantage. Further investigation through larger 

cohorts of pts is needed to validate these findings. 


Safety and efficacy of dose escalated liposomal amphotericin B in adult 

leukemia patients with refractory invasive fungal infections: A single 

institution report. Presenting Author: Sherry Mathew, Memorial Sloan- 


Background: Leukemia patients are at risk for invasive fungal infections(IFI). 

Empiric therapy of suspected IFI is begun due to fever despite 

appropriate antibiotics during neutropenia or infiltrates on chest CT. 

Liposomal amphotericin B (L-AmB) is used for empiric anti-fungal therapy 

at 3-5 mg/kg. Data is lacking on the efficacy of L-AmB dose escalation in 

patients with CT progression and clinical decline. Methods: Patients who 

received 10 mg/kg of L-AmB from 2002-11. They were required to be �18 

years old and escalated from 5 to 10 mg/kg L-Amb for at least 7 doses. 

Patient information was collected from pharmacy and medical records. 

Successful treatment was defined as resolution of fever at least 1 week after 

high dose L-AmB and/or improvement or stability on chest CT. Renal and 

hepatic toxicity was assessed. Clinical remission was defined as recovery of 

a normal neutrophil count. IRB approval was obtained for this study. 

Results: 58 patients were evaluated. At the time of presumed or probable 

IFI, 19 had completed induction therapy, 5 had received supportive 

therapy, and 34 had received 2 or more cycles of therapy. High dose L-AmB 

was begun for CT findings and fever, CT findings only, and fever only in 14, 

26, and 17 patients, respectively. Patients received a median of 15 doses 

of high dose L-AmB, and all received concomitant therapy with an 

echinocandin except two: 1 received nothing and 1 received voriconazole. 

Treatment success was seen in 28 (48%) patients. Twenty-nine (50%) 

patients were alive at 12 weeks and 10 (17%) patients proceded to BMT. 

Only 11 (39%) of the responding patients achieved a clinical remission. All 

patients received IV hydration and electrolyte repletion. Six patients had a 

grade 2 increase in serum creatinine and 10 patients developed grade 2 or 

3 hepatic toxicity. There were no grade 4 adverse events. Conclusions: 

Although it has been reported that L-AmB at 10mg/kg was inferior to 3 

mg/kg in untreated patients, our study supports a safe dose escalation 

strategy to 10mg/kg in treating progressive presumed or probable IFI and 

should be considered a clinical alternative for these high risk patients. 


Time to ATRA in suspected newly diagnosed acute promyelocytic leukemia 

and association with early death rate at a non-cancer center institution: Are 

we meeting the target? Presenting Author: Gulam Abbas Manji, Albany 

Medical Center, Albany, NY 

Background: ATRA administration in suspected APL patients (sAPL) is 

thought to impact early death rate (EDR) (Tallman and Manji, Blood Cells 

Mol Dis. 2011). Delay in ATRA therapy at specialized centers was 

associated with EDR (Altman et al Blood 2011). EDR within this study was 

significantly lower compared to the SEER database (12% vs 17.3%) and 

hence may not reflect overall delay in ATRA therapy. We determined time to 

ATRA therapy in sAPL, and fraction of sAPL that did not have disease. 

Methods: Retrospective analysis of patients that received ATRA for newly 

diagnosed s APL between 01/01/98-12/31/11 at Albany Medical Center. 

Time to hematologist evaluation, ATRA ordered and administered, and 

mortality data was collected from cancer registry, medical record, and 

chemo-pharmacy database. Results: A total of 39 patients with newly 

diagnosed sAPL were administered ATRA (46% male, mean age 50y). APL 

diagnosis: 29/39 (75%) true APL (APL); 9/10 ATRA-treated non-APL 

(A-nAPL); and one patient for whom cytogenetic data unavailable. EDR 

amongst APL was 5/29 (17%) compared to 2/9 (22%) within A-nAPL. Time 

variables were compared between APL patients that died early (�30d) to 

those that survived 30 days, and included: time to hematologist response 

(0.9d vs. 0.4d); time to ATRA ordered (2.9d vs. 2.0d); time to ATRA 

administered (3.4d v. 2.2d); and time elapsed between hematologist 

response to ATRA administered (2.5d v. 1.9d), respectively. Cryoprecipitate 

was administered to 1/5 (20%) patients who expired within 30d 

compared to 10/23 (43%) who survived. Overall mortality for APL was 9/29 

(31%) compared to 4/9 (44%) for A-nAPL group. Compared to recent 

reports, time to ATRA administration in our institution was later (2.0d vs. 

2.4d). Conclusions: Our data indicate that APL patients who survived 30d 

received ATRA early. EDR at our institution is comparable to that reported 

by SEER database and may be attributed to delay in ATRA administration. 

Higher fraction of patients that survived 30d received cryoprecipitate. 

Hence aggressive blood product support may contribute to improved 

survival. Timing at which these products were administered is currently 

being evaluated. 



Epigenetically induced expression of CD30 in T-PLL: A rationale for the use of 

brentuximab vedotin. Presenting Author: Zainul Hasanali, Penn State Hershey 

Medical Center, Hershey , PA 

Background: T-cell prolymphocytic leukemia (T-PLL) is characterized by high 

lymphocyte counts, skin involvement and enlarged organs. Treatment with 

alemtuzumab (alem) induces complete remission (CR) in �50% of patients, 

duration is short (median: 6 mos). Therapy with the histone deacetylase 

inhibitors (HDACi) vorinostat (SAHA) or romidepsin (romi) and cladribine 

(2-CdA), may augment mAb activity. Methods: Five T-PLL patients were studied 

(Table). Diagnosis was made by pathology, flow cytometry and TCR studies. Alem 

(30 mg sq d1,3,5) and 2-CdA (5mg/m2 d1-5), followed by alem, 2-CdA and 

SAHA (400mg qdX5days) or romi (14mg/m2d 1,8,15) was given. One patient 

with skin lesions expressed CD30 and received brentuximab vedotin (SGN-35). 

Results: All patients achieved CR (mean: 10; median: 8 mos). Relapsed patients 

responded with repeat dosing. Genes assayed indicate involvement of the MAPK 

pathway (p53, DUSP2, TRIB1, C/EBP). mRNA expression of the membrane receptor 

CD30 (TNFRSF8) increased following therapy in 4/5 patients (mean: 14; Range: 

1.3-69 fold). CD30 protein was confirmed by IHC and Western blotting. One patient 

with relapsed T-PLL involving skin had a dramatic clearing of lesions and blood counts 

after one dose of SGN35. Conclusions: Therapy with HDACi and 2-CdA overcomes 

resistance and augments clinical activity of alem and SGN-35, as evidenced by 

derepression of CD30 and response to treatment. We present a rationale for 

epigenetic resensitization to mAbs and their drug conjugates (ADC) in T-PLL. A 

prospective multicenter clinical trial is warranted. 

Patient characteristics. 

Age, years 

Range 64-77 

Median 71 

Sex 

Male 3 

Female 2 

Karnofsky score 90% (5) 

WBC at diagnosis 

Range 120-300 

Median 211 

Peripheral blood flow 

CD4� 5 

CD8� 2 

CD2� 5 

CD5� 5 

CD7� 5 

Treatment 

Alemtuzumab 5 

Cladribine 5 

Vorinostat 3 

Romidepsin 1 

Brentuximab vedotin 1 

TCR-rearrangement 5 

Remission 5/5 (100%) 

Remission duration (months) 

Pt 1 16, 8� 

Pt 2 8, 5, 4 

Pt 3 6* 

Pt 4 13, 1* 

Pt 5 6, 3� 

Current status 

Alive 2 

Hematologic remission 2 

CD30 mRNA expression fold change after initial treatment 

Pt 1 �69.0 

Pt 2 �1.3 

Pt 3 -3.5 

Pt 4 �11.8 

Pt 5 �2.8, �4.2† 

Average �11.8 

Std. dev. -/� 27.3 

* Patient deceased with no evidence of disease. 

† Fold change after treatment of relapse. 


The prognostic role of serum albumin in patients receiving induction 

chemotherapy for acute myeloid leukemia (AML). Presenting Author: 

Hossein Sadrzadeh, Massachusetts General Hospital/Harvard Medical 

School, Boston, MA 

Background: Serum albumin has been investigated as a prognostic tool in 

the care of patients with hematologic malignancies, including multiple 

myeloma and myelodysplastic syndromes. However, its prognostic utility in 

patients with AML is unknown. We hypothesized that a lower serum 

albumin is associated with worse outcomes following induction chemotherapy 

for AML. Methods: We conducted a retrospective medical record 

review of 166 adult, non-promyelocytic AML patients who had received 

induction chemotherapy at Massachusetts General Hospital from 1992 to 

2007. Patient characteristics were summarized as numbers and percentages 

for categorical variables. The Kaplan Meier method was used to 

estimate median disease-free survival (DFS) and overall survival (OS). We 

dichotomized our patients by serum albumin �3 and �3, and determined 

the association of albumin with 60-day survival and complete remission 

(CR) rate using Fisher’s exact test. Association of albumin with DFS and OS 

was summarized using Cox regression in both univariate and multivariable 

analyses. Results: Of 166 patients, 125 (75%) achieved CR and 143 

(86%) were alive at 60 days following diagnosis. After risk-adjusting for age 

and LDH, we found that a serum albumin level �3 mg/dL was associated 

with decreased 60-day survival (OR 0.30, p�0.015) and CR rate (OR 0.41, 

p�0.02) compared to patients with serum albumin �3. There was no 

association between serum albumin and DFS (p�0.88) or OS (p�0.31). As 

expected, younger age was associated with better induction outcomes. 

Conclusions: Serum albumin was negatively associated with short-term 

outcomes in patients receiving induction chemotherapy. A serum albumin 

level less than 3, clinically relevant to oncologic patients, was associated 

with a significantly decreased CR rate and lower 60-day survival after 

induction chemotherapy. This data suggests that serum albumin, a 

surrogate commonly used for nutritional status and suppressed in inflammatory 

comorbid states, has prognostic utility for AML patients undergoing 

induction chemotherapy. 


445s 


A seasonal pattern of presentation in younger patients with de novo acute 

myeloid leukemia (AML). Presenting Author: Benjamin Jacob Drapkin, 

Massachusetts General Hospital/Harvard Medical School, Boston, MA 

Background: Seasonal variation in AML has been studied in a wide variety of 

populations and locations, with primarily negative results. These investigations 

may have been undermined by the heterogeneity of the disease, as de 

novo and secondary AML can vary in disease presentation and trajectory, 

likely reflecting distinct pathogenesis.We investigated seasonal variation in 

the incidence of AML diagnosed at Massachusetts General Hospital (MGH) 

from 1992 through 2011, focusing on de novo disease among younger 

patients. Methods: We assembled a database of 511 biopsy-proven cases of 

adult-onset AML (age � 18 years), from the MGH electronic medical 

record, using a systematic search algorithm with IRB approval. We 

subdivided this database into three cohorts: (1) de novo AML diagnosed 

prior to age 50 (2) de novo AML diagnosed after age 50, and (3) secondary 

AML, preceded by chemotherapy, myelodysplasia or myeloproliferative 

disease. Diagnosis dates were grouped into quarters (Jan-Mar, Apr-Jun, 

Jul-Sep, Oct-Dec). Divergence of quarterly incidence from a null hypothesis 

of uniformity was evaluated by chi square analysis. Results: Among patients 

under 50-years-old with de novo AML, we found a 44% increase in 

incidence between October and December (Table, p�0.04). There was no 

significant variation throughout the rest of the calendar year. Furthermore, 

the incidence of both de novo AML diagnosed after age 50 and secondary 

AML conformed to a uniform quarterly distribution. As expected, the 

majority of AML patients under age 50 demonstrated intermediate-risk 

cytogenetics, most frequently normal karyotype. Conclusions: We found a 

significantly increased incidence of de novo AML in younger patients 

between the months of October and December, diagnosed at MGH from 

1992 through 2011. This may reflect a local environmental or infectious 

exposure that is not relevant to the pathogenesis of AML in older patients or 

those in whom AML develops due to prior therapy or previous hematological 

disorder. Investigation of this exposure is ongoing. 

Quarter All cases Under 50 y/o Over 50 y/o Secondary 

Jan-Mar 23% 17% 26% 23% 

Apr-Jun 25% 23% 25% 27% 

Jul-Sep 25% 24% 24% 26% 

Oct-Dec 27% 36% 26% 24% 

Total patients 511 108 182 221 

p value 0.51 0.04 0.97 0.77 

6619^ General Poster Session (Board #24F), Mon, 1:15 PM-5:15 PM 

Initial characterization of the toxicity and efficacy of elacytarabine (CP- 

4055), a novel antileukemic agent, using a multidimensional exposureresponse 

relationship model. Presenting Author: Murray P. Ducharme, 

Learn and Confirm Inc., Quebec, QC, Canada 

Background: Elacytarabine (CP-4055), an elaidic acid ester of ara-C, is a 

novel antineoplastic agent developed to treat hematologic malignancies 

(HM). It is metabolized to active ara-CTP and inactive ara-U. In 3 studies, 

diverse elacytarabine monotherapy doses and regimens were given to 

patients with advanced HM and solid tumours. This analysis aimed to 1) 

describe the pharmacokinetics (PK) of elacytarabine in these patients and 

2) investigate the relationship between PK and toxicity and efficacy in HM. 

Methods: Population PK analyses were run with ADAPT 5 (ITS) and 

included 146 patients given a 2h, 4h or 120h continuous infusion (CIV) of 

elacytarabine. Elacytarabine, ara-C and ara-U plasma concentrations (Cp) 

were simultaneously modeled and explained. Standard model discrimination 

criteria were used to select the best model. With the model, different 

dosing regimens were simulated to find average exposure and % of patients 

with efficacious or toxic exposure. A multi-dimensional exposure-response 

relationship (MDERR) was developed with pre-clinical and clinical data. 

Results: The best model was a 2-compartment (CPT) model with linear 

elimination and formation rates for the metabolism of elacytarabine to 

ara-C. Mean PK parameters were Vc � 4.12 L/m2 ,CL�5.27 L/h/m2 and 

T1/2 � 7.57 h. Elacytarabine PK included a peripheral CPT with a 

non-linear distribution process to reflect saturable binding to red blood 

cells, otherwise its PK was linear. Ara-C and ara-U PK were described by 2and 

1-CPT linear models, respectively. The MDERR model related efficacy 

and toxicity thresholds to elacytarabine dosing regimens, and indicated 

that a 120 h CIV dosing regimen is preferable, allowing elacytarabine to 

exceed efficacious Cp for longer than the other investigated regimens. A 

minimum dose of 1000 mg/m2 /day is needed for most patients to receive 

efficacious exposure. Conclusions: Elacytarabine is a promising antileukemic 

agent for patients with advanced HM. Its PK, toxicity and efficacy 

were characterized in patients given diverse dosing regimens. An MDERR 

model, which will be further refined or confirmed in upcoming clinical 

trials, was proposed. 




Azacitidine as induction therapy of elderly patients with acute myelogenous 

leukemia. Presenting Author: Cyrus Khan, West Penn Allegheny Health 

System, Pittsburgh, PA 

Background: Effective alternative treatment of elderly patients (aged � 60 

years) with acute myelogenous leukemia (AML) remains challenging. 

Elderly patients with AML respond poorly to standard induction regimens 

and have high treatment related mortality. In a prior retrospective analysis 

of elderly patients with AML performed at our institution, azacitidine (AZA) 

showed an overall response rate (ORR) of 60% with limited toxicity. 

Methods: This is a prospective, phase II open-label study using AZA in 

patients �60 years with AML. Inclusion criteria: Newly-diagnosed non-M3 

AML and ECOG � 2. Patients with circulating blast count �30,000/mcl 

were treated with hydroxyurea until � 30,000/mcl. AZA was administered 

at 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until 

disease progression or significant toxicity. Results: In all, 15 patients were 

enrolled last follow-up being 8/2/11. The mean age of patients is 74 years 

(range: 64–82). Mean ECOG score was 1. Mean baseline bone marrow 

blast count was 52% (range: 25–92%). ORR was 46% (n�7) with 

complete response (CR) in 3 (20%) patients and partial response (PR) in 2 

(13%) patients according to NCI response criteria, and hematologic 

improvement (HI) in 2 (13%) patients according to IWG response criteria. 

The mean number of days on treatment was 198 (range: 13–724). The 

mean time to best response among responders was 95 days (range: 

44-279). The mean number of days hospitalized for diagnosis plus 

treatment or disease-related complication was 19 (range: 5–56), with the 

majority of therapy administered in an outpatient setting. Mean overall 

survival (OS) from diagnosis for all patients was 355 days (range: 13–908) 

and mean OS for responders was 532 days (range: 120–908). Nonhematological 

toxicity was limited to mild injection site skin reaction and 

fatigue in 73% (11/15). No treatment-related deaths were observed. The 

dose and schedule of AZA remained constant in a majority of the patients. 

Conclusions: This study suggests that a 5-day schedule of SC AZA at 100 

mg/m2 to elderly patients with newly-diagnosed AML is a feasible, 

well-tolerated and effective alternative to standard induction chemotherapy. 


Use of granulocytes concentrates from a single high yield apheresis to 

support more than one patient. Presenting Author: Fleur M. Aung, University 


Background: Allogeneic granulocyte transfusion therapy is sometimes the 

only therapeutic option in immunocompromised neutropenic leukemic/ 

HSCT patients with life threatening bacterial and fungal infections. 

Collection of larger cell doses of granulocyte concentrates (GC) by automated 

apheresis following G-CSF/steroids administration has renewed 

interest and its use has grown steadily. Methods: Donors were recruited from 

family/friends of the patients and informed consent was obtained. GCs were 

collected via donor stimulation with a single subcutaneous dose of G-CSF 

(600 mcg). First time donors received an oral dose of dexamethasone (8 

mg). GCs were harvested by Hetastarch-assisted leukapheresis 12 hours 

later via peripheral venous access with the continuous flow cell separator 

Spectra (COBE Caridian BCT, Lakewood, CO). Results: GCs were collected 

from 93 donors (67M: 26F; age median 40 (19-73 years) and 1½xblood 

volume processed median 7048 (3212-8085 mL). The pre/post wbc were 

median 8.1 (4.1-22.8)/ 42.7 (22.4-77.5). The volume collected was 

based on the post G-CSF wbc count (� 35 K/UL - 800 mL; �35 K/UL 

between 600-700 mL). The original yield (10 x10e) was median 9.7 

(5.1-17.2 units), volume median 718 (538-860 mL) and WBC median 

132.7 (84.2 -241.6 K/UL per bag). The Split GCs were median 4.48 

(2.70-7.72 units), with neutrophils median 87% (54-97% per bag). GCs 

were transfused to 51 patients (31M: 20F; age median 58 [19-83 years]) 

who received median 3.5 (1-18 split units), containing wbcs median 

10734.69 [5778-42 -162698.09 (x10^3/uL)/unit) and achieved a WBC 

increment median 0.2 (0.0-8.3K/UL). Conclusions: The GCs were split due 

to the primary care team’s reluctance to transfuse the entire volume of the 

product due to volume restrictions or for some other medical reason. The 

same rationale to split platelets from high yield single apheresis was used 

to split our GC products. We found that GCs from each donor was utilized 

maximally and also brought partial relief to other patients who lacked 

donors. We would like to make the case that when adequate numbers of 

GCs are collected it may be feasible to split the unit. This may offer a 

glimmer of hope to other patients in need of GCs who lack a donor network 

support. 


Phase I dose escalation study of bortezomib in combination with lenalidomide 

in patients with myelodysplastic syndromes (MDS) and acute myeloid 

leukemia (AML). Presenting Author: Philip C. Amrein, Massachusetts 

General Hospital/Harvard Medical School, Boston, MA 

Background: Both bortezomib (Bz) and lenalidomide have clinical activity in 

patients with MDS and AML. We conducted a phase I dose escalation study 

to determine the maximal tolerated dose (MTD) of Bz in combination with 

lenalidomide. Methods: Patients with MDS (IPSS score � 0.5 or therapyrelated) 

received Bz by IV bolus on Days 1, 4, 8, and 11 and lenalidomide 

10 mg/day PO on Days 1-21 in 28 day cycles for up to 9 cycles. Three doses 

of Bz were tested (0.7, 1.0, or 1.3 mg/m2 ). Cohorts consisted of 3-6 

patients; the dose of Bz was escalated if there were � 2 dose limiting 

toxicities (DLTs). Growth factor support and transfusions were permitted. 

Dose limiting toxicities (DLTs) were assessed during the first cycle and were 

defined as severe neutropenia (absolute neutrophil count � 250/ul), 

thrombocytopenia (platelet count � 10,000/ul), grade � 2 neurotoxicity, 

or other grade � 3 non-hematologic toxicity. Following determination of the 

MTD, enrollment opened to patients with relapsed and refractory AML and 

those with untreated high risk disease for whom induction therapy was not 

indicated. Responses were assessed by IWG 2006 criteria for MDS and 

IWG 2003 criteria for AML. Results: 23 patients (14 men) were enrolled; 

one patient was inevaluable due to disease progression prior to starting 

protocol therapy. The median age was 73 years (range 54-87). There was 1 

DLT observed, neutropenia, in 6 patients treated with 1.0 mg/m2 Bz and no 

DLTs at 0.7 or 1.3 mg/m2 . The median number of cycles was 2 (range 2-9). 

Grade � 3 toxicities possibly attributable to the treatment at any dose level 

were: anemia (2), thrombocytopenia (10), leukopenia (3), infection (1), 

rash (2), dyspnea (1), dizziness (1), hypotension (1), pneumonia (2) and 

neuropathy (1). Among the 14 patients with MDS, 1 patient with RARS 

experienced a CR and 2 with RAEB-2 experienced marrow CR (mCR). 

Among the 8 patients with AML, there was 1 CR. Conclusions: The maximal 

tested dose of Bz (1.3 mg/m2 ) in combination with lenalidomide is safe. 

Responses were seen in MDS and high risk AML. Future testing of this 

regimen is planned. 


Novel risk factors for osteonecrosis of the jaw in multiple myeloma: A 

RADAR report. Presenting Author: Jaimee S. Holbrook, Department of 

Dermatology, Northwestern University Feinberg School of Medicine, Chicago, 

IL 

Background: Osteonecrosis of the jaw (ONJ) was identified in 2001 and is 

commonly seen in multiple myeloma (MM). The objective of this study is to 

evaluate novel risk factors in MM cases from a retrospective database. We 

hypothesized that ONJ may be related to stem cell transplant, chronic 

kidney disease and active smoking. Methods: We conducted a retrospective 

case-control study of 231 MM cases (from January 1, 1998 to September 

30, 2010) identified from the electronic data warehouse (EDW) at 

Northwestern University (NU). The EDW is cross-institutional and integrates 

clinical data across NU. It comprises more than 2.3TB of data on 

roughly 2 million patients. The search terms used were: bisphosphonates, 

pamidronate, zoledronic acid, multiple myeloma, plasma cell disorders, 

osteonecrosis of the jaw, jaw abscess, dental abscess, among other terms 

described in literature. Data was abstracted onto a standardized form by 2 

trained abstractors and validated by a clinician reviewer (BJE). Known and 

hypothesized new risk factors were abstracted, including duration of 

myeloma, treatment used, duration of bisphosphonate use, renal function 

indices, chemotherapy (vincristine, doxorubicin (A), dexamethasone (D) , 

thalidomide (T), cisplatin (P), cyclophosphamide (C), etoposide (E), novel 

agents [bevacizumab, sorafenib, angiostatin]) GCSF, smoking, and MM 

clinical stage. Analyses included T test, Wilcoxon, and log rank analysis. 

Results: ONJ occurring after MM diagnosis was identified in 33 cases out of 

a total of 233 cases of MM. ZOL, VAD, DT-PACE, and diabetes were more 

common in ONJ cases. Log rank analysis identified 2 risk factors for ONJ, 

the use of DT-PACE (p� 0.003), and complete and partial remission 

(p�0.007). Stem cell transplant and chronic kidney disease were not 

associated with ONJ. Conclusions: We identified novel risk factors for ONJ 

in MM, mainly partial or complete remission and use of DT-PACE. These 

results should prompt clinicians to heightened awareness and increased 

surveillance for the symptoms of ONJ for patients treated with DT-PACE. 



Adverse events (AEs) and the return of myelofibrosis (MF)-related symptoms 

after interruption or discontinuation of ruxolitinib (RUX) therapy. 

Presenting Author: Srdan Verstovsek, University of Texas M. D. Anderson 


Background: RUX is a JAK1/JAK2 inhibitor that demonstrated significant 

clinical benefit in patients (pts) with MF in COMFORT-I (NCT00952289), 

a phase 3, randomized (1:1), double-blind, placebo (PBO)-controlled study 

(N�309). Methods: Pts assessed MF-related symptoms daily using the 

modified Myelofibrosis Symptom Assessment Form v2.0; Total Symptom 

Score (TSS) was calculated from individual scores for abdominal discomfort, 

pain under left ribs, early satiety, night sweats, itching, and bone/ 

muscle pain. Therapy was interrupted if platelet or absolute neutrophil 

count fell below 50,000/�L or 500/�L, respectively. AEs were evaluated 

during treatment interruption or discontinuation. The protocol suggested 

an optional tapering strategy and possible addition of steroids if RUX 

therapy was discontinued for reasons other than thrombocytopenia. Results: 

In RUX-treated patients with treatment interruption, TSS gradually returned 

to baseline levels over approximately 1 week. The most common AE 

leading to treatment interruption or discontinuation in each group was 

thrombocytopenia (n�11, RUX) and abdominal pain (n�4, PBO). Of 

these, only 1 RUX pt discontinued for thrombocytopenia. A summary of 

new onset/worsening AE data after treatment interruption or discontinuation 

is presented (Table). Of 58 pts who discontinued study treatment, 23 

(n�10, RUX; n�13, PBO) experienced a total of 43 SAEs (19, RUX; 24, 

PBO) that showed no specific pattern or difference between treatment 

groups. Four of 21 RUX-treated pts had dose tapering following study drug 

discontinuation. Conclusions: Apart from the expected return of MF-related 

symptoms, there was no pattern of AEs to suggest that RUX interruption or 

discontinuation is associated with a specific withdrawal syndrome. 

RUX (N�155) PBO (N�151) 

Treatment interruption, n 49 54 

Mean duration, days 16 9 

Grade >3 AEs, n 8 7 

SAEs, n 3 

3 

Gastrointestinal hemorrhage; Anemia; pulmonary edema; 

fatigue and neutropenic hepatic encephalopathy 

fever; urosepsis 

and acute gout 

Treatment discontinuation, n 21 37 

Grade >3 AEs, n 12 17 

SAEs, n 10 13 

6626^ General Poster Session (Board #26B), Mon, 1:15 PM-5:15 PM 

Health-related quality of life (HRQoL) and symptom burden in patients 

(Pts) with myelofibrosis (MF) in the COMFORT-II study. Presenting Author: 

Jean-Jacques Kiladjian, Hôpital Saint-Louis et Université Paris Diderot, 

Paris, France 

Background: Ruxolitinib has demonstrated rapid and durable reductions in 

splenomegaly and improved disease-related symptoms and QoL in 2 phase 

3 studies (COMFORT-I and -II) in pts with primary MF (PMF), postpolycythemia 

vera-MF (PPV-MF), or post-essential thrombocythemia-MF 

(PET-MF). The prevalence of individual symptoms among these pts has not 

been defined. We evaluated the baseline HRQoL and symptoms among pts 

enrolled in COMFORT-II. Methods: COMFORT-II is a randomized, openlabel, 

multicenter, phase 3 study comparing ruxolitinib with best available 

therapy. HRQoL and symptoms were assessed at baseline using the 

European Organisation for the Research and Treatment of Cancer QoL 

Questionnaire–Core 30 (EORTC QLQ-C30) and Functional Assessment of 

Cancer Therapy–Lymphoma (FACT-Lym); this analysis summarizes these 

scores for all pts, regardless of assigned treatment. Results: In COMFORT-II 

(N � 219), 52% of pts were aged � 65 years and 57% were male. By IPSS 

criteria (Cervantes et al. 2009), 40% had intermediate-2 and 60% had 

high-risk MF. Mean (95% CI) EORTC global health status/QoL (53.7 

[50.6-56.7]; median, 50.0) and FACT-General total scores (73.0 [70.8- 

75.2]) were comparable to those for pts of similar age with other cancers 

(Oliva et al. 2011: median global health status score of 50 for acute 

myeloid leukemia [AML]). The most frequent symptoms (reported as “quite 

a bit” or “very much”) were fatigue (54%), dyspnea (30%), insomnia 

(30%), pain (29%), night sweats (23%), and itching (21%), and there were 

differences in baseline symptoms across MF subtypes (Table). Conclusions: 

This analysis shows that pts with MF experience severe disease-related 

symptoms and have diminished HRQoL similar to pts with AML, but 

because pts with MF have a longer life expectancy (an average of 2.3 to 4 

years for high and intermediate-2 risk pts, respectively), they may suffer 

with a reduced QoL for many years. 

% “quite a bit” or “very much” 

PMF 

(N � 116) 

PPV-MF 

(N � 68) 

PET-MF 

(N � 35) 

Fatigue 59.2 46.1 53.2 

Dyspnea 28.7 30.2 31.2 

Insomnia 32.7 25.4 28.2 

Pain 25.9 28.6 41.9 

Night sweats 21.3 27.3 18.2 

Itching 16.8 28.8 21.3 

Weight loss 12.1 22.7 6.3 


6625^ General Poster Session (Board #26A), Mon, 1:15 PM-5:15 PM 

Association of cytokine levels and reductions in spleen size in COMFORT- 

II, a phase III study comparing ruxolitinib to best available therapy (BAT). 

Presenting Author: Claire N. Harrison, Guy’s and St. Thomas’ NHS 

Foundation Trust, London, United Kingdom 

Background: Ruxolitinib is a potent and selective oral JAK1/2 inhibitor that 

has been approved for the treatment of myelofibrosis (MF). Ruxolitinib has 

demonstrated rapid and durable reductions in splenomegaly and improved 

disease-related symptoms and quality of life (QoL) in 2 phase 3 studies 

(COMFORT-I and –II) in patients (pts) with primary MF (PMF), postpolycythemia 

vera-MF (PPV-MF), or post-essential thrombocythemia-MF 

(PET-MF). This analysis evaluated associations between cytokine levels 

and spleen size reductions in the COMFORT-II study. Methods: COM- 

FORT-II is a randomized (2:1), open-label, phase 3 study comparing the 

safety and efficacy of ruxolitinib with BAT. Spleen volume was measured by 

MRI every 12 weeks and spleen length by palpation at each study visit. 

Plasma samples were analyzed using Rules Based Medicines Human MAP 

v1.6; 89 cytokines were measured at BL and wks 4, 24, and 48. Simple 

linear regression was used to evaluate the correlation between BL or change 

from BL in cytokine levels with % change of spleen size. Results: In the 

ruxolitinib arm, association was found between changes in TNF-� and 

leptin levels and % spleen volume reduction at wk 24 (TNF-�: N� 93; 

correlation coefficient [R] � 0.43; false discovery rate adjusted P value [P] 

� .01; leptin: N � 96; R � -0.28; P � .09) and wk 48 (TNF-�:N� 86; R 

� 0.43; P � .01; leptin: N � 87; R � -0.34; P � .02) that was not 

observed with BAT and was independent of JAK2V617F status. For 

ruxolitinib-treated JAK2V617F� pts, higher leptin levels at BL were 

associated with greater % spleen length reductions at wk 48 (N � 45; R � 

-0.44; P � .11). A clear trend was observed for increased leptin levels that 

preceded weight gain on ruxolitinib treatment. For ruxolitinib-treated 

JAK2V617F� pts, decreased IL-8 at wk 4 was associated with % spleen 

volume reductions at wk 24 (N � 68; R � 0.28; P � .24) and wk 48 (N � 

60; R � 0.38; P � .15). Conclusions: This analysis has shown statistically 

significant associations between changes in cytokine levels and spleen size 

reductions. Further analysis is in progress to determine associations 

between cytokine levels and QoL or symptoms and to confirm these 

observations in an independent data set. 


Post hoc analysis of association between treatment response and various 

indicators of efficacy and safety in a randomized phase III trial of 

decitabine in older patients with acute myeloid leukemia. Presenting 

Author: Mark D. Minden, Princess Margaret Hospital, Toronto, ON, Canada 

Background: In a recent, large phase III trial (NCT00260832; Kantarjian, 

JCO; in press), 485 patients �65y with newly diagnosed acute myeloid 

leukemia (AML) received, every 4 wks, treatment choice (TC) of either 

supportive care or cytarabine (20 mg/m 2 subcutaneous injection, 10 

consecutive days) or decitabine (DAC) 20 mg/m2 (1-h intravenous [IV] 

infusion, 5 consecutive days). This post hoc analysis investigated relationships 

between response to treatment and indicators of efficacy and safety. 

Methods: Response was defined as morphologic complete remission (CR), 

or CR with incomplete blood count recovery (CRi) or partial response (PR). 

Transfusions (red blood cell [RBC] or platelets [PLT]), IV antibiotic use, and 

dose modifications were tabulated for responders and nonresponders to 

DAC or TC during the treatment period. Results: Fewer responders than 

nonresponders had dose modifications (30.4% vs 64.5%, respectively; 

P�.0001). Antibiotic use and transfusions were similar in both groups. 

Overall survival for responders was 16.1–18.5 mo vs 4.2–4.9 mo for 

nonresponders. Conclusions: These data suggest that response to DAC or TC 

treatment predicts clinically relevant benefits, with fewer dose modifications 

in older patients with newly diagnosed AML. The number of 

transfusions and antibiotic use was impacted by the longer survival time of 

responders vs nonresponders. Data on the impact of early response are 

being analyzed. 

Parameter* 

Nonresponders 

(n�383) 

447s 

CR�CRi�PR responders 

(n�102) p value † 

Overall survival, median, mo 

IV antibiotic use 

4.2–4.9 16.1–18.5 – 

Number of patients 383 102 

Yes, n (%) 

PLT transfusions 

77 (20.1) 14 (13.7) .143 


Mean (SD) 11.64 (14.7) 13.67 (21.7) .447 

Median (range) 

RBC transfusions 

7 (1–110) 7 (1–136) 


Mean (SD) 10.68 (12.2) 14.38 (14.5) .023 

Median (range) 

Dose modifications 

7 (1–102) 11 (1–89) 


Yes, n (%) 247 (64.5) 31 (30.4) �.0001 

*All patients who had both response and parameter data. † Based on 2 sample t test to compare 

means; 2 proportion Z test to compare proportions. 




Regional variation in treatment costs and survival for elderly patients with 

myelodysplastic syndromes. Presenting Author: Xiaomei Ma, Yale University 

School of Medicine, New Haven, CT 

Background: Myelodysplastic syndromes (MDS) occur primarily in the 

elderly (�65 years). The expected 5-year cost for an elderly MDS patient 

tops $63,200 in 2009 US$. This study assessed regional variation in the 

cost of care and survival for elderly MDS patients. Methods: Using the 

Surveillance Epidemiology and End Results–Medicare data, we identified 

primary MDS patients aged 66-99 years diagnosed from 2001-2007, had 

continuous fee-for-service coverage for Parts A and B, and had no history of 

other cancer. We assigned patients to Dartmouth Atlas of Health Care 

Hospital Referral Regions (HRRs) based on their residence at time of 

diagnosis. We also selected controls from a 5% sample of Medicare 

beneficiaries without cancer and matched controls 1:1 to patients by HRR, 

age, sex, pre-diagnosis cost and comorbidity. All Medicare claims through 

2009 were tallied, and MDS-related costs were defined as the difference 

between the payments for a patient and a matched control. Results: With 

6244 patients in 73 HRRs, the average 3-year MDS-related cost varied 

across HRRs, ranging from $12,900 to $83,600 (2009 US$). Patients in 

high-spending regions had more comorbidities and higher Medicare costs 

before diagnosis and were more likely to be racial minorities and live in 

lower-income areas. Three-year survival ranged from 13.0% to 62.1%. 

However, there was no significant correlation between 3-year costs and 

3-year survival (��-0.06, p�0.61). The hazard ratios (HR) for higher 

spending regions compared to the lowest-expenditure region were near 1, 

after controlling for covariates including MDS subtype (2nd quartile: 

HR�1.03, 95% CI: 0.94-1.12; 2nd quartile: HR�1.04, 95% CI: 0.95- 

1.14; 4th quartile: HR�0.98, 95% CI: 0.90-1.08). Conclusions: We 

observed considerable regional variation in Medicare expenditure on elderly 

MDS patients during the first 3 years post-diagnosis. However, patients in 

higher cost regions had similar 3-year survival to patients in lower cost 

regions. Given the substantial economic burden of MDS and Medicare’s 

current fiscal challenges, it is important to further assess the factors 

associated with higher regional costs and to improve the care of MDS 

patients in a cost-efficient way. 


Preliminary safety and efficacy of ruxolitinib in patients (pts) with primary 

and secondary myelofibrosis (MF) with platelet counts (PC) of 50– 

100x109 /L. Presenting Author: Moshe Talpaz, Comprehensive Cancer 

Center, University of Michigan, Ann Arbor, MI 

Background: Ruxolitinib (RUX) has demonstrated clinical benefit as therapy 

for MF. This study explores the safety and efficacy of RUX in pts with MF 

and low PC, where clinical data are limited. Methods: In this phase II study, 

pts with intermediate-1 to high-risk MF, and PC of 50–100x109 /L started 

RUX at 5 mg BID. Doses could be increased in 5 mg QD increments every 4 

weeks (wks) beginning at wk 4. Doses were decreased or held for PC 

�35x109 /L and �25x109 /L respectively. Assessments: Total Symptom 

Score (TSS, using the modified MF Symptom Assessment Form v2.0, and 

comprised of scores from 0�absent to 10�worst imaginable for night 

sweats, itching, bone/muscle pain, early satiety, abdominal discomfort and 

pain under left ribs); Patient Global Impression of Change (PGIC, a 7-point 

scale ranging from “very much improved” to “very much worse”); spleen 

size by palpation and by MRI (data not yet available); and safety. Results: At 

the time of analysis, 23 pts had completed �4 wks on study. At baseline: 

mean PC�72x109 /L; high (4%), intermediate-2 (52%) and intermediate-1 

(44%) risk group; mean spleen length�16.6 cm; mean TSS�25.5. At the 

time of analysis, 4%, 40%, 26%, 26% and 4% of pts were receiving RUX 5 

mg QD, 5 mg BID, 5 mg AM/10 mg PM, 10 mg BID, and 10 mg AM/15 mg 

PM, respectively. At wk 4 (all pts on 5 mg BID), mean TSS improved 14%; 

13% had �50% improvement. At wk 8 (52% on 5 mg AM/10 mg PM), 

mean TSS improved 23%; 30% had �50% improvement. Mean spleen 

length reduction of 22% (wk 4) and 27% (wk 8) was observed, and PGIC 

scores of “much improved” or “very much improved” were reported in 35% 

(wk 4) and 39% (wk 8) of pts. There were no Grade 4 PC, no dose holds for 

AEs and no discontinuations; 1 pRBC transfusion-dependent pt had Grade 

4 anemia. Three pts experienced a total of 4 SAEs (fever; hypnagogic 

dreams; and spleen pain/pneumonitis) which resolved while on treatment. 

Conclusions: Effects on spleen size, PGIC, and TSS, even over the first 

weeks at low doses, are superior to those observed in the placebo group in 

the COMFORT-I study. These preliminary findings suggest a dosing strategy 

starting with 5 mg BID RUX with subsequent dose optimization may be 

efficacious and well tolerated in MF pts who have low platelets. 


History of autoimmunity to predict clinical response to DNA methyltransferase 

inhibitors (DNMTI) in myelodysplastic syndromes (MDS), and 

MDS-derived acute myeloid leukemias (AML). Presenting Author: Ashkan 

Emadi, The Johns Hopkins University, Baltimore, MD 

Background: MDS is comprised of a heterogeneous group of clonal myeloid 

disorders. Chronic immune stimulation has been reported as a trigger for 

the development of a subset of MDS, with increased autoreactive cytotoxic 

T cells present in the bone marrow. Autoimmunity has been associated with 

MDS and other marrow failures. DNMTIs, 5-azacytidine and decitabine, are 

approved for the treatment of MDS. In addition to epigenetic impacts, 

these agents may have immunomodulatory effects, including augmentation 

of MAGE-related anti-tumor response. These reports and clinical observations 

led us to hypothesize that MDS patients with a history of autoimmunity 

may be more responsive to DNMTIs. Methods: To identify patients with 

MDS, a retrospective database review (2007-2011) was performed at 

Johns Hopkins Hospital (JHH) and Massachusetts General Hospital (MGH). 

The MGH data also included those with AML whose disease had progressed 

from MDS. Past medical history of autoimmune disorders, diagnosis, blood 

counts, flow cytometry and cytogenetics were reviewed. Patients with 

aplastic anemia, paroxysmal nocturnal hemoglobinuria or non-malignant 

etiologies of cytopenia were excluded. Patients with MDS were further 

studied if they were treated with DNMTI. Results: Of 137 patients with MDS 

or MDS/AML, 23 had a documented history of autoimmunity in the medical 

record. Of these, 15 (65.2%) experienced a response to therapy as defined 

by the International Working Group. Of 114 patients without a documented 

history of autoimmunity, 34 (29.8%) achieved a response during therapy, a 

significantly lower percentage as compared to those with autoimmune 

conditions (p-value 0.002, t-test). The majority of responding patients with 

a history of autoimmunity displayed a normal karyotype (9 of 15 patients). 

Conclusions: A history or co-presence of an autoimmune disorder may 

predict a high likelihood of achieving a clinical response to DNMTIs. 

Correlative studies in this unique population of patients with MDS and 

MDS/AML and prospective clinical studies are needed to improve our 

understanding of the possible mechanism of action of DNMTIs in these 

patients. 


Correlation of TCR diversity with immune reconstitution after cord blood 

transplant. Presenting Author: Ryan Emerson, Adaptive Biotechnologies, 

Seattle, WA 

Background: Umbilical cord blood is an important source of hematopoietic 

stem cells for allogeneic transplants used to treat hematologic disorders 

and malignancies. Stem cells from cord blood has several advantages over 

other sources (peripheral blood or marrow) including reduced incidence of 

graft-versus-host disease (GvHD) which allows less strict donor-patient 

HLA-type matching requirements. However, hematopoietic recovery (both 

myeloid and platelet engraftment) and immune reconstitution is significantly 

delayed in CBT patients resulting in patients remaining at high risk 

of infection for an extended period of time. Though the high risk of 

infections to patients is well-documented and recognized, physicians lack 

an objective means to monitor each patient’s progress toward functional 

reconstitution of the adaptive immune system. Our project aims to test if 

our measure of TCR diversity is a better proxy of immune reconstitution in 

CBT patients. Methods: To do this, we compare our proposed measure of 

immune reconstitution, TCRB CDR3 sequence diversity and richness over 

time, against the observed clinical course of severe infection in patients 

who have received CBT. Previously, peripheral blood mononuclear cells 

(PBMC) were collected and cyropreserved from 35 CBT recipients at six 

time points, pre-transplant, and 28, 56, 100, 180, and 365 days 

post-transplant. Concordantly, clinical outcomes for these patients were 

collected for up to four years post-transplant. We use a t-test to test if size 

of TCR repertoire differs between CBT patients with non-relapse related 

mortality and all other CBT patients. Results: Our TCR sequencing method 

was successful at measuring immune reconstitution, and TCR diversity is 

predictive of subsequent mortality from severe infection by 56 days 

post-transplant. Conclusions: TCR repertoire sequencing is a viable method 

to monitor immune reconstitution. 



Post hoc analysis of relationship between baseline white blood cell count 

and renal and hepatic function and response in a randomized phase III trial 

of decitabine in patients age 65 or older with acute myeloid leukemia. 

Presenting Author: Jacques Delaunay, University of Nantes, Nantes, 

France 

Background: A phase III trial (NCT00260832) in patients (N�485) �65y 

with newly diagnosed acute myeloid leukemia (AML) was conducted 

(Kantarjian, JCO; in press). Every 4 wk, patients received decitabine (DAC) 

20 mg/m 2 (1-h intravenous infusion, 5 successive days) or treatment 

choice (TC) with either supportive care or cytarabine (20 mg/m2 subcutaneous 

injection daily, 10 successive days). This post hoc analysis examined 

whether baseline (BL) renal and hepatic function and white blood cell 

(WBC) counts were associated with response to DAC or TC. Methods: For 

patients with available data, BL WBC count and markers of renal function 

(blood urea nitrogen [BUN], creatinine) and liver function (ALT, AST, 

albumin) were tabulated for patients with/without a response to DAC or TC. 

Response was defined as morphologic complete remission (CR), CR with 

incomplete blood count recovery (CRi), or partial remission (PR). Results: 

Nonresponders had a higher mean BL creatinine vs responders (86.78 vs 

80.23 mmol/L, respectively; P�.005); with no differences in BL BUN 

levels. There were no other between-group differences. Conclusions: This 

analysis suggests that there is no relationship between BL WBC or hepatic 

function and response to treatment with DAC or TC. Although there was no 

difference in BL BUN, higher mean creatinine levels in nonresponders may 

suggest a prognostic relationship but further studies are needed to clarify. 

Parameter 

Nonresponder 

to DAC or TC 

Responder to DAC or TC 

(CR�CRi�PR) P value 

WBC (10 9 /L) 

n 372 101 

Mean (SD) 9.25 (13.98) 7.02 (12.25) .118 

Median (range) 3.72 (0.33-126.60) 2.70 (0.43-95.57) 

ALT (U/L) 

n 372 100 

Mean (SD) 25.32 (35.53) 20.79 (14.53) .054 

Median (range) 18 (5-614) 17 (6-103) 

AST (U/L) 

n 371 101 

Mean (SD) 23.82 (15.93) 21.74 (9.84) .106 

Median (range) 20 (5-203) 18 (9-65) 

Albumin (g/L) 

n 377 102 

Mean (SD) 34.18 (5.47) 35.07 (5.34) .139 

Median (range) 35 (19-48) 36 (16-44) 

BUN (mmol/L) 

n 377 102 

Mean (SD) 6.97 (2.65) 6.48 (2.27) .064 

Median (range) 6.40 (1.3-23.7) 6.15 (2.9-19.5) 

Creatinine (mmol/L) 

n 377 102 

Mean (SD) 86.78 (27.08) 80.23 (18.88) .005 

Median (range) 81 (38-254) 78 (44-169) 

TPS6634 General Poster Session (Board #29A), Mon, 1:15 PM-5:15 PM 

Dasatinib plus SMO antagonist versus dasatinib alone for treating patients 

(pts) with newly diagnosed Philadelphia chromosome-positive (Ph�) chronic 

myeloid leukemia in chronic phase (CML-CP): Design of CA180-363, a 

phase II, open-label randomized trial. Presenting Author: Geralyn C. 

Trudel, Bristol-Myers Squibb, Montreal, QC, Canada 

Background: Dasatinib 100 mg once daily (QD) is approved as first-line 

therapy for pts with newly diagnosed Ph� CML-CP and those who are 

resistant or intolerant to prior therapy, including imatinib, based on 

demonstrated efficacy and tolerability. BMS-833923 (SMO antagonist), 

selectively blocks hedgehog (Hh) pathway signaling by binding to and 

antagonizing Smoothened (SMO), preventing downstream signaling and 

activation of target genes. In preclinical studies, SMO loss or inhibition 

reduces hematopoietic stem cell renewal, induces CML stem cell depletion, 

and inhibits imatinib-resistant CML cell growth (Dierks, Cancer Cell 

2008; Zhao, Nature 2009). In pts with CML, Hh signaling genes (Sonic 

hedgehog, SMO, and Gli1) are significantly upregulated compared with 

control pts (Long, J Exp Clin Cancer Res 2011), suggesting that drug 

resistance and disease recurrence may be overcome by targeting the Hh 

signaling pathway. Methods: CA180-363 is a phase 2 trial to assess 

dasatinib activity with or without SMO antagonist in pts with newly 

diagnosed Ph� CML-CP. Pts receive dasatinib 100 mg QD for 12 months 

and are then randomized 1:1 to continuing dasatinib 100 mg QD with or 

without SMO antagonist up to 24 months, followed by dasatinib 100 mg 

QD alone until end of study (60 months). Randomization is stratified by 

Sokal score at diagnosis and major molecular response (MMR) at 12 

months (yes/no). Eligible pts are aged �18 years, have an Eastern 

Cooperative Group (ECOG) performance status of 0-2, and previously 

untreated Ph� CML-CP diagnosed within 6 months of enrollment. Primary 

endpoint (evaluated in pts who do not achieve MMR prior to randomization) 

is comparison of MMR rates for dasatinib alone vs dasatinib plus SMO 

antagonist. Other endpoints (evaluated in all pts) are complete molecular 

response, progression-free survival, event-free survival, transformation-free 

survival, and safety of the combination regimen. Recruitment started in 

September 2011 (14 pts enrolled to date); estimated primary completion 

date is November 2014. ClinicalTrials.gov ID: NCT01357655. 


449s 


Phase II study of short CHOP-rituximab combination with early consolidation 

with ibritumomab-tiuxetan-Y90 (IT-Y90 ) in non-pretreated patients age 

65 to 80 with CD20� diffuse large B-cell lymphoma (DLBCL). Presenting 

Author: Frederic Peyrade, Anticancer Center, Centre Antoine-Lacassagne, 

Nice, France 

Background: IT-Y90was approved in follicular lymphoma, and some data 

indicates that it could be used in DLBCL. It has been reported that early 

TEP-TDM negativity is associated with a longer survival in DLBCL, which 

suggest that these patients could benefit of a less intensive protocol. 

Methods: We conducted an international, open-label, phase II nonrandomised 

study, in patients aged between 65 and 80 with age-adjusted 

(aa) IPI score of 0 and 1 and CD20� DLBCL. The primary objective was to 

evaluate the efficacy of 3 cycles of RCHOP14 followed by, in case of 

complete response (CR), an injection of IT-Y90 . Results: Thirty patients 

(M/F� 1) were included. Median age was 72.6 years (range 65 - 80). 

Patients had a stage III/IV, elevated LDH and IPI�1 in 38%, 16.6 and 

57% respectively. 25 patients received the full treatment. Five obtained an 

uncomplete FDG-PET response and were excluded after 2 RCHOP cycles. 

23 patients received the full IT-Y90 dosage (0.4mCi/Kg) and two received 

the attenuated dosage (0.3mCi/Kg). Mean treatment time was 54 days 

(median 52; min 48-max 69). The CR rate after RCHOP treatment was 

85% [95% CI: 65-94]. No treatment-related deaths occurred. Grade III-IV 

neutropenia and thrombocytopenia was observed in 45% and 4%, respectively. 

Five patients experienced at least one febrile neutropenia. After 

IT-Y90 , mean duration time for platelets �50G/l was 2.08 weeks (median 

2; min 0-max 5). Two patients required platelet transfusion. With a median 

follow-up of 29.5 months [95% CI: 23-39], the estimated 3-year PFS was 

90% [95% CI: 80-100] and the 3-year OS was 100% [95% CI: 100-100]. 

Among patients treated with 90Y-IT, only 3 relapsed were recorded (at 6, 16 

and 24 months). Conclusions: this study suggested the feasibility, and 

efficacy of a short regimen including one injection of IT-Y90for selected 

DLBCL in complete response after 3 cycles of RCHOP14. This results need 

to be confirmed by further studies. 

TPS6635 General Poster Session (Board #29B), Mon, 1:15 PM-5:15 PM 

Targeting microenvironment-mediated resistance in leukemias: Phase I 

trial of mobilization and elimination of FLT3-ITD� acute myelogenous 

leukemia (AML) stem/progenitor cells by plerixafor/g-CSF/sorafenib. Presenting 

Author: Michael Andreeff, University of Texas M. D. Anderson 


Background: FLT3-ITD AML are associated with poor prognosis. We 

identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 

2008; Borthakur G., Haematologica, 2010). FLT3-ITD is associated with 

overexpression of chemokine receptor CXCR4 and we found increased in 

vivo activity of S combined with CXCR4 inhibitor Plerixafor (P) and G-CSF 

(G) (Zeng Z et.al. Blood 2009). Here we report first data testing this 

concept in patients with R/R FLT3-ITD AML. Methods: G (10 ug/kg) and 

P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400-600mg), S on d 1 

- 28(one cycle). G/P was held when blasts � 5x104/ uL. CD34, 38, 123, 

CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were measured by 

flow cytometry. Results: 10 patients have been treated so far : 2 achieved 

CRp, 4 PR and 4 failed (NR), for an overall response rate of 6/10; 3/6 

responders and 4/4 NR were previously treated with FLT3 inhibitors. 4/10 

pts. developed hyperleukocytosis (and missed 1 to 5 doses of G/P), 6 skin 

rash and 3 hypertension. Analysis of cells mobilized in 22 cycles revealed a 

29-fold increase in WBC, 41-fold in absolute blasts, 77-fold in granulocytes. 

Increase in circulating stem/progenitor cells was as follows: CD34�: 

231-fold, CD34�/38- : 90-, CD34�/38-/123�(LSC) : 148-, CXCR4�: 

139-, VLA-4� : 68- and CD44�: 82-fold. Increase in LSC was correlated 

with baseline blasts and VLA4, not with CXCR4. FISH confirmed mobilization 

of leukemic cells. Increased levels of pERK and pAKT were observed in 

mobilized cells. Conclusion: The combination of G-CSF�Plerixafor appears 

superior in increasing circulating leukemic blasts and stem/progenitor cells 

in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast 

increase 2.1-fold; Uy et al. Blood, in press). Treatment resulted in 2/10 

CRp and 4/10 PRs. Mobilized stem/progenitor cells displayed increased 

MAPK/AKT signaling and increased CXCR4 expression. This is the first 

clinical report of G-CSF/Plerixafor for the “mobilization” of AML cells, 

aimed at removing them from their protective bone marrow microenvironment. 

The initial results are providing proof-of–principle of this concept. 



TPS6636 General Poster Session (Board #29C), Mon, 1:15 PM-5:15 PM 

A single-arm, open-label, multicenter study of complete molecular response 

(CMR) in patients with newly diagnosed Philadelphia chromosome– 

positive (Ph�) chronic myeloid leukemia in chronic phase (CML-CP) 

treated with nilotinib. Presenting Author: Michael R. Savona, Sarah 

Cannon Center for Blood Cancers, Tennessee Oncology, PLLC, Nashville, 

TN 

Background: With more-potent tyrosine kinase inhibitors, increasingly 

sensitive methods are required to monitor treatment response and quantify 

minimal residual disease (MRD). Molecular monitoring is recommended by 

National Comprehensive Cancer Network and European LeukemiaNet 

guidelines; major molecular response (MMR) correlates with optimal 

long-term outcomes. CMR, while implying absence of BCR-ABL transcripts, 

is defined by levels undetectable by current technology (generally 

�4.5 logs reduced below a standardized baseline using quantitative 

real-time polymerase chain reaction [RT-PCR]). Newer technologies that 

can detect larger reductions will be important in analyzing correlations 

between decreased disease burden and long-term outcomes and may assist 

in selecting patients for “stopping” therapy. Methods: This US study plans 

to enroll 100 adults with newly diagnosed Ph� CML-CP within 6 months of 

diagnosis to receive nilotinib 300 mg twice daily (BID) for up to 2 years. 

BCR-ABL transcripts are quantified using RT-PCR at a central laboratory. 

An exploratory molecular assay (digital detection [DiD]) with an additional 

�1-log sensitivity and mutation detection and quantification will be 

evaluated. Primary endpoint: the rate of confirmed CMR at 24 months 

(CMR confirmed by second PCR sample within 3 months; �4.5-log 

reduction of BCR-ABL from standardized baseline on the international 

scale [IS], equivalent to BCR-ABL �0.0032% IS). Dose escalation to 400 

mg BID is allowed per protocol. Secondary endpoints: rate of, time to, and 

duration of complete cytogenetic response (CCyR), MMR, and CMR; rate of 

and time to loss of CCyR, MMR, and CMR and to progression to accelerated 

phase/blast crisis; rate of CMR in dose-escalated patients; and event-free, 

progression-free, and overall survival. Exploratory endpoints: BCR-ABL 

trends and correlation of mutations with response. The DiD assay data will 

provide information on BCR-ABL trends below the current CMR threshold 

and assist in evaluating lower levels of MRD. 


Prospective, observational registry of branded imatinib (IM) and nilotinib 

(NIL) exposure in pregnant women: Voluntary post-authorization safety 

study. Presenting Author: Matthews Juma, Novartis Pharmaceuticals, East 

Hanover, NJ 

Background: Family planning decisions for cancer patients of childbearing 

age are impacted by their diagnosis. IM and NIL are category D drugs 

(demonstrated risk to the fetus based on mechanism of action and findings 

in animals; however, the benefits of therapy may outweigh the potential risk 

to the fetus); women should be advised not to become pregnant when 

taking these drugs. Limited data exist concerning safety of these drugs 

during pregnancy and consequences of interrupting treatment. The registry 

does not recommend patients receiving IM or NIL become pregnant, but 

serves only to document exposures that occur, and collect information on 

pregnancy outcome, maternal course of disease, and infant follow-up. 

Methods: The registry intends to enroll 150 women (�18 years) treated with 

branded IM and NIL within 6 mo before or during pregnancy (generic IM 

and NIL reports are excluded). Schedule of visits and treatment is 

according to local standard of care. Women are divided into 2 exposure 

cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs) 

within 14 d of conception or at any time during pregnancy; 2) interrupted 

TKI: received TKIs within 6 mo before conception but interrupted TKIs in 

preparation for/due to pregnancy. To identify signals of teratogenicity, the 

registry uses a general population baseline rate of birth defects, and the 

prevalence of defects in cohorts 1 and 2 may be compared. Cases are 

quantitatively analyzed for the emergence of unique defects or patterns of 

defects. Primary objective: monitor TKI-exposed pregnancies to estimate 

the prevalence of birth defects (calculated by dividing number of birth 

defects by total number of exposed live births from cohort 1). Secondary 

objectives are to: 1) determine the impact of treatment interruption on 

maternal disease status; 2) assess and estimate the prevalence of serious 

adverse pregnancy outcomes; and 3) assess and estimate the prevalence of 

developmental delays and functional deficits among infants during the first 

year of life. Maternal disease status is analyzed, comparing disease status 

at registration, pregnancy outcome, and 1 y after birth, stratified by length 

of TKI interruption. 


VALOR, an adaptive design, pivotal phase III trial of vosaroxin or placebo in 

combination with cytarabine in first relapsed or refractory acute myeloid 

leukemia. Presenting Author: Farhad Ravandi, University of Texas M. D. 


Background: The promising phase 2 activity/tolerability profile of vosaroxin 

with cytarabine in first relapsed or refractory AML (N�69) with median 

overall survival (OS) 7.1 mo, combined CR 28% (CR 25%), median LFS 25 

mo and 30-day all-cause mortality 3%, supported phase 3 trial. VALOR 

(NCT01191801), a phase 3, randomized, controlled, double-blind trial, 

evaluates vosaroxin and cytarabine versus placebo and cytarabine in 

patients with first relapsed or refractory AML and incorporates an adaptive 

design. Primary objective is OS; secondary/tertiary objectives include CR 

rates, safety, EFS, LFS, and transplantation rate. Key eligibility criteria: 

persistent AML or first relapsed AML after 1 or 2 induction cycles that 

include at least 1 regimen of cytarabine with an anthracycline/anthracenedione; 

adequate cardiac, hepatic, renal function; and adults with no upper 

age restriction. Methods: VALOR is recruiting patients at over 100 sites in 

14 countries in North America, Europe, and Australia/NZ. Enrollment 

opened Dec 2010; 183 patients enrolled through Dec 2011. Adaptive 

design: Base case assumed 40% improvement in median OS (hazard ratio, 

HR�0.71), 90% power, 2-sided alpha of 0.05. At the interim analysis 

(50% events), DSMB may recommend a 50% sample size increase from 

450 to 675 evaluable patients if results indicate a larger sample size is 

required to reduce the risk of failing to confirm a clinically meaningful OS 

benefit (Mehta, Pocock, Stat Med 2010). In consideration of FDA and EMA 

guidance on Data Monitoring Committees and adaptive design with respect 

to trial integrity, operational bias, firewalls, and data confidentiality and 

archival, VALOR uses the Access Control Execution System (ACES ) to 

store, share, and archive confidential DSMB reports in a secure environment 

with an audit trail, and to facilitate communication between the 

DSMB and trial sponsor. The DSMB periodically reviews a combination of 

blinded and unblinded analyses while the study team remains blinded as 

specified in the DSMB charter. The DSMB recommended VALOR continue 

as planned after reviewing safety data in Dec 2011. 


JAKARTA: A phase III, multicenter, randomized, double-blind, placebocontrolled, 

three-arm study of SAR302503 in patients with intermediate-2 

or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or 

post-essential thrombocythemia (ET) MF with splenomegaly. Presenting 

Author: Animesh Dev Pardanani, Mayo Clinic, Rochester, MN 

Background: SAR302503 is an orally administered selective JAK-2 inhibitor 

being evaluated for the treatment of MF. In a phase 1 study, 

SAR302503 reduced spleen size and disease-related symptoms and 

provided clinical benefit, including a reduction in the JAK2V617F allele 

burden, with an acceptable safety profile in patients with primary MF, 

post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing 

open-label extension of this trial confirmed the durability of those results 

and found that doses between 400–500 mg/day of SAR302503 represented 

the optimal balance between safety and efficacy (Pardanani, ASH 

2011;Abs 3838). These results led us to initiate a Phase 3 trial in 

December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500 

mg/day, compared with placebo, for the treatment of patients with MF 

(NCT01437787; EFC12153). Methods: Eligibility criteria include age of at 

least 18 years, platelets �50,000/�l, ECOG PS 0–2, and a diagnosis of 

high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF 

according to IPSS criteria (Blood 2009;113:2895). Patients are being 

randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or 

placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned 

treatment will continue as long as patients are deriving benefit or until 

progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or 

in case of progression before completion of 6 cycles according to predefined 

criteria. The primary endpoint is spleen response (�35% reduction 

in spleen volume by MRI/CT at the end of cycle 6). Key secondary 

objectives are symptom response rate and durability of spleen response. 

Additional secondary endpoints include assessment of allele burden and 

bone marrow fibrosis reduction. It is planned to randomize 75 patients per 

treatment group at approximately 130 sites worldwide. 



An open-label, multicenter, expanded access study assessing the safety 

and efficacy of oral ruxolitinib administered to patients with primary 

myelofibrosis (PMF), post-polycythemia myelofibrosis (PPV MF) or postessential 

thrombocythemia myelofibrosis (PET-MF). Presenting Author: 

Philipp D. le Coutre, University of Medicine Berlin, Charité Campus 

Virchow, Berlin, Germany 

Background: Myelofibrosis (MF) can be primary in origin or can progress 

from polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). 

MF is characterized by cytopenias, reactive bone marrow fibrosis, splenomegaly, 

and constitutional symptoms including weight loss, fever, and 

night sweats. MF is associated with dysregulation of the Janus kinase 

pathway, irrespective of JAK2V617F mutation status. Recently, ruxolitinib 

(INCB018424) was approved for the treatment of MF on the basis of results 

from 2 phase 3 trials (COMFORT-I and -II). These trials demonstrated 

marked reductions in splenomegaly and symptom burden, and improvements 

in health-related quality of life (QoL) measures. Methods: JAK 

Inhibitor rUxolitinib in Myelofibrosis Patients (JUMP) is a global, phase 3b 

expanded access trial (NCT01493414) designed to assess the safety and 

efficacy of ruxolitinib in adult pts with PMF, PPV-MF or PET-MF who are 

treatment naïve, and are intolerant of, or had progressed on any prior 

therapy. Inclusion criteria: peripheral blast count of �10%, adequate liver 

and renal function and intermediate-2 or high risk MF according to IPSS 

criteria or intermediate-1 risk MF with palpable spleen length � 5 cm. The 

primary endpoint is to assess the safety of ruxolitinib. Additional endpoints 

include the proportion of pts with a � 50% reduction in palpable spleen 

length, % change in white blood cell and platelet counts from baseline 

(BL), and change in packed red blood cell transfusion requirements. 

Changes from BL in QoL scores will be assessed using validated ECOG PS, 

FACT-Lymphoma, and FACIT instruments. Pts with a BL platelet count � 

200,000/�L will receive oral ruxolitinib 20 mg BID; pts with a BL platelet 

count of 100,000/�L to 200,000/�L will receive 15 mg BID; dose 

modifications are permitted for safety and efficacy. Global enrollment is 

open and currently includes 277 pts. This is planned to be the largest study 

ever conducted in pts with MF. 

Country #ofPts 

Austria 24 

Belgium 15 

Brazil 24 

Germany 173 

Spain 28 

Argentina 3 

Canada 3 

Netherlands 3 

Italy 4 

Total 277 

TPS6642^ General Poster Session (Board #31C), Mon, 1:15 PM-5:15 PM 

A phase Ib, open-label, dose-finding study of ruxolitinib in patients (pts) 

with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis 

(PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF) and 

baseline platelets (PLTs) 50 to

452s Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers 


Is consolidation chemotherapy after concurrent chemoradiotherapy beneficial 

for locally advanced non-small cell lung cancer? A pooled analysis of 

the literature. Presenting Author: Satomi Yamamoto, National Hospital 

Organization Kinki-Chuo Chest Medical Center, Sakai, Japan 

Background: There is a growing interest on the efficacy of maintenance 

chemotherapy to metastatic non-small cell lung cancer (NSCLC) and 

adjuvant chemotherapy to early stage NSCLC. However, the role of 

consolidation chemotherapy (CCT) after concurrent chemo-radiotherapy in 

locally advanced NSCLC is undetermined. Methods: We systematically 

searched PubMed for phase II/III trials examining survival of locallyadvanced 

NSCLC treated with concurrent chemo-radiotherapy between 

January 1, 1995 and October 31, 2011. Median overall survival (mOS) and 

corresponding 95% confidence interval (CI) were collected from each study 

and pooled. We extracted log-transformated hazards and its standard errors 

under the assumption that survival follows an exponential distribution, and 

computed a pooled mOS and its 95% CI using random-effect model. 

Collected trial arms were divided into two groups by the presence of CCT: 

Arm with CCT (CCT�) and without CCT (CCT-). Results: Forty-five studies 

were identified including 9 phase III studies and 36 phase II studies with 

51 arms (CCT�: 29, CCT-: 22). Clinical data were comparable in clinical 

stage, performance status, cancer histology, gender, and median age 

between the two groups. I2 values for assessing heterogeneity were 15.3, 

9.1 and 24.2% in overall, CCT� and CCT- studies, respectively. There was 

no statistical difference in pooled mOS between CCT� (18.5 month, 

95%CI: 16.7-20.5) vs CCT- (18.1 month, 95%CI: 16.5-20.2). In regard to 

the � grade 3 toxicities in pneumonitis, esophagitis, and neutropenia, 

there was no difference between the two groups throughout the whole 

treatment courses. In random effect models, predicted hazard ratio of 

CCT� to CCT- was 0.98 (95%CI: 0.8-1.13, p�0.7574). These models 

estimated that addition of CCT could not yield more than 3 months of 

survival prolongation for patients with locally advanced NCSLC. Conclusions: 

The pooled analysis on publication basis failed to provide evidence that 

consolidation chemotherapy yields significant survival benefit for locally 

advanced NSCLC. 


Phase II study of pemetrexed (P) plus carboplatin (Cb) or cisplatin (C) with 

concurrent radiation therapy followed by pemetrexed consolidation in 

patients (pts) with favorable-prognosis inoperable stage IIIA/B non-small 

cell lung cancer (NSCLC). Presenting Author: Hak Choy, University of Texas 

Southwestern Medical Center, Dallas, TX 

Background: There is no consensus chemotherapy regimen with concurrent 

radiation therapy (CRT) for inoperable stage IIIA/B NSCLC. P synergizes 

with ionizing radiation, as well as with Cb and C in preclinical models. 

These doublets have shown efficacy and favorable toxicity profiles in phase 

II/III trials. Methods: In this open-label randomized phase II trial, 98pts 

with inoperable stage IIIA/B NSCLC (all histologies) were randomized (1:1) 

to P 500 mg/m2 plus Cb AUC 5 (PCb) or P 500 mg/m2 plus C 75 mg/m2 (PC) intravenously (IV) every 21 days for 3 cycles. All pts received CRT 

64–68 Gy (2 Gy/day, 5 days/week, Days 1–45). Consolidation P 500 

mg/m2 IV every 21 days for 3 cycles began 3 weeks after completion of 

CRT. The primary endpoint was 2-year overall survival (OS); secondary 

endpoints included median OS, time to progression (TTP), overall response 

rate (ORR), and toxicity. Results: Since Jun 2007, 98 pts were enrolled 

(PCb: 46; PC: 52).Pts were followed until Oct 2011. Mean dose compliance 

was PCb: 95.7% P, 97.1% Cb; PC: 89.7% P, 89.1% C. Mean dose 

compliance for CRT was PCb: 95.7%; PC: 88.1%. CRT dose interruptions 

occurred in PCb: 32.6% and PC: 40.4%. Two-year OS was PCb: 45.2% 

(95% confidence interval [CI], 29.3-59.8); PC: 57.6% (95% CI, 41.6- 

70.7); p�0.270. Median OS (months) was PCb: 18.7 (95% CI, 12.9-not 

assessable [N/A]); PC: 27.0 (95% CI, 23.2-N/A). Median TTP (months) 

was PCb: 8.8 (95% CI, 6.0-10.7); PC: 13.1 (95% CI, 8.3-N/A); p�0.057. 

The ORR rates were PCb: 52.2% (complete response [CR], 6.5%; partial 

response [PR], 45.7%); PC: 46.2% (CR, 3.8%; PR, 42.3%). Grade 4 

treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 

6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. No 

drug-related deaths were reported. Conclusions: While conclusions are 

limited by the size of the trial, this study suggests OS and TTP advantages 

for the C-containing arm. Both combinations with CRT appear well 

tolerated. 


GILT study: Oral vinorelbine (NVBo) and cisplatin (P) with concomitant radiotherapy 

(RT) followed by either consolidation (C) with NVBo plus P plus best 

supportive care (BSC) or BSC alone in stage (st) III non-small cell lung cancer 

(NSCLC): Final results of a phase (ph) III study. Presenting Author: Rudolf M. 

Huber, Medizinische Klinik Innenstadt, München, Germany 

Background: Concurrent chemo-radiotherapy (CT-RT) is considered as a standard 

in st III NSCLC. Published trials with C after CT-RT show encouraging but 

discordant results. This ph III was set up to assess C in st III NSCLC. Methods: 

Patients (pts) received NVBo 50 mg/m² D1, D8, D15 � P 20 mg/m² D1-D4 q4w / 

2 cycles (cy) � RT (66 Gy / 33 Fr). C for OR�SD pts: NVBo 60-80 mg/m² D1D8 

� P 80 mg/m² D1q3w/2cy�BSC (Arm A) or BSC (Arm B). PFS was the 

primary endpoint. Results: From 07/05 to 05/09, 279 pts received CT/RT and 

201 pts (72%) were randomised to receive CT�BSC or BSC as C. Toxicity (tox) 

G3-4 (% pt) CT-RT/ C (Arm A/B): anaemia 3.2/3.5/1.1; thrombopenia 2.5/1.2/ 

0.6; neutropenia (N) 11.2/11.7/5.7; febrile N 1.4/1.0/0; nausea (G3) 5.0/4.7/ 

2.9; vomiting (G3) 3.9/3.5/2.0; anorexia 3.6/1.2/3.0; dysphagia 1.8/2.3/1.0; 

fatigue 3.3/ 2.3/1.0; pneumonia/ pneumonitis 2.6/0/2.0; CT-RT pain 2.2; 

CT-RT oesophagitis 8.6; 3 toxic deaths. Conclusions: In this ph III, NVBo�P�RT 

reports a high level of efficacy (OR 60.7%; DCR 86.0%) and low tox. The DCR is 

significantly improved in pts who received C with NVBo� P in eval pts 

(p�0.0084). Lung tox was not enhanced by using NVBo�P as C. However no 

survival advantage for C was achieved. 

Randomisation (N�201) 

CT-RT 

N�242 eval /279 

CT�BSC 

N� 76 eval /96 

BSC 

N�89 eval/ 105 

p 

Male (%) 71.0 71.9 71.4 

Median age 

(y, range) 

60.3 [33.9-75.7] 60.3 [34.1-75.9] 59.5 [40.4-75.1] 

SCC/ADC* (%) 53.0 / 36.2 54.2 / 36.5 53.3 / 36.2 

St IIIA / IIIB (%) 17.6 / 82.4 20.8/ 79.2 19.0 / 81.0 

ORR ITT (%) 95% CI 55.6 [49.5-61.5] 29.2 [20.4-39.4] 24.8 [16.8-34.2] p�0.48 

SCC / ADC* (%) 

60.5 / 54.5 34.6 / 25.7 23.6 / 28.9 

ORR eval (%) 95% CI 60.7 [54.3-66.9] 36.8 [26.0-48.6] 29.2 [20.0-39.8] p�0.30 

SCC / ADC* (%) 

66.9 / 57.6 42.9 / 33.3 28.3 / 31.4 

DCR ITT (%) 78.5 66.7 56.2 p�0.12 

DCR eval (%) 86.0 84.2 66.3 P�0.0084 

Median time 

Registration-Rando (m) 

3.0 2.9 

Median PFS ** (m) 6.4 [5-8.7] 5.5 [3.8-7.4] p�0.63 

Median OS ** (m) 20.8 [13.5-25.3] 18.5 [13.6-24.7] p�0.87 

4 year survival ** (%) 25.3 21.4 

* SCC: Squamous; ADC: Adenocarcinoma. ** Calculated from the time of randomisation, after CT-RT, on ITT. 


A phase III study comparing amrubicin and cisplatin (AP) with irinotecan 

and cisplatin (IP) for the treatment of extended-stage small cell lung cancer 

(ED-SCLC): JCOG0509. Presenting Author: Yoshikazu Kotani, Department 

of Respiratory Medicine, Kobe University Hospital, Kobe, Japan 

Background: IP is the standard treatment for ED-SCLC, however often cause 

severe diarrhea. AP have shown promising activity in SCLC with fewer 

diarrhea. We conducted a phase III trial comparing AP with IP. Methods: 

Eligibility criteria included patients (pts) with chemotherapy-naïve, ED- 

SCLC, aged 20 to 70, and ECOG PS 0-1. Pts were randomized to receive 

either IP or AP, balancing for site, sex, and PS. IP comprised administration 

of I (60 mg/m2 ) iv on days 1, 8, and 15, and P (60 mg/m2 ) iv on day1,every 

4 weeks. AP comprised administration of A (40 mg/m2 ) iv on day 1-3, and P 

(60 mg/m2 ) iv on day1, every 3 weeks. The planned sample size was 141 

pts in each arm with a one-sided alpha of 5% and power of 70% and a 

non-inferiority margin of hazard ratio (HR) as 1.31. The primary endpoint 

was overall survival (OS). The secondary endpoints were response rate (RR), 

progression-free survival (PFS), adverse events (AEs), and quality of life 

(QOL). We evaluated pts’ QOL twice: at the baseline and after completion of 

the second course. Results: 284 pts were randomized to IP (n�142) and AP 

(n�142). Median age was 63, 84% were male, and 56% had PS 0. When 

191pts enrolled, more febrile neutropenia (FN) was observed in AP than 

anticipated, and the initial dose of A was decreased from 40 mg/m2 to 35 

mg/m2 . At the second interim analysis conducted after the completion of 

patient accrual, the median OS of AP (15.0 m) was much worse than that of 

IP (18.3 m) and the HR (1.41; 96.3% CI, 1.03-1.93) exceeds even the 

non-inferiority margin, so the Data and Safety Monitoring Committee 

recommended early publication of the results. Median PFS was 5.7 (IP) vs. 

5.2 months (AP) (HR 1.43, 95% CI, 1.13-1.82). RR was 69.5% (IP) vs. 

77.9% (AP) (p�0.14). AEs in IP and AP arm were Grade 4 neutropenia 

(22.5% vs. 78.6%), G3-4 FN (10.7% vs. 32.1%), and G3-4 diarrhea 

(7.1% vs.1.4%). Proportion of improvement in physical status of QOL was 

37.1%(IP) vs. 31.7%(AP), (odds ratio 0.72; 95%CI, 0.43-1.22; P�0.227). 

Conclusions: AP showed more bone marrow suppression than expected 

although it caused less diarrhea. The non-inferiority of AP to IP was not 

demonstrated and IP remains the standard treatment for ED-SCLC. 




Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first 

cycle or the third cycle of cisplatin and etoposide chemotherapy to 

determine the optimal timing of TRT for limited-disease small cell lung 

cancer. Presenting Author: Keunchil Park, Department of Medicine, 

Samsung Medical Center, Sungkyunkwan University School of Medicine, 


Background: Concurrent thoracic radiotherapy (TRT) with chemotherapy 

has been regarded as optimal treatment for limited-disease small cell lung 

cancer (SCLC). However, the issue on how early TRT should be commenced 

is not yet defined. Methods: A total of 219 patients with limited-disease 

SCLC, who were enrolled from July 2003 to June 2010, received four 

cycles of cisplatin plus etoposide (cisplatin 70 mg/m2 on day 1 and 

etoposide 100 mg/m2 on days 1 to 3 every 3 weeks). We randomly assigned 

these patients to receive concurrent TRT, beginning with the first cycle 

(initial arm) or the third cycle (delayed arm) of chemotherapy. In both arms, 

patients received 2.1 Gy once-daily in 25 fractions over a period of five 

weeks, with a total dose of 52.5 Gy. Patients with partial or complete 

response were recommended to receive prophylactic cranial irradiation 

(PCI). Results: Approximately 82% of patients completed planned four 

cycles of chemotherapy with 52.5 Gy TRT (81.1% and 82.4% in the initial 

and delayed arm, respectively). After a median follow-up of 4.9 years 

(range, 1.2 – 8.1 years), the median overall survivals were 24.1 and 26.8 

months (P�0.60) in the initial and delayed arm, respectively. Progressionfree 

survival and complete response rates were 12.2 vs. 12.1 months 

(P�0.94) and 36.0% vs. 38.0% (P�0.77) in the initial and delayed arms, 

respectively. PCI was given to 49.5% and 55.6% of patients in the initial 

and delayed arms, respectively (P � 0.37). Febrile neutropenia was 

significantly more frequent with the initial arm, occurring in 21.6% of 

patients, as compared with 10.2% in the delayed arm (P � 0.02). All grade 

esophagitis occurred in 45.0% and 37.0% of the initial and delayed arms, 

respectively (p � 0.23). Conclusions: TRT (52.5 Gy, once daily) beginning 

with the third cycle of chemotherapy showed comparable survival outcomes 

and complete response rates with TRT beginning with the first cycle of 

chemotherapy, with a lower frequency of febrile neutropenia. 


Comprehensive genomic characterization of squamous cell carcinoma of 

the lung. Presenting Author: Ramaswamy Govindan, Washington University 

School of Medicine, St. Louis, MO 

Background: A third of patients with non-small cell lung cancer are 

diagnosed with squamous cell carcinoma (SCC) histology. This report 

describes findings from the comprehensive genomic analyses of 178 SCC 

samples. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, 

RNA, and miRNA sequencing along with DNA copy number profiling, 

quantification of mRNA expression and promoter methylation on surgically 

resected samples from previously untreated patients with stage I-III SCC of 

the lung. Results: The demographics of 178 patients enrolled in the study: 

median age 68 years (range: 40-85); female 47 (26%) and history of 

tobacco smoking 171 (96%). Over 30 sites of significant somatic copy 

number alteration (SCNA) were identified. Exome sequencing of 178 lung 

SCC and matched normal samples revealed 13 significantly mutated genes 

with a False Discovery Rate (FDR) of �0.01 and high expression levels, 

including TP53, CDKN2A, PTEN, KEAP1, and NFE2L2. Apart from the 

near universal loss of TP53 and CDKN2A, alterations in the NFE2L2/ 

KEAP1 and PI3K/AKT pathways were found in 35% and 43% of tumors 

analyzed. mRNA expression profiling revealed four distinct expression 

subtypes, each one enriched with distinct mutations and SCNAs - classical 

(37%): NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased 

global methylation and the highest rate of tobacco use; basal (24%): 

alterations in FGFR kinases; secretory (24%): PDGFRA alterations; primitive 

(15%): RB1 mutations. Rearrangements involving several known 

tumor suppressors were detected by whole genome shotgun sequencing of 

20 tumor/normal pairs and confirmed by RNA sequencing including PTEN, 

RB1, NOTCH1, NF1 and CDKN2A. CDKN2A loss by one of several 

mechanisms (deletion, mutation, rearrangement with loss of function and 

methylation) was observed in 72% of specimens. Potential therapeutic 

targets for clinical trials with currently available drugs were identified in 

127 patients (75%). Conclusions: SCC of the lung is a distinct molecular 

subtype of lung cancer potentially amenable to distinct molecularly 

targeted therapies. 


SWOG 0802: A randomized phase II trial of weekly topotecan with and without 

AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small 

cell lung cancer (E-SCLC). Presenting Author: Jeffrey Warren Allen, University of 

Tennessee Health Science Center, Memphis, TN 

Background: Topotecan (T) (oral and IV) is the only FDA-approved second-line 

chemotherapy for patients with SCLC. Weekly T is associated with less toxicity 

than the daily x 5 regimen. AVE0005 (aflibercept) (A) is a novel recombinant 

human fusion protein which binds to circulating VEGF, thereby inhibiting its 

interaction with cell surface receptors. We sought to evaluate the efficacy and 

toxicity of weekly IV T (4 mg/m2) with or without A (6 mg/kg Q21D) in patients 

with relapsed SCLC following one line of platinum-based chemotherapy for E or 

limited-stage (L) SCLC. Methods: Patients were randomized 1:1 to T or A�T. 

Eligible patients had adequate organ function, ECOG PS 0-1, and no recent 

bleeding or cardiac events. Patients with brain metastases stable for � 3 months 

prior to study entry were allowed. Primary endpoint was 3-month PFS. Patients 

were stratified as platinum-sensitive (PS) or platinum-refractory (PR). PR 

patients had progressed within 90 days of last chemotherapy for E and 6 months 

for L. This report is limited to the PR stratum. Results: 98 patients were 

registered. 1 was ineligible and 1 withdrew consent, leaving 96 evaluable for the 

primary endpoint (91 for toxicity (see Table for characteristics)). 3-month PFS 

was 26% for A�T versus 9% for T (P�0.01). Overall survival was similar in each 

arm (4.6 mos (A�T) versus 3.9 mos (T) (P�0.25)). There was 1 partial response 

with A�T. Disease control rate (DCR) was 28% with A�T and 12% with T. 

Toxicity was mainly hematologic with 14% and 19% of patients experiencing a 

Grade 4 event with T and A�T, respectively. There was one treatment-related 

death with T (renal failure). Conclusions: This study met its primary endpoint of 

improved 3-month PFS with A�T (p�0.01), warranting further study in the PR 

setting. Clinical benefit with A�T was achieved primarily through improved DCR. 

Toxicity was manageable and less than is seen with standard dose T. Accrual to 

the PS cohort is ongoing. 

Patient characteristics. 

T(n�46) A�T(n�50) 

Age (median) 63 60 

Gender 

Male (%) 

Female (%) 

Race 

Caucasian (%) 

Other (%) 

PS 

0(%) 

1(%) 

Stage 

Extensive (%) 

Limited (%) 

67 

33 

83 

17 

39 

61 

70 

30 


Prognostic and predictive effects of KRAS mutation subtype in completely 

resected non-small cell lung cancer (NSCLC): A LACE-bio study. Presenting 

Author: Frances A. Shepherd, Princess Margaret Hospital, University of 


Background: We reported previously that KRAS is weakly prognostic and not 

significantly predictive of benefit from adjuvant chemotherapy (ACT) in 

NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer 

(CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies, 

but recent reports suggest that this may not be true for all mutation 

subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations 

in NSCLC differ from those of CRC. To explore the influence of KRAS 

mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio. 

Methods: KRAS mutation was determined in blinded fashion in 3 laboratories 

by direct sequencing. Exploratory analyses were performed to identify 

relationships between mutation status and subtype, overall (OS) and 

disease-free survival (DFS) using a Cox model stratified by trial and 

adjusted for covariates. Results: KRAS subtype was available in 1,532 

patients (756 observation [OBS], 776 ACT). There were 300 mutations 

(275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no 

difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v 

wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI 

0.47-2.17) mutations. A trend for benefit from ACT was observed in WT 

(HR ACT v OBS 0.89 CI 0.76-1.04, p�0.15) but not in patients with codon 

12 mutations (HR 0.95, CI .67-1.35, p�0.77). In patients with codon 13 

mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2, 

p�0.001), test for equality among 3 HRs p�0.002. Results were similar 

for DFS. Among codon 12 mutations, there was no prognostic effect based 

on specific amino acid substitution. Patients with G12A or G12R mutations 

appeared to derive greater benefit from ACT (HR 0.66 p�0.48) compared 

to those with G12C or G12V (HR 0.94 p�0.77) or G12D or G12S (HR 1.39 

p�0.48) or WT, but the differences were not significant (comparison of 4 

HRs p�0.76). Conclusions: In this study, patients with KRAS codon 13 

mutations had significantly poorer outcomes with ACT. These results 

require further confirmation and should be interpreted with caution in view 

of the small number of patients with codon 13 mutations. Supported by 

unrestricted grants from Sanofi Aventis and LNCC. 


453s 

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83 

17



Accuracy of FDG-PET to diagnose lung cancer in the ACOSOG Z4031 trial. 

Presenting Author: Eric L Grogan, Vanderbilt University Medical Center, 

Nashville, TN 

Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) 

is recommended for diagnosis and staging of known or suspected NSCLC. 

Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer 

demonstrated high sensitivity 94% and specificity 83% but were performed 

in select centers. The purpose of this study is to evaluate the 

accuracy of FDG-PET to diagnose NSCLC and examine enrolling site 

differences in the national prospective ACOSOG Z4031 trial. Methods: 

1,074 patients with clinical stage I (cT1-2N0M0) known or suspected 

NSCLC were enrolled between 2004 and 2006 in the Z4031 study and 

underwent surgical resection. The final diagnosis was determined by 

pathological examination. FDG-PET results were abstracted from radiology 

interpretations included in the case report forms. FDG-PET avidity was 

categorized based on either radiologist description or reported maximum 

standard uptake value (SUV). The four categories were: not avid and not 

cancerous (SUV�0), low avidity and likely not cancerous (SUV�0 and 

�2.5), avid and probably cancerous (SUV�2.5 and �5) and highly avid 

and likely cancerous (SUV�5). Sensitivity analysis of FDG-PET diagnostic 

accuracy was performed for varying levels of avidity and by preoperative 

lesion size. Differences in accuracy by enrolling site were examined. 

Results: There were 51 enrolling sites in 39 cities with 969 eligible 

participants. Preoperative FDG-PET results were available for 682 participants. 

Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% 

(95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and 

negative predictive values were 85% and 26%, respectively and accuracy 

improved with lesion size. There were 80 false positive scans and 69% were 

granulomas. False negative scans occurred in 101 patients (11were 

�10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine 

tumors responsible for 64%, 12%, 10% and 8% of false 

negative results, respectively. Specificity did not differ between the 8 sites 

with �25 patients (p�0.74). Conclusions: In a national surgical population 

with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed 

poorly compared to published studies. Reasons for poor test performance 

should be explored. 


11:30 AM-12:30 PM 

The SELECT study: A multicenter phase II trial of adjuvant erlotinib in 

resected epidermal growth factor receptor (EGFR) mutation-positive nonsmall 

cell lung cancer (NSCLC). Presenting Author: Joel W. Neal, Stanford 

University, Palo Alto, CA 

Background: Cancers with activating EGFR mutations are exquisitely 

sensitive to EGFR tyrosine kinase inhibitors (TKIs) and retrospective data 

suggests adjuvant TKIs may improve outcomes in EGFR mutants. This 

prospective trial investigates the safety and efficacy of adjuvant erlotinib in 

EGFR mutation-positive NSCLC. Methods: Patients (pts) with surgically 

resected stage IA-IIIA NSCLC harboring activating EGFR mutations were 

treated with 150 mg/day of erlotinib for 2 years (y) after completion of any 

standard adjuvant chemotherapy and/or radiotherapy. The trial was designed 

to enroll 36 patients, and powered to demonstrate a primary 

endpoint of 2 y disease free survival (DFS) exceeding 85%, which would 

suggest improvement over the historically expected 70% 2 y DFS in early 

stage EGFR-mutant NSCLC (J Thorac Oncol 6:569). Results: Thirty-six pts 

were enrolled at five sites between 1/08 and 11/09; 53% stage I; 19% 

stage II; 28% stage IIIA. Toxicities were typical of erlotinib; no grade 4 or 5 

events or pneumonitis occurred. 8 pts (22%) required one dose reduction 

to 100 mg/day and 5 (14%) two reductions to 50 mg/day for grade 3 or 

persistent grade 2 toxicities. 11 pts discontinued before 2 full years (�1 

month (mo) [4], 1-12 mo [2] and 12-23 mo [5]) for toxicities [6], patient 

preference [3], prostate cancer [1] and recurrence [1]. After a median 

follow-up of 2.5 y, the 2 y DFS from enrollment is 94% (95% CI 80%, 

99%). 10 patients have recurred, 1 during erlotinib treatment and the 

others after stopping erlotinib (interval before recurrence 2 mo [1], 6-12 

mo [4], �12 mo [4]). Genotyping on repeat biopsies from seven of the 

recurrent cases is underway, as is assessment of response to subsequent 

erlotinib therapy. Two pts have died of recurrence: one at 1.5 y who stopped 

erlotinib after 1 mo for toxicity, and one at 2 y who progressed while on 

erlotinib. Conclusions: This is the first prospective study to report the 

efficacy of adjuvant erlotinib in NSCLC pts with EGFR mutations. This 

approach is feasible and yields excellent 2y DFS compared to historical 

genotype-matched controls. This trial was subsequently expanded to 100 

pts to permit subgroup analysis by stage. 


11:30 AM-12:30 PM 

Stages I-II non-small cell lung cancer treated using either lobectomy by 

video-assisted thoracoscopic surgery (VATS) or stereotactic ablative radiotherapy 

(SABR): Outcomes of a propensity score-matched analysis. Presenting 

Author: Suresh Senan, Department of Radiation Oncology, VU University 

Medical Center, Amsterdam, Netherlands 

Background: VATS procedures are increasingly used in early-stage NSCLC. 

As high local control rates are also seen with stereotactic ablative 

radiotherapy (SABR), we performed a propensity score-matched analysistocompare 

loco-regional control (LRC) after both treatments. Methods: 

Patients with stage I-II NSCLC treated at 6 hospitals (1 university and 5 

regional hospitals) with VATS lobectomy were eligible. Details of SABR 

patients were obtained from a single-institutional database. All VATSlobectomies 

were performed in accordance with ESTS guidelines. Patients 

were matched using propensity scores based on cTNM, age, gender, 

Charlson comorbidity score, lung function and performance score. Matching 

was performed blinded to all outcomes. Excluded were: synchronous 

lung tumors, COPD GOLD class 4 or history of prior lung cancer. A total of 

86 VATS- and 527 SABR patients were eligible for matching (1:1 ratio, 

caliper distance of 0.025 without replacement). Loco-regional failure was 

defined as recurrence in/adjacent to the radiation planning target volume or 

surgical margins, the ipsilateral hilum or mediastinum. Recurrences were 

either biopsy-confirmed or PET-positive and reviewed by a tumor board. 

Patients upstaged during VATS and those developing recurrence were 

treated in accordance with national guidelines. Results: The matched 

cohort consisted of 128 patients with cT1-3N0 NSCLC following SABR 

(n�64) or VATS-lobectomy (n�64). Median follow-up was 30 and 16 

months, respectively. The groups were well matched on baseline variables. 

SABR patients had better LRC rates at 1- and 3-years (96.8% and 93.3% 

vs. 86.9% and 82.6%, respectively, p� .03). Three-year progression-free 

survival (PFS) did not significantly differ after SABR (79.3% versus 

63.2%, p � .09). Distant recurrence rates and overall survival (OS) did not 

significantly differ. Conclusions: Although loco-regional control was superior 

after SABR compared to VATS-lobectomy, PFS and OS did not differ at 

this time-point. Our findings support the current randomized controlled 

trial evaluating both treatments (ACOSOG Z4099). 


11:30 AM-12:30 PM 

Pilot SCAT trial: Spanish customized adjuvant chemotherapy (CT) based on 

BRCA1 mRNA expression levels (l) in resected stage II-IIIA non-small cell 

lung cancer (NSCLC) patients (p). Presenting Author: Jose Miguel Sanchez, 

Hospital M. D. Anderson Internacional, Madrid, Spain 

Background: Surgical resection is the standard treatment in early stages of 

NSCLC. Nonetheless, long-term survival rate even after surgical resection 

is disappointing. Several randomized trials and meta-analyses confirmed 

the survival benefit of adjuvant cisplatin-based CT for stage II and IIIA. 

BRCA1 is a component of multiple DNA repair pathways, functions as a 

molecular determinant of response to cytotoxic chemotherapeutics agents, 

and is an independent prognostic variable in resected p. Since BRCA1 

mRNA expression has been linked to differential sensitivity to cisplatin and 

antimicrotubule drugs, BRCA1 expression may provide additional information 

for customizing adjuvant CT. Methods: Completely resected p with 

pathological lymph node involvement (N1, N2) received 4 cycles of 

customized adjuvant CT according BRCA1 l. Low l: gemcitabine-cisplatin, 

intermediate l: docetaxel-cisplatin, high l: docetaxel. Overall survival (OS) 

was the primary endpoint. Multivariate analysis for time to relapse (TTR) 

and survival was performed. Results: Eighty-three p were elegible. Most of 

the patients were male (83%). Type of surgery: 23% pneumonectomy, and 

77% lobectomy or bilobectomy. Fifty-three per cent had low BRCA1 l, 

33,7% intermediate l, and 13,3% expressed high l. Most of the tumors 

with adenocarcinoma histology had low l (71%). With a median follow-up of 

41.6 months (m), median TTP for the whole group was 22.9 m (13.4- 

32.5): 20.3 m for low l, 56.5 m for intermediate l, and 51.9 m for high l 

(P�0.31). Median OS for the whole group was 63.6 m (33.3-93.9): 55 m 

for low l, and not reached for intermediate and high l (P�0.58). Forty-three 

p (51.8%) are still alive. Conclusions: Selection of customized CT based on 

BRCA1 expression l is feasible and could increase time to relapse and 

survival in resected N1-N2 p. No statistical differences for survival: 55 

months for gemcitabine-cisplatin, and not reached for docetaxel-cisplatin 

and for docetaxel as single agent. Randomized phase III SCAT trial with the 

addition of a non-pharmacogenomic control arm is ongoing (372 patients 

included). 




11:30 AM-12:30 PM 

Feasibility trial of adjuvant chemotherapy with docetaxel (DOC) plus 

cisplatin (CDDP) followed by maintenance chemotherapy of S-1 in completely 

resected non-small cell lung cancer (NSCLC): Thoracic Oncology 

Research Group (TORG) 0809. Presenting Author: Seiji Niho, Division of 

Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, 

Japan 

Background: Maintenance chemotherapy could prolong overall and/or 

progression-free survival in advanced NSCLC. S-1 is an oral anticancer 

agent comprised of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium 

oxonate. The TORG 0809 study was conducted to evaluate the 

feasibility and efficacy of maintenance chemotherapy of S-1 following 

DOC�CDDP in patients (pts) with curatively resected stage II and IIIA 

NSCLC. Methods: Pts received 3 cycles of DOC (60mg/m2 d1) plus CDDP 

(80mg/m2 d1), q3-4w, and subsequently S-1 at 40mg/m2 twice a day for 

14 consecutive days, q3w, for more than 6 months (max 1 year). The 

primary endpoint was determination of feasibility, which was defined as the 

proportion of pts who had completed maintenance for 8 cycles of S-1 or 

more. If the lower confidence interval (CI) of this proportion was 50% or 

more, the feasibility of the treatment was considered confirmed. The 

sample size was set to be 125. Results: Between Jun 2009 and Nov 2010, 

131 pts were enrolled, of whom 129 pts were eligible and assessable. The 

median age was 63 (23-74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 

30, IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 pts, 

109 pts (84.5%) completed 3 cycles of DOC�CDDP. 106 pts initiated the 

maintenance S-1 and 66 pts (51.2%, 95% CI: 42.5-59.8) completed 8 

cycles or more S-1 treatment; this percentage was less than our previously 

defined criterion for treatment feasibility, since 32 pts terminated maintenance 

S-1 at 3 cycles or less. Grade 3/4 toxicities during the maintenance 

S-1 included anemia (7.3%), neutropenia (3.7%), anorexia (3.7%), 

dyspnea (1.8%), infection with neutropenia of grade 0 to 2 (1.8%). Febrile 

neutropenia was not observed. One pt developed interstitial pneumonia and 

sepsis, resulting in treatment-related death. Recurrence-free survival data 

will be presented. Conclusions: The toxicity level was acceptable, although 

the results did not meet our criterion for feasibility. Modification of the 

treatment schedule of maintenance S-1, such as a 2-week rest period 

rather than 1-week, might improve treatment compliance. 


11:30 AM-12:30 PM 

Quantitating pathologic response to neoadjuvant chemotherapy in KRASmutated 

versus nonmutated lung cancers. Presenting Author: Jamie E. 

Chaft, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Trials of neoadjuvant chemotherapy in non-small cell lung 

cancers (NSCLC) have demonstrated that pathologic response correlates 

with downstaging and survival. There is controversy as to whether KRAS 

mutated patients (pts) have the same benefit with adjuvant chemotherapy 

as non-mutated pts however the impact of KRAS mutations on response to 

neoadjuvant therapy has not been reported. Methods: Pts with resectable 

stage I-III non-squamous NSCLCs were treated with 4 cycles of cisplatin, 

docetaxel, and bevacizumab, followed by surgical resection. Tumors were 

tested for KRAS mutations. Percent treatment effect (necrosis, inflammation, 

fibrosis) was quantified histologically. Pts were followed until disease 

recurrence and/or death. Binary variables were compared using the Fisher’s 

Exact Test. Survival was assessed by pathological response based on the 

literature (�90 vs �90%) using the Kaplan-Meier method, stratified by 

stage (IB-IIB vs. III) and by KRAS mutation. Results: We accrued 51 pts. 

34/51 (67%) had clinical stage IIIA disease. 48 had molecular testing: 

14/48 (29%) had KRAS mutations and 4/48 (8%) had EGFR mutations. 

The median follow-up was 2 years (yr) (range, 3-63 months). 41 pts had 

resection and analysis for pathological response. The 2 yr disease free 

survival (DFS) and overall survival (OS) were superior in the 11/41 (27%) 

with �90% versus those with �90% treatment effect: DFS 91% vs. 56%, 

p�0.029 and OS 100% vs. 60%, p�0.013. These outcomes remained 

significant when adjusted for stage. For pts with KRAS mutations, 0 of 10 

tumors analyzed had �90% treatment effect whereas 11 of 31 (35%) pts 

with wild-type KRAS had �90%, p�0.039. There was an inferior median 

OS for KRAS mutated pts (22 months) compared to pts without a known 

KRAS mutation, (Not Reached, p�0.03). Conclusions: Following neoadjuvant 

chemotherapy, pts with tumors having �90% necrosis had improved 

survival. There were no patients with KRAS mutation that achieved �90% 

treatment effect in response to cisplatin, docetaxel, and bevacizumab. 

Adaptive adjuvant trial strategies to improve upon outcomes of those with 

�90% necrosis at resection and new approaches specifically targeting 

KRAS-mutated NSCLCs are needed. 


11:30 AM-12:30 PM 

MAGE-A3 cancer immunotherapeutic in resected stage IB-III NSCLC 

patients with or without sequential or concurrent chemotherapy. Presenting 

Author: Jean-Louis Pujol, CHU - Maladies Respiratoires, Montpellier, 

France 

Background: Previous trials with the MAGE-A3 recombinant (rec) protein 

formulated with an immunostimulant have shown induction of specific 

immune responses and signals of clinical activity in different cancer 

diseases. In this phase I/II study (NCT 00455572), we evaluated the safety 

profile of the MAGE-A3 cancer immunotherapeutic (CI), formulated with 

the rec MAGE-A3 protein and the AS15 immunostimulant, and the 

induction of specific immune response with or without adjuvant chemotherapy 

(CT). Methods: MAGE-A3 CI was administered i.m. 8q3w in 

resected MAGE-A3� stage IB-III NSCLC patients (pts). Three cohorts (C) 

were evaluated: Immunization with concurrent cisplatin plus vinorelbine 

(C1), sequentially after the same CT (C2) or with no CT (C3). The 

anti-MAGE-A3 humoral and cellular immune responses were evaluated by 

ELISA and intracellular cytokine staining (T cells producing both IFNg and 

TNF) respectively. Adverse Events (AEs) were graded according to CTCAE v. 

3.0. Results: A total of 38/55 treated pts received the 8 doses schedule 

(15/19 in C1, 14/18 in C2, 9/18 in C3). Almost all pts reported at least one 

AE, mostly general constitutional disorders and administration site reactions. 

Six patients reported related grade 3 AEs. No related grade 4-5 AE or 

related SAE were reported. Immunogenicity results in the total treated 

population are reported in the table below. Conclusions: In this trial, 

patients in cohorts 2 and 3 correspond to the two populations enrolled in 

the Phase III MAGRIT trial evaluating the same MAGE-A3 CI. The phase I/II 

results suggest that this CI is well tolerated and induces in all treated pts 

specific antibodies against MAGE-A3 after 4 doses in presence or not of 

concurrent or sequential adjuvant CT. About 25% of the treated pts are 

considered as CD4 responders in presence or not of concurrent or 

sequential adjuvant CT. 

C1 

n/N 

C2 

n/N 

455s 

C3 

n/N 

Cohort 

Seropositivity* 

- 

- 

- 

After 4 doses 

15/15 

15/15 

12/12 

After 8 doses 

15/15 

13/13 

9/9 

CD4 response** 4/11 4/15 2/8 

CD8 response** 1/11 1/15 0/8 

n: number of seropositive/responding patients; N: Total number of pts with 

available samples; *: Anti-MAGE-A3-Antibodies; **: Responders are pts with a 

response ratio baseline/any timepoint ��4 folds. 


11:30 AM-12:30 PM 

Updated results of a phase III trial comparing standard thoracic radiotherapy 

(RT) with or without concurrent daily low-dose carboplatin in 

elderly patients (pts) with locally advanced non-small cell lung cancer 

(NSCLC): JCOG0301. Presenting Author: Hiroaki Okamoto, Yokohama 

Municipal Citizen’s Hospital, Yokohama, Japan 

Background: We previously reported the superiority of combined chemoradiotherapy 

(CRT) over RT alone in elderly pts with locally advanced 

NSCLC (Atagi et al. ECCO2011). One and a half years follow-up data from 

last accrual are presented. Methods: Pts older than 70 years with unresectable 

stage III NSCLC were randomized to either RT alone (RT arm), a total 

dose of 60 Gy, or CRT arm including the same RT plus concurrent 

chemotherapy with carboplatin 30 mg/m2 /day, 5 days/week � 20 days. The 

primary endpoint was overall survival (OS). The planned sample size was 

100 pts in each arm with one-sided alpha of 5% and 80% power to detect a 

difference in median survival time (MST) from 10 months in RT arm to 15 

months in CRT arm. Results: Between Sep 2003 and May 2010, 200 pts 

were randomized. Baseline characteristics were similar in the RT (n�100) 

vs CRT (n�100) arms: median age, 77 vs 77 years; stage IIIB (n), 46 vs 

49; PS 0/1/2 (n), 41/55/4 vs 41/56/3. The second planned interim analysis 

was performed 10 months after the completion of accrual. In accordance 

with the pre-specified stopping rule, the JCOG Data and Safety Monitoring 

Committee recommended early publication of this trial because of the 

difference in OS favoring the CRT arm. In the updated analysis, OS was 

better in the CRT arm than the RT arm (HR � .64, 95% CI � .46-.89, 

one-sided p � .0033 by stratified log-rank test). In each arm (RT/CRT), 

MST was 16.5 mo/22.4 mo with 3-year OS of 14.3%/34.6%, response rate 

of 44.9%/54.6% (p�.201) and median progression-free survival of 6.9 

mo/8.9 mo (p�.003). Gr 3/4 toxicities were (RT/CRT): neutropenia 

0%/57.3%, infection 4.1%/12.5%, dysphagia 0%/1.0%, late RT toxicities 

7.4%/7.5%. The pattern of relapse site and post-protocol treatment were 

almost similar between the arms. Even after an adjustment by the Cox 

regression analysis with six variables [stage, PS, sex, age, histology, 

smoking status], CRT arm showed better survival (HR�.71, p�.038). 

Conclusions: The CRT using daily carboplatin is considered to be the 

standard treatment for elderly pts with locally advanced NSCLC. 




11:30 AM-12:30 PM 

SWOG S0533: A pilot trial of cisplatin (C)/etoposide (E)/radiotherapy (RT) 

followed by consolidation docetaxel (D) and bevacizumab (B) (NSC- 

704865) in three cohorts of patients (pts) with inoperable locally advanced 

stage III non-small cell lung cancer (NSCLC). Presenting Author: Antoinette 

J. Wozniak, Karmanos Cancer Institute, Wayne State University, 

Detroit, MI 

Background: Bevacizumab combined with chemotherapy has improved 

survival in the treatment of advanced NSCLC. This pilot trial was conducted 

to determine if bevacizumab could be incorporated into the standard 

chemotherapy/RT for locally advanced NSCLC. Methods: Pts with unresectable 

stage III NSCLC, PS 0-1, and adequate organ function were eligible. 

Pts were accrued in two strata, low and high risk (squamous histology, 

hemoptysis, tumor with cavitation or near a major vessel). Pts were treated 

with C 50mg/m2 (d 1 and 8), E 50mg/m2 (d 1-5) for 2 cycles concurrent 

with RT (64.8 Gy at 1.8 Gy/fx for 36 fxs) followed by consolidation D 

75mg/m 2 

and B 15 mg/kg for 3 cycles (Cohort 1). If safety was established 

then accrual would continue to Cohort 2 (B, d 15, 36, 57) and then Cohort 

3 (B d 1, 22, 43). Results: 29 pts (17 Low, 12 High) were registered, all to 

Cohort 1. 26 pts (stage IIIB 19 pts, squamous 4 pt, adenosquamous 1 pt) 

were evaluable. 25 completed chemo/RT. Grade 3/4 toxicities during 

chemo/RT included: neutropenia 10 pts, thrombocytopenia 2, anemia 2, 

febrile neutropenia 3, esophagitis 2, pneumonitis 1. 21 were assessed for 

safety with D/B consolidation. The major adverse events during D/B 

consolidation were pneumonitis (Gr 3-2pt)and2episodes of fatal 

hemoptysis in the high risk group resulting in closure of this stratum. The 

low risk stratum subsequently closed because of poor accrual. Median 

overall survival was 23 mos for low risk pts and 17 mos for the high risk 

stratum. Conclusions: In this trial, bevacizumab could not be successfully 

integrated into chemo-radiation for stage III NSCLC, particularly in pts 

considered at high risk for hemoptysis. The trial suffered from several 

temporary closures as mandated by CTEP when new bevacizumab-related 

toxicities were reported, contributing to slow accrual. In lower risk pts the 

data are insufficient to determine safety or efficacy. Supported in part by 

the following PHS Cooperative Agreement grant numbers awarded by the 

National Cancer Institute, DHHS: CA32102 and CA38926. 


11:30 AM-12:30 PM 

Favorable outcomes with chemoradiation and surgery for locally advanced 

non-small cell lung cancer: The BC Cancer Agency Vancouver experience. 

Presenting Author: Wen Wen Shan, University of British Columbia, Vancouver, 

BC, Canada 

Background: The role of surgery following concurrent platinum-based 

chemotherapy and radiation for locally advanced non-small cell lung 

cancer (NSCLC) remains controversial, with high surgical mortality rates 

reported in a large randomized clinical trial. In this retrospective study, we 

evaluated the safety and efficacy of concurrent chemoradiation with or 

without surgery over an 11 period at the BC Cancer Agency. Methods: 

Patients were identified by the Vancouver Centre Pharmacy database. 

Charts were reviewed and data extracted included patient characteristics, 

weight loss, performance status, and method of mediastinal staging. 

Outcome measures were overall survival, pathological response rate, and 

treatment-associated morbidity and mortality. Results: Between January 

1999-2010, 177 patients were identified with locally advanced NSCLC 

(stage IIIA/B) treated with platinum and etoposide and �40Gy radiation 

therapy, with or without surgical resection. The majority of treatment plans 

were reached by a multidisciplinary conference consensus. 74% (n�131) 

of patients received chemoradiation alone (bimodality therapy) and 36% 

(n�46) received chemoradiation followed by surgical resection (trimodality 

therapy). Among the trimodality therapy group, 16 patients underwent 

pneumonectomy and 30 lobectomy. Conclusions: In this series, bimodality 

therapy for patients with locally advanced NSCLC had similar treatment 

associated mortality and survival outcomes as reported in the literature. 

Trimodality therapy was associated with low treatment mortality rates and 

favourable survival. These two groups cannot be directly compared in this 

retrospective study. However, these results support a multidisciplinary 

approach to identify and carefully select patients with locally advanced 

NSCLC to undergo additional surgical resection following concurrent 

chemoradiation. 

Treatment-associated complications and survival. 

Bimodality Trimodality 

Complications 

Hospitalization 24% 11% 

Death on treatment 5% 2% 

Survival 

Median OS 19.6 mo 68 mo 

5-year OS 17.5% 53.2% 


11:30 AM-12:30 PM 

A randomized, multicenter phase II study investigating additional weekly 

cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell 

lung carcinoma: Reporting on the efficacy. Presenting Author: Michel M. van den 

Heuvel, Medical Oncology Department, The Netherlands Cancer Institute/Antoni 

van Leeuwenhoek Ziekenhuis, Amsterdam, Netherlands 

Background: Modest benefits from concurrent chemoradiotherapy (CRT) in 

patients with locally advanced NSCLC warrant more effective treatment regimen. 

Cetuximab, a monoclonal antibody against the epidermal growth factor receptor 

has shown activity in NSCLC. Feasibility data and toxicity have been published 

previously. We report treatment outcome of a multicenter phase II study of the 

combination of high dose accelerated RT and daily dose cisplatin with or without 

weekly cetuximab. Methods: Patients with locally advanced NSCLC received 

accelerated RT (66 Gy in 24 fractions) and concurrent daily cisplatin (6 mg/m2 ) 

with (Arm A) or without (Arm B) additional weekly cetuximab (400 mg/m2 loading dose one week prior to the RT start followed by weekly 250 mg/m2 ). The 

Objective Local Response Control (OLRC) was determined at 6 and 24 weeks 

after treatment using response evaluation criteria in solid tumours criteria. 

Results: Between Feb 2009 and May 2011, 102 patients were included. Median 

follow-up was 13 months. Patients and tumor characteristics are shows in the 

Table. Stage distribution was: II (8%), IIIa (51%), and IIIb (40%). The CRT was 

well tolerated. The OLRC at 24 weeks was 79% in Arm A and 80% in Arm B. The 

one-year progression free survival and overall survival were 58% (45%-76%) and 

76% (64%-91%) for Arm A and 49% (35%-68%) and 72% (58%-89%) for Arm 

B respectively. Conclusions: The addition of cetuximab to low dose cisplation 

CRT does not improve OLRC in an unselected patient cohort but data on 

longterm disease control and survival are to be awaited. 

Characteristics of patients treated with concurrent chemoradiotherapy. 

CRT CRT � cetuximab 

Age (years, range) 63 (37-78) 62 (29-80) 

Female / Male 29% / 71% 33% / 67 % 

Ethnic origin (Asian/non-Asian) 2%/98% 6%/94% 

Staging: 

4% 

12% 

-IIa/b 

54% 

47% 

-IIIa 

-IIIb 

41% 

41% 

Histology: 

32% 

33% 

-Adeno 

28% 

24% 

-Large cell 

38% 

41% 

-Squamous 

-Other 

2% 

2% 

Smoking history 

3%/49%/49% 

3%/37%/61% 

(Never/former/current) 

42%/56%/2% 

39%/61%/0% 

PS 0/1/2 

FEV1 (%) 

87% (39%-151%) 

77% (40%-121%) 

GTV (cm3 ) 

PTV (cm 3 ) 

107 (25-907) 

547 (66-1766) 

120 (5-460) 

451 (49-1855) 

SUVmax 13.7 (6.3-35.9) 10.9 (6.2-31.8) 


11:30 AM-12:30 PM 

Comparison between diameters of the whole nodule and solid area and the 

proportion of GGO in the tumor shadow on HRCT in predicting less-invasive 

lung cancer and recurrence after complete resection in patients with 

clinical N0 NSCLC. Presenting Author: Haruhisa Matsuguma, Division of 

Thoracic Surgery, Tochigi Cancer Center, Utsunomiya, Japan 

Background: Prediction of less-invasive lung cancer is important in selecting 

candidates for limited surgical resection. A greater proportion of 

ground-glass opacity (%GGO) is well-known to be strongly associated with 

less-invasive lung adenocarcinoma. Recently, the diameter of the solid area 

(SolidØ) has been reported to also be a simple and better marker for the 

same purpose compared to the diameter of the whole nodule (NoduleØ). 

The aim of this study was to confirm that SolidØ can completely replace 

%GGO in predicting less-invasive lung cancer. Methods: From 1987 to 

2009, 433 patients with clinical T1a-2bN0 NSCLC underwent complete 

resection, and their preoperative HRCT images were preserved in DICOM 

format. NoduleØ and SolidØ were precisely measured using software. 

%GGO was calculated using the method we previously published (Eur J 

Cardiothorac Surg 25:1102-6, 2004). Less-invasive lung cancer was 

defined as having no vascular, lymphatic, nor pleural invasion. We 

compared the three parameters with regard to predicting less-invasive lung 

cancer and recurrence. Results: Among the 433 patients, 220 were male, 

367 had an adenocarcinoma histology, and 58 experienced recurrence. 

Table shows percentages and numbers of non-less-invasive lung cancer 

cases. Among each category of SolidØ, greater %GGO is associated with 

less-invasive lung cancer. ROC analysis also showed that the area under the 

curve of %GGO was the highest (0.859, 95% CI 0.824 – 0.893), followed 

by SolidØ (0.806, 0.767 – 0.846), and NoduleØ (0.671, 0.620 – 0.721). 

Regardless of SolidØ, no patient with a greater %GGO (� 50%) experienced 

recurrence. Conclusions: Although SolidØ is a better prognostic 

indicator of non-invasiveness compared to NoduleØ, %GGO remains 

important. 

SolidØ %GGO 0-9% 10-49% 50-79% 80-100% 

31mm~ 22/22 (100) 30/33 (91) 1/3 (33) 0/0 (0) 

25~30mm 15/21 (71) 28/31 (90) 3/5 (60) 0/0 (0) 

21~25mm 36/30 (87) 38/64 (59) 0/4 (0) 0/0 (0) 

16~20mm 40/49 (82) 48/76 (63) 3/12 (25) 0/1 (0) 

11~15mm 14/22 (64) 24/59 (41) 2/27 (7) 0/3 (0) 

6~10mm 3/5 (60) 3/7 (43) 0/18 (0) 0/19 (0) 

0~5mm 0/1 (0) 0/2 (0) 0/2 (0) 0/23 (0) 




11:30 AM-12:30 PM 

Vorinostat (V) intratumoral levels and biomarker response in a window of 

opportunity trial in patients with resectable aerodigestive tract cancer. 

Presenting Author: Konstantin H. Dragnev, Dartmouth-Hitchcock Medical 

Center, Lebanon, NH 

Background: Aerodigestive tract cancer (ADT) is the leading cause of 

cancer-related death in the US. New effective treatments are needed. 

Among a panel of drugs causing growth inhibition of lung cancer cells and 

repression of cyclin D1, the histone deacetylase inhibitor V was found most 

potent. To translate studies into the clinic, a window of opportunity trial of V 

was conducted. Methods: Pts with resectable ADT received 400 mg V once 

daily orally for 7 days prior to surgical resection. Serum samples were 

obtained before the last V dose and at the time of biopsy. Tumor tissue was 

immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized 

in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay. 

Post- versus pre-treatment tumor biopsies were scored for necrosis, acute 

and chronic inflammation, and immunohistochemical changes in Ki-67, 

cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results: 

15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent 

resection and had adequate pretreatment samples. Median age 66, 4 

women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8 

adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and 

tumor (7pts) concentrations above the detection limits. There was considerable 

interindividual variation in plasma V concentrations (7.3-192.4 

ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V 

levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had 

KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50% 

had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation 

in the post-treatment biopsies. Most cases with KRAS mutations 

had biomarker responses. Changes in multiple biomarkers were observed 

across the range of intratumoral V levels. Conclusions: This is the first report 

of V concentrations in human tumors. Preoperative treatment with V 

achieved intratumoral concentrations comparable to serum with evidence 

of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses 

in resected ADT. The results demonstrate the value of window of opportunity 

trials in the investigation of novel cancer therapeutics. 


11:30 AM-12:30 PM 

Predictors of survival after resections of synchronous lung cancers located 

in mutiple lobes: A multi-institutional pooled analysis. Presenting Author: 

Tawee Tanvetyanon, H. Lee Moffitt Cancer Center & Research Institute, 

Tampa, FL 

Background: Surgical resection is a treatment option for patients with 

multiple primary lung cancers. However, for synchronous disease, it is 

often difficult to differentiate this condition from metastatic disease, 

especially when cancers are distributed in multiple lobes or in both lungs. 

Some people believe that surgery should be avoided when patients have 

bilateral cancers or when all cancers have the same histology. To date, 

however, available evidences are limited by small sample size. Methods: 

Studies (published 2008-2011) of curative resection for patients with 

synchronous (� 2-year interval) multiple lung cancers located in � 2 lobes, 

but without radiographic evidence of distant metastasis, were identified 

from literature. Corresponding authors were contacted and individual 

patient data were obtained. Patients with multiple cancers, but localized 

only to one lobe, were not included. Databases were pooled and multivariable 

Cox Proportional Hazard models were fit to adjust for confounders. 

Results: There were 467 patients included from 6 studies. Median overall 

survival was 52.0 months (95% CI: 45.6-63.7). Postoperative (30-day) 

mortality rate was 1.9%. In a multivariable model, study site or having 

pneumonectomy did not independently impact on survival. However, age, 

gender, nodal stage, tumor location, and histological similarity were 

independent predictors of survival. Advanced age increased mortality 

(p�0.012). Male sex increased mortality compared with female: HR 1.64 

(95% CI: 1.23-2.19, p�0.0008). N2 or N1 increased mortality over N0: 

HR 1.85 (95% CI 1.29-2.66, p�0.0008) and 1.97 (1.43-2.73, 

p�0.0001), respectively. Unilateral location increased mortality over 

bilateral location: HR 1.62 (95% CI 1.23-2.13, p�0.0002). Different 

histology increased mortality over similar histology: HR 1.45 (95% CI 

1.11-1.90, p�0.0069). Conclusions: In this largest multi-institutional 

database of resected multiple lung cancers of multiple lobes to date, we 

found no evidence of inferior survival among patients having bilateral 

cancers or having all cancers with the same histology. In fact, the survival 

among such patients appears superior to their counterparts. 


11:30 AM-12:30 PM 

Use of a proliferation-based mRNA signature to predict outcome in 

early-stage non-small cell lung adenocarcinoma. Presenting Author: Carmen 

Behrens, University of Texas M. D. Anderson Cancer Center, Houston, 

TX 

Background: Adjuvant treatment of patients with early-stage lung adenocarcinoma 

is based on post-surgical pathological staging and patient performance 

status. Disparate outcomes within each staging group suggest that 

additional prognostic markers could improve our understanding of riskbenefit 

and potentially lead to better treatment decisions. A proliferationbased, 

mRNA expression profile was applied to public microarray data of 

surgically treated lung adenocarcinomas and a cohort of FFPE samples to 

test its potential prognostic utility. Methods: Public expression data 

(Director’s Consortium, DC) were derived from Affymetrix HG-U133A 

arrays. Clinical FFPE samples were assayed by quantitative PCR. A cell 

cycle progression (CCP) score was calculated from the expression average 

of 31 cell cycle genes normalized by 15 housekeeper genes. The prognostic 

value of the CCP score to predict stage I and II patient outcomes was 

evaluated by Cox proportional hazards analysis with disease-related death 

as the primary outcome measure. Results: In 256 DC cases, the CCP score 

was a significant predictor of death in univariate (p�0.0001) and multivariate 

analysis (p�0.001, HR 1.57, 95%CI 1.20-2.05) using age, stage, 

gender, smoking status and treatment as covariates. Similarly, in a second 

data set (GSE31210, n�204) the CCP score was highly associated with 

death (univariate, p�0.001; multivariate analysis, p�0.003, HR 1.81, 

95% CI 1.24-2.66). Using quantitative PCR, the signature was applied to 

381 FFPE samples with a median follow-up of 5 years collected at the MD 

Anderson Cancer Center and the European Institute for Oncology. In the 

presence of clinical covariates (as above and tumor size and pleural 

invasion), the CCP score remained the most significant predictor of death in 

univariate (p�0.0003) and multivariate analysis (p�0.007, HR 1.50, 

95% CI 1.11-2.02). Conclusions: A 46 gene mRNA signature is a 

significant predictor of disease-related death in early-stage lung adenocarcinoma, 

providing independent prognostic value in the presence of clinical 

variables. This molecular predictor of cancer survival will be studied in 

additional cohorts for its ability to impact clinical treatment decisions. 


11:30 AM-12:30 PM 

Prognostic impact of the number of examined lymph nodes (LNs) in 

resected node negative (pNo) non-small cell lung cancer (NSCLC). Presenting 

Author: Obiageli Uchenna Ogbata, University of Tennessee Health 

Science Center, Memphis, TN 

Background: In the US, 29% of patients undergo curative-intent surgery for 

NSCLC. Absence of LN metastasis and the extent of LN examination 

influence survival. 44% of patients with pathological node negative (pN0) 

disease die within 5 years. There is no consensus on the optimal number of 

LNs to be examined to determine pN0 stage. We hypothesized that patients 

with few examined nodes may have missed nodal metastasis and increasing 

the number of LNs examined would improve survival. Methods: Retrospective 

SEER database analysis of NSCLC resections from 1998 to 2002, with 

survival updated to 2008. Patients with first primary, pN0 NSCLC, with one 

or more LNs examined, met our study criteria. Cox regression and 

competing risk models were used for survival analysis. A p value �0.05 was 

considered statistically significant. Results: 8,137 patients met inclusion 

criteria and were evaluated. A median of 6 LNs were examined in this 

cohort. Patients who underwent pneumonectomy and lobectomy had more 

LNs examined than those who had sub-lobar resections. Higher number of 

LNs examined was associated with better overall survival (OS) and lung 

cancer specific survival (LCSS), at a plateau of 8 LNs for both outcomes 

(Table). Having mediastinal LNs examined also resulted in increased OS 

and LCSS (p�0.05). Conclusions: The pathologic assessment of LNs in 

surgical specimens is often suboptimal. Examining more LNs may have 

increased the likelihood of correct staging. Lower numbers of LNs examined 

probably result in understaging. Examining 8 or more total LNs and 

mediastinal LNs examined improved both OS and LCSS. 

#ofLN 

examined 

Hazard 

ratio 

for OS 

P value 

for OS 

95% CI 

for OS 

Hazard 

ratio 

for LCSS 

P value 

for LCSS 

457s 

95% CI 

for LCSS 

2 0.97 0.652 0.85 – 1.11 0.88 0.138 0.74 – 1.04 

3 0.93 0.262 0.81 – 1.06 0.87 0.101 0.74 – 1.02 

4 0.94 0.342 0.82 – 1.07 0.82 0.026 0.69 – 0.98 

5 0.83 0.008 0.72 – 0.95 0.78 0.008 0.66 – 0.94 

6 0.82 0.008 0.71 – 0.95 0.77 0.004 0.64 – 0.92 

7 0.86 0.052 0.74 – 1.00 0.76 0.005 0.62 – 0.92 

8 0.78 0.003 0.66 – 0.92 0.71 0.002 0.58 – 0.88 

9 0.85 0.052 0.73 – 1.00 0.79 0.026 0.64 – 0.97 

10 0.81 0.022 0.68 – 0.86 0.75 0.016 0.60 – 0.95 




11:30 AM-12:30 PM 

The effect of comorbidity on stage-specific survival in resected non-small 

cell lung cancer patients. Presenting Author: MARK Krasnik, Rigshospitalet, 

Copenhagen, Denmark 

Background: TNM classification has been the traditional cornerstone of 

decision-making in treatment choices of lung cancer. In addition to TNM 

stage and lung function, there is no other objective information to support 

this decision. Severe comorbidity affects overall survival, and may be an 

independent prognostic factor. In this study we quantified the effect of 

comorbidity on stage-specific survival in resected non-small cell lung 

cancer (NSCLC) patients in a large population-based setting. Methods: 

Among 3,152 NSCLC patients from the Danish Lung Cancer Registry who 

underwent surgical resection between 1 January 2005 and 31 December 

2010, mortality hazard ratios were calculated during three consecutive 

time periods following surgery (0-1 month, 1 month - 1 year and �1 year) 

according to Charlson comorbidity score (CCS 0, 1-2, 3�), ECOG performance 

status, lung function, age, sex, pathological T and N stage according 

to the revised 7th edition TNM lung cancer staging system, using Cox 

proportional hazard modelling. The Kaplan-Meier method was used to 

describe stage-specific survival according to the Charlson comorbidity 

score. Results: Increasing severity of comorbidity was independently 

associated with significantly higher death rates throughout the three 

periods of follow-up [HR1.18 for CCS 1-2 and 2.06 for CCS 3� in 0-1 

month, 1.13 for CCS 1-2 and 1.57 for CCS 3� during 1 month - 1 year and 

1.14 for CCS 1-2 and 1.84 for CCS 3� after 1 year]. Stage-specific 

five-year survival in patients with severe comorbidity (CCS 3�) was 

significantly lower than in patients without comorbid disease [e.g., 38% 

(95% CI 23-53%) for pT1 and CCS 3� vs. 69% (62-75%) for pT1 and CCS 

0]. Conclusions: This study shows that severe comorbidity affects survival of 

NSCLC patients undergoing surgical resection by as much as a single stage 

increment. As the survival of NSCLC patients after different treatment 

regiments is mainly based on the TNM classification, further research is 

necessary to fully identify which patients are most likely to benefit from 

surgery, but also to provide a basis for developing a better prediction 

instrument for the survival after combination treatment involving radiotherapy 

and chemotherapy. 


11:30 AM-12:30 PM 

Randomized phase III study comparing etoposide and cisplatin (EP) with 

irinotecan and cisplatin (IP) following EP plus concurrent accelerated 

hyperfractionated thoracic radiotherapy (EP/AHTRT) for the treatment of 

limited-stage small-cell lung cancer (LD-SCLC): JCOG0202. Presenting 

Author: Kaoru Kubota, National Cancer Center Hospital East, Kashiwa, 

Japan 

Background: Four cycles of EP plus AHTRT is the standard treatment for 

LD-SCLC. IP demonstrated statistically significant overall survival (OS) 

improvement compared to EP for extensive-stage SCLC (JCOG9511; Noda, 

et al.NEJM, 2002). EP plus AHTRT followed by 3 cycles of IP is feasible 

with acceptable toxicities for LD-SCLC (Kubota, et al. CCR,2005). Methods: 

Eligibility criteria included patients with previously untreated LD-SCLC 

with measurable lesion, ECOG PS of 0-1, age: 20��, ��70 years old. 

Eligible patients received one cycle of EP (etoposide 100 mg/m2 on days 

1-3 and cisplatin 80mg/m2 on day 1) plus AHTRT (1.5 Gy b.i.d. total 45 

Gy/3 weeks). Patients who achieved CR, good PR, PR or SD with induction 

EP/AHTRT were randomized to receive either 3 cycles of consolidation EP 

or IP (irinotecan 60 mg/m 2 and cisplatin 60 mg/m2 on days 1, 8, 15). 

Patients with CR or good PR after consolidation chemotherapy received 

prophylactic cranial irradiation. The primary endpoint is OS after the 

randomization. The planned sample size for randomization is 250 with a 

one-sided alpha of 2.5% and at least 70% power to detect a difference 

between gruops, 30% in EP versus 42.5% in IP group in 3-year survival. 

Results: From Sep 2002 to Sep 2006, 281 patients from 36 institutions 

were registered. After the induction EP/AHTRT, 258 patients were randomized 

to consolidation EP (n�129) or IP (n�129). Patient demographics 

were well balanced between the two groups. At the final analysis, the 

superiority of IP in OS was not demonstrated (hazard ratio of IP to EP, 

1.085 [95%CI: 0.80-1.46]; one sided p�0.70, stratifield log-rank test). 

Grade 3/4 neutropenia (95%/78%), anemia (35%/39%), thrombocytopenia 

(21%/5%), neutropenic fever (17%/14%), diarrhea (2%/10%) were 

observed in EP and IP groups, respectively. Conclusions: EP plus AHTRT 

followed by 3 cycles of IP failed to demonstrate survival advantage over 4 

cycles of EP plus AHTRT which still is the standard treatment for LD-SCLC. 

EP IP 

Median OS 3.2 years 2.8 years 

3-year OS 53% 47% 

5-year OS 36% 34% 

Median PFS 1.1 years 1.0 year 


11:30 AM-12:30 PM 

Randomized phase II trial comparing two schedules of thoracic radiotherapy 

(TRT) in limited disease small-cell lung cancer (LD SCLC). 

Presenting Author: Bjørn Henning Grønberg, Department of Cancer Research 

and Molecular Medicine, Norwegian University of Science and 

Technology and The Cancer Clinic, St. Olavs Hospital-Trondheim University 

Hospital, Trondheim, Norway 

Background: Concurrent chemotherapy and TRT is standard therapy for 

SCLC if all lesions can be included in a radiotherapy field (LD). Several 

schedules of TRT are used. One study showed that two fractions a day 

improved local control and overall survival (OS), but this schedule has not 

been compared to a commonly used 3 wks schedule. Methods: Eligible pts 

had LD SCLC and PS 0-2. Pleural fluid was accepted if negative cytology. 

Pts received 4 cycles of PE (cisplatin 75 mg/m2 IV day 1 and etoposide 100 

mg/m2 IV day 1-3 q 3 wks) and were randomly assigned to 3 wks of 3D 

conformal TRT [A] 42 Gy (2.8 Gy x 1/day) or [B] 45 Gy (1.5 Gy x 2/day). TRT 

started 3-4 wks after the first PE. All responders received prophylactic 

cranial irradiation (PCI) 2 Gy x 15 � 6 wks after last PE. Pts reported health 

related quality of life (HRQoL) on EORTC QLQ C30 � LC13. Primary 

endpoint: 1-year local failure. Secondary: OS, toxicity and HRQoL (dysphagia 

and dyspnea; a difference � 10 points was considered significant). 75 

pts were required in each arm to show a 30% improvement of local disease 

control with ��.05 and ��.8. Results: 159 eligible pts were enrolled at 18 

sites in Norway May 05 – Jan 11 (A: 85, B: 74). Median age 60 (40-85); 

52% men, 84 % PS 0-1, 11% pleural fluid. Mean no. of PE-cycles was 3.8, 

97% completed TRT, 82 % PCI (no difference between arms). Response 

rates were similar (A: 92%, B: 94%; p�.8), but more pts on Arm B had CR 

(A: 13%, B: 35%; p�.01). There was no difference in local failure as first 

site of progression at 1 year (A: 17%, B: 12%; p�.4) or 1-year PFS (A: 

44%, B: 50% ; p�.4). There was similar grade 3-4 esofagitis (A: 33%, B: 

37 %; p�.7) and pneumonitis (A: 6 %, B: 7 %; p�.9). 2 pts (1 on each 

arm) died from pneumonitis. Pts in Arm B reported more dysphagia (A: 64 

points, B: 73 points), but not more dyspnea (A: 29 points, B: 28 points). 

1-year OS was similar (A: 77%, B: 76%; p�.9). Currently, 2-year survival 

among those followed � 2 years (n�130) favors Arm B (A: 40%, B: 55%; 

p�.09) and so far (all pts followed � 1-year; 103 events) median OS favors 

Arm B (A: 18.7 mos, B: 26.6 mos; p�.34). Conclusions: Twice daily TRT 

resulted in more CRs, slightly more dysphagia, similar 1-year local control 

and 1-year PFS. There are indications of improved 2-year and median OS in 

this arm. 


11:30 AM-12:30 PM 

Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 

in patients with advanced malignant pleural mesothelioma (MPM). Presenting 

Author: Lee M. Krug, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: CBP501, a synthetic duodecapeptide, enhances the cytotoxicity 

of cisplatin in cell lines and xenografts, including NCI-H226 human 

mesothelioma. CBP501 increases cisplatin influx into tumor cells through 

an interaction with calmodulin, and inhibits cell cycle progression by 

abrogating DNA repair at the G2 checkpoint. Phase I clinical trials 

combining CBP501 with cisplatin alone or with pemetrexed showed 

acceptable safety profiles and suggested activity. The most common 

toxicity of CBP501 is infusion-related urticaria, which is easily managed 

with diphenhydramine. Methods: Chemotherapy-naive patients with unresectable 

MPM were stratified by histology (epithelioid vs other) and 

performance status (PS 0-1 vs 2) and randomized 2:1 to Arm A: 

pemetrexed/cisplatin plus CBP501 25 mg/m2 IV (42 pts planned), or Arm 

B: pemetrexed/cisplatin alone at standard doses (21 pts planned). Patients 

continued on treatment until progression or intolerance; no maintenance 

therapy was delivered. The primary endpoint is progression free survival 

(PFS) in Arm A; if � 23 of the 42 patients remain free of progression more 

than 4 months, the combination will be deemed worthy of further study. In 

addition to standard CT imaging to assess response and PFS, PET scans, 

pulmonary function tests, and mesothelin levels were performed. Results: 

Enrollment was completed in October 2011. 65 pts from 14 institutions 

were randomized, and 63 were treated. Patient characteristics in the two 

arms were similar and as follows: median age 65, 82% male, 71% 

epithelioid histology, 8% PS2. Grade 3/4 treatment-related toxicities were 

uncommon, no different than expected from standard chemotherapy, and 

comparable in the two arms. 70% of patients treated with CBP501 had 

infusion reactions, all grade 1-2. The best overall response rate in evaluable 

patients (modified RECIST, investigator assessed) was 12/37 (32%) (95% 

CI 18-50) in Arm A, and 3/22 (14%) (95% CI 3-35) in Arm B. The median 

number of chemotherapy cycles was 5.5 in Arm A, 5 in Arm B. Conclusions: 

Data on the primary endpoint of PFS in Arm A are maturing and will be 

presented at the meeting. 




11:30 AM-12:30 PM 

Amatuximab, a chimeric monoclonal antibody to mesothelin, in combination 

with pemetrexed and cisplatin in patients with unresectable pleural 

mesothelioma: Results of a multicenter phase II clinical trial. Presenting 

Author: Raffit Hassan, National Cancer Institute, Bethesda, MD 

Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody 

to mesothelin, a cell surface glycoprotein highly expressed in many cancers 

including malignant mesothelioma (MM). Based on safety of amatuximab 

in phase I clinical trial and pre-clinical studies showing synergy in 

combination with chemotherapy, a single arm phase II study of amatuximab 

plus pemetrexed (P) and cisplatin (C) was initiated in pts. with MM. 

Methods: Eligibility criteria included pts. with unresectable epithelial or 

biphasic pleural MM, no prior chemotherapy and KPS � 70%. Pts. 

received amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m2 andC75 

mg/m2 (PC) given on day 1, of each 21 day cycle for 6 cycles. Pts. with 

objective response or stable disease received amatuximab monotherapy 

until disease progression. Primary endpoint was progression-free survival 

(PFS) at 6 months. Secondary endpoints were overall survival (OS), 

objective response rate and safety of amatuximab with PC. Results: From 

2/2009 to 10/2010, 89 pts. were enrolled at 26 sites. Pt. characteristics: 

median age 67 yrs. (range 46-80), 78% male, 70% with KPS �90%, 89% 

epithelial MM, 11% biphasic MM and 88% had stage III/IV disease. 

Median number of PC plus amatuximab cycles was 5 (range 1-6) and 56 

(63%) pts. received single agent amatuximab. In addition to the expected 

toxicity from PC, hypersensitivity reactions (12.4%; Grade 3/4�4.5%) 

from amatuximab were noted. By independent radiological review 30 

(39%) pts. had partial response and 39 (51%) had stable disease. PFS at 6 

months was 52% (95% CI: 39.5-63.5) with a median PFS of 6.1 months 

(95% CI: 5.4-6.5). As of 1/10/12 the median OS was 14.5 months (95% 

CI: 12.4-18.5) with 31 pts. still alive and 7 pts. receiving maintenance 

amatuximab. Conclusions: Amatuximab in combination with PC was generally 

well-tolerated in this study with 90% of pts. having an objective tumor 

response or stable disease by independent radiological review. Although 

PFS is not significantly different from historical results of PC alone, the 

median OS is 14.5 months with 35% of pts. still alive. Updated OS and 

biomarker data will be presented at the meeting. 


11:30 AM-12:30 PM 

Next-generation sequencing of thymic malignancies. Presenting Author: 

Milan Radovich, Indiana University School of Medicine, Indianapolis, IN 

Background: Thymic malignancies are rare with ~500 cases in the US per 

year. Apart from standard chemotherapy, treatment options are limited. 

Further, the challenge of histologic subtyping of these tumors along with an 

inadequate understanding of the transcriptional biology is a hindrance to 

the development of targeted therapies. Methods: Thymic malignancies and 

normal tissues were obtained from the Indiana University Simon Cancer 

Center. The WHO subtypes of our samples include: (4) type A, (2) A/B, (1) 

B2, (5) B3, (1) C, and (3) normal tissues. RNA was sequenced on a Life 

Technologies SOLiD sequencer. For gene expression, reads were mapped to 

the genome using BioScope and outputs imported into Partek GS. In 

Partek, statistical comparison of gene expression as well as PCA & 

clustering analyses were performed. Results: Unsupervised hierarchical 

clustering of gene expression values revealed 100% concordance between 

gene expression clusters and WHO subtype. A subsequent unsupervised 

clustering of 705 pre-miRNAs also showed substantial concordance 

between clusters and subtype. By analyzing the dendrograms, A&A/B 

tumors were significantly different from B type tumors, as well as C and 

normal. A substantial differentiator was a large cluster of overexpression in 

A&A/B tumors that was nearly absent in the others on chr19q13.42 

corresponding to the miR-515 cluster (43 miRNAs). When comparing A & 

A/B tumors vs. B type tumors, 1334 genes are differentially expressed (258 

downregulated) (FDR�5%). 95/258 genes are predicted to be downregulated 

by the miR-515 cluster including several transcription factors and 

tumor suppressors. When looking at mutations, we detected no recurrent 

gene fusions, though we are detecting several point mutations and small 

insertion deletions. These are being followed up by exome sequencing. 

Conclusions: Analyses reveal that RNA-seq can be used to accurately 

subtype Thymic Malignancies and the development of an expression based 

diagnostic is feasible. Further, these data support that the main differentiator 

of thymomas may lie in the expression of a single miRNA cluster. In 

addition, several mutations in key pathways are implicated. Ongoing 

analyses include: alternative splicing, noncoding RNAs, viral analysis and 

exome sequencing. 

459s 


11:30 AM-12:30 PM 

Comparison of prognostic impact between metabolic and radiologic response 

after induction chemotherapy for resectable malignant pleural 

mesothelioma: A multicenter study. Presenting Author: Yasuhiro Tsutani, 

Hiroshima University, Hiroshima, Japan 

Background: Induction chemotherapy followed by extrapleural pneumonectomy 

(EPP) for resectable malignant pleural mesothelioma (MPM) is 

controversial. To select optimal candidates for EPP, we evaluates the 

usefulness of metabolic response on fluorodeoxyglucose-positron emission 

tomography (FDG-PET) compared with radiologic response on highresolution 

computed tomography (HRCT) after induction chemotherapy to 

predict prognosis for patients with resectable MPM who underwent EPP in 

the setting of multicenter study. Methods: We performed HRCT and 

FDG-PET before and after induction platinum-based chemotherapy on 50 

patients with clinical T1-3 N0-2 M0 MPM who underwent EPP � 

postoperative hemithoracic radiation. A decrease of more than 30% in 

tumor maximum standardized uptake value (SUVmax) was defined as a 

metabolic responder. Radiologic response using modified RECIST or 

metabolic response and surgical results were analyzed. Results: In all 

cohort patients, median overall survival (OS) from diagnosis was 20.5 

month (95% confidence interval [CI], 15.0-26.0 month). Fourteen patients 

were classified as metabolic responders (28%) and 36 as nonresponders 

(72%). Metabolic responders significantly correlated to OS with 

median OS for metabolic responders of not reached (3-year OS of 60.0%) 

versus 18.7 month (95% CI, 13.3-24.2 month, 3-year OS of 26.5%) for 

non-responders (P � .025). No correlation was observed between OS and 

radiologic response with median OS for radiologic responders of 25.7 

month (n � 20, 95% CI, 14.5-37.0 month, 3-year OS of 35.8%) versus 

17.7 month (n � 30, 95% CI, 12.8-22.6 month, 3-year OS of 35.1%) for 

non-responder (p � .216). Based on the multivariate Cox analyses, 

decreased SUVmax (%) (p � .010) was a significantly independent factor 

for OS as well as epithelioid subtype (p � .044). Conclusions: Metabolic 

response on FDG-PET has higher predictive value of prognosis than 

radiologic response on HRCT after induction chemotherapy for patients 

with resectable MPM. Patients with metabolic responder and/or epithelioid 

subtype can be good candidates for EPP after induction chemotherapy. 


11:30 AM-12:30 PM 

Phase II study of cixutumumab (IMC-A12) in thymic malignancies. 

Presenting Author: Arun Rajan, National Cancer Institute, Bethesda, MD 

Background: The IGF-1 receptor (IGF-IR) is expressed in thymoma (T) and 

thymic carcinoma (TC). Prolonged SD has been seen with anti-IGF-IR 

therapy in thymic tumors in phase I trials. Cixutumumab (C) is a fully 

human IgG1 monoclonal antibody (ab) that targets IGF-IR. Methods: 

Patients (pts) with recurrent T or TC, PS 0-2, measurable disease, and 

normal organ function received C at 20 mg/kg IV q3wks until progression or 

intolerable toxicity. Primary endpoint was response rate. Correlative studies 

included immune cell subset (central memory, effector memory, naïve and 

regulatory T cells), circulating endothelial progenitor (CEP) cell, serum 

IGF-1 and IGF-IR in PBMCs, anticytokine ab, and tumor mutational 

analysis. Results: Forty-five pts enrolled from two centers (20 female, 

T�33, med age 52 yrs, range, 26-86). Median number of prior systemic 

treatments: 3 (range, 1-11). Median number of cycles of C administered: 6 

(range, 1-41). In 30 evaluable T pts there were 4 (13%) PR, 23 (77%) SD, 

and 3 (10%) PD. Corresponding numbers in 12 TC pts were 0, 5 (42%) and 

7 (58%). Median PFS for T and TC was 40 and 9 wks respectively. 

C-related grade 3/4 AEs were hyperglycemia (8%), hyperuricemia, weight 

loss, lipase elevation, chest wall pain (5% each) and AST elevation (3%). 

Two pts died while on study: one due to respiratory insufficiency related to T 

after 5 cycles and one due to worsening myasthenia and an acute coronary 

event after 13 cycles. In 8 of 33 T pts autoimmune (AI) symptoms 

developed (4 new-onset) due to immune thrombocytopenic purpura, 

myositis, myocarditis, colitis, PRCA and food allergy. In the first 13 pts a 

trend towards increased numbers of central and effector memory T cells 

and a decrease in naïve T cells and CEPs was seen. High-titer anticytokine 

abs, including anti-IFNa, anti-IL-12, and anti-IL-17A, were found in 13/27 

pts tested. No EGFR, KRAS or BRAF mutation, HER2 amplification or ALK 

translocations were detected in 11 tumors analyzed. Conclusions: C 

monotherapy is well tolerated and active in T. Accrual will continue until 37 

T pts are enrolled. Activity in TC is unworthy of further investigation. CEP 

and immune cell subset analysis suggests therapy may impact angiogenesis 

and immune response. Development of AI symptoms during treatment 

needs further evaluation. 




Epidermal growth factor receptor mutation status and adjuvant chemotherapy 

in resected advanced non-small cell lung cancer. Presenting 

Author: Si-Yu Wang, Cancer Center, Sun Yat-sen University, Guangzhou, 

China 

Background: Mutations in the epidermal growth factor receptor (EGFR) are 

associated with response to chemotherapy in patients with advance 

NSCLC. The purpose of this study was to assess the association of 

mutations in the EGFR tyrosine kinase domain and the efficacy of adjuvant 

chemotherapy in patients with fully resected IIIA-N2 NSCLC tumors. 

Methods: Tumor samples (n �150) from patients in our prior trial with 

IIIA-N2 NSCLC who either had or had not received paclitaxel/vinorelbine 

plus carboplatin chemotherapy following removal of the tumor were 

analyzed for EGFR mutations in exons 19 and 21. The association of the 

presence of EGFR mutations and survival following treatment was assessed. 

Results: Mutations were identified in 33 (22%) patients (n�13 in 

the no chemotherapy [observation] arm and n�20 in the chemotherapy 

arm). Fourteen patients (9.3%) had deletion mutations in exon 19, and 19 

patients (12.7%) had a substitution mutation in exon 21. Compared with 

patients wild-type for EGFR, patients with EGFR mutations had numerical 

but not statistically significant improved disease-free survival (35 months 

[95% CI, 14.6-55.4] versus 23 months [95% CI, 17.3-28.7], respectively, 

P�0.339) and overall survival (36 months [95% CI, 27.9 to 44.1] versus 

26 months [95% CI, 20.1 to 31.9], respectively p�0.271) regardless of 

treatment. Patients with wild-type EGFR had greater overall survival with 

chemotherapy compared to no adjuvant therapy (HR�1.920; 95%CI, 

1.245-2.963; p�0.003). In contrast, EGFR mutant patients in the 

observation group compared to the chemotherapy group had longer median 

disease-free survival (35 months [95% CI, 20.9 to 49.1] versus 27 months 

[95% CI, 5.3 to 48.7], respectively, p�0.671) and overall survival (33 

months [95% CI, 24.2 to 41.8] versus 40 months [95% CI, 31.8 to 48.2] 

respectively, p �0.360). Conclusions: In this study, the status of mutations 

in exons 19 and 21 of EGFR was associated with different clinical 

outcomes in patients with resected IIIA-N2 NSCLC tumors either treated 

with or without adjuvant chemotherapy. These findings suggest that a 

patient’s treatment should be customized to their EGFR mutational status. 


Intrapleural combination bevacizumab with cisplatin therapy for non-small 

cell lung cancer caused by non-small cell lung cancer. Presenting Author: 

Nan Du, Department of Oncology, First Affiliated Hospital, Chinese PLA 

General Hospital, Beijing, China 

Background: Malignant pleural effusion (MPE) is a common complicate of 

advanced non-small cell lung cancer (NSCLC). Bevacizumab, a humanized 

monoclonal antibody to VEGF, has been shown to be efficient in suppressing 

the pleural fluid accumulation; however, it has not been reported that 

whether bevacizumab can be used intrapleurally for the treatment of MPE. 

The present study is to evaluate the efficacy and safety of combined 

intrapleural therapy with bevacizumab and cisplatin, an antineoplastic 

agent, in controlling MPE. Methods: A total of 65 NSCLC patients with MPE 

were randomly assigned to one of two groups: intrapleural bevacizumab 

(300mg) with cisplatin (60mg) therapy (n�35) and intrapleural cisplatin 

(60mg) therapy (n�30). Results: The curative efficacy following combination 

or cisplatin mono therapy were 85.71% and 56.67%, respectively, 

being combination therapy group (p�0.05) is significantly higher. In 

addition, the combination therapy showed a higher efficacy in the patients 

with VEGF positive (p�0.01). Among the 25 cases that showed initial 

resistance to chemotherapy, 22 responded well to the combination 

therapy. Furthermore, combined bevacizumab with cisplatin therapy significantly 

reduced the VEGF expression, as shown by quantitative RT-PCR. All 

procedures were well tolerated by the patients, with wwwno severe side 

effect detected. Conclusions: Intrapleural combined bevacizumab with 

cisplatin therapy was effective and safe in managing MPE caused by 

NSCLC; the expression level of VEGF in MPE can be a prognostic marker for 

bevacizumab therapy. 


Adjuvant carboplatin, docetaxel, bevacizumab, and erlotinib versus chemotherapy 

alone in patients with resected non-small cell lung cancer: A 

randomized phase II study of the Sarah Cannon Research Institute (SCRI). 

Presenting Author: David Michael Waterhouse, Oncology Hematology 

Care/SCRI, Cincinnati, OH 

Background: Adjuvant chemotherapy improves overall survival (OS) in 

patients (pts) with resected non small cell lung cancer (NSCLC). Bevacizumab 

and erlotinib improve survival in pts with advanced unresectable 

NSCLC. This randomized phase II multicenter pilot study examined the 

safety and efficacy of chemotherapy and bevacizumab followed by bevacizumab 

and erlotinib vs. chemotherapy alone in pts with resected NSCLC. 

Methods: Eligible pts had completely resected (R0) stage IB, II, or IIIA 

NSCLC (TNM 6th Ed.), any NSCLC histology, and an ECOG PS 0-1. Pts were 

excluded for preoperatively confirmed N2 disease; N2 disease found at 

surgery was allowed. Pts were randomized 1:1 to carboplatin AUC�5, 

docetaxel 60 mg/m2 , and bevacizumab 15 mg/kg IV d1 q 21 days x 4, 

followed by maintenance bevacizumab 15 mg/kg d1 and erlotinib 150 mg 

PO daily x 8 cycles (Arm A) or carboplatin AUC�6 and docetaxel 75 mg/m2 IV d1 q 21 days x 4 (Arm B). The primary endpoint was 1-year disease-free 

survival (DFS); safety, 2-year DFS, and OS were secondary endpoints. 

Results: 106 pts were enrolled from 2/2008 to trial closure 1/2012 (A�54; 

B�52). Baseline features were balanced: age 63 yrs (42–87); 54% male; 

IB (46%), IIA (8%), IIB (27%), IIIA (18%); adenocarcinoma (61%), 

squamous (31%). Arm A received a median of 7 cycles (1-12); Arm B 4 

cycles (1-4). 1- and 2-year DFS by stage are shown in the table. The 1-year 

DFS for all stages were 78% (A) and 88% (B) (p�.66). The 3-year OS for all 

stages were 81% (A) and 63% (B). Neutropenia was the most common 

grade 3/4 hematologic toxicity (A 18%; B 29%). Severe non-hematologic 

toxicity was rare: fatigue (A 6%), diarrhea (B 6%). Bronchopleural fistulae 

occurred in 2 pts (1 per arm), and grade 3 gastrointestinal hemorrhage was 

seen in 1 pt (A). Conclusions: This pilot study demonstrated that bevacizumab 

and erlotinib could be safely added to platinum-doublet chemotherapy 

in the adjuvant setting in all histologies. Larger randomized studies 

will best define the roles of these agents in pts with resectable NSCLC. 

IB II IIIA 

A B A B A B 

N�24 N�25 N�19 N�19 N�11 N�8 

1-year DFS 93% 91% 83% 100% 100% 83% 

2-year DFS 84% 91% 71% 83% 75% 83% 


A prospective phase II study of induction erlotinib therapy in stage IIIA-N2 

non-small cell lung cancer. Presenting Author: Wenzhao Zhong, Guangdong 

Lung Cancer Institute, Guangdong General Hospital and Guangdong 

Academy of Medical Sciences, Guangzhou, China 

Background: Stage IIIA NSCLC represents a heterogeneous group of 

patients with ipsilateral mediastinal (N2) lymph nodes involvement. The 

epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) 

provide dramatic responses in patients with non-small cell lung cancer 

(NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate 

the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: 

Patients with resectable NSCLC of stage IIIA-N2 were assigned to either 

induction erlotinib arm or induction gemcitabine/carboplatin(GC) arm 

based on the EGFR mutations analysis (NCT00600587) . Study Design: 

Phase II, factorial Assignment, Safety/Efficacy; Primary outcome measures: 

Response to Induction Therapy; Estimated enrollment: 5 cases with 

partial response in the erlotinib arm. Results: From January 2008 till June 

2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or 

PET/CT have been enrolled. Twelve cases with EGFR mutation were 

assigned to the erlotinib arm (30-42 days), while 12 cases harboring 

wild-type EGFR received the GC regimen (3 cycles). The primary end point 

of the response rates were 58% (7/12) for the erlotinib arm and 33% (4/12) 

for the GC arm (P�0.49). The pathological N2 complete response rates 

were 17% for the erlotinib arm and 25% for the GC arm (P�0.64). In the 

erlotinib arm, the most common failure model after initial therapy was 

distant metastases (9/10), especially brain metastases (3/9). The median 

progression free survival time was 7 months for the erlotinib arm and 9 

months for the GC arm (P�0.27). The median overall survival was 27 

months for the erlotinib arm and 23 months for the GC arm (P�0.52). In 

addition, four cases in the erlotinib arm got partial response to the 2nd 

EGFR-TKI therapy after progression to erlotinib induction therapy and the 

following thoracotomy. Conclusions: Induction erlotinib therapy in IIIA-N2 

NSCLC with EGFR activating mutation is a promising strategy. Distance 

metastases were major failure model. A multicenter, randomized, phase II 

study evaluating efficacy and safety of erlotinib vs GC as neoadjuvant 

therapy for stage IIIA-N2 NSCLC patients with EGFR mutations 

(NCT01407822) is currently recruiting participants. 




Matched-pair comparison of outcome of patients with clinical stage I 

non-small cell lung cancer treated with resection or stereotactic radiosurgery. 

Presenting Author: Julia Shelkey, Penn State Hershey Medical 

Center, Hershey, PA 

Background: Stereotactic body radiotherapy (SBRT) is an alternative to 

surgery alone for certain patients with clinical stage I non-small cell lung 

cancer (NSCLC), but comparing their effectiveness is difficult because of 

differences in patient selection and staging. Methods: Two databases were 

combined which contained 132 patients treated by lobectomy (LR) and 48 

by sublobar resection (SLR) and 137 patients managed with SBRT after 

negative staging between 1999-2009. We compared rates of overall 

survival (OS), disease-free survival (DFS), and locoregional control (LRC) 

between patients treated with surgery and SBRT to each other and in 

relation to possible prognostic factors. We then performed a matched-pair 

analysis comparing surgery and SBRT results. Median follow-up for the 

entire study population was 25.8 months. Results: On univariate analysis, 

OS was significantly correlated with histology, the Charlson Comorbidity 

Index, tumor size, aspirin use, and use of SBRT; DFS was correlated only 

with histology; and no variable was significantly correlated with LRC. 

Multivariate analysis found improved OS in patients with adenocarcinoma 

and those undergoing surgical resection. The NSCLC “not otherwise 

specified” histology was associated with poorer DFS. Overall survival was 

significantly poorer for SBRT patients in the matched-pair analysis than for 

patients treated with surgery, but DFS and LRC were not significantly 

different between these groups. Conclusions: Our retrospective study has 

demonstrated similar LRC and DFS in patients treated with SBRT or 

surgery, but worse OS in the former group, when patients were matched for 

prognostic factors. Our investigation suggests that randomized trials are 

needed to eliminate selection bias in treatment assignment in order to 

accurately compare outcomes between these approaches. 


A phase II study of cisplatin (P), S-1 (S), and concurrent thoracic 

radiotherapy (TRT) for locally advanced non-small cell lung cancer (LA- 

NSCLC): Okayama Lung Cancer Study Group trial 0501. Presenting 

Author: Daizo Kishino, National Hospital Organization Yamaguchi-Ube 

Medical Center, Ube-shi, Yamaguchi, Japan 

Background: We previously reported an efficacy and safety of fractionated 

schedule ofP and docetaxel (D) (days 1, 8, 29, and 36, each) and 

concurrent TRT (DP-TRT) for LA-NSCLC (JCO 2010). Although the median 

survival time (MST: 26.3 months) was excellent, grade 3 or greater 

pneumonitis (10%) and esophagitis (14%) were observed and treatmentrelated 

death was 3%.Thus, further improvement in the safety as well as 

efficacy is strongly warranted. S, an oral fluoropyrimidine, is a new active 

agent possessing a radio-sensitizing effect. Additionally, combining S and 

P offered an active and safe regimen for metastatic NSCLC. The objective 

of this study was to assess the efficacy and safety of S � P with concurrent 

TRT for LA-NSCLC. Methods: Patients with stage IIIA/IIIB, aged �75 years 

and PS 0-1, and without any prior chemotherapy were eligible for this 

study. Patients were treated with P (40 mg/m² on day 1, 8, 29 and 36) and 

S (40 mg/m²/dose b.i.d. on days 1-14 and 29-42) and TRT (60 Gy/30 fr 

over 6 weeks starting on day 1). Primary endpoint was response rate (RR), 

and required sample size was 48 patients. Results: Between 2006 and 

2009, 48 patients were enrolled (37 men; median age, 66 years; PS 0/1, 

36/14; IIIA/IIIB, 23/25; sq/non-sq, 22/26). Partial response was observed 

in 37 patients (77%; 95% confidence interval: 63-88%). The response 

rate was higher in older patients (�65 yrs) than younger (�65 yrs) (89% vs. 

64%, p�0.041). At a median follow-up of 40 months, median progressionfree 

survival and MST were 9.3 months and 31.3 months, respectively. No 

difference in efficacy (response and survivals) was observed stratified by 

histology (sq vs. non-sq). Toxicities were generally mild, including G3/4 

neutropenia (44%), G3/4 thrombocytopenia (13%), G3 febrile neutropenia 

(8%) and G3 pneumonitis (4%). No one developed Gr3/4 esophagitis. No 

toxic deaths occurred. Conclusions: This chemoradiotherapy regimen yielded 

a favorable overall survival data. Also, it was well-tolerated in patients with 

LA-NSCLC as compared with concurrent DP-TRT therapy especially in term 

of TRT-related toxicities. A phase III trial of this regimen vs. DP-TRT is now 

planned. 

461s 


Amplification of fibroblast growth factor receptor type 1 gene (FGFR1) in 

samples from 101 NSCLC patients (pts) with squamous cell carcinoma 

(SCC) histology. Presenting Author: Alex Martinez Marti, Medical Oncology 

Department, Vall d’Hebron University Hospital, Barcelona, Spain 

Background: The FGFR1 gene is located in the chromosomal region 8p12 

and encodes a transmembrane receptor tyrosine kinase. Amplification of 

FGFR1 has been reported in lung cancer, predominantly in SCC (in up to ~ 

20%) and has been considered a potential target for treatment with 

anti-FGFR1 agents. Different methods and cutoff levels to determine 

FGFR1 amplification have been reported but as yet no consensus has been 

reached on standard method. The aim of this study is to assess FGFR1 

amplification determined by FISH analysis in a set of samples from 

101SCC pts and to explore their clinical features. Methods: Tumor samples 

from 101SCC pts diagnosed at our institution from August 2007 to August 

2011 were screened for FGFR1 amplification by FISH using the ZytoLight 

SPEC FGFR1/CEN8 probe. FGFR1 was considered FISH positive with a 

ratio � 2.2 and FISH FGFR1 was polysomic with 3 or more signals in 

�30% of tumor cells, any other result was considered as negative. For 

exploratory analyses FGFR1 amplification was considered positive if a 

median of 6 or more gene copies were identified and FISH were polysomic 

with more than 2 gene copies but less than 6. Results: Pts characteristics: 

median age 76 yrs (range 45-80), 91% male, 33% current smokers, 67% 

former smokers, stage: 8% IA/ 15% IB/ 11% IIA/ 11% IIB/ 24% IIIA, 12% 

IIIB/ 19% IV. With a median follow up of 48 months, the median overall 

survival was 18 months. FISH FGFR1 was positive (ratio � 2.2) in 7 (6.9%) 

pts: 6 were male, 4 former smokers. FISH FGFR1 was considered negative 

but polysomic (3 or more signals in �30% of tumor cells) in 43/94 (45%) 

pts. If we use for FISH positivity a cutoff of 6 or more copies only 3 patients 

were considered as positive for FGFR1 amplification (2 were also FISH 

positive by ratio�2.2). All those 5 patients considered FISH negative by 

gen copy number (but positive by ratio) were polysomic. Conclusions: In our 

experience FGFR1 amplification detected by FISH isrelatively uncommon 

in SCC, although a relevant proportion of FGFR1 FISH negative tumors had 

polysomy. Standarization of methods to determine FGFR1 amplification 

and the potential clinical significance of the presence of FGFR1 polysomy 

are needed. 


Predictors for locoregional recurrence for clinical stage III-N2 non-small 

cell lung cancer with nodal downstaging after induction chemotherapy and 

surgery. Presenting Author: Feiran Lou, Memorial Sloan-Kettering Cancer 


Background: Pathologic downstaging following induction chemotherapy in 

patients with stage III-N2 NSCLC is a well-known positive prognostic 

indicator. However, the predictive factors for locoregional recurrence (LRR) 

in these patients are largely unknown. Methods: Between 1998-2008, 153 

patients with clinically or pathologically-staged III-N2 NSCLC from two 

cancer centers in the United States were treated with induction chemotherapy 

and surgery. All patients had pathologic N0-1 disease, and no one 

received postoperative radiotherapy. LRR were defined as disease recurrence 

at the surgical site, lymph nodes (levels 1-14 including supraclavicular) 

or both. Overall survival (OS) was calculated using the Kaplan and 

Meier method and comparisons were made using the log-rank test. 

Univariate and multivariate Cox proportional hazards model were used to 

assess the association of LRR and risk factors. Results: The median follow 

up time for survivors was 39.3 months. Baseline pretreatment N2 nodal 

involvement was staged by either pathologic confirmation (18.2%) or 

PET/CT (81.8%). Overall, the 5 year LRR rate was 30.8% (n�38), with 

LRR being the first site of failure in 51% (22 of 43). The 5 year OS for 

patients with LRR compared to those without was 21% versus 60.1%, 

respectively (p�0.001). Using multivariate analysis, significant predictor 

for LRR was pN1 versus pN0 disease at time of surgery (p�0.001, HR 

3.43, 95% CI 1.80-6.56) and trended for squamous histology (p�0.072, 

HR 1.93, 95% CI 0.94-3.98). The 5-year LRR rate for N1 versus N0 

disease was 62% versus 20%, respectively. Neither single versus multistation 

N2 disease (p�0.291) nor initial staging by mediastinoscopy versus 

PET/CT (p�0.306) were predictors for LRR. We found that N1 status was 

also predictive for higher distant recurrence rate (p�0.021, HR 1.91, 95% 

CI 1.10-3.30) but only trended for poorer OS (p�0.123, HR 1.48, 95% CI 

0.90-2.44). Conclusions: LRR remains high in resected stage III-N2 

NSCLC patients after induction chemotherapy and nodal downstaging, 

particularly in patients with persistent N1 disease. Postoperative radiotherapy 

may be needed for these high-risk patients. 




Higher incidence of EGFR exon 19 deletion in younger (age 40 or younger) 

patients with adenocarcinoma of the lung. Presenting Author: Eri Sugiyama, 

Division of Thoracic Oncology, National Cancer Center Hospital East, 

Kashiwa, Chiba, Japan 

Background: The proportion of younger patients (� 40 years) with lung 

cancer is reported to be 2-5%. The most frequent histologic type of them is 

adenocarcinoma, however little is known about the pathological and 

molecular characteristics of younger patients with lung adenocarcinoma. 

Methods: Between July 1992 and April 2011, a total of 7443 patients were 

diagnosed as lung cancer in National Cancer Center Hospital East and 165 

patients of whom (2.2%) who were 40 years or younger were identified. 

Among them, 44 patients with adenocarcinoma who underwent surgical 

resection were selected for this study. In addition, 185 elderly patients with 

� 40 years who underwent surgical resection matching gender and 

smoking status were selected as a control group. Histological predominant 

growth pattern and any coexisting variant pattern, the status of EGFR 

mutations were compared between these two groups. Results: The median 

age in � 40 years patients was 37 years (range, 21 to 40 years) and that in 

elderly patients was 68 years (range, 42 to 83 years). Between these two 

groups, there were no significant differences in the distribution of histological 

predominant growth patterns (lepidic; 31.8% vs. 26.5%, papillary; 

34.1% vs. 37.3%, acinar; 9.1% vs. 16.2%, and solid; 25.0% vs. 20.0%, 

p�0.78) and the incidence of EGFR mutations (40.9% vs. 45.9%; 

p�0.55). However, signet-ring cell component were significantly found in 

the younger patients than elderly (11.4% vs. 0%; p�0.01). The incidence 

of EGFR exon 19 deletion was significantly higher in younger patients than 

elderly, in contrast, that of EGFR exon 21 L858R was significantly higher in 

elderly patients (exon 19 del; 31.7% vs. 18.9%, L858R; 4.6% vs. 25.4%, 

p�0.0091). Three of 17 adenocarcinomas (17.7%) with EGFR-wild type 

in younger patients showed positive for ALK translocation. Conclusions: 

Younger patients with lung adenocarcinoma showed significantly higher 

proportion of EGFR exon 19 deletion genotype and containing histologically 

signet-ring cell component comparing with elderly patients. EGFR 

exon 19 deletion genotype may be related to pathogenesis of lung 

adenocarcinoma in younger patients. 


Molecular profiling of patients with non-small cell lung cancer (NSCLC) 

using bronchoscopic ultra-micro sampling. Presenting Author: Yuichi 

Sakairi, Department of General Thoracic Surgery, Graduate School of 

Medicine, Chiba University, Chiba, Japan 

Background: Genetic information is essential for molecular targeted therapy 

for personalized medicine, although tissue sampling for genetic analysis 

remains challenging. In this study, we investigated the utility of bronchoscopic 

ultra-micro samples compared with conventional histological materials 

for multiple gene analyses for NSCLC. Methods: Patients with NSCLC 

proven by on-site cytological examinations during bronchoscopic survey 

were eligible. Following conventional needle aspiration biopsy by flexible 

bronchofiberscope (from primary lesion) or convex probe endobronchial 

ultrasound (from lymph nodes), the used needle was rinsed with 20 ml of 

saline and this ultra-micro sample (MS) was used for both cytological 

diagnosis and genetic analysis. DNA and RNA were extracted from each 

sample. Gene mutations [EGFR (epidermal growth factor receptor), K-ras, 

BRAF] and anaplastic lymphoma kinase (ALK) fusion genes were examined 

by high resolution melting analysis and direct sequencing. The results of 

cytological diagnoses and gene profiles using MS were compared to 

conventional histological diagnoses. Results: A total of 79 lesions (30 

primary and 49 metastatic nodes) from 76 patients were eligible. Adenocarcinoma 

(N � 46), squamous cell carcinoma (N � 25), and NSCLC (N � 8) 

were pathologically confirmed in histological lesion cores; however, only 29 

malignancies (37%) were detected with MS. DNA and RNA could be 

extracted from all histological samples and MS. In 35 cases, genetic 

disorders were identified, including EGFR mutations (N � 12), K-ras 

mutations (N � 5), BRAF mutation (N � 1), ALK fusion genes (N � 3), and 

silent mutations (N � 13); these results were identical for both histological 

samples and MS. Conclusions: Bronchoscopic ultra-micro samples (biopsy 

needle rinse fluids) are useful for multiple genetic examinations. 


A phase II trial of induction gefitinib monotherapy followed by cisplatindocetaxel 

and concurrent thoracic irradiation in patients with EGFRmutant 

locally advanced non-small-cell lung cancer (LA-NSCLC): 

LOGIK0902/OLCSG0905 intergroup trial. Presenting Author: Akiko 

Hisamoto, Department of Respiratory Medicine, Okayama University Hospital, 

Okayama, Japan 

Background: We previously reported efficacy and safety of cisplatindocetaxel 

and concurrent thoracic radiotherapy (TRT) for LA-NSCLC 

(Segawa Y and Kiura K. JCO 2010). However, its cure rate remains 

unsatisfied, and further improvement in the treatment outcome is strongly 

warranted. Recently, systemic chemotherapy has been individualized by 

intensive anti-cancer researches through the discovery of certain molecular 

targets in the metastatic NSCLC. Especially, gefitinib, EGFR tyrosine 

kinase inhibitor, is quite active and now one of the standard chemotherapy 

for untreated metastatic EGFR-mutant NSCLC (Maemondo M and Inoue A. 

NEJM 2010). Even in the locally advanced setting, approximately 30% of 

Japanese NSCLC patients possess EGFR-mutant tumors. Given all of these 

backgrounds, investigation on the role of adding gefitinib monotherapy to 

the standard concurrent chemoradiotherapy might cause a new paradigm 

shift in this setting. Methods: Patients have to meet the following eligibility 

criteria: LA-NSCLC; active tumor EGFR mutations (exons 19 and 21) but 

without 790M; measurable lesions; performance status (PS) of 0 or 1; age 

� 75 years; and V20 � 35%. The primary endpoint is set as 2-year 

progression-free survival (PFS) rate; assuming that 75% in eligible patients 

would indicate potential usefulness, whereas 60% would be the lower limit 

of interest (� � 0.05, ß � 0.20), the estimated accrual number is 46 

patients. The secondary endpoint includes toxicity, response rate and 

overall survival. Patients will receive the induction treatment, specified as 

gefitinib monotherapy (250 mg/body) for 8 weeks. Patients who have not 

progressed during the induction therapy will receive cisplatin and docetaxel 

(40 mg/m2 ; days 1, 8, 29, 36, each) and concurrent three-dimensional 

conformal TRT (2-Gy, single, daily fractions for 5 consecutive days each 

week to provide a total dose of 60 Gy). Enrollment began in 2010, and will 

complete by 2015. UMIN registration number of 000005086. 


Relationship between tumor size and survival in non-small cell lung cancer 

(NSCLC): An analysis of the Surveillance, Epidemiology, and End Results 

(SEER) registry. Presenting Author: Jianjun Zhang, University of Texas 


Background: Tumor size is a known prognostic factor for early stage (I and II) 

NSCLC, but its significance in node positive or locally advanced NSCLC has 

not been determined. We sought to evaluate its prognostic value in early 

and locally advanced NSCLC and create a nomogram incorporating tumor 

size and other prognostic variables to predict survival. Methods: The SEER 

registry was queried for patients (pts) with NSCLC, aged 20-103 and 

diagnosed between 1998 and 2003. Pts with extra-pulmonary metastases 

or distant lymph node metastases were excluded. Tumor size was analyzed 

as a continuous variable. Other demographic variables included age, 

gender, race, histology, primary tumor extension, node status and primary 

treatment modality (surgery vs radiation). Log-rank test was performed to 

evaluate the relationship between these variables and overall survival (OS). 

Cox proportional hazard model was used to evaluate whether tumor size was 

an independent prognostic factor. Results: 52,287 eligible pts were divided 

into 16 subgroups based on primary tumor extension and node status. For 

example, in group 1, tumor was confined to one lung with no nodes 

involved; pts in group 12 had tumor invading the mediastinum (T4 by 

extent) and positive ipsilateral mediastinal nodes. Tumor size had a 

significant effect on OS in almost all groups after adjustment for age, sex, 

race, histology, node status, primary tumor extension and primary treatment 

modality. Our model incorporating tumor size had significantly better 

predictive accuracy (larger C index) than our alternative model not 

including this information (p�0.0001). We then developed a nomogram 

incorporating tumor size, age, gender, race, histology, nodule stage, and 

tumor extension with the intent to predict OS. In subsequent bootstrap 

verification, the predicted 2-year OS from the nomogram was almost 

identical to the actual observed 2-year OS with a very slim biases of 

estimates. Conclusions: Tumor size is an independent prognostic factor, 

including pts with node positive or locally advanced NSCLC. We successfully 

created a nomogram incorporating tumor size and other clinical 

variables to predict survival. 




Breath analysis for early detection of lung cancer. Presenting Author: 

Geetha D. Vallabhaneni, Winship Cancer Institute, Emory University, 

Atlanta, GA 

Background: Lung cancer (LC) is the leading cause of cancer death 

worldwide. Early detection is critical to reduce LC related mortality. Breath 

analysis can be used as a non invasive diagnostic tool in conjunction with 

CT screening. We assessed the diagnostic value of breath volatile organic 

compounds (BVOCs) in the alveolar breath of female non-small cell lung 

cancer (NSCLC) patients. Methods: This is a prospective case-control study 

that enrolled newly diagnosed NSCLC and cancer-free female controls. The 

study aims: 1) To compare the BVOC signature in female NSCLC patients to 

a control group without LC 2) To compare the BVOC signature between 

NSCLC and breast cancer (BC) patients. The study was restricted to women 

because the pilot data was generated from female subjects with BC. 

Consenting eligible patients provided a total of five deep breath samples 

into a proprietary breath sampler developed at the Georgia Tech Research 

Institute (GTRI) for collecting alveolar breath. Breath samples were 

collected five minutes apart from each subject. The collected samples were 

analyzed for BVOCs using thermal desorption/gas chromatographic/mass 

spectrometric (TD/GC/MS) technique. Statistical differences in BVOCs in 

breath samples from cases and controls were assessed using this technique. 

Support vector machine classification method was employed to 

compare the BVOCs pattern between LC and BC patients. Results: We 

enrolled 25 NSCLC and 25 cancer-free subjects. TD/GC/MS analysis 

identified a total of 422 BVOCs among the controls and NSCLC subjects. 

75 unique BVOCs that were significantly different between cases and 

controls were employed for statistical modeling. This 75 BVOCs signature 

has a sensitivity of 0.75, a specificity of 0.75 and a classification accuracy 

of 75% for NSCLC and controls. Statistical analysis on the full BVOCs data 

set from NSCLC and previously collected BVOCs data from BC patients 

achieved a classification accuracy of 88%. Conclusions: Unique BVOCs 

pattern can identify patients with established NSCLC. Future studies in 

at-risk patients will assess the utility of this approach as a less invasive and 

minimal risk screening tool for early detection of NSCLC. Supported by the 

Kennedy Seed Grant awarded by the Winship Cancer Institute of Emory 

University. 


Case-control study of prophylactic cranial irradiation in nonmetastatic 

non-small cell lung cancer. Presenting Author: Simon Cheng, Department 

of Radiation Oncology, Columbia University Medical Center, New York, NY 

Background: Prophylactic cranial irradiation (PCI) reduces the incidence of 

brain metastases in NSCLC patients after primary therapy, but its impact 

on survival is uncertain. We report on the largest study of survival in 

patients treated with and without PCI for non-small cell lung cancer 

(NSCLC). Methods: We reviewed 17 Surveillance, Epidemiology and End 

Results (SEER) registries for a retrospective study on patients who had PCI 

as part of their primary treatment for NSCLC from 1988 - 97. Cases were 

limited to those with non-metastatic (Stage I-III) NSCLC. To balance the 

cohorts, we matched each PCI patient with four non-PCI patients on stage, 

histology, race and sex. Associations between treatment type, clinical 

factors, and demographics were assessed using the Chi-squared test. 

Survival time was calculated as the number of months from diagnosis to the 

date of death. Survival was censored as of the last month when patients 

were known to be alive. Overall (OS) and cancer cause-specific survival 

(CSS) were investigated using the Kaplan-Meier, competing risks, Cox 

proportional hazards, and log-rank tests. Results: We found 472 PCI 

matched to 1,888 non-PCI patients. Characteristics were balanced across 

groups: race (p � 1.00), sex (p � 0.95), histology (p � 1.00), stage (p � 

1.00), and surgery (p � 0.81). PCI group was younger, median age 64 vs 

68 (p � 0.01). PCI vs no PCI median OS was 8 vs 10 months (p � 0.01). 

OS was 14% vs 28% at 2 years and 5% vs 12% at 5 years, PCI vs no PCI 

respectively (p � 0.01). Stage III OS was also different; 10% vs 21% at 2 

years, PCI vs no PCI respectively (p � 0.01). Median CSS was the same at 9 

months in both groups. Median follow-up was 14 years. Conclusions: PCI 

was not associated with improved OS or CSS in these NSCLC patients, and 

PCI may have a detrimental effect on OS. In limited-stage small cell lung 

cancer, a retrospective SEER analysis during the 1988 – 97 period showed 

a survival benefit in treated patients with PCI, which has been confirmed 

with prospective studies. To date, 4 prospective trials examining PCI for 

NSCLC have shown a reduced incidence of brain metastases, but the effect 

on survival is unclear. Further investigation is needed to determine whether 

PCI for NSCLC increases the risk of other causes of death. 

463s 


Outcomes of combined modality treatment in elderly patients with stage III 

non-small cell lung cancer. Presenting Author: Ludimila Cavalcante, Mount 

Sinai Medical Center, Miami Beach, FL 

Background: The use of combined modality treatment (CMT) has been 

demonstrated to improve survival in patients with inoperable, locally 

advanced NSCLC. Elderly patients have been traditionally excluded from 

prospective clinical trials investigating CMT and thus the optimal treatment 

strategy for these patients remains unclear. We retrospectively evaluated 

the outcomes of elderly patients who received concurrent and sequential 

chemoradiation. Methods: All lung cancer patients age 70 or older who 

received chemotherapy and radiation treatment at Mt. Sinai Medical Center 

for stage III NSCLC between 1997 and 2010 were analyzed from tumor 

registry data. Among 282 lung cancer elderly patients diagnosed with stage 

III disease, 64 patients (22.7 %) received CMT as part of their treatment. 

Patients who underwent surgery and palliative radiation were excluded. 

Statistical analysis was performed by log-rank, Kaplan-Meier methods, and 

t-test. Results: Median age at diagnosis for the CMT group was 75 years 

(70-87), male/female: 34/30, TNM: T4N0-1: 12, T3N1: 1, TXN2: 41, 

TXN3: 10. Concurrent chemoradiation was delivered in 43 cases and 

sequential in 21 cases. RT doses ranged from 50 to 63 Gy. The most 

common chemotherapy regimens used were carboplatin and taxol (44 %) 

and carboplatin and etoposide (15%). The most common treatment-related 

toxicities were esophagitis (42%), anemia (39%), and pneumonia (24%). 

Median survival (MST) was 19 months and 11 months in the concurrent 

and sequential chemoradiation groups (p�0.67). Observed two, three and 

five-year overall survival (OS) in the CMT group was 49.1%, 27.5%, and 

12.5%, respectively. Conclusions: Although CMT is not commonly used in 

elderly patients with lung cancer, the treatment is feasible and beneficial 

for selected patients in the community setting. Interestingly, the MST of 

elderly patients who received CMT in this cohort was comparable to that of 

younger historical controls with CMT. There was also a trend for increased 

survival in the concurrent versus sequential chemoradiation group. 


Correlation of pretreatment surgical staging and PET SUVmax with outcomes 

in NSCLC. Presenting Author: Giancarlo Moscol, Albert Einstein 

Medical Center, Philadelphia, PA 

Background: The AJCC staging does not recognize the number of involved 

mediastinal lymph nodes (LN), nodal stations or PET findings as prognostic 

factors in non-small cell lung cancer (NSCLC). Most clinical studies report 

poorer survival with greater number of involved LN and maximal tumor 

standardized uptake value (SUVmax) � 5. We hypothesized that clinical 

outcomes can be predicted by (1) number of involved LN, (2) number of 

involved nodal stations, (3) SUVmax of primary tumor and (4) SUVmax of 

mediastinum. Methods: Records of patients diagnosed with NSCLC stages 

I-IIIA from 1/1/99 to 12/31/10 were reviewed. Data collected included age, 

type of surgery, AJCC stage, number of LN/stations sampled and SUVmax 

of primary tumor/mediastinum. Primary outcomes were tumor recurrence 

and death. Descriptive statistics were used to summarize demographics. 

Prognostic factors were analyzed by a multivariate analysis using Cox’s 

proportional hazard model. Survival was estimated by the Kaplan-Meier 

method. Results: There were 369 patients with complete clinical data; 207 

underwent surgical staging with mediastinoscopy (62) or VATS/open 

thoracotomy (145). The median number of LN sampled was 9 (range 1-35) 

and the median number of stations biopsied was 3 (range 1-9). PET was 

performed in 89 patients; 59 scans showed tumor SUVmax � 5. A total of 

65/207 patients received chemotherapy. With median follow-up time of 29 

months (range 1-116), 73 recurrences and 90 deaths were observed. Cox 

analysis showed greater recurrence risk for patients with 4 or more involved 

LN (HR� 4.66, CI�1.19-18.18, p�0.027) and higher mortality for 

patients with tumor SUVmax � 5 (HR�14.83, CI�2.32-94.9, p�0.004). 

Outcomes did not correlate with the number of involved nodal stations 

(p�0.76 for recurrence, p�0.51 for mortality) or with SUVmax of mediastinum 

(p�0.17 for recurrence, p�0.93 for mortality). Conclusions: The 

number of involved LN was an independent prognostic factor for recurrence 

but not for mortality. A tumor SUVmax �5 was independently associated 

with greater mortality. The number of involved stations and the SUVmax of 

mediastinum did not correlate with worse outcomes. Our results are limited 

due to the small number of cases with PET/CT scans and short follow-up. 




5-day dosing schedule of temozolomide in relapsed sensitive or refractory 

small cell lung cancer (SCLC) and methyl-guanine-DNA methyltransferase 

(MGMT) analysis in a phase II trial. Presenting Author: Alexander Edward 

Dela Cruz Drilon, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: MGMT promoter methylation and loss of MGMT activity are 

associated with improved sensitivity to alkylating agents. We recently 

reported that the oral alkylating agent temozolomide is active in 2nd- and 

3rd-line treatment of relapsed SCLC at 75mg/m2 /day for 21 out of 28 days 

(Pietanza et al, Clin Can Res 2012). Here we evaluate the 5-day dosing 

schedule of temozolomide in a second cohort of patients and analyze 

MGMT activity in both cohorts of patients on the same study. Methods: 

Patients with disease progression after 1 or 2 prior chemotherapy regimens 

received temozolomide at 200mg/m2 /day for 5 out of 28 days (n�25). 

Those with sensitive (S-SCLC, n�16) and refractory (R-SCLC, n�9) 

disease were enrolled to assess safety. Available tumor tissue from patients 

treated according to either schedule was assessed for MGMT promoter 

methylation status by PCR and MGMT expression by immunohistochemistry 

(IHC). Results: An overall response rate of 12% was noted (3 partial 

responses: 1 S-SCLC, 2 R-SCLC). 4 patients had stable disease for at least 

3 cycles. Median progression-free survival and overall survival for all 

patients were 1.3 months and 7.9 months, respectively. Grade �3 

thrombocytopenia and neutropenia was observed in 20% with a shorter 

mean duration of myelosuppression compared to the 21-day schedule. 

Results from MGMT evaluation of tumor samples from both dosing 

schedules were combined. Promoter methylation of MGMT was not 

significantly associated with response (p�0.23). However, patients that 

lacked MGMT expression by IHC had a higher response rate compared to 

those with MGMT-positive tumors (43% vs. 13%, p � 0.052; see table). 

Conclusions: The 5-day dosing schedule of temozolomide is both active and 

safe in patients with relapsed SCLC. A strong trend toward increased 

response was demonstrated in patients with MGMT-negative tumors 

compared to patients with MGMT-positive tumors by IHC. A trial combining 

temozolomide with the PARP inhibitor, ABT888, is planned. 

MGMT expression by IHC (n�38) PR 

Response 

SD � POD p 

Negative (n � 14) 43% (n�6) 57% (n�8) 0.052 

Positive (n � 24) 13% (n�3) 88% (n�21) 


Are the presenting characteristics and prognosis of primary salivary 

gland-type lung cancers (SG) similar to those of other non-small cell lung 

cancers (NSCLC)? Presenting Author: John M. Varlotto, Penn State Hershey 

Cancer Institute, Hershey, PA 

Background: SG, both adenoid cystic (ACC) and mucoepidermoid (ME) 

sub-types, are rare lung cancers. We choose to investigate the incidence of 

these rare sub-types and assess their difference in presentation and 

prognostic characteristics in comparison to adenocarcinomas (Ad) and 

squamous cell carcinomas (SCC) during the same time period. Methods: 

The SEER-17 database was used to collect data during the years 1988- 

2008. Differences between populations were determined by the chi-square 

test. Survival curves were generated as Kaplan-Meier techniques. Cox 

proportional hazards test was used to compare survival differences. Results: 

During the 20-year study period, ACC (n �100) and ME (n� 178) 

accounted for 0.03% and 0.06% of NSCLCs. Mean follow-up was 34.5 

months for all patients. In comparison to ACC, patients with ME were 

significantly more likely to be younger (52 yr vs. 60yr), Asian(11.7% vs. 

7%), have Stage I disease (62.9% vs 24.0%), and less likely to be in the 

mainstem bronchi (17.2% vs. 6.3%). In comparison to patients with 

patients presenting with either SCC or Ad, both ME and ACC were 

significantly less likely to present with Stage IV disease (26.6% SCC, 

41.29% Ad, 16.73% SG), have nodal involvement (35.1% SCC, 27.4% 

Ad, 23.37% SG), and be older (70 SCC, 68 Ad, 58 years SG). Stratified by 

stage and treatment, there was no survival (OS) or disease-specific survival 

difference (DSS) between ACC and ME. The OS of the combined group of 

ME and ACC was significantly better stage per stage than either Ad (Hazard 

ratio (HR) range � 0.26- 041), and SCC (HR range � 0.17-0.56). Lung 

Cancer-Specific survival at 2,3,5 years for surgically-resected Stage I ACC 

and ME were 83.5%, 80.4%, and 80.4%; and 82.6%, 78.0% and 78%, 

respectively. Conclusions: Patients with ACC and ME have rare sub-types of 

lung cancer that present differently and have better survival than patients 

presenting with either of the more common histologic sub-types (SCC and 

Ad) of NSCLC. We encourage prospective, multi-institutional studies of 

these rare sub-types so that care can be optimized. Optimal care may differ 

for SG because of their stage per stage better prognosis than other NSCLCs. 


High-throughput targeted resequencing of lung adenocarcinoma. Presenting 

Author: Byung Chul Kim, Personal Genomics Institute, Genome 

Research Foundation, AICT, Suwon, South Korea 

Background: The mutational profiles are crucial for cancer diagnosis and 

classification, which lead to tailoring the best therapeutic strategy to each 

patient. Here, we present target sequencing of 30 hot spot genes in lung 

adenocarcinoma to identify new hot spot mutations in never-smoker, 

female lung adenocarcinoma patients. Methods: We targeted 30 genes that 

are known to be mutated frequently in lung adenocarcinoma. The exome 

capture was done using selector technology and sequencing was done using 

Illumina GA IIx Genome Analyzer. Exomic short reads from Illumina 

Pipeline 1.4 were aligned to human genome (NCBI build 36) with BWA 

0.5.0. Variations and small indels were called by Samtools 0.1.7 and 

filtered by custom R scripts. Potential effects of these identified alterations 

were assessed with sequence analysis. Results: On average, 1.5 billion 

bases were uniquely mapped, and mean depth and coverage of exon regions 

were 38X and 96%, respectively. Filtering of data against public SNP 

database (dbSNP130), resulted in ~2,000 novel genetic alterations per 

sample, including single nucleotide variations, and small insertion and 

deletions in protein-coding regions. Among them, there were novel variants 

in LTK and EPHA5 genes. Conclusions: Our results demonstrated the 

feasibility of high-throughput mutation profiling with lung adenocarcinoma 

samples. We identified novel variants in hot target genes, which may 

provide an insight into the tumorigenesis signaling of lung adenocarcinoma. 


Would screening benefit 75- to 84-year-old patients with non-small cell 

lung cancer (NSCLC)? Presenting Author: Jessica Lake, Penn State College 

of Medicine, Hershey, PA 

Background: The Lung Cancer Screening Trial has shown an overall survival 

(OS) benefit and reduced lung cancer mortality in the 55-74 age group 

(gp). We chose to evaluate whether NSCLC patients aged 75-84 are 

increasing in the USA and whether they would benefit from aggressive 

therapy. Methods: SEER-17 was used to calculate NSCLC rates during the 

years 2000-2008. SEER-9 was used to estimate the proportional change in 

both 55-74 and 75-84 gp from 1973-2008. OS was analyzed in a modern 

population from SEER-17 (2004-2008) to assess the effects of increasingly 

aggressive therapy (observation(Ob), radiation (RT) or lobectomy 

(LB)) for a proposed screening population with T1N0 tumors. Chi-square 

test and Cox Regression (CR) were used to evaluate OS. Paired T-tests 

assessed changes in rates and proportions over time. Results: The 55-74 gp 

rose from 64.4% in 1973 to 67.25% in 1984, but fell to 58.8% by 2008, 

while the 75-84 gp rose from 12.1% in 1973 to 24% in 2008 (p�0.01), 

similar in both sexes. The rates/100,000 have been increasing in the 

75-84 gp (p�0.02), mainly in females (p�0.003) while the rates in the 

55-74 gp did not vary, but fell for men (p�0.03). In the Ob gp (n�1344), 

NSCLC was the most common cause of death (COD) in the 55-74 (29.8%) 

and 75-84 gp (40.6%), more than all other CODs combined (median 

survival (MS) � 11mn). CR revealed that OS was associated with the 55-74 

gp (0.59) and females (0.62) (p � 0.001). In the RT gp (n�1870), MS was 

14mn and lung cancer was the most common COD at 27.7% (55-74) and 

28.8% (75-84), again more than all other CODs combined. CR found that 

females (0.68) and black race (0.72) had better OS (p�0.017), but age 

was not. MS was 24 mn in the LB group (n�9384). COD from NSCLC and 

all other CODs was 8.2% and 6.1% (55-74) and 10.9% and 11.4% 

(75-84). CR showed that 55-74 (0.36), females (0.58), and Asians (0.73) 

had lower death rates (all p�0.015). Mean OS between the 55-74 (26.0) 

and 75-84 (24.2) gp showed a small yet significant difference. Conclusions: 

Rates and proportions of NSCLC have been steadily increasing in the 75-84 

gp. These data show that COD by lung cancer decreased significantly with 

increasingly aggressive treatment and treatment reduced the effects of age 

gp on survival. We feel that screening may be of benefit to the 75-84 gp. 




Prognostic value of MAGE-A3 and PRAME gene expression in non-smallcell 

lung cancer (NSCLC). Presenting Author: Albert Linder, Lungenklinik 

Hemer, Hemer Nordrhein-Westfalen, Germany 

Background: We investigated the expression of some cancer–testis genes 

and their association with disease prognosis. Here we report our results for 

the expression, in resected NSCLC samples, of two tumor-specific antigens 

(Ags): MAGE-A3 and PRAME, both under evaluation in clinical trials. 

Methods: We conducted a single-center, uncontrolled, retrospective study 

of tissue from resected stage I–III NSCLC patients (pts): 650 were in stage 

I, 215 in stage II and 395 in stage III. 1260 FFPE tumor tissue samples 

from the tumor tissue bank of the Department of Pathology, Lungenklinik 

Hemer (Germany), were tested for MAGE-A3 and PRAME expression by 

specific qRT-PCR assays. The prognostic value of these Ags was determined 

by estimating the median overall survival (OS), disease-free interval 

(DFI) and disease-free survival (DFS). Results: Expression rates were 36% 

for MAGE-A3 and 66% for PRAME. The co-expression rate was 30%. 

Almost all tumors expressing MAGE-A3 also expressed PRAME. We 

observed no difference overall in Ag expression according to stage, tumor 

size and pts’ age. Squamous tumors expressed MAGE-A3 and PRAME more 

frequently than did adenocarcinomas (43 vs. 27 % and 80 vs. 44% 

respectively), and PRAME expression rates were higher in males than in 

females (70 vs. 53%). In the overall population, which included stages 

IA–IIIB, no prognostic value was detected for the expression of either Ag. In 

subset analyses, we found in 83 stage IIIB pts a trend to worse OS linked to 

MAGE-A3 expression (HR�1.977, p�0.0312). In 395 stage IB pts, 

PRAME expression was associated with worse OS (HR�1.483, p�0.0344) 

and DFS (HR�1.492, p�0.0167). Conclusions: The MAGE-A3 expression 

rate found is consistent with the results observed in the phase III MAGRIT 

trial (J-H Kim et al., 2011). No prognostic value for either PRAME or 

MAGE-A3 was observed in the overall population, in contrast to previous 

reports with smaller sample sizes (Gure et al., 2005, Boli et al., 2002) and 

in other tumors (Vourch’jourdain et al., 2009, Epping et al., 2008). We 

observed a trend toward poor prognostic value of MAGE-A3 in stage IIIB pts 

and of PRAME in stage IB pts. 


Prognostic role of FOXP3/CD4 ratio in resectable NSCLC. Presenting 

Author: Marta Usó, Fundación para la Investigación del Hospital General 

Universitario de Valencia, Valencia, Spain 

Background: Tregs play a critical role in immune tolerance to tumor cells 

and have been related to prognosis. The aim of this study was to determine 

the expression of Tregs makers genes by RT-PCR and to correlate them with 

clinico-pathological and prognostic variables in NSCLC. Methods: RNA was 

isolated from frozen lung specimens (tumor and normal lung) from 

resectable NSCLC patients (n�175). RT-PCR was performed to analyze the 

expression of: CD4, CD8A, CTLA-4, FoxP3, IL-10, CD25, CD127 and 

TGF�-1. Relative expression was normalized by an endogenous gene 

(GUSB) using the Pfaffl formulae. Statistical analyses were considered 

significant at p�0.05. Results: Tumor samples had significantly lower 

expression of CD127 (x0.45) and a tendency toward higher expression of 

CD25 (x1.81), FoxP3 (x1.57) and CTLA-4 (x1.53) compared to normal 

lung tissues, reflecting a Treg phenotype infiltrating the tumor. Survival 

analyses revealed that patients with higher FoxP3 expression had reduced 

OS (median 29.8 vs 67 months, p� 0.026). We also found that those 

patients with high levels FoxP3/CD4 ratio had worse TTP and OS (median 

22.1 months vs NR, p� 0.021 and 29.8 vs NR months, p�0.003, 

respectively). A multivariable Cox regression model for TTP and OS was 

built using variables that were found significant in the univariate analysis 

(nodal involvement, histology, tumor size, PS, and FoxP3/CD4 ratio). This 

analysis revealed that FoxP3/CD4 ratio was an independent prognostic 

marker for both TTP and OS (see table). Conclusions: FoxP3 is a transcription 

factor necessary and sufficient for induction of the immunosuppressive 

functions in Tregs. In concordance, our results indicate that higher levels of 

FoxP3/CD4 ratio in tumor samples is a poor prognostic markers for TTP and 

OS. Furthermore, the multivariable COX regression analysis showed that 

FoxP3/CD4 ratio is an independent prognostic marker. Therefore, this ratio 

could be used as a new biomarker of prognosis in resectable NSCLC. 

Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII. 

TTP OS 

HR 95% IC P HR 95% IC P 

Histology 1.14 1.01-1.29 .027* - - - 

Nodal involvement 1.38 1.06-1.81 .016* 1.34 1.00-1.80 .045* 

Tumor size 2.505 1.449-4.330 .001* 2.030 1.173-3.512 .011* 

FoxP3/CD4 ratio 2.11 1.24-3.63 .006* 2.42 1.38-4.24 .002* 

465s 


Prognostic value of pathologic complete response to preoperative chemotherapy 

in early-stage non small cell lung cancer: Combined analysis of two 

IFCT randomized trials. Presenting Author: Guillaume Mouillet, University 

Hospital, Besançon, France 

Background: Our study aimed to evaluate whether pathologic complete 

response (pCR) in early-stage non-small cell lung cancer (NSCLC) following 

neoadjuvant chemotherapy resulted in improved outcome and to determine 

predictive factors for pCR. Methods: Eligible patients with stage IB or II 

NSCLC were included in two consecutive Intergroupe Francophone de 

Cancérologie Thoracique (IFCT) phase III trials evaluating platinum-based 

neoadjuvant chemotherapy, with pCR defined by the absence of viable 

cancer cells in the resected surgical specimen. Results: Among the 492 

patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year 

overall survival (OS) was 80.0% compared to 55.8% in the non-pCR group 

(p�0.0007). In multivariate analyses, pCR was a favorable prognostic 

factor of OS (RR�0.34; 95% CI�0.18-0.64) in addition to squamous cell 

carcinoma (SCC), weight loss �5%, and stage IB disease. Five-year 

disease-free survival (DFS) was 80.1% in the pCR group compared to 

44.8% in the non-pCR group (p�0.0001). Two patients (4.9%) in the pCR 

group experienced disease recurrence compared to 193 patients (42.8%) 

in the non-pCR group. SCC subtype was the only independent predictor of 

pCR (OR�4.30; 95% CI�1.90-9.72). Conclusions: Our results showed 

that pCR after preoperative chemotherapy was a favorable prognostic factor 

in Stage IB-II NSCLC. Our study is the largest published series evaluating 

pCRs following preoperative chemotherapy. The only factor predictive of 

pCR was SCC. Identifying molecular predictive markers for pCR may help in 

distinguishing patients likely to benefit from neoadjuvant chemotherapy 

and in choosing the most adequate preoperative chemotherapy regimen. 


A systematic analysis of high-dose radiation in the treatment of surgically 

unresectable, locally advanced non-small cell lung cancer. Presenting 

Author: Madhusmita Behera, Department of Hematology and Medical 

Oncology, Emory University School of Medicine, Atlanta, GA 

Background: The 5-year survival rate for locally advanced non-small cell 

lung cancer (NSCLC) is � 25% with concomitant chemoradiotherapy. 

High-dose radiation appears to confer additional benefit based on surrogate 

endpoints from relatively small clinical trials. However, survival advantage 

of higher-dose radiation delivered by conventional fractionation of 1.8-2 Gy 

is unclear. We conducted a systematic review of pooled outcome data from 

published results of studies that evaluated the role of high-dose radiation in 

the management of locally advanced NSCLC. Methods: A detailed search of 

published clinical trials was conducted using computerized databases 

(MEDLINE, EMBASE, Cochrane library) and meeting proceedings. Single 

arm studies using high dose (�66Gy) or randomized trials of high versus 

standard radiation dose (60-63Gy) for locally advanced NSCLC were 

selected. A systematic analysis of extracted data was performed using 

Comprehensive Meta Analysis (Version 2.2.048) software under the random 

effect model. Clinical outcome in patients treated with high versus 

standard radiation dose was compared using point estimates for weighted 

values of median overall survival (OS), progression free survival (PFS), and 

response rate (RR). Treatment-related toxicities data between the two arms 

was compared using T-test and chi-square test. Results: Analytic data was 

retrieved from the results of 44 eligible studies reported between 1994 and 

2012. The studies enrolled 3699 patients, 62% males, 2095 and 1604 

treated with standard and high dose radiation respectively. The weighted 

median age was 63 and 61 years (p�0.66) for standard and high dose 

patients respectively. The weighted median OS was 19.1 vs. 16.4 months 

(p� 0.97); weighted RR of 76% vs. 70% (p�0.79) and survival rates after 

up to 3 years of follow up of 39% vs. 46% (p�0.45) for standard and high 

dose arms respectively. There was no significant difference in the rate of 

grade �3 toxicities between the two treatment groups. Conclusions: 

High-dose radiation therapy does not result in improved survival over 

standard radiotherapy dose in patients with locally advanced NSCLC. 




miRNA profiling in resectable NSCLC by multiplex next-generation sequencing. 

Presenting Author: Sandra Gallach, Fundación para la Investigación 

del Hospital General Universitario de Valencia, Valencia, Spain 

Background: Early-stage NSCLC has a relapse rate around 40% within 5 

years. With the advent of microRNA (miRNA), which seems to regulate 

many genes critical for tumorigenesis, there is a growing interest in the 

characterization of miRNAome in NSCLC specimens and to correlate them 

with prognosis. Next generation sequencing is a useful tool to study the 

miRNA content of solid tumors. Here, we applied high-throughput SOLiD 

transcriptome sequencing to study miRNAs expression in a cohort of 

early-stage NSCLC patients (tumor vs normal lung). Methods: RNA was 

isolated from frozen lung specimens (tumor and normal lung) from 

resectable NSCLC patients (n�35). Samples with a RIN � 7 were analyzed 

and enriched in the miRNA fraction. miRNAs were sequencing using a 

bar-code multiplex SOLiD protocol. Data normalization was carried out by 

rescaling all data according to their counts. Readings were mapped against 

mature and no-mature miRNAs using miRBase. Statistical analysis was 

performed with CLCbio software and considered significant when padj�0.005. 

Results: Using the SOLiD high throughput sequencing, we 

performed a systemic miRNA expression profiling analysis of paired 

samples (tumor vs normal lung). A total of 1268 miRNAs (mature and 

no-mature) have been detected in at least one sample. The differential 

expression between normal and tumor samples shown that 6 miRNAs 

(miR-193b, miR-182, miR-96, miR-148a, miR-299, miR-590) were 

upregulated and 7 (miR-145, miR-133a, miR-218, miR-125a, miR-30a, 

miR-126 and miR-139) were down-regulated significantly in tumor samples 

compared with normal lung tissues. We are performing studies using 

qRT-PCR in an independent cohort to further validate these findings. 

Conclusions: The deep sequencing technology used for differential miRNA 

expression is useful and novel. The use of barcoding allows multiplexing 

and lowers cost per sample. Several miRNAs were differentially expressed 

between tumor and normal tissue, but this point needs to be further 

validated in an independent cohort. Supported by grants TRA09-0132 

(MICINN) and RD06/0020/1024 (ISCIII). 


Comparative effectiveness of five treatment strategies for early-stage 

non-small cell lung cancer in the elderly. Presenting Author: Shervin 

Shirvani, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Early-stage lung cancer incidence among older adults is 

expected to increase due to demographic trends and CT-based screening, 

yet optimal treatment in the elderly remains controversial. Using the 

SEER-Medicare cohort spanning 2001-2007, we determined survival 

outcomes associated with five strategies used in contemporary practice. 

Methods: Treatment strategy and covariates were determined in 10,923 

patients age�66 with stage IA-IB non-small cell lung cancer. Cox regression, 

adjusted for patient and tumor factors, compared overall and 

disease-specific survival for lobectomy, sublobar resection, conventional 

radiation, stereotactic body radiotherapy (SBRT) and observation. In a 

second analysis, propensity-score matching was used for pairwise comparison 

of SBRT with other strategies. Results: Median age was 75 years and 

29% had substantial comorbidity. Treatment distribution was lobectomy 

(59%), sublobar resection (11.7%), conventional radiation (14.8%), 

observation (12.6%), and SBRT (1.1%). In unmatched Cox regression with 

median follow up of 3.2 years, SBRT was associated with the lowest risk of 

death within six months of diagnosis (HR 0.47; 95%CI 0.37-0.61; referent 

is lobectomy). After six months, sublobar resection and SBRT were 

associated with similar overall survival (P�0.51) and were both modestly 

worse than lobectomy. With propensity-score matching, survival after SBRT 

was similar to lobectomy (HR 0.90; 95%CI 0.64-1.27). Conventional 

radiation and observation were associated with poor outcomes in all 

analyses. Disease-specific survival outcomes followed similar trends. 

Conclusions: This population-based experience provides strong support of 

SBRT as an alternative to surgery or conventional radiation for select 

patient populations. Evaluation of this new therapy in randomized trials is 

urgently needed. 


SOX2 and FGFR1 gene copy number in surgically resected non-small cell 

lung cancer (NSCLC). Presenting Author: Luca Toschi, Humanitas Cancer 

Center, Rozzano, Italy 

Background: SOX2 is a member of the SRY-related HMG-box family of 

transcription factors and has been shown to be frequently amplified and 

overexpressed in squamous cell lung cancer, with conflicting results 

regarding its prognostic relevance. Similarly, FGFR1, a transmembrane 

tyrosine kinase receptor belonging to the fibroblast growth factor receptor 

family, has been recently reported to be amplified in squamous cell lung 

carcinomas, suggesting a potential role for FGFR1 as a therapeutic target in 

NSCLC. Aim of the present study is to evaluate SOX2 and FGFR1 gene copy 

number in surgically resected NSCLCs, to investigate their prognostic 

relevance and their association with clinico-pathological characteristics. 

Methods: SOX2 and FGFR1 gene copy number was assessed by fluorescence 

in situ hybridization (FISH) in tissue microarray cores from 447 

surgically resected NSCLCs. Each patient was given a score ranging from 1 

to 6 according to increasing mean copy number per cell of each gene, with 

6 indicating true gene amplification. Results: SOX2 and FGFR1 FISH was 

successfully performed in 445 patients (pts), which were grouped as � 

(score 5-6) and - (score 1-4). Using this scoring system 105 (23.6%) pts 

tested SOX2�, while 74 (16.6%) pts resulted FGFR1�. True gene 

amplification for SOX2 and FGFR1 was observed in 19 (4.3%) and 37 

(8.3%) cases, respectively. SOX2� and FGFR1� status was significantly 

associated with squamous histology (p�.001). Additionally, SOX2� pts 

had a significantly higher chance of being former/current smokers, male 

and FGFR1�. FGFR1 gene status had no prognostic impact in the whole 

population and in the squamous cell carcinoma subgroup. Conversely, 

SOX2� pts had significantly longer overall survival compared with SOX2pts 

(HR 0.68, p�.020). When restricting survival analysis to squamous cell 

histology, stage I-II SOX2� pts had a significant survival advantage 

compared with SOX2- group (HR 0.38, p�.006), while no difference was 

observed in stage III-IV pts. Conclusions: Increased SOX2 and FGFR1 gene 

copy number is a common event in lung cancer pts with squamous cell 

histology. SOX2 gene gain is a favorable prognostic factor in surgically 

resected pts, particularly in early stage squamous cell cancers. 


FGFR1 amplification in squamous cell lung cancers. Presenting Author: 

Michele L. Cote, Karmanos Cancer Institute, Wayne State University, 

Detroit, MI 

Background: Squamous cell carcinoma of the lung (SqCCL) is the second 

most common type of lung cancer. There are currently no established 

targeted therapies that take advantage of SqCCL-specific genetic abnormalities. 

Amplification of the fibroblast growth factor receptor type 1 gene 

(FGFR1) has been identified as a driver event in breast cancers and in 

SqCCL. The demographic characteristics and prognosis of patients with 

these tumors remains to be defined. Methods: DNA from 123 surgically 

resected, fresh frozen, and clinically annotated SqCCLs was extracted 

using a resin-based or phenol-based methodology. DNA quantity and 

quality was assessed using the Quantifiler kit (ABI). Specimen histology 

was validated, and the proportion of tumor cells was �60%. Copy number 

variation (CNV) analysis was performed using quantitative PCR with 

primers specific for exons 12 and 16 of FGFR1 and data analysis using 

CopyCaller (ABI). Samples with a predicted CNV of at 2 or greater in at least 

one exon were scored as amplified. Chi-squared tests were used to examine 

clinical and demographic differences between patients with and without 

amplification of FGFR1. Survival differences were examined by Kaplan 

Meier and Cox regression models. Results: Men comprised the majority of 

the population (n�91, 74%) and most cases were pathological stage I 

(n�75, 61%) or stage II (n�32, 26%). Thirty (24.4%) tumors showed 

amplification of FGFR1. There was no association between amplification 

and sex (p�0.18) or stage (p�0.37). The majority of the patients were 

white (n�114, 92.7%), but the proportion of tumors that were amplified 

was higher among non-whites (5/9, 55.5%) than whites (25/114, 21.9%, 

p�0.02). Overall, median survival was 32.2 months. In univariate survival 

analysis, amplification was associated with an increased hazard of death 

(HR�1.55, Wilcoxon p�0.03). Tumor stage at diagnosis was also associated 

with increased risk of death (HR�1.67, p�0.0009). Only stage 

remained a significant predictor of death in the multivariate survival models 

(HR�1.65, p�0.004). Conclusions: Somatic amplification of FGFR1 is a 

relatively common event in SqCCL and may be associated with race and 

overall survival. 




Survival following segmentectomy and lobectomy for stage I non-small cell 

lung cancer. Presenting Author: Cardinale B. Smith, Division of Hematology 

and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School 

of Medicine, New York, NY 

Background: Although lobectomy is considered the standard surgical 

treatment forstage IA non–small cell lung cancer (NSCLC), limited resections 

are frequently performed for patients with poor lung function or high 

operative risk. Recent studies suggest that segmentectomy may be the 

superior limited resection procedure. The objective of this study was to 

compare survival among patients with stage IA (�3cm) NSCLC undergoing 

lobectomy vs. segmentectomy. Methods: Using theSurveillance, Epidemiology 

and End Results registry we identified 15,180 cases of stage IA NSCLC 

that underwent lobectomy or segmentectomy. We used logistic regression 

to determine propensity scores for patients undergoing segmentectomy 

based on the patient’s preoperative characteristics. Overall and lung 

cancer-specific survival of patients treated with lobectomy versus segmentectomy 

was compared after adjusting, stratifying, or matching patients 

based on their propensity score. We also performed secondary analyses in 

subgroups of age (�70 vs. �70 years) and tumor size �2 cm. Results: 

Overall, 1,200 (8%) patients underwent segmentectomy. Among the entire 

cohort, analyses adjusting for propensity scores did not demonstrate a 

difference in outcomes among patients treated with lobectomy versus 

segmentectomy, (adjusted hazard ratio [HR] for overall survival 1.11, 95% 

confidence interval [CI]: 0.94 – 1.30 and lung cancer-specific survival 

1.11, 95% CI: 0.98 – 1.25). Similarly, secondary analyses showed no 

difference in overall (HR: 1.12, 95% CI: 0.90 – 1.40) and lung cancerspecific 

survival (HR: 1.04, 95% CI: 0.88 – 1.24) among patients with 

tumors �2 cm (T1a tumors). For patients �70 years of age, no difference 

in overall survival was observed (HR: 0.97, 95% CI: 0.73 – 1.28); however, 

a lung cancer-specific survival advantage of lobectomy was observed (HR: 

1.19, 95% CI: 1.00 – 1.40). Finally, among those �70 years overall 

survival (HR: 1.03, 95% CI: 0.87 – 1.22) and lung cancer-specific survival 

(HR: 1.18, 95% CI: 0. 97 – 1.44) showed equivalence of the two surgical 

groups. Conclusions: Segmentectomy and lobectomy may lead to equivalent 

survival rates among patients with stage IA NSCLC. These study 

findings should be confirmed in prospective studies. 


Prospective study of tumor suppressor gene (TSG) methylation as a 

prognostic biomarker in surgically resected non-small cell lung cancer 

(NSCLC). Presenting Author: Christopher G. Azzoli, Memorial Sloan- 


Background: In the New England Journal of Medicine, Brock et al. (2008) 

published a nested case-control study which tested the association 

between early recurrence of NSCLC after surgical resection, and TSG 

promoter methylation in tumor and lymph nodes detected by methylationspecific 

PCR (MSP). They reported that promoter methylation of the TSGs 

p16, CDH13, RASSF1A, and APC was significantly associated with early 

recurrence in 51 patients with stage I NSCLC compared to matched 

patients without early recurrence. We attempted to confirm these findings. 

Methods: In a prospective study, fresh frozen tumor tissue was acquired 

after surgical resection in 107 patients with stage I-IIIA NSCLC between 

2003-2008. The promoter methylation status of the same 4 genes 

examined by Brock, et al (p16, CDH13, RASSF1A, APC), as well as 6 

additional TSGs (MGMT, WIF-1, METH-2, GSTP1, SOCS3, DAPK) were 

assessed in the tumor tissue using quantitative MSP (MethyLight assay), 

with any amount of methylation scored as positive. Methylation status was 

correlated with clinical features, pathologic stage, disease-free survival 

(DFS), and overall survival (OS). Results: No significant associations were 

observed between promoter methylation of individual TSGs and DFS. No 

significant associations were observed between the number of methylated 

TSGs and DFS, or OS. Increased RASSF1A methylation was observed in 

poorly-differentiated and undifferentiated tumors compared to tumors that 

were well- or moderately-differentiated (p�0.031). Increased WIF-1 methylation 

and GSTP1 methylation were associated with increasing T (p�0.01) 

and N stage (p�0.028), respectively. Squamous cell carcinomas (SQCCs) 

were characterized by increased p16 methylation (p�0.0314) and decreased 

APC methylation (p�0.0146) compared to tumors of non-SQCC 

histologies. Conclusions: In this prospective study, we did not confirm that 

the promoter methylation of p16, CDH13, RASSF1A, and APC, or 6 other 

TSGs, was prognostic for early recurrence in surgically resected NSCLC. 

467s 


Phase II study of concurrent cetuximab (C225) plus definitive thoracic 

radiotherapy (XRT) followed by adjuvant docetaxel in poor prognosis 

patients with locally advanced non-small cell lung cancer (LA-NSCLC). 

Presenting Author: Thomas J. Dilling, H. Lee Moffitt Cancer Center & 


Background: Recursive partitioning analysis has shown that ECOG PS � 2, 

male gender, or age � 70 are prognostic of poor outcome in LA-NSCLC pts. 

Concurrent chemoradiotherapy improves survival, but toxicity is concerning 

in this frail pt cohort. We therefore opened this trial of concurrent 

definitive-dose XRT (70 Gy in 35 fractions) and C225 (250 mg/m2 /dose), 

followed by adjuvant C225 and docetaxel (60 mg/m2 q3weeks x 3 cycles). 

Methods: Eligible patients had pathologically-proven LA-NSCLC (stage IIA – 

“dry” IIIB), not surgically resectable. They had ECOG PS 2 OR weight loss 

�5% in 3 months OR age �70. The primary objective was progression-free 

survival (PFS). Secondary objectives included overall survival (OS) and 

overall response rate (ORR). Results: From 5/2008 to 11/2010, 32 pts were 

evaluated for our single-institution, IRB-approved prospective clinical trial. 

3 pts were screen-failures and 2 more withdrew consent prior to treatment, 

leaving 27 evaluable patients. 1 was removed due to poor therapy 

compliance and 2 were taken off trial due to grade 3 toxicity from the C225 

loading dose, but were followed under intent-to-treat analysis. Median 

follow-up and OS was 10.5 months. Median PFS was 7.8 months. ORR � 

59.3%. 8 early/sudden deaths were reported, so the trial closed early: 

radiation pneumonitis (RP) was the apparent cause in 1 and probably/ 

possibly in 4 others, with insufficient information in 2 additional pts; 1 pt 

died of failure to thrive. Of the remaining pts, 3 developed grade 3� RP and 

2 had grade 2 RP. Conclusions: Pts enrolled on this trial had improved OS 

compared with poor-PS historical controls (10.5 vs 6.3 months) and 

comparable OS compared with good-PS historical controls (10.5 vs 11.9 

months) treated with RT (Werner-Wasik M et al. Int J Radiat Oncol Biol 

Phys. 2000;48:1475-82). However, pulmonary toxicity is a concern. 

Analysis of RP events is ongoing. Updated results will be presented at the 

meeting. 


Preoperative survivin, ERCC1, and PTEN expression in stage III non-small 

cell lung cancer (NSCLC) patients (pts) treated with neoadjuvant and 

definitive chemoradiation and association with overall survival (OS). 

Presenting Author: Marta Batus, Rush University Medical Center, Chicago, 

IL 

Background: Thoracic radiation and concurrent chemotherapy consisting of 

platinum based doublets has produced modest improvement in long term 

survival for patient with locally advanced (LA) NSCLC. There is relatively 

little information regarding molecular profiles and outcome in LA-NSCLC 

patients (pts) treated with chemoradiation. The objective of this retrospective 

study is to evaluate potential relationships between expression of DNA 

repair enzyme ERCC1 and enzymes involved in cell survival – survivin and 

PTEN. Methods: Stage III NSCLC pts who were treated with chest radiation 

(40-60Gy) and concurrently with platinum doublet and who had sufficient 

pretreatment tissue were included in this study. Immunohistochemistry 

was used to detect nuclear and cytoplasmic expression (frequency 0-4 and 

intensity 0-4) of survivin, and PTEN, and for nuclear expression of ERCC1. 

Product of intensity and frequency was calculated for all markers and 

correlated with overall survival (OS). Results: 97 pts had adequate tumor 

samples for analysis. 53 women, median age 67. 48 pts with ERCC1 prod 

��6 had longer OS than 41 pts with ERCC1 prod �6 (19.6 vs 1.0 months, 

p�0.034). 16 pts with ERCC1 prod �6, PETN prod ��6 and survivin prod 

�4 had significantly lower OS than 68 pts with ERCC1��6, PETN �6 and 

survivin ��4 (17.2 vs 40.2 months, p�0.001). Conclusions: The association 

of inferior survival in LA-NSCLC pts whose tumors express high 

survivin, low PTEN, and high ERCC1, suggests that combining inhibitors of 

survivin and or of PI3KCA with chemoradiation and developing strategies to 

inhibit DNA repair might improve outcomes in this group of pts. 




Phase II trial: Concurrent chemotherapy and radiotherapy with nitroglycerin 

in locally advanced non-small cell lung cancer patients. Presenting 

Author: Dolores De la Mata, Instituto Nacional de Cancerología, Mexico 

City, Mexico 

Background: The treatment of choice for locally advanced non small cell 

lung cancer (NSCLC) is concurrent chemoradiation (CRT). However, efforts 

to improve treatment results include targeted therapy and the use of 

radiosensitizers. Nitroglycerin (NTG), a nitric oxide (NO) donor agent, 

reduces expression of Hypoxia-Induced Factor, which is associated to both 

chemo and radio resistance. Methods: This is phase II trial in patients with 

locally advanced NSCLC treated with chemotherapy (CT) based on cisplatin 

and vinorelbin with NTG concurrent with radiation therapy. A 25 mg NTG 

patch was administered to the patients during the first 5 days of each 

induction treatment cycle and during chemo-radiotherapy. Blood samples 

of VEGF were taken before any treatment and after two cycles of CT. The 

protocol is registered with ClinicalTrials.gov, number NCT00886405. 

Results: 35 patients were enrolled in this trial. Median Follow up was 16.6 

months (SD �13.6). Mean age was of 59.9 years (�10.8), 68.6% of the 

patients were smokers. ECOG status was 0 in 22.9%, 1 in 65.7% and 2 in 

11.5%, respectively. Histopathology was adenocarcinoma in 68.6%, 

epidermoid in 17.1% and undifferentiated in 14.3%. Stage distribution 

was: IIIa, 57.6% and IIIb, 42.5%. All patients completed CRT treatment 

and four underwent surgical treatment. Toxicity profile related to NTG was 

grade 1 and 2 headache in 17.1%. Grade 3 and 4 toxicities were 

esophagitis (17.1%), neutropenia (62.9%), and nausea (5.7%). Sixty-four 

per cent of patients achieved partial response after CT and 75.8% after 

CRT. PFS was 11.8 months (95%, IC 7.8-15.6) and OS was 42.9 months 

(95%IC 31.3-52.1). After two cycles of CT, plasma VEGF levels were 

significantly lower (Median 132�79 vs. 53�78 pg/ml, p�0.001). No 

differences on PFS and OS were found between patients with a reduction � 

93 pg/ml (median of differences between VEGFR before and after chemotherapy). 

Conclusions: The addition of NTG to induction CT, and concurrent 

CRT on locally advanced NSCLC patients seems to increase the response 

rate, PFS and OS with an acceptable toxicity profile. A prospective trial is 

warranted to confirm these findings. 


Multicenter phase II study of concurrent high-dose (72Gy) threedimensional 

conformal radiotherapy (3D-CRT) without elective nodal 

irradiation with chemotherapy using cisplatin and vinorelbine for unresectable 

stage III non-small cell lung cancer (NSCLC). Presenting Author: 

Hidehito Horinouchi, Division of Internal Medicine and Thoracic Oncology, 

National Cancer Center Hospital, Tokyo, Japan 

Background: The optimal dose of radiotherapy remains unclear in concurrent 

chemoradiotherapy for unresectable stage III NSCLC. We previously 

concluded that the recommended dose for further trial was 72Gy in a phase 

I study (Sekine et al., Int J Radiat Oncol Biol Phys. 953-959, 2012). 

Methods: Eligible patients (unresectable stage III NSCLC, age between 20 

and 74, PS 0-1, V20 � 30%) received cisplatin (80 mg/m2 day 1) and 

vinorelbine (20 mg/m2 days 1 and 8) repeated every 4 weeks for 3-4 cycles. 

The 3D-CRT started at the first day of chemotherapy at a total dose of 72 Gy 

in 36 fractions. The primary endpoint was a 2-year survival rate and the 

planned sample size was 60 to reject the rate of 45% under the expectation 

of 65% with a power of 90% and an alpha error of 5%. Results: Thirty-one 

patients from 4 institutions were enrolled between May 2009 and March 

2010. This trial was terminated early due to slow accrual and grade 5 

pulmonary toxicities in 2 patients. There were 25 men and 6 women with a 

median (range) age of 59 (32-72) years. Of these, 23 had adenocarcinoma 

and 21 had stage IIIA disease. The median (range) V20 value was 20 

(9-30). The full planned dose of radiotherapy could be administered in 30 

(97%) patients, and 26 (84%) of the patients received 3-4 cycles of 

chemotherapy. During the chemoradiotherapy, grade 3-4 febrile neutropenia, 

infection and esophagitis were noted in 5, 4 and 1 of the 31 patients, 

respectively. After completion of the planned chemoradiotherapy, 5 patients 

had grade 3 or higher radiation pneumonitis, and 2 (6%) of these 

patients died at 6.6 and 7.3 months after the treatment started. The overall 

response rate was 97% (95% confidence interval: 83.3-99.9). Twenty-four 

patients are alive and thirteen patients experienced recurrence (2 had 

loco-regional recurrences, 7 had distant recurrence and 4 had mixed 

recurrence pattern) at a median follow up of 16.4 months. Conclusions: 

Concurrent high-dose (72Gy) 3D-CRT with chemotherapy using cisplatin 

and vinorelbine may have a too excessive incidence of pulmonary toxicities 

to warrant any further evaluation. 


Mediastinal lymph node examination and survival in resected early-stage 

non-small cell lung cancer in the Surveillance, Epidemiology, and End 

Results (SEER) database. Presenting Author: Raymond U. Osarogiagbon, 

Boston Baskin Cancer Foundation, Germantown, TN 

Background: Pathologic nodal stage is a key prognostic factor in resectable 

non-small cell lung cancer (NSCLC). Mediastinal lymph node (MLN) 

metastasis connotes a poor prognosis. Yet, some NSCLC resections in the 

US do not include MLN examination. Methods: We analyzed SEER data 

from 1998 to 2002 to quantify the long-term survival impact of failure to 

examine MLN in resected NSCLC. We used Kaplan-Meier methods to 

compare the unadjusted survival difference between patients with, and 

without, MLN examination. We used Cox proportional hazards and competing 

risk models to serially adjust for the impact of risk factors on survival 

differences. Results: Sixty-two percent of patients with pathologic N0 or N1 

NSCLC had no MLN examined. Men, African-Americans, patients with 

more advanced stage, and those who had less than pneumonectomy were 

less likely to have MLN examination. Five-year all-cause mortality (46.9% v 

51.7%, p�.001), and lung cancer-specific mortality (31.5% v 36%, 

p�.001), rates were higher in those without MLN examination. After 

adjustment for potential confounders, MLN examination was associated 

with a 6% reduction in all-cause mortality (HR, 0.94; CI, 0.89-0.99; 

p�.014), and 10% reduction in lung cancer-specific mortality (HR, 0.90; 

95% CI, 0.84-0.96; p�.002) rates. The excess risk in 1 year’s cohort of 

U.S. lung resections was 2,700 lives over 5 years. Conclusions: Failure to 

examine MLN was a common practice in �MLN-negative� NSCLC resections, 

which significantly impaired long-term survival. Efforts to understand 

the etiology of this quality gap, and measures to eliminate it, are warranted. 


Anatomic segmentectomy versus lobectomy for clinical stage I non-small 

cell lung cancer: A propensity-matched analysis. Presenting Author: 

Matthew J. Schuchert, Department of Cardiothoracic Surgery, University of 

Pittsburgh Medical Center, Pittsburgh, PA 

Background: Although anatomic segmentectomy is considered a “compromised” 

procedure by many surgeons, new information from several retrospective, 

single-institution series has countered negative premises regarding 

tumor recurrence and patient survival. The primary objective of this study 

was to utilize propensity score matching to compare outcomes following 

these anatomic resection approaches for stage I NSCLC. Methods: Patients 

undergoing lobectomy (n�392) vs. segmentectomy (n�793) for clinical 

stage I NSCLC were matched 1:1 using a propensity score that accounted 

for the potential confounding effects of pre-operative patient variables. 

Matching based on propensity scores produced 312 patients in each group. 

Primary outcome variables included recurrence-free and overall survival. 

Factors affecting survival were assessed by proportional hazards (Cox) 

regression and Kaplan-Meier survival function estimates. Results: Perioperative 

mortality was 1.2% in the segmentectomy group and 2.5% in the 

lobectomy group (p�0.38). Ninety-day mortality was 2.6% and 4.8% 

(p�0.20), respectively. At a mean follow-up of 5.4 years, no differences 

were noted in locoregional (5.5% vs. 5.1%, p�1.00), distant (14.8% vs. 

11.6%, p�0.29) or overall recurrence rates (20.2% vs. 16.7%, p�0.30) 

when comparing segmentectomy with lobectomy. Furthermore, no significant 

differences were noted in time to recurrence (p�0.415) or overall 

survival (p�0.258) when comparing the matched groups. Five year 

freedom from recurrence (95% CI) was: Segment 0.70 [95% CI: (0.63, 

0.78) vs. Lobe 0.71 [95% CI: 0.64, 0.78]. Overall survival (95% CI) was: 

Segment 0.54 [95% CI: (0.47, 0.51) vs. Lobe 0.60 [95% CI: 0.54, 0.67]. 

Segmentectomy was not found to be an independent predictor of recurrence 

(HR: 1.11, 95% CI: 0.87, 1.40) or overall survival (HR � 1.17, 95% 

CI: 0.89.1.52). Conclusions: In this large propensity-matched comparison, 

anatomic segmentectomy is associated with similar time to recurrence and 

overall survival rates when compared to lobectomy for clinical stage I 

NSCLC. These results will need further validation by prospective, randomized 

trials (CALGB 140503). 



7072^ General Poster Session (Board #38G), Sat, 1:15 PM-5:15 PM 

Size distribution and metastasis in discarded intrapulmonary lymph nodes 

(LN) after lung cancer resection. Presenting Author: Laura Elizabeth Miller, 

University of Tennessee Health Science Center, Memphis, TN 

Background: Lymph node (LN) status is the most important prognostic 

determinant after resection of lung cancer. 18% of a SEER cohort and 12% 

of a Memphis cohort had no LNs examined (pNx). Patients with pNx have 

inferior survival to T-category matched pN0 patients with at least 1 LN 

examined. The optimal number of LN needed to safely declare a patient 

pN0 may be �10. Less than 20% of resections in SEER achieve this. We 

hypothesized that a significant number of intrapulmonary LNs are left 

unexamined and some may harbor metastatic disease. We report the size 

characteristics of materials examined in a re-dissection protocol to test this 

hypothesis. Methods: Prospective study of lung resection specimens redissected 

after signout of the final pathology report. Remnant lung material 

was dissected with thin cuts and all LN-like material was retrieved for 

microscopic examination, irrespective of size or location. The size of 

non-LN tissue, LN without metastasis and LN with metastases were 

compared using the Wilcoxon-Mann-Whitney test. Results: 112 specimens 

were examined and 1,094 LN-like materials were retrieved. 749 (69%) 

proved to be LN tissue. 71 (10%) LNs retrieved had metastasis. Non-LN 

tissue was significantly smaller than LN tissue (p�0.0001). LNs with 

metastasis were significantly larger than those without metastasis (p 

�0.0001). 60% of materials �2cm were LNs with metastasis. 7% of 

materials �1cm were LN with metastasis. 52% of LNs with metastasis, 

and 55% of LNs without metastasis measured from 0.5 to 1.5cm (Table). 

Majority of LNs �2cm had metastatic disease, but 40% did not; a notable 

proportion of LNs with metastasis were small. Nearly equal percentages of 

LNs with and without metastasis were found in the range of 0.5-1.5cm. 

Conclusions: Statistical differences in size between lymph nodes with and 

without metastasis is clinically meaningless due to broad overlap. LN size 

alone is not an adequate predictor of LN metastasis. 

Size (cm) Size range (cm), n (%) 

Mean Median 0-0.5 >0.5-1 >1-1.5 1.5-2 >2 

Non-LN, n�345 0.48 0.4 252 (73) 66 (19) 17 (5) 10 (3) 0 (0) 

LN without 0.69 0.6 281 (42) 302 (45) 72 (11) 15 (2) 8 (1) 

metastasis 

n�678 

LN with 1.32 1.2 8 (11) 20 (28) 17 (24) 14 (20) 12 (17) 

metastasis 

n�71 


Factors influencing recurrence following anatomic lung resection for 

non-small cell lung cancer. Presenting Author: Rodney Jerome Landreneau, 

University of Pittsburgh Shadyside Medical Center, Pittsburgh, PA 

Background: Anatomic lung resection provides the patient with the best 

chance for cure in the setting of early-stage non-small cell lung cancer 

(NSCLC). Despite complete (R0) resection, up to 20-30% of patients will 

develop recurrent disease. In the current study, we analyze the impact of 

surgical and pathologic variables upon recurrence patterns following 

anatomic lung resection for clinical stage I NSCLC. Methods: A total of 

1,192 patients (394 segmentectomies, 805 lobectomies) with clinical 

stage I NSCLC were evaluated. The primary outcome variable was recurrence. 

Multivariate analysis was performed based upon clinical (age, 

gender, comorbidities), surgical (operation, approach, surgical margin) and 

pathological (pleural invasion, tumor size and histology) variables. Predictors 

of recurrence were identified by proportional hazards regression. 

Differences in recurrence patterns between groups are illustrated by log 

rank tests applied to Kaplan-Maier estimates. Results: A total of 243 

recurrences (20.3%) were recorded at a mean follow-up of 35.6 months 

(71 locoregional, 172 distant). There was no significant difference in 

recurrence patterns when comparing segmentectomy and lobectomy. 

Multivariate analysis demonstrated that a margin:tumor ratio � 1, angiolymphatic 

invasion and the presence of only mild-moderate tumor inflammation 

were predictors of recurrence risk. Conclusions: Recurrence following 

anatomic lung resection is influenced predominantly by pathological 

variables (tumor size, angiolymphatic invasion, tumor inflammation). 

Optimization of surgical margin in relation to tumor size may improve 

outcomes. Extent of resection (segmentectomy vs. lobectomy) does not 

appear to have an impact on recurrence-free survival when adequate 

margins are obtained. These data have implications regarding the potential 

use of adjuvant therapy in selected Stage I patients at high risk for 

recurrence. 

Segmentectomy 

(n�394) 

Lobectomy 

(n�805) P value 

Recurrence 81(20.4%) 162 (20.1%) 0.88 

Locoregional 23 (5.9%) 48 (6.0%) 1.00 

Distant 58 (11.9%) 114 (14.1%) 0.79 

5-yr freedom from recurrence 69% 70% 0.53 

469s 


N0321: A phase II study of bortezomib, paclitaxel, carboplatin (CBCDA), 

and radiotherapy (RT) for locally advanced non-small cell lung cancer 

(NSCLC). Presenting Author: Steven E. Schild, Mayo Clinic, Scottsdale, AZ 

Background: In preclinical studies, combinations of bortezomib and RT 

result in synergistic tumor killing (Cancer Chemother Pharmacol. 2007;59: 

207-15). Our group reported the results from the phase I portion of this 

study previously (J Clin Oncol. 200;28 (suppl; abstr 7085)). Based on 

these data, we undertook a phase II study of bortezomib in combination 

with paclitaxel/CBCDA and RT. Methods: Based on results from our 

previously reported phase I trial, systemic therapy included bortezomib 

(1.2 mg/m² IV days 1,4,8,11), paclitaxel (175 mg/m² IV day 2), and 

carboplatin (CBCDA; AUC�6 day 2) given every 3 weeks for 2 cycles. 

Thoracic radiotherapy (RT) included 60Gy/30 daily fractions starting day 1. 

The primary endpoint was the 12-month survival rate. If 41 or more of these 

60 patients (68%) were alive at least 12 months after study entry, the trial 

would be deemed as positive and further study would be warranted. Results: 

27 pts were enrolled to the phase II portion: M/F�17/10; stage IIIA/ 

IIIB�13/14; ECOG PS 0/1�9/18; and median age: 58 (range 43-79). 18 

pts (67%) completed therapy per protocol. At a planned interim analysis, 

23 of 26 evaluable patients (88.5%, 95% CI: 70-98%) survived for at least 

6 months, which exceeded the boundary of 21 or more needed to continue 

to full accrual. This trial could have continued per protocol, but was closed 

early due to slow accrual. With a median follow-up of 15.0 months in the 

17 patients still alive, the 12-month survival rate was 71% (95% CI: 49 – 

85). The median OS was 19 months (95% CI: 11 – no upper). Grade 3 or 

higher adverse events (regardless of attribution) were reported in 22 (82%) 

patients. Grade 4/5 adverse events were reported in 15 (56%) patients. 

There was one grade 5 event (pneumonitis). The most common (5 or more 

patients) grade 3/4 adverse events were fatigue (22%), leukopenia (63%), 

neutropenia (67%), and thrombocytopenia (44%). Conclusions: The addition 

of bortezomib resulted in high levels of severe hematologic toxicity, but 

also demonstrated evidence of activity with a 12-month survival rate of 

71% and a median OS of 19 months. Further testing of this regimen in a 

larger study appears warranted. 


The Lung Cancer Symptom Scale (LCSS) as a prognostic indicator of overall 

survival in malignant pleural mesothelioma (MPM) patients: Post hoc 

analysis of a phase III study. Presenting Author: Ping Wang, Eli Lilly and 

Company, Indianapolis, IN 

Background: To determine the patients likely to benefit from therapy, 

clinicians seek factors associated with outcomes. This analysis investigates 

prognostic effect of baseline patient-reported symptoms on overall survival 

(OS) in the presence of demographic/clinical factors among MPM patients. 

Methods: Intent-to-treat patients (N�448) were included in the analysis. 

LCSS consists of 6 symptom items and 3 general items, each ranging from 

0 (no symptoms) to 100 (worst). Average symptom burden index (ASBI) 

was the mean of 6 symptom items. Patients were classified into subgroups 

based on ASBI: low symptom burden (LSB; ASBI�25) and high symptom 

burden (HSB; ASBI �25). Univariate Cox models were used to determine 

the prognostic effect of 7 demographic/clinical factors, 9 LCSS items, and 

ASBI on OS. Multivariate Cox model was used to determine the prognostic 

effect of ASBI in the presence of 7 demographic/clinical factors. Kaplan- 

Meier curves of OS were generated for patients with LSB and HSB and 

compared using both univariate and multivariate Cox models. Results: In 

the univariate analysis, significant prognostic effects on OS were observed 

for baseline Karnofsky performance status (KPS; 90-100 vs. 70-80, hazard 

ratio [HR]�0.45, p�0.0001) and baseline stage (I/II/III vs. IV, HR�0.63, 

p�0.0001). In addition, significant prognostic effects were observed for 5 

LCSS symptom items (anorexia, cough, dyspnea, fatigue, and pain), 3 

LCSS general items (interference with activity level, symptom distress, and 

quality of life; HRs�1.08-1.20 for every 10 points worsening, all p�0.02), 

as well as ASBI (HR�1.32, p�0.0001). In the multivariate Cox model, 

ASBI remained a significant prognostic factor of OS (HR�1.22, p�0.0001), 

along with baseline KPS and stage. Patients with LSB (N�265) had 

significantly better OS than those with HSB (N�181) (12.9 vs. 6.9 

months, HR�0.46, unadjusted p�0.0001; HR�0.59, p�0.0001 adjusted 

for the 7 demographic/clinical variables). Conclusions: The results 

suggest that baseline patient-reported symptoms as measured by LCSS 

provide distinct prognostic information in the presence of demographic and 

clinical measures in MPM. 




NGR-hTNF as second-line treatment in malignant pleural mesothelioma 

(MPM). Presenting Author: Gilda Rossoni, Department of Oncology, Istituto 

Scientifico San Raffaele, Milan, Italy 

Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) 

peptide for selectively targeting tumor necrosis factor (TNF) to cancer 

endothelial cells. Tumor hypervascularity is an independent predictor of 

poor overall survival (OS) in MPM patients (pts). Methods: We report 

long-term results of a phase II trial that assessed NGR-hTNF in MPM pts 

with performance status (PS) � 2 and radiologic progressive disease (PD) 

after a pemetrexed-based regimen. NGR-hTNF was given at 0.8 �g/m2 every 3 weeks (q3w) in 43 pts and weekly (q1w) in 14 pts. Primary endpoint 

was progression free survival (PFS), with restaging done q6w by MPMmodified 

RECIST criteria, while secondary aims included disease control 

(DC) rate and OS. We also tested the impact on outcome of neutrophil to 

lymphocyte ratio (NLR) at baseline (median 3; interquartile range 2-5). 

Median follow-up was 32.5 months (95% CI 27.5-37.5). Results: Baseline 

characteristics were (n�57): median age 57 years; M/F 35/22; PS 0/1-2 

31/26; EORTC score good/poor 45/12. Median treatment free interval on 

prior therapy was 4.3 months. Only one drug-related grade � 3 adverse 

events (AEs) was noted, common grade 1/2 AEs being transient chills 

(75%). No higher toxicity was reported using the q1w schedule. Median 

PFS was 2.8 months (95% CI 2.2-3.3). DC rate was 46% (95% CI 32-59; 

26/57 pts; 1 partial response, 25 stable diseases) and was maintained for a 

median time of 4.7 months (95% CI 4.0-5.4). OS rates at 1 and 2 years 

were 47% and 16%, respectively. Median OS was longer in pts with DC 

than in those with early PD (16.2 and 8.3 months, respectively; p�.02). 

According to schedule, 6-month PFS rates were 11% and 36% and 2-year 

OS rates were 12% and 29% for q3w and q1w, respectively. In pts with DC, 

median PFS were 4.4 and 9.1 months and median OS were 13.3 and 24.8 

months for q3w and q1w, respectively. By Cox analyses, a PS of 0 (p�.01) 

and a low baseline NLR (p�.004) were the only variables associated with 

improved OS. Median OS in pts stratified by NLR � 2,3to4,and�5were 15.7, 10.5, and 4.2 months, respectively (p�.0002 for trend). Conclusions: 

NGR-hTNF showed promising PFS and OS in this study. A double-blind 

phase III trial is currently testing best investigator choice � NGR-hTNF 

q1w in pemetrexed-pretreated MPM pts (NCT01098266). 


Elevated PDGFRB gene copy number gain as prognostic in resected 

malignant pleural mesothelioma. Presenting Author: Anne S. Tsao, University 


Background: PDGF/PDGFR pathway has been implicated in malignant 

pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the 

incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway 

protein expression by immunohistochemistry (IHC) in the tumor cell 

cytoplasm, membrane, nucleus, and stroma, and correlate it to patient 

clinical outcome. Methods: 88 archived tumor blocks from resected MPM 

with full clinical information were used to perform the analyses. IHC 

biomarkers for PDGFR�,� and p-PDGFR�, and fluorescence in situ 

hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s 

rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP 

plots, and Kaplan-Meier method were used to assess the biomarkers and 

their correlation to clinical outcome. Results: There were several correlations 

identified between the IHC biomarkers; however, none associated 

with patient demographics or histology subtype, with the exception of high 

cytoplasmic PDGFR� occurring in patients with no prior known asbestos 

exposure (p�0.029). In the CNG analysis, PDGFRB gene CNG in � 10% of 

tumor cells had lower cytoplasmic p-PDGFR� (p�0.029), while PDGFRB 

gene CNG in � 40% of tumor cells had a higher cytoplasmic PDGFR� 

(p�0.04). PDGFRB gene CNG status did not associate with patient 

demographics or tumor characteristics. Patients with PDGFRB CNG � 

40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25 

(95% CI 0.09, 0.72), p�0.0096]. In the patients with PDGFRB CNG � 

40% of cells, the addition of chemotherapy appeared to also improve RFS 

(p�0.017). In the multi-covariate analyses for RFS, there was no association 

with any IHC biomarker. In the overall survival (OS) analysis, having 

PDGFRB gene CNG � 40% of tumor cells correlated with an improved OS 

[HR 0.32 (95% CI 0.11, 0.89), p�0.029] and the addition of perioperative 

chemotherapy led to a trend towards improved OS (p�0.089). 

Conclusions: PDGFRB CNG � 40% of tumor cells is a potential prognostic 

biomarker in surgically resected MPM tumors. Adding chemotherapy to 

patients with PDGFRB CNG � 40% of cells improved RFS and led to a 

trend towards improved OS. Future validation of this biomarker in prospective 

trials is needed. 


Phase II trial of anti-transforming growth factor-beta (TGFß) monoclonal 

antibody GC1008 in relapsed malignant pleural mesothelioma (MPM). 

Presenting Author: James Stevenson, University of Pennsylvania, Philadelphia, 

PA 

Background: TGF� is a pleiotropic cytokine overexpressed by MPM. Based 

on preclinical data documenting a key role for TGF� in promoting growth 

and progression of MPM, we are conducting a phase II trial of GC1008 in 

patients (pts) with progressive MPM. Methods: Pts with progressive MPM by 

modified RECIST criteria and PS 0-1 with 1-2 prior systemic therapies (at 

least 1 pemetrexed-based) are eligible. Treatment plan: GC1008 3mg/kg 

IV over 90 minutes every 21 days. Responses are assessed by modified 

RECIST every 6 weeks. The primary endpoint is progression-free survival 

(PFS) rate at 3 months; secondary objectives include safety with GC1008, 

response rate by modified RECIST, time to progression (TTP), and overall 

survival (OS). Results: The modified Gehan stage 1 stopping criterion of 

1/13 pts with 3 month PFS has been exceeded. To date, 13 pts (10 PS 0; 3 

PS 1) with MPM (median age 69; 2F, 11M; 11 epithelial, 1 sarcomatoid, 1 

biphasic) enrolled. Treatment-related toxicities include G1/2 fatigue (3 

pts), nausea (1 pt) and xerosis (1 pt). Other adverse events possibly related 

to GC1008 were rapid disease progression in 1 pt after 2 cycles, and G2 

skin keratoacanthoma in 1 pt after 5 cycles. Three pts met the primary 

objective of 3 month PFS at 4.1, 4.2 and 9 months each. Stable disease 

(SD) was seen in 3 pts (23%). Median TTP is 1.4 months (95% CI 1.2-�); 

median OS is 13 months (95% CI 6-�). Increased serum mesothelin levels 

have closely tracked disease progression. Serum from 6/13 pts showed new 

antibodies against MPM tumor lysates as measured by immunoblotting. 

Two of 3 pts with SD had anti-tumor antibody responses. Mean baseline 

plasma level of TGF� was 2447 pg/ml but did not correlate with baseline 

plasma TGF� or TTP. Conclusions: GC1008 was well tolerated in pretreated 

MPM patients. SD occurred in 3 pts, all with prior disease progression. 

Evidence for humoral anti-tumor immunity was seen in nearly half of 

enrollees and in 2 of 3 pts with SD. OS compares favorably to prior 

single-agent studies in pretreated MPM. 

7079^ General Poster Session (Board #39F), Sat, 1:15 PM-5:15 PM 

Phase II trial of BNC105P as second-line chemotherapy for advanced 

malignant pleural mesothelioma (MPM): Australasian Lung Cancer Trials 

Group and NHMRC Clinical Trials Centre Collaboration. Presenting Author: 

Anna K. Nowak, School of Medicine and Pharmacology, University of 

Western Australia, Perth, Australia 

Background: BNC105P is a tubulin polymerization inhibitor that acts as a 

Vascular Disrupting Agent (VDA), has direct cytotoxic effects, and had 

preclinical and phase I activity in MPM. This aim of this study was to 

determine activity and safety of BNC105P as second-line therapy after 

pemetrexed and a platin in MPM. Methods: Eligible patients had progressive 

MPM, prior pemetrexed and platinum, measurable disease by modified 

RECIST, ECOG 0-1, and adequate organ and cardiovascular function. 

Important exclusions included recent thromboembolic, cardiovascular or 

cerebrovascular disease, or therapeutic anticoagulation. Pts received 

BNC105P (16 mg/m2 IV) Day 1 � 8 q21d until progression or toxicity. The 

primary endpoint was centrally reviewed objective tumour response rate 

(RR); the Simon 2-stage design assumed a RR of interest of 20% and a RR 

of no interest of 5%, with � � � � 0.05. Continuation past first stage 

accrual required �1 objective response in 24 patients. Results: 30 subjects 

were accrued over 10 months (90% male; median age 65 (range 41-83); 

77% ECOG PS 1; histology epithelioid (67%), biphasic (10%), sarcomatoid 

(7%), other/unspecified (17%)). All pts received at least one dose of 

study drug; pts received a median of 2 cycles and median dose intensity 

was 100%. No significant haematologic, biochemical, peripheral neurotoxic 

or cardiac adverse events (AEs) including hypertension were observed. 

Grade 3 or 4 AEs occurred in 10 pts (33%). There were 2 deaths on study: 1 

due to stroke, the other due to pneumonia and respiratory failure. We 

observed 1 partial response (3%) and 13 pts with SD as their best response 

(43%). Median progression free survival was 1.5 mo (95% CI 1.4-2.4); 

median overall survival was 8.7 mo (95% CI 3.8-NR). Lung function and 

QOL data was collected. Biomarker analyses correlating to pharmacological 

changes induced by BNC105P are ongoing and will be presented. 

Conclusions: BNC105P was safe and tolerable but its single agent response 

rate failed to meet the pre-specified primary endpoint of interest. 




Circulating tumor cell (CTC) as a significant clinical marker in epithelioidtype 

malignant pleural mesothelioma (MPM). Presenting Author: Kazue 

Yoneda, Hyogo College of Medicine, Nishinomiya, Japan 

Background: Circulating tumor cell (CTC) is a surrogate of distant metastasis, 

and our preliminary study suggested that CTC detected by an 

EpCAM-based immuno-magnetic separation system (“CellSearch”) was a 

useful clinical marker in the diagnosis of malignant pleural mesothelioma 

(MPM) (Tanaka F. et al ASCO 2008). Methods: Patients who presented at 

our institute to receive pleural biopsy with suspicion of MPM were 

prospectively enrolled. CTCs in 7.5mL of peripheral blood were quantitatively 

evaluated with the CellSearch system. Results: Among 136 eligible 

patients, 104 were finally diagnosed with MPM, and 32 were with 

non-malignant diseases (NM). CTC was positive (CTC�1) in 32.7% 

(37/104) of MPM pts, and in 9.4% (3/32) of NM pts (p�0.011). 

CTC-count was significantly higher in MPM (range, 0-9) than in NM (range, 

0-1; p�0.007). According to a ROC curve analysis, the CTC-test provided a 

significant diagnostic performance in discrimination between MPM and 

NM (AUC� 0.623; P�0.036). Among MPM pts, CTC-positivity and 

CTC-count were significantly increased with tumor progression (p�0.026 

and p�0.008, respectively). For all MPM pts, there was no significant 

difference in overall survival between CTC-positive and negative pts. 

However, in a planned subset analysis, CTC was a significant factor to 

predict poor prognosis (median survival time, 8.0 months for CTC-positive 

pts, and 20.3 months for negative pts; p�0.012) in pts with epithelioidtype 

MPM in which CTC was exclusively positive; a multivariate analysis 

confirmed that CTC, along with PS, was an independent prognostic factor 

(HR�2.38; P�0.006). Conclusions: CTC was a significant diagnostic 

marker in discrimination between MPM and NM. CTC-positivity was a 

significant and independent prognostic factor to predict a poor prognosis of 

epithelioid MPM. 

Epithelioid Non-epithelioid 

No. of pts 79 25 

CTC-positive pts 32 (40.5%) 2 (8.0%) 

OS (median) 8.0m (CTC�1) vs. 20.3m 3.3m (CTC�1) vs. 5.7m 

(CTC�0) 

(CTC�0) 

(p�0.012) 

(p�0.482) 


Malignant pleural mesothelioma (MPM) in elderly patients: A multicenter 

survey. Presenting Author: Federica Grosso, Oncology SS Antonio e Biagio 

General Hospital, Alessandria, Italy 

Background: The incidence of malignant pleural mesothelioma (MPM) in 

elderly patients (pts) is increasing in Western countries. Elderly pts with 

MPM are under-represented in clinical trials, and there are no specific 

guidelines for their management. The aim of this study was to perform a 

retrospective survey on this patient population in four Oncology Departments 

with high MPM accrual and expertise. Methods: The clinical records 

of elderly pts (�70 years old) with MPM referred to the participating 

centers from January 2005 to November 2011 were reviewed. For each 

patient, age and gender, histology, Eastern Cooperative Oncology Group 

Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and 

treatment modalities were collected. The study endpoint was overall 

survival (OS). Results: Out of a total of 610 cases, 210 elderly pts were 

identified (34% of the whole MPM population observed in the study 

period). Pts characteristics were: median age 75 yrs (range 70-92), M/F 

132/78, epithelial/non-epithelial histology 140/70, ECOG-PS 0/1/2/ 

unknown 130/67/9/4. CCI was 0 in 128 pts (61%), �4 in 59 pts (28%). 

Treatment was multimodality therapy including surgery in 16, chemotherapy 

in 153 (73%) and best supportive care only in 41 pts (19%). 

Chemotherapy was mainly pemetrexed-based. Median OS was 11.3 months. 

Non-epithelial histology, age �75 yrs and the presence of comorbidities 

(CCI �1, p�.003; CCI �4, p�0.0001) were significantly correlated to a 

shorter OS. Conclusions: Pemetrexed-based chemotherapy is feasible in 

selected elderly pts with MPM. Comorbidity is a significant prognostic 

factor, and should be carefully considered in patient selection. Prospective 

dedicated trials in elderly pts with MPM selected according to comorbidity 

scales are warranted. 

471s 


Phase II study of bortezomib with cisplatin as first-line treatment of 

malignant pleural mesothelioma (MPM): EORTC 08052. Presenting Author: 

Mary O’Brien, The Royal Marsden Hospital, Sutton, United Kingdom 

Background: Cisplatin is one of the most active drugs available in MPM 

while bortezomib has shown some activity in single agent phase II studies 

against MPM. This was a prospective phase II study of cisplatin and 

bortezomib (CB) in the first line treatment of MPM. Methods: Patients with 

histological proven MPM, with performance status (PS) 0/1, were eligible. 

The doses were cisplatin 75mg/m2 /3 wks and bortezomib 1.3mg/m2 day 1, 

4, 8, 11 every 3 wks. The primary end-point was progression free survival 

rate at 18 wks (PFSR�18). The 2-stage Simon design (a�0.1; b � 0.05, 

P0�0.50 and P1�0.675) was used. In the first step of the study 37 eligible 

patients were planned. If more than 19 patients were alive and free of 

progression at 18 wks the total sample size was increased to 76 eligible 

patients. Results: Between 2007 and 2010 82 patients were entered. The 

median follow-up time is 32.3 months The median age was 55 years 

(range: 22-77yrs), male/female: 55/27 , PS 0/1: 9/73, Stage T1: 10%; T2: 

42%, T3: 25%; T4: 23% and N0: 57%; N1: 4%; N2: 33%; N3: 6%. The 

median number of cycles received was 4 and 38% received 6 cycles. 

Cisplatin/ bortezomib dose intensity was 98/ 80%. Toxicity (grade 3/4): 

neutropenia 10%, thrombocytopenia 11%, anaemia 1%. Grade 3-4 

hyponatraemia/ hypokalaemia occurred in 46/ and 17%. Grade 2 tinnitus, 

grade 3 fatigue occurred in 16%, and 12%, of patients. Motor/sensory/ 

other neurotoxicity was grade 1: 6/28/7%, grade 2: 2/26/2% and grade 3: 

1/7/2% respectively. There were 2 toxic deaths at 32 and 74 days due to 

acute pneumonitis and cardiac arrest. The PFRS-18 (including symptomatic 

progression) was 53% (80% confidence intervals, CI, 42-64%). The 

overall survival was 13.5 months (95% CI 10.5-15) with 56% (95% CI 

44-66%) alive at 1 year. The PFS was 5.1 months (95% CI 3.3-6.5). 

Conclusions: On the basis of the PFRS-18, the null hypothesis could not be 

rejected, although CB gave predictable toxicity and was as active as other 

reported regimens in MPM. 


SWOG 0722: A phase II study of mTOR inhibitor everolimus (RAD001) in 

malignant pleural mesothelioma (MPM). Presenting Author: Linda L. 

Garland, Arizona Cancer Center, Tucson, AZ 

Background: MPM preclinical studies demonstrate activation of AKT 

pathway proteins, including mTOR, and provide the rationale to test 

everolimus, an mTOR inhibitor, in MPM. Methods: Unresectable MPM 

patients (pts) after 1-2 systemic regimens (including a platinum-based 

regimen), with PS 0-1, measurable disease and adequate organ function 

were treated with daily oral everolimus 10 mg. Study endpoints were 

progression-free survival (PFS) at 4 months, response rate,overall survival 

(OS), and frequency/severity of toxicities. Results: 61 pts were registered 

between 12/2008 and 9/2011; there were 57 evaluable pts for the primary 

endpoint of 4-month PFS. Median age was 65.9 yrs; M/F 43/14; prior 

regimens (1/2: 58%/42%); PS 0/1 (21%/79%); epithelial subtype 61%; 

biphasic 7%; NOS 28%; pending 4%. 5 pts remain on treatment. 

Preliminary data for 35 of 57 pts are as follows: RR 0% by standard RECIST 

and DCR of 14/35 (40%); data by mod RECIST are not yet available. 

Estimated 4-month PFS was 34% with an estimated median PFS of 3 

months. The null hypothesis of 4-month PFS � 30% could not be rejected 

(p�0.28). 41 pts have died; median OS is estimated at 5 months. Frequent 

grade 1-3 toxicities were fatigue (55.4%), hypertriglyceridemia (41.1%), 

anemia (39.3%), nausea (33.9%), oral mucositis (32.1%), anorexia 

(32.1%), diarrhea (26.8%), and hyperglycemia (26.8%). One pt each had 

grade 4 and grade 5 dyspnea. Conclusions: The trial did not achieve the 

primary endpoint of an improvement of PFS at 4 months from 30% to 50%. 

Inhibition of mTOR using single agent everolimus is not active in unselected 

MPM patients. Other strategies for targeting the activated AKT 

pathway in MPM remain of interest. 




Outcomes of sarcomatoid malignant pleural mesothelioma, a distinct 

clinical entity. Presenting Author: Elisabetta Gattoni, Oncology ASL21, 

Casale Monferrato, Italy 

Background: Sarcomatoid malignant pleural mesotheliomas (SMPM), accounting 

for 10% of MPM, are resistant to chemotherapy (CT) with median 

survival in the range of 6 months. Here we report on clinical outcome of a 

large series of SMPM patients treated at our Oncological Department, 

located in a particularly asbestos-polluted area in Piedmont (Italy). 

Methods: Patients consecutively diagnosed, treated and included in our 

MesoDB between 1993 and 2010 were considered for this study. Clinical 

and pathological data, treatments, response to CT and outcomes were 

analyzed for the present study. Diagnosis was always confirmed by the same 

expert pathologist. Results: Data of 672 patients were considered for the 

analysis. Among these, 53 (8%) were diagnosed with SMPM (17F/36M). 

Median age was 67,6 years. Asbestos exposure was occupational certain in 

12, possible in 15, domestic in 3 and environmental in 23. The predominant 

symptom at diagnosis was thoracic pain in 34 patients (64%), 

followed by dyspnea in 16 (30%), fatigue and weight loss in 2 and palpable 

mass in 1. The predominant radiological finding at diagnosis was diffuse 

pleural thickening in 23 patients (43%), pleural effusion in 14 (26%), 

pleural effusion and pleural thickening in 10 (19%), localized mass in 4 

(8%), unknown in 2 (4%). Forty-eight patients received first line CT with 

the following regimens: carboplatin/cisplatin and pemetrexed in29, pemetrexed 

in 8, cisplatin and raltitrexed in 3, cisplatin and gemcitabine in 3, 

gemcitabine in 2, doxorubicin based combination in 3 patients. The 

median number of cycles was 4. Overall response rate to first line CT was as 

follows: 11 SD (21%), 31 PD (58%) and 6 (11%) patients were not 

evaluable for response. Median progression free survival was 3.3 (95%CI 

2.6-4.1) months. Eleven patients received a second line CT and no 

responses or disease stabilization was observed. Median OS was 7.6 

months. Conclusions: This large series of SMPM suggests that standard CT 

has only negligible impact on the prognosis, underlying a highly unmet 

clinical need. SMPM patients should be treated within phase I-II studies 

with investigational agents. Research should focus to a deeper knowledge 

of tumor biology and to the identification of druggable targets. 


Phase II study of amrubicin (AMR) combined with carboplatin (CBDCA) for 

refractory relapsed small cell lung cancer (SCLC): North Japan Lung Cancer 

Group 0802. Presenting Author: Ryota Saito, Tohoku University Hospital, 

Sendai, Japan 

Background: AMR, a new anthracycline agent, has achieved some promising 

results for advanced SCLC both in the first-line and the second-line 

setting. However the efficacy of AMR alone against refractory relapsed 

SCLC was relatively low in previous studies. This study was conducted to 

evaluate the safety and efficacy of the combination of AMR plus CBDCA in 

patients with refractory relapsed SCLC. Methods: Patients with advanced 

SCLC who relapsed within 90 days after the completion of first-line 

chemotherapy received AMR (30 mg/m2 , day1-3) and CBDCA (AUC 4.0, 

day 1) every 3 weeks. The primary endpoint of this study was overall 

response rate (ORR), and secondary endpoints were progression-free 

survival (PFS), overall survival and toxicity profile. Assuming that ORR of 

45% in eligible patients would indicate potential usefulness while ORR of 

20% would be the lower limit of interest, with alpha � 0.10 and beta � 

0.10, at least 24 patients were required. Results: From September 2008 to 

May 2011, 30 patients were enrolled from 10 institutions. One patient was 

excluded because of ineligible histology. Patient characteristics were: 

Male/Female 26/3; median age 67 (range 50-81); Performance status 

0/1/2 9/16/4. The median number of treatment cycles were 4 (range 1-7). 

The objective responses evaluated by RECIST were: CR 0, PR 10, SD 14, 

PD 5. The ORR was 34% and the disease control rate was 83%. Median 

PFS was 3.5 months and median survival time was 7.3 months. Grade 3-4 

neutropenia was observed in 23 patients (79%) and grade 3-4 thrombocytopenia 

was observed in 7 patients (24%). One patient (3%) suffered from 

grade 3-4 febrile neutropenia. Other grade 3 non-hematological toxicities 

such as infection, interstitial lung disease, hyponatremia, hypoglycemia, 

were observed in 7 patients (24%). No treatment related death was 

observed. Conclusions: This is the first prospective study of AMR combined 

with CBDCA for refractory relapsed SCLC, which was effective and well 

tolerated. Further investigation of this treatment is warranted. 


NGR-hTNF and doxorubicin in relapsed small-cell lung cancer (SCLC). 

Presenting Author: Raffaele Cavina, Humanitas Cancer Center, Rozzano, 

Italy 

Background: By selectively damaging tumor vasculature, NGR-hTNF (asparagine-glycine-arginine 

human tumor necrosis factor) is able to improve 

intratumoral uptake of doxorubicin (D). A phase I trial selected NGR-hTNF 

0.8 �g/m2 /day(d)1 and D 75 mg/m2 /d1 every 3 weeks (q3w) for phase II. 

Methods: SCLC pts failing one or more platinum-based regimen received 

NGR-hTNF until progressive disease (PD) and D up to 550 mg/m2 . This 

phase II trial (n�27 pts) had progression-free survival (PFS) as primary end 

point, with tumor response assessed q6w by RECIST, while secondary end 

points included adverse events (AEs), disease control rate (DCR), and 

overall survival (OS). Results: Among 28 pts enrolled (median age 63 years; 

M/F 19/9; PS 0/1-2 13/15; prior lines 1/2-3 20/8), 16 pts had platinumresistant 

(R) disease (PD�3 months) and 12 pts platinum-sensitive (S) 

disease (PD�3 months). At baseline, median neutrophil to lymphocyte 

ratio (NLR) was 4 (range 1-20). A total of 114 cycles were given (range 

1-10), with 13 pts (46%) having � 4 cycles and 9 pts (32%) � 6 cycles. 

No grade 3/4 AEs related to NGR-hTNF were noted, while grade 1/2 AEs 

were transient chills (61%). NGR-hTNF did not apparently increase 

D-related AEs. Median PFS was 3.2 months (95% CI 2.6-3.8) and 1-year 

OS rate was 34%. Overall, DCR was 55% (95% CI 35-74), comprising 6 

partial responses (22%; median duration: 6.3 months) and 9 stable 

diseases (33%; median duration: 4.1 months). Mean changes from 

baseline in target tumor size after 2, 4, and 6 cycles were -9%, -29%, and 

-32%, respectively for R disease and -11%, -20%, and -43%, respectively 

for S disease. In pts pretreated with � 2 lines, DCR was 75%, median PFS 

was 5.1 months, and 1-year OS rate was 44%. In pts with R or S disease, 

DCR were 50% and 58% (p�.72), median PFS were 2.7 and 4.1 months 

(p�.07), and 1-year OS rates were 27% and 42% (p�.65), respectively. At 

multivariate analyses, PFS was not related to baseline characteristics, 

while an improved OS was associated only with a low NLR. The 1-year OS 

rate was 48% in pts with NLR � 4 and 10% in pts with NLR � 4(p�.007), 

while in pts with NLR � 4, 1-year OS rate was 46% in R disease and 50% 

in S disease. Conclusions: This combination is well tolerated and active in 

platinum resistant and sensitive SCLC and further development is of 

interest. 


Clinical trial design in small cell lung cancer: Surrogate endpoints and 

statistical evolution. Presenting Author: Myles Nickolich, Case Comprehensive 

Cancer Center, Cleveland , OH 

Background: Small cell lung cancer (SCLC) is a devastating disease for 

which little recent therapeutic advance has been achieved. SCLC trial 

design and reporting may have an impact on the interpretation of studies 

conducted. Furthermore the use of surrogate endpoints in SCLC has not 

been explored. Methods: Through examining all phase II and III SCLC trials 

published in the Journal of Clinical Oncology (8,471 patients from 66 trials 

between 1983-2010), we examined how SCLC trial reporting and design 

has evolved, determining if the type I error, power, and sample size 

calculations were provided. We assessed primary endpoints for all trials and 

sought to discover if response rate (RR) or progression-free survival (PFS) 

correlated with overall survival (OS). We analyzed response and survival 

outcomes for associations using Pearson correlation coefficient and differences 

between data groups by ANOVA followed by Tukey’s multiple 

comparison procedure. Results: There were increased reporting trends of 

statistical design in power (16.7% in 1986-1996 to 77.8% of trials in 

2006-2010 [p�0.001]) and type I error (22.2% in 1986-1996 to 72.2% 

in 2006-2010 [p�0.005]). 72.2% of trials published in 1986-1996 

failed to report a primary endpoint whereas only 5.56% of trials in 

2006-2010 failed to do so (p�0.004). Of phase II trials, primary endpoint 

was identified as RR in 65%, OS in 25%, and PFS in 10% (p�0.0001). 

There is a strong correlation between RR and both PFS (p�0.013) and OS 

(p�0.012) in extensive-stage disease (ED) but not limited-stage disease 

(LD) (p�0.978 for PFS, p�0.193 for OS). This correlation is for partial 

response rate (pRR) but not complete response rate. RR (p�0.029) 

exhibits a negative trend over time with a dramatic and significant decrease 

in RR across all studies starting in 2005. A strong positive correlation exists 

between PFS and OS for LD (p�0.036) and ED (p�0.058). We found no 

change in median overall survival (p�0.383). Conclusions: Over time there 

has been improvement in reporting the essential statistical data for proper 

interpretation of SCLC trials. No change in survival was seen over the past 

28 years. RR should be evaluated as a surrogate endpoint for OS in ED but 

not LD. pRR correlates with OS and PFS in both LD and ED. 




Efficacy of rechallenge chemotherapy in patients with sensitive relapsed 

small cell lung cancer. Presenting Author: Kazushige Wakuda, Division of 

Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan 

Background: Treatment efficacy of rechallenge chemotherapy recommended 

for patients with sensitive-relapse small cell lung cancer (SCLC) 

has not been fully clarified. Methods: We defined sensitive relapse as 

treatment-free interval (TFI) � 90 days. Sixty-five sensitive-relapse SCLC 

patients who received second-line chemotherapy at the Shizuoka Cancer 

Center between September 2002 and May 2011 were separated into those 

treated with rechallenge chemotherapy (rechallenge group) and those 

treated with other regimens (other group) for comparison and analysis of 

treatment efficacy. Results: No significant differences in age, gender, ECOG 

performance status at relapse, disease extent at diagnosis, or response to 

first-line treatment were found between the two groups, but TFI was 

significantly longer in the rechallenge group, which included 19 sensitiverelapse 

patients. The other group included 46 sensitive-relapse patients, 

21 of whom received amrubicin. There was no significant difference in 

overall survival (OS) between the two groups (median survival time (MST): 

rechallenge group 14.4 months, other group 13.1 months, p � 0.51). In 

the patients treated with amrubicin, MST was 12.6 months. Comparing the 

rechallenge group with the patients treated with amrubicin, there was also 

no significant difference in OS (p � 0.38). Both the rechallenge and other 

group included 11 patients with ex-sensitive relapse (TFI � 180 days). 

There was no significant difference in OS between the two groups (MST 

15.7 vs. 26.9 months, p � 0.46). Conclusions: Rechallenge chemotherapy 

did not prove superior to other chemotherapies, suggesting that monotherapy, 

such as amrubicin, might be reasonable as second-line chemotherapy 

for sensitive-relapse SCLC patients. 


Phase II trial of huKS-IL2 with cyclophosphamide (CTX) in patients with 

extensive disease small-cell lung cancer (ED-SCLC). Presenting Author: 

Oleg Gladkov, Chelyabinsk Regional Clinical Oncology Dispensary, Chelyabinsk, 

Russia 

Background: huKS-IL2 immunocytokine is a humanized antibody specific 

for EpCAM, fused at its Fc end to two molecules of IL2. Results of a phase 

1b study of huKS-IL2 plus low-dose CTX, and preclinical data, provided a 

rationale to evaluate this combination in SCLC, which is often EpCAMpositive. 

Methods: Patients (pts) with ED-SCLC responding (PR/CR) to 4 

cycles of first-line Pt-based chemotherapy were randomized 1,5:1 to 

receive huKS-IL2/CTX or best supportive care (BSC). Pts in the huKS-IL2/ 

CTX arm received six 21-day cycles of CTX 300 mg/m2 on day (d) 1, and 1.5 

mg/m2 /d huKS-IL2 on d2–4, followed by 21-d cycles of CTX on d1 and 

huKS-IL2 on d2 until progression. Pts were stratified for prophylactic 

cranial irradiation (PCI) and response to chemotherapy. Primary endpoint 

was PFS rate at 6 months (mo). Secondary endpoints included OS rates at 

12 and 18 mo from start of Pt-based chemotherapy, median PFS and OS, 

safety, and immunogenicity. Results: 108 pts (64 huKS-IL2/CTX arm, 44 

BSC arm) were randomized and treated. Baseline characteristics were 

balanced between arms; however, higher % of males (75 vs 61.4%) and of 

ECOG PS 0 (45.3 vs 38.6%) were observed in the active arm. Median age 

was 61.7 (32; 81) and 59.2 (45; 74) years in the active and BSC arm, 

respectively. Most pts were in PR at randomization (2 pts–1ineach arm – 

had CR). PCI was used in 15 (23.4%) and 11 (25%) pts in the active and 

BSC arm, respectively. No significant differences in PFS or OS were 

observed in the active vs BSC arm: PFS rate was 6.4 vs 12.2%; median PFS 

was 1.5 vs 1.4 mo; OS rates at 12 and 18 mo were 52 vs 61% and 24 vs 

29%, respectively; median OS was 12.3 vs 14.1 mo. One PR (45% 

reduction vs randomization baseline) was observed in the active arm. In a 

subset of pts who received PCI, median PFS was 1.7 vs 1.5 mo, median OS 

21.5 vs 14.3 mo in the active vs BSC arm, respectively. AEs observed more 

frequently in the active arm were flu-like symptoms, rash, hypotension, 

lymphopenia, LFT and creatinine elevations; all Grade 3/4 AEs related to 

huKS-IL2 were reversible/manageable. Conclusions: HuKS-IL2/CTX was 

well tolerated, but showed no benefit in pts with ED-SCLC in PR/CR after 

chemotherapy. A trend for improved PFS and OS was observed in pts who 

received prior PCI. 

473s 


Genome-wide association study of survival in small cell lung cancer 

patients treated with irinotecan and cisplatin chemotherapy. Presenting 

Author: Ji-Youn Han, Center for Lung Cancer, National Cancer Center, 

Goyang, South Korea 

Background: The prognosis of patients with extensive-disease small-cell 

lung cancer (ED-SCLC) remains poor. Despite a high initial response rate to 

chemotherapy, most patients die from rapid recurrence. We conducted a 

genome-wide analysis study (GWAS) to examine whether germline genetic 

variations are prognostic factors in ED-SCLC patients treated with irinotecan 

and cisplatin (IP) chemotherapy. Methods: We prospectively collected 

blood samples from 139 patients who participated in two phase II studies 

of IP chemotherapy as first-line therapy and conducted a GWAS using 

overall survival (OS) as the endpoint. Germline DNA was genotyped using 

the Affymetrix 5.0 or 6.0 array sets. Associations between OS and single 

nucleotide polymorphisms (SNPs) were investigated using multivariate Cox 

regression analysis. Adjustments for age, performance status (PS) and 

gender were made. We selected most promising SNPs with p�1�10�6 in 

the GWAS allelic association analyses. Results: A total of 426,019 SNPs 

were genotyped and 343,530 SNPs passed quality control (HWE, p�10-7 , 

minor allele frequency�1%). We found 7 SNPs showing a significant 

association with OS. Patients harboring rs16950650 CT, rs7186128 AG 

or GG, rs17574269 AG, rs8020368 CC, rs4655567 CC, rs2166219 TT 

and rs2018683 TT genotypes showed shorter OS compared to patients 

with control alleles. Hazards ratios of death for each risk variants were 30.2 

(95% CI, 8.3-109.0, p�2.1X10-7 ), 2.5 (95% CI, 1.7-3.5, p�3.8X10-7 ), 

7.6 (95% CI, 3.4-16.6, p�4.5X10-7 ), 3.4 (95% CI, 2.1-5.5, p�3.5X10-7 ), 

4.9 (95% CI, 2.7-9.0, p�3.1X10-7 ), 5.8 (95% CI, 2.9-11.7, p�8.4X10-7 ) 

and 7.8 (95% CI, 3.4-17.7, p�8.0X10-7 ), respectively. Among these 

SNPs, rs4655567, rs8020368, rs2018683 and rs17574269 were significantly 

associated with a refractory relapse. In multivariate logistic analysis 

including age, gender and PS, rs8020368 CC genotype showed higher risk 

of refractory relapse than patients with TT or TC genotype (HR�14.9 [95% 

CI, 1.9-114.8], p�0.010). Conclusions: This exploratory GWAS identified 

several candidate SNPs that might predictive for the outcome of patients 

with ED-SCLC receiving IP chemotherapy. 


Randomized phase II study of recombinant human endostatin in combination 

with chemotherapy in previously untreated extensive-stage small-cell 

lung cancer (NCT00912392). Presenting Author: Shun Lu, Shanghai Lung 

Cancer Center, Shanghai Chest Hospital, Shanghai, China 

Background: Endostar (recombinant human endostatin) is a novel antiangiogenesis 

drug developed in China for non-small cell lung cancer (NSCLC). 

Because of promising efficacy signals, we performed a randomized phase II 

trial to assess the efficacy and safety of adding endostar to first-line 

standard chemotherapy for treatment of chemonaive extensive-stage smallcell 

lung cancer (SCLC). Methods: Extensive-stage SCLC patients with a 

performance status 0-2 were randomly assigned to endostar group (endostar 

7.5mg/m2 D1-D14 with carboplatin AUC�5 plus etoposide 60mg/m2 D1-D5 of a 21-day cycle for six cycles) or the control group (the same dose 

of carboplatin plus etoposide). Patients in endostar treatment group with 

CR, PR and SD were treated with single-agent endostar until progression or 

unacceptable toxicity. The primary end point is progression-free survival 

(PFS). The secondary end points are overall survival (OS) and response rate 

(RR). Results: 140 patients were enrolled from June 2009 to June 2011, 

and 137 patients were included in full analysis set. 68 patients were 

randomly assigned to the endostar treatment and 69 patients to the control 

group. Median age was 57 years and 80.9% for male in the endostar group 

while median age was 58 years and 85.5% for male in the control group. 

Median PFS was similar for endostar and control group (6.2 v 5.9 months, 

P�0.163, HR 0.762; 95%CI 0.519-1.119). Median overall survival (OS) 

was also similar for both groups (12.4 v 12.3 months, P�0.475, HR 

0.835; 95%CI 0.508-1.371). Overall RR were 76.5% for endostar group 

and 68.1% for the control group (p�0.275). 20 patients in the endostar 

group completed six cycles of therapy and subsequently treated with 

single-agent endostar as maintenance therapy and the median PFS and OS 

were 6.8 and 12.4 months respectively. The rate of � 3 grade adverse 

events occurred in both groups was similar and no new or unexpected safety 

signals for endostar were observed. Conclusions: The addition of endostar to 

carboplatin plus etoposide for treatment of extensive stage SCLC didn’t 

improve the PFS significantly, with an acceptable toxicity profile. And no 

improvement in OS was observed. 




Circulating tumor cells (CTCs) in patients (pts) with small cell lung cancer 

(SCLC) as a marker of disease burden and therapeutic response, and 

predictor of disease relapse. Presenting Author: Anjana Ranganathan, 


Background: Currently there are no validated biomarkers for assessment or 

prediction of disease burden or activity in SCLC. Enumeration of CTCs by 

CellSearch is FDA approved, highly reproducible and validated in other 

malignancies. Application as a prognostic and predictive marker in SCLC is 

limited due to a lack of studies documenting serial monitoring in pts on 

therapy. Methods: We are conducting a prospective study serially enumerating 

CTCs in pts with newly diagnosed SCLC. CTC number (per 7.5 ml 

peripheral blood) and percentage of CTCs demonstrating DNA damage and 

apoptosis based on �H2AX and M30 staining respectively, are being 

assessed prior to initiation of chemotherapy, during each cycle and at 

relapse. We are correlating CTC number with disease stage, number of 

metastatic sites, response to therapy, and time to progression (TTP). 

Results: 21 SCLC pts are evaluable. 9 pts with limited disease (LD) had 

median baseline CTC value of 1 (0-8); only 2 of 9 pts had �5 CTCs. 12 pts 

with extensive disease (ED) had median baseline CTC value of 80.5 

(0-37780); 8 of 12 pts had �5 detectable CTCs (p value 0.02). Amongst 

the 12 pts with ED, median baseline CTC count was higher in pts with �3 

(n�3) compared to 1-2 sites of metastatic disease (n�9) (2668 vs 71; p 

value 0.52). Median percentage of CTCs positive for �H2AX and M30 was 

also higher for pts with �3 compared to 1-2 metastatic sites (83, 164.5 vs. 

2, 7.5) (p-value 0.40, 0.69). Serial CTC data are available on 3 pts with 

ED; all had responsive disease and reduction in CTC number to 0-1 after 2 

cycles of chemotherapy. As this protocol is ongoing, correlation of CTCs 

with updated response status and TTP will be presented at the ASCO 

meeting. Conclusions: CTCs can be isolated and serially enumerated in pts 

with SCLC. Baseline CTCs correlate directly with disease stage. In pts with 

� 3 metastatic sites, baseline CTCs tend to be greater and show higher 

levels of DNA damage and apoptosis compared to those with 1-2 metastatic 

sites. Reduction in CTCs is associated with radiographic response to 

therapy. Correlation between absolute number at baseline and TTP is not 

yet known. 


A phase II study of second-line bendamustine in relapsed or refractory 

small cell lung cancer (SCLC). Presenting Author: Christine Marie Lovly, 

Vanderbilt Ingram Cancer Center, Nashville, TN 

Background: Bendamustine is an alkylating agent with a nitrogen mustard 

group and purine-like benzimidazole group. Bendamustine in combination 

with carboplatin has shown efficacy as first line therapy in extensive stage 

SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JCO 

2007]. This study aims to investigate the efficacy and safety of single agent 

bendamustine as 2nd or 3rd line therapy in patients with extensive-stage 

disease, small-cell lung cancer (ED-SCLC). Methods: This is an open-label, 

single-arm, multicenter phase II trial. Eligible patients had previously 

treated ED-SCLC, up to 2 prior regimens, ECOG performance status 0-2, 

evaluable/measurable disease, and adequate marrow, renal and hepatic 

function. Patients with stable treated brain metastases were allowed. 

Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 

3 weeks) for up to 6 cycles. Evaluation occurred every 2 cycles. Primary 

endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity. 

Results: 48 patients were enrolled; 56% were male and 96% were 

Caucasian. 33 patients were evaluable for response. There was 1 CR, 9 PR, 

13 SD (48% disease control rate) and 10 PD. Median TTP was 3.37 

months (95% CI 2.30 to 4.47 months). At the time of analysis, 13 patients 

were alive and with a median overall survival of 4.77 months (95% CI 3.67 

to 6.07 months). 5 patients (10.4%) required dose reductions due to AEs, 

2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to 

pneumonia. Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), 

infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%), 

and diarrhea (8.3%). Conclusions: These data indicate that single agent 

bendamustine appears to be well tolerated and effective in the second or 

third line setting for patients with SCLC. 


NCIC IND.190: A phase I trial of MK-0646 in combination with cisplatin 

and etoposide in extensive-stage small cell lung cancer (ES SCLC). 

Presenting Author: Peter Michael Ellis, Juravinski Cancer Centre, Hamilton, 

ON, Canada 

Background: Increased serum levels of insulin like growth factor (IGF), plus 

overexpression of the IGF-receptor (IGFR) are implicated in SCLC cell 

growth and proliferation, making suppression of the IGFR a potential 

therapeutic target. MK-0646 is a monoclonal antibody directed against the 

IGFR. The aim of this study was to determine the recommended phase II 

dose (RP2D) of cisplatin, etoposide plus MK-0646. Methods: We conducted 

a phase I study of two dose levels of MK-0646 (DL1 5mg/kg, DL2 

10mg/kg IV weekly) in combination with cisplatin (25mg/m2 ) and etoposide 

(100mg/m2 ) IV D1-3, q21d, for patients with chemotherapy-naive ES 

SCLC, PS 0-2. Patients with treated stable brain metastases were eligible. 

Patients completing 4-6 cycles of combination therapy could continue 

single agent MK-0646 until disease progression. Primary outcome was 

determination of the RP2D. Secondary outcomes included ORR (RECIST 

1.1), and toxicity (CTCAEv3). Results: A total of 12 patients were treated 

(DL1 – 3, DL2 – 9). The median age was 63 years (48-70), with 6 males 

and 6 females. Most subjects were good ECOG PS (PS1–8,PS2–4)and 

had 4 or more sites of disease (n�8). No DLTs were observed in DL1 or 

DL2. In an expanded DL2 cohort, 1 patient died from neutropenic sepsis 

during cycle 1. The median number of treatment cycles of chemotherapy 

was 4 (DL1) or 5 (DL2) and MK-0646 was 6 (DL1&2). Dose delays were 

observed for chemotherapy (DL1 - 2, DL2 – 6) and MK-0646 (DL1 – 3, DL2 

– 7). The confirmed ORR was 72.7% (PR 8, SD 2, PD 1, non-evaluable 1). 

Grade �3 toxicities (any cycle) occurring in more than 1 patient included: 

neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia 

(17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 

hyperglycemia was observed in 1 of 3 (DL1) and 5 of 9 (DL2). Eight SAEs 

were observed in 3 patients (thrombosis, febrile neutropenia, infection, 

syncope, fatigue 2, dyspnea, back pain). Conclusions: MK-0646 can be 

combined at full dose with standard doses of cisplatin and etoposide 

(25mg/m2 and 100mg/m2 D1-3) with a RP2D of MK-0646 10mg/kg/week. 

The observed toxicities are consistent with that expected from cisplatin and 

etoposide except for hyperglycemia, which appears dose dependent. 


ABEL trial: A phase II randomized trial adding bemiparin (B) to chemoradiotherapy 

(CT-RT) in limited-stage small cell lung cancer (SCLC)—Final 

results. Presenting Author: Bartomeu Massuti, Alicante University Hospital, 

Alicante, Spain 

Background: Low molecular weight heparins (LMWH) could improve therapeutic 

outcomes in patients with advanced cancer. Heparin binding growth 

associated molecule is a member of growth factors involved in proliferation, 

angiogenesis and metastases in SCLC. LMWH associated with CT increase 

survival in cancer patients (Cochrane DB Systematic Reviews 2011). 

LMWH do not increase hemorrhagic events when used in neoplastic 

patients. Methods: Open randomized phase II multicentric trial to assess 

efficacy and safety of adding bemiparin to standard CT-RT in patients with 

SCLC with limited disease. CT: Cis/carboplatin � etoposide x 4-6 cycles. 

Concurrent early thoracic RT (45-50 Gy) and prophylactic cranial irradiation 

in case of response. Patients (p) were randomly allocated to addition of 

B at daily subcutaneous dose of 3.500 UI during 26 weeks. Primary 

end-point: progression free survival (PFS). Secondary end-points: response 

(RECIST), safety profile (CTC), venours thromboembolic (VTE) and hemorrhagic 

events incidence and overall survival (OS). Sample size 130 p. 

Preplanned interim analysis after inclusion 30 p. Results: From October-05 

to January/10 39 p were included. Study was closed after interim analysis 

due to poor recruitment. 38 evaluable p. ITT analysis: 20 CR-RT � Bvs18 

CT-RT. No significant disbalance in patient characteristics and prognostic 

factors. Median PFS 58.6 weeks (CT-RT�B) vs 38.8 w (CT-RT) (HR 2.576; 

Log-rank p�0,018). RR: 65% (CT-RT�B) vs 55% (CT-RT) (NS); Median 

OS 161.8 w (CT-RT�B) vs 49.3 w (CT-RT) (HR 2.96; Log-rank p�0,012). 

2-year survival rate: 68.6% (CT-RT�B) vs 29.4% (CT-RT) (p�0,0042). 

Safety: G3-4 AE: 50% vs 67%; bleeding events: 10% vs 27% (NS); 

thrombocytopenia 15% vs 50% (p�0.024); VTE: 0 vs 22% (p�0.041). 

Conclusions: Addition of B (3.500 u/daily s.c. during 26 w) to CT-RT in 

SCLC with LD significantly increases PFS and OS. B does not increase 

hemorragic events and significantly reduces VTE. In spite of early closure of 

the trial due to poor accrual, these results warrants further research in this 

approach trying to improve current outcomes of SCLC. ClinicalTrials.gov Id: 

NCT00324558. 




Investigation of PARP1 as a therapeutic target in small cell lung cancer. 

Presenting Author: Lauren Averett Byers, University of Texas M. D. 


Background: Small cell lung cancer (SCLC) is an aggressive malignancy that 

differs from non-small cell lung cancer (NSCLC) in its metastatic potential 

and response to treatment. To date, no molecularly-targeted agent has 

prolonged survival of SCLC patients. Using a proteomic approach, we 

previously identified high expression of the DNA repair protein poly 

(ADP-ribose) polymerase 1 (PARP1) in SCLC cell lines and tumors. Here we 

test in vitro sensitivity of SCLC to PARP inhibition or knockdown. Methods: 

Cell lines were treated with PARP inhibitor olaparib or AG014699 for 14d 

�/- chemotherapy. Relative cell viability was assessed by cell count. siRNA 

against PARP1 was compared with scrambled siRNA and mock transfected 

cells. To assess DNA repair, RAD51 foci were counted after 1�M or5�M 

olaparib and after 8Gy irradiation (RT). Results: SCLC cell lines were highly 

sensitive to PARP inhibition by olaparib (IC50s �0.5 �M for H69; �2�M 

in H524, H82, and H526) and AG014699 (IC50s �0.5 �M for H82, H69, 

and H524; 2.2 �M for H526 and H841). In contrast, A549 (NSCLC) was 

resistant to both drugs (IC50s �8�M). Because BRCA1/2 and PTEN 

mutations are associated with greater sensitivity to PARP inhibitors, we 

compared SCLC sensitivity with that of BRCA1-mutated (HCC1395) and 

PTEN-mutated (MDA-MB-468) breast lines. As expected, HCC1395 and 

MDA-MB-468 were sensitive to both PARP inhibitors. Remarkably, however, 

SCLC cell lines were as sensitive or more so. Combination of olaparib 

with topotecan or irinotecan (commonly used in SCLC) decreased tumor 

cell viability more than either agent alone (p �0.03). Consistent with the 

drug studies, knockdown of PARP1 by siRNA decreased growth of SCLC 

compared with that of controls. RAD51 foci increased in SCLC after 

olaparib treatment (�4-fold) and RT (�18-fold). Conclusions: SCLC lines 

were as sensitive to PARP inhibition as BRCA1- or PTEN-mutated breast 

cancer lines. Moreover, PARP inhibition enhanced the effect of chemotherapy 

on SCLC lines. Increased formation of RAD51 foci in SCLC cells 

after olaparib or RT suggests a deficiency in homologous recombination 

that may account for the sensitivity to PARP inhibitors. These results 

support the investigation of PARP inhibition as a novel therapeutic 

approach in SCLC lung cancer. 


Impact of PET staging in limited-stage SCLC. Presenting Author: Eric 

Xanthopoulos, Department of Radiation Oncology, University of Pennsylvania 

School of Medicine, Philadelphia, PA 

Background: Although PET/CT has been established for the initial staging of 

NSCLC, it is still unproven for SCLC. This study examines clinical outcome 

in patients with limited-stage SCLC staged with and without PET/CT. 

Methods: An institutional database was reviewed to identify all patients that 

presented with limited-stage SCLC and treated definitively with concurrent 

chemoradiation. Overall survival and associations were assessed by the 

Kaplan-Meier approach, log-rank tests and Cox modeling. Results: From 

01/04 – 08/10, 54 consecutive limited-stage SCLC patients were treated 

with concurrent chemoradiation at the University of Pennsylvania. 40 

patients underwent PET staging; 14 underwent CT staging only; all had MR 

of the brain. Patient characteristics were well distributed, including age (p 

� 0.35), race (p � 0.21), sex (p � 0.93), dose (45 Gy, p � 0.89), and 

fractions per day (p � 0.89). PET-staged patients had median survival of 

32 vs 15 months in patients without PET (p � 0.03). Survival rate was 

57% vs 29% at 24 months. Median time to distant failure of 29 vs 11 

months (p � 0.05). Median time to local failure was 41 vs 12 months (p � 

0.03). Median followup was 38 months in the 19 surviving PET-staged 

patients and 40 in the 2 surviving non-PET patients (p � 0.59). Lack of 

PET-staging (OR � 0.92, p � 0.04) and race (OR � 1.02, p � 0.03) 

associated with increased distant failure on multivariate Cox analysis. Only 

PET-staging (OR � 0.93, p � 0.04) associated with increased overall 

survival on univariable Cox modeling. Conclusions: Median and overall 

survival of PET-staged SCLC patients compared favorably with those who 

were not. These findings are presumably due primarily to identification of 

CT-occult distant disease by PET. This study underscores the value of PET 

in staging patients with SCLC. 

475s 


Expression pattern and biologic relevance of Bcl-2 and Mcl-1 in pulmonary 

neuroendocrine tumors. Presenting Author: Rajasree Pia Chowdry, Emory 

University, Atlanta, GA 

Background: Bcl-2 protein overexpression is frequently described in small 

cell lung cancer (SCLC) but the biological relevance remains unclear. To 

better elucidate the role of Bcl2 dysfunction in SCLC, we assessed the total 

and the biologically relevant phosphorylated forms of the anti-apoptotic 

Bcl2 family members (Bcl2, pBcl-2, Mcl-1, pMcl-1) in pulmonary neuroendocrine 

(NE) tumors. Methods: We analyzed archival samples of pulmonary 

carcinoid, SCLC and large-cell NE carcinoma (LCNEC) by immunohistochemistry 

(IHC) using specific antibodies. Protein expression was assessed 

by light microscopy using standard scoring of intensity (0, 1, 2 and 3) and 

percent cell staining and correlated with age, gender, smoking status, 

tumor type, stage and survival. Significant differences in expression pattern 

and correlation with clinical variables were assessed by Wilcoxon twosample 

test, t-test, ANOVA, Spearman and Pearson correlation coefficients 

and Cox regression model. Results: We retrieved 77 cases: carcinoid (16) 

SCLC (41) and LCNEC (20); median age (61 yrs), gender (62% females). 

Bcl2 and pBcl2 expression was higher in SCLC and LCNEC compared to 

benign carcinoid tumor. pBcl-2 showed stronger correlation with adverse 

features including smoking, malignant histology, higher stage at diagnosis 

and worse survival. No significant association of Mcl1 or pMcl-1 expression 

with clinical or pathologic parameters. Conclusions: pBcl-2 expression 

pattern and correlation with adverse prognostic features indicate a key role 

in SCLC biology and relevance as a therapeutic target. 

Biomarker Carcinoid SCLC LCNEC P value 

Cytoplasmic Bcl-2 7 97 124 0.0005 

Cytoplasmic pBcl-2 42 132 83 0.0007 

Cytoplasmic Mcl-1 230 232 253 0.5327 

Cytoplasmic pMcl-1 

Correlation of biomarkers and OS 

131 173 165 02919 

HR (95% CI) 

Cytoplasmic Bcl-2 1.01 (1.00-1.02) 0.0167 

Cytoplasmic pBcl-2 1.57 (1.09-2.26) 0.0165 

Cytoplasmic Mcl-1 1.12 (0.73-1.70) 0.6131 

Cytoplasmic pMcl-1 

Correlation of biomarkers and PFS 

0.96 (0.67-1.40) 0.8462 

HR (95% CI) 

Cytoplasmic Bcl-2 1.01 (1.00-1.02) 0.0072 

Cytoplasmic pBcl-2 1.39 (1.02-1.89) 0.0383 

Cytoplasmic Mcl-1 1.19 (0.82-1.73) 0.3531 

Cytoplasmic p-Mcl1 1.00 (1.00-1.01) 0.0402 


A phase II trial of pazopanib in relapsed/refractory small cell lung cancer 

(SCLC). Presenting Author: Leena Gandhi, Dana-Farber Cancer Institute, 

Boston, MA 

Background: Despite response to initial therapy, SCLC has high rates of 

relapse or distant metastasis and limited 2nd-line therapeutic options. 

Angiogenesis is an essential part of cell invasion, dissemination, and 

outgrowth of distant metastases and therefore is a potential therapeutic 

target in SCLC. Pazopanib (Votrient, GSK) is a potent, competitive inhibitor 

of the tyrosine kinase activity of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and 

c-kit. We initiated a phase II single-arm trial of pazopanib in relapsed or 

refractory SCLC to determine impact on disease progression. Methods: 

Patients were eligible if they had progressive disease following up to two 

lines of prior therapy. Patients were treated at the FDA-approved dose of 

800 mg pazopanib once daily. The primary endpoint was progression-free 

rate (PFR) at 8 weeks. Secondary endpoints included median progressionfree 

survival, overall survival, and safety. The trial followed a Simon 2-stage 

design to limit accrual if no therapeutic benefit was observed. Results: To 

date, 27 of 30 planned subjects have been enrolled since October 2010. 

Two did not complete cycle 1 and were considered inevaluable for 

response. Major toxicities (mostly grade 1/2) were those previously described 

including nausea, fatigue, hypertension, electrolyte abnormalities, 

and AST/ALT elevations (grade 3 in 4 subjects). Three subjects were 

removed from study due to toxicity: 1 with grade 3 nausea, 1 with grade 3 

drop in the cardiac ejection fraction, and 1 with multiple grade 2 toxicities 

including diarrhea, fatigue, and nausea. A fourth was removed due to grade 

1 hemoptysis despite clinical response. The PFR at 8 weeks of 21 subjects 

evaluable for response to date was 52%; 4 of these 11 subjects had 

chemo-refractory disease. There were no confirmed responses, but tumor 

regressions ranged from 2-20%. Median progression-free survival is 14.1 

weeks. Conclusions: In patients with SCLC, single-agent pazopanib demonstrated 

a notable rate of stable disease (including among chemo-refractory 

patients) and a median PFS that exceeds that of historical PFS rates of � 2 

months on ineffective 2nd-line therapies. These data suggest that the 

potential for pazopanib in SCLC treatment should be further investigated. 




Amrubicin and carboplatin with pegfilgrastim in patients with extensivestage 

small-cell lung cancer (ES-SCLC): A phase II study of the Sarah 

Cannon Research Institute (SCRI). Presenting Author: Dianna Shipley, 

Tennessee Oncology, PLLC/Sarah Cannon Research Institute, Nashville, 

TN 

Background: Amrubicin is a novel anthracycline associated with high 

objective response rates (ORR) in patients (pts) with relapsed SCLC. 

Amrubicin improved the ORR and progression-free survival (PFS) in 

relapsed SCLC vs. topotecan, but not overall survival (OS) in a phase III 

study. Amrubicin with cisplatin/carboplatin for elderly Japanese pts was 

safe and active. We conducted a multicenter phase II study evaluating 

amrubicin and carboplatin in newly diagnosed ES-SCLC. Methods: Eligible 

pts had untreated ES-SCLC, measurable/evaluable disease (RECIST v. 1.1) 

and an ECOG PS �2. Pts received 4 cycles of amrubicin 30 mg/m2 on days 

1-3 and carboplatin AUC�5 both IV day 1 every 21 days with restaging 

every 6 weeks. Pegfilgrastim 6 mg sq was administered on day 4 of each 

cycle. The primary endpoint was 1-year OS. Secondary endpoints included 

ORR, PFS, OS, and toxicity. Results: 78 pts were enrolled from 3/2010 to 

7/2011. Baseline characteristics included: median age 65 yrs (range 

45-84); 56% female. 64% completed 4 cycles of treatment. Eleven (14%) 

pts showed complete responses and 47 (60%) pts partial responses, for an 

ORR of 74% (95% confidence interval 65%-82%). Twelve (15%) pts had 

stable disease. Median PFS and OS were 5.3 and 9.5 months, respectively. 

The 1-year OS was 36%. Grade 3/4 myelosuppression was the most 

common toxicity (thrombocytopenia 44%, neutropenia 34%, febrile neutropenia 

12%, anemia 26%), but was manageable. Severe non-hematologic 

toxicities (�5%) included hypokalemia 17%, fatigue 13%, dehydration 

10%, hyponatremia 10%, pneumonia 9%, and nausea/vomiting 8%. 1 pt 

died from sepsis and another from aspiration pneumonia. Conclusions: 

First-line ES-SCLC treatment with amrubicin and carboplatin induced 

several complete responses and is considered highly active. Myelosuppression 

was managed effectively with growth factor support. These results are 

comparable to historical data with platinum-doublet chemotherapy. A 

larger randomized study would be required to best assess this regimen’s 

impact on survival. 


Incidence of venous thromboembolism in lung cancer and its effect on 

survival. Presenting Author: Mohammad Mozayen, McLaren Regional 

Medical Center, Michigan State University, Flint, MI 

Background: Lung cancer is a major risk factor of venous thromboembolism 

(VTE). The incidence of VTE in different histological patterns of lungs 

cancer and its impact at the disease outcome is not well studied. We aim to 

evaluate the incidence rate of VTE in lung cancer and its effect on survival. 

Methods: Patients (pts) with lung cancer diagnosis from cancer database of 

community hospital were reviewed. Pts’ medical records were checked for 

VTE over 3 years after diagnosis. Pts’ demographics, pathology, TNM stage 

and overall survival were studied. Development of VTE was primary 

outcome and 3 year overall survival was the secondary outcome. Results: A 

total 2,164 pts with lung cancer between 1995 and 2008 were included. 

Median age of the study population was 70 years. Males were 53%, African 

Americans were 7%. 200 pts (9%) were diagnosed with VTE. Out of 1783 

pts with non-small cell lung cancer (NSCLC), 176 pts (9.9%) had VTE 

whereas out of 381 pts with small cell lung cancer (SCLC) 24 pts (6.3%) 

had VTE (p�0.015). Among NSCLC pts, 13.5% of pts with adenocarcinoma 

had VTE, whereas 6.6% of pts with squamous cell carcinoma had 

VTE (p�0.05). The incidence of VTE in stages I, II, III, IV of all pts were 

(8.4%, 7.3%, 13%, 7.5%) (p�0.007) respectively. In NSCLC, three years 

overall survival of pts with and without VTE was 22% and 24% respectively 

(p�0.34). In SCLC, three years overall survival of pts with and without VTE 

was 21% and 11% respectively (p�0.09). Conclusions: There is a higher 

incidence of VTE in non-small cell lung cancer than in small cell lung 

cancer. Among the NSCLC, VTE’s incidence was higher in adenocarcinoma 

than squamous carcinoma. VTE maybe higher at advanced stages (stage 

III) in both NSCLC and SCLC combined. There was no significant difference 

in the 3 years overall survival of lung cancer patients with and without VTE. 


Comparison of treatment patterns, health care utilization, and direct costs 

in elderly patients with distant-stage small cell lung cancer (SCLC) versus 

non-small cell lung cancer (NSCLC) using the SEER-Medicare database. 

Presenting Author: Sudeep Karve, RTI Health Solutions, Research Triangle 

Park, NC 

Background: Limited data exist on real-world treatment patterns, healthcare 

utilization, and associated costs of advanced SCLC among elderly patients 

in the US, and there are no recent comparisons between patients with 

advanced SCLC and advanced NSCLC. Methods: We retrospectively analyzed 

administrative claims data for elderly patients (�65 years) from the 

linked Surveillance, Epidemiology and End Results (SEER)-Medicare 

database for 2000-2008. Patients with a new diagnosis of distant stage 

lung cancer receiving cancer-directed therapy (ie, surgery, radiation, 

biologics, and/or chemotherapy) were grouped by tumor type (SCLC 

[n�5,855] vs NSCLC [n�24,090]). Survival was compared using Kaplan- 

Meier Log-rank; categorical measures with Chi-square statistics; and 

continuous measures with t-tests. Results: Compared to SCLC patients, a 

significantly greater proportion of patients with NSCLC received radiation 

therapy (75.6% vs 65.4%; p�0.001) and surgery (13.6% vs 7.8%; 

p�0.001). Chemotherapy was received by 85.5% of SCLC patients and 

60.3% of NSCLC patients (p�0.001). Significantly higher proportions of 

SCLC patients also received red blood cell (20.7% vs 10.9; p�0.001) and 

platelet transfusions (5.6% vs 1.8%; p�0.001) as well as growth factor 

support (58.9% vs 39.5%; p�0.001). Survival did not differ significantly 

between groups (p�0.424), with the mean (10.4 months vs 11.1 months) 

and median (7.4 months vs 5.9 months) survival for SCLC and NSCLC 

noted accordingly. Total lifetime lung cancer-related costs ($44,167 vs 

$37,932; p�0.001) and all-cause costs ($70,548 vs $67,175; p�0.001) 

per patient for SCLC exceeded those for NSCLC. The primary drivers of cost 

included resource utilization across 3 care settings: hospitalizations, office 

visits, and hospital outpatient visits. Conclusions: Overall total lifetime and 

disease-related costs per advanced SCLC and NSCLC patient were high, 

and costs for SCLC exceeded those for NSCLC. Survival estimates coupled 

with per patient costs for both cancers underscores the unmet medical 

need for patients with distant stage SCLC and NSCLC. 


A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, 

doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of 

advanced or recurrent thymic malignancies. Presenting Author: Anish 

Thomas, National Cancer Institute, Bethesda, MD 

Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) 

pan-inhibitor with single agent activity in thymic malignancies. PAC has 

activity against thymic cancers. Synergy between Bel and several chemotherapeutic 

agents, including P, A, and C, has been demonstrated in 

preclinical models. Methods: Patients with histologically confirmed, treatment 

naive advanced thymic malignancies, PS�2, measurable disease, 

and adequate renal, hepatic and hematopoietic functions were eligible. 

Ph1 evaluated safety and tolerability of the combination using increasing 

dose levels (DL) of Bel (1000-2000 mg/m² over 48 h CIVI) and PAC 

(50/50/500 mg/m² IV/cycle) (3�3 dose escalation schema), administered 

every 21 days for no more than 6 cycles followed by optional maintenance 

Bel every 4 weeks. Primary end point of Ph2 is overall response rate (ORR). 

Results: From March 2010 to January 2012, 13 patients were enrolled [7 

thymoma (T), 6 thymic carcinoma (TC); 8 in Ph1 and 5 in Ph2; median age: 

49 years (range, 23-76)]. In Ph1, 6 patients were treated at DL1 (Bel 1000 

mg/m2� PAC) and 2 patients at DL2 (Bel 2000 mg/m2� PAC). Dose 

Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 

neutropenia and thrombocytopenia. Recommended phase II dose (RP2D) 

was set at DL1. Most common grade 3/4 treatment-related adverse events 

(AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) 

thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, 

hypokalemia, elevated AST, prolonged QTc and infusioncatheter 

related thromboembolic complications (23% each). Outcomes 

included one complete response (CR; T at DL1), 6 partial responses (PR; 4 

T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in 

Ph1 and Ph2). Four patients previously deemed unresectable underwent 

surgical resection. Conclusions: Belinostat in combination with PAC has 

activity in thymic malignancies with a predicable AE profile. ORR was 54% 

including 33% PR in the TC subgroup. RP2D of the combination has been 

defined. Accrual to Ph2 part and molecular profiling of patient tumors is 

ongoing. 




A prospective, phase II trial of induction chemotherapy with docetaxel/ 

cisplatin for Masaoka stage III/IV thymic epithelial tumors. Presenting 

Author: Silvia Park, Division of Hematology-Oncology, Department of 

Medicine, Samsung Medical Center, Sungkyunkwan University School of 

Medicine, Seoul, South Korea 

Background: Thymic epithelial tumors (TETs), thymoma and thymic carcinoma, 

are the most common tumor of the anterior mediastinum. Initial 

complete resection is the most powerful prognostic indicator of survival. 

However, it is obviously related to stage. Here, we report the result of a 

prospective phase II study of neoadjuvant docetaxel/cisplatin in patients 

with locally advanced TETs. Methods: In this open-label, phase II, nonrandomized 

study, patients with histologically proven, Masaoka stage III/IV 

TETs at presentation were enrolled. Patients received docetaxel 75mg/m2 I.V for 1 hr, followed by I.V cisplatin 75mg/m2 over 1.5hr on day 1 of every 

3 week. After 3 cycles of chemotherapy, subsequent surgical resection was 

performed, if resectable. Results: From March 2007 to July 2011, a total of 

27 TETs patients were entered into the trial. The median age was 54 

(range, 15-68), and Masaoka stage at presentation was III (n�8, 29.6%), 

IVA (n�17, 63.0%), and IVB (n�2, 7.4%). Histologic type by the WHO 

includes type B1 (n�2, 7.4%), B2 (n�3, 11.1%), B3 (n�5, 18.5%), and 

thymic carcinoma designated as type C (n�16, 59.3%). After completion 

of neoadjuvant chemotherapy, 17 (63.0%) achieved PR and 10 (37.0%) 

had SD. Nineteen patients (70.4%) underwent surgical resection, and 8 

patients did not (surgeons’ decision, n�5; patients’ refusal, n�2; radiation 

therapy, n�1). Of the 19 patients undergoing surgical resection, 17 

(89.5%) had complete resections and 2 (10.5%) did not. Major side 

effects of chemotherapy include grade 3 anorexia (n�1), nausea (n�2), 

diarrhea (n�3), alopecia (n�1). After completion of surgical resection, 

adjuvant therapy was performed as follows: radiotherapy (RT, n�8), 

chemotherapy (CTx, n�6), radiotherapy with chemotherapy (RT � CTx, 

n�2) and observation (n�3). Overall, 4yr OS and PFS was 79.4% and 

40.6%. Patients with complete resection showed 93.8% of 4yr OS and 

50.2% of 4yr PFS whereas patients without complete resection showed 

47.6% of 4yr OS and 26.7% of 4yr PFS, respectively (OS, p�0.06; PFS, 

p�0.27). Conclusions: Neoadjuvant docetaxel/cisplatin was well tolerated 

and feasible, and improved the surgical respectability in patients with 

advanced TETs. 


A 19-gene prognostic GEP signature (DecisionDx-Thymoma) to determine 

metastatic risk associated with thymomas. Presenting Author: Yesim 

Gokmen-Polar, Indiana University School of Medicine, Indianapolis, IN 

Background: The treatment of thymomas is predominantly based on the 

stage of disease. Histologic classification is of limited value as all types of 

thymomas can give rise to metastases. In order to better predict the 

metastatic behavior of these tumors, we performed genome-wide gene 

expression analysis and identified a set of genes associated with presence 

or absence of metastases. In the current study, we sought to further develop 

and validate the gene signature using quantitative RT-PCR analysis. 

Methods: Thymomas with archived blocks and long-term follow-up data 

were reviewed. This training set study consisted of 50 cases, including 34 

cases on which the discovery microarray analysis had been performed. RNA 

was extracted from 5 x 10-micron thick sections in a CAP-accredited CLIA 

certified laboratory and analyzed by RT-PCR using custom TLDA cards on 

an ABI7900HT instrument. Expression data and biostatistical analysis 

were performed using GeNorm and JMP Genomics (SAS). Predictive 

modeling using Partition Tree Analysis (PTA) and Logistic Regression 

Analysis (LRA) was performed. Metastasis-free survival (MFS) was assessed 

using Kaplan-Meier analysis. Results: A 19-gene expression profile 

(GEP) signature was developed using a cohort of 50 thymomas for 

predicting metastasis. PTA yielded ROC of 0.97 (met. accuracy � 96%, 

non-met. accuracy � 81%), while LRA yielded ROC of 0.895 (met. 

accuracy � 87%, non-met. accuracy � 85%). PTA classification showed 

5-year MFS rates of 100% and 31% for predicted low risk (Class 1) and 

high risk (Class 2) of metastasis (median MFS � NR and 4.1 yrs, resp., 

P�0.0001 Log-Rank), respectively. LRA showed 5-year MFS rates of 

100% and 17% for predicted Class 1 and high risk Class 2 of metastasis 

(median MFS � NR and 2.9 yrs, resp., P�0.0001 Log-Rank), respectively. 

Analysis of additional cohorts is ongoing. Conclusions: We have successfully 

completed development of a 19-gene signature (DecisionDx-Thymoma) 

that appears to predict metastatic behavior of thymomas more accurately 

than traditional staging. If validated in larger cohort, this signature will 

provide insight for the future management of patients with this rare 

malignancy. 

477s 


Neoadjuvant treatment of primary inoperable or local recurrent thymoma 

with octreotide LAR to improve tumor resectability. Presenting Author: 

Berthold Schalke, Department of Neurology, University of Regensburg, 

Regensburg, Germany 

Background: The therapeutic outcome for unresectable, locally advanced, 

malignant thymoma is poor. Most important factor for long-term survival in 

thymoma patients is complete resection (R0) of the tumor. The study was 

performed to evaluate the efficacy of octreotide LAR plus prednisone in 

patients with primary inoperable or local recurrent thymoma to reduce 

tumor size. Methods: This was an open label, single-arm study in patients 

with inoperable or local recurrent thymoma. Patients were considered 

unlikely to achieve R0 resection at enrollment. Octreotide LAR was 

administered once every 2 weeks in combination with prednisone. Two 

stages were planned according to Fleming’s one sample multiple testing 

procedure for phase II clinical trials. The objective of the study was to show 

that octreotide LAR is effective in this patient population with respect to 

tumor shrinkage. Response was defined as decrease in tumor volume of at 

least 20% at month 3 as compared to baseline. Results: 17 thymoma 

patients at Masaoka stage III were recruited. Octreotide LAR showed a 

response in 15 of 17 patients (88.24%) at week 12. Two patients had 

discontinued the study before week 12 due to unsatisfactory therapeutic 

effect or adverse events. At Week 12, 5 patients (29.41%) operable for 

radical resection. 10 patients (58.82%) were not operable for radical 

resection. 16 of 17 patients (94.12%) experienced adverse events (AEs). 

The most frequent AEs were gastrointestinal disorders (70.59%), infections 

and infestations (64.71%), and blood/lymphatic system disorders 

(41.18%). Conclusions: Octreotide LAR was shown to be effective in 

patients with inoperable thymoma with respect to tumor shrinkage.Octreotide 

LAR was generally well tolerated. The reported AEs are in 

accordance with the known safety profile. 


Factors affecting survival of patients with Masaoka stage IV thymic 

epithelial tumors (TET). Presenting Author: Yaman Suleiman, Indiana 

University School of Medicine, Indianapolis, IN 

Background: Thymoma and thymic carcinoma (TC) are rare tumors, but 

represent the most common neoplasms of the anterior mediastinum. The 

vast majority of TET present in early stages with little data existing on 

factors influencing survival in patients with advanced or stage IV disease. 

Methods: A retrospective analysis was performed on patients with confirmed 

TET (histology and with tissue blocks) seen at IUSCC diagnosed between 

1976 and 2011. Patient demographics including Masaoka stage, histology, 

and sites of metastasis were linked with progression free survival (PFS) 

and overall survival (OS). Results: Our analysis included 102 patients with 

stage IV TET: 50 presented de novo and 52 developed stage IV disease 

following primary treatment. When stratified by tumor histology (thymoma 

or TC), patients with TC had considerably poorer PFS (p�1.87x10-7 ) and 

OS (p�7.72x10-8 ). The median PFS for TC was 13 months (range 4 to 39) 

and the MST was 36 months (range 4 to 115). PFS at 5-years was 21% and 

0% but the five-year OS was 84% and 29% for thymoma and TC, 

respectively. Ten year OS was 55% for patients with thymoma and 0% for 

those with TC. Pleural (�3 vs. �3) metastases were significantly associated 

with a better PFS (p�0.036) and OS (p�0.0003). The PFS and OS of 

patients with lung nodules trended with those with pleural metastasis. 

Patients with pleural metastasis and lung nodules sites did considerably 

better than those with visceral disease (PFS, p�0.004, OS, p�2.09x10-5 ). 

Conclusions: Patients with TC have significantly poorer PFS and OS when 

compared to thymoma confirming that TC is a distinct clinical entity from 

thymoma. Patients with thymoma may have prolonged survival, despite 

having residual disease. Although current staging places patients with 

pleural metastasis (Masaoka stage IVA) and those with lung nodules (stage 

IVB) as separate categories, our data would suggest that those with lung 

nodules have similar survival with those who have pleural metastasis. 




Factors influencing outcome in thymic epithelial tumors (TET). Presenting 

Author: Ryan Frederick Porter, Indiana University School of Medicine, 


Background: TET represent a heterogeneous collection of rare tumors, 

thymoma and thymic carcinoma (TC). Prognosis is often based on WHO 

histology and Masaoka Stage (MS) with small series often lacking long-term 

follow-up or advance stage disease. We examined predictors of relapse, 

disease-free survival (DFS) and overall survival (OS) based on WHO 

classification and MS. Methods: A retrospective analysis was performed on 

patients(pts) with TET seen at IUSCC from 1976 to 2011 with available 

tissue blocks. MS, WHO histology, demographics, autoimmune coexistence 

and non-TET neoplasms were correlated with DFS and OS (via 

Kaplan-Meier analysis). Results: Of 251 pts identified, MS at diagnosis was 

I(n�74), II(n�43), III(n�71), IVa(n�38), IVb(n�12) and indeterminate 

(n�13). The histology were thymoma (n�195) and TC (n�56). Median age 

was 51(10-88) and (M:F �121:130). Autoimmune disease was present 

(n�82) (myasthenia gravis n�52) and non-TET neoplasms (n�36). 

Therapy after diagnosis included surgery alone (n�115), radiation (n�29), 

chemo (n�71), chemo-radiotherapy (n�29), indeterminate(n�7). Median 

follow up was 69 months (1 to 399.5). DFS for stages I,II,III at 5 years was 

83%, 71% and 39%; DFS was associated with MS (p�.001) and WHO 

classification (p�.028). The 5yr and 10yr OS for stages I, II, III, IVa, IVb 

were 90%, 94%, 80%, 55%, 14% and 65%, 52%, 53%, 28%, 0%. The 

5yr OS for WHO classification were: A/AB-89%, B1/B2/B3-98% and 

C-30% and 10yr survivals were 89%, 62%, 0%. OS was associated with 

MS (p�.01) , WHO classification (p�.001) and autoimmune disease 

(p�.03). Late relapses (�5yr) occurred in 13 (23%) pts, including 3 with 

Stage I and 2 with WHO A classification. Conclusions: MS, WHO classification 

and autoimmune disorders were statistically significant with OS and 

with DFS for MS and WHO. TC prognosis is significantly worse than 

thymoma. The improved OS with autoimmune disease requires further 

investigation but raises the possibility of benefit derived from earlier 

diagnosis and/or heightened immune surveillance. These data support the 

notion that all TET, regardless of histologic subtype or clinical stage, are 

malignant with a capacity for metastasis. As relapses beyond 5 years are 

common, lifelong follow-up for TET is recommended. 


Vinorelbine plus cisplatin versus gefitinib in resected non-small cell lung 

cancer haboring activating EGFR mutation (WJOG6410L). Presenting 

Author: Hirohito Tada, Department of General Thoracic Surgery, Osaka City 

General Hospital, Osaka, Japan 

Background: Vinorelbine plus cisplatin after completely resected stage II-III 

non-small cell lung cancer (NSCLC) is a standard therapy. Stage IV 

non-small cell lung cancer (NSCLC) harboring mutations in the epidermal 

growth factor receptor (EGFR) is quite sensitive to tyrosine kinase inhibitors 

(TKIs). Three randomized trials demonstrated that gefitinib is superior to 

platinum based chemotherapy in progression free survival. Retrospective 

analysis of adjuvant TKIs therapy for patient with resected lung cancer 

harboring EGFR mutation showed favorable trend toward improvement in 

disease free survival (DFS) and overall survival (OS). (J Thorac Oncol. 

2011;6: 569–575) BR19 comparing adjuvant gefitinib vs. placebo for 

completely resected NSCLC without any selection of biomarker was closed 

early and did not show any benefit of adjuvant gefitinib, even in the EGFR 

mutation positive cohort. The randomized trial in adjuvant therapy with 

erlotinib vs. placebo for patients with overexpression of EGFR protein has 

complete enrolment already. We conduct the first randomized phase III 

trial comparing adjuvant gefitinib with chemotherapy in patients with 

completely resected stage II-III NSCLC harboring EGFR mutations. Methods: 

Patients who have undergone complete resection and have EGFR mutation, 

deletions in exon 19, or L858R point mutation at exon 21 and without 

T790M mutation are randomly assigned gefitinib 250mg a day for 2 years 

or vinorelbine 25mg/m2 days 1 and 8, plus cisplatin 80mg/m2 day 1, every 

3 weeks for 4 courses. The primary endpoint is DFS and secondary 

endpoints are OS and safety. On the basis of previous studies, we assume 

the hazard ratio of DFS is 0.65. To demonstrate this improvement in DFS, 

230 patients in total would be needed during 3-year accrual period. This 

trial has begun from September 12 among 22 institutes in Japan. Until now 

(January 31. 2012), 13 cases have been enrolled. Five cases were enrolled 

in latest 1 month. 


International tailored chemotherapy adjuvant trial: Itaca trial. Presenting 

Author: Silvia Novello, University of Turin, Orbassano, Italy 

Background: This is an ongoing phase III multicenter randomized trial 

comparing adjuvant pharmacogenomic-driven chemotherapy, based on 

thymidilate synthase (TS) and excision-repair cross-complementing -1 

(ERCC1) gene expression versus standard adjuvant chemotherapy in 

completely resected stage II-IIIA non-small cell lung cancer (EudraCT #: 

2008-001764-36). Methods: In all registered patients, before randomization, 

expression of ERCC1 and TS is assessed by qRT-PCR on paraffinembedded 

tumor specimens in a central laboratory. Randomization is 

stratified by stage and smoking status. Trial was emended on Feb, 2011 

with the 7th staging system. Primary end point is overall survival; secondary 

end points include recurrence-free survival, therapeutic compliance, toxicity 

profile and comparative evaluation of ERCC1 and TS mRNA versus 

protein. It is assumed that the 5-year survival in the control arm is 45% and 

the hazard reduction associated to the experimental treatment is 30%. 

With a power of 90% to detect the estimated effect with log-rank test, a 

significant level of 5% (2 tails), 336 events have to be observed; the 

expected total number of patients is 700. The final statistical analysis will 

group together all control arms and all tailored chemotherapies groups. 

Efficacy analysis will be done on an intent-to-treat basis. Cox proportional 

hazard model will be used for estimating hazard ratios after adjusting for 

relevant variables. Within 45 days post-surgery, patients in each genetic 

profile are randomized to receive either a standard chemotherapy selected 

by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/ 

gemcitabine) or an experimental treatment (tailored arms) selected as 

follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) 

high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 

and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS) 4 

cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered 

for a total of 4 cycles on a 3-weekly basis. Currently, 312 patients 

have been randomized from 26 institutions mainly located in Italy and 

Germany (average enrolment: 13 patients/month). 


Postoperative follow-up of lung cancer: Randomized trial comparing two 

follow-up programs in completely resected non-small cell lung cancer 

(IFCT-0302). Presenting Author: Virginie Westeel, Besançon University 

Hospital, Besançon, France 

Background: There are no robust data published on the follow-up after 

surgery for non-small cell lung cancer (NSCLC). Current international 

guidelines are informed by expert opinion. Most of them recommend 

regular follow-up with clinic visit and thoracic imaging, either chest X-ray of 

Chest CT-scan. The IFCT-0302 trial addresses the question whether a 

surveillance program with chest CT-scan and fiberoptic bronchoscopy can 

improve survival compared to a follow-up only based on physical examination 

and chest x-ray. There is no such trial ongoing over the world. Methods: 

The IFCT-0302 trial is a multicenter open-label controlled randomized 

phase III trial. The objective of the trial is to compare two follow-up 

programs after surgery for stage I-IIIa NSCLC. The primary endpoint is 

overall survival. Patients are randomly assigned to arm 1, minimal 

follow-up, including physical examination and chest x-ray; or arm 2, a 

follow-up consisting of physical examination and chest x-ray plus chest CT 

scan and fiberoptic bronchoscopy (optional for adenocarcinomas). In both 

arms, follow-up procedures are performed every 6 months during the first 

two postoperative years, and every year between the third and the fifth 

years. The main eligibility criteria include: completely resected stage I-IIIA 

(6th UICC TNM classification) or T4 (in case of nodules in the same lobe as 

the tumor) N0 M0 NSCLC, surgery within the previous 8 weeks. Patients 

who have received and/or who will receive pre/post-operative chemotherapy 

and/or radiotherapy are eligible. Statistical considerations: 1,744 patients 

is required. Accrual status: 1,568 patients from 119 French centers had 

been included. The end of accrual can be expected for September 2012. 

Ancillary study: Blood samples are collected in 1000 patients for genomic 

high density SNP micro-array analysis. This collection will contribute to the 

French genome wide association study (gwas) of lung cancer gene susceptibility, 

and the genetic factors predictive of survival and lung cancer 

recurrence will be analyzed. 



TPS7112 General Poster Session (Board #43G), Sat, 1:15 PM-5:15 PM 

IFCT-GFPC-0701 MAPS trial, a multicenter randomized phase III trial of 

pemetrexed-cisplatin with or without bevacizumab in patients with malignant 

pleural mesothelioma (MPM). Presenting Author: Gerard Zalcman, 

Caen University Hospital, Caen, France 

Background: MPM median OS does not exceed 13 months with pem/CDDP 

doublet. U.S. Intergroup phase II trial of gemcitabine/CDDP, with or 

without bevacizumab, gave an appealing 15.6 months median OS in the 

bevacizumab arm. French Intergroup aimed to test pem/CDDP with 

bevacizumab (PCB), in a randomized phase III trial. Methods: Eligible 

patients had unresectable histologically proved MPM, no prior chemo, PS 

0-2, no thrombosis, nor bleeding. Primary endpoint: The primary outcome 

will be survival. The secondary endpoint will be Progression-Free Survival. 

Patients received pem 500 mg/m2 , CDDP 75 mg/m2 (PC),at D1, and 

vitamin B12 �B9 substitution, with (arm B) or without bevacizumab (arm 

A), 15 mg/kg Q21D, for 6 cycles. Arm B nonprogressive patients received 

bevacizumab maintenance therapy until progression or toxicity. 445 

patients to be recruited during a period 48 months, with at least 24 months 

of follow-up, and 385 events (deaths), will be needed to assure a power of 

80% and detect at least a 4.3 months of median survival increase. This 

hypothesis leads to a Hazard Ratio (HR) of 1.33 and a 3-years survival of 

14.7% in control arm and 23.6 % in experimental arm, with an absolute 

difference of 8.9% in survival rates. Accrual status: The first patient was 

included in February 2008. On January 31, 2012, 257 patients from 85 

French centers had been enrolled. The end of accrual can be expected for 

September 2013. Ancillary studies: For molecular biomarker analyses, 

thoracoscopic tissue specimens (TS, ERCC1, MSH2, TUBB3, NF2, p16, 

RASSF1A methylation,15 microRNAs ) and blood samples (micro-RNAS, 

VEGF, osteopontin, SRMP) at diagnosis are centrally collected. Finally, a 

prospective study comparing PET-CT to standard CT with central blinded 

analysis, is currently on-going for evaluation of response, and accuracy of 

modified RECIST criteria for mesothelioma. 

479s 


CA184-156: A randomized, multicenter, double-blind, phase III trial 

comparing the efficacy of ipilimumab (Ipi) plus etoposide/platinum (EP) 

versus EP in subjects with newly diagnosed extensive-stage disease small 

cell lung cancer (ED-SCLC). Presenting Author: David R. Spigel, Sarah 

Cannon Research Institute, Nashville, TN 

Background: EP (4-6 cycles) is standard of care 1st-line therapy for 

metastatic SCLC, and no multinational studies have reported any improvement 

beyond that reported for EP. Evidence of an ongoing immune 

response to SCLC tumors suggests that immunotherapy that enhances this 

immune response to SCLC may enhance the clinical benefit of EP. Ipi, a 

fully human monoclonal antibody which blocks CTLA-4, augments antitumor 

immune responses. Because some responses to Ipi may differ from 

those observed with cytotoxic therapies, immune-related response criteria 

(irRC) were derived from WHO criteria to better capture response patterns 

observed with Ipi. A randomized Phase 2 study of Ipi with paclitaxel/ 

carboplatin (PC) in pts with ED-SCLC showed significant improvement in 

progression-free survival (PFS), as measured by irRC, over PC alone in pts 

receiving Ipi and PC in a phased regimen (Ipi started after 2 cycles of PC). 

Furthermore, addition of Ipi did not exacerbate PC toxicity, and immunerelated 

adverse events were managed using protocol-specific guidelines. 

This multicenter phase III study in pts with ED-SCLC (ClinicalTrials.gov 

identifier NCT01450761) will determine whether adding Ipi to EP increases 

OS vs EP alone. Methods: EP consists of 4 cycles of etoposide (100 

mg/m2 , IV on Days 1-3 every 3 weeks [Q3W]) and cisplatin (75 mg/m2 , IV) 

or carboplatin (AUC�5, IV) once Q3W. Pts will be randomized to receive 4 

doses of Ipi (10 mg/kg, IV) in Arm A or placebo in Arm B, Q3W during 

induction, starting after 2 cycles of EP (phased schedule). Eligible pts will 

then receive blinded study drug (Ipi in Arm A; placebo in Arm B) Q12W 

until disease progression or unacceptable toxicity. The primary objective is 

to compare OS. Secondary objectives are to compare OS in those who 

receive blinded study drug, compare PFS between study arms, and to 

estimate best overall response rate and duration of response. First-line 

ED-SCLC pts with ECOG performance �1 will be included. Pts with 

symptomatic CNS metastases or a history of autoimmune disease will be 

excluded. The study will randomize 1100 pts at a 1:1 ratio. 


480s Lung Cancer—Non-small Cell Metastatic 

LBA7500 Oral Abstract Session, Mon, 3:00 PM-6:00 PM 

LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus 

pemetrexed and cisplatin as first-line treatment for patients with advanced 

adenocarcinoma of the lung harboring EGFR-activating mutations. Presenting 

Author: James Chih-Hsin Yang, National Taiwan University Hospital, 

Taipei, Taiwan 








SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) 

with or without cetuximab (C) in recurrent or progressive non-small cell 

lung cancer (NSCLC) after platinum-based therapy. Presenting Author: 

Edward S. Kim, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: SELECT investigated whether the addition of C to standard 

chemotherapy improved progression-free survival (PFS) in patients (pts) 

with recurrent or progressive NSCLC after failure of platinum-based 

therapy. Methods: SELECT was a multicenter, open label, randomized 

phase III trial. Per investigator choice, pts received either P (500 mg/m2 )or 

D (75 mg/m2 ) on day 1 and then were randomized within each group to 

chemotherapy plus C (400/250 mg/m2 ) (initial/weekly) or chemotherapy 

alone. Therapy was given for up to six 3-week cycles; pts randomized to C 

continued weekly monotherapy until disease progression or unacceptable 

toxicity. The primary objective was PFS for PC vs. P as determined by an 

Independent Review Committee (IRC). Secondary endpoints included 

overall survival (OS), objective response rate (ORR) and duration of 

response (DOR) by IRC, and safety. Preplanned subgroup analyses for 

epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry 

and histology were performed. Results for PC vs. P only are 

presented. Results: Between Jan 2005 and Feb 2010, 938 total pts were 

randomized. Baseline demographics were comparable between PC (n�301) 

andP(n�304): median age 64 years; male 60%; Caucasian 88%; KPS 

80-100/60-70 84%/16%; squamous/non-squamous 24%/76%. Median 

PFS (months) PC: 2.89 and P: 2.76 (hazard ratio [HR] �1.03 [95% 

confidence interval (CI)�0.87-1.21]; p�0.76). Median OS (months) PC: 

6.93 and P: 7.79 (HR�1.01 [95% CI�0.86-1.20]; p�0.86). ORR PC: 

6.6% and P: 4.3% (odds ratio �1.59 [95% CI�0.78-3.26]; p�0.20). 

Median DOR (months) PC: 4.17 and P: 6.93 (HR�1.58 [95% CI�0.74- 

3.36]; p�0.24). There were no statistical differences in efficacy based on 

histology or EGFR staining intensity. More drug-related AEs/SAEs were 

observed in the PC arm, with differences mainly attributable to skin 

toxicities, GI (diarrhea/stomatitis), and hypomagnesemia. Conclusions: The 

addition of C to P did not improve efficacy in this pt population. Further 

biomarker analyses are planned. The safety profiles for C and P were 

consistent with existing data and no new safety signals were observed. 


TAILOR: Phase III trial comparing erlotinib with docetaxel in the secondline 

treatment of NSCLC patients with wild-type (wt) EGFR. Presenting 

Author: Marina Chiara Garassino, U.O. Oncologia Medica, A.O. Fatebenefratelli 

e Oftalmico, Milan, Italy 








Phase II double-blind, randomized study of selumetinib (SEL) plus 

docetaxel (DOC) versus DOC plus placebo as second-line treatment for 

advanced KRAS mutant non-small cell lung cancer (NSCLC). Presenting 

Author: Pasi A. Janne, Dana-Farber Cancer Institute, Boston, MA 

Background: KRAS mutations are the most common (~20%) oncogenic 

alteration in NSCLC. There are no effective targeted therapies for this 

subset of NSCLC. Selumetinib (AZD6244, ARRY-142866) inhibits MEK1/2 

signaling downstream of KRAS. We prospectively evaluated SEL � DOC vs 

DOC � placebo in advanced KRAS mutant NSCLC based on preclinical 

observations (NCT00890825). Methods: Patients (pts) with stage IIIB-IV, 

KRAS mutant NSCLC, who had received prior chemotherapy, received iv 

DOC 75 mg/m2 , and po SEL 75 mg or placebo BD. The primary endpoint 

was overall survival (OS); secondary endpoints included: progression-free 

survival (PFS), objective response rate (RR), duration of response, change 

in tumor size, proportion of patients alive and progression-free at 6 mo, and 

safety and tolerability. Results: Between April 2009 and June 2010, 422 

pts were screened across 67 centers in 12 countries; 113 had KRAS 

mutant NSCLC and 87 were randomized (DOC, 43; SEL/DOC, 44). 

Baseline characteristics were balanced (DOC vs SEL/DOC): WHO PS 0, 

49%/48%; Female, 54%/52%; KRAS codon 12, 90%/93%. Median 

number of cycles: DOC, 4; SEL/DOC, 5. Most frequent grade 3/4 hematologic 

toxicity (DOC vs SEL/DOC): neutropenia (54.8%/67.4%), febrile 

neutropenia (0%/15.9%); most frequent grade 3/4 non-hematologic toxicity: 

dyspnea (11.9%/2.3%) asthenia (0%/9.1%), respiratory failure (4.8%/ 

6.8%), acneiform dermatitis (0%/6.8%). Discontinuation due to AEs was 

similar: 18.2% SEL/DOC vs 11.9% DOC. OS was longer for SEL/DOC vs 

DOC (9.4 mo vs 5.2 mo; 56 events, median follow-up 219 days) but did not 

reach statistical significance; hazards were non proportional (HR 0.80; 

80% CI 0.56, 1.14; 1-sided p�0.2069). All secondary endpoints, 

including RR (DOC 0%, SEL/DOC 37%; p�0.0001) and PFS (DOC 2.1 mo, 

SEL/DOC 5.3 mo; 71 events; HR � 0.58; 80% CI 0.42, 0.79; 1-sided 

p�0.0138), were significantly improved for SEL/DOC vs DOC. Conclusions: 

This is the first prospective study to demonstrate a clinical benefit of a 

targeted therapy (SEL � DOC) for patients with KRAS mutant cancer of any 

type. Our findings could have implications for the treatment of NSCLC and 

other KRAS mutant cancers. 



Analysis of resistance mechanisms to ALK kinase inhibitors in ALK� 

NSCLC patients. Presenting Author: Robert Charles Doebele, University of 


Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions 

derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover, 

next generation ALK kinase inhibitors are in development. Unfortunately, 

drug resistance develops after initial benefit (acquired) or occurs in 

patients who never derive a benefit (intrinsic). This study aimed to define 

molecular mechanisms of resistance to ALK kinase inhibitors in ALK� 

non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK� crizotinibtreated 

NSCLC patients experienced radiologic disease progression, of 

whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS 

progression, a biopsy was attempted on 19. One of the patients without 

tissue post-crizotinib then proceeded to a second generation ALK inhibitor 

and tissue was obtained post progression on this drug. We performed 

molecular analysis and initiated cell lines from tumor tissue for these 19 

patients. Results: 15 patients had material evaluable for molecular analysis. 

Six patients (40%) developed secondary mutations in the kinase 

domain of ALK. Two novel mutations were identified in samples from ALK� 

NSCLC patients, F1174C and D1203N. Two patients each demonstrated 

G1269A or L1196M mutations. Two patients each, one with a resistance 

mutation, exhibited new onset ALK copy number gain (CNG). Four patients 

demonstrated the presence of another oncogenic driver (1 with EGFR 

mutation; 3 with KRAS mutation) with or without a persistent ALK gene 

rearrangement. One patient lacked an ALK gene fusion on progression 

biopsy, but had no identifiable alternate oncogene alteration. 3 patients 

retained ALK positivity with no identifiable resistance mechanism. Data on 

additional patients and an in vitro model of copy number gain will be 

presented. Conclusions: ALK kinase inhibitor resistance in ALK� NSCLC 

occurs through a diverse array of kinase domain mutations, ALK gene 

fusion CNG, and emergence of second (same cell) or separate (different 

cell) oncogenic drivers. In order to overcome resistance it will be important 

to differentiate patients that preserve ALK dominance (secondary mutations 

and CNG) versus those that have diminished ALK dominance 

(separate or second oncogenic drivers). 


A randomized phase III trial of single-agent pemetrexed (P) versus 

carboplatin and pemetrexed (CP) in patients with advanced non-small cell 

lung cancer (NSCLC) and performance status (PS) of 2. Presenting Author: 

Rogerio Lilenbaum, Cleveland Clinic Florida, Weston, FL 

Background: No standard of care exists for patients with advanced NSCLC 

and PS 2 and clinical practice ranges from supportive care to combination 

chemotherapy. Methods: In a Brazilian multicenter phase III randomized 

trial, advanced NSCLC patients, with any histology at first, amended to 

non-squamous only, PS 2, no prior chemotherapy, and adequate organ 

function, were randomized to P alone (500 mg/m2) or CP (AUC 5 � same 

P) administered every 3 weeks for 4 cycles. Stratification factors included 

stage (IIIB vs. IV); age (�70 vs. �70); and weight loss (�5 kgvs.�5kg). 

The primary endpoint was overall survival and the study was powered to 

demonstrate an improvement in median survival from 2.9 to 4.3 months 

based on a prior CALGB trial. Results: A total of 217 patients were enrolled 

from 8 centers in Brazil and 1 in the US from April 2008 to July 2011. 

Twelve patients were ineligible and excluded. The 2 arms (P�102; 

CP�103) were balanced for patient characteristics. 14 patients had 

squamous and another 12 had unknown histology. The response rates were 

P � 10% and CP � 24% (p�0.019). In the ITT population, the median 

PFS was P � 3.0 mo and CP � 5.9 mo (HR�0.46, 95% CI 0.34; 0.63, 

p�0.001) and median OS was P � 5.6 mo vs. CP � 9.1 mo (HR�0.57, 

95% CI 0.41; 0.79, p�0.001). 1-year survival rates were 22% and 39% 

respectively. Similar results were seen when squamous patients were 

excluded from the analysis. Grade ¾ anemia (5.5%; 12%) and neutropenia 

(2.8%; 5.6%) were more frequent in CP. There were 4 treatment-related 

deaths in the CP arm. 30% of patients in each arm received 2nd line therapy 

Conclusions: Combination chemotherapy with CP significantly improves 

survival, with acceptable safety, in eligible patients with advanced NSCLC 

and PS 2, and represents a new standard. 


481s 


Multiplex testing for driver mutations in squamous cell carcinomas of the 

lung. Presenting Author: Paul K. Paik, Memorial Sloan-Kettering Cancer 


Background: While the majority of lung adenocarcinomas (ADCL) harbor an 

identifiable driver mutation, targeted therapies for squamous cell lung 

carcinomas (SQCLC) have lagged in development due to a paucity of 

druggable oncogenic events. Three targets, which together occur in up to 

50% of SQCLC, have been recently identified (FGFR1 amplification, DDR2 

mutations, PIK3CA mutations/PTEN loss). Comprehensive molecular analysis 

of SQCLC tumors by The Cancer Genome Atlas is ongoing, with new 

therapeutic targets on the horizon. Methods: We have instituted prospective, 

multiplex testing of SQCLC tumors (Squamous Cell Lung Cancer 

Mutation Analysis Program, “SQ-MAP”). Tests include FISH for FGFR1 

amplification (defined as FGFR1:CEP8 � 2in�10% of cells), IHC for loss 

of PTEN expression, and Sequenom MassARRAY for PIK3CA mutations 

(and others, below). We are also incorporating targeted exon sequencing 

(Agilent SureSelect/Ion Torrent) of a panel of over 80 lung cancer 

oncogenes and tumor suppressors in preparation for future studies. All 

tests were performed on formalin-fixed paraffin-embedded samples and 

with Institutional Review Board/Biospecimen Utilization Committee approval. 

Results: 40 SQCLC patient specimens have been processed through 

SQ-MAP over 3 months. 8 samples were excluded (insufficient tissue in 4, 

reclassification to ADCL in 4). Data are available for 28 patients. PTEN IHC 

was performed on 15 samples to date. Molecular results are summarized in 

the table. Events were non-overlapping. Results for the �80 gene sequencing 

component will be described. Based on SQ-MAP, accrual to 2 approved 

clinical trials (FGFR1 inhibition; PI3K inhibition) has begun, with a third 

planned (DDR2 mutations). Conclusions: Actionable defects were detected 

in 60% (95% CI: 37-75%) of SQCLC specimens. Mutation data for �80 

other oncogenes and tumor suppressors will be available shortly (including 

DDR2). SQ-MAP serves as a platform supporting both personalized care 

and research. 

Test Frequency 95% CI 

FGFR1 amplification 25% (7/28) 11-45% 

PTEN loss, complete 20% (3/15) 5-49% 

PIK3CA mutation 11% (3/28) 2-28% 

KRAS mutation 4% (1/28) 0-18% 

EGFR mutation 0% 

BRAF mutation 0% 

HER2 mutation 0% 

AKT1 mutation 0% 

NRAS mutation 0% 

MEK1 mutation 0% 

Any 60% 37%-75% 


PARAMOUNT: Final overall survival (OS) results of the phase III study of 

maintenance pemetrexed (pem) plus best supportive care (BSC) versus 

placebo (plb) plus BSC immediately following induction treatment with 

pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell 

lung cancer (NSCLC). Presenting Author: Luis Paz-Ares, University Hospital 

- Virgen del Rocio, Seville, Spain 










Clinical activity of crizotinib in advanced non-small cell lung cancer 

(NSCLC) harboring ROS1 gene rearrangement. Presenting Author: Alice 

Tsang Shaw, Massachusetts General Hospital Cancer Center, Boston, MA 

Background: Chromosomal rearrangements of the ROS1 receptor tyrosine 

kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1 

rearrangements lead to expression of oncogenic ROS1 fusion kinases and 

sensitivity to ROS kinase inhibition. We examined the efficacy and safety of 

crizotinib, a small molecule tyrosine kinase inhibitor of MET, ALK and ROS, 

in patients with advanced, ROS1-rearranged NSCLC. Methods: Patients 

with advanced NSCLC harboring ROS1 rearrangement, as determined 

using a break-apart FISH assay, were recruited into an expansion cohort of 

a phase 1 study of crizotinib. Patients were treated with crizotinib at the 

standard oral dose of 250 mg BID. The objective response rate (ORR) was 

determined based on RECIST 1.0. The disease control rate (DCR; stable 

disease [SD] � partial response [PR] � complete response [CR]) was 

evaluated at 8 weeks. Results: Thirteen patients within the ROS expansion 

cohort received crizotinib and all were evaluable for response. The median 

age was 47 yrs (range 31–72), and all but one of the patients were 

never-smokers. All patients had adenocarcinoma histology. 12/13 patients 

were tested for ALK rearrangement and all were negative. The median 

number of prior treatments was 1 (range 0–3). To date, the ORR is 54% 

(7/13), with 6 PRs and 1 CR, with 6 responses achieved by the first 

restaging scan at 7–8 wks. There was 1 additional unconfirmed PR at the 

time of data cut-off. The DCR at 8 wks was 85% (11/13). Median duration 

of treatment was 20 wks (range 4�–59�). All responses are ongoing, and 

12 patients continue on study. One patient had disease progression at first 

restaging and was discontinued from the study. The pharmacokinetics and 

safety profile of crizotinib in this group of patients were similar to that 

observed in patients with ALK-positive NSCLC. Conclusions: Crizotinib 

demonstrates marked antitumor activity in patients with advanced NSCLC 

harboring ROS1 rearrangements. Like ALK, ROS defines a distinct subpopulation 

of NSCLC patients for whom crizotinib therapy may be highly 

effective. This study represents the first clinical validation of ROS as a 

therapeutic target in cancer. 


Discovery of recurrent KIF5B-RET fusions and other targetable alterations 

from clinical NSCLC specimens. Presenting Author: Marzia Capelletti, 


Background: Many NSCLCs have driving oncogenic alterations including in 

EGFR, KRAS, ERBB2, BRAF, ALK and ROS1. Clinically effective drugs are 

approved for EGFR and ALK and clinical trials are underway for other 

genomic targets. Thus having a means of identifying genomic alterations in 

routine formalin fixed paraffin embedded (FFPE) clinical specimens is 

critical. Methods: We sequenced 24 FFPE NSCLC specimens with a next 

generation sequencing (NGS) assay that captures and sequences 2574 

coding exons of 145 cancer relevant genes plus 37 introns from 14 genes 

often rearranged in cancer. Tumors from 643 additional patients were 

genotyped for KIF5B-RET. Results: We identified 50 alterations in 21 genes 

with at least one in 83% (20/24) of tumors (range 1-7). In 72% (36/50) of 

NSCLCs, at least one alteration was associated with a current clinical 

treatment or targeted therapy trial, including mutations in KRAS, BRAF, 

EGFR, MDM2, CDKN2A, CCNE1, CDK4, NF1 and PIK3CA. We also found 

an 11,294,741 bp pericentric inversion on chromosome 10 generating a 

novel gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET 

(K15:R12) in a Caucasian never smoker. This fusion gene contains the 

kinesin motor and coiled-coil domains of KIF5B and the entire RET tyrosine 

kinase domain. In 643 additional tumors we identified 11 fusion positive 

patients who were all wild type for known oncogenes (frequency of 6.3% 

(10/159)). Four unique KIF5B-RET variants were found: 8 K15:R12, 3 

K16:R12, 1 K22:R12 and 1 K15:R11. We introduced K15:R12 into 

Ba/F3 cells and observed IL-3 independent growth consistent with oncogenic 

transformation. KIF5B-RET Ba/F3 cells were sensitive to sunitinib, 

sorafenib and vandetinib, multi-targeted kinase inhibitors that inhibit RET, 

but not gefitinib, an EGFR kinase inhibitor. Sunitinib, but not gefitinib, 

inhibited RET phosphorylation in these cells. Conclusions: We identified 

both known and novel genomic alterations from NSCLC FFPE specimens 

using a single test. Our findings suggest that RET inhibitors should be 

tested in prospective clinical trials in NSCLC patients bearing KIF5B-RET 

rearrangements and that NGS is a feasible approach to stratifying patients 

for treatment based on their genomic profiles. 


Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in 

patients with advanced non-small-cell lung cancer (NSCLC). Presenting 

Author: Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer 

Center at Johns Hopkins University, Baltimore, MD 

Background: BMS-936558 is a fully human mAb that blocks the programmed 

death-1 (PD-1) co-inhibitory receptor expressed by activated T 

cells. We report here that BMS-936558 mediates antitumor activity in 

heavily pretreated patients (pts) with advanced NSCLC, a tumor historically 

not considered to be responsive to immunotherapy. Methods: BMS-936558 

was administered IV Q2WK to pts with various solid tumors, including 

NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort 

expansion. Pts with advanced NSCLC previously treated with at least 1 prior 

chemotherapy regimen were eligible. Pts received up to 12 cycles (4 

doses/cycle) of treatment or until PD or CR. Clinical activity was assessed 

by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 75 NSCLC 

pts were treated at 1 (n�17), 3 (n� 19), or 10 mg/kg (n�39). ECOG 

performance status was 0/1/2 in 24/49/2 pts. Tumor histology was 

squamous (n�17), non-squamous (n�52), or unknown (n�6). The number 

of prior therapies was 1 (n�9),2(n�20), �3 (n�45), or unknown 

(n�1). Ninety-five percent of pts had received platinum-based chemotherapy 

and 40% had a prior tyrosine kinase inhibitor. Sites of metastatic 

disease included lymph node (n�50), liver (n�12), lung (n�62), and bone 

(n�13). Median duration of therapy was 10 wk (max 100 wk). Common 

related AEs were fatigue (17%), nausea (11%), pyrexia (7%), pruritus 

(7%), dizziness (7%), and anemia (7%). The incidence of grade 3-4 related 

AEs was 8%. There was 1 drug-related death due to pulmonary toxicity. 

Clinical activity was observed at all dose levels (Table) and in multiple 

histologies. Several pts had prolonged SD. Some had a persistent decrease 

in overall tumor burden in the presence of new lesions and were not 

categorized as responders. At the time of data lock, of 10 OR pts, 3 had 

responses lasting �6 mo and 5 were on study with response duration of 

1.8-5.5 mo. Conclusions: BMS-936558 is well tolerated and has encouraging 

clinical activity in pts with previously treated advanced NSCLC. Further 

development of BMS-936558 in pts with advanced NSCLC is warranted. 

Dose (mg/kg) na ORb uPRc RRd (%) 

1 18 1 - 6 

3 18 3 2 28 

10 

aResponse evaluable pts. 

bCR or PR. 

cUnconfirmed PR. 

dResponse rate [(OR � uPR) ÷ n]. 

37 6 1 19 


11:30 AM-12:30 PM 

A randomized double-blind trial of carboplatin plus paclitaxel (CP) with 

daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor 

receptors, or placebo (PLA) in patients (pts) with previously untreated 

advanced non-small cell lung cancer (NSCLC): NCIC Clinical Trials Group 

study BR29. Presenting Author: Scott Andrew Laurie, Ottawa Hospital 

Cancer Centre, Ottawa, ON, Canada 

Background: In NCIC CTG study BR24, CED 30 mg/d � CP increased 

objective response rate (RR) and progression-free survival (PFS), but there 

were concerns regarding toxicity in some pts. BR29 tested a lower dose of 

CED 20 mg/d limiting accrual to pts without significant weight loss/ 

hypoalbuminemia. Methods: Consenting, eligible adult pts with advanced 

incurable NSCLC of any histology were randomized to receive CED 20 mg/d 

or PLA with up to 6 cycles of C (AUC � 6) P (200 mg/m2 ); non-progressing 

pts continued CED/PLA after CP until progression, unacceptable toxicity or 

pt request. The primary endpoint was overall survival (OS). An interim 

analysis (IA) for PFS was planned after 170 events in the first 260 pts; the 

study would continue if the hazard ratio (HR) for PFS was � 0.7. Accrual 

continued until the required number of events was reached then held 

pending IA. Results: The trial was halted when the IA (n�260) revealed a 

HR for PFS of 0.89 (95% CI 0.66-1.20). A final analysis including all 306 

randomized pts (median age 62, male 55%, PS 0 26%, PS 1 74%, 

adenocarcinoma 64%, squamous 13%, other histology 23%. RR was 

significantly higher with CED (52% vs 34 %, p � 0.001). For CED/PLA, 

respectively, median OS and PFS were 12.2/12.1 [HR: 0.95 (0.69-1.30, 

p�0.74)] and 5.5/5.5 months [HR: 0.91 (0.71-1.18, p�0.5)]. Grade �3 

hypertension (15% vs 3%, p�0.0002), anorexia (7% vs 1%, p�0.02) and 

diarrhea (16% vs 1%, p�0.0001) were all significantly increased with 

CED; there were 2 deaths possibly-related to CED [1 each hemorrhage, 

leukoencephalopathy (prior radiation)]. Conclusions: Adding a lower dose of 

CED to CP increased RR and toxicity, but not PFS or OS. 



11:30 AM-12:30 PM 

Randomized phase II study of carboplatin and paclitaxel with either 

linifanib or placebo for advanced nonsquamous NSCLC. Presenting Author: 

Suresh S. Ramalingam, Winship Cancer Institute, Emory University, 

Atlanta, GA 

Background: Linifanib is a potent and selective inhibitor of VEGF and PDGF 

receptors with modest single-agent activity in NSCLC. We evaluated the 

combination of linifanib with carboplatin (C) and paclitaxel (P) for first-line 

therapy of advanced non-squamous NSCLC. Methods: Patients (pts) with 

stage IIIB/IV, non-squamous NSCLC, stratified by ECOG PS and gender, 

were randomized to receive up to six 3-wk cycles of C (AUC 6 mg/ml/min) 

and P (200 mg/m2 ) with daily placebo (Arm A), linifanib 7.5 mg (Arm B), or 

linifanib 12.5 mg (Arm C). The primary endpoint was progression-free 

survival (PFS); secondary endpoints included overall survival (OS), 12 m 

survival rate, and objective response rate (ORR). Safety was assessed by 

NCI-CTCAE v3.0. Results: 138 pts were randomized at 37 sites in 6 

countries. Baseline characteristics were: median age, 61 y; men, 57%; 

smoker, 84%. Efficacy results are shown in the table. Thrombocytopenia 

was the only Grade 3/4 AE significantly higher on linifanib (Arm B: 16.7%; 

Arm C: 29.8%) vs. placebo (2.1%). Other adverse events (AEs) related to 

the dose of linifanib were diarrhea, thrombocytopenia, hypertension, 

weight loss, palmar-plantar erythrodysaesthesia syndrome, and hypothyroidism. 

Analysis of samples for predictive biomarkers including serum VEGF 

and placental growth factor are underway. Conclusions: The addition of 

linifanib to chemotherapy was tolerable at the doses tested and resulted in 

a significant improvement in PFS, with a modest survival improvement for 

Arm C in first-line therapy of advanced non-squamous NSCLC. 

Arm A 

N�47 

Arm B 

N�44 

Arm C 

N�47 

Median PFS, m [95% CI] 5.4 [4.2, 5.7] 8.3 [4.2, 10.8] HR 0.51, P�0.022* 7.3 [4.6, 10.9] HR 0.64, P�0.118* 

Median OS, m [95% CI] 11.3 [8.8, 17.0] 11.4 [6.6, 14.8] 

13.0 [8.3, 18.9] 

HR�1.08, P�0.779* 

HR�0.89, P�0.650* 

12 m survival rate, % 45 44 54 

ORR, % 25.5 43.2 31.9 

Received 2L therapy, n 26 13 18 

*Stratified log-rank test; p value compared with CP � placebo. 


11:30 AM-12:30 PM 

Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a 

phase II randomized discontinuation trial (RDT). Presenting Author: Beth 

A. Hellerstedt, US Oncology Research, LLC, McKesson Specialty Health, 

The Woodlands, TX, and Texas Oncology, Central Austin Cancer Center, 

Austin, TX 

Background: Dysregulation of MET and VEGFR2 signaling has been observed 

in NSCLC and MET upregulation has been implicated in resistance 

to EGFR inhibitors. Cabozantinib (cabo) is an oral, potent inhibitor of MET 

and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we 

report on the metastatic NSCLC cohort which included patients who 

received prior EGFR and VEGF pathway targeted therapy. Methods: All 

eligible patients (pts) were required to have measurable disease at 

baseline. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. 

Tumor response (mRECIST) was assessed q6 wks. Treatment � wk 12 was 

based on response: pts with PR continued open-label cabo, pts with SD 

were randomized to cabo vs placebo, and pts with PD discontinued. Results: 

Enrollment to this cohort is complete (n � 60); all pts are unblinded. 

Baseline characteristics: median age 67 years; adenocarcinoma 72% and 

squamous cell 28%; 6 pts with known EGFR mutation (of 28 tested), all 

having received prior erlotinib; bone metastases 20%; median prior lines of 

therapy 3 (range 0 - 6); prior exposure to anti-EGFR therapy 50%, prior 

exposure to anti-VEGF pathway therapy 32%. Median follow-up was 2 

months (range 0.4 - 22.3 months). At Wk 12, ORR per RECIST was 10% 

and overall disease control rate (PR�SD) was 40%. Objective tumor 

regression was observed in 30/47 pts (64%) with post-baseline tumor 

assessments, some of whom had known driver mutations in KRAS (3 pts) or 

EGFR (4 pts). 24 pts (40%) completed Lead-in stage with 15 randomized 

to continue cabo (N � 8) or to placebo (N � 7). No differences with respect 

to PFS were observed between treatment arms in the randomized phase of 

the study. Median PFS from study day 1 for all pts was 4.2 months. Most 

common Grade 3/4 AEs were fatigue (13%), Palmar-plantar erythrodyesthesia 

(8%), diarrhea (7%) and asthenia (7%); one related Grade 5 AE of 

hemorrhage was reported during Lead-in stage. Conclusions: Cabo treatment 

demonstrates activity in heavily pretreated metastatic NSCLC pts 

with 4.2 months median PFS, 10% RECIST response, and 64% rate of 

objective tumor regression. The safety profile of cabo was comparable to 

that seen with other VEGFR TKIs. Future studies are warranted in NSCLC. 


483s 


11:30 AM-12:30 PM 

CALGB 30704: A randomized phase II study to assess the efficacy of 

pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line 

treatment of advanced non-small cell lung cancer (NSCLC). Presenting 

Author: Rebecca Suk Heist, Massachusetts General Hospital Cancer 


Background: Second line chemotherapy improves survival modestly and 

new strategies are needed. This trial was designed to evaluate the paradigm 

of an anti-VEGF strategy with or without standard chemotherapy in 

previously treated NSCLC. Methods: Patients with Stage IIIB/IV NSCLC, PS 

0-1 progressive after first-line chemotherapy were eligible for randomization 

to P (pemetrexed 500 mg/m2 d1), S (sunitinib 37.5 mg d1-21), or 

P�S (pemetrexed 500 mg/m2 d1 � sunitinib 37.5 mg d1-21). Pts were 

stratified by PS (0/1), stage (IIIB/IV), and gender (M/F). Primary objective 

was 18-week PFS rate; secondary objectives were response, OS, and 

toxicity. Target accrual was 225. The study was terminated early due to 

decreasing accrual rates. Results: Between 4/08 and 9/11, 130 pts 

registered; 128 pts treated (P�41, S�46, P�S�41). Median follow-up 

99 weeks. Baseline characteristics in the three arms (P/S/P�S) were well 

balanced: Male (54%/54%/54%); PS 0 (32%/35%/34%); Stage IV (88%/ 

83%/93%). Histology was predominantly adenocarcinoma (66%/57%/ 

66%); squamous was allowed (10%/15%/15%). Toxicity was higher in the 

S-containing arms: Grade 3/4/5 hematologic toxicity: P 5/0/0 (12%), S 

8/1/0 (21%), P�S 5/9/0 (36%); Grade 3/4/5 non-hematologic toxicity 

(excluding disease related deaths): P 6/2/0 (20%), S 21/3/1 (58%), P�S 

21/3/1 (63%). The 18-week PFS rate in the three arms was: P 51% 

(38-69), S 36% (24-54), P�S 47% (34-65). There is an overall statistically 

significant difference in OS between the three arms (2-sided 

p�0.0179) with HR 0.65 (95%CI: 0.38-1.13) for P/S; HR 0.47 (95%CI: 

0.27- 0.82) for P/P�S. Median OS was 10.5 mo (8.3-22.5) for P, 7.0 mo 

(6.0-13.0) for S, 6.7 (4.1-10.4) mo for P�S. Median PFS was 4.4 mo 

(1.7-8.8) for P, 3.3 mo (2.7-4.3) for S, 3.7 mo (2.5-4.3) for P�S(p�0.3). 

Fewer patients in the P�S arm received any subsequent therapy (29%) 

than either P (54%) or S (57%). Conclusions: Pemetrexed had a superior 

toxicity profile to either sunitinib or the combination of pemetrexed and 

sunitinib. OS was significantly better with P alone compared to the two 

S-containing arms, with P�S performing worst for OS. 


11:30 AM-12:30 PM 

Randomized phase III trial of S-1 plus cisplatin versus docetaxel plus 

cisplatin for advanced non-small-cell lung cancer (TCOG0701). Presenting 

Author: Nobuyuki Katakami, Institute of Biomedical Research and Innovation, 

Kobe, Japan 

Background: Although molecularly targeted therapy improves outcome of 

selected patients with advanced non-small-cell lung cancer (NSCLC), most 

of the patients ultimately become candidates of cytotoxic chemotherapy, 

which is the cornerstone of patient management. S-1 plus cisplatin (SP) 

has shown activity and good tolerability in phase II settings. Docetaxel plus 

cisplatin (DP) is the only third-generation regimen that demonstrated 

statistically significant improvement of overall survival and quality of life by 

head to head comparison with a second-generation regimen, vindesine plus 

cisplatin, in patients with advanced NSCLC. Methods: Patients with 

previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and 

adequate organ functions were randomized to receive either oral S-1 80 

mg/m2 /day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on 

day 8 every 5 weeks or docetaxel 60mg/m2 on day 1 plus cisplatin 80 

mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint is 

overall survival (OS). Non-inferiority study design was employed as upper 

confidence interval (CI) limit for HR�1.322. Secondary endpoints include 

progression-free survival (PFS), response, safety, and quality of life (QOL). 

Results: From April 2007 to December 2008, 608 patients from 66 sites in 

Japan were randomized to SP (n�303) or DP (n�305). Patient demographics 

were well balanced between the two groups. Two interim analyses were 

preplanned. At the final analysis, total of 480 death events were observed. 

The primary endpoint was met. OS for SP was non inferior to DP (median 

survival, 16.1 v 17.1 months, respectively; HR�1.013; 96.4% CI, 

0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the 

DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% v 

1.0%), grade 3/4 neutropenia (73.4% v 22.9%), grade 3/4 infection 

(14.5% v 5.3%), grade 1/2 alopecia (59.3% v 12.3%) were observed in the 

SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and 

LC-13 favored for the SP arm. Conclusions: S-1 plus cisplatin is a standard 

first-line chemotherapy regimen for advanced NSCLC. 




11:30 AM-12:30 PM 

Three-arm randomized phase II study of carboplatin (C) and paclitaxel (P) 

in combination with cetuximab (CET), IMC-A12, or both for advanced 

non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based 

therapy: An Eastern Cooperative Oncology Group (ECOG) 

study (E4508). Presenting Author: Nasser H. Hanna, Indiana University, 


Background: Pre-clinical evidence supports the clinical investigation of 

inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal 

growth factor receptor (EGFR) alone and in combination with one 

another in patients (pts) with NSCLC. Methods: Pts w/ chemotherapy-naïve, 

advanced NSCLC, not eligible for bevacizumab-based therapy, ECOG PS 

0/1 were eligible. Pts with uncontrolled or untreated brain mets and/or 

severe hyperglycemia were ineligible. Pts were randomized to receive: C 

AUC6iv� P 200 mg/m2 iv on day 1 every 3 wks combined with either CET 

iv weekly (arm A), IMC-A12 iv every 2 wks (arm B), or both (arm C). Patients 

with non-progressive disease (PD) after 12 weeks of therapy were permitted 

to continue on maintenance antibody therapy until PD. The primary 

objective was PFS. Secondary objectives included OS and toxicity. The 

design required 180 eligible patients and had an 88% power to detect a 

60% increase in median PFS for either comparison (arm A vs C or arm B vs 

C) (1-sided 0.10 level test). Results: Characteristics for arms A (n�39)/B 

(n�42)/C (n�48): males were 51%/57%/54%; median age was 60, 62, 

60; PS 0 49%/52%/60%; stage IV 87%/83%/94%; adenocarcinoma 

44%/26%/42%. The study was closed prematurely due to safety concerns 

after 129 eligible pts were treated. 13 patients died during treatment 

(A�6; B�2; C�5), including 9 w/in ~1 mo of starting therapy. G3-5 

toxicities, all attributions, A/B/C: anemia 16%/7%/13%; neutropenia 

27%/29%/42%; febrile neutropenia 7%/5%/4%; thrombocytopenia 7%/ 

10%/13%; pneumonia 9%/2%/6%; hyperglycemia 2%/10%/15%; rash 

5%/2%/8%; hyponatremia 2%/5%/17%; thromboembolic events 2%/10%/ 

0%; fatigue 16%;22%/13%. The estimated median PFS and OS for arms 

A/B/C were 3.4, 4.3, and 4.1 mos and 11.7, 8.6, and 8.4 mos, 

respectively. Conclusions: Based upon apparent lack of efficacy and 

excessive premature deaths, this study does not support the continued 

investigation of C � T � IMC-A12 alone or in combination with CET in pts 

with advanced NSCLC not eligible for bevacizumab. 


11:30 AM-12:30 PM 

Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C) 

or placebo (P) in advanced non-small cell lung cancer. Presenting Author: 

Karen L. Reckamp, City of Hope, Duarte, CA 

Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a 

potential mechanism of resistance to epidermal growth factor receptor 

(EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated 

in part through an EGFR-independent activation of MAPK/Erk by the COX-2 

metabolite PGE2. In addition, PGE2 promotes downregulation of Ecadherin 

and epithelial to mesenchymal transition. We hypothesize that 

EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI 

efficacy by increasing tumor E-cadherin expression and blocking PGE2mediated 

resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV 

NSCLC who progressed following at least one line of therapy or refused 

standard chemotherapy were randomized to E (150mg/day)/HD-C 

(600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking 

status and ECOG PS. The primary endpoint was PFS with 80% power to 

detect a 50% improvement; assessments were performed every 2 cycles. 

Secondary endpoints included response rate, OS and evaluation of molecular 

markers in tissue and serum to assess targeting COX-2-related pathways 

and evaluate EGFR TKI-resistance. All pts were required to have pretreatment 

tissue available. Results: 107 pts were enrolled with comparable 

baseline characteristics in both arms. Disease control rate (DCR) was 

similar in both arms, and a trend toward improved PFS was seen in the 

E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild 

type revealed a significantly increased PFS while those with EGFR mutation 

had similar PFS in both groups. Safety analysis showed similar toxicity in 

both arms. Additional biomarker correlations will be presented. Conclusions: 

The combination of E/C in metastatic NSCLC with HD-C is well tolerated 

and demonstrates significantly improved efficacy in EGFR wt population. 

This warrants further study into the COX-2-dependent mechanisms of 

primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388, 

K12 CA01727 and medical research funds from the Dept of Veterans’ 

Affairs. 

E/HD-C (n�54) E/P (n�53) p value 

PFS (mo) 5.4 2.9 0.31 

PFS (EGFR mut, mo) 10.8 9.2 0.73 

PFS (EGFR wt, mo) 3.6 1.8 0.045 

PFS (EGFR na, mo) 2.7 2.7 0.96 

DCR (%) 59 55 0.70 


11:30 AM-12:30 PM 

SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of 

erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma 

(BAC) and adenocarcinoma with BAC features (adenoBAC), and in neversmokers 

with primary NSCLC adenocarcinoma (adenoCa). Presenting 

Author: Howard Jack West, Swedish Cancer Institute, Seattle, WA 

Background: Despite recent changes to lung adenoCa pathologic classification, 

adv stage BAC remains a definable and clinically applicable entity. 

Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung 

adenoCa, have emerged as relevant clinical subpopulations with a high 

probability of clinical benefit from epidermal growth factor receptor (EGFR) 

tyrosine kinase inhibitors (TKIs), likely related to the high proportion of 

activating mutations in the EGFR gene in such pts. Based on these results 

and the potential for increased clinical activity conferred by addition of B to 

E, SWOG initiated a pair of phase II trials of this combination in pts with 

adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS 

pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 

78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 

trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV 

q21 days until progression or prohibitive toxicity. Tumor tissue submission 

for pathologic review and assessment of molecular markers was mandated. 

Results: Pt demographics of the two trials are as shown in the table below. 

RECIST response rate among 61 BAC pts on S0635 with measurable 

disease was 18%, and among 53 NS pts on S0636, it was 47%. Median 

progression-free survival is 5 and 8 months (mo) on S0635 and S0636, 

respectively; median overall survival (OS) is 17 and 26 mo on S0635 and 

S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and 

hypertension; no treatment-related deaths were reported. Molecular marker 

studies will be presented separately. Conclusions: In populations selected 

by clinical parameters, E withB is associated with modest toxicity and 

encouraging clinical efficacy that exceeded the prespecified OS threshold 

of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS 

pts. 

Trial Median age (range) Treatment naïve Performance status 0/1 Race 

S0635 (BAC) 69.2 (39.1-92.8) 12% 96% 92% White 

8% Black 

S0636 (NS) 61.3 (31.2-84.8) 13% 97% 66% White 

25% Asian 

5% Black 

4% Other 

7519^ Poster Discussion Session (Board #9), Tue, 8:00 AM-12:00 PM and 

11:30 AM-12:30 PM 

A randomized placebo-controlled phase III study of intercalated erlotinib 

with gemcitabine/platinum in first-line advanced non-small cell lung 

cancer (NSCLC): FASTACT-II. Presenting Author: Tony Mok, The Chinese 

University of Hong Kong, Hong Kong, China 

Background: FASTACT, a randomized, phase 2 study in advanced NSCLC, 

found that intercalated erlotinib with 1st-line platinum-based chemotherapy 

(CT) significantly prolongs progression-free survival (PFS) (HR 

0.47, p�0.0002) versus CT alone (Mok et al. JCO 2009). FASTACT-II is a 

confirmatory, randomized, phase 3, placebo-controlled, double-blind study 

in a large patient population Methods: Patients with untreated stage IIIB/IV 

NSCLC and ECOG PS 0/1 were randomized (1:1) to receive up to 6 cycles of 

gemcitabine (1,250 mg/m2 on d1 and 8) plus platinum (carboplatin 

5�AUC or cisplatin 75 mg/m2 on d1) q4w, with either intercalated 

erlotinib (150 mg/day on d15–28) or placebo. Non-progressing patients 

received maintenance erlotinib or placebo until progression, unacceptable 

toxicity or death. Stratification was by disease stage, histology, smoking 

status and CT regimen. Primary endpoint was PFS; secondary endpoints 

included overall response rate (ORR), overall survival (OS), safety, QoL and 

biomarker analyses. Results: From Apr 2009 to Sep 2010, 451 patients 

were randomized to receive erlotinib (n�226) or placebo (n�225). 

Baseline demographics were well balanced across the arms; overall, 49% 

were never smokers, 40% were female and 76% had adenocarcinoma. PFS 

was significantly prolonged with erlotinib vs placebo: median 7.6 vs 6.0 

months, respectively; HR 0.57 (95% CI 0.46–0.70); p�0.0001. ORR was 

significantly improved with erlotinib vs placebo: 42.9% vs 17.8%; 

p�0.0001. A non-significant trend towards longer OS was seen with 

erlotinib vs placebo (median 18.3 vs 14.9 months; HR 0.78 [95% CI 

0.60–1.02]; p�0.069); 73% of placebo patients received a 2nd-line 

EGFR TKI. Except for skin rash with erlotinib, there was no clinically 

significant difference in toxicity between arms. A total of 283 patients 

(62.7%) provided samples for biomarker analyses, including EGFR mutation 

status, results of which will be presented. Conclusions: Intercalation of 

erlotinib with CT significantly prolonged PFS in 1st-line advanced NSCLC. 

Biomarker analysis will determine the significance of this regimen in 

patients with or without activating EGFR mutations. 



11:30 AM-12:30 PM 

Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial 

of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line 

treatment for Chinese patients with EGFR mutation-positive advanced 

non-small cell lung cancer (NSCLC). Presenting Author: Caicun Zhou, 

Shanghai Pulmonary Hospital, Tongji University School of Medicine, 

Shanghai, China 

Background: The OPTIMAL study demonstrated significant superiority for E 

versus GC in terms of progression-free survival (PFS), objective response 

rate, tolerability and quality of life (QoL) in first-line advanced NSCLC 

patients with EGFR activating mutations (Act Mut�). Here we report OS 

data from OPTIMAL (ClinicalTrials.gov NCT00874419). Methods: Chemotherapy-naive 

Chinese patients with advanced NSCLC and EGFR Act 

Mut�, ECOG performance status (PS) 0–2 and measurable disease were 

randomized to E (150 mg/day), or GC, and stratified by histology, smoking 

status and mutation type. OS at final data cut-off (15 Nov 2011) was 

evaluated for the entire intent-to-treat (ITT) population. Subgroup analysis 

of OS by gender, histology, smoking status, PS, presence of skin rash and 

type of mutation was performed. Details of second- or later-line therapy 

were also documented for each patient. Results: A total of 165 patients 

were randomized to treatment and 154 patients received at least one dose 

of study drug (ITT population; E, n�82; GC, n�72). A total of 7 patients 

are still responding to erlotinib in the E arm. Post-study therapy included 

chemotherapy (doublet, n�38, or mono, n�8), or experimental drugs in 

clinical trials (n�10) in the E arm, and EGFR tyrosine kinase inhibitor (TKI) 

therapy (n�49) or chemotherapy (n�7) in the GC arm. Post-study 

treatment was not received by 26 and 16 patients in the E and GC arms, 

respectively. A total of 84 deaths were reported (E, n�47; GC, n�37). OS 

did not differ significantly between the two treatment arms (HR�1.065, 

p�0.6849), and no significant difference in OS was observed in the 

different subgroups. Conclusions: The lack of a statistically significant 

difference in OS in the OPTIMAL study was possibly due to a high level of 

cross-over to EGFR TKI therapy in the GC arm. However, the significant 

benefits reported with E in terms of PFS, QoL and tolerability in this study 

suggest that E should be considered as one of the standard first-line 

treatments for patients with advanced EGFR Act Mut� NSCLC. 


11:30 AM-12:30 PM 

EGFR compound mutants and survival on erlotinib in non-small cell lung 

cancer (NSCLC) patients (p) in the EURTAC study. Presenting Author: 

Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain; Pangaea 

Biotech, USP Institut Universitari Dexeus, Barcelona, Spain 

Background: When EGFR compound mutants (exon 19 deletions or L858R 

plusT790M) are present at the time of clinical resistance to erlotinib, 

patients attain longer overall survival (OS) (Oxnard et al. CCR 2011). The 

H1975 cell line, harboring L858R plus T790M prior to treatment, is 

sensitive to gefitinib (Sordella et al. Science 2004; Faber et al. Cancer 

Discovery 2011), though the compound mutant may become dominant 

after multiple passages in vitro, leading to resistance (Pao et al. PLoS Med 

2005). Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) 

randomized 174 p with EGFR exon 19 deletions or L858R mutations to 

receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 

months (m) vs 5.2 m, respectively (P�0.0001). No differences in OS were 

observed.123 p with remaining available pre-treatment tumor tissue were 

re-analyzed for the concomitant presence of the T790M mutation with an 

allelic discrimination Taqman assay in the presence of a PNA clamp 

designed to inhibit the amplification of the exon 20 wild-type (wt) allele. 

This assay is capable of detecting the T790M allele at a ratio of 1:5000 wt 

alleles. Results: The T790M mutation was detected in 21/64 (32.8%) p in 

the erlotinib arm and 26/59 (44.1%) in the chemotherapy arm. PFS was 

12.1 m for p with mutant T790M in the erlotinib arm, 8.8 m for p with wt 

T790M in the erlotinib arm, 6.3 m for p with mutant T790M in the 

chemotherapy arm, and 4.5 m for p with wt T790M in the chemotherapy 

arm (P�0.0001). OS was not reached for p with mutant T790M in the 

erlotinib arm, 16.1 m for p with wt T790M in the erlotinib arm, 22.6 m for 

p with mutant T790M in the chemotherapy arm, and 18.4 m for p with wt 

T790M in the chemotherapy arm (P�0.04). Conclusions: Our unexpected 

finding that p with EGFR compound mutants attain the maximum benefit 

from erlotinib suggests a need for more sensitive assays to detect EGFR 

compound mutants and for studies of inhibitors targeting the EGFR T790M 

mutation. Whole genome sequencing may provide greater understanding of 

the genetic factors involved in the differences in OS. 


485s 


11:30 AM-12:30 PM 

Updated overall survival results of WJTOG 3405, a randomized phase III 

trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the 

first-line treatment for patients with non-small cell lung cancer harboring 

mutations of the epidermal growth factor receptor (EGFR). Presenting 

Author: Tetsuya Mitsudomi, Department of Thoracic Surgery, Aichi Cancer 

Center Hospital, Nagoya, Japan 

Background: WJTOG3405 met its primary endpoint of progression free 

survival (PFS) (9.2 months (mo.) for G vs. 6.3 mo. for CD, hazard ratio (HR) 

0.489, 95% confidence interval (CI): 0.336-0.710). (Mitsudomi et al., 

Lancet Oncol., 2010). However, the impact on overall survival (OS) was not 

clear then because of relatively short follow-up period. Methods: Overall 

survival (OS) was re-evaluated using updated data (data cutoff, 31 July, 

2011, median follow-up, 34 months) for 172 patients. Results: Eighty-two 

events had occurred (48%). Median survival time (MST) for G arm was 36 

mo. (95% CI: 26.3 -) which was not significantly different from 39 mo. 

(95% CI: 31.2 -) for CD arm (HR 1.185, 95% CI 0.767-1.829). 

Multivariate analysis using Cox proportional hazards model revealed that 

none of covariates (treatment arm, smoking status, sex, age, postoperative 

recurrence or IIIB/IV, and mutation type) significantly affected OS. In the G 

arm, MST of patients with exon 19 deletion (36 mo.) was comparable to 

that of patients with L858R (35 mo.). In the CD arm, 78 patients (91%) 

received EGFR-TKI as the 2nd or later line treatment, whereas in the G arm, 

52 patients (61%) received platinum doublet. Accordingly, 130 patients 

received both platinum doublet and EGFR-tyrosine kinase inhibitor (TKI) 

and 34 patients received EGFR-TKI without platinum doublet in their 

whole courses of therapy. MST for the former and the latter group were 36 

months (95% CI: 31.2-45.7) and 45 months (95% CI: 25.6-), without 

significant difference. Conclusions: This update OS analysis revealed that G 

for advanced NSCLC with EGFR mutation offers distinct survival benefit of 

3 years. There was no difference in OS whether the first-line treatment was 

G or CD, in accordance with the precedent studies. The reason why PFS 

difference was not translated into OS difference is probably due to high 

cross over rate to EGFR-TKI. However, it was noteworthy that 40% of 

patients in the G arm could be managed without platinum doublet and yet 

had similar outcome. 


11:30 AM-12:30 PM 

Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion 

mutations within the tyrosine kinase domain of EGFR. Presenting Author: 

Daniel Botelho Costa, Beth Israel Deaconess Medical Center/Harvard 


Background: Epidermal growth factor receptor (EGFR) mutations (M) define 

an important subgroup of non-small-cell lung cancer (NSCLC). Most 

patients whose tumors harbor exon 19 deletions or L858R EGFR M have 

responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors 

(TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR 

M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all 

NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR 

TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled 

genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR 

TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs 

using site-directed mutagenesis and introduced them into Ba/F3 cells for in 

vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel 

malignant pleural effusion-derived cell line. Results: The disease control 

rate of gefitinib or erlotinib was significantly higher in EGFR exon 20 

insertion M located within the C-helix (3/3,100%) when compared to M 

following the C-helix (1/14, 7%; p�0.00059). The NSCLC with EGFR- 

A763_Y764insFQEA (located within the C-helix of EGFR) achieved a 

partial response to erlotinib that lasted 18 months. Most other exon 20 

insertion M-positive NSCLCs did not respond (p�0.07). Eight representative 

exon 20 insertion M were studied (including EGFR- 

A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV, 

D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA, 

were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells 

with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to 

nanomolar C of erlotinib. A patient-derived cell line with EGFR- 

A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by 

nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion 

mutations are resistant to EGFR TKIs, and in specific EGFR- 

A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical 

implications for the care of the 10,000 cases of EGFR exon 20 insertion M 

NSCLC diagnosed yearly and points towards the need to define the 

molecular mechanisms that underlie differential responses to EGFR TKIs. 




11:30 AM-12:30 PM 

Chemotherapy with erlotinib or chemotherapy alone in advanced NSCLC 

with acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Presenting 

Author: Sarah B. Goldberg, Massachusetts General Hospital Cancer 


Background: EGFR-mutant NSCLC has an oncogene-addicted phenotype 

that confers sensitivity to EGFR TKIs. Prior data suggests EGFR addiction 

persists after development of TKI resistance, leading many clinicians to 

continue TKI along with chemotherapy (chemo); however, this strategy has 

not been formally evaluated. Methods: An institutional database was 

reviewed to identify patients (pts) with advanced NSCLC and acquired 

resistance to EGFR TKIs by Jackman criteria. Pts were included if they 

subsequently received chemo. Objective response rate (RR) to chemo/ 

erlotinib or chemo alone was assessed by blinded radiographic review and 

compared by Fisher’s exact test and multivariable logistic regression. 

Progression-free survival (PFS) and overall survival (OS) from TKI failure 

(defined as chemo initiation date) were compared by log-rank test and 

multivariable Cox analysis. Results: 78 pts were eligible (34 chemo/ 

erlotinib, 44 chemo alone). 70 pts (90%) had a documented EGFR 

mutation and were on TKI for a median of 15 months (range 4-51); in the 8 

pts with unknown genotype the median duration on TKI was 11 months 

(range 5-16). Baseline characteristics were well balanced except more pts 

received erlotinib as initial TKI in the chemo/erlotinib group. RR was 

evaluable in 57 pts and was higher with chemo/erlotinib compared to 

chemo alone (41% vs 18%; OR 0.31, 95% CI 0.09, 1.04; p�0.08). RR 

adjusted for chemo regimen and time to TKI failure yielded OR 0.20 (95% 

CI 0.05, 0.78; p�0.02), favoring chemo/erlotinib. Median PFS was 4.4 

months in the chemo/erlotinib group and 4.2 months in the chemo alone 

group (crude HR�0.84, 95% CI 0.52, 1.38; p�0.50; adjusted HR 0.79, 

95% CI 0.48, 1.29; p�0.34). There was no significant difference in OS in 

the crude or adjusted analyses. Conclusions: This is the first study, to our 

knowledge, to show that continuation of an EGFR TKI with chemo 

compared to chemo alone significantly increases the RR in pts with 

advanced NSCLC and acquired TKI resistance, though we did not observe 

an impact on PFS or OS. Continued concurrent TKI may be a valuable 

strategy, particularly for pts with symptomatic progression, when a higher 

response rate may be beneficial. Further study is warranted. 


11:30 AM-12:30 PM 

Continuation of EGFR/ALK inhibition after local therapy of oligoprogressive 

disease in EGFR mutant (Mt) and ALK� non-small cell lung cancer (NSCLC). 

Presenting Author: Andrew James Weickhardt, University of Colorado Cancer 

Center, Denver, CO 

Background: This study aimed to investigate the benefits of local treatment of 

limited disease progression and continuation of crizotinib (C) or EGFR-TKI in 

patients with ALK� or EGFR-Mt metastatic NSCLC, respectively. Methods: 

Patients with advanced ALK� NSCLC treated with C (n�38) and EGFR-Mt 

NSCLC treated with EGFR TKIs (erlotinib or gefitinib) (n�27) were identified. 

Patients were evaluated for initial response, site of first progression (CNS or extra 

CNS (eCNS)) and median progression free survival (PFS1). A subset of patients 

with limited sites of progression (oligoprogressive disease) suitable for local 

therapy received either radiation or surgery to these sites and continued on the 

same TKI. The subsequent pattern of progression and median progression free 

survival from the time of first progression (PFS2) were recorded. Results: In 38 

ALK� patients, PFS1�9.0 months on C. In 27 EGFR-Mt patients, PFS1�13.8 

months on EGFR-TKI. CNS was the first site of progression in 13/28 (46%) of 

ALK� patients and 5/23 (22%) EGFR-Mt patients. 25 of 51 patients who 

progressed (49%) were deemed suitable for local therapy (15 ALK�, 10 

EGFR-Mt; 24 with radiotherapy (Body: 3 XRT, 9 SBRT; CNS: 7 WBRT, 5 SRS), 1 

with surgery (adrenalectomy)) and continuation of the same targeted therapy. 

19/25 patients progressed post local therapy, median PFS2 � 6.2 months. In 

patients who progressed at PFS1 only in the CNS, there was a trend to longer 

PFS2 than patients who progressed at PFS1 in eCNS (7.1 months vs 4.0 

months, p�0.26). 60% who progressed only in the CNS at PFS1, progressed 

eCNS at PFS2 (n�10). Conclusions: Progression of oncogene addicted NSCLC 

on relevant targeted therapies is often suitable for local therapy (oligoprogressive 

disease). Continuation of the targeted therapy following local therapy is 

associated with �6 months of additional disease control. 

Sites of first progression and median PFS1 and PFS2 in patients continuing TKI 

after local therapy of oligoprogressive disease. 

Site of progression Number of patients 

PFS1 

(months) 

PFS2 

(months) 

CNS 1st site of prog. 10 10.9 7.1 

eCNS 1st site of prog. 15 9.6 4.0 

All patients 25 10.0 6.2 

* Includes 3 patients who prog. eCNS and CNS at PFS1. 


11:30 AM-12:30 PM 

Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a 

drug-free interval in EGFR-mutant advanced non-small cell lung cancer 

(NSCLC) with acquired resistance. Presenting Author: Stephanie Heon, 


Background: Patients (pts) with advanced NSCLC and sensitizing EGFR 

mutations who initially respond to gefitinib or erlotinib eventually develop 

acquired resistance to the TKIs. Anecdotal and retrospective reports 

suggest that EGFR-TKI resistant cancers can respond again to gefitinib or 

erlotinib after an interval off the TKI. This retrospective study was 

undertaken to investigate the impact of EGFR-TKI retreatment after a 

drug-free interval in EGFR mutant NSCLC with acquired resistance to 

gefitinib or erlotinib. Methods: Pts with stage IV or relapsed NSCLC with 

sensitizing EGFR mutations and acquired resistance to EGFR-TKI seen at 

the DFCI/MGH between 8/00 and 8/11 who were retreated with single 

agent gefitinib or erlotinib after an EGFR-TKI-free interval were identified 

from a prospective trial. The objective tumor response (CR, PR, SD, PD) 

was determined using RECIST 1.1. Results: 19 pts were eligible and had 

adequate scans for radiographic assessments after the reinstitution of an 

EGFR-TKI. The response rate and median PFS to the initial course of 

gefitinib (n�4) or erlotinib (n�15) were 16/19 (84%) and 9.8 months 

(95% CI, 7.8-11.3) respectively. All pts were retreated with erlotinib after 

1 to 4 intervening systemic regimens. The median interval from EGFR-TKI 

discontinuation to erlotinib retreatment was 11 months (range, 2-46). 4 of 

the 19 pts (21%) had PD as the best response to erlotinib retreatment, 14 

(74%) had SD for at least 1 month, and 1 (5%) had a PR. The median PFS 

was 4.4 months (95% CI, 3.0-6.7). 3 pts remained on erlotinib without 

progression for 6 months. 3 pts had their tumors rebiopsied before (n�2) or 

during (n�1) erlotinib retreatment; 1 of the 3 had EGFR T790M in 

association with the initial sensitizing EGFR mutation, and another had a 

secondary PIK3CA mutation. Conclusions: Our findings suggest that erlotinib 

retreatment is an option for EGFR mutated NSCLC with acquired 

resistance to EGFR-TKI after a drug-free interval and progression on 

intervening therapy. Additional advanced NSCLC pts without a documented 

EGFR mutation who fulfill the clinical definition of acquired 

resistance are undergoing review to expand our cohort. 


11:30 AM-12:30 PM 

Local therapy as a treatment strategy in EGFR-mutant advanced lung 

cancers that have developed acquired resistance to EGFR tyrosine kinase 

inhibitors. Presenting Author: Helena Alexandra Yu, Memorial Sloan- 


Background: The utility of EGFR directed therapy for the treatment of EGFR 

mutant lung cancer is limited by the development of acquired resistance 

(AR) to EGFR tyrosine kinase inhibitor (TKI) therapy, which occurs after a 

median of 16 months (mos). There are no approved targeted therapies after 

disease progression on EGFR TKI therapy. Local therapy for oligometastatic 

disease is used with regularity in other solid tumors, and can lead to long 

term survival in selected individuals. EGFR mutant lung cancers with AR to 

TKI therapy can follow an indolent course that is amenable to local therapy 

to treat progression of disease when used in conjunction with continued 

EGFR inhibition. Outcomes following local therapy in this setting have not 

been assessed. Methods: Patients (pts) with AR to EGFR TKI’s who received 

local therapy excluding treatment of CNS metastases or local therapy prior 

to AR were identified in an IRB-approved prospective registry of 184 pts 

with AR enrolled from August 2004- November 2011. We collected 

treatments as well as progression free survival (PFS) and overall survival 

(OS) after local therapy. Results: 18 pts received local therapy. Treatments 

included surgical resection and radiation to lung, lymph nodes, adrenal 

gland or bone. Median age was 57, 56% were women, and 61% were never 

smokers. 14 had EGFR Exon 19 deletions, and 4 L858R. The median time 

to development of AR on TKI was 19 mo (range 5-33). Known mechanisms 

of AR included T790M (11 pts), MET amplification (1 pt) and small cell 

transformation (1 pt). The median PFS after local therapy was 10 mo (95% 

CI: 4-NA), median time from local therapy until change in systemic therapy 

was 22 mo (95%CI: 6 - 30), and median OS from local therapy was 41 mo 

(95% CI: 26-NA). Local therapy was tolerated well, with 85% of pts 

restarting TKI therapy within one month of completing local therapy. 

Conclusions: Local therapy is well tolerated and in combination with 

continued EGFR TKI therapy prolongs time until change in systemic 

therapy is required and may lead to outcomes that are superior to currently 

available treatment options in selected individuals. 



11:30 AM-12:30 PM 

Rebiopsy of non-small cell lung cancer patients with acquired resistance to 

EGFR-TKI: Comparison between T790M mutation-positive and -negative 

populations. Presenting Author: Akito Hata, Division of Integrated Oncology, 

Institute of Biomedical Research and Innovation, Kobe, Japan 

Background: The secondary epidermal growth factor receptor (EGFR) 

mutation T790M accounts for approximately half of acquired resistances to 

EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated 

the presence of T790M predicts a favorable prognosis and indolent 

progression, compared to the absence of T790M after TKI failure. However, 

rebiopsy to confirm T790M status can be challenging due to limited tissue 

availability and procedural feasibility, and little is known regarding the 

differences among patients with or without T790M. Methods: We investigated 

73 patients harboring EGFR sensitive mutations who had undergone 

rebiopsy to confirm the emergence of T790M after TKI failure. The peptide 

nucleic acid-locked nucleic acid PCR clamp method was used in EGFR 

mutational analyses. Patient characteristics (age, gender, smoking history, 

performance status, EGFR mutation site, initial TKI, response to initial TKI, 

line of initial TKI, progression-free survival with initial TKI, and biopsy site) 

and postprogression survivals (PPS) after initial TKI failure, were retrospectively 

compared in patients with and without T790M. Results: We identified 

T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal 

fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions 

(25 lung tissue, 24 pleural effusion, and 3 lymph node) (p � 0.0225). 

Other characteristics had no statistical association with the detection of 

T790M. Median PPS in patients with T790M was 34.0 months, and in 

those without T790M, 14.5 months (p � 0.0038). Although none of our 

patients received TKIs continuously after initial failure, 56 (77%) patients 

were re-administered TKIs. Regardless of T790M status, PPS in patients 

with TKI re-administration (23.4 months) was significantly longer than 

without re-administration (10.4 months) (p � 0.0085). Conclusions: The 

emergence of T790M in CNS is rare compared with other lesions. Patients 

with T790M after TKI failure have significantly better prognosis than those 

without T790M. The effectiveness of TKI re-administration or continuous 

administration beyond progression is suggested after initial TKI failure. 


11:30 AM-12:30 PM 

First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine 

kinase inhibitor, for patients with EGFR-mutant lung cancers. Presenting 

Author: Mark G. Kris, Memorial Sloan-Kettering Cancer Center, New York, 

NY 

Background: Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and 

showed superior activity vs. reversible EGFR tyrosine kinase inhibitors in 

EGFR-mutant lung cancer models, including resistant forms. This openlabel 

Phase II study evaluates dacomitinib as 1st-line treatment (tx) for 

patients (pts) with lung cancers. Pts with sensitizing EGFR deletions/ 

mutations in exons 19 or 21 are reported here. Methods: Pts had stage 

IIIB/IV adenocarcinoma, no prior systemic tx, had smoked �10 pack years 

(none within 15 years of enrollment) or had known EGFR mutation. Pts 

received dacomitinib orally once daily continuously at 45 mg, or 30 mg 

with the option to escalate to 45 mg; evaluation was every 28 days. 

Endpoints included progression-free survival rate at 4 months (PFS at 4M, 

primary); PFS, and partial response (PR) rate. Results: 92 pts enrolled; 47 

had EGFR mutation in exons 19 (n�25) or 21 (n�22), 33 were female and 

27 Asian. 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a 

PR (PR rate � 74%; 95% CI: 59–86; exon 19 � 72%; exon 21 � 76%). 

PR rates and preliminary PFS were not significantly different for exons 19 

and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary 

PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS 

was 17 months (95% CI: 13–24). Median tx duration was 13.1 months. For 

pts with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7% 

(n�14; 95% CI: 0–34) and 33% (n�14; 95% CI: 11–58), respectively, 

and for pts with EGFR unknown lung cancers, 46% (n�22; 95% CI: 

24–68) and 68% (n�24; 95% CI: 45– 83), respectively. 7 pts had lung 

cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all 

92 pts, common side effects included dermatitis acneiform (grade 3/4 � 

17%/0) and diarrhea (14%/0). 3/46 pts with EGFR exon 19 or 21 

mutations discontinued tx due to drug-related toxicity. Conclusions: 74% of 

pts in this cohort with EGFR exon 19 or 21 mutant lung cancers 

experienced PRs with 1st-line dacomitinib; preliminary PFS rate was 77% 

at 1 year; preliminary median PFS was 17 months; further research is 

planned in this pt population. As dacomitinib is well tolerated, with 

preclinical activity against HER2, a cohort of pts with HER2 mutant lung 

cancers is recruiting. 


487s 


11:30 AM-12:30 PM 

Concordance of driver mutations in primary and matched metastasis from 

patients with non-small cell lung cancer (NSCLC) using next-generation 

sequencing (NGS). Presenting Author: Stéphane Vignot, Institut Gustave 

Roussy, INSERM U981, Villejuif, France 

Background: Progress in treating NSCLC continues to be limited by high 

recurrence rates after definitive treatment of localized disease and frequent 

presentation with metastatic disease. In these pts, diagnostic samples are 

often limited in size and may be inadequate for genotyping necessary in 

this disease. In applying genomic profiling to aid treatment planning for 

patients with metastatic NSCLC, it is critical to determine whether archived 

primary tumor adequately reflects the genomic spectrum of the patient’s 

metastatic disease or whether biopsy of a metastatic site is required. We 

undertook this study using NGS technology to characterize paired primarymetastatic 

biopsy genomic profiles. Methods: Primary and matched metastatic 

tumor pairs plus adjacent normal tissue from 15 pts with NSCLC 

(adenocarcinoma 9/squamous 4/large cell 2) and heavy smoking history 

were analyzed using a targeted NGS assay in a CLIA laboratory (Foundation 

Medicine). Genomic libraries were captured for 3230 exons in 182 

cancer-related genes plus 37 introns from 14 genes often rearranged in 

cancer and sequenced to average median depth of 778X with 99% of bases 

covered �100X. Results: Among the 30 tumors, 373 somatic alterations 

were identified; 96 were known NSCLC drivers including: TP53 (14 pts), 

KRAS (4 pts), SOX2 (4 pts), STK11 (2 pts), CDKN2A (2 pts) and 

SMARCA4 (2 pts) in full agreement with their respective histological type. 

In all cases (15/15), primary and metastatic tumors from the same patient 

demonstrated 90% driver mutation concordance (74/82, 95 % CI, 82- 

95%). For other mutations, the majority of which are likely passengers, the 

69% (201/291) concordance rate was significantly lower (p� .001).The 

total number of alterations between primaries (190) and metastases (183) 

was remarkably similar. Conclusions: These results suggest that genomic 

profiles of primary tumor can identify the key somatic alterations present in 

matched NSCLC metastases and therefore is a suitable specimen for 

clinical decision making in the majority of cases. Our data does not support 

the routine need for a new biopsy upon recurrence since variability in 

mutational status is low. 


11:30 AM-12:30 PM 

A randomized discontinuation phase II trial of ridaforolimus in non-small 

cell lung cancer (NSCLC) patients with KRAS mutations. Presenting 

Author: Gregory J. Riely, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: Mutations in KRAS are present in ~25% of patients with 

advanced NSCLC. Preclinical data support the role of mammalian target of 

rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an 

inhibitor of mTOR which has been shown to have efficacy in advanced 

endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR 

inhibitor was previously evaluated in unselected patients with advanced 

NSCLC and found to have a response rate �5%. We hypothesized that by 

enrichment for patients with NSCLC and KRAS mutations, treatment with 

ridaforolimus would be associated with prolonged stable disease relative to 

available standard treatments for NSCLC. Methods: Patients with stage 

IIIB/IV non-small cell lung cancer with KRAS mutation who had received 

prior chemotherapy for NSCLC began treatment with oral ridaforolimus 40 

mg once daily on a 5 day/week schedule. After 8 weeks, patients with 

�30% tumor shrinkage remained on ridaforolimus and patients with 

�20% tumor growth discontinued treatment. Patients with stable disease 

were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of 

the study was progression-free survival (PFS) after randomization. Results: 

79 patients were enrolled (40 women, median age 58 [range 28-85]). The 

overall response rate (CR�PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%). 

28 patients with stable disease at 8 weeks were randomized to ridaforolimus 

or placebo. Median PFS based on investigator assessment from 

randomization was significantly longer with ridaforolimus (4 months) than 

placebo (2 months, p�0.013, HR 0.36). Median OS from randomization 

was 18 months in the ridaforolimus treated arm and 5 months in the 

placebo treated group, (HR 0.46, p�0.09). The most common grade �3 

adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia 

(10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%). 

Conclusions: In patients with KRAS mutant NSCLC who had stable disease 

after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged 

progression-free survival. Further evaluation of ridaforolimus in this patient 

population is warranted. 




11:30 AM-12:30 PM 

Characteristics of NSCLCs harboring NRAS mutations. Presenting Author: 

Kadoaki Ohashi, Vanderbilt University, Nashville, TN 

Background: We sought to determine the frequency and clinical characteristics 

of patients with non-small cell lung cancers (NSCLCs) harboring NRAS 

mutations. We used preclinical models to identify targeted therapies likely 

to be of benefit against NRAS mutant lung cancer cells. Methods: We 

reviewed data in the Catalogue of Somatic Mutations in Cancer (COSMIC) 

and clinical history from patients with NSCLC whose tumors underwent 

systematic screening for driver mutations including NRAS. Patient characteristics 

examined included age, gender, race, smoking history, disease 

stage, treatment history, and overall survival (OS). 6 NSCLC cell lines with 

NRAS mutations were screened for sensitivity against multiple targeted 

agents. Gene expression was profiled using Affymetrix U133A arrays in 5 

NRAS mutant NSCLC cell lines, 8 with EGFR mutations and 17 with KRAS 

mutations. Results: Among 4524 patients with NSCLC tested, NRAS 

mutations were present in 29 (0.64%). The types of substitutions found 

were Q61H/K/L/R and G12A/C/D/R/S, with NRAS Q61L the most common 

(n�14; 48%). One tumor had a concurrent KRAS mutation. 83% had 

adenocarcinoma histology, with no significant differences in gender. While 

90% of patients were former or current smokers, smoking-related G:C�T:A 

transversions were significantly less frequent in NRAS than in KRASmutant 

NSCLC (KRAS: 66%, NRAS: 13%, p�0.05). Systemic chemotherapy 

showed limited efficacy in 7 patients with metastatic disease 

(median OS 7 mos). 5 of 6 NRAS mutant lung cancer cell lines were 

sensitive to the MEK inhibitors, AZD6244 and GSK1120212, while other 

targeted agents (against EGFR, ALK, MET, IGF-1R, PIK3CA, BRAF) were 

minimally effective. Gene expression profiles of NRAS mutant cell lines 

were distinct from those with KRAS or EGFR mutations. Conclusions: NRAS 

mutations define a distinct subset of NSCLCs (~1%) with potential 

sensitivity to MEK inhibitors. While NRAS gene mutations are more 

common in current/former smokers, the types of mutations are not those 

classically associated with smoking. 


11:30 AM-12:30 PM 

Native and rearranged ALK copy number and rearranged ALK cell count in 

NSCLC: Implications for ALK inhibitor therapy. Presenting Author: D. Ross 

Camidge, University of Colorado Cancer Center, Aurora, CO 

Background: ALK rearranged NSCLC responds well to ALK inhibitors. 

Clinically, �15% cells showing rearrangements by break-apart FISH 

classifies tumors as ALK(�). Native ALK copy number gain has also been 

reported. We explored the significance of native and rearranged ALK copy 

number on crizotinib outcomes and whether �15% reflected a clear 

biological distinction in the frequency of ALK(�) cells. Methods: Copy 

number and genomic status of ALK assessed by FISH. A total of 1426 

NSCLC clinical specimens, 174 ALK(�) and 1252 ALK(-) by standard 

criteria, and 26 NSCLC cell lines (2 ALK(�) and 24 ALK(-)) were 

investigated. Results: Native ALK gene mean copy number was significantly 

higher in ALK(-) than in ALK(�) cases (2.8, SD 0.93, range 1.2-11.4 vs. 

1.8, SD 0.79; range 0.6 to 5.2; p�0.01). Frequency of native ALK copy 

number gain (�3 copies/cell in �40% cells) was 19% in ALK(�) and 62% 

in ALK(-) tumors (p�0.001). In ALK(-) tumors, abundant focal amplification 

of native ALK was rare (0.8%); scanty amplification (�10% tumor 

cells) occurred in 1.1%, and duplication of the entire native ALK or of the 

ALK 3’ end occurred in 3.5%. Among ALK(-) cell lines, mean native ALK 

copy number ranged 2.1-6.9 and was not correlated with in vitro crizotinib 

sensitivity (IC50s 0.34-2.8 uM). In (�) patients, neither native or rearranged 

ALK copy number, nor percentage cell count correlated with 

maximal tumor shrinkage or PFS with crizotinib. Clinical specimens with 

0-9%, 10-15%, 16-30%, 31-50% and �50% of ALK� cells were found in 

79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Conclusions: 

Lower native ALK copy number in ALK(�) NSCLC suggests ALK fusion 

occurs early, preceding chromosomal instability. Elevated native ALK copy 

number rarely reflects focal amplification and native ALK copy number 

increases alone are not associated with sensitivity to ALK inhibition in vitro. 

Neither native or rearranged copy number, nor positive cell count within 

ALK(�) tumors influences clinical benefit from ALK inhibition. As 8.5% of 

ALK(-) cases fall within 5% of the established �15% cell positive 

threshold, further investigation of ALK status by other diagnostic techniques 

in this subset may be warranted. 


11:30 AM-12:30 PM 

Results of a global phase II study with crizotinib in advanced ALK-positive 

non-small cell lung cancer (NSCLC). Presenting Author: Dong-Wan Kim, 

Seoul National University Hospital, Seoul, South Korea 

Background: Approximately 3–5% of NSCLC harbors ALK gene rearrangements. 

Crizotinib is a first-in-class, oral, small-molecule competitive ALK 

inhibitor with anti-MET activity. Methods: PROFILE 1005 is an ongoing 

global, multicenter, open-label, single-arm, phase II study evaluating the 

safety and efficacy of crizotinib (250 mg BID in 3-week cycles) in patients 

with advanced ALK-positive NSCLC who progressed after �1 chemotherapy 

for recurrent/advanced/metastatic disease. Tumor response was 

evaluated by RECIST 1.1 every 6 weeks. Patient-reported symptoms and 

global quality of life (QOL) were assessed using the EORTC QLQ-C30 and 

LC-13 at baseline, day 1 each cycle and at end of treatment. Results: As of 

June 2011, 439 patients were evaluable for safety and 255 patients for 

tumor response. Median age was 53 years. The majority of patients were 

female (53%), never smokers (65%), and had adenocarcinoma (92%), 

ECOG PS 0–1 (83%) and �2 prior chemotherapy regimens (85%). Among 

patients evaluable for efficacy, median treatment duration was 25 weeks 

(77% of patients still ongoing). ORR was 53% (95% CI: 47–60), disease 

control rate at 12 weeks was 85% (95% CI: 80–89), median duration of 

response was 43 weeks (96% CI 36–50) and median PFS was 8.5 months 

(95% CI: 6.2–9.9). The most frequent treatment-related AEs were visual 

effects (50%), nausea (46%), vomiting (39%), and diarrhea (35%), mostly 

grade 1–2. 29 patients (6.6%) had treatment-related SAEs, including 

dyspnea and pneumonitis (4 patients each; 0.9%), and febrile neutropenia 

and renal cyst (2 patients each; 0.5%). A statistically significant (p�0.05) 

and clinically meaningful (� 10 points) improvement from baseline was 

observed for patient-reported overall pain, pain in chest, cough, dyspnea, 

insomnia, fatigue and global QOL. Conclusions: Crizotinib demonstrated a 

high response rate and PFS, favorable tolerability profile and improvement 

in patient-reported symptoms. These results provide strong evidence for 

crizotinib as a standard of care for advanced ALK-positive NSCLC. 


Association of epithelial to mesenchymal transition with efficacy of 

EGFR-TKIs in non-small cell lung cancer patients with EGFR wild type. 

Presenting Author: Shengxiang Ren, Shanghai Pulmonary Hospital, Tongji 

University School of Medicine, Shanghai, China 

Background: The epithelial to mesenchymal transition (EMT) is a fundamental 

biological process during which epithelial cells change to a mesenchymal 

phenotype, it has a profound impact on cancer progression and 

treatment. The purpose of this study was to investigate the role of EMT to 

predict the efficacy of epidermal growth factor receptor tyrosine kinase 

inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) 

patients. Methods: We evaluated the correlation between EMT and sensitivity 

to EGFR-TKIs in advanced NSCLC patients. Immunohistochemistry was 

used to examine the expression of EMT markers, E-cadherin, fibronectin, 

N-cadherin and vimentin and ARMs was used to detect the EGFR mutation 

in tumor specimens obtained before the treatment. The EMT phenotype 

status was determined according to the expression of E-cadherin, fibronectin, 

N-cadherin and vimentin. Results: 101 patients enrolled into this study 

and 97 had enough tissue to perform the EMT examination. The median 

age was 59 years old, male/female:56/45, never smoker/smoker: 71/30, 

adenocarcinoma/non-adeno: 73/28, PS 0-1/2-3: 83/18, Stage IIIB/IV: 

2/99, 1st /2nd-4th line: 13/88. The response rate and progression free 

survival(PFS) in the whole population were 45.5% and 7.6 months 

respectively. EMT test revealed that 46(47.4%) samples were epithelial 

phenotype, while 51(52.6%) were mesenchymal phenotype. 38 of 79 

patients harbour activating EGFR mutation. Among the patients with EGFR 

wild type or unknown status, patients with an epithelial phenotype had a 

higher response rate(40% Vs 17.6%, P�0.056) and significantly longer 

PFS(7.6 m Vs 3.8 m, P�0.045) than these with a mesenchymal phenotype. 

However, the response rate(85.7% Vs 64.7%, P�0.249) and 

PFS(15.2 m Vs 12.2 m, P�0.420) were similar in the patients with 

activated EGFR mutation. Conclusions: Patients with an epithelial phenotype 

got more benefit from the treatment of EGFR-TKIs in the advanced 

EGFR wild type NSCLC patients, which indicated that the EMT might be a 

potential marker to guide the individual therapy of EGFR-TKIs in this 

subpopulation. 



A randomized, double-blind, placebo-controlled phase II study of tigatuzumab 

(CS-1008) in combination with carboplatin/paclitaxel in patients 

with chemotherapy-naive metastatic/unresectable non-small cell lung cancer 

(NSCLC). Presenting Author: Joachim Von Pawel, Asklepios Klinikum 

Gauting, Munich, Germany 

Background: Tigatuzumab (T), a humanized monoclonal antibody that acts 

as a DR5 agonist induces apoptosis in human cancer cell lines and has 

shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor 

types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: 

Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC 

stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 

were enrolled at 15 European sites. Pts received T or placebo (PL) IV � 

carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. 

In the case of complete response (CR)/partial response (PR) or stable 

disease, T or PL was given as maintenance therapy. The dosage regimen 

was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks 

thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary 

endpoint: progression-free survival (PFS); secondary endpoints: overall 

survival (OS) and objective response rate (ORR) (CR � PR), safety. Efficacy 

was assessed in both the full population and a prospectively-defined FCGR 

genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage 

IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy 

analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 

6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR � 0.96; 95% CI: 0.6, 1.6. 

Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 

14.5) for PL (HR � 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm 

and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts 

(n � 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a 

non-significant trend towards increased PFS with T vs PL (HR � 0.47; 95% 

CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only 

increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% 

with PL). The number of treatment cycles was similar in both treatment 

arms. Conclusions: T does not improve the efficacy of C/P as treatment for 

systemic therapy-naïve, unselected advanced NSCLC pts. T was well 

tolerated and is being investigated in other settings. 


A novel targeted oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor 

and its implications for patients with non-small cell lung cancer 

(NSCLC): A phase I clinical trial. Presenting Author: Simon Ekman, 

Department of Oncology, Uppsala University Hospital, Uppsala, Sweden 

Background: The small-molecule IGF-1R inhibitor picropodophyllin (PPP) 

is the active compound in the oral suspension AXL1717. PPP has shown 

extensive preclinical antitumor effects against a wide range of cancers 

supporting its use as a single agent treatment. Methods: The clinical phase 

Ia/b study on advanced progressive cancer patients with various solid 

tumors and without remaining treatment options aimed at establishing the 

recommended phase II dose (RPTD) and the maximum tolerated dose 

(MTD) of AXL1717. Phase Ia consisted of single day dosing and phase Ib 

multiday dosing (to an accumulated total of 28 days of treatment; 2*28 

days following amendment) with 3 weeks intermission between treatments. 

Non-progressing patients could continue treatment in the extension study 

without time limitation (treated 119 weeks). PK samples were obtained at 

10 different time-points after the morning dose when appropriate. Results: 

Phase Ia included 16 patients treated with 78 BID doses ranging from 

5-2900 mg AXL1717 BID without any dose-limiting toxicity. Phase Ib 

included 39 patients treated with doses between 290-930 mg BID in 

periods between 7-28 days, totally for 147 weeks. Phase Ib showed that 

AXL1717 was well tolerated and neutropenia was the only detected 

dose-related, reversible, dose-limiting toxicity (DLT). RPTD dose was set at 

390 mg BID to minimize neutropenia. Although the study was not designed 

for efficacy assessment, some patients, mainly with NSCLC, showed signs 

of clinical benefit, including 3 partial responses and 12 patients with stable 

disease. The 15 patients with NSCLC and treatment duration of more than 

2 weeks with single agent AXL1717 in 3rd or 4th line showed a median 

time to progression of 31 weeks and a survival time of 60 weeks with 4 

patients being alive at cut-off. Down-regulation of IGF-1R on granulocytes 

and increases of serum IGF-1 were seen. The systemic exposure of 

AXL1717 was dose-dependent and sufficient for antitumor effects. 

Conclusions: AXL1717 has a good safety profile and demonstrated promising 

clinical benefits in this severely ill and heavily pretreated patient cohort, 

especially in patients with NSCLC. 


489s 


Intratumoral heterogeneity of EGFR mutation and clinical significance in 

Chinese patients with advanced non-small cell lung cancer. Presenting 

Author: Hua Bai, Peking University School of Oncology, Beijing Cancer 

Hospital and Institute, Beijing, China 

Background: Whether exist intratumoral heterogeneity of epidermal growth 

factor receptor (EGFR) gene mutation remains controversial. This study 

aims to evaluate intratumoral heterogeneity of EGFR and its clinical 

significance in patients with non-small cell lung cancer (NSCLC). Methods: 

Samples were collected from 85 patients with stage IIIa-IV who had 

palliative surgery resection. All of the bulk tissues had been routinely 

detected EGFR mutation, in which contained 30 wild-type and 55 

mutant-type EGFR. 28–34 tumor foci for each sample were microdissected. 

EGFR mutation was detected by ARMS. EGFR copy number was 

detected by FISH. 23 patients received EGFR-tyrosine kinase inhibitor 

(TKIs) therapy. Results: 1740 tumor foci from 55 EGFR mutant-type 

(Group-M) and 959 foci from 30 wild-type cases(Group-W) were fractionated. 

Mean mutation contents were 73.9%(1285/1740) in Group-M and 0 

in Group-W. Accordingly, 28.2%(24/85)consisted of cells with both 

wild-type and mutated-type EGFR, with the proportion of EGFR mutant 

cells ranging from 1% to 90%, whereas 71.8%(61/85) samples contained 

pure mutant-type (n�31) or wild-type EGFR cells(n�30). 31 patients 

(36.5%) presented EGFR FISH positive. The patients with mutation 

heterogeneity, regardless of high or low mutation contents, presented lower 

EGFR copy number than those with pure mutation cases (16.7% vs 

71.0%,p�0.05). Among 23 patients who received EGFR-TKIs therapy, the 

mean mutation content was higher in partial response (71.1%) and stable 

disease group (43.4%) than in progressive disease group (5.0%) (p�0.005). 

Conclusions: This study showed that the heterogeneity of EGFR mutation 

was found in introtumoral region with different degree. The response to 

EGFR-TKIs was correlated with EGFR mutant content. 


Differential progression-free survival (PFS) to erlotinib according to EGFR 

exon 19 deletion type in non-small cell lung cancer (NSCLC) patients (p) in 

the EURTAC study. Presenting Author: Enric Carcereny Costa, Catalan 

Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain 

Background: Different exon 19 deletion types have shown different in vitro 

sensitivity to erlotinib, with the lower IC50 for deletion E746_A750 

(ELREA) (Yuza et al. Cancer Biol Ther 2007). This information prompted us 

to examine outcome according to type of exon 19 deletion in the EURTAC 

study. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) 

randomized 174 p with EGFR exon 19 deletions or L858R mutations to 

receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 

months (m) vs 5.2 m, respectively (P�0.0001). Exon 19 deletions were 

divided into two groups: ELREA vs non-ELREA deletions. Results: Exon 19 

deletions were present in 57 p in the erlotinib arm and in 58 p in the 

chemotherapy arm. ELREA deletions were found in 41 p (71.9%) in the 

erlotinib arm and in 38 p (65.5%) in the chemotherapy arm. Non-ELREA 

deletions were found in 16 p in the erlotinib arm and in 20 p in the 

chemotherapy arm. There were no differences in p characteristics between 

treatment arms according to type of deletion. PFS for p with ELREA 

deletions was 9.4 m in the erlotinib arm and 4.6 in the chemotherapy arm 

(HR, 0.36; P�0.0004). PFS for p with non-ELREA deletions was not 

reached in p in the erlotinib arm and was 5.3 m for p in the chemotherapy 

arm (HR, 0.17; P�0.001). The multivariate analysis identified erlotinib 

arm (P�0.001) and non-ELREA deletions (P�0.001) as independent 

markers of longer PFS. Overall survival (OS) for p with ELREA deletions was 

17 m in the erlotinib arm and 18.4 in the chemotherapy arm (P�0.575). 

OS for p with non-ELREA deletions was not reached in the erlotinib arm and 

19.5 m in the chemotherapy arm (P�0.216). Response rate (RR) for p with 

ELREA deletions was 53.6% in the erlotinib arm vs 15.7% in the 

chemotherapy arm (P�0.004). RR for p with non-ELREA deletions was 

68.7% in the erlotinib arm vs 10% in the chemotherapy arm (P�0.001). 

Conclusions: To date, no biological reason has been identified that can 

explain the greater sensitivity to erlotinib in p with non-ELREA exon 19 

deletions. Our findings indicate the need to define the type of deletion prior 

to treatment since this information can be helpful in predicting the 

duration of response. 




A phase II multicenter study of aflibercept (AFL) in combination with 

cisplatin (C) and pemetrexed (P) in patients with previously untreated 

advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC). 

Presenting Author: Hongbin Chen, Roswell Park Cancer Institute, Buffalo, 

NY 

Background: AFL is a recombinant human fusion protein that acts as a 

decoy receptor and prevents the interaction of vascular endothelial growth 

factor (VEGF)-A, VEGF-B, and placental growth factor with their receptors. 

This study evaluated the efficacy and safety of AFL in combination with 

first-line chemotherapy of C and P in NSCLC. Methods: This phase II, single 

arm, open label, multicenter trial in patients with previously untreated, 

locally advanced, or metastatic NSCLC excluded patients with squamous 

histology, cavitating lesions, ECOG � 1, uncontrolled hypertension, or 

brain/CNS metastases. All patients received IV AFL 6 mg/kg, P 500 mg/m2 , 

and C 75mg/m2 , every 3 weeks for up to 6 cycles. For those who completed 

the combined chemotherapy, Q3W administration of AFL was to continue 

until disease progression, intolerable toxicity, or any other cause for 

withdrawal. The primary endpoints were objective response rate (ORR) and 

progression free survival (PFS). Planned sample size was 72 patients. 

Results: The study was closed prematurely due to 3 confirmed cases of 

reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 

patients were enrolled. Median age was 61.5 years; 54.8% were male, 

85.7% white and 50% ECOG 0. A median of 4 cycles of AFL was 

administered. The most common treatment-emergent adverse events 

(TEAEs) of any grade were nausea (69%) and fatigue (67%), with 

hypertension (36%) as the most common grade 3/4 TEAE. The 3 patients 

with RPLS were Caucasian women. Two had a history of hypertension and 

both experienced elevated BP and reduced CrCl. Of the 38 patients 

evaluable for response, ORR was 26.3% (95% CI, 12.3-40.3%) and 

median PFS was 5 months (95% CI, 4.3-7.1). Conclusions: The rate of 

RPLS observed in this study with AFL � C � P was higher than anticipated. 

A meta-analysis of safety from three large placebo-controlled studies 

reported no RPLS among 1333 patient treated with AFL � chemotherapy, 

and none was reported in prior combination studies of AFL � PorAFL� C 

� docetaxel. Though the study was stopped early, ORR and PFS were in 

accordance with most historical first-line NSCLC studies. 


Phase II study of the HSP90 inhibitor AUY922 in patients with previously 

treated, advanced non-small cell lung cancer (NSCLC). Presenting Author: 

Edward B. Garon, David Geffen School of Medicine, University of California 

Los Angeles, Los Angeles, CA 

Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. 

A Phase I study in advanced solid tumors provided a recommended 

Phase II dose of 70 mg/m2 . HSP90 acts as a chaperone of client proteins, 

including those relevant in NSCLC pathogenesis. This Phase II study 

assessed AUY922 in pts with previously treated advanced NSCLC stratified 

by molecular status. Methods: Pts with advanced NSCLC who progressed 

following �2 prior lines of chemotherapy, received AUY922 70 mg/m2 as a 

1-hr infusion once-weekly. Pts were assigned to 4 strata: EGFR activating 

mutations (EGFR mut), KRAS mut, ALK rearranged (ALK�), or EGFR/KRAS/ 

ALK wild type (wt). Phase II Bayesian hypothesis testing design allowed 

sharing of information between strata based on assessing similarity in 

observed response data. Primary endpoint was confirmed (RECIST) objective 

response rate (ORR) or stable disease (SD) at 18 wks. Secondary 

endpoints included OS, PFS, and safety/tolerability. Results: A total of 112 

pts (median age 60 years; 45% male; 86% adenocarcinoma; 28 [25%] pts 

KRAS mut; 35 [31%] EGFR mut; 14 [12%] ALK�; 31 [28%] EGFR/KRAS/ 

ALK wt) were treated at the December 16th 2011 cutoff. Most pts were 

heavily pretreated: 61% had received �3 prior systemic regimens; 64% 

had WHO PS 1 or 2. Mean duration of exposure was 9.1 wks. The most 

frequent adverse events (AEs, any grade [Gr]) were diarrhea (73%), visual 

AEs (71%), and nausea (43%). Most AEs were Gr 1/2; Gr 3/4 AE’s were rare 

(all �10%). The study is ongoing, and 29 pts were still receiving treatment 

at the cutoff date. Preliminary clinical activity of AUY922 (RECIST; 

investigator assessed) was seen with partial responses in 13/101 (13%) 

pts: 2/8 (25%) ALK� pts, 6/33 (18%) EGFR mut pts, 4/30 (13%) 

EGFR/KRAS/ALK wt pts, 0/26 (0%) KRAS mut pts, and 1/4 (25%) pts of 

unknown status. In ALK� pts, responses were seen in crizotinib (CRZ)naive 

pts, and SD was seen with tumor shrinkage in CRZ-resistant pts. PFS 

data will be presented. Conclusions: AUY922 had an acceptable safety 

profile and demonstrated preliminary activity in heavily pretreated pts with 

advanced NSCLC. This trial demonstrates clinical activity of AUY922 in 

EGFR mut and EGFR/KRAS/ALK wt NSCLC pts in addition to ALK� pts. 


Skin toxicity associated with outcome to erlotinib in non-small cell lung 

cancer (NSCLC) patients (p) with EGFR mutations in the EURTAC study. 

Presenting Author: Cristina Buges, Catalan Institute of Oncology, Hospital 

Germans Trias i Pujol, Barcelona, Spain 

Background: Rash is reported in 75% of p treated with erlotinib and has 

been associated with improved overall and progression-free survival (PFS) 

in unselected p although not specifically in p with EGFR mutations. 

Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 

174 p with EGFR exon 19 deletions or L858R mutations to receive 

erlotinib or chemotherapy. Overall PFS was 9.7 months (m) vs 5.2 m, 

respectively (P�0.0001). Rash was defined according to NCI CTC v3.0 and 

dichotomized by grades 0-1 vs 2�. Grade 2 is macular or popular eruption 

or erythema with pruritus or other associated symptoms, localized desquamation 

or other lesions covering �50% of body surface area. We examined 

outcome in the erlotinib arm according to rash grade. Results: 16pinthe 

erlotinib arm had no rash (grade 0), 30 had grade 1, and 40 had grade 2�. 

80% of cases of rash grade 2� occurred in p with exon 19 deletions, while 

only 20% were in p with L858R mutations (P�0.039). There were no 

differences in rash grade according to sex, age or smoking status. PFS was 

11.2 m in p with rash grade 2� and 8.4 m in p with grade 0-1 (HR, 0.52; 

P�0.018). There was no correlation between rash grade 0-1 vs 2� and 

response or overall survival (OS). Interestingly, when p were divided into 

those with no rash (16 p) and those with grade 2� (40 p), PFS was 11.2 m 

for p with grade 2� vs 2.7 m for p with no rash (P�0.031), and OS was 

24.9 m for p with grade 2� vs 16.1 m for p with no rash (P�0.033). 

Conclusions: Although the biological reasons for the association of skin rash 

with better outcome to erlotinib have not been elucidated, this sub-analysis 

of the EURTAC trial has enabled us to confirm for the first time that skin 

rash – especially grade 2� - can predict better outcome to erlotinib in p 

with EGFR mutations. In addition, the correlation between rash and type of 

EGFR mutation warrants further investigation. 


GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, 

dual-acting monoclonal antibody (mAb) designed to enhance antibodydependent 

cellular cytotoxicity (ADCC), in combination with first-line 

cisplatin and pemetrexed in metastatic nonsquamous NSCLC. Presenting 

Author: James F. Spicer, King’s College London, Guy’s Hospital Campus, 


Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth 

Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown 

promising clinical activity in phase I and in the neoadjuvant treatment of 

head and neck cancer. This phase Ib study (NCT01185847) aimed to 

determine the safety, pharmacokinetics (PK), activity and recommended 

phase II dose (RP2D) of GA201 in combination with chemotherapy in 

non-squamous NSCLC. Methods: Successive cohorts received GA201 

1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with 

chemotherapy at standard doses. Data cut off was 7 months after enrolling 

the last patient. Results: 14 patients (4 female) with performance status 

0-1 were enrolled. No maximum tolerated dose was reached. Most common 

adverse events (AEs – all grades) included rash (100%), hypomagnesaemia 

(71%), infusion-related reactions (64%), mucosal inflammation (57%) 

and anemia (50%). AEs of � grade 3 included rash (71%), skin fissure 

(21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median 

timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction 

for 4 patients and discontinuation for 1 patient. There were 6 confirmed 

partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with 

stable disease ��9 weeks. Duration of response ranged between 5 and 42 

weeks (3 patients still ongoing). Preliminary biomarker analysis shows a 

correlation between tumor-infiltrating CD16� immune cells and target 

lesion shrinkage at first tumor assessment [R(spear)�-0.65 (p�0.02)]; no 

apparent correlation between EGFR H-score and response was found. PK 

data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The 

RP2D of GA201 in combination with chemotherapy was established to be 

1400 mg. The incidence of EGFR associated rash was high and guidelines 

to reduce its severity were implemented with a noted improvement in 

tolerability. Promising antitumor activity was observed. Biomarker data 

support the mode of action of GA201 via ADCC. A randomized phase II trial 

of this combination is ongoing and fully recruited. 



FGFR1 amplification and EGFR mutation in Chinese squamous cell lung 

cancer. Presenting Author: Zhigang Wei, Department of Thoracic Medical 

Oncology, Department of Thoracic Surgery, Peking University School of 

Oncology, Beijing Cancer Hospital and Institute, Beijing, China 

Background: Squamous cell lung cancer (SCC) lacks for effective targeted 

therapies. FGFR1 amplification has emerged as a potential biomarker. This 

study aimed to explore clinicopathologic characteristics of FGFR1 amplification 

in Chinese SCC patients and further explore the correlation between 

FGFR1 amplification and EGFR mutations. Methods: One hundred seventyseven 

SCC patients were included in this retrospective study. Gene copy 

number of FGFR1 and EGFR mutations were detected by fluorescence in 

situ hybridization (FISH) and denaturing high-performance liquid chromatography 

(DHPLC), respectively. Results: FGFR1 amplifications were detected 

in 24.9% (44/177) Chinese SCC patients. FGFR1 amplification in 

SCC was more common in male (28.0%, 40/143) and smokers (28.7%, 

39/136) than female (11.8%, 4/34, p�0.049) and nonsmokers (12.2%, 

5/41, p�0.032). FGFR1 amplification and EGFR mutations were mutually 

exclusive (p�0.006), fourty-one of 139(29.4%) patients with wild-type 

EGFR had FGFR1 amplification, while 3 of 38 (7.9%) patients with EGFR 

mutation had FGFR1 amplification. Conclusions: FGFR1 amplification was 

common in Chinese squamous cell lung cancer, and mutually exclusive 

with EGFR mutations. 


Delay of chemotherapy through use of post-progression erlotinib in patients 

with EGFR-mutant lung cancer. Presenting Author: Geoffrey R. Oxnard, 


Background: 1st-line tyrosine kinase inhibitor (TKI) therapy for patients 

(pts) with EGFR-mutant lung cancer prolongs progression free survival 

(PFS) and improves quality of life. When pts develop acquired resistance to 

TKI, chemotherapy is the only approved systemic treatment. Anecdotal 

evidence suggests that change of therapy can be delayed in some pts 

through continued TKI beyond progression (PD), but the effectiveness of 

this approach has not been quantified. Methods: Through an IRB-approved 

mechanism, pts with advanced lung cancer and EGFR sensitizing mutations 

treated on 3 prospective trials of 1st-line erlotinib were identified. 

Only pts with RECIST PD while on erlotinib were studied. Time from PD 

until use of an alternate systemic therapy (or death) and characteristics at 

PD (development of new extra-thoracic metastases or cancer-related 

symptoms) were assessed. Results: 42 eligible pts were identified with the 

following characteristics: median age 70, 86% female, 93% non-Asian, 

50% never-smokers, 83% adenocarcinoma, 100% EGFR-mutant (55% 

exon 19, 36% exon 21, 9% exon 18). Median PFS on erlotinib was 13 

months. After PD, alternate systemic therapy was delayed �3 months in 19 

pts (45%; 95%CI: 31%-60%), through a combination of post-PD erlotinib 

(16 pts), radiation (6 pts), and/or surgery (3 pts), or on observation alone (2 

pts). These 19 pts commonly had exon 19 deletions and were more likely to 

have no cancer-related symptoms at PD (Table), and had a median post-PD 

survival of 29 months. Alternate systemic therapy was delayed �12 

months in 8 pts (19%). Conclusions: In a subset of pts with EGFR-mutant 

lung cancer and acquired resistance to TKI, chemotherapy can be delayed 

with the aid of post-PD TKI and local treatment modalities. This indolent 

PD is likely due to ongoing tumor EGFR dependence. In pts who are 

tolerating TKI and have asymptomatic progression, we recommend this 

palliative treatment strategy as an option for delaying chemotherapy and 

maximizing quality of life. 

Delay of alternate systemic therapy 

>3m 

(n�19) 



Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in 

patients with advanced nonsquamous non-small cell lung cancer (NSCLC): 

Asian subgroup analysis. Presenting Author: Yukito Ichinose, National 

Kyushu Cancer Center, Fukuoka, Japan 

Background: MONET1 evaluated overall survival (OS) in patients (pts) with 

nonsquamous NSCLC receiving motesanib (an oral VEGFR 1, 2 and 3, 

PDGFR and Kit inhibitor) plus C/P compared with pts receiving placebo 

plus C/P. Analysis of the total population (N�1090) showed that motesanib 

� C/P did not significantly improve OS vs C/P alone (primary 

endpoint). Here we present results of a subgroup analysis of Asian pts. 

Methods: Asian pts (Japan, S. Korea, Philippines, Hong Kong, Taiwan, 

Singapore) with stage IIIB/IV or recurrent nonsquamous NSCLC and no 

prior systemic therapy for advanced NSCLC were analysed. Pts were 

randomized to up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 

mg/m 2 ) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) 

orally continuously. Results: 227 Asian pts (incl. 106 Japanese pts) with 

nonsquamous NSCLC were randomized (Arm A/B, n�110/117); 198 had 

adenocarcinoma (n�97/101). Median age was 60 y (range 30–78); 80% 

had stage IV disease. At the time of analysis, 139 pts had died (118 pts 

with adenocarcinoma). Pts received a median of 164 days of motesanib vs 

125 days of placebo (vs 106 and 126 days in non-Asian pts). Median 

follow-up was 63 wks. Efficacy results are shown in the table. Motesanib/ 

placebo-related AEs were seen in 94/74% of pts respectively; Gr �3 

related AEs in 48/22%. Most common emergent AEs were (Arm A/B) 

alopecia (78/76%), diarrhea (63/33%), and nausea (55/43%); gallbladder 

disorders (Gr 1–2) were seen in 9/2% of pts. Gr �3 AEs more frequent in 

Arm A vs B included neutropenia (36/22%) and hypertension (13/3%). 

Emergent Gr 5 events were seen in (Arm A/B) 5/4% vs 16/11% in 

non-Asian pts. Conclusions: In contrast to non-Asian pts, in the subgroup of 

Asian pts with advanced nonsquamous NSCLC, motesanib plus C/P 

treatment was associated with increased OS, PFS, and objective response 

rates (ORR) compared with C/P alone, with no excess of treatment-related 

mortality. 

Asian subgroup All non-Asian pts 

Motesanib �C/P (n�110) Placebo � C/P (n�117) Motesanib �C/P(n�431) Placebo � C/P (n�432) 

Median OS (mos) 

Median PFS (mos) 

20.9* 

7.0 

14.5 10.9 10.7 

† ORR (%) 62 

5.3 5.5 5.4 

† 27 34* 25 

CR �1 0 �1 �1 

PR 61 27 33 25 

*p�0.05; †p�0.001 vs placebo � C/P 


A randomized phase II study of axitinib in combination with pemetrexed/ 

cisplatin (pem/cis) as first-line therapy for nonsquamous non-small cell 

lung cancer (NSCLC). Presenting Author: Chandra Prakash Belani, Penn 

State Hershey Cancer Institute, Hershey, PA 

Background: Axitinib is a potent and selective second-generation inhibitor 

of VEGF receptors 1, 2, and 3 that has promising single-agent activity in 

advanced NSCLC. Efficacy and safety of axitinib (in 2 dosing schedules) 

combined with pem/ciswere evaluatedfor non-squamous NSCLC. Methods: 

Patients with confirmed stage IIIB, IV, or recurrent non-squamous NSCLC 

and ECOG performance status (PS) 0 or 1 were stratified by gender and PS, 

and randomized 1:1:1 to receive six 21-day cycles of axitinib continuously 

plus pem/cis (arm I); axitinib on Days 2 through 19 followed by a 3-day 

interruption plus pem/cis (arm II); or pem/cis alone (arm III). Axitinib was 

administered at a starting dose of 5 mg BID. Pem/cis (500/75 mg/m2 ) was 

infused on Day 1 of each cycle. Primary endpoint was progression-free 

survival (PFS). Results: Baseline characteristics of patients in arm I 

(n�55), arm II (n�58), or arm III (n�57) ranged between 59–62 yr 

median age; 62–65% male; 71–85% White; 73–85% current/exsmokers; 

and 43–47% PS 0. There were no significant differences in PFS 

or overall survival (OS) between axitinib-containing arms I and II compared 

with pem/cis alone, but objective response rates (ORR) were higher (Table). 

Most common all causality grade 3 adverse events (AEs) in arm I, II, and III, 

respectively, were hypertension (20%, 17%, 0%); neutropenia (18%, 

10%, 9%); nausea (16%, 5%, 7%); vomiting (13%, 5%, 4%); fatigue 

(11%,16%,16%); and anemia (7%, 14%, 9%). Grade 4 AEs observed in 

�1 patient were asthenia and pulmonary embolism (2 patients each in arm 

II). Conclusions: Axitinib combined with pem/cis was generally well tolerated, 

but efficacy was not significantly better than pem/cis alone in 

non-squamous NSCLC. 

Median PFS (95% CI), mo 

HR (95% CI) vs Arm III 

P 

Median OS (95% CI), mo 

HR (95% CI) vs Arm III 

P 

ORR (95% CI), % 

Treatment Difference, % 

(95% CI) vs Arm III 

P 

Arm I Arm II Arm III 

8.0 (6.5, 10) 

0.892 (0.560, 1.423) 

0.355 

16.6 (12.6, 22.4) 

1.079 (0.663, 1.756) 

0.632 

45.5 (32.0, 59.4) 

19.2 (1.7, 36.6) 

0.013 

7.9 (6.2, 9.5) 

1.019 (0.640, 1.623) 

0.545 

14.7 (11.5, 18.1) 

1.391 (0.871, 2.222) 

0.891 

39.7 (27.0, 53.4) 

13.4 (-3.7, 30.3) 

0.069 

7.1 (5.8, 9.2) 

– 

15.9 (11.1, –) 

– 

26.3 (15.5, 39.7) 

– 


Final results of a randomized, double-blind, phase II study of gemcitabine 

plus vandetanib or plus placebo in the treatment of advanced (stage 

IIIB/IV) non-small cell lung cancer (NSCLC) elderly patients (ZELIG study 

NCT00753714). Presenting Author: Cesare Gridelli, SG Moscati Hospital, 

Avellino, Italy 

Background: Vandetanib (V) is a once-daily oral inhibitor of VEGFR, EGFR 

and RET signaling. Single-agent gemcitabine (G) is a standard of care 

option for unselected patients (pts) unfit for doublet platinum based 

chemotherapy. This study assessed the progression-free survival (PFS) 

benefit of G�V compared to G plus placebo (P) in pts with advanced NSCLC 

aged � 70 years. Methods: Eligible pts (stage IIIB/IV NSCLC; WHO PS 0-2; 

all histologies; chemonaïve, aged �70) were randomized 1:1 to receive G 

1200 mg/m2 i.v. day 1 and 8 of each 21-day cycle, up to 6 cycles plus V 

100 mg/day or plus P until progression/toxicity. The primary objective was 

PFS (80% power to detect a hazard ratio [HR] � 0.667). Secondary 

endpoints included overall survival (OS), objective response rate (ORR), 

disease control rate (DCR), and safety. Results: Between Oct 2008-May 

2010, 124 pts (median age 75 yrs (70-84); 72.6% male; 57.2% WHO PS 

0-1; 74.2% past/never-smoker; 58.1% adenocarcinoma; 89.5% stage IV) 

were randomized to G�V (n�61) or G�P (n�63). Baseline characteristics 

were similar in both arms. At data cut-off (Apr11), 87.9% pts 

progressed and 73.4% pts had died. PFS was significantly prolonged for 

G�V (HR�0.729; 95% CI 0.484-1.096; p�0.0417), median PFS 

G�V�6.0 months, G�P�5.5 months. No differences were seen in ORR 

(14.8% and 12.7%; p � 0.74), DCR (72.1% and 66.7%; p �0.51), OS 

(HR�1.024 [95% CI 0.667-1.571] p�0.8960), proportion of pts alive at 

1-year G�V�31.1% and G�P�30.2% (p�0.90). Adverse events (AEs) 

observed for V 100 mg were generally consistent with previous NSCLC 

studies of V 100 mg. Common AEs (any grade) occurring with a greater 

frequency in the G�V arm included skin toxicity (34.4% vs 15.9%) and 

hypertension (9.8% vs 3.2%). Diarrhea and neutropenia were similar in 

both arms (14.8% and 14.3%; 19.7% and 19.0%). Conclusions: Despite a 

marginally statistically significant improvement in PFS the study did not 

met the primary and secondary end points. The combination G�V was well 

tolerated in this clinical setting. 


Molecular marker analysis of SWOG S0636, a phase II trial of erlotinib and 

bevacizumab in never-smokers with advanced NSCLC. Presenting Author: 

Philip C. Mack, University of California, Davis, Sacramento, CA 

Background: S0636 investigated the combination of erlotinib and bevacizumab 

in never-smoking NSCLC patients with confirmed adenocarcinoma 

histology (H. West ASCO 2011). Patient eligibility was not restricted by 

molecular selection. Median PFS and OS were encouraging at 8 and 26 

months. An analysis of molecular markers was undertaken, focusing 

initially on the EGFR pathway. Methods: EGFR analysis included gene copy 

number, mutation and protein expression. Copy number was conducted by 

FISH using the Colorado scoring system. An immunohistochemistry H score 

was developed for EGFR protein expression analysis, ranging from 0 to 

400. Specimens were evaluable from 42 of the 85 eligible patients. 

Results: FISH positivity was identified in 17/35 pts (49%), 11 with high 

polysomy and 6 with true gene amplification. EGFR activating mutations 

were seen in 10/33 pts (30%). IHC H-score �200 was observed in 17/40 

pts (43%). All EGFR markers were significantly correlated with one 

another. In the EGFR WT subgroup, FISH-positive patients outperformed 

FISH-negative pts (mPFS 20 vs, 6 months, p�0.06). Conclusions: Careful 

analysis of EGFR markers (mutation, FISH and IHC) identified S0636 

patients with favorable PFS and encouraging trends for OS. EGFR FISH and 

IHC provided additional predictive information beyond that of EGFR 

mutation status. Supported in part by DHHS: CA32102 and CA38926, and 

in part by Genentech. 

Group N mPFS (mos) p value mOS (mos) 2-Year OS p value 

FISH positive 17 20 NR 0.82 

FISH negative 18 6 0.02 17 0.39 0.08 

EGFR mutant 10 36 NR 0.53 

EGFR wild type 23 8 0.09 26 0.57 0.69 

FISH � OR mutant 20 20 NR 0.72 

FISH – AND WT 13 6 0.03 15 0.40 0.08 

IHC: 0-100 11 6 ref. 18 0.25 ref. 

101-200 12 8 0.26 NR 0.61 0.27 

201-400 17 19 0.03 NR 0.74 0.06 



Radiographic assessment and therapeutic decisions at RECIST progression 

in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors. 

Presenting Author: Mizuki Nishino, Dana-Farber Cancer Institute, Boston, 

MA 

Background: EGFR mutated advanced NSCLC treated with EGFR TKIs 

typically progresses after initial response due to acquired resistance. TKI 

therapy is often continued beyond RECIST progression (PD). We investigated 

the frequency of this practice and patterns of RECIST PD via imaging 

findings, as well as the association between patient characteristics and 

discontinuation of TKI among patients (pts) who progressed while on TKI. 

Methods: Among a cohort of 101 advanced NSCLC pts with sensitizing 

EGFR mutations treated with first-line erlotinib or gefitinib at DFCI, 70 pts 

treated between 2002 and 2010 had at least two CT scans for retrospective 

radiographic assessments using RECIST1.1; 56 pts had experienced PD by 

the data closure date of June 2011. Results: Among 56 pts experiencing 

PD, 46 (82%) were female, median age was 63 (range 35-79), 28 (50%) 

were never-smokers, 32 (57%) had distant mets, 32(57%) had exon 19 

deletion, and 50 (89%) received erlotinib. 49 pts (88%) continued TKI 

therapy for at least 2 mos beyond retrospectively assessed PD. 31/32 

(97%) pts who progressed by increase of target lesions continued TKI. 

13/16 (81%) pts who progressed by new lesion remained on TKI. Two pts 

with PD in non-target lesions discontinued therapy at PD. 5/6 (83%) pts 

with both increase of target lesions and new lesion at PD continued TKI. In 

49 continuing pts, the median time from RECIST PD to termination of TKI 

was 10.1 mos (range: 2.2-64.2 mos). 15/49 (31%) pts who continued TKI 

received additional chemo compared to 0/7 pts who discontinued (Fisher’s 

p�0.17). Pts who discontinued therapy (n�7) were significantly younger 

(median 48 yrs) than those who continued TKI at PD (median 64 yrs, 

Wilcoxon p�0.003). Median OS beyond RECIST PD among those who 

continued TKI was 31.8 mos (95% CI 15.9- not reached) and though 

underpowered, this did not appear to be impacted by TTP when adjusted in 

a Cox model (p�0.84). Conclusions: 88% of EFGR-mutant NSCLC pts who 

progressed on first-line TKI continued therapy beyond RECIST PD, which is 

not the single determining factor for terminating TKI in EGFR-mutant 

NSCLC pts. Additional progression criteria specific to this population are 

needed to better guide therapeutic decision making. 


N0821: A phase II first-line study of a combination of pemetrexed (P), 

carboplatin (C), and bevacizumab (B) in elderly patients with good 

performance status (PS < 2). Presenting Author: Grace K. Dy, Roswell Park 

Cancer Institute, Buffalo, NY 

Background: In a retrospective exploratory analysis of E4599, patients (pts) 

� 70 yo had a higher frequency of and more severe toxicities without 

apparent survival benefit from the addition of B to C�paclitaxel. We 

hypothesized that in this pt population, B will have better safety and 

efficacy profile when used in combination with C�P. Methods: Pts �/� 70 

yo with previously untreated stage IIIB/IV (TNM 6th ed) nonsquamous 

NSCLC, ECOG PS 0-1, measurable disease and adequate organ function 

were eligible. C at AUC 6, P at 500 mg/m2 and B at 15 mg/kg were 

administered on day 1 of each 21-day cycle for up to 6 cycles followed by 

maintenance P�B in patients with CR, PR or SD. The primary endpoint was 

6-month progression-free survival (PFS) rate. The treatment would be 

considered promising based on a single arm one-stage binomial design if 

34 or more successes out of 55 patients were observed. This design had an 

exact significance level of 0.05 at 93% power to detect a true success rate 

of at least 70%. Polymorphisms in VEGFA, FPGS, GGH, SLC19A1 and 

TYMS in germline DNA were correlated with treatment outcome. Results: 

58 eligible pts were enrolled; 29 males/29 females. Median age was 75. 

Median treatment cycles received was 6. Grade 3 or higher adverse events 

(AE) were reported in 49 (85%) pts. There were no treatment-related 

deaths. The most common grade 3/4 AEs(regardless of attribution) were 

hypertension (10%), fatigue (28%), dehydration (9%), neutropenia (43%) 

and thrombocytopenia (21%). There were 3 (5%) grade 3/4 hemorrhagic 

events. 8 (14%) had grade 4 neutropenia and 3 (5%) had grade 4 

thrombocytopenia. Grade 3/4 ischemic/thromboembolic events occurred in 

6 pts (10%). Thirty-four out of the first 54 (63%, 95% CI: 48.7-75.7%) 

evaluable pts met the primary endpoint (4 pts were lost to follow-up prior to 

6 months). The confirmed ORR was 37.9% (95% CI: 25.5-51.6%). 

Median time to treatment failure was 4.8 months (95% CI: 3.9-6.4). 

Median PFS was 7.1 months (95% CI: 5.9-11.7), median OS was 13.7 

months (95% CI: 9.4-15.7). Results of SNP analysis will be presented. 

Conclusions: C�P�B followed by maintenance P�B is an active and 

tolerable first-line regimen for elderly patients with good PS. 


493s 


Phase II study of pemetrexed (Pem) and cisplatin (Cis) plus cetuximab 

(Cet) followed by Pem and Cet maintenance therapy in patients (Pts) with 

advanced nonsquamous non-small cell lung cancer (NSCLC). Presenting 

Author: Gerald Schmid-Bindert, University Medical Center, Mannheim, 

Germany 

Background: A prospective, nonrandomized, multicenter study was conducted 

to assess the effect of adding cet to pem and cis in pts with 

advanced nonsquamous NSCLC. Methods: 113 Caucasian performance 

status 0-1 pts received 1st line pem (500 mg/m2 ) and cis (75 mg/m2 )on 

day 1 (21d cycle) for 4-6 cycles and cet (400 mg/m2 loading dose followed 

by 250 mg/m2 ) weekly. Non-progressive pts received pem 500 mg/m2 on 

day 1 (21d cycle) plus cet (250mg/m2 weekly) until progression. Pts 

received vitamin B12/folic acid and dexamethasone. Primary endpoint was 

objective response rate (ORR) (RECIST 1.0). Secondary endpoints were 

progression free survival (PFS), 1 year survival rate, translational research 

(TR) and safety. Results: Pts’ characteristics: median age 59.7 years, 64% 

male, 50% PS 0, 92% stage IV, and 78% adenocarcinoma. All pts 

completed � 1 cycle of induction therapy and 45% and 43% completed � 

1 cycle of maintenance with pem and cet, respectively. ORR (n�109) was 

38.5% (80% CI 32.2-45.1), all partial responses. Disease control rate 

(response/stable disease) was 59.6% (80% CI: 53.1-65.9). Median PFS 

was 5.82 months (80% CI: 4.40-6.70). One year survival rate was 0.45 

(80% CI: 0.39-0.51). Significant associations were seen between high 

EGFR by IHC and increased PFS (cytoplasm: HR�0.46, p�0.035; 

membrane: HR�0.41, p�0.008), and between high nuclear TTF-1 and 

increased ORR (OR�7.73, p�0.021) / PFS (HR�0.21, p�0.001) / OS 

(HR�0.25, p�0.035). Of 113 pts evaluated for safety, 73 (64.6%) pts 

had drug related CTC Grade 3/4 adverse events (AE): most frequent were 

neutropenia (14.2%), rash (15%), and vomiting (8.8%). Drug related 

serious AEs were reported in 27.4% pts: most frequent were anemia 

(5.3%), neutropenia (5.3%), vomiting (3.5%), and rash, renal failure, 

diarrhea and fatigue (1.8% each). There were 2 potential on-study drug 

related deaths (sudden death and large intestinal perforation). Conclusions: 

Pem, cis and cet appeared efficacious and tolerable. These results support 

further evaluation in a randomized trial. The TR outcomes are hypothesis 

generating given the study’s size and nonrandomized nature. 


Targeting EGFR and ERBB3 in lung cancer patients: Clinical outcomes in a 

phase I trial of MM-121 in combination with erlotinib. Presenting Author: 

Lecia V. Sequist, Massachusetts General Hospital Cancer Center, Boston, 

MA 

Background: Erlotinib is effective in NSCLCs with wild-type EGFR and 

shows enhanced benefit in EGFR mutation-positive cancers. However, 

resistance invariably develops, often involving persistent ErbB3 signaling 

and activation of the PI3K/AKT survival pathway. We present the full results 

of the Phase 1 study evaluating the safety and tolerability of erlotinib plus 

MM-121 a fully human IgG2 monoclonal antibody (mAb) to ErbB3. 

Methods: Eligible patients had advanced stage NSCLC, and ECOG 0-2. 

Seven cohorts were enrolled, evaluating varying levels of the MM-121 and 

erlotinib, as well as alternate MM-121 infusion schedules. Tumor response 

was assessed every 8 weeks. Dose levels were determined by safety and 

pharmacokinetic (PK) data, and immunogenicity, efficacy endpoints and 

exploratory biomarker evaluations were performed. Results: From February 

2010 – July 2011 32pts entered the study (median age 63y; 45% male; 

18% ECOG 0, 82% ECOG 1. 56% had adenocarcinoma and 30% pts 

received 3 or more lines of prior therapies (range 0-7) with 91% having had 

prior platinum. 65% had wild-type EGFR status and were never treated or 

never responded to EGFR-TKIs (EGFRwt) and 28% had acquired resistance 

to erlotinib treatment (EGFRresist). The most common toxicities (any 

grade) observed were diarrhea (82%), rash (64%), and fatigue (64%). 

DLTs observed in different cohorts were diarrhea, mucositis, rash and 

failure to thrive. Clinical activity was observed including 1 PR (an EGFR TKI 

naïve EGFR mutant) and 14 SD. Average duration of disease stabilization 

was 21.6 wks (range 7.1 -89.3 wks). Median PFS is 8.1 weeks and the 16 

week PFS rate was 41% in the overall population. For EGFRwt and 

EGFRresist pts the median PFS were 7.7 weeks and 15.1 weeks, and the 

16 week PFS rates were 32% and 44%, respectively. 7/20 EGFRwt pts and 

5/9 EGFRresist pts achieved SD. Conclusions: This study suggests that the 

combination of erlotinib and MM-121 has an acceptable safety profile in 

heavily pre-treated NSCLC patients with and without EGFR mutations. 

Early signals of patient benefit were seen and a large randomized phase II 

study is ongoing. 




Interim analysis of afatinib monotherapy in patients with metastatic 

NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a 

trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy 

following progression on afatinib monotherapy. Presenting Author: Martin 

H. Schuler, Department of Medical Oncology, West German Cancer Center, 

University Duisburg-Essen, Essen, Germany 

Background: The benefit of sustained ErbB family blockade in NSCLC 

patients with acquired resistance (AR) to EGFR TKIs is unknown. We 

investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 

(ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic 

NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase 

III, randomized, open-label, multi-center trial. Patients with pathologically 

confirmed Stage IIIB/IV metastatic NSCLC after �1 line of chemotherapy 

who failed E/G received oral afatinib 50 mg until disease progression (Part 

A). After progression, patients with clinical benefit (�12 wks) were eligible 

to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice 

chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; 

CT scan every 6 wks). Available tumor samples were collected for central 

EGFR mutation testing; local mutation data were also collected. An interim 

analysis of Part A, assessing afatinib monotherapy, is reported. Results: 

Part A enrolled April 2010 through to May 2011; 1154 patients received 

afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were 

female, 43% were Asian, 54% were never smokers. Best response to prior 

E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for 

afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor 

response, 648 (56%) had SD. For EGFR mutation positive patients (n�49, 

centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative 

patients (n�35). When applying clinical enrichment criteria for AR, PFS 

was 4.2 mths for those with enrichment (n�597) vs. 2.8 mths for those 

without (n� 557; logrank test p�0.0001). The most common grade 3/4 

adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 

patients remain on treatment. Conclusions: Afatinib monotherapy provided 

a clinically meaningful benefit in this large, treatment-refractory NSCLC 

trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs 

achieved prolonged disease control upon continued ErbB blockade. 


Final overall survival and updated biomarker analysis results from the 

randomized phase III ICOGEN trial. Presenting Author: Yan Sun, Cancer 

Hospital, Chinese Academy of Medical Sciences, Beijing, China 

Background: A total of 399 pretreated patients with advanced NSCLC were 

randomly assigned to receive gefitinib or icotinib in the phase III ICOGEN 

trial, the first head-to-head phase III trial of EGFR-TKIs. The results of the 

primary endpoint, PFS, have been reported previously. This report represents 

the final OS and biomarker analysis results. Methods: EGFR mutation 

was evaluated by using Scorpion ARMS (QIAGEN, n�152). Overall survival 

was analyzed by Cox proportional-hazards model analysis at 82% maturity. 

Results: Median OS was 13.3 months for icotinib and 13.9 months for 

gefitinib (hazard ratio [HR] � 0.90; 95% CI, 0.79 to 1.02; P � .109). The 

EGFR mutation rate was 43% in the icotinib group and 59% in the gefitinib 

group. Compared to wild type patients, patients with EGFR mutation had 

longer PFS (median, 6.2m vs. 2.3m; P�.00001) as well as OS (median, 

20.5m vs. 7.7m; P�.00001). There were no significant differences in PFS 

or OS between the two treatment groups in EGFR mutation-positive 

subgroup (median PFS, 7.8m vs. 5.3m for icotinib and gefitinib, respectively, 

P �.3162; median OS, 20.9m vs. 20.2m for icotinib and gefitinib, 

respectively, P �.7611.) or in EGFR mutation-negative subgroup (median 

PFS, 2.3m vs. 2.2m for icotinib and gefitinib, respectively, P �.1531; 

median OS, 7.8m vs. 6.9m for icotinib and gefitinib, respectively, P 

�.7885.). Conclusions: There is no statistically significant difference 

between icotinib and gefitinib in PFS or OS when given to NSCLC patients. 

This suggests that icotinib can provide similar OS benefits to gefitinib in 

advanced NSCLC patients. Moreover, EGFR mutation status is the strongest 

predictor in identifying which patients are most likely to benefit from 

icotinib. 


Afatinib monotherapy in patients with metastatic squamous cell carcinoma 

of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: 

Interim subset analysis from a phase III trial. Presenting Author: Joo-Hang 

Kim, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, 

South Korea 

Background: Patients with squamous NSCLC have limited treatment options. 

For those deriving benefit from EGFR TKIs, it is unclear whether 

sustained ErbB family blockade offers benefit upon progression. We 

evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) 

and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC 

who had failed chemotherapy and E/G. Here we describe a pre-specified 

analysis of those with squamous histology in Part A. Methods: This 

randomized Phase III, open-label, multi-center trial enrolled patients with 

pathologically confirmed metastatic NSCLC after failing �1 line of cytotoxic 

chemotherapy and E/G. In Part A, patients received oral afatinib 50 

mg until disease progression. Those with clinical benefit (�12 wks) who 

progressed were eligible to receive afatinib plus paclitaxel or investigator’s 

choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). 

Following an amendment, an interim analysis of Part A was performed to 

assess afatinib monotherapy. Results: Patient enrolment into Part A was 

from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) 

had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, 

respectively (by investigator). Median age was 63 yrs, 71% were male, 76% 

were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the 

squamous histology subset. Of 91 patients, 42 had PFS �3 mths; 13 had 

PFS of �6 mths. In evaluable patients (n�77), 1 CR and 3 PRs were 

confirmed; 51 and 22 patients had best overall response of SD and PD, 

respectively. Of the 31 patients with PD on prior E/G with no intervening 

chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on 

afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A 

were diarrhea (13%) and rash/acne (12%). The safety profile in the 

squamous histology subset was similar to that observed for the whole trial. 

Conclusions: Afatinib monotherapy demonstrated encouraging activity in 

treatment-refractory NSCLC patients with squamous histology that merits 

further evaluation. 


A randomized phase III study of a cisplatin (CDDP) and docetaxel (DOC) 

with or without irinotecan (CPT) in pts with advanced NSCLC: Okayama 

Lung Cancer Study Group OLCSG 0403 trial. Presenting Author: Toshiaki 

Okada, Chugoku Central Hospital, Fukuyama, Japan 

Background: CDDP-based doublet chemotherapy provides a significant but 

modest survival prolongation in untreated advanced NSCLC with MST of 

around 12 months. Based on the favorable efficacy profile in our previous 

phase II trial of triplet chemotherapy with CDDP, DOC, and CPT (response 

rate: 57.1%, MST: 17 months) (JTO 2007), we conducted a phase III study 

to compare this regimen with CDDP and DOC doublet therapy in the 

first-line setting. Methods: Pts were randomly allocated to the triplet 

therapy (A arm; CDDP 60 mg/m2 , day 1; DOC 60 mg/m2 , day 1; and CPT 60 

mg/m2 , day 2; q3 wks, determined based on our phase I study result) or a 

standard doublet chemotherapy (B arm; CDDP 80 mg/m2 , and DOC 60 

mg/m2 , day 1; q3 wks). The primary endpoint was OS whilst secondary 

endpoints included response rates, PFS, and toxicity. Results: Between 

2004 and 2009, 120 pts were enrolled (A/B: 60 pts each). Objective 

response was comparable between the arms (18 pts [30%] each, p � 

0.571). As for toxicity, grade 3-4 neutropenia, principal toxicity, was 

observed in 93% vs. 58% (p � 0.001). Although grade 3 febrile 

neutropenia was observed in 53% and 18% of the pts (p � 0.001), none of 

whom further developed toxic deaths. At a median follow-up time of 64.2 

months, median PFS time and 1-year PFS rate were 5.3 vs. 4.3 months and 

13.3% vs. 11.7%, respectively (stratified logrank test; p � 0.872). There 

was also no difference in OS (MST, 16.8 vs. 12.2 months; 1-year OS rate, 

68.0% vs. 53.0%; stratified logrank test; p � 0.846). Subgroup analysis 

for OS showed that never smokers (HR � 0.366; 95% CI � 0.072-1.866) 

tended to benefit from the triplet chemotherapy compared with eversmokers 

(HR � 1.380; 95% CI � 0.771-2.473) despite no statistical 

significance (p for interaction � 0.150). Similar trend in interaction 

between treatment effect and smoking status was also observed in PFS. 

Conclusions: This triplet chemotherapy failed to produce a significant 

antitumor activity as compared with the standard doublet therapy. 



A phase II study of erlotinib monotherpay in patients with previously treated 

advanced non-small cell lung cancer (NSCLC) without EGFR gene mutation 

who have never/light smoking history: NEJ006/TCOG0903. Presenting 

Author: Yoshiki Ishii, Dokkyo Medical University School of Medicine, 

Shimotoga, Japan 

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase 

inhibitors (TKIs) have demonstrated good response in NSCLC harboring 

EGFR gene mutation. However, survival benefit from erlotinib was observed 

also in NSCLC patients with wild type (wt) EGFR gene in subsets of several 

phase III trials. Additionally, smoking status could be a predictive factor of 

erlotinib efficacy, This study aimed to evaluate the efficacy of erlotinib in 

Japanese NSCLC patients with wt-EGFR and find a biomarker that predicts 

the efficacy of erlotinib other than EGFR gene mutation. Methods: The 

primary endpoint was an objective response rate. Secondary endpoints 

included disease control rate, overall survival, and safety. Advanced NSCLC 

patients without EGFR gene mutation who had received one to three prior 

chemotherapy regimens and who had never smoked or light smoked 

(Brinkman Index: less than200) were eligible in this study. EGFR gene 

status was evaluated by the PNA-LNA PCR clamp method. Erlotinib was 

administered daily (150mg/day) until disease progression or unacceptable 

toxicities. Results: Forty seven patients were enrolled between March 2010 

and November 2011. One patient was excluded for evaluation because 

having mutation of EGFR. Efficacy and safety were evaluated among 46 

patients. Best responses were PR 7 (15.2%), SD 12 (26.1%), PD 26 

(46.4%), NE 1 (2.2%). Response rate and disease control rate were 15.2% 

(95%CI: 4.9-25.5%) and 41.3 % (95%CI 27.1-55.5%) respectively. 

Grade 3 or 4 adverse events were anorexia (4), skin rash (2), neutropenia 

(1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer (1), 

and cerebral infarction (1).Two patients suffered grade 3 interstitial lung 

disease. Conclusions: This is the first report to evaluate Erlotinib efficacy in 

selected NSCLC who do not possess EGFR gene mutation. Erlotinib showed 

significant anti-tumor activity in pretreated never or light smoked Japanese 

NSCLC patients without EGFR gene mutation. The results of biomakr 

analysis will be presented at the meeting. 


Elderly and younger patients with non-small cell lung cancer (NSCLC) 

derive similar benefit from second-line chemotherapy: A retrospective 

subset analysis of second-line chemotherapy trials conducted from the 

Hellenic Cooperative Research Group (HORG). Presenting Author: Sofia 

Agelaki, Department of Medical Oncology, University General Hospital of 

Heraklion, Heraklion, Greece 

Background: Elderly patients (pts) achieve a similar survival benefit, with 

acceptable toxicity, from first-line chemotherapy for the treatment of 

advanced NSCLC compared with their younger counterparts. There have 

been no second-line trials specifically designed for elderly pts and few data 

exist on the efficacy and tolerability of second-line therapy in this 

population. Moreover, little if any information exists on the frequency of 

administration of second-line chemotherapy in these pts. Methods: The files 

of 2004 pts with advanced NSCLC enrolled into first-line chemotherapy 

trials performed by HORG from 1995 to 2007 were reviewed. A total of 600 

pts who received second-line chemotherapy within the context of clinical 

trials were identified. Patients’ data were analysed for efficacy and toxicity 

according to age. Results: Second-line chemotherapy was administered in 

24% and 34% of pts �65 and �65 years old after failure of prior therapy 

(p�0.0001). A total of 219 (24.8%) of 600 pts who received second-line 

treatment were �65 years old (median age 70 yrs, range 65-82). Response 

rates to second-line therapy were 11.9% for older pts compared to 12.3% 

for younger pts (p�ns). TTP was 2.8 and 3.1 months for older and younger 

pts, respectively (p�ns). Elderly pts receiving second-line chemotherapy 

had a median survival of 7.7 months compared with 8.2 months for younger 

pts (p�ns). Similar rates of haematological and non-haematological 

toxicities were encountered between the two groups. Conclusions: The 

participation of elderly pts to second-line chemotherapy trials was lower 

compared to younger patients. There was no significant difference in 

outcome or toxicity between elderly and younger pts. For elderly pts with 

advanced NSCLC and good performance status, second-line chemotherapy 

is appropriate. However, specific second-line trials in older pts are required 

since those included in the current analysis were probably highly selected 

to fit the inclusion criteria. 


495s 


First-line gefitinib for elderly patients with advanced non-small cell lung 

cancer (NSCLC) harboring EGFR mutations: A combined analysis of NEJ 

studies. Presenting Author: Sodai Narumi, Department of Respiratory 

Medicine, Tohoku University Graduate school of Medicine, Sendai, Japan 

Background: The first-line treatment with gefitinib has been established as a 

standard of care for advanced NSCLC patients with EGFR mutation by 

previous studies including NEJ002. Since the percentage of elderly 

population in those studies was lower than that of real situation, further 

validation of its usefulness for elderly patients with EGFR-mutated NSCLC 

is warranted. Methods: The efficacy and safety data of fit elderly patients 

(70 years or older with PS 0-2) with EGFR-mutated NSCLC who received 

the first-line gefitinib in NEJ001 (phase 2), NEJ002 (phase 3), and 

NEJ003 (phase 2) were combined. Same population treated with the 

first-line carboplatin plus paclitaxel in NEJ002 (n�34) were also examined 

their efficacy and safety for reference. Regarding the toxicity and quality of 

life (QOL), the comparison between elderly patients and younger patients 

(� 70 years old) both treated with first-line gefitinib in NEJ002 was also 

performed. Results: Data from 71 patients (7 from NEJ001, 33 from 

NEJ002, 31 from NEJ003) treated with first-line gefitinib were combined. 

Patients’ characteristics were as follows; mean age: 76.8 years (range 

70-89), female: 73%, never smoker: 75%, PS 0-1: 92%. Overall response 

rate (73.2%) and median progression-free survival (14.3 months) in this 

group were significantly better than those in the reference group (26.5% 

and 5.7 months, respectively). Despite fewer patients received second-line 

chemotherapy in the first-line gefitinib group, its median overall survival 

(30.8 months) was not inferior to that of reference group (26.4 months). 

Regarding toxicities such as liver dysfunction, rash, diarrhea, and pneumonitis, 

and QOL examined by self questionnaires, there were no difference 

between the elderly patients and younger patients in NEJ002. Conclusions: 

First-line gefitinib still achieved high efficacy with acceptable toxicity in fit 

elderly patients with advanced NSCLC harboring EGFR mutation. Considering 

that elderly patients tend to receive fewer treatment lines compared 

with younger patients, first-line gefitinib would be strongly recommended 

for this population to avoid the risk of missing its administration. 


Randomized phase II trial of carboplatin combined with weekly paclitaxel 

(CP) and docetaxel alone (D) in elderly patients (pts) with advanced 

non-small cell lung cancer (NSCLC): NJLCG 0801. Presenting Author: 

Shunichi Sugawara, Sendai Kousei Hospital, Sendai, Japan 

Background: Standard first-line chemotherapy for elderly NSCLC pts has 

been considered as a monotherapy with vinorelbine or gemcitabine globally. 

However, we have demonstrated the high efficacy of CP for elderly pts 

in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered 

as an alternative option for this population in Japan according to the result 

of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select 

the proper candidate for future phase III trial. Methods: Eligible pts were 

aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG 

performance status 0-1; adequate organ function; written informed consent. 

Pts were randomized to receive carboplatin (AUC 6) on day 1 and 

paclitaxel (70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on 

day 1) every 3 weeks. The primary endpoint was overall response rate 

(ORR), and secondary endpoints were progression-free survival (PFS), 

overall survival, and toxicity profile. Assuming that ORR of 40% would be 

potential usefulness while ORR of 20% would be the lower limit of interest, 

40 pts in each arm were required if expect 10% loss to follow up. Results: 

Between July 2006 and September 2010, 84 pts were enrolled and 41 pts 

in CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% 

male; 72% stage IV). Median treatment cycle was 4 in each arm (CP, range 

1-6; D, range 1-8). ORRs were 51% (95%CI: 36-66%) and 26% (95%CI: 

12-39%) in the CP and D arm, respectively. With a median follow-up of 

18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, 

respectively (Logrank, P�0.0027). Grade 3 or severer toxicities were as 

follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 

7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 

25%). One treatment-related death due to neutropenia, pneumonia, and 

lethal arrhythmia occurred in D arm but none in CP arm. Conclusions: The 

platinum doublet CP achieved higher activity with an acceptable toxicity 

profile for elderly pts with advanced NSCLC compared to monotherapy with 

D. The superiority of CP to the monotherapy in this trial is consistent with 

results of recent IFCT-0501 trial (Lancet 2011). 




Rare and complex mutations of epidermal growth factor receptor (EGFR) 

and efficacy of tyrosine kinase inhibitor (TKI) in patients with non-small 

cell lung cancer (NSCLC). Presenting Author: Bhumsuk Keam, Department 

of Internal Medicine, Seoul National University Hospital, Seoul, South 

Korea 

Background: Other than in-frame deletional mutation (MT) in exon 19 and 

Leu858Arg point MT in EGFR gene, there are many rare and complex MT. 

The purpose of this study was to investigate was to clarify the clinical 

significance of rare and complex MT, and the efficacy of EGFR TKI in these 

patients. Methods: Rare MTs were defined any MT other than deletional MT 

in exon 19, Leu858Arg in exon 21, and Thr790Met in exon 20. Complex 

MT was defined two different EGFR MTs co-occurring within the single 

tumor sample. We have analyzed consecutive database of NSCLC patients 

who were treated with either gefitinib or erlotinib at Seoul National 

University Hospital between Jan. 2002 and Dec. 2011. For analysis of 

EGFR MT, coding sequences from exon 18 to 21 were amplified by nested 

PCR and subjected to direct sequencing methods. Results: Among the 

1,159 TKI treated patients, 301 patients had EGFR MT (177 patients 

(58.8%) with del-19, 104 patients (34.6%) with Leu858Arg, and 20 

patients (6.6%) with rare MT). Twenty-three (7.6%) patients have complex 

MT, and 55 (18.3%) patients have Gln787Gln polymorphism particularly 

associated with Leu858Arg MT. Identified rare MT were follows; exon 18: 

Leu692Phe, Glu707Lys, Glu709Gly, Lys714Asn, Gly7Ala, Thr725Thr, 

exon 19: Ala755Asp Lys737Thr, exon 20: Val786Met, exon21: Ala871Gly, 

Gly873Gln, Leu833Val, Val834Leu, Arg836Cys, Pro848Leu, Ala859Thr, 

Leu861Gln. When categorizing 3 groups (group A: classic MT alone, group 

B: complex MT with classic � rare MT, group C: rare MT alone or complex 

MT with rare MTs), response rate (RR) to TKI was different between each 

groups (RR� 78.7% in group A vs. 69.2% in group B vs. 38.5% in group C, 

respectively, P � 0.001). Progression-free survival (PFS) was also poorer in 

rare MT (median PFS: 12.1 mo vs. 7.6 mo vs. 2.1 mo, respectively, P� 

0.020,). Gln787Gln polymorphism of exon 21 was not associated with RR 

or PFS (P� 0.101, P� 146, respectively) Conclusions: In this large case 

series, NSCLC patients who harboring rare MT other than del-19 and 

Leu858Arg, does not seems response to EGFR TKI. However, complex MT 

with the classical MT showed similar treatment efficacy toward EGFR TKI 

with that of classical MT alone. 


Phase I/II study of amrubicin and nedaplatin in patients with untreated, 

advanced non-small cell lung cancer. Presenting Author: Hiroaki Senju, 

National Nagasaki Medical Center, Ohmura, Japan 

Background: We conducted a phase I/II study of combination chemotherapy 

with nedaplatin (CDGP) and amrubicin (Amr) for patients with untreated, 

advanced non small-cell lung cancer (NSCLC). Methods: Eligible patients 

were having adequate organ function and PS of 0-1. CDGP was given on day 

1 and amrubicin on days 1, 2 and 3. The treatment was repeated every 3 

weeks. We fixed the dose of CDGP as 100 mg/m2, and escalated the dose of 

amrubicin from a starting dose of 25 mg/m2 by 5mg/m2 per each levels 

until the maximum tolerated dose (MTD). The MTD was defined as the dose 

level at which at least two of three or two of six patients experienced a 

dose-limiting toxicity (DLT). Results: Between June 2009 and May 2011, 

36 patients were enrolled. In the phase I study, two DLTs occurred in six 

patients at level 2; dose level 1 was therefore recommended (25 mg/m2 

Amr, 100mg/m2 CDGP). DLTs included cerebral infarction and grade 4 

thrombocytopenia. In the phase II study, including phase I study, a total of 

36 patients were enrolled and 132 cycles of chemotherapy were conducted. 

Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 

thrombocytopenia occurred in 75%, 16.6% and 19.4% in all cycles, 

respectively. Febrile neutropenia occurred in 4cycles (3%) but all of them 

were controllable. Eighteen patients achieved a partial response and the 

overall response rate was 51.4%. Conclusions: Combination of CDGP and 

Amr was highly effective and well tolerable in patients with untreated, 

advanced NSCLC. 


A phase II study of erlotinib followed by chemotherapy on progression in an 

unselected population of advanced non-small cell lung cancer (NSCLC) 

patients. Presenting Author: Leora Horn, Vanderbilt-Ingram Cancer Center, 

Nashville, TN 

Background: Erlotinib is now accepted as first line therapy for advanced 

NSCLC patients with EGFR mutated tumors. However, some patients with 

EGFR wild-type tumors may benefit as well, and there are no accepted 

biomarkers to define this subset of patients or to define which patients 

benefit from chemotherapy. We conducted a single arm phase II trial of 

erlotinib followed by chemotherapy on progression (carboplatin � paclitaxel 

�/- bevacizumab) in treatment naïve patients with stage IV NSCLC. 

Methods: In this multicenter prospective phase II trial, patients with stage 

IV NSCLC were eligible for enrollment. Blood, frozen tissue and FFPE 

biopsies for molecular analysis were mandatory at the time of study entry 

and optional at the time of progression on erlotinib. Additional eligibility 

included ECOG performance status (PS) 0-2, measurable disease, and 

adequate marrow, renal and hepatic function. Patients with stable treated 

brain metastases were allowed. Patients were treated with erlotinib 150 mg 

daily until disease progression at which time they underwent a biopsy and 

were switched to carboplatin/paclitaxel �/- bevacizumab. Disease status 

was assessed after 4 weeks of erlotinib to detect early progression. Results: 

From 10/07 to 06/11, 127 patients were enrolled: 59% male, 90% 

Caucasian, 6% African American, 4% Asian, 30% never smokers. 7 

patients failed screening. Among evaluable patients on erlotinib, 13% had 

PR, 48% SD, and 27% PD. Median PFS on erlotinib was 4.7 months (95% 

CI 3.5 to 8.3 months). In patients who went on to receive chemotherapy on 

protocol, 24% had PR, 27% SD, and 20% PD. In patients who went on to 

receive chemotherapy on protocol median progression-free survival (PFS) 

on chemotherapy was 8.1 months (95% CI 5.5 to 10.9 months). Among 

the 55 patients who did not receive chemotherapy, 23 had a decline in PS, 

14 patients refused, 2 patients enrolled on another protocol, and 6 patients 

had other therapy. Conclusions: This is the first study to report on PFS in 

unselected NSCLC patients following first line therapy with erlotinib. 

Translational studies on this large prospectively collected cohort of tissue 

samples prior to initiation of erlotinib are ongoing. 


Older patient participation in SWOG lung cancer trials: Comparative 

analysis from 1993 to 2008. Presenting Author: Paul Joseph Hesketh, 

Lahey Clinic, Tufts University School of Medicine, Burlington, MA 

Background: In 1999, SWOG published a study demonstrating the underrepresentation 

of patients 65 years and older on clinical trials (Hutchins 

NEJM). A second report published in 2006 demonstrated increasing 

proportions of patients � 65 years (31% 1997-2000; 38% 2001-2003) 

being enrolled into SWOG trials (Unger JCO). Older patient enrollment was 

still disproportionately low compared to the US cancer population. The 

current analysis focuses on patients with lung cancer from 1993-2008. 

Methods: The proportions of enrollment onto SWOG lung cancer treatment 

trials by age (65-69, 70-79, �80 years) and gender were computed for 

4-year time intervals between 1993 and 2008; corresponding rates in the 

US were derived from US Census and National Cancer Institute SEER data. 

Proportions in the SWOG trials were compared to the SEER proportions 

using a 1-sample binomial test of proportions. Time trends within SWOG 

were evaluated using linear regression. Results: The proportion of patients 

65-69 was significantly higher than the US population between 1993 and 

2004, but was not significantly different after 2004. Proportions of 

patients on SWOG trials 70-79 years old and � 80 were significantly 

smaller than the US population. Females were underrepresented from 

1993-2004. Between 2005 and 2008 female enrollment was not significantly 

different from the US population. Conclusions: Currently, the 

proportion of patients 65-69 years of age and of female gender enrolled in 

SWOG trials is representative of the general lung cancer population. 

Although some progress has been made in increasing trial participation of 

patients � 70, enrollment remains disproportionately low. The disparity is 

most evident in patients � 80. Continued efforts are needed to increase 

older patient participation in lung cancer trials. Supported in part by PHS 

Cooperative Agreement grants awarded by the National Cancer Institute: 

DHHS, CA32102 and CA38926. 

1993-1996 1997-2000 2001-2004 2005-2008 

SEER SWOG SEER SWOG SEER SWOG SEER SWOG 

Age 65-69 16% 20%� 16% 19%� 16% 19%� 16% 17% 

Age 70-79 34% 18%� 35% 18%� 36% 24%� 37% 23%� 

Age > 80 16% 1%� 17% 1%� 18% 3%� 20% 4%� 

Female gender** 42% 34%� 45% 39%� 47% 39%� 49% 46% 

� p � -.01; ** time trend p�0.05. 



Phase II study of amrubicin (AMR) for patients (pts) with non-small cell 

lung cancer (NSCLC) as third-line or fourth-line chemotherapy: Hokkaido 

Lung Cancer Clinical Study Group trial (HOT) 0901. Presenting Author: 

Toshiyuki Harada, Hokkaido Social Insurance Hospital, Sapporo, Japan 

Background: Although an increasing number of NSCLC pts receive thirdline 

chemotherapy with the established benefit of second-line chemotherapy, 

the role of cytotoxic agent in this setting has not yet been well 

defined prospectively. AMR, third-generation synthetic anthracycline agent, 

has found favorable clinical activity and acceptable toxicity for NSCLC as 

well as small cell lung cancer. This prospective trial was conducted to 

evaluate the efficacy and safety of AMR for NSCLC pts as third-line or 

fourth-line chemotherapy. Methods: Eligible pts had a performance status 0 

to 2, failure of second-line or third-line chemotherapy, and adequate organ 

function. Pts received AMR 35 mg/m2 intravenously on days 1-3 every 3 

weeks. The primary endpoint was disease control rate (DCR: CR � PR � 

SD). Secondary endpoints were overall survival (OS), progression-free 

survival (PFS), response rate (CR � PR), and toxicity profile. The estimated 

accrual was 37 pts to confirm a DCR of 50% as desirable target level and a 

DCR of 30 % as uninteresting with alpha � 0.05 and beta � 0.20. Results: 

From August 2009 to May 2011, 41 pts were enrolled from 10 institutions. 

Patient characteristics were: male/female 29/12; median age 66 (range 

43–74); performance status 0/1/2 16/24/1; adenocarcinoma/squamous 

cell carcinoma/large cell carcinoma/not other specified 30/8/2/1; EGFR 

mutation positive/negative/unknown 7/26/8; treatment lines 3rd/4th 26/ 

15. The median number of treatment cycles was 2 (range 1-9). The 

objective responses were CR 0, PR 4, SD 22, PD 14, and NE 1, giving a 

DCR of 61.0% (95% CI, 46.0-75.9%). Overall response rate was 9.8% 

(95% CI, 0.6-18.8%). Median PFS was 2.6 months, whereas median 

survival time was not reached. Grade 3/4 hematological toxicities were 

neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile 

neutropenia (17%). Grade 3/4 non-hematological toxicities were anorexia 

(12%), nausea (10%), and pneumonitis (2%). No treatment-related death 

was observed. Conclusions: AMR shows significant clinical activity with 

acceptable toxicities as third-line or fourth-line chemotherapyfor advanced 

NSCLC. 


Cutaneous toxicity secondary to erlotinib therapy in patients with non-small 

cell lung cancer in the NCIC CTG BR.21 study: Time course and correlation 

with survival. Presenting Author: Roman Perez-Soler, Montefiore Medical 

Center/Albert Einstein College of Medicine, Bronx, NY 

Background: Cutaneous rash often develops in erlotinib-treated patients 

(pts) and is thought to be associated with improved response and survival. 

This analysis focuses on incidence, severity, and time course of skin rash 

secondary to erlotinib, as well as the correlation between rash development 

and overall survival (OS) in pts in the NCIC CTG BR.21 (NCT00036647) 

trial. Methods: Pts with stage IIIB or IV non–small cell lung cancer (NSCLC) 

who had failed first- or second-line chemotherapy were randomized 2:1 to 

erlotinib or placebo. Cutaneous toxicity was graded per NCI CTC v2.0 and 

managed at the discretion of the treating investigator. This retrospective 

analysis used a landmark approach, dividing pts into rash and no-rash 

groups, by the appearance of rash by week 10. Results: A total of 366 of 

488 erlotinib-treated pts (75%) and 40 of 243 placebo-treated pts (16%) 

developed rash at any time point. Of the former, 75% of rash episodes 

occurred by week 2. The incidence of grades 1 and 2 rash peaked at week 

3; grade 3 rash peaked at week 5. The erlotinib dose was reduced in 48 pts 

(10%) due to rash. In most erlotinib-treated pts with rash, severity 

decreased or plateaued over time (Table). Some 311 erlotinib-treated pts 

(rash group) developed rash by week 10. Median OS in the erlotinib-treated 

rash (n�311) and no-rash (n�65) groups were 37.4 and 11.1 weeks, 

respectively (hazard ratio�0.51 [95% confidence interval, 0.38–0.68]; 

P�.0001). Baseline factors significantly associated with prolonged OS in 

the rash population included race (Asian vs white), number of affected 

organs (�3 vs�3), and smoking status (never vs ever). Conclusions: For 

most pts, rash secondary to erlotinib presented within the first 2 weeks, 

peaked during weeks 3–5, decreased thereafter, and did not necessitate 

dose reduction, thus supporting SATURN results (Perez-Soler, ASCO 

2011, abst. 7610). Development of rash by week 10 of erlotinib therapy 

was associated with significantly improved OS. 

Initial grade n* 

Lesser 

Grade at last assessment, no. (%) 

Same Greater 

1 207 – 175 (85) 32 (15) 

2 125 51 (41) 71 (57) 3 (2) 

3 19 12 (63) 6 (32) 1 (5) 

4 2 0 (0) 2 (100) 0 (0) 

* Of 353 pts with rash grade levels evaluated over time. 


497s 


Treatment with EGFR tyrosine kinase inhibitors beyond progression in 

long-term responders to erlotinib in advanced non-small cell lung cancer: A 

case-control study of overall survival. Presenting Author: Martin Faehling, 

Klinik für Kardiologie und Pneumologie, Klinikum Esslingen, Esslingen, 

Germany 

Background: EGFR-tyrosine kinase inhibitor (TKI) such as erlotinib lead to 

prolonged disease stabilization in some patients with advanced NSCLC. It 

is so far not clear how to treat patients who progress after prolonged 

response to erlotinib. TKI therapy beyond progression with added chemotherapy, 

radiotherapy or best supportive care (BSC) may improve survival 

compared to chemotherapy, radiotherapy or BSC alone. Methods: We 

retrospectively analyzed all NSCLC patients treated with erlotinib at our 

institutions since 2004 who progressed after at least stable disease on 

erlotinib for at least six months (n�41). Twenty-seven patients were 

treated with TKI beyond progression (TKI patients), of whom 24 received 

erlotinib and 3 afatinib. Fourteen patients did not receive further TKI 

treatment after progression (controls). Overall survival (OS) from progression 

on TKI and OS from diagnosis of lung cancer was analyzed for the 

whole population and case-control subpopulations of pairs matched for 

gender, smoking status, and histology. Results: Treatment with TKI and 

chemotherapy was well tolerated with no increase in grade 3 and 4 

toxicities. TKI-patients had a significantly longer OS from progression on 

TKI (case control: median 21.0 vs. 3.0 months, HR 0.175) and longer OS 

from diagnosis of lung cancer (case control: median 28.5 vs. 15.3 months, 

HR 0.335). Conclusions: In long-term erlotinib responders, treatment with 

TKI beyond progression in addition to chemotherapy or radiotherapy is 

feasible and well tolerated with limited toxicity. TKI-treatment beyond 

progression improved OS compared to treatment with TKI-free chemotherapy 

or radiotherapy. 


Efficacy of pemetrexed as second-line therapy in advanced NSCLC after 

either treatment-free interval or maintenance therapy with gemcitabine or 

erlotinib in IFCT-GFPC 05-02 phase III study. Presenting Author: Olivier 

Bylicki, Hospices Civils de Lyon, Lyon, France 

Background: Continuous exposure of tumor cells to maintenance therapy in 

advanced NSCLC might lead to resistance to subsequent treatments. 

IFCT–GFPC 0502 study showed a progression-free survival (PFS) benefit 

with gemcitabine (G) or erlotinib (E) maintenance compared to observation 

(O) after cisplatin-G induction chemotherapy. The trial included a predefined 

second-line therapy with pemetrexed (P), allowing post-hoc assessment 

of its efficacy according to previous maintenance treatment or 

treatment-free interval. Methods: Stage IIIB/IV NSCLC patients (pts) with a 

PS of 0-1 were randomized after 4 cycles of cisplatin-G chemotherapy to O 

or to receive maintenance therapy with G or E until disease progression. P 

was given as second-line treatment on disease progression in all arms. PFS 

and OS were assessed from the beginning of P therapy according to 

randomization arm. Tumor response to P and tolerance were also analyzed. 

Results: Of the 464 pts randomized to either O (155), G (154) or E (155), 

360 pts (78 %) received P as second-line therapy, i.e. 130 (84%), 114 

(74%) and 116 (75%) in O, G and E arm, respectively. Baseline 

characteristics remained well balanced between arms (overall median age 

of 58 years, 28% female, 91% stage IV, 41% PS 0, 65/19/16%, 

adenocarcinoma/squamous/other, 10% non-smokers and 56% responders 

to induction CT). Median number of delivered P cycles was 3 (1-40) in all 

arms. Response rate was 19%, 7% and 15% for non-squamous pts in O, G 

and E, respectively. Median PFS did not significantly differ between G and 

O (4.2 vs 3.9 months, HR [95% CI] 0.81 [0.62-1.06]) or E and O (4.2 vs 

3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant 

improvement with G vs O (HR 0.81 [0.61-1.07]) or E vs O (HR 0.80 

[0.61-1.05]), with a median of 7.5, 8.3 and 9.1 months for O, G and E, 

respectively. Results were similar when analysis was restricted to nonsquamous 

pts. Grade 3-4 treatment-related AEs were similar in O (33.1%), 

G (31.6%) and E (25%). Conclusions: Maintenance therapy with continuation 

of G or switch to E does not impair the efficacy of second-line P by 

comparison with administration after a treatment-free interval. 




Prospective randomized phase II trial of oral vinorelbine (NVBo) and 

cisplatin (P) or pemetrexed (Pem) and P in first-line metastatic or locally 

advanced non-small cell lung cancer (M or LA NSCLC) patients (pts) with 

nonsquamous (non SCC) histologic type: NAVoTRIAL01—Preliminary 

results. Presenting Author: Jaafar Bennouna, Institut de Cancerologie de 

l’Ouest/Site René Gauducheau, Nantes, France 

Background: NVBo�P is considered as a standard treatment (trt) in M or LA 

NSCLC. The recent approval of Pem�P as front line chemotherapy (CT) for 

non-SCC demonstrates that today, histology could become a “new guidance” 

to treat patients (pts). Phase III trial (Scagliotti. JCO 2008) showed 

efficacy of Pem�P in patients with non-SCC pts. Moreover, the higher 

chemosensitivity of non-SCC is recognised and reported with other chemotherapies 

(Ardizzoni.JNCI 2007). In GLOB 3 study, NVBo�P also showed 

better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan.Ann of 

Oncol 2009). This trial was set up to assess the efficacy of NVBo�P 

compared to Pem�P for pts with non-SCC histological type. The primary 

end-point was disease control rate (DCR) including overall response rate 

(ORR) and stable disease (SD). Methods: Pts were randomised to receive 

NVBo 80 mg/m² D1D8 (60 at Cycle 1) � P 80 mg/m² D1 q3w or Pem 500 

mg/m² � P 75 mg/m² D1 q3w. After 4 cycles of trt, for pts showing a 

disease control, single agent as continuation maintenance (CM) was 

proposed until progression or toxicity. Given that Pem�P is now considered 

as a reference trt in non-SCC, pts were randomised on a 2/1 basis and 

stratified according to stage (IIIB - IV - relapse), non-SCC confirmed by 

histology or cytology, gender, smoking status and centre. Results: From 

10/09 to 02/11, 153 pts were randomised to receive NVBo�P (102 pts) or 

Pem�P (51 pts). The efficacy between the 2 arms is similar: The ORR/DCR 

(Recist 1.1) after 4 cycles of trt are 26%/75% in the NVBo arm (100 eval 

pts in ITT population) and 24%/78% in the Pem arm (50 eval pts in ITT 

population). At the end of December 2011, 7 patients are still treated in 

CM: 5 pts in the NVBo arm and 2 pts in the Pem arm. Conclusions: The2CT 

regimen, NVBo�P orPem�P have a similar efficacy in terms of ORR/DCR 

for pts with advanced non-SCC NSCLC. These results appear to be in line 

with the published data. As the analysis is currently in progress, final 

results including safety data, PFS and OS will be presented during the 

meeting. 


The relevance of stable disease (SD) as a surrogate end-point in advanced 

non-small cell lung cancer (NSCLC) patients treated with erlotinib (E) as 

the second/third line. Presenting Author: Francesco Grossi, Lung Cancer 

Unit, National Institute for Cancer Research, Genova, Italy 

Background: SD has often been viewed as a result with an uncertain clinical 

value.With the advent of E in advanced NSCLC, increasing numbers of 

patients (pts) achieve SD as a best response. A common observation in 

clinical practice is that a high proportion of patients receiving E have 

durable SD.The aim of this analysis was to compare the progression-free 

survival (PFS) and overall survival (OS) in pts with advanced NSCLC who 

achieved confirmed SD or complete/partial response (CR�PR) after second/ 

third line treatment with E. Methods: Data from 684 Italian pts from the 

TRUST trial (Tiseo M et al. Lung Cancer 2008) were analyzed. E was 

administered orally at 150 mg per day and was continued until disease 

progression, development of unacceptable toxicity or patient’s refusal. We 

define confirmed SD (cSD) if the patients’ PFS was �5 months (response to 

E was evaluated per protocol every two months) and reconfirmed SD (rSD) if 

the patients’ PFS was �8 months. Results: Pts’ characteristics included the 

following: median age, 67 years (31-89); females/males� 219/465 pts 

(32%/68%); never/former smokers� 191/493 pts (28%/72%); squamous/ 

adeno/BAC/large cell/NOS� 163/361/26/21/113 pts (24%/53%/4%/3%/ 

16%); ECOG PS 0-1/2-3� 557/127 pts (81%/19%). In 83 pts (12%), E 

was administered as the first-line therapy in pts who were unable to receive 

chemotherapy; 305 pts (45%) had received 1 prior line of chemotherapy, 

and 296 pts (43%) had received 2 prior lines of chemotherapy. A total of 

428 pts were evaluable for a response: 44 pts (10%) exhibited CR�PR, 

226 pts (53%) attained SD, which consisted of 139 pts (32%) with cSD 

and 83 pts (19%) with rSD. The median PFS estimates (with 95% CI) were 

13.1 months (9.8-16.4) for CR�PR pts, 9.9 months (8.2-11.4) for cSD 

pts and 14 months (12-16) for rSD. The median OS estimates (with 95% 

CI) were 24.0 months (17-31) for CR�PR pts, 17.9 months (14.4-21.5) 

for cSD pts and 24.9 months (18.1-31.7) for rSD. Conclusions: Our 

findings are the first to demonstrate the relevance of achieving stable 

disease with E treatment. Pts obtaining cSD or rSD had durable PFS and 

OS comparable, particularly for rSD, with PFS and OS of those having 

CR�PR. 


Difference in incidence and pattern of salvage treatment after failure to 

first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR- 

TKI) monotherapy and standard cytotoxic chemotherapy in pts with 

advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: 

Okayama Lung Cancer Study Group experience. Presenting Author: Yuka 

Kato, Okayama University Hospital, Okayama, Japan 

Background: EGFR-TKI (E) therapy yielded a better PFS than standard 

cytotoxic chemotherapy (C) therapy and a comparable OS in untreated pts 

with EGFR-mt tumors, suggesting each of the treatments is now crucial for 

such subpopulation. But, it has not been fully evaluated yet which of each 

should be initiated first, and to what degree both of two are actually 

administered in early line setting in the treatment course. We here 

investigated a potential difference in incidence and pattern of delivery of 

subsequent crossover therapy after failure to each of the treatments in pts 

with EGFR-mt tumors. Methods: Consecutive 79 pts with advanced EGFR-mt 

NSCLC were retrospectively assessed who underwent E therapy (n � 39) or 

standard C therapy (n � 40) in the 1st-line setting between 2007 and 

2011. Results: In E group 16 (41%) of 39 pts were still on 1st-line E 

therapy. Nine (39%) of the remaining 23 could not receive standard C 

therapy after failure to E therapy due to symptomatic CNS metastasis(mets) 

in 6, skeletal events in 2, and patient refusal in 1, whilst in C group only one 

(3%) of 40 failed to receive subsequent E therapy because of relapse 

(carcinomatous lymphangitis) (�2-test; p � .001). Also, at the time of 

relapse to the 1-st line therapy, PS deteriorated more frequently in E group 

(8/23 vs. 7/40; p � .042) and, relapse with symptomatic CNS mets 

seemed frequently observed in E group (6/23 vs. 4/40; p � .093). 

Multivariate analysis revealed type of regimens undergone in the 1st-line 

setting (E vs. C) correlated with failure of administration of subsequent 

crossover therapy (odd ratio: 3.224, 95%CI: .1.032 – 5,417, p � .004). 

Conclusions: It seems that pts with EGFR-mt tumors who were treated with 

1st-line C had better opportunity to receive post-progression E therapy than 

those treated with 1st-line E had chance to receive subsequent C therapy, 

possibly due to difference in PS deterioration rate and relapse pattern. 


KIF5B-RET: Discovery of a novel fusion oncogene in lung adenocarcinomas 

by a systematic screen for tyrosine kinase fusions and identification of 

patients for a RET targeted therapy trial. Presenting Author: Yoshiyuki 

Suehara, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: The mutually exclusive pattern of major targetable driver 

oncogenes in lung adenocarcinomas (ADC) suggests that other similar 

driver oncogenes may exist. We therefore performed a systematic screen for 

tyrosine kinase (TK) fusions in cases without known driver oncogenes by 

measuring aberrantly high RNA expression of kinase domain (KD) exons 

relative to more 5’ exons. Methods: We studied 74 patients whose lung ADC 

lacked mutations in KRAS, EGFR, BRAF, HER2, and ALK fusions. A 

NanoString-based assay was designed to query the transcripts of 90 TKs at 

two points: 5’ to the KD and within or 3’ to the KD. Tumor RNAs were 

hybridized to the NanoString probes and analyzed for outlier 3’ to 5’ 

expression ratios. The assay was validated on samples with known ALK and 

ROS fusions. Presumed novel fusion events were followed up by rapid 

amplification of cDNA ends (RACE) and confirmatory RT-PCR. Results: The 

NanoString assay identified aberrant 5’ to 3’ ratios in ROS and RET in 2 

cases, respectively, out of 74. RACE analysis isolated a novel GOPC-ROS 

fusion in the former and a novel KIF5B-RET fusion in the latter, both 

confirmed by RT-PCR. Further screening by RT-PCR for KIF5B-RET 

identified one more positive sample in the study set that had not been 

detected by NanoString. At the RNA level, both fusions joined exon 15 of 

KIF5B to exon 12 of RET, thus retaining a portion of the dimerization 

domain of KIF5B and the entire KD of RET, analogous to RET fusions in 

papillary thyroid carcinoma (TC). One KIF5B-RET patient was a 60 y.o. 

female never smoker, the other, a 73 y.o. male former smoker. Conclusions: 

The novel KIF5B-RET fusion described here and also recently reported by 

Ju YS et al. (Genome Res, Dec 22, 2011) defines a new subset of lung ADC 

with a potentially targetable driver oncogene. Based on these genetic data 

and the preclinical activity of the RET inhibitor XL184 (Exelixis) in 

papillary TC and its known activity in medullary TC with RET mutations, we 

have initiated prospective testing for KIF5B-RET as part of our lung ADC 

screening panel in anticipation of a planned phase 2 trial with XL184 in 

patients with KIF5B-RET or related variant RET fusions. 



Family history of lung cancer in never smokers with non-small cell lung 

cancer (NSCLC) and its association with tumors harboring epidermal 

growth factor receptor (EGFR) mutations. Presenting Author: Elizabeth 

Mary Gaughan, Beth Israel Deaconess Medical Center/Harvard Medical 

School, Boston, MA 

Background: Inherited susceptibility to lung cancer is an understudied 

subject, however it has been described among never smokers (�100 

cigarettes/lifetime). Never smokers with NSCLC comprise an important 

subgroup of patients enriched for tumors harboring oncogene aberrations in 

the EGFR and ALK genes. We aimed to better characterize the incidence of 

family history of lung cancer in the setting of routine tumor genotyping 

among never smokers with NSCLC. Methods: Clinicopathologic data plus 

tumor genotype (EGFR, KRAS, ALK) from 230 consecutive never smokers 

seen at Beth Israel Deaconess Medical Center and Dana-Farber Cancer 

Institute was compiled. We retrospectively analyzed the incidence of a 

family history of any cancer and lung cancer in these patients. Results: In 

our cohort, the average age was 56 years, 67% of the patients were women, 

75% were white, 41% had advanced NSCLC and 87% had adenocarcinoma 

histology. In these tumors, 98/230 (43%) had an EGFR mutation, 

16/155 (10%) had KRAS mutations and 27/127 (17%) had an ALK 

translocation. Family history of any cancer was common (57%) and specific 

family history of lung cancer was present in 42/230 cases (18%). Out of 

thecases with a family history of any cancer, 22/53 (41.5%) EGFRmutated, 

1/6 (17%) KRAS-mutated and 3/20 (15%) ALK-translocated 

cohorts had a family history of lung cancer. The rate of family history of lung 

cancer to family history of cancer was significantly higher in the EGFRmutated 

cohort when compared to the ALK translocated plus KRASmutated 

cohorts (p�0.023). Conclusions: Family history of lung cancer is 

common in never smokers with NSCLC, and there seems to be a particular 

link in families in which the proband has an EGFR-mutated tumor. Further 

study of families with EGFR-mutated NSCLC may yield insights into the 

pathogenesis of this tumor type. 


NGR-hTNF plus chemotherapy as first-line therapy of non-small cell lung 

cancer (NSCLC). Presenting Author: Vanesa Gregorc, Department of 

Oncology, Istituto Scientifico San Raffaele, Milan, Italy 

Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis 

factor) is a selective vascular targeting agent able to improve intratumoral 

chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC 

patients (pts), stratified by histology (nonsquamous or squamous) and PS 

(0 or 1), were randomized to cisplatin 80 mg/m2 /day(d)1 plus either 

pemetrexed 500 mg/m2 /d1 (nonsquamous) or gemcitabine 1,250 mg/m2 / 

d1�8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or 

without (arm B) NGR-hTNF 0.8 �g/m2 /d1 q3w until progression. Progression 

free survival (PFS) was primary end point of this phase 2 trial 

(��20%, ��20%, HR�0.62, and n�102). Secondary end points included 

adverse events (AEs), response rate (RR) and overall survival (OS). 

Results: 59 pts were assigned to arm A and 57 to arm B. Baseline 

characteristics in arm A/B were: median age 62/63; male 34/37; PS 1 

21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the 

nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm 

A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group, 

88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm 

B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue 

7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to 

NGR-hTNF or bleeding in pts with squamous histology were noted. Median 

follow-up was 12.4 months. In the whole study population, median (m)PFS 

was 5.8 vs 5.7 months (HR�0.95), RR was 23% vs 19%, and 1-year OS 

was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset, 

a trend toward longer mPFS in arm A compared to arm B was noted in pts 

with a PS of 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs 

3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the 

squamous subset, mPFS was 5.1 vs 3.9 months (HR�0.71) and mOS was 

14.2 vs 10.8 months (HR�0.73) in arm A and B, respectively. In these pts, 

ORR was 36% in arm A and 23% in arm B, while median changes from 

baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and 

-41%, respectively in arm A, and -18%, -22%, and -14%, respectively in 

arm B. Conclusions: Regardless of histology, NGR-hTNF can be safely given 

with standard chemotherapy, showing tolerability and hint of activity in 

squamous NSCLC. 


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Comparison of the KRAS/EGFR mutation profile and survival of “collegiate 

smokers” and never smokers with advanced lung cancers. Presenting 

Author: Anna M. Varghese, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: In practice, we encounter patients (pts) with lung cancers who 

state they smoked only while in college. The impact of this degree of 

tobacco use on cancer biology is unknown. We have shown that EGFR 

mutations are less common in pts who smoked � 15 pack years (PY). We 

hypothesize that among pts with lung cancer the KRAS / EGFR mutation 

profile and overall survival (OS) of “collegiate smokers” (former smokers 

who smoked between 101 lifetime cigarettes and 5 PY) will be distinct 

from never smokers and former smokers with � 15 PY. Methods: We 

collected age, sex, stage, and survival for pts evaluated from 2004 - 2009 

with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK 

testing was not available routinely during this time. Smoking history was 

obtained using a patient completed survey. The Fisher exact test was used 

to compare mutation profiles. The log rank test was used to compare OS. 

Results: Smoking history and clinical data were available for 852 pts with 

Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never 

smokers, 178 current smokers, and 367 former smokers. Of the former 

smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251 

had smoked � 15 PY. The KRAS / EGFR mutation profiles by smoking 

history are shown below (Table). The KRAS / EGFR mutation profile of 

“collegiate smokers” is distinct from those of pts who were never smokers 

(p � .001) and former smokers with � 15 PY (p � .001) but similar to that 

of pts who were former smokers with 5-15 PY (p � 0.9). Median OS after 

diagnosis of stage IIIB/IV lung cancer for “collegiate smokers” was 25 

months (mos), compared to 32 mos for never smokers (p � 0.4) and 21 

mos for former smokers with � 15 PY (p � 0.63). Conclusions: “Collegiate 

smokers” are a distinct group of pts with a higher incidence of KRAS 

mutations and lower incidence of EGFR mutations compared to never 

smokers. These data suggest that even a small amount of cigarette smoking 

influences the biology of lung cancer. These findings reinforce the 

importance of doing mutation testing routinely for all pts with lung cancer 

to guide clinical care. 

Total EGFR KRAS 

N N % N % 

Never smokers 307 149 49 13 4 

�Collegiate smokers� 55 15 27 8 15 

Former smokers with > 15 pack years 251 27 11 100 40 


Thymidylate synthase (TS) gene expression in patients with ALK positive 

(�) non-small cell lung cancer (NSCLC): Implications for therapy. Presenting 

Author: David R. Gandara, University of California Davis Cancer Center, 


Background: ALK� NSCLC represents a molecular target-defined patient 

population highly responsive to the ALK inhibitor crizotinib. Previous 

reports have also suggested increased sensitivity of ALK� NSCLC to the 

chemotherapeutic agent pemetrexed. Thymidylate synthase (TS) is a 

candidate predictive biomarker for pemetrexed activity. Here we report 

analysis of the Response Genetics Inc. (RGI) database for this association 

and implications for therapy. Methods: ALK fusion was identified by a novel 

RT-PCR assay (Danenberg et al: ASCO 2010). For TS, RNA from microdissected 

formalin-fixed paraffin-embedded tumors was analyzed as previously 

described, reported as the ratio of gene expression to �-actin. For 

reference, a TS level �2.33 is the cutpoint for sensitivity. Results: TS levels 

were available from 63 ALK� patients and 1,698 ALK- control lung 

adenocarcinoma patients. All ALK� patients had adenocarcinomas without 

EGFR or KRAS mutations. Median age: 59.0 (range 33-88), gender 

(male/female) 32/31 (51%/49%). Median TS RNA level in ALK� patients 

was 2.02, range (0.55-19.44), and in ALK- patients was 3.32 (0.36- 

53.51), p�0.0001 (Mann-Whitney test). The majority of ALK� patients 

(N�43, 68%) had a TS level �2.33 cutpoint, compared to only 32% of 

ALK- patients (N�551, p�0.0001). Conclusions: This analysis demonstrates 

relatively low TS gene expression in ALK� patient tumors as 

determined by RT-PCR. These data provide a mechanism of action 

supportive of pemetrexed sensitivity for ALK� NSCLC. 

TS expression N Median 95% CI Range Mean 95% CI p value 

ALK� patients 63 2.02 1.60-2.11 0.55-19.44 2.53 1.89-3.16 �0.0001 

ALK- patients 1698 3.32 3.15-3.45 0.36-53.51 7.87 1.68-14.05 




Correlation between thymidylate synthetase (TS) expression and progressionfree 

survival (PFS) in patients receiving pemetrexed (pem) for advanced 

NSCLC: A prospective study. Presenting Author: Marianne Nicolson, 

Aberdeen Royal Infirmary, Aberdeen, United Kingdom 

Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to 

be associated with TS expression. Our primary objective was to assess the 

correlation between TS and PFS, prospectively. Methods: Context: A Phase 

II, single-arm, exploratory, multicenter, UK study with appropriate approvals 

and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC 

histology, stage IIIB/IV. Patients (n�70) received pem/cisplatin induction 

x 4. Non-progressive patients continued on maintenance pem until tumor 

progression or discontinuation. All patients were followed until death or 

study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) 

were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for 

median PFS (mPFS) and Cox regression to determine the statistical 

correlation between PFS and TS IHC nuclear score, (continuous variable) 

were performed. Maximal Chi-square analysis identified the optimal association 

cutpoints between PFS and low vs. high TS scores. Results: Patient 

demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) 

had adenocarcinoma; 15 were not otherwise specified. Maintenance pem 

was started in 43/70 (61.4%) patients. Evaluable patients had at least one 

dose of study treatment and a valid TS score (n�60). For the evaluable 

population, the mPFS from start of induction was 5.5 months (95% CI 

3.9-6.9). A statistically significant correlation between PFS and TS IHC 

nuclear scores was observed [p�0.0001, HR� 1.01 (95% CI 1.01, 

1.02)], suggesting higher TS values are associated with shorter PFS. When 

the population was dichotomized at the identified optimal H-score cutpoint 

of 70, the mPFS in the low expression group (n�40) was 7.1 months 

(5.7-8.3) compared to 2.6 months (1.3-4.1) in the high expression group 

(n�20) [adjusted p�0.0015, HR�0.28 (95% CI 0.16-0.52)]. Similar 

trends with cytoplasmic TS IHC (p�0.09) and TS qPCR (p�0.05) levels 

were observed. Statistical correlations were seen among the TS levels. Data 

is preliminary. Conclusions: Study suggests statistically significant association 

between low TS IHC nuclear expression and improved PFS in this 

Phase 2 single-arm trial. 


Expression of folate pathway regulators and pemetrexed (pem) activity in 

patients (pts) with advanced non-small cell lung cancer (NSCLC). Presenting 

Author: Letizia Gianoncelli, Humanitas Cancer Center, Rozzano, Italy 

Background: Thymidylate synthase (TS) expression has been reported to 

predict pem activity in pts with advanced NSCLC. Besides TS, pem inhibits 

multiple enzymes of the folate pathway including dihydrofolate reductase 

(DHFR), glycinamide ribonucleotide formyltransferase (GART) and aminoimidazole 

carboxamide ribonucleotide formyltransferase (AICAR). Aim of 

present study was to investigate whether these or other biomarkers 

influence pem activity in NSCLC pts. Methods: Advanced pretreated NSCLC 

pts who received at least two cycles of single agent pem were considered 

eligible if they had available tumor tissue to assess at least one of the 

proposed biomarkers. TS, DHFR, GART and AICAR protein expression was 

assessed by immunohistochemistry (IHC) in FFPE tumor samples. Pts were 

grouped as IHC� and IHC– according to staining intensity. Additionally, 

presence of EGFR and KRAS mutations was investigated. Results: Ninetysix 

pts were included in the study. The majority of subjects was male 

(72%), smokers (93%), with adenocarcinoma (72%). Response rate (RR), 

disease control rate (DCR), progression-free survival (PFS) and overall 

survival (OS) were 12%, 47%, 2.3 and 9.5 months, respectively. Most pts 

resulted TS-(72%), AICAR-(82%), DHFR� (68%), GART- (61%). EGFR 

and KRAS mutations were identified in 15% and 25% of assessable cases. 

None of the biomarkers was significantly associated with pts characteristics 

(gender, histology, smoking status), nor with RR or DCR. GART- pts 

experienced longer PFS when compared with the GART� group (HR 0.56, 

p�.052), while no difference was observed according to TS, DHFR and 

AICAR status. A significantly longer OS was observed for TS- (HR 0.52, 

p�.012), GART- (HR 0.50, p�.037) and AICAR- (HR 0.40, p�.028) pts. 

No significant difference in the distribution of EGFR mutant pts receiving 

EGFR TKIs after pem failure was observed between IHC� and IHC- groups. 

Conclusions: Low TS, GART and AICAR protein expression predicts significantly 

prolonged survival in single agent pem-treated pts with advanced 

NSCLC. The lack of PFS difference according to TS and AICAR status 

suggests prognostic rather than predictive relevance for these biomarkers. 


A randomized, double-blinded, phase II study of paclitaxel/carboplatin 

(PC) plus CT-322 versus PC plus bevacizumab (Bev) as first-line treatment 

for advanced nonsquamous non-small cell lung cancer (NSCLC). Presenting 

Author: Eugene Henry Paschold, Piedmont Hematology-Oncology 

Associates, Winston-Salem, NC 

Background: CT- 322 is a pegylated protein engineered from the tenth type 

III human fibronectin domain thatspecifically blocks VEGFR-2 signaling by 

all known ligands. This international randomized study assessed the 

efficacy and safety of PC � CT-322 compared to PC � Bev as first-line 

treatment for advanced non-squamous NSCLC. Methods: In addition to 

paclitaxel 200 mg/m2and carboplatin AUC 6 given on day 1 of a 21 day 

cycle(maximum 6 cycles), subjects, stratified by ECOG performance 

status, disease stage, and site, were randomized 1:1 to receive either 

CT-322 2 mg/kg on days 1, 8, and 15 (arm A) or Bev 15 mg/kg on day 1 and 

placebo on days 8 and 15 (arm B). CT -322 and Bev/placebo were 

continued as maintenance until disease progression, unacceptable toxicity, 

or withdrawal of consent. The primary endpoint was progression-free 

survival (PFS); secondary endpoints included overall survival (OS), response 

rate, and safety. Results: 255 subjects were randomized to arm A 

(n�127) or arm B (n�128). Baseline characteristics were wellbalanced. 

After a median follow- up of 13.8 months, 9 subjects on arm A and 24 on 

arm B remained on study treatment. The median treatment duration was 19 

weeks in arm A and 26.3 weeks on arm B. The median PFS in arm A was 

5.6 months compared to 6.8 months in arm B (HR 1.51, 1 -sided 

p�0.997). In all prespecified subgroups, PFS was favored in arm B. The 

response rate was 25.2% in arm A compared to 32.8% in arm B. Median 

OS was 12.5 months in arm A compared to 15.2 months in arm B. The 

most common grade � 3 adverse events (Arm A vs B) were neutropenia 

(47.2% vs 49.2%), thrombocytopenia (11.8% vs 6.3%), and fatigue 

(10.2% in both arms). Grade � 3 hypertension was more frequently 

reported in arm A (8.7% vs 3.1%). Grade � 3 venous thrombosis (5.5% vs 

6.3%), proteinuria (1.6% vs 2.3%), and bleeding events (0.8% vs 1.6%) 

were similar. Conclusions: PC � CT-322 failed to improve PFS, OS, or 

response rate compared to PC � Bev. However, thesafety profile in the PC 

� CT-322 arm was consistent with the anti-angiogenic mechanism of 

action, suggesting that CT-322 has biological activity as an inhibitor of 

VEGFR-2. 


Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic 

and VEGF pathways: Association with survival of platinum-treated stage IV 

non-small cell lung cancer (NSCLC) patients. Presenting Author: Sinead 

Cuffe, Princess Margaret Hospital, University of Toronto, Toronto, ON, 

Canada 

Background: Two potentially important host pathways in lung cancer 

systemic therapy are: (i) the pharmacogenetic pathway of platinum agents 

(DNA repair, metabolism, and multidrug resistance genes); and (ii) the 

vascular endothelial growth factor (VEGF) pathway. We investigated the 

relationship between SNPs in these two pathways and clinical outcome in 

platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV 

NSCLC patients underwent SNP genotyping for the platinum-related (48 

SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were 

selected from the literature and through tagging. Association of SNPs and 

overall (OS) and progression free survival (PFS) were assessed using 

multivariate Cox proportional hazards models. Results: 72% were Caucasian; 

73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 

54% received � one line of systemic therapy; 10% received anti-VEGF 

therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top 

significant SNPs in the platinum-related pathway were in ABCC2 

(rs8187710 and rs2756109, r2�0.68). The G variants of the top SNP, 

ABCC2 rs8187710 (4554G�A), were associated with worse OS (adjusted 

hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p�0.0005) and PFS (aHR, 

1.97; 95%CI: 1.2-3.4; p�0.01). Functionally, 4554G�A impairs ATPase 

activity and is associated with higher cellular accumulation of ABCC2 

substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated 

with cisplatin resistance and clinical outcome in other cancers [PMID: 

17145840]. Within the VEGF pathway, the top significant SNPs were in 

the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, 

r2�1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); 

p�0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p�0.004. 

VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer 

risk [PMID: 21751195], but has not been assessed in lung cancer. 

Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated 

with OS and PFS in this cohort of platinum-treated advanced NSCLC 

patients. Future studies should assess whether these are predictive or 

prognostic markers. 



Sorafenib and continued erlotinib or sorafenib alone in patients with 

advanced non-small cell lung cancer progressing on erlotinib: A randomized 

phase II study of the Sarah Cannon Research Institute (SCRI). 

Presenting Author: Victor Gian, Tennessee Oncology, PLLC/Sarah Cannon 

Research Institute, Nashville, TN 

Background: Erlotinib is an oral epidermal growth factor receptor kinase 

inhibitor used in the treatment of advanced non-small-cell lung cancer 

(NSCLC). Resistance develops in patients (pts) who initially respond to 

erlotinib leading to progressive disease (PD). Sorafenib is an oral inhibitor 

of vascular endothelial and platelet-derived growth factor receptors and Raf 

kinases which play important roles in PD. This randomized phase II study 

evaluated the role of sorafenib and continued erlotinib or sorafenib alone in 

pts with progressive NSCLC following initial benefit with erlotinib. Methods: 

Eligible pts had IIIB/IV NSCLC, an ECOG PS 0-2, and had received �2 

lines of therapy with the last being single-agent erlotinib. Pts must have PD 

following clinical benefit (complete/partial response/stable disease) from 

erlotinib for �8 weeks. Pts were randomized 1:1 to continue erlotinib at the 

dose administered at the time of PD with the addition of sorafenib 400 mg 

orally twice daily (Arm A) or to sorafenib alone (Arm B). Cycles were 28 days 

with restaging every 2 cycles. The primary endpoint was progression-free 

survival (PFS). Results: 52 pts were enrolled from 2/2008 to 3/2011 (A 24; 

B 28). Baseline characteristics were balanced between arms and included: 

median age 65 years (41-87); 65% female; 69% adenocarcinoma/large 

cell; and 96% PS �2. 41% of pts were either never smokers or smoked 

�100 cigarettes/lifetime. Pts received a median of 8 weeks of treatment 

per arm (0.6–67 weeks). The median PFS was 3.1 (95% CI 1.7-3.7) and 

2.3 (1.7-3.6) months for A and B, respectively (p�.84). There were no 

grade 3/4 hematologic toxicities in either arm except grade 3 anemia in 1 pt 

(A). Severe nonhematologic toxicities in �5% included: fatigue 17%(A)/ 

7%(B); diarrhea 17%/0; dehydration 13%/7%; hand-foot skin reaction 

8%/8%, and anorexia 4%/7%. Conclusions: Sorafenib has modest activity 

when used in combination with erlotinib or as a single agent in pts with PD 

following benefit with erlotinib alone. Additional study to identify potential 

subsets of refractory pts who might derive the greatest benefit from 

sorafenib are warranted. 


ALK and MET genes in advanced lung adenocarcinomas: The Lung Cancer 

Mutation Consortium experience. Presenting Author: Marileila Varella- 

Garcia, Department of Medicine/Medical Oncology, University of Colorado 

Cancer Center, Aurora, CO 

Background: The Lung Cancer Mutation Consortium (LCMC) consisting of 

14 US Cancer Centers was established to evaluate a panel of molecular 

mutations in advanced lung adenocarcinoma. ALK gene fusions and MET 

gene amplification were assessed by FISH in CLIA certified laboratories. 

Methods: Molecular tests were performed in stage IIIB or IV lung adenocarcinoma. 

To date, FISH assays have been completed in 901 patients for ALK 

(ALK break-apart, Abbott Molecular) and in 654 patients for MET (in 

house/Abbott Molecular reagents). ALK� specimens were defined by split 

3’ALK/5’ALK signals (gap �2 signal diameters) or single 3’ALK signals in 

�15% of tumor cells. MET gene amplification (MET�) was defined by ratio 

mean MET/mean CEP7 �2. Results: The ALK� patient subset (N�75, 

8.3%) compared to the ALK- had significantly lower age at diagnosis (52 

vs. 60, p�0.001) and less frequent heavy smoking history (61% neversmokers 

among ALK� vs. 31% among ALK-, p�0.001; pack-year for 

current/former smokers 17 vs. 40, p�0.003). Liver metastases were 

significantly more frequent among ALK� than ALK- (23% vs.10%, 

p�0.004); no difference was detected in bone, brain and adrenal gland 

metastases. MET� (N�29, 4.4%) was significantly associated with female 

sex (72% female among MET� vs. 39% among MET-, p�0.001) and 

marginally more frequent in patients with adrenal metastasis; no difference 

was detected for age at diagnosis and smoking history. Follow-up on 73 

ALK� patients indicated that 56% received crizotinib as targeted therapy. 

Response was unknown in 8% and unreportable in 22% patients enrolled 

in ongoing randomized trials. Among patients with evaluable response, 

complete response, partial response, stable disease, and progressive 

disease were found respectively in 3%, 66%, 28%, and 3%. Conclusions: 

The LCMC successfully tested ALK and MET FISH in a large number of lung 

adenocarcinomas. It was demonstrated that directing positive patients to 

specific interventions is feasible, and that grouping of testing and trials 

within consortia may maximise relevant trial accrual in rare molecular 

subtypes. Supported by NCI-GO award. Submitted on behalf of the LCMC. 


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Clinical characteristics of KRAS mutations in NSCLC and their impact on 

outcomes to first-line chemotherapy. Presenting Author: Mohit Butaney, 


Background: KRAS is one of the most commonly mutated oncogenes in 

non-small cell lung cancer (NSCLC). While the impact of EGFR mutations 

and EML4-alk translocations has been well-described, there is limited 

information about the impact of these somatic mutations on response to 

chemotherapy. Methods: We retrospectively reviewed the demographics 

and clinical outcomes of patients with KRAS mutations and compared 

these to patients who were KRAS wild-type (WT). Eligible pts received 

1st-line IV chemo for stage IV NSCLC at DFCI and had known information 

about both KRAS and EGFR status. Since the biology and impact of EGFR 

mutations on response to chemo is well-described, we excluded such pts 

from the analysis. The primary endpoint was progression-free survival (PFS) 

with first-line chemo; secondary endpoints included radiographic response 

rate (RR) and overall survival (OS). Results: Between 2/05 and 8/11, there 

were 63 eligible KRAS pts and 97 eligible WT pts. The groups were similar 

in age (median 65yrs in both groups), % female (K 62, WT 54) race (K 89% 

white/6% black, 5% other; WT 86% white,/6% black/8% other), histology 

(K 90%adeno/8% NSCLC NOS; WT 86% adeno/9%NSCLC NOS), and % of 

pts receiving 1/2/3 agents in 1st line (K 11/56/33; WT 18/53/30). KRAS 

pts were less likely to be never or light smokers (4% vs 33% for WT). 

Nonsmokers were more likely to harbor KRAS transition rather than 

transversion mutations (3 transition, 1 transversion), while the converse 

held for smokers (51 transversions, 8 transitions). Median PFS was similar 

for KRAS vs WT (K .65 vs WT 4.8 months, p�0.81). RR (29% for both 

groups), disease control rates (K 73% vs WT 78%), and median OS (K 13.5 

vs WT 12.1 months, p�.525) were also similar. Outcomes of KRAS pts to 

2nd line chemotherapy (PFS 2.2, OS 8.6) are similar to those seen for WT 

patients in this setting. There was no significant difference in outcomes 

based on gender, smoking status, drug received (pemetrexed-based vs 

taxane based), or specific KRAS genotype. Conclusions: Pts with KRAS 

mutations experience similar outcomes to standard chemotherapy as those 

who are wild-type for EGFR and KRAS. Going forward, these data can serve 

as a reference for control arms of KRAS-specific randomized trials. 


Weekly nab-paclitaxel in combination with carboplatin as first-line therapy 

in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC). 

Presenting Author: Mark A. Socinski, University of Pittsburgh Medical 

Center, Pittsburgh, PA 

Background: The median age of advanced NSCLC pts in the US is 71 years; 

yetelderly pts (�70 years) are generally undertreated, with only �30% 

receiving systemic therapy. Hence, better, more tolerable therapeutic 

options are needed for this cohort. In a phase III trial nab-paclitaxel (nab-P, 

130 nm albumin-bound paclitaxel particles) � carboplatin (C) vs solventbased 

paclitaxel (sb-P) � C, significantly improved ORR, the primary 

endpoint (25% vs 33%, P � 0.005), with a 1-month improvement in OS (P 

� NS) and improved safety. This analysis evaluated efficacy and safety in 

pts �70 and �70 years old. Methods: Pts with untreated stage IIIB/IV 

NSCLC and with an ECOG score of 0/1 were randomized 1:1 (stratified by 

age [�70 vs �70 years], region, stage, gender, and histology) to C AUC 6 

day 1 and either nab-P 100 mg/m2 on days 1, 8, 15 or sb-P 200 mg/m2 day 

1 q 21 days. ORR and progression-free survival (PFS) were determined by 

blinded centralized review. Results: Of the phase III study population, 15% 

were elderly (156/1052; 74 pts in the nab-P/C and 82 in the sb-P/C arms). 

Most elderly pts were male (72%), Caucasian (71%), and had stage IV 

disease (64%). In pts both �70 and �70 years old, ORR was higher in the 

nab-P/C vs sb-P/C arm (�70: 34% vs 24%, P � 0.196; �70: 32% vs 

25%, P � 0.013). In pts �70 years old, PFS trended in favor of nab-P/C 

(median 8.0 vs 6.8 months, HR: 0.687, P � 0.134); OS was significantly 

improved (median 19.9 vs 10.4 months, HR: 0.583, P � 0.009). In 

contrast, PFS (6.0 vs 5.8 median months, HR: 0.903, P � 0.256) and OS 

(11.4 vs 11.3 median months, HR: 0.999, P � 0.988) were similar for 

both treatment arms in pts �70 years old. Adverse events were similar in 

pts �70 years old vs the entire study population, with less grade 3/4 

neutropenia (P � 0.05) and neuropathy (P � 0.05) and increased 

thrombocytopenia (P � NS) and anemia (P � 0.05) in the nab-P/C vs 

sb-P/C arms. In pts �70 years old, patient-reported FACT-taxane subscales 

revealed significantly less neuropathy, pain, and hearing loss in the nab-P/C 

vs sb-P/C arms (P � 0.001). Conclusions: In elderly pts with advanced 

NSCLC, nab-P/C as first-line therapy was well tolerated and led to improved 

ORR and PFS, with significantly longer OS vs sb-PC. 




EML4-ALK-gene rearrangement comparative analysis in circulating tumor 

cells and in tumor tissue of patients with lung adenocarcinoma. Presenting 

Author: Marius Ilie, Laboratory of Clinical and Experimental Pathology, 

Hospital Pasteur, Academic Hospital, Nice, France 

Background: The implementation of new theranostic biomarkers in Oncology 

is leading to impressive therapeutic improvements. In patients with 

lung cancer, the possibility to use Circulating Tumor Cells (CTCs) as a 

non-invasive theranostic approach is a clinically appealing challenge. 

Adenocarcinomas with EML4-ALK rearrangement are a new molecular 

subgroup of lung tumors with very good response to Crizotinib, an ALK 

inhibitor. We have thus aimed at developing an informative assay characterizing 

the ALK-gene status in CTCs isolated from patients with lung cancer. 

Methods: CTCs were isolated preoperatively using Isolation by Size of 

Epithelial Tumor cells method (ISET) from 65 patients with lung adenocarcinoma 

and blindly screened for ALK-gene status. ALK break-apart 

fluorescence in situ hybridization (FISH) (LSI ALK dual colour probes set) 

and immunochemistry using an anti-ALK antibody (5A4 clone) were blindly 

performed on CTCs and corresponding tumor tissues and results were 

compared. Results: Two patients consistently showed ALK-gene rearrangement 

and strong ALK protein expression in CTCs and corresponding tumor 

samples. Negative results (both ALK FISH and ALK immunochemistry) 

were found in CTCs and corresponding tumor samples from the other 63 

patients. Conclusion: We have developed an approach allowing to characterize 

ALK-gene status in CTCs from patients with lung cancer and shown 

consistent results in CTC and tumor tissues. These preliminary results 

encourage larger studies and open new avenues for non-invasive, real-time, 

theranostic monitoring of cancer patients. 


Frequency of anaplastic lymphoma kinase (ALK) positive tumors among 

African American non-small cell lung cancer (NSCLC) patients. Presenting 

Author: Shirish M. Gadgeel, Karmanos Cancer Institute, Wayne State 

University, Detroit, MI 

Background: ALK gene rearrangement is a recently identified molecular 

alteration in the tumors of a small proportion of NSCLC patients. Previous 

reports have shown that the rate of EGFR gene mutations may vary in 

NSCLC patients of different ethnic background. It is unclear if similar 

differences exist with regards to ALK positivity. We analyzed ALK expression 

in tumors of AA NSCLC patients and also assessed the epidemiologic 

features and outcomes of these patients, as well as the occurrence of 

known oncogene mutations. Methods: We identified 260 tumor tissues of 

AA NSCLC patients, enrolled on several epidemiologic studies conducted 

at our institution. Immunohistochemistry, using the anti-Alk D5F3 antibody 

(Cell Signaling Technology) was used to visualize ALK expression. 

Fifty-three of these tumors also underwent mutation analysis using the 

OncoCarta Panel V1 (Sequenom) to evaluate 238 mutations in 19 

oncogenes. Results: Of the 260 tumors analyzed, 6 (2.3%, 95% CI- 

0.5-4.1%) were ALK positive. All ALK positive patients had adenocarcinoma 

histology (6/157) while no patients with other NSCLC histologies 

were ALK positive, p�0.04. There was no difference in the rate of positivity 

based on sex, 1% (1/99) in males versus 3.1% (5/161) in females, 

p�0.27. Consistent with prior studies, patients with ALK positive tumors 

were slightly younger (median age 56 years vs 61 years, p � 0.27) and the 

positive rate was higher in never smokers 11% (2/18) than in ever smokers 

1.6%, p�0.06. There was no correlation of ALK positivity with the stage of 

the disease at diagnosis. The survival of ALK positive and negative patients, 

adjusted for age, sex and stage, was similar (HR�0.77; 95% CI 0.19- 

3.13). Fifty-three tumors have been assessed for oncogene mutations in 

addition to ALK expression. Of these, 2 (3.8%) were ALK positive and 

neither of these tumors carried other tested mutations such as EGFR, Kras, 

PIK3 or AKT. Conclusions: The rate of ALK positive tumors among 

African-American NSCLC patients is similar to the general population and 

the demographic features of ALK positive AA patients is also similar to the 

general ALK positive NSCLC patient population. 


Safety and efficacy analysis by histology of weekly nab-paclitaxel in 

combination with carboplatin as first-line therapy in patients (pts) with 

advanced non-small cell lung cancer (NSCLC). Presenting Author: Markus 

Frederic Renschler, Celgene Corporation, Summit, NJ 

Background: Treatment of advanced NSCLC differs by histology, with fewer 

options and poorer outcomes in pts with squamous histology. In a phase III 

trial of nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) 

� carboplatin (C) vs solvent-based paclitaxel (sb-P) � C, the primary 

endpoint of ORR was significantly improved from 25% to 33%, p � 0.005, 

with a 1-month improvement in OS (p � NS) and improved safety. This 

analysis evaluated efficacy and safety by histology. Methods: Pts with 

untreated stage IIIB/IV NSCLC were randomized 1:1 (stratified by age, 

histology, region, stage, and gender) to C AUC 6 day 1 and either nab-P 100 

mg/m2 on days 1, 8, 15 or sb-P 200 mg/m2 day1q21days. ORR and PFS 

were determined by blinded centralized review. Results: In squamous pts, 

nab-P/C produced a significantly higher ORR (41% vs 24%, p � 0.001), 

similar PFS (5.6 vs 5.7 mo, HR: 0.865) and �1-month improvement in OS 

(10.7 vs 9.5 mo, HR: 0.890) vs sb-P/C (Table). nab-P/C was as effective as 

sb-P/C in nonsquamous pts for ORR (26% vs 25%, p � 0.808), PFS (6.9 

vs 6.5 mo, HR: 0.933), and OS (13.1 vs 13.0 mo, HR: 0.950). In both 

squamous and nonsquamous pts, nab-P/C vs sb-P/C produced lower rates 

of grade 3/4 neuropathy (3% vs 11% and 3% vs 12%, respectively, p � 

0.001 both), neutropenia (43% vs 51%, p � NS, and 50% vs 63%, p � 

0.008), and higher but manageable rates of anemia (27% vs 4% and 28% 

vs 9%, p � 0.001 both) and thrombocytopenia (21% vs 7% and 16% vs 

11%, p � 0.001 both). Conclusions: In pts with advanced NSCLC, nab-P/C 

demonstrated a favorable risk-benefit profile as a first-line therapy regardless 

of histology. Significantly improved ORR and a positive trend in OS 

were observed in pts with squamous histology. 

Squamous 

ORR, % 

95% CI 

Median PFS, mo 

95% CI 

Median OS, mo 

95% CI 

Nonsquamous 

ORR, % 

95% CI 

Median PFS, mo 

95% CI 

Median OS, mo 

95% CI 

nab-P/C sb-P/C RR/HR P 

n � 229 

41 

35, 47 

5.6 

5.5, 6.7 

10.7 

9.4, 12.5 

n � 292 

26 

21, 31 

6.9 

6.0, 8.1 

13.1 

11.5, 16.1 

n � 221 

24 

19, 30 

5.7 

5.4, 6.7 

9.5 

8.6, 11.6 

n � 310 

25 

20, 30 

6.5 

5.6, 7.0 

13.0 

11.1, 14.3 

1.680 

1.271, 2.221 

0.865 

0.680, 1.101 

0.890 

0.719, 1.101 

1.304 

0.788, 1.358 

0.933 

0.750, 1.159 

0.950 

0.779, 1.158 

�0.001 

0.245 

0.284 

0.808 

0.532 

0.611 


Update on the large-scale screening of ALK fusion oncogene transcripts in 

archival NSCLC tumor specimens using multiplexed RT-PCR assays. 

Presenting Author: Tianhong Li, University of California, Davis, Sacramento, 

CA 

Background: The ALK inhibitor crizotinib offers a new standard of care for 

advanced NSCLC patients with EML4-ALK fusion oncogenes. We previously 

reported a 4.0% frequency of EML4-ALK fusion oncogene transcripts 

detected in 1889 NSCLC specimens in the RGI database (Li et al., ASCO 

2011). Methods: Patented single and multiplexed RT-PCR assays suitable 

for rapid and accurate detection of all variants of ALK fusion oncogene 

transcripts were used as previously described, including all 9 known 

EML4-ALK fusion gene transcripts and ALK RNA levels (Danenberg, ASCO 

2010). The sensitivity and specificity on archival formalin-fixed, paraffinembedded 

tumor specimens are 99% and 100%, respectively. We here 

update the detection of EML4-ALK fusion transcripts in the RGI database. 

Results: Between 12/2009 and 09/2011, 4750 NSCLC specimens in the 

RGI database were tested for the presence of ALK fusion transcripts. We 

found 152 (3.2%) NSCLC cases with EML4-ALK fusion positivity, including 

87 (57.2%) V1, 15 (9.9%) V2, 47 (30.9%) V3, and 3 (2.0%) V5a 

variants. Median age (range): 61.1 (33-96). Female: 74 (49%). All 

EML4-ALK-positive tumors were adenocarcinomas. No EGFR or K-Ras 

mutation was detected in ALK fusion-positive samples. Expression of 

chemotherapy-related biomarkers was available from 63 (female: 31, 

49%) EML4-ALK-positive cases in the database: 43 (68%) had low TS 

level of �2.33; 40 (63.5%) had low ERCC1 level of �1.7, and 25 (40%) 

had low RRM1 level of �0.97. Conclusions: This RT-PCR assay provides a 

tool for rapid, large-scale screening of NSCLC FFPE tissues for EML4-ALK 

fusion gene transcripts. The relative value of this RT-PCR assay as a 

companion diagnostic test for drugs targeting ALK merits evaluation in 

comparison with the FDA approved ALK FISH test. 



Survival outcome segregated by KRAS mutation status in newly diagnosed 

stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with 

first-line chemotherapy. Presenting Author: Anna K. Brady, University of 


Background: KRAS mutations (MT) form a distinct subset of NSCLC, 

generally considered to have poor prognosis. Although KRAS MT is a 

well-establised prognostic and predictive marker in colorectal cancer, its 

role in NSCLC remains ambiguous. Pts with KRAS MT NSCLC do not 

respond well to epidermal growth factor receptor (EGFR) directed tyrosine 

kinase inhibitor therapy, but little is known about the ability of KRAS MT to 

predict outcome after first-line chemotherapy in newly diagnosed advanced 

or recurrent NSCLC. Methods: We analyzed outcomes of consecutive pts 

with newly identified Stage IV non- squamous NSCLC treated at University 

of Pennsylvania (Penn) between 05/2008 and 7/2010 and then compared 

survival based on KRAS status [MT vs wild type (WT)] using chi square, 

Kaplan-Meier methods, and Cox regression models. Results: Of 106 

consecutive new pts with Stage IV non squamous NSCLC treated at Penn, 

49 (46%) underwent molecular analysis for KRAS MT. Fifteen (34%) were 

KRAS MT. Of 34 KRAS WT pts, 6 were positive for EGFR MT. The median 

age of all 49 pts was 61 years; 83% were Caucasian, 45% male and 60% 

had a �10 pack year smoking history. Median duration of follow up is 16.4 

mos. Majority of pts (92%) had adenocarcinoma histology. Most pts (88%) 

had ECOG PS 0-1 at presentation. Forty three pts received first line 

platinum-based combination chemotherapy (platinum and pemetrexed in 

31 pts). KRAS MT was associated with smoking (p�0.04), but not with 

gender or age. Overall survival (OS) of pts with KRAS MT was similar to 

KRAS WT pts [median OS 15.6 vs. 19.0 mos; HR 1.24 (95% CI 

0.57-2.67)]. Univariate analyses demonstrated superior OS among women 

compared to men (HR 0.40, 95% CI 0.20-0.85) in the entire pt cohort. 

Conclusions: In our population of stage IV non squamous NSCLC, pts with 

KRAS MT had similar OS to those with KRAS WT tumors. OS was slightly 

higher in KRAS WT pts, but this may have been confounded by the 

inclusion of 6 EGFR MT pts in this cohort. The potential prognostic or 

predictive role of KRAS MT in NSCLC pts undergoing chemotherapy 

requires further prospective study. 


Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy 

number (GCN) for discrimination of response and outcome to figitumumab 

in NSCLC. Presenting Author: Murry W. Wynes, Division of Medical 

Oncology, University of Colorado Denver, Aurora, CO 

Background: Early clinical data suggested figitumumab (F), an anti-IGF-1R 

antibody, had clinical activity in several tumor types. However, two phase 

III studies, A4021016 carboplatin/paclitaxel (CP) �/- F in 1st line 

treatment or A4021018 erlotinib (E) �/- F in 2nd line therapy for patients 

with advanced NSCLC, were closed prematurely due to futility. Neither 

study used biomarker driven selection criteria. The aim of this study was to 

retrospectively examine the phase III specimens in order to determine if 

IGF-1R PE or GCN could discriminate response and/or outcome to F. 

Methods: IGF-1R PE was determined by immunohistochemistry (IHC) and 

the tumor specimens were scored using the H-score method (0-300) with 

separate enumeration of membranous and cytoplasmic components and 

then combination of these scores. GCN was evaluated by bright field silver 

in situ hybridization (SISH) with recording the average copy number for 50 

tumor cells. Results: IHC was evaluable in 25 CP�F, 20 CP, 27 E�F and 

26 E specimens whereas SISH was evaluable in 24, 17, 21 and 22 

specimens, respectively. Median PE for membrane, cytoplasm and both in 

A4021016 were 130, 110 and 120 and in A4021018 they were 135, 140 

and 140. Median GCN was 1.88 and 1.98 for A4021016 and A4021018, 

respectively. There were no significant differences in PE or GCN between 

treatment arms within each study. Neither PE nor GCN were able to 

discriminate between response/non-response or disease control/progression 

in either study. Likewise, neither study showed a significant difference 

in OS or PFS when using the median cut-points for either PE or GCN. 

Conclusions: Neither IGF1R PE or GCN were able to discriminate response 

or outcome in the limited quantity of specimens available from two studies 

that examined the IGF-1R targeted therapy figitumumab. 



Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced 

non-small cell lung cancer (NSCLC) patients treated with crizotinib. 

Presenting Author: Ravi Salgia, The University of Chicago, Chicago, IL 

Background: Crizotinib is an ALK inhibitor indicated in the US for advanced 

ALK-positive NSCLC. Visual effects reported by patients treated with 

crizotinib were characterized using the Visual Symptom Assessment 

Questionnaire (VSAQ). Methods: Patients with previously treated, advanced 

ALK-positive NSCLC were administered 250 mg BID crizotinib in an 

ongoing phase II study (PROFILE1005, NCT00932451; Pfizer). Patients 

completed the VSAQ at day 1 of each 21 day cycle and at end of treatment. 

The VSAQ has a recall period of 3 weeks and consists of 7 questions 

assessing presence, frequency, timing, duration and degree of bother of 

visual effects and their impact on Activities of Daily Living (ADL). The 

visual effects assessed included appearance of overlapping shadows/after 

images, flashing lights and streamers/strings/floaters, difficulty adapting to 

lights and seeing at night. Patients rated degree of bother on a 5-point scale 

ranging from ‘not at all’ to ‘extremely’. Impact on ADL was measured using 

a 10-point scale (0: no effect; 10: completely prevented ADL). Frequency 

analyses were performed. Results: As of June 1 2011, visual effects as 

identified by VSAQ were reported by 63% (114/182) of patients at cycle 2 

(C2), 57% at C3 (85/149), 52% at C4 (64/123) and 41% at C5 (46/112). 

The most commonly experienced visual events were appearance of flashing 

lights (C2:81%; C3:82%; C4:84%; C5: 76%), streamers/strings/floaters 

(C2: 83%; C3:78%; C4: 81%; C5:87%) and overlapping shadows/after 

images (C2:70%; C3:77%; C4:87%; C5:84%). Most patients reported 

each event to last �1 minute (C2:61%; C3:71%; C4:77%; C5: 70%). 

Majority of patients reported event frequency at each cycle of � 7 days/wk 

(50–78%). Patients reported that the visual effects occurred mostly in the 

morning (52–62%) and/or evening (62–73%). Majority of patients reported 

that visual effects were not at all or a little bothersome (C2:62%; 

C3:61%; C4:66%; C5:65%). Majority of patients indicated no or minimal 

impact on ADL (C2:80%; C3:80%; C4:83%; C5:87%). Conclusions: Visual 

effects identified by VSAQ in patients treated with crizotinib were frequent, 

but were reported to be transient with no or minimal impact on ADL. 


Clinical presentation of hepatotoxicity-associated crizotinib in ALKpositive 

(ALK�) advanced non-small cell lung cancer (NSCLC). Presenting 

Author: Patrick Schnell, Pfizer Inc., New York, NY 

Background: Severe hepatotoxicity has been observed with most receptor 

tyrosine kinase inhibitors. Crizotinib, a first-in-class oral inhibitor of ALK, 

was recently FDA approved for the treatment (tx) of advanced (ALK�) 

NSCLC. We provide a review of hepatotoxicity in the crizotinib clinical 

development program. Methods: Relevant tx-emergent adverse event (AE) 

reports from 2 pooled single-arm trials in patients (pts) with ALK� NSCLC 

who received crizotinib 250 mg BID (n�588) up to Jun 2011 were 

reviewed. Five reports of severe hepatotoxicity received through Dec 13, 

2011 were also evaluated. Results: Incidence of elevation in ALT and AST 

lab values by CTCAE grade are shown in the table. Additionally, 16 

all-grade (7 grade 3 or 4) cases of pertinent hepatic events have been 

reported. Transaminase elevations generally occurred in the first 2 months 

of tx and were usually reversible. Pts usually resumed tx at a lower dose 

without recurrence; however, 4 (�1%) required permanent discontinuation 

from tx. Five (�1%) cases of severe, potentially drug-related hepatotoxicity 

(2 fatal) were reported through Dec 13, 2011, with an estimated exposure 

of 1400 pts. Pts presented with fatigue, nausea, anorexia, weakness, and 

abdominal pain. Time from starting crizotinib to onset of hepatotoxicity was 

�6 weeks in 4 cases, while significant transaminase elevation was 

observed after 6 months in the fifth case. Significant hepatic metastases 

and abnormal enzymes at baseline were present in 1 (fatal) case, while 

baseline transaminases were normal in 3 cases, or just above the upper 

limit of normal in 1 case. Conclusions: Crizotinib is uncommonly associated 

with severe hepatotoxicity and was reported in �1% of pts. Nausea, 

malaise, decreased appetite, vomiting, and abdominal pain may indicate 

hepatic toxicity. ALT and total bilirubin should be monitored monthly and 

as clinically indicated. Discontinuation of crizotinib is recommended when 

severe drug-induced hepatic toxicity is suspected or diagnosed. 

Causality/grade 

N � 588 

Increased ALT 

n (%) 

503s 

Increased AST 

n (%) 

All causality 

All grade 86 (14.6) 63 (10.7) 

Grade 3/4 30 (5.1) 14 (2.4) 

Tx related 

All grade 73 (12.4) 52 (8.8) 

Grade 3/4 24 (4.1) 10 (1.7) 




A large retrospective analysis of the activity of pemetrexed (PEM) in 

patients (pts) with ALK-positive (ALK�) non-small cell lung cancer 

(NSCLC) prior to crizotinib (CRIZ). Presenting Author: Giorgio V. Scagliotti, 

University of Turin, Orbassano, Italy 

Background: Retrospective small cohort studies suggest ALK� NSCLC may 

be particularly sensitive to PEM. Methods: PROFILE 1005 (NCT00932451; 

Pfizer) is a large phase 2 multi-center, single-arm study of CRIZ in 

previously treated ALK� NSCLC. Eligibility criteria included pts with 

progressive disease from the PEM arm of companion trial PROFILE 1007. 

We retrospectively assessed objective response rate (ORR) and time to 

progression (TTP; 1st dose to objective progression) in pts who received 

PEM prior to CRIZ. ORR with CRIZ post-PEM was assessed. Results: Of the 

439 ALK� pts enrolled as of June 2011, 369 (84.1%) received prior PEM 

(single agent or combination; any line advanced/metastatic) with a cumulative 

ORR of 18.7%. In pts who received PEM combinations 1st-line (1L; 

n�120) or 2nd-line (2L; n�60), ORR was 24.2% and 16.7%; and median 

TTP was 6.9 months (mo; 95% CI: 6.0–7.4) and 6.9 mo (95% CI: 

4.8–8.8), respectively. In pts who received 2L single-agent PEM (n�80), 

ORR was 12.5% and median TTP was 5.3 mo (95% CI: 3.0–6.6). In pts 

treated with PEM 3rd-line (3L) or later (n�138), ORR was 16.7%. By line 

of PEM treatment, ORR was lower and TTP shorter than that reported in 

small ALK� cohorts evaluating multiple lines of treatment. In 2L, previously 

reported ORR and median PFS with single-agent PEM in adenocarcinoma 

NSCLC were 12.8% (n�158) and 3.5 mo (n�283), and comparable 

to our findings. Pts who received 2L single-agent PEM (n�80) subsequently 

achieved higher ORR with CRIZ (54%; 95% CI: 42–65). Similar 

analyses in the 1L and 3L groups are ongoing. Conclusions: This retrospective 

study in predominantly never-smokers with ALK� NSCLC reports lower 

ORR and shorter TTP with PEM than that reported in smaller retrospective 

ALK� NSCLC cohorts. This finding may be in part due to the inclusion of 

crossover pts from PROFILE 1007. This analysis and previous reports 

observed a tendency to a higher response rate and better PFS or TTP with 

PEM than in unselected populations in 2L, which may not be specifically 

related to ALK status but to a higher sensitivity to cytotoxic agents in 

never-smokers. Results from an ongoing phase 3 trial (PROFILE 1007) will 

provide additional information. 


Clinical benefit from pemetrexed before and after crizotinib exposure in 

patients with ALK positive non-small cell lung cancer (ALK� NSCLC). 

Presenting Author: Eamon Berge, University of Colorado Health Sciences 

Center, Aurora, CO 

Background: Crizotinib (Criz) produces high response rates and prolonged 

progression free survival (PFS) in ALK� NSCLC. Retrospective analyses 

suggest enhanced sensitivity to pemetrexed (Pem) in Criz-naïve ALK� 

NSCLC. Different biological mechanisms of Criz resistance have recently 

been discovered. Clinical cross-resistance between Criz and Pem has not 

been previously investigated. Methods: Patients with stage IV ALK� NSCLC 

treated in sequence with Pem then Criz (Pem-Criz), or Criz then Pem 

(Criz-Pem) were identified. Excluding CNS only progression events when no 

new systemic treated was started, PFS was compared using Cox Proportional 

Hazards. Correlations between molecular features of ALK positivity 

and Pem PFS were analyzed using Spearman correlations. Treatment 

sequence effect was explored using Fisher’s exact test. Results: We 

identified 19 Pem-Criz and 9 Criz-Pem ALK� patients. Pem was given as 

monotherapy in 37% vs. 66%, and as median 2nd vs. 3rd line cytotoxic in 

the Pem-Criz and Criz-Pem groups, respectively. For the Pem-Criz group,median 

PFS was 8.9 months with Pem (range: 1-21.5 months), and 14.7 

months with Criz (range:2.9� -27.5 months). For the Criz-Pem group, 

median PFS was 8.4 months with Criz (range: 2-29 months), and 4.4 

months with Pem (range: 0.5-10.5� months). Patients were more likely to 

progress on Pem given after Criz than before, but confidence intervals were 

wide (HR 1.51, 95% CI 0.626-3.66). Neither native or rearranged signal 

copy number, nor percent cells ALK� in the tumors correlated with PFS on 

Pem. Conclusions: Both Criz and Pem appear to be active drugs in 

ALK�NSCLC given in either order. Numerically, benefit from Pem was less 

when given post-Criz compared to pre-Criz, however this difference was not 

statistically significant. Several potential confounders exist in our small 

dataset (notably differences in line of therapy and use in combo vs. 

monotherapy). To fully address whether there may be a significant 

difference in overlap of induced specific drug resistance mechanisms, the 

clinical effect of Criz/Pem sequencing should be explored in a larger series 

adjusting for confounding effects. 


Clinical characteristics of ALK� NSCLC patients (pts) treated with crizotinib 

beyond disease progression (PD): Potential implications for management. 

Presenting Author: Gregory Alan Otterson, Department of Internal 

Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, 

OH 

Background: Crizotinib is a first-in-class oral ALK inhibitor for the treatment 

(tx) of advanced ALK-positive (ALK�) NSCLC. Dramatic and prolonged 

responses to crizotinib are common, but pts do experience PD. Methods: 

Clinical characteristics of ALK� NSCLC pts enrolled onto two multicenter, 

single arm trials of crizotinib (A8081001, PROFILE 1005) with investigatordefined 

PD who were allowed to continue crizotinib if, in the investigator’s 

opinion, there was reasonable evidence of ongoing clinical benefit were 

assessed. A period of �2 wks was chosen as a reasonable minimum 

duration of post-PD crizotinib tx. Results: As of 1 June 2011, 146 pts 

(A8081001, n�61, PROFILE 1005, n�85) had PD. PD was observed in 

new lesions only (1 organ site, n�62; �1 organ site, n�18), target � new 

lesions (� 1 organ site, n�55), clinical PD (n�9), and no site assessment 

(n�2). Most common new lesions in single organ sites were brain (brain 

MRI not mandatory; n�25), liver (n�20), bone (n�4), and kidney (n�1). 

Of the 146 pts, 78 (53%) received crizotinib post-PD for at least 2 wks, 

91% of whom had ECOG PS 0 or 1 at PD. In these 78 pts, PD was observed 

in new lesions only (1 organ site, n�39; �1 organ site, n�4), target � new 

lesions (� 1 organ site, n�29), and clinical PD (n�6); the most common 

sites for single organ PD were brain (n�20), liver (n�9), and other (n�10). 

Best response before PD (% CR/PR, SD, PD) was 62/27/12 in the 78 pts 

who received �2 weeks’ tx post-PD and 31/37/32 in the 68 pts who 

received �2 weeks’ tx post-PD or discontinued. Median duration of 

crizotinib tx post-PD (n�78) was 10 weeks (range 2–84). 20 pts with PD in 

brain only (concurrent local tx or radiation permitted) continue to receive 

crizotinib (range 3–82 weeks post-PD). Conclusions: Following initial 

crizotinib tx, PD most commonly occurred at a single organ site in ALK� 

NSCLC pts. The majority of pts receiving crizotinib post-PD had good PS, 

and tended to have single-site PD (most often the brain or liver), and a prior 

response on crizotinib. Given these observations, pts may be able to 

continue with crizotinib for a period of time following clinical or documented 

progression. 


A first-in-human phase I/II study of ALK inhibitor CH5424802 in patients 

with ALK-positive NSCLC. Presenting Author: Katsuyuki Kiura, Department 

of Respiratory Medicine, Okayama University Hospital, Okayama, Japan 

Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase 

constitutively activated in a subset of non-small cell lung cancer (NSCLC) 

following chromosomal gene translocation. CH5424802 was identified as 

a potent, selective, and oral ALK inhibitor with a unique chemical scaffold, 

showing preferential antitumor activity against NSCLC cells expressing 

EML4-ALK fusion in vitro and in vivo (Cancer Cell, 2011). Our results 

support the potential of CH5424802 as a new therapeutic opportunity for 

patients (pts) with ALK-positive NSCLC. Methods: Pts with ALK-positive 

NSCLC received CH5424802 twice daily orally until progressive disease or 

toxicity was observed. In the phase I portion, dose was escalated using an 

accelerated titration scheme. The primary objectives were to investigate the 

safety, tolerability and pharmacokinetic (PK) parameters under fasting 

conditions, and to determine the recommended dose (RD) for use in the 

phase II portion. The primary objectives of the phase II portion were to 

investigate the efficacy and safety at the RD. The phase I portion was 

amended to include an investigation under non-fasting conditions in 

addition to fasting conditions. Results: 15 pts (M/F: 9/6) were treated with 

CH5424802 under fasting conditions in 6 cohorts (20 mg bid to 300 mg 

bid) and 9 pts (M/F: 2/7) were treated under non-fasting conditions in 2 

cohorts (240 mg bid and 300 mg bid). Median age was 42.5 years. The 

highest dose level defined in the protocol (300 mg bid) did not reach the 

MTD. Thus, a DLT was not determined. Toxicities were mild to moderate. 

The most frequent toxicity was grade 1 myalgia. Grade 3 toxicity (cases) 

occurred as follows; hypophosphatemia (2), neutropenia (2), blood CPK 

increased (1) and hypermagnesemia (1). PK data from the fasting cohorts 

showed dose-dependent increases of Cmax and AUC. All pts at all dose 

levels achieved tumor regression. At dose levels 240 mg bid or more under 

fasting conditions, all 7 pts with measurable lesions achieved a partial 

response. So far, 11 pts have been on study treatment � 6 months. 

Conclusions: CH5424802 was well tolerated with promising efficacy in pts 

with ALK-positive NSCLC. The phase II portion is ongoing. 



MIMEB: A phase II trial to evaluate FDG-PET/FLT-PET and DCE-MRI for 

early prediction of efficacy in patients with advanced non-small cell lung 

cancer treated with erlotinib and bevacizumab. Presenting Author: Matthias 

Scheffler, Lung Cancer Group Cologne, Department I of Internal 

Medicine and Center for Integrated Oncology, University Hospital Cologne, 

Cologne, Germany 

Background: Since the introduction of targeted therapy into the treatment of 

NSCLC, molecular imaging tools gain in importance for assessment of 

pharmacodynamics, pharmacokinetics and prediction of therapeutic outcome. 

Tumor metabolism (by FDG-PET), proliferation (by FLT-PET), and 

vascularization (by DCE-MRI) can be noninvasively assessed to quantify the 

effects of targeted therapy on tumor biology. We set up a trial to evaluate 

the effects of combined erlotinib (E) and bevacizumab (B) treatment in 

patients with advanced non-squamous cell NSCLC and to identify prospectively 

patients who benefit from this combination. Methods: Patients with 

non-squamous NSCLC stage IV without prior systemic therapy received at 

least six weeks of combined E and B. FLT and FDG-PET scans as well as 

DCE-MRI-scans were performed at baseline, after 1 week of therapy and 

after 6 weeks of therapy. Standard uptake values of the PET scans and 

vascularization parameters of the DCE-MRI scans were analyzed and 

coregistrated. Tumor specimens were analysed within a network screening 

panel. The primary objective of this trial was to evaluate the accuracy of the 

imaging tools for early prediction of nonprogression and PFS and its 

association with molecular markers. Results: Of the 40 patients, all 

received FDG-PET analyses, whereas FLT-PET was performed in 38 

patients and DCE-MRI in 36 patients. Median OS was 13.4 months, 

median PFS was 5.9 months. Until January 2012, tissue specimens from 

25 patients have been genetically analysed. First results show that even 

patients with KRAS, PI3K and BRAF mutations profiting from the combination 

either by response or prolonged PFS could be identified by early 

imaging assessment. Conclusions: The efficacy of E �B in unselected 

patients with NSCLC was comparable with platinum-based chemotherapy. 

In order to identify imaging-based predictive biomarkers to identify the 

subpopulation of patients with pronounced benefit of this combination 

FDG-, FLT- PET and DCE–MRI were successfully implemented in the 

treatment plan. Results of the imaging analysis and the correlation with 

tissue-based biomarkers will be presented. 


Impact of disease progression (DP) date determination method on post 

progression survival (PPS) and DP metrics in advanced lung cancer. 

Presenting Author: Sumithra J. Mandrekar, Mayo Clinic and NCCTG, 

Rochester, MN 

Background: Overall survival (OS) can be partitioned into progression-free 

survival (PFS) and PPS. PPS helps to understand trial results, especially 

when PFS and OS data on trial treatment effects are discordant. At ASCO 

2011, we reported that the magnitude of difference in the PFS estimates 

using different DP date methods was large enough to alter trial conclusions. 

Here, we investigate the impact of the DP date method on 1) PPS 

estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). 

Methods: Individual patient (pt) data from 14 trials were pooled. DP date 

was determined using: reported progression date (RPD) (method 1, M1), 

one day after last progression-free (PF) scan (M2), and midpoint between 

last PF scan and RPD (M3). PPS was estimated using the method of 

Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 

4, and 6 months (mos) using Cox proportional hazards model was used to 

assess the impact of DP status (progression versus no-progression) on SOS 

(using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts 

reported DP. As expected, the PPS estimates were the lowest for RPD, 

highest for M2, and in-between for M3 (a direct consequence of the DP 

date method); with no difference by arm for the randomized trials. 

Regardless of the DP date method, patients who were progression-free had 

improved SOS (NSCLC: Hazard ratio, HR��0.33; p � 0.0001; SCLC: 

HR��0.48; p � 0.002) at each landmark time point, with comparable 

concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to 

discriminate patients with different SOS outcomes. Conclusions: While the 

DP date methods do not impact the predictive utility of the DP metrics, they 

significantly impact PPS estimates. The translation of a significant treatment 

effect on PFS to an effect on OS is influenced by PPS (longer PPS 

dilutes effect on OS). Standards for declaring DP date are thus critical to 

trial design and for trial go/no-go decisions. 

Progression date determination 

method 

NSCLC (10 trials; n�610) 

(median OS � 9.6) 

Median PFS, and PPS estimates (mos) 

SCLC (4 trials; n�114) 

(median OS � 8.7) 

PFS PPS PFS PPS 

Method 1 4.3 3.8 2.8 4.7 

Method 2 2.5 5.9 1.2 7.1 

Method 3 3.4 4.7 2.0 5.6 


505s 


Meta-analysis of progression-free survival as a predictor of overall survival 

in locally advanced or metastatic non-small cell lung cancer trials. 

Presenting Author: Evadne Jane Turner, Boehringer Ingelheim Pty Ltd, 

Sydney, Australia 

Background: Access to new oncology treatments for non-small-cell lung 

cancer (NSCLC) could be expedited if progression free survival (PFS) was 

accepted by payers as a valid endpoint predictive for overall survival (OS). 

We investigated the relationship between PFS and OS in advanced NSCLC, 

which has previously been limited by available data. Methods: A systematic 

review of the published literature was conducted (1988 to August 2011; 

Medline/Embase/Cochrane). Identified studies were assessed against the 

following criteria for inclusion in the analysis: randomised design; NSCLC; 

advanced disease (Stage IIIb or IV); pharmacological treatment in 2 or more 

groups; reported outcomes included median OS and median PFS. For each 

pair of treatment groups compared, the median OS difference and the 

median PFS difference were calculated. The data were analysed with 

locally weighted least squares regression (LOWESS) to validate the linear 

relationship. Unweighted and weighted linear regression was used to test 

the significance of the relationship between OS difference and PFS 

difference. Results: A total of 124 clinical trials, with 40,568 patients, 

were included in the analysis. The studies ranged from middle aged cohorts 

to the elderly. Median performance status (ECOG/WHO) was 1. 70% of 

studies were first line and therapy type was predominantly chemotherapy 

(57%). 19 studies (15%) reported use of crossover or rescue therapy. 

Weighted linear regression demonstrated a highly significant linear relationship 

between OS difference and PFS difference (Table). The results 

suggest that a 1 month difference in PFS is associated with approximately 

1.3 months difference in OS. Conclusions: Analysis of NSCLC trials showed 

the treatment effect on PFS was predictive of the treatment effect on OS. 

With increased use of multiple lines of treatment and crossover/rescue 

therapy in new NSCLC trials OS differences are frequently confounded, 

making PFS an important outcome for health care decision making. 

Statistic 

Parameter Estimate SE 95% CI t-statistic p value 

Intercept -0.260 0.209 (-0.674, 0.154) -1.242 0.214 

Slope 1.317 0.160 (1.000, 1.634) 8.226 �0.001 

R-squared 36.6% 


Metastatic NSCLC: Treatment patterns, outcomes, and costs of newer 

agents. Presenting Author: Adrian G. Sacher, Division of Medical Oncology 

and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, 

ON, Canada 

Background: New therapies for metastatic NSCLC have improved survival in 

clinical trials. The increased cost of these agents has led to variable drug 

funding and treatment across jurisdictions. Here we review patterns, 

real-world outcomes and costs of metastatic NSCLC treatment in the 

province of Ontario. Methods: All patients diagnosed with metastatic 

NSCLC from 2005-2009 were identified from the Ontario Cancer Registry 

with demographic, histologic and mortality data. Treatment records from 

the Ontario New Drug Funding Program and centralized treatment database 

were linked. Statistical analysis involved Wilcoxon rank sum, Kruskal- 

Wallis, Cochran-Armitage trend and likelihood ratio tests where appropriate. 

Results: 8113 metastatic NSCLC patients were identified. The median 

age was 68; 39% had adenocarcinoma, 14% squamous carcinoma and 

43% histology not otherwise specified. Most were treated in regional cancer 

centers (92%). The majority (76%) did not receive systemic therapy; 23% 

received first-line chemotherapy, most commonly platinum doublets. More 

patients received systemic therapy over time (19% in 2005 v 26% in 

2009, p �0.0001). Older patients (p �0.0001) and those with squamous 

histology (p �0.0001) were less likely to receive systemic therapy. Center 

of diagnosis did not affect the likelihood of treatment (p�0.46). The 

median time from diagnosis to death was significantly greater among 

patients selected to receive chemotherapy (9.3 v 3.2 months, p �0.0001), 

and with cisplatin/gemcitabine compared to other doublets (10.7 v 8.2 

months, p�0.004). 31% of treated patients received second-line chemotherapy, 

predominantly with docetaxel (52%) or pemetrexed (41%). 

Pemetrexed use increased significantly over time (8% in 2005 v 71% in 

2009, p�0.0001), as did the mean drug cost of second-line therapy 

($5939/patient in 2005 v $10,057 in 2009). A longer median survival was 

also seen with pemetrexed in adenocarcinoma (17.9 v 15.2 months for 

docetaxel, p �0.02). Conclusions: Most metastatic NSCLC patients do not 

undergo systemic treatment. First- and second-line treatment outcomes in 

this population-based study were similar to clinical trials, confirming better 

outcomes with new agents at greater cost. 




Does change in health-related quality of life (HRQoL) score predict 

survival? Analysis of a lung cancer RCT. Presenting Author: Divine Ewane 

Ediebah, European Organisation for Research and Treatment of Cancer 

Headquarters, Brussels, Belgium 

Background: Over 60 cancer clinical trials have shown that baseline 

health-related quality of life (HRQoL) scores are prognostic for patient 

survival. Few studies have investigated the added value of change in 

HRQoL scores. Our aim was to investigate if change in HRQoL scores from 

baseline over time is also associated with survival. Methods: We analyzed 

data from an EORTC 3-arm randomized clinical trial (RCT) in advanced 

non-small-cell lung cancer (NSCLC) patients, comparing 

gemcitabine�cisplatin, versus paclitaxel�gemcitabine, versus standard 

arm paclitaxel�cisplatin. HRQoL was measured in 394 patients using the 

EORTC QLQ-C30 at baseline and after each chemotherapy cycle. The 

prognostic significance of sex, age and WHO performance status (0-1 vs. 2) 

and the 15 QLQ-C30 subscales were assessed with Cox proportional hazard 

models stratified for treatment (level of significance 0.05). Changes in 

HRQoL scores from baseline to each chemotherapy cycle assessment were 

categorized as “improved”, “stable” and “worsened” using a threshold of 

10 points difference. Due to expected attrition, the analysis was limited to 

changes from baseline up to cycle 3. Results: There were 248 patients in 

cycle 1, 212 in cycle 2 and 196 in cycle 3. We performed analyses 

separately using data at cycle 1, cycle 2, and cycle 3. In all analyses, 

HRQoL in various subscales and socio-demographic and clinical variables 

(physical functioning (hazard ratio [HR] 0.91, 95% CI 0.85-0.98; 

p�0.0103), pain (1.11, 1.05-1.17; p� 0.0004), age (0.98, 0.97-1.00, 

p�0.0413) and WHO performance status (1.77, 1.09-2.89; p�0.0218) 

at cycle 1; pain (1.11, 1.03-1.20; p�0.0016), age (0.98, 0.96-1.00; 

p�0.0217) and sex (0.63, 0.42-0.95; p�0.0081) at cycle 2; and role 

functioning (0.93, 0.88-1.00; p�0.0128) and age (0.98, 0.96-1.00; 

p�0.0081) at cycle 3) predicted survival; however, change in HRQoL was 

only an independent predictor for improvement at cycle 1. Conclusions: Our 

findings suggest that change from baseline over time in HRQoL, as 

measured on subscales of the EORTC QLQ-C30, contains added prognostic 

value for survival independent of baseline HRQoL scores. Further work is 

needed to assess the robustness and sensitivity of these findings. 


Pilot trial of molecular profiling and targeted therapies in advanced thoracic 

malignancies: Non-small cell lung cancer, small cell lung cancer and 

thymic malignancies (CUSTOM). Presenting Author: Ariel Lopez-Chavez, 


Background: For decades, clinical trial design strategies have relied upon 

the broad classification of tumors into tumor site and histopathology. 

Several lines of evidence have shown that a molecular approach to patient 

selection may be better in its capacity to improve patient outcomes. 

CUSTOM is an innovative clinical trial that allows for the parallel evaluation 

of multiple targeted therapies in molecularly selected patients with 

multiple cancer histological subtypes and the prospective evaluation of 

multiple molecular biomarkers. Methods: All patients with advanced lung 

cancer and thymic malignancies and a good performance status are eligible 

independently of previous lines of treatment. The trial begins with tumor 

biopsy and molecular profiling using a multi-platform approach to identify 

oncogenic alterations in more than 34 genes for treatment allocation (12 

genes) and exploratory purposes. Depending upon the specific biomarker 

identified, patients are then triaged into 5 experimental arms. Erlotinib for 

sensitizing EGFR mutations; AZD6244 for KRAS, NRAS, HRAS and BRAF 

mutations; MK2206 for PIK3CA, AKT and PTEN mutations and PIK3CA 

amplification; Lapatinib for ERBB2 mutations or amplification; Sunitnib 

for KIT mutations and PDGFRA mutations and amplification. Patients not 

eligible for the experimental treatment arms are enrolled into a standard 

treatment arm. Upon disease progression patients are eligible for repeat 

biopsy and molecular profiling in order to identify molecular changes and 

mechanisms of resistance. All patients are followed until death. The 

primary endpoint is response rate and secondary endpoints include 

progression-free survival, duration of response and overall survival. With 

three disease types and five experimental drugs, there are 15 possible 

treatment arms which will be under active consideration. For each of these, 

the study will be conducted as an optimal two-stage phase II trial in order to 

rule out an unacceptably low 10% clinical response rate in favor of a 

modestly high response rate of 40%. As of January 11, 2012, two hundred 

and sixteen patients have been enrolled. 


Three-year survival in stage IV non-small cell lung cancer (NSCLC): The 

importance of metastatic distribution. Presenting Author: Daniel D. Karp, 


Background: Although long term survival (LTS) is an important goal of lung 

cancer treatment, those with metastatic disease at presentation have a 

median of only 8-9 months in most series with a small “tail” on the survival 

curve. We analyzed a large cohort of Stage IV pts by performance status 

(PS), smoking history, number and sites of disease to assess factors 

associated with 36 month survival. Methods: From 2004–2008, 526 newly 

diagnosed untreated pts with Stage IV NSCLC received initial treatment at 

our institution. Sites of disease were analyzed according to lung, brain, 

bone, liver, adrenal, skin, malignant effusion, lymphangitic, bulky pleural 

disease, and “other”. No patient had definitive surgery. Results: Overall, 

58/526 pts (10.8%) survived 36 months or more. 453 pts died within 36 

months. 15 pts alive with follow-up time less than 36 months were removed 

from further analysis. Of those, 38/58 (65.5%) had only 1 metastatic site 

(p�0.001). 14 (24.1%) had 2 sites, only 6 (10.3%) had 3 or more sites. 

Those 19 pts with lung to lung spread were the most common (32.8%) with 

LTS – reflecting the M1 status in the new International Staging System. 

Only 1 LTS pt had liver mets at diagnosis – a solitary lesion treated with 

radiofrequency ablation. 20 pts had PS�0 (0.019) and 29 had PS�1 

(NS). PS�2 pts made up 6. 2 pts had PS�3 initially. 1 unknown. Only 

6/58 (10.3%) were current smokers, 23 (39.7%) were never-smokers 

(p�0.001). Adenocarcinoma made up 65.5%. Conclusions: Progress in 

lung cancer survival has been slow. Very few LTS pts have more than 1 site 

of metastatic disease at presentation, virtually none with liver disease 

(p�0.02). Number of metastatic sites and presence of liver metastases 

appear to be important stratification variables for lung cancer clinical trials. 


TIME: A phase IIb/III randomized, double-blind, placebo-controlled study 

comparing first-line therapy with or without TG4010 immunotherapy 

product in patients with stage IV non-small cell lung cancer (NSCLC). 

Presenting Author: Elisabeth A. Quoix, Strasbourg University Hospital, 

Strasbourg, France 

Background: TG4010 is an immunotherapy product based on a poxvirus 

(MVA) coding for the MUC1 tumor-associated antigen and interleukin-2. A 

previous study, TG4010.09, which evaluated the combination of first-line 

chemotherapy with and without TG4010 in advanced NSCLC, achieved its 

primary endpoint based on 6-month progression-free survival (PFS) and 

showed that the pre-treatment level of activated Natural Killer (aNK) cells 

may be a potential predictive biomarker for TG4010 efficacy (E. Quoix et 

al., Lancet Oncol. 2011;12:1125-33). Methods: TIME is a double-blind 

phase IIb/III study comparing the combination of first-line therapy with 

TG4010 or placebo in stage IV NSCLC patients, Performance Status (PS) 0 

or 1 with a MUC1 expressing tumor by immunohistochemistry. The Phase 

IIb part of the study aims at prospectively validating aNK level as a 

predictive biomarker with PFS as a primary endpoint, by comparing the two 

treatment arms in two subgroups defined according to the level of aNK cells 

at baseline (normal or high). Bayesian criteria, derived from the TG4010.09 

study results, will be used to confirm that, with a large probability, the true 

hazard ratio is �1 in patients with normal level of aNK cells and �1 in 

patients with high level of aNK cells. The Phase III part of the study will 

then compare, by using a frequentist approach, the two treatment arms 

with overall survival as a primary endpoint in the patient population 

confirmed to be of interest in the Phase IIb part. The phase III part is 

powered to detect a 27% reduction in the hazard rate of death. Phase IIb 

and III parts of the study will enroll respectively 206 and 800 patients. A 

dynamic minimization procedure will be applied at randomization for 

histology, prescription of bevacizumab, type of chemotherapy, PS and 

center. If qualifying for, patients will receive maintenance therapy after 

chemotherapy according to labeling. The study TIME is open to recruitment 

and referenced in ClinicalTrials.gov with the identifier NCT01383148. 



CA184-104: Randomized, multicenter, double-blind, phase III trial comparing 

the efficacy of ipilimumab (Ipi) with paclitaxel/carboplatin (PC) 

versus placebo with PC in patients (pts) with stage IV/recurrent non-small 

cell lung cancer (NSCLC) of squamous histology. Presenting Author: Martin 

Reck, Hospital Großhansdorf, Großhansdorf, Germany 

Background: Years of research in advanced NSCLC have not improved 

outcomes for the squamous subtype beyond those of standard platinum 

doublets. Evidence of responses to immune therapies in NSCLC of 

squamous cell histology supports investigation in this subtype. Ipi, a fully 

human monoclonal antibody which blocks CTLA-4, augments antitumor 

immune responses. Ipi improved overall survival (OS) in advanced melanoma, 

with side effects managed using product-specific treatment guidelines; 

immune-related response criteria (irRC) were derived from WHO 

criteria to better capture response patterns observed with Ipi. A randomized 

Phase 2 study of Ipi/PC in Stage IV NSCLC pts showed significant 

improvement in progression-free survival (PFS), as measured by mWHO or 

irRC, with a trend toward improved OS, over chemotherapy alone in pts 

receiving phased Ipi/PC (Ipi started after 2 cycles of PC). Phased Ipi/PC 

appeared to show efficacy in tumors of squamous histology. Addition of Ipi 

did not exacerbate PC toxicity, and immune-related adverse events were 

managed using protocol-specific guidelines. A Phase 3 trial (ClinicalTrials- 

.gov identifier NCT01285609) is examining whether phased Ipi/PC will 

prolong OS in chemotherapy-naïve pts with squamous NSCLC. Methods: 

Stage IV/recurrent squamous NSCLC with ECOG 0-1 will be included; pts 

with CNS metastases or history of autoimmune disease will be excluded. 

Pts are randomized to receive 2 cycles of PC (175 mg/m2 and AUC�6, 

respectively; IV), followed by 4 cycles of study drug (Ipi in Arm A, placebo in 

Arm B; IV) with 4 additional cycles of PC (total 6 cycles). Pts without 

progressive disease (PD) after induction receive maintenance therapy with 

blinded study drug Q12W until PD per mWHO. The study will randomize 

920 pts 1:1 between arms. The primary endpoint of this study is OS; 

secondary endpoints include OS among pts who receive blinded therapy, 

PFS and best overall response rate. 

TPS7613^ General Poster Session (Board #53G), Sat, 1:15 PM-5:15 PM 

The GALAXY Trial (NCT01348126): A randomized IIB/III study of 

ganetespib (STA-9090) in combination with docetaxel versus docetaxel 

alone in subjects with stage IIIB or IV NSCLC. Presenting Author: Glenwood 

D. Goss, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada 

Background: Hsp90 is a molecular chaperone required for proper folding 

and activation of many cancer-promoting proteins and is recognized as a 

key facilitator of cancer cell growth and survival. In pre-clinical models, 

Hsp90 inhibition causes degradation of multiple client proteins and leads 

to cancer cell death. Ganetespib is a resorcinolic Hsp90 inhibitor that has 

shown potent anti-tumor activity in patients with lung, breast, and other 

cancers that had progressed on standard treatment agents. Moreover, 

combination of ganetespib with docetaxel results in synergistic antiproliferative 

effects in several human non-small cell lung carcinoma (NSCLC) 

tumor xenografts. Ganetespib is well tolerated and is devoid of severe liver 

or common ocular toxicities that have been observed with some other 

Hsp90 inhibitors. Diarrhea is the most common adverse event and is 

manageable with appropriate supportive care. In a recent report, ganetespib 

administered at 200 mg/m2 weekly showed activity in pretreated patients 

with advanced NSCLC patients with ELM4-ALK translocation and KRAS 

mutations. Methods: Stage 1 (240 subjects): randomized, international 

open-label Phase 2B study in subjects that progressed on or after one prior 

systemic therapy for stage IIIB or IV NSCLC: patients are prospectively 

stratified for ECOG performance status, histology, total LDH, interval since 

diagnosis, and smoking status. Co-primary endpoints are PFS in the ITT 

population, and PFS in patients with KRAS mutations. Main secondary 

endpoints include ORR, disease control rate, OS and clinical activity in 

different molecular subtypes, including BRAF, HER2, EGFR, EML4-ALK. 

Patients on the control arm are treated with docetaxel 75 mg/m2 on day 1 of 

a three-week cycle. In the combination arm, ganetespib 150 mg/m2 is 

given on day 1 (with docetaxel) and day 15 of a three-week cycle. At the 

time of submission 90 subjects had been enrolled in Stage 1. 


507s 


AvaALL: Open-label randomized phase IIIb trial evaluating the efficacy and 

safety of standard of care with or without continuous bevacizumab (BV) 

treatment beyond disease progression in patients (pts) with advanced 

nonsquamous non-small cell lung cancer (NSCLC) after first-line (1L) 

treatment with BV plus platinum-doublet chemotherapy (CT). Presenting 

Author: Cesare Gridelli, SG Moscati Hospital, Avellino, Italy 

Background: Pts with NSCLC have a poor prognosis upon progression 

following 1L CT. Although the disease may have progressed on 1L CT, it is 

likely still dependent on VEGF-mediated pathways. Thus, persistent VEGF 

suppression along with second- and third-line cytotoxic regimens may yield 

clinical benefit. Analyses have associated this strategy with improved 

survival in NSCLC (Nadler et al, Oncologist 2011) and mCRC (Grothey et al 

JCO 2008). Methods: AvaALL (MO22097; NCT01351415), a multicenter 

(144 centers, 20 countries) open-label randomized (1:1) 2-arm phase IIIb 

study, recruits pts with advanced non-squamous NSCLC that has progressed 

after 1L treatment with BV plus a platinum-doublet and at least 2 

cycles of BV maintenance monotherapy. Pts in the experimental arm 

receive BV at the same dose from induction (7.5 or 15 mg/kg IV on D1 of 

every 21-day cycle) continuously along subsequent lines, plus investigator’s 

choice of second-line agent (limited to pemetrexed, docetaxel, or 

erlotinib) and subsequent lines of treatment. Pts in the control arm receive 

investigator’s choice of agent alone in second and subsequent lines of 

treatment, but no further BV treatment. Stratifications include nature of 

second-line standard treatment, number of cycles of BV maintenance (�6 

vs. �6) and smoking status. The primary endpoint is overall survival (OS). 

Secondary endpoints include 6-, 12-, and 18-month OS rates, progressionfree 

survival, time to progression at second and third progressive disease 

(PD), response rate, disease control rate, duration of response at second 

and third PD, and safety of BV across multiple lines of treatment. 

Exploratory objectives include quality of life assessment through multiple 

treatment lines, and biomarker analysis. Assuming a median OS beyond PD 

of 7.9 months in the control group and 10.1 months in the treatment arm 

(HR 0.78), 528 events are required to achieve 80% power for the log-rank 

test at a 2-sided significance level of 5%. Enrollment began in June 2011. 


ASPIRATION: Phase II study of continued erlotinib beyond RECIST 

progression in Asian patients (pts) with epidermal growth factor receptor 

(EGFR) mutation-positive non-small cell lung cancer (NSCLC). Presenting 

Author: Keunchil Park, Samsung Medical Center, Seoul, South Korea 

Background: First-line erlotinib (an EGFR tyrosine-kinase inhibitor) significantly 

increased progression-free survival (PFS) vs chemotherapy in phase 

III trials of pts with EGFR mutation-positive NSCLC. Discontinuation of 

erlotinib on RECIST disease progression (PD) may lead to rapid disease 

flare-up; continued erlotinib beyond RECIST PD may extend clinical benefit 

by slowing progression of this life-threatening disease. We describe 

ASPIRATION, a large, Asian, multicenter, single-arm, open-label, phase II 

trial (NCT01310036), which will increase understanding of first-line 

erlotinib and erlotinib continuation beyond RECIST PD in pts with 

EGFR-mutated NSCLC. Methods: Pts (n�204) �18 yrs with stage IV/ 

recurrent NSCLC, �1 measurable lesion (�10mm), ECOG performance 

status (PS) 0-2 and positive EGFR mutation status established by local 

pathology laboratory (that underwent voluntarily QA/QC) are eligible. All pts 

receive erlotinib 150mg/day. Tumor response is evaluated using RECIST 

(v1.1). The primary endpoint is PFS. At investigator’s discretion, pts may 

continue on erlotinib beyond RECIST PD, e.g. if they have slow PD (�6 

months of partial response/stable disease), asymptomatic minimal PD, or 

new brain metastasis controlled locally. Pts should not continue erlotinib if 

they have extracranial PD with symptoms; rapid PD and/or worsening of PS; 

or life-threatening complications. Pts continuing erlotinib who present with 

second RECIST PD will discontinue. Secondary endpoints include objective 

response rate, disease control rate, overall survival, and safety. For the 

exploratory biomarker study, pre-treatment tumor tissue blocks are collected; 

remaining tissue (after EGFR mutation testing for eligibility) will be 

analyzed centrally to study the association of biomarkers and clinical 

outcomes. Pre-treatment and post-treatment plasma and serum samples 

will be obtained at various time points for biomarker assays, including 

EGFR mutations and other candidate NSCLC biomarkers. Recruitment 

began in Apr 2011; the estimated final data collection for the primary 

endpoint is Dec 2014. 




ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced 

(adv) non-small cell lung cancer (NSCLC)—A randomized double-blind 

phase III study. Presenting Author: Michael Boyer, Sydney Cancer Centre, 

Camperdown, Australia 

Background: D is a highly selective irreversible small molecule inhibitor of 

all catalytically active members of the HER (human epidermal growth 

factor receptor) family of tyrosine kinases. In a randomized phase II trial in 

patients (pts) who had received 1–2 prior systemic therapy regimens for adv 

NSCLC, D demonstrated significantly longer progression-free survival (PFS) 

vs. E in the overall population (12.4 vs. 8.3 weeks; HR�0.66, P�0.012), 

with benefit consistent across several clinical and molecular subgroups. 

Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks 

for D and E, respectively (HR�0.55, P�0.006). Methods: Based on phase 

II data, a randomized, double-blinded phase III clinical trial (ARCHER; 

NCT01360554) was designed to compare the efficacy of D with E in two 

co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv 

NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic 

pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 

prior chemotherapy regimens, ECOG PS 0–2, and tissue available for 

molecular analysis will be randomized to receive D 45 mg or E 150 mg 

orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been 

enrolled. The primary endpoint is PFS. Secondary endpoints include overall 

survival, objective response rate, duration of response, safety and tolerability, 

and pt-reported outcomes of health-related quality of life and disease-/ 

treatment-related symptoms. Study design provides 90% and 80% power 

to detect �33% and �45% improvement in PFS in all pts receiving D vs. 

E, and in pts with KRAS W T NSCLC, respectively, and HR �0.75 and 

�0.69 using a 1-sided stratified log-rank test at a significance level of 

0.015 and 0.01, respectively. The final primary analysis stratified log-rank 

test will include ECOG PS, KRAS mutation status and EGFR mutation 

status as stratification factors. The sample sizes above will also allow the 

assessment of OS in the co-primary populations with adequate power. 

Post-hoc analyses will be performed to explore EGFR, HER family, and 

KRAS mutation status, as well as other tumor-derived biomarkers collected 

from all pts in this trial. 


Prophylactic cranial irradiation after reaching complete response, partial 

response, or stable disease in non-small cell lung cancer patients treated 

with epidermal growth factor receptor tyrosine kinase inhibitors (ProACT). 

Presenting Author: Amanda Tufman, Ludwig Maximilians University Munich, 

Munich, Germany 

Background: Patients with non-small cell lung cancer (NSCLC) who respond 

to treatment with epidermal growth factor receptor tyrosine kinase inhibitors 

(EGFR TKIs) seem to be at increased risk of central nervous system 

relapse, and may benefit from prophylactic cranial irradiation (PCI) more 

than other NSCLC patients. Methods: This study investigates the safety and 

efficacy of combining PCI with EGFR TKIs in stage IV NSCLC. Patients with 

stage IV NSCLC, no evidence of brain metastases, and an indication for first 

or later line therapy with an EGFR TKI will be enrolled. Those with complete 

response (CR), partial response (PR), or stable disease (SD) following 6 

weeks of therapy and no evidence of brain metastases on MRI will be 

treated with PCI. Neurocognitive function, depression indices, quality of 

life, symptoms, and ability to function independantly will be assessed at 

baseline, before PCI, and at 6 week and then 3 month intervals following 

PCI. MRI will be repeated 6 weeks following PCI and at 3 month intervals, 

and serum markers of blood brain barrier permeability (neuron-specific 

enolase (NSE), protein S100 beta) will be assessed at all visits. Safety data 

will be formally reviewed after the first 10 patients. The primary endpoint 

for efficacy is overall survival. Secondary endpoints include progression 

free survival, site of progression, quality of life and neurological disability. 

Planed subgroup analyses based on mutation status, line of treatment with 

TKIs, comorbidity, precise histology and molecular biology will be carried 

out. 


The MetLUNG study: A randomized, double-blind, phase III study of 

onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in 

patients with advanced, MET-positive non-small cell lung cancer (NSCLC). 

Presenting Author: David R. Spigel, Sarah Cannon Research Institute/ 

Tennessee Oncology PLLC, Nashville, TN 

Background: Increased Met signaling is associated with poor prognosis in 

NSCLC and can result in acquired resistance to epidermal growth factor 

receptor (EGFR)-targeted drugs in EGFR-mutant lung tumors. Onartuzumab 

(MetMAb) is a humanized monovalent monoclonal antibody that 

binds to Met with high specificity, preventing HGF ligand binding and 

blocking downstream signaling. Onartuzumab has shown anticancer activity 

in preclinical studies (Merchant et al. AACR 2008:Abstr. 1336) and in a 

phase I study of patients with advanced solid tumors (Moss et al. Ann Oncol 

2010;21(Suppl. 8):Abstr. 504P). In a phase II study, patients with 

Met-positive tumors (�50% of tumor cells stain 2� or 3� intensity by IHC) 

(Met Dx�) who received onartuzumab � erlotinib had nearly twofold 

reduction in the risk of disease progression and threefold reduction in the 

risk of death compared with erlotinib alone (Spigel et al. J Clin Oncol 

2011;29(Suppl.):Abstr. 7505). An increased incidence of peripheral 

edema was observed in patients treated with onartuzumab. Methods: This is 

a randomized, phase III, multicenter, double-blind, placebo-controlled 

study. Adults with Met Dx� tumors who failed at least 1 but no more than 2 

prior lines of platinum-based chemotherapy for advanced NSCLC are 

eligible. Around 480 patients will receive (1:1) erlotinib (150 mg PO daily) 

� placebo or onartuzumab (15 mg/kg IV Q3W) until disease progression, 

unacceptable toxicity, patient/physician decision to discontinue, or death. 

Patients are stratified for Met expression (2� vs 3�), prior lines of therapy 

(1 vs 2), histology (squamous vs nonsquamous) and EGFR-activating 

mutation status (yes vs no). The primary endpoint is OS. Secondary 

endpoints include PFS, response rates, safety, patient-reported outcomes, 

and PK. An IDMC will monitor safety every 6 months after the 1st patient is 

enrolled and evaluate 1 interim analysis when ~67% of the total OS events 

have occurred. This study is open for accrual; further details can be found 

on ClinicalTrials.gov (NCT01456325). 


Weekly nab-paclitaxel in combination with carboplatin as first-line therapy 

in patients (pts) with advanced non-small cell lung cancer (NSCLC): 

Analysis of patient-reported neuropathy and taxane-associated symptoms. 

Presenting Author: Vera Hirsh, McGill University – Royal Victoria Hospital, 

Montreal, QC, Canada 

Background: Neuropathy and its associated symptoms are dose-limiting 

toxicities of taxane-based regimens. Measuring disease symptoms has 

utility for maintaining a balance between the benefits and costs of 

treatment. In a phase III trial nab-paclitaxel (nab-P, 130 nm albuminbound 

paclitaxel particles) � carboplatin (C) vs solvent-based paclitaxel 

(sb-P) � C significantly improved the primary endpoint of overall response 

rate (ORR) (25% vs 33%, P � 0.005), with a 1-month improvement in 

median overall survival (OS; P � NS), and an improved tolerability profile in 

pts with advanced NSCLC. Here we report on patient-assessed neuropathy 

and taxane-associated symptoms, important factors in a palliative patient 

setting. Methods: Pts with untreated stage IIIB/IV NSCLC were randomized 

1:1 to C AUC 6 day 1 and either nab-P 100 mg/m2 on days 1, 8, 15 (n � 

521) or sb-P 200 mg/m2 day1(n� 531) q 21 days. Treatment was 

continued until disease progression. Safety was assessed per the Common 

Terminology Criteria for Adverse Events (CTCAE) v3.0. The mean change 

from baseline to day 1 of each cycle for the neuropathy, pain, and hearing 

subscales of Functional Assessment of Cancer Therapy (FACT)-Taxane v 

4.0 were assessed. Results: 1031 (98%) pts completed FACT-Taxane at 

baseline, and 987 (94%) during follow-up or at completion of treatment. 

Baseline scores for neuropathy and pain were well balanced. Significant 

treatment effects favoring nab-P/C were noted for patient-reported neuropathy 

(P � 0.001), neuropathic pain hands/feet (P � 0.001), and hearing 

loss (P � 0.002). Physician-assessed rates of neuropathy were significantly 

lower in the nab-P/C arm vs the sb-P/C arm: 47% vs 63%, P � 0.001, all 

grades; 3% vs 12%, P � 0.001, grade 3/4, respectively. More pts treated 

with nab-P/C vs sb-P/C had no neuropathy (53% vs 47%, P � 0.001). 

Conclusions: nab-P/C was associated with statistically and clinically 

significant reductions in patient-reported neuropathy, neuropathic pain in 

the hands and feet, and hearing loss compared with sb-P/C. Patientreported 

outcomes for neuropathy were consistent with physician assessment. 



A multicenter randomized phase III trial of customized chemotherapy 

versus standard of care for first-line treatment of elderly patients with 

advanced non-small cell lung cancer (EPIC). Presenting Author: George R. 

Simon, Hollings Cancer Center, Medical University of South Carolina, 

Charleston, SC 

Background: Personalizing therapy based on an individual patient’s molecular 

profile is a potentially promising approach to optimize efficacy with the 

available agents. Optimizing efficacy in the elderly is particularly relevant 

owing to their increased propensity to suffer therapy-induced toxicity. In 

this proposal we will attempt to demonstrate optimization of therapy in 

good performance EGFR mutation negative elderly patients by taking in to 

consideration the histology of the tumor, the ERCC1 (marker of platinum 

resistance), RRM1 (for gemcitabine resistance) and TS (for pemetrexed 

resistance) status. Methods: Untreated advanced stage NSCLC patients age 

�70 years with measurable disease will be enrolled. Patients will be 

randomized in a 2:1 randomization to experimental arm (A) or standard arm 

(B). In arm A, treatment with single or dual-agent chemotherapy will be 

selected based on histology, ERCC1 (E), RRM1(R) and TS (T) expression at 

the RNA level. The cut off for high (�, therefore resistant) or low (-, 

therefore sensitive) expression have been previously defined. Patients with 

squamousNSCLC who are E-R� will be treated with single agent carboplatin, 

E�R- with gemcitabine, E-R- with carboplatin and gemcitabine and 

E�R� with docetaxel or vinorelbine. In non-squamous NSCLC patients 

E-T� will be treated with carboplatin, E�T- withpemetrexed, E-T- with 

carboplatin and pemetrexed, E�T�R- with gemcitabine and E�T�R� 

with docetaxel or vinorelbine. In arm B treatment with single or dual-agent 

chemotherapy will be at the discretion of the care provider, i.e., standard of 

care. The primary endpoint of the trial is overall survival (OS). The 

secondary endpoint is progression-free survival (PFS). The tertiary endpoint 

is disease response. Treatment will continue to maximum of 6 cycles if 

tolerated or until disease progression. A sample size of 453 patients will 

give us 90% power to detect a three-month improvement in median survival 

(8 to 11 months; corresponding to a HR of 0.73) with the log rank test at a 

significance level of 5%(1-sided) allowing for a 10% failure rate in gene 

analyses. 



509s

510s Lymphoma and Plasma Cell Disorders 


CALGB 50401: A randomized trial of lenalidomide alone versus lenalidomide 

plus rituximab in patients with recurrent follicular lymphoma. 

Presenting Author: John Leonard, Weill Cornell Medical College, New York, 

NY 

Background: Lenalidomide (L) and rituximab (R) are active as single agents 

in follicular (FL) and other B-cell lymphomas, although combination 

strategies have not been previously assessed in a randomized fashion. 

Methods: CALGB 50401 is a randomized phase II study, initially designed 

to evaluate 3 regimens: R alone (375 mg/m2 weekly x 4), L alone (15 mg 

cycle 1, then escalated to 20 mg cycles 2-12, administered days 1-21 q 28 

days x 12 cycles) or the combination of L� R (other 2 arms combined). The 

R alone arm was discontinued due to slow accrual with 3 enrolled subjects. 

Eligibility included recurrent FL, prior therapy with rituximab alone or in 

combination, and TTP of � 6 months from last rituximab dose. Prophylactic 

ASA or LMW heparin was recommended for patients at high risk for 

thrombosis. Results: Of 94 pts registered to L or LR, 89 (45 L and 44 LR) 

received at least one dose and had adequate data for analysis. Baseline 

characteristics include median age 63 (range 34-85) and 60% with 

intermediate- or high-risk FLIPI. Grade 3-4 adverse events (AE) were most 

commonly neutropenia (16% L,19% LR), fatigue (9% L, 14% LR) and 

thrombosis (16% - 7 pts L, 4% - 2 pts LR, p�0.158), and overall were seen 

in 49% (L) and 52% (LR) with 9% grade 4 in each arm. The full regimen 

was completed in 33% (L) and 59% (LR) of patients, with the difference 

due to more progressions or non-responders in the L group. In both arms 

about 19% of subjects discontinued therapy early due to AEs and dose 

intensity was over 80%. Objective response rates are L - 49% (13% CR) 

and LR - 75% (32% CR). With a median follow-up of 1.5 years (range 0.1- 

3.6 years), median EFS is 1.2 years (L) and 2.0 years (LR), p�0.0063, 

log-rank test. Conclusions: Lenalidomide � rituximab is more active than 

lenalidomide alone in patients with recurrent FL with similar toxicity. A 

trend toward lower thrombosis risk with LR may relate to greater anti-tumor 

efficacy. The LR regimen warrants further study in FL including as a 

backbone for addition of novel agents in relapsed and frontline settings. 


ABVD (8 cycles) versus BEACOPP (4 escalated cycles �> 4 baseline) in 

stage III-IV high-risk Hodgkin lymphoma (HL): First results of EORTC 

20012 Intergroup randomized phase III clinical trial. Presenting Author: 

Patrice P. Carde, Institute Gustave Roussy, Villejuif, France 

Background: Escalated BEACOPP and derivatives achieved superior time to 

treatment failure (FFTF) over COPP/ABVD, resulting in higher overall 

survival (OS) for advanced HL. However, later clinical trials have failed to 

confirm OS superiority over ABVD. Methods: Eligibility criteria: clinical 

stage III/IV HL, International prognostic score (IPS) � 3, age�60. We 

compared ABVD (8 cycles) vs. BEACOPP (escalated 4 cycles � baseline 4), 

without irradiation. Randomization was stratified for institution and IPS. 

Primary endpoint was EFS, defined as treatment discontinuation, no 

complete response (CR) after 8 cycles, progression, relapse or death. 

Additional endpoints were CR, progression free survival (PFS), OS, quality 

of life and secondary malignancies. Outcomes were reviewed by study 

coordinators to ensure consistency across pts. Results: From 2002-2010, 

549 pts were randomized (ABVD 275, BEACOPP 274): stage IV 74%, PS 

0, 1, 2: 34, 48 and 17%, B-symptoms 81%, median age 35.2y, males 

75%. IPS was 4 or higher for 59% of pts. Histology reviewed no HL in 4 

cases. CR was 83% in both arms. With a median follow-up of 3.8 yrs, EFS 

at 4 yrs was 63.7% vs. 69.3% (HR � 0.86, 95%CI�0.64 to 1.15, 

p�0.312). PFS at 4 yrs was 72.8% vs. 83.4% (HR � 0.58, 95%CI�0.39 

to 0.85, p�0.005). OS at 4 yrs was 86.7 vs. 90.3 (HR � 0.71, 

95%CI�0.42 to 1.21, p�0.208). Toxic deaths occurred in 6 and 5 pts, 

with early discontinuation (prior to cycle 5) in 12 & 26 pts, respectively. 

There were 5 crossovers to BEACOPP and 10 to ABVD. Second malignancies 

occurred in 8 ABVD and 10 BEACOPP pts (myelodysplasia/leukemia 2 

and 4, lung 2 and 1, NHL 3 and 2, other 1 and 3); cumulative incidence 

curves did not differ significantly. Conclusions: The primary endpoint (EFS) 

was similar between treatment arms. However, more progressions/relapses 

were observed with ABVD, while early discontinuations were more frequent 

with BEACOPP. Nevertheless, even in this high-risk group, OS was not 

improved with BEACOPP. Additional considerations (treatment burden and 

cost, fertility issues, long term relapses and immediate and late morbidity) 

may guide physician/patient decisions toward ABVD or BEACOPP. 


A phase III randomized intergroup trial (S0016) comparing CHOP plus 

rituximab with CHOP plus iodine-131-tositumomab for front-line treatment 

of follicular lymphoma: Results of subset analyses and a comparison 

of prognostic models. Presenting Author: Oliver W. Press, Fred Hutchinson 

Cancer Research Center, Seattle, WA 

Background: Advanced follicular lymphomas (FL) are considered incurable 

with chemotherapy and there is no consensus on the best treatment. 

Outcomes are variable, but can be partially predicted by defined prognostic 

factors. SWOG and CALGB compared the safety and efficacy of 2 

immunochemotherapy regimens in a Phase III trial enrolling 554 patients 

between 3/1/2001 and 9/15/2008. Methods: Patients were eligible if they 

had bulky stage II, III or IV FL and had not received prior therapy. Patients 

randomized to CHOP-R received 6 cycles of CHOP every 21 days � 6 doses 

of rituximab. Patients randomized to CHOP-RIT received 6 cycles of CHOP, 

followed by consolidative radioimmunotherapy with tositumomab/iodine 

I-131 tositumomab. A Cox proportional hazards multi-variable regression 

analysis assessed the prognostic impact of age, stage, LDH, LN size and 

number, performance status, hemoglobin, �2 microglobulin, BM involvement, 

and B symptoms. The prognostic value of 3 multi-variable models 

were compared. Results: Outcomes were outstanding with either CHOP-R or 

CHOP-RIT (2 yr PFS: 76% vs 80% [ p �0.11]; 2 yr OS: 97% vs 93% [p 

�0.08], respectively). Subset analyses so far have not identified any 

subgroups clearly benefitting to a greater degree from CHOP-R or CHOP- 

RIT in terms of both PFS and OS. Cox multivariable regression analysis 

identified serum-�2M, LDH level, and FLIPI index as the strongest 

prognostic factors associated with worse PFS and OS. Conclusions: Both 

regimens produced outstanding PFS and OS, and no statistically significant 

differences between them were observed. FLIPI, FLIPI2, and LDH � �2M 

models were all strong predictors of patient outcomes. A combination of 

LDH � �2M was as good as the FLIPI index, and was simpler to apply. 

(Supported in part by NCI grants CA32102 and CA38926 from the NCI and 

GlaxoSmithKline.) 

PFS OS 

Parameter 

HR (95% Cl) p HR (95% Cl) p 

LDH 1.59 (1.17-2.17) .003 2.46 (1.49-4.07) .0004 

Serum-�2M 1.70 (1.27-2.28) .0004 2.22 (1.31-3.76) .003 

�2M and LDH 2.25 (1.51-3.31) �.0001 3.96 (2.02-7.78) �.0001 

FLIPI 2.28 (1.54-3.35) �.0001 3.65 (1.82-7.18) .0002 


Plasma viral DNA as a marker of tumor response in EBV(�) Hodgkin 

lymphoma in a phase III study (E2496). Presenting Author: Jennifer Ann 

Kanakry, Johns Hopkins School of Medicine, Baltimore, MD 

Background: Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma 

(HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid 

(EBER) in tumor cells. Studies have suggested a correlation in HL between 

plasma EBV DNA and EBER ISH. We previously studied the DNase 

sensitivity of plasma EBV DNA and found plasma EBV of patients with 

EBV(�) HL was not protected from DNase digestion, consistent with 

tumor-derived DNA, while plasma EBV of patients with HIV without EBV(�) 

tumors was protected from DNase digestion, consistent with virion DNA. 

We sought to determine whether plasma EBV could serve as a surrogate for 

EBER ISH and whether reappearance of plasma EBV predicts treatment 

failure. Methods: Specimens from a Cancer Cooperative Intergroup Trial 

(E2496/Stanford V versus ABVD for HL) were used to compare pretreatment 

plasma EBV DNA copy number, assessed by real-time quantitative 

PCR, with EBV status by EBER ISH. An ROC analysis was performed using 

patients with both pretreatment plasma EBV and EBER results (n�121), 

identifying a cutoff of 60 viral copies/100 �L plasma (95% concordance, 

92% sensitivity, 96% specificity for EBV status by EBER). Using this 

cutoff, pretreatment plasma specimens (n�274) were designated EBV(�) 

(n�54) or EBV(-) (n�220), as were serial follow-up specimens. Cox 

proportional hazard models were constructed to evaluate plasma EBV as a 

prognostic factor for failure-free survival (FFS). FFS was estimated by the 

Kaplan-Meier method. Results: Pretreatment EBV(�) plasma was associated 

with treatment failure with a hazard ratio of 2.1 (95% CI 1.2-3.6, 

p�0.01) after adjusting for International Prognostic Score, treatment arm, 

and histology. Of the EBV(�) patients with follow-up specimens (n�45), 

patients with EBV(�) plasma beyond 1 month of therapy (n�9) had inferior 

FFS compared to those who cleared their plasma of EBV (n�36), (3-year 

FFS 44% versus 69%, respectively; log rank p�0.03). Conclusions: HL 

patients with EBV(�) plasma at baseline have inferior FFS compared to 

others. Among patients with EBV(�) plasma at baseline, those in whom 

plasma EBV persists or reappears after initiation of therapy have inferior 

FFS. Such patients may benefit from experimental or intensified therapies. 



High-dose chemotherapy followed by allogeneic stem cell transplantation 

in high-risk relapsed and refractory aggressive non-Hodgkin lymphoma: 

Results of a prospective study of the German high-grade non-Hodgkin 

lymphoma study group. Presenting Author: Bertram Glass, Asklepios Klinik 

St. Georg, Hamburg, Germany 

Background: The role of allogeneic stem cell transplantation (alloSCT) in 

high-risk aggressive NHL is poorly defined; the role of graft-versuslymphoma 

effect is unclear. Reduced intensity conditioning has shown 

limited efficacy in patients with refractory disease. Methods: Patients with 

primary refractory disease, early relapse (�12 months) or relapse after 

autologous SCT of aggressive B-cell (n�61) or T-cell (n�23) NHL were 

enrolled from June 2004 to March 2009. Myeloablative conditioning 

(fludarabine 125mg/m2 , busulfan 12mg/kg, cyclophosphamide 120 mg/ 

kg) was followed by alloSCT from related (n�24) or unrelated (n�60) 

donors. 57/84 patients received a 10 HLA-loci compatible graft. Results: 

Overall survival at 3 years was 42% (95% CI, 31% to 52%), progressionfree 

survival (PFS) was 40% (95% CI 29% to 50%). Non-relapse mortality 

(NRM) was 12% at 100 days and 35% at one year. Graft-versus-host 

disease (GVHD) and infection were the predominant causes of NRM. 

Relapse rate was 30% with latest relapse at day �327. Patients with an 

HLA fully compatible donor (plus ATG with unrelated donors) (n�40) had 

the best outcome (NRM at 1y 10.4 vs 57.2%, PFS at 3y 64.7% vs 31.8%, 

p � 0.0001). GVHD � grade I correlated with improved PFS (HR 0.45, 

p�0.0088). Patients with refractory disease or early relapse (n�60) 

experienced PFS at 3y of 33%. Conclusions: Lymphoma-debulking (highdose) 

chemotherapy followed by alloSCT shows excellent results in heavily 

pretreated patients with early relapse or primary refractory aggressive 

lymphoma. There was evidence of graft-versus-lymphoma activity in this 

setting. For patients with a fully matched (10/10) related or unrelated 

donor the results compare favorably to autoSCT or alloSCT following 

reduced-intensity conditioning. 


R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage 

follicular lymphoma: Final results of FOLL05 trial from the Fondazione 

Italiana Linfomi (FIL). Presenting Author: Massimo Federico, Department 

of Oncology and Haematology, University of Modena and Reggio Emilia, 

Modena, Italy 

Background: The optimal chemotherapy regimen for patients with advanced, 

active follicular lymphoma (FL) has not been established yet. We 

conducted a randomized trial comparing R-CVP with R-CHOP and R-FM. 

Methods: Previously untreated patients with advanced FL were randomly 

assigned to receive 8 doses of rituximab associated to 8 cycles of CVP, or 6 

cycles of CHOP or FM (fludarabine 25 mg/m2 day 1-3, mitoxantrone 10 

mg/m2 day 1). No maintenance therapy was allowed. The principal study 

end point was Time to Treatment Failure (TTF). Events in TTF were failure 

of induction therapy, progressive or relapse disease and death from any 

causes. In order to show a hazard ratio between each experimental arms 

and standard arm of 0.53 we planned to accrue 534 patients (178 per arm) 

with 4 years of accrual and 1 year of follow-up. Statistical tests were 

two-sided with an alpha error of 0.05, adjusted by Bonferroni for multiple 

arm comparison, and power of 90%. Results: Between March 2006 and 

September 2010, 534 patients were enrolled; 30 were subsequently 

excluded due to violation of inclusion criteria. Median patient age was 56 

years (range 30-75), 63% of patients had stage IV disease, 37% had 3-5 

FLIPI and 27% 3-5 FLIPI2 scores. At the end of induction treatment the 

overall response rate (CR� PR) for the whole group was 91% (p�0.247). 

After a median follow-up of 34 months 208 events for TTF were recorded; 

3-year TTF was 46%, 64% and 61% for patients treated with R-CVP, 

R-CHOP and R-FM respectively (R-CHOP vs R-CVP p�0.007; R-FM vs 

R-CVP p�0.021; R-FM vs R-CHOP p�0.969). The 3-year overall survival 

rate (OS) was 98%, 95% and 93% for R-CVP, R-CHOP and R-FM group, 

respectively (P�NS). Patients treated with R-FM had a higher rate of g 

III-IV neutropenia (64% vs 28% R-CVP, p�0.001; and vs 50% R-CHOP, 

p�0.015). During follow-up second malignancies were registered as late 

events in 23 patients (2%, 3% and 8% in R-CVP, R-CHOP and R-FM, 

respectively). Conclusions: This trial showed that R-CVP was associated 

with an inferior 3-year TTF and PFS compared with R-FM and R-CHOP. OS 

was similar among study arms but R-FM showed a higher rate of secondary 

tumors. 


511s 


A pooled analysis of 1,144 patients with HIV-associated lymphoma: 

Assessment of lymphoma-, HIV-, and treatment-specific factors on clinical 

outcomes. Presenting Author: Stefan K. Barta, Albert Einstein College of 

Medicine, Bronx, NY 

Background: Non-Hodgkin Lymphoma (NHL) remains the most common 

malignancy in patients with HIV. Outcomes have significantly improved 

over the last decade, but there is no accepted consensus regarding the 

optimal initial therapeutic approach. Our objective was to assess the 

effects of clinical factors on response and survival. Methods: We performed 

a systematic review to search for prospective clinical phase II or III trials 

that assessed therapeutic interventions for HIV-associated NHL and 

assembled individual patient data from 16 trials published between 2000 

and 2011 including 1144 patients (median N�62/trial, range 17-195). 

Treatment factors included type of chemotherapy (CHOP, N�642; 

EPOCH, N�178; CDE, N�191; intensive regimens, N�155) and rituximab 

use (N�542). Endpoints included complete response (CR), progression-free 

survival (PFS), and overall survival (OS). We used logistic 

regression and Cox proportional hazard models adjusted for age, sex, 

age-adjusted International Prognostic Index (IPI), baseline CD4 count, 

baseline HIV viral load, use of concurrent antiretroviral therapy, and 

histology. Odds ratios (OR) � 1 for CR denote improved CR, and hazard 

ratios (HR) � 1 indicate reduced risk of progression or death. Results: 

Among the lymphoma- and HIV-specific covariates evaluated, only a higher 

IPI score was associated with inferior CR rate, PFS and OS (p�0.001). 

Rituximab was associated with a higher CR rate (OR 1.75; p�0.017), 

better PFS (HR 0.39, p�0.001) and OS (HR 0.39, p�0.001); patients 

with a higher baseline CD4 count benefited more from rituximab (HR for OS 

0.57 if baseline CD4 count �100/ul vs. �100/ul; p�0.001). For all 

histologies, initial therapy with the EPOCH regimen resulted in a better CR 

rate (OR 1.78, p�0.039), PFS (HR 0.61, p�0.032) and OS (HR 0.47, 

p�0.001) when compared to CHOP. Conclusions: In this pooled analysis 

including 1144 patients with HIV-associated NHL, the addition of rituximab 

to chemotherapy was associated with significantly improved CR rate, 

PFS, and OS, specifically for patients with a baseline CD4 count �100/uL. 

Treatment with infusional EPOCH was also more effective than CHOP. 


A subgroup analysis of small lymphocytic and marginal zone lymphomas in 

the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A 

randomized phase III study comparing two different rituximab dosing 

strategies for low tumor burden indolent non-Hodgkin lymphoma. Presenting 

Author: Michael E. Williams, University of Virginia Medical Center, 

Charlottesville, VA 

Background: Management of low tumor burden (LTB) indolent lymphoma in 

the rituximab (R) era is uncertain. We hypothesized that R could delay the 

need for chemotherapy and that maintenance R (MR) would be superior to 

R retreatment (RR) at progression. E4402 is a randomized phase III study 

comparing MR and RR for previously untreated, LTB (by GELF criteria) 

small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) and 

FL. Results for the FL subset was previously presented (Kahl, et al. Blood 

2011; 118(21): LBA 6); we now report outcomes for the non-FL patients 

(pt). Methods: Pt received R 375 mg/m2 weekly x 4, with responders 

randomized to MR (1 doseRq3mo)orRR(Rqwkx4atprogression), each 

continued until treatment failure. The primary endpoint, time to treatment 

failure (TTTF), was defined as progression within 6 mo of last R, no 

response to RR, initiation of alternative therapy, or inability to complete 

protocol therapy. Pt were evaluated q 3 mo, with CT scans q 6 mo. 

Secondary endpoints: time to first cytotoxic therapy (TTCT), quality of life 

(QOL) and safety. Results: From 11/03 to 9/08,137 non-FL pt were 

enrolled. Complete or partial response was achieved in 57 (41%), who were 

randomized to MR (n�32) or RR (n�25). 136 pt were stage III-IV (1 IE), 

and all had PS 0-1; for MR vs RR, median age 66 vs 64, and M:F 47:53% 

vs. 28:72%, respectively. The mean no. of R doses/pt (incl. 4 induction 

doses) was 17.9 (range 5- 30) for MR and 5.8 (range 4-12) for RR. With a 

median follow-up of 4.3 yr, TTTF was 3.74 yr for MR vs. 1.07 yr for RR 

(p�.0002; HR 4.95). At 3 yr, 100% of MR vs. 70% of RR pt (p�.0002) 

remained free of cytotoxic therapy. Grade 3-4 toxicities occurred in 2 MR 

pt, 1 neutropenia and 1 encephalopathy. Conclusions: A planned subgroup 

analysis of non-FL pt showed significant benefit in TTTF and TTTC for MR 

but with 2 grade 4 toxicities. This differs from the FL pt in this trial, for 

whom response to induction was higher (70 vs. 41%; p�.0001) and where 

no TTTF benefit was observed with MR. LTB non-follicular indolent 

lymphoma pt who achieve a CR or PR to induction R benefit from MR 

therapy. 




Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly 

patients with de novo multiple myeloma. Presenting Author: Brigitte Kolb, 

University Hospital, Reims, France 

Background: Melphalan-prednisone � thalidomide (MPT) or bortezomib 

(MPV) are approved in frontline MM patients (pts) �65 years. Both 

regimens demonstrated significant benefit over MP alone in terms of PFS 

and OS but this benefit could be hampered by the risk of peripheral 

neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has 

demonstrated promising activity and favorable toxicity profile, with low 

rates of PN. This phase I/II study was designed to determine the maximum 

tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this 

combination in newly diagnosed MM �65. Methods: In Phase I, Cfz was the 

only escalating agent starting at 20 mg/m2 (level 1) with maximal planned 

dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for 

nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m² 

were given on days 1 to 4, for all dose levels. Based on toxicity assessment, 

the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD 

determination was based on occurrence of Dose limiting toxicities (DLTs) 

during the first cycle only. DLTs were defined as any grade 4 hematologic 

toxicity or preventing administration of 2 or more of the 8 Cfz doses of the 

first treatment cycle except grade 4 thrombocytopenia without bleeding or 

grade 4 neutropenia lasting � 7 days; or grade � 3 febrile neutropenia; or 

any other grade � 3 nonhematologic toxicity. Results: As of January 20th 

2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6 

at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There 

were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the 

MTD was considered to be 36 mg/m². Then, 16 additional pts were 

included in the phase II at level 3. Overall, 40 pts have been enrolled into 

the phase I/II study and 26 pts are evaluable for response. The ORR was 

92% including 42% at least VGPR. These results compare favorably to 

those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80 

and 85%, respectively) in the same population. Conclusions: Frontline 

carfilzomib (36 mg/m2) � MP is a tolerable and very effective combination 

in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy 

data to be presented at the meeting. 


Stringent complete response (sCR) in patients (pts) with newly diagnosed 

multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide 

(LEN), and dexamethasone (DEX). Presenting Author: Andrzej J. Jakubowiak, 

University of Chicago, Chicago, IL 

Background: Combination treatment (tx) with CFZ, LEN, and DEX (CRd) is 

well tolerated and highly active in NDMM. In a phase 1/2 study, CRd 

provided rapid reduction of disease by 68% after cycle (C) 1 and 94% 

�partial response (PR) at a median of 8C, including 65% �very good PR 

and 53% �near CR (nCR), which improved to 79% �nCR after C12 (ASH 

2011, Abstr 631). Here, we examine the clinical significance of the 

response rates with longer follow-up. Methods: Pts with NDMM were treated 

in 28-day (d) C with CFZ 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), LEN 25 mg 

PO (d1–21) and DEX 40/20 mg PO weekly (C1–4/5–8). After C4, 

autologous stem cell transplant (ASCT) candidates achieving �PR could 

collect stem cells but then continued CRd with the option to proceed to 

ASCT. After C8, pts received CRd maintenance, using the last tolerated 

doses, with LEN/DEX at the same schedule but a modified CFZ schedule 

(d1, 2, 15, 16). Response was assessed by IMWG criteria plus nCR. 

Results: As of Nov 30, 2011, median follow-up was 14 mo (range 4–25) 

with 33/53 (62%) pts achieving �nCR and 42% sCR. After a median of 

13C (range 1–25), 36 pts completed C8 and continued CRd maintenance, 

64% achieving sCR. 20/22 pts in CR evaluated for minimal residual 

disease (MRD) by multiparameter flow cytometry had no MRD. Progressionfree 

survival (PFS) rate was 97% at 12 and 92% at 24 mo. All pts who 

achieved sCR have maintained response for a median of 9 mo (range 

1–20). Extended CRd tx was well tolerated. During CRd maintenance, the 

most common toxicities (all grades) were lymphopenia (30%), leukopenia 

(26%), and fatigue (25%), and peripheral neuropathy remained limited 

(11%, all G1/2). There were no tx discontinuations due to toxicity during 

maintenance and limited dose modifications (CFZ 19%, LEN 28%, DEX 

31%). Conclusions: CRd is highly active in NDMM, providing rapid and 

deep responses. Extended tx was well tolerated and resulted in improved 

depth of response with a high sCR rate and a significant proportion of pts 

without evidence of MRD. Responses were durable with very promising 

PFS. All pts who achieved sCR remained on CRd with sustained sCR. These 

results compare favorably to other frontline regimens. 


A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and 

dexamethasone (CYCLONE) in patients with newly diagnosed multiple 

myeloma. Presenting Author: Joseph Mikhael, Mayo Clinic, Scottsdale, AZ 

Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its 

target with favorable toxicity profile that has shown significant activity in 

relapsed multiple myeloma (MM). Here we used carfilzomib as the center of 

a 4 drug induction regimen designed for MM patients pre stem cell 

transplant (SCT). Methods: We conducted a phase I safety run in 6 patients 

with no DLT observed before expanding to phase II. The phase II regimen is 

shown below. Treatment was for 4 cycles with expected SCT post induction. 

For the phase II portion of this trial, the primary endpoint is the proportion 

of patients who have � very good partial response to treatment. All patients 

received herpes zoster prophylaxis and ASA daily. Results: Twenty seven 

patients were enrolled. Median age was 65 (range 27-74). ORR for 

evaluable patients (n�17) at phase II dosing is 100%: CR 35%, VGPR 

48%, PR 18% after 4 cycles of CYCLONE. Grade 3 toxicity was reported in 

52% of patients and 14% experienced a grade 4 toxicity. Grade 3/4 

toxicities occurring in �5% of patients included fatigue, neutropenia, 

lymphopenia, thromboembolism, myopathy. Toxicities of any grade seen in 

�20% of patients included fatigue, constipation, lethargy, thrombocytopenia, 

somnolence, creatinine increased, malaise. Four patients (20%) 

developed grade 1 sensory neuropathy; no higher grade or painful neuropathy 

was evident. All patients are alive. All patients advancing to SCT 

successfully collected stem cells. One patient with t(4;14) disease who was 

not transplanted has progressed. 94% remain progression free. Conclusions: 

The 4 drug CYCLONE regimen has remarkable efficacy (83% �VGPR) and 

manageable toxicity in newly diagnosed patients with multiple myeloma. 

Especially notable was the low incidence of neuropathy and depth of 

response (CR 35%) after only 4 cycles. Given the relative lack of toxicity an 

extension of this regimen at higher doses of carfilzomib (20/45mg/m2 ) has 

been initiated. 

Agent Dose level Route Day Cycle length 

Carfilzomib 20 mg/m2 cycle 1 

27mg/m2 IV 1, 2, 8, 9, 15, 16 28 days 

� cycle 2 

Thalidomide 100 mg Orally 1-28 28 days 

Cyclophosphamide 300 mg/m2 Orally 1,8,15 28 days 

Dexamethasone 40 mg Orally 1,8,15,22 28 days 


PANORAMA 2: A phase II study of panobinostat in combination with 

bortezomib and dexamethasone in patients with relapsed and bortezomibrefractory 

multiple myeloma. Presenting Author: Melissa Alsina, H. Lee 


Background: Patients (pts) with multiple myeloma (MM) refractory to 

bortezomib (BTZ) and an immunomodulatory drug have limited treatment 

options and a poor prognosis. In a phase I study of pts with relapsed or 

relapsed/refractory MM treated with panobinostat (PAN) � BTZ, clinical 

responses were observed overall and in pts with BTZ-refractory disease. We 

report results in PANORAMA 2, a trial in relapsed and BTZ-refractory pts. 

Methods: PANORAMA 2 is a single-arm, phase II study of PAN � BTZ � 

dexamethasone (Dex) in pts with relapsed and BTZ-refractory MM. Treatment 

phase 1 (TP1) consists of eight 3-week cycles of oral PAN � 

intravenous BTZ � oral Dex. Pts demonstrating clinical benefit enter 

treatment phase 2 (TP2) which consists of four 6-week cycles of PAN � 

BTZ � Dex. The primary endpoint is overall response (� partial response 

[PR]) in TP1. Results: Fifty-five pts with BTZ-refractory MM were enrolled 

with 10 pts ongoing and 28 in follow-up. The median age was 61 years 

(range 41-88 years). Pts were heavily pretreated: the median number of 

prior regimens was 4 (range 2-11), and most pts (64%) received prior 

autologous stem cell transplant. Twenty-seven (49%) and 36 (65%) pts 

had BTZ and Dex in their most recent prior line of therapy, respectively. 

Eighteen pts achieved � PR for an overall response rate of 33% (1 near 

complete response and 17 PR), and 13 pts achieved MR for a clinical 

benefit rate of 56%. Three pts achieved a VGPR. Eighteen pts completed 

TP1 and entered TP2, and 2 have completed � 12 cycles. Common 

adverse events (AEs) of any grade included thrombocytopenia (66%), 

fatigue (64%), diarrhea (62%), nausea (58%), dyspnea (40%), anemia 

(38%), decreased appetite (36%), and dizziness (36%). Common grade 

3/4 AEs included thrombocytopenia (58%), fatigue (17%), anemia (15%), 

pneumonia (15%), neutropenia (13%), and diarrhea (13%). Only 1 pt 

(2%) experienced grade 3/4 peripheral neuropathy. Conclusions: PAN 

synergizes with BTZ in recapturing responses in heavily pretreated, 

BTZ-refractory MM pts. The combination of PAN and BTZ is a promising 

treatment for pts with BTZ-refractory MM that is generally well tolerated, 

with several pts receiving therapy long term. 



Phase I trial of obatoclax mesylate in combination with bortezomib for 

treatment of relapsed multiple myeloma. Presenting Author: A. Keith 

Stewart, Mayo Clinic, Scottsdale, AZ 

Background: Obatoclax mesylate (GX15-070MS) is a BH3 mimetic that 

inhibits Bcl-2 protein family members including MCL-1, a dominant target 

in myeloma (MM). Obatoclax (OBX) inhibited viability of 14 MM cell lines 

(mean IC50 215 nM) and primary MM samples while exhibiting pre clinical 

synergy with bortezomib (BTZ). Sensitivity correlated with basal levels of 

Mcl-1 and Bcl-XL, but not Bcl2, Bim, Bax or Bak expression. Methods: We 

report a phase I trial of OBX in combination with BTZ. Eligibility required 

measureable disease, � 1 prior MM therapy, �10 cycles of prior BTZ and 

did not progress on prior BTZ therapy, creatinine �2 ULN. Starting dose 

level 1 was OBX 14 mg/m2 24-hour continuous iv. infusion days 1, 8, 15 of 

a 21-day cycle. BTZ given at 1.3mg/m2 iv. days 1, 4, 8 and 11. After 

protocol amendment OBX level 1 dosing was 30 mg/m2 , level 2 was 40 

mg/m2 IV both by continuous 3 hour infusion days 1, 8 and 15 on a 21 day 

schedule. Pre med. with famotidine was required. Results: Eleven patients 

were accrued, median age 62 (range: 46-77), median time from diagnosis 

was 4.7 years. Median of 2.5 cycles (range: 1-10). Median follow-up for 

patients still alive is 11.6 months (range: 0.9-35.5). At dose level 1, there 

were 2 DLTs. After amendment 8 patients were accrued (3 hour infusion): 4 

at amended dose level 1 and 4 at dose level 2. All patients are now off 

treatment. 10 patients are evaluable for response: 2 patients at original 

dose level 1 (2 PR), 3 patients at dose level 1 (2 PR, 1 MR), no patients at 

dose level 2 responded: overall PR of 40%, clinical benefit response in 

50% (95% CI: 19-81%). 6 patients had disease progression and 2 patients 

died. 4 DLTs were seen: at original dose level 1 grade 4 thrombocytopenia 

and delay of therapy � 15 days. At dose level 2, 1 patient had grade 3 

somnolence, a 2nd patient grade 3 euphoria and grade 4 thrombocytopenia. 

No DLTs were seen at amended dose level 1. Common adverse events 

of any grade included GI, hematologic and neurologic e.g. euphoria, 

decreased level of consciousness, psychosis, speech. Conclusions: In 

summary MTD is OBX 30mg/m2 by 3 hour iv infusion once weekly, BTZ 1.3 

mg/m2 days 1,4,8, and 11. Major toxicities were central neurologic and 

hematologic. This P2C consortium study was supported by NCI N01- 

CM62205. 


Efficacy and side-effect profile of long-term bisphosphonate therapy in 

patients (pts) with multiple myeloma (MM): MRC myeloma IX study results. 

Presenting Author: Gareth J Morgan, Institute of Cancer Research, Royal 

Marsden Hospital, London, United Kingdom 

Background: Bisphosphonates (BPs) are recommended in pts with osteolytic 

lesions from MM. However, data on the long-term efficacy and safety of 

BPs beyond 2yissomewhat limited. The MRC Myeloma IX study has 

already revealed significant overall survival (OS) and progression-free 

survival (PFS) benefits for zoledronic acid (ZOL) over clodronate (CLO) in 

MM pts (N � 1960) initiating chemotherapy (Morgan GJ, et al. Lancet. 

2010). We now report the efficacy and safety of BP therapy with long-term 

follow-up. Methods: Newly diagnosed MM pts were randomized to ZOL (4 

mg IV q 21-28 days) or CLO (1600 mg/day PO) plus antimyeloma therapy. 

BPs continued at least until disease progression. PFS and OS were 

estimated using Kaplan-Meier methodology. Hazard ratios (HRs) were 

calculated using stratified Cox models. Adverse events (AEs) were monitored 

continuously and analyzed using cumulative incidence functions. 

Results: At a median follow-up of 5.8 y in 1960 evaluable pts, ZOL 

improved PFS (HR � 0.88; P � .01) and OS (HR � 0.88; P � .03) vs CLO. 

Both BPs were generally well tolerated, and acute renal failure events were 

similar between groups (ZOL 5.2% vs CLO 5.8% at 2 y, with incidence 

plateaued thereafter). Overall incidence of confirmed osteonecrosis of the 

jaw (ONJ) has remained low (ZOL 3.7% vs CLO 0.5%; P � .0001). ONJ 

incidence was lower among pts receiving thalidomide-containing regimens 

(1.4%) vs no thalidomide (2.76%; P � .041). Events were generally 

low-grade, most occurred between 8 and 30 mo (median time to ONJ � 

23.7 mo), and cumulative incidence plateaued at ~36 mo. Ten pts had 

data on ONJ recovery: complete recovery in 4 pts, improvement in 2 pts, no 

change in 3 pts in the ZOL group; and no change in 1 CLO pt. Dental 

surgery or trauma preceded ONJ in 6 ZOL pts. Conclusions: ZOL provided 

sustained PFS and OS improvements vs CLO during long-term therapy in 

the MRC Myeloma IX study. Overall incidence of AEs was similar between 

groups, with no notable changes during long-term therapy. ONJ incidence 

remained low during long-term (� 2.5 y) therapy and was reduced in pts 

receiving thalidomide (possibly because of anticytokine effects of this 

agent). 



Bendamustine, bortezomib, and dexamethasone (BVD) in elderly patients 

with relapsed/refractory multiple myeloma (RRMM): The Intergroupe Francophone 

du Myélome (IFM) 2009-01 protocol. Presenting Author: Philippe 

Rodon, Hematology, General Hospital, Blois, France 

Background: Bortezomib (V) plus dexamethasone (D) is a treatment of 

choice of RRMM. In small series, the addition of an alkylator was 

beneficial. Bendamustine (B) showed a high activity in advanced MM. The 

IFM 2009-01 trial evaluates the combination of B, V and D in elderly pts 

with MM progressive on or after 1st line therapy. Methods: We conducted a 

phase 2 trial combining B 70 mg/m2 D1-8, V 1.3 mg/m2 D1-8-15-22 and D 

20 mg D1-8-15-22 every 28 days. 4 cycles were administered. In 

responders (PR or better), 2 additional cycles were provided followed by a 

maintenance phase with 6 cycles given every 2 months. Inclusion criteria 

were progression on or after 1 prior line of therapy, measurable disease, PS 

ECOG �3, ANC � 1.5x109 /l, platelets � 100x109 /l, creatinine � 250 

mcmol/l, AST and ALT � 3xULN. Pts with prior exposure to bortezomib 

were excluded. Response was evaluated according to IMWG criteria. 

Primary end point was response at end of cycle 4, secondary objectives 

overall response rate (ORR), progression-free survival (PFS), overall survival 

(OS) and toxicity. Results: The present analysis was restricted to the first 4 

cycles. From 03/2010 to 07/2011, 73 pts were included, median age 75.8 

years (range 66-86). Median time from diagnosis to inclusion was 29 

months. All pts received only 1 prior therapy: MP in 12, MP-thalidomide in 

44, lenalidomide-dexamethasone (LD) in 14, other in 3. 42 pts (57.5%) 

were responders at end of cycle 4 [CR: 8 (10.9%), VGPR: 9 (12.3%), PR: 

25 (34.2%), SD: 10 (13.6%), progression: 11 (15%), early discontinuation: 

10 (13.6%)]. 6pts/10 were in PR and 1pt/10 in VGPR at time of 

discontinuation. ORR was 67.1% (49/73 pts). 11 pts died (MM: 6, sepsis: 

4, renal failure: 1). Adverse events grade 3-4 were neutropenia: 16 pts, 

thrombocytopenia: 7 pts, sepsis: 12 pts, gastro-intestinal: 8 pts, anaphylaxis: 

1 pt. 2 pts had DVT. Peripheral neuropathy grade�1 occurred in 9 

pts, all grade 2. Treatment was stopped in 20 pts (lack of efficacy: 11, 

toxicity: 9). Conclusions: These results compare favorably with those 

achieved with VD or LD. The triplet BVD combination is very effective and 

tolerable in elderly pts with MM in 1st progression. 


Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in 

patients (pts) with relapsed/refractory multiple myeloma (RRMM): Outcomes 

in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). 

Presenting Author: Ravi Vij, Washington University School of Medicine, St. 

Louis, MO 

Background: Response and survival outcomesare poor in pts with RRMM 

who are refractory to BORT and immunomodulatory drugs. POM�LoDEX 

has demonstrated activity in pts with advanced multiple myeloma who have 

received multiple lines of therapy. This analysis evaluates outcomes in pts 

with disease refractory to LEN, BORT, or both, as well in pts with disease 

refractory to both LEN and BORT who had received prior transplant. 

Methods: In the MM-002 phase II trial, pts received POM (4 mg/day on days 

1–21 of each 28-day cycle) alone (n�108) or in combination with LoDEX 

(40 mg/week) (n�113). Refractory disease was defined as documented 

progression during treatment or within 60 days of the last dose of 

treatment. Response rates were assessed using European Group for Bone 

Marrow Transplantation (EBMT) criteria by independent adjudication 

committee. Results: Patients who received POM�LoDEX were refractory to 

LEN (77%), BORT (73%), or both (61%). Forty-two percent were refractory 

to both LEN and BORT and had received prior transplant. Overall, 20% of 

pts achieved � PR, median PFS was 3.5 months, and 1-year survival rate 

was 59%. Response rates and duration were comparable in pts with disease 

refractory to LEN, BORT, or both, and in pts who had received prior 

transplant (response rate 25-34%, median duration of response 5.7-7 

months). Survival outcomes were similar across the groups (median PFS 

3.8-4.6 months; 1-year survival rate 60-67%). Conclusions: POM, given at 

4 mg/day on days 1–21 of each 28-day cycle in combination with LoDEX, 

40 mg/week, is effective in pts with RRMM refractory to LEN, BORT, or 

both, and including those with prior transplant. These results suggest a lack 

of cross-resistance between POM and LEN, and confirm activity not only in 

BORT-refractory pts but also those for whom transplant has failed. 

Refractory to: 

LEN 

n�87 BORT 

n�82 

LEN and BORT 

n�69 

LEN and BORT 

with prior transplant 

n�47 

POM�LoDEX 

> PR, % 25 29 28 34 

> MR, % 41 46 46 53 

Median duration of response, months* 7 5.8 6.2 5.7 

Median PFS, months 3.8 3.8 3.8 4.6 

1-year survival rate, % 

* In patients achieving �PR. 

65 60 61 67 


513s



Phase I study of twice-weekly dosing of the investigational oral proteasome 

inhibitor MLN9708 in patients (pts) with relapsed and/or refractory 

multiple myeloma (MM). Presenting Author: Sagar Lonial, Winship Cancer 

Institute, Emory University, Atlanta, GA 

Background: MLN9708 is the first oral proteasome inhibitor to enter clinical 

investigation in MM. This study (NCT00932698) assessed safety, MTD, 

and response rate with twice-weekly oral MLN9708 in pts with relapsed 

and/or refractory MM, and characterized plasma pharmacokinetics (PK) 

and blood pharmacodynamics. Methods: Pts aged �18 yrs with measurable 

MM received MLN9708 on d 1, 4, 8, and 11 of 21-d cycles. In the 

dose-escalation phase, pts required �2 prior therapies (including bortezomib, 

thalidomide/lenalidomide, and corticosteroids). At the MTD (2.0 

mg/m2 ), pts were enrolled to relapsed and refractory [RR], bortezomibrelapsed 

[VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion 

cohorts. Results: 57 pts (53% M) were enrolled, 37 to the expansion 

cohorts (16 RR, 14 VR, 6 PI naïve, 1 CZ). Median age was 65 yrs (range 

50-86). Median number of prior lines of therapy was 4 (range 1-28); 88%, 

84%, 61%, and 5% had prior bortezomib, lenalidomide, thalidomide, and 

carfilzomib, respectively. Pts have received a median of 3 cycles (range 

1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received �13 

cycles. Drug-related AEs were seen in 89% of pts, including fatigue (46%), 

thrombocytopenia (40%), and nausea (30%); 63% had drug-related grade 

�3 AEs, including thrombocytopenia (33%), neutropenia (14%), fatigue 

(9%), and rash (7%). Only 6 (11%) pts had drug-related peripheral 

neuropathy (PN; no grade �3). 7 pts discontinued due to AEs. 2 pts died on 

study, due to PD and an unrelated cardiac disorder. Of 46 responseevaluable 

pts, 6 have achieved �PR, with 1 sCR (PI naïve cohort) and 5 

PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR pt has 

achieved MR, with duration of disease control of up to 18.6 mo. PK 

analyses showed MLN2238 (biologically active hydrolysis product) has 

linear plasma PK (0.8-2.23 mg/m2 ), Tmax of 0.5-1.25 hr, and terminal 

half-life of 4-6 d. A dose-dependent increase in whole blood 20S 

proteasome inhibition was observed. Conclusions: Current data suggest 

MLN9708 has clinical activity in heavily pretreated MM pts, with durable 

responses/disease control, and is generally well tolerated with infrequent 

low-grade PN. 


Daratumumab, a CD38 mab, for the treatment of relapsed/refractory 

multiple myeloma patients: Preliminary efficacy data from a multicenter 

phase I/II study. Presenting Author: Torben Plesner, Vejle Hospital, Vejle, 

Denmark 

Background: Daratumumab (HuMax-CD38) is a human CD38 monoclonal 

antibody with broad-spectrum killing activity; it effectively kills CD38expressing 

tumor cells via antibody-dependent cell-mediated cytotoxicity 

(ADCC), complement-dependent cytotoxicity (CDC) and apoptosis. From an 

ongoing first-in-human (FIH) dose-escalation study (ClinicalTrials.gov 

CT00574288), it has been shown that daratumumab has an acceptable 

safety profile (Gimsing: ASH 2011 abstract 1873). The objectives of this 

FIH study are to establish the safety profile and MTD. In addition efficacy is 

evaluated. Methods: Pts �18 years and previously diagnosed with MM 

requiring systemic therapy and considered relapsed or refractory (RR) to at 

least two different prior lines of therapy and not eligible for salvage ASCT 

were enrolled. The design of this study encompasses an accelerated 

dose-escalation based on a classical 3�3 design. Daratumumab is administrated 

overa9wkperiod encompassing 2 pre-doses and 7 full-doses. The 

doses range from 0.005 mg/kg to 24 mg/kg. The decision to dose escalate 

is based on recommendation by an external Independent Data Monitoring 

Committee. Evaluation of efficacy data was according to Rajkumar (Blood 

2011;117:4691-5). The results presented in this abstract are based on 

preliminary data analyzed before database lock. Results: Data from 23 pts 

including the 4 mg/kg group are collected. Preliminary efficacy evaluation 

is based on best paraprotein response as reflected by change in serum 

and/or urine M-component. For groups � 1 mg/kg, 3/17 pts achieved a 

reduction in serum M-component (12%, 14%, 19%), in the 2 mg/kg group, 

1/3 pts had a reduction in urine M-component (55%), and in the 4 mg/kg 

group, 3/3 pts had a reduction in the serum M-component of 49%, 55, and 

64%, respectively. In the 4 mg/kg group a marked reduction in the 

percentage of plasma cells in the bone marrow was seen in all pts (80%, 

89%, and 97%). The toxicity was manageable. Conclusions: Daratumumab 

treatment resulted in reductions in M-component and bone marrow plasma 

cells in pts with RR MM. Toxicity has been manageable. Additional data 

will be presented at the meeting. 

8018^ Clinical Science Symposium, Mon, 11:30 AM-1:00 PM 

Phase II, randomized, double blind, placebo-controlled study comparing 

siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/ 

refractory multiple myeloma. Presenting Author: Robert Z. Orlowski, 


Background: Preclinical studies of siltuximab (S), a chimeric anti-IL-6 

mAb, in combination with bortezomib (B) indicate an additive to synergistic 

effect in multiple myeloma (MM) cell lines. This randomized study 

evaluated the safety and efficacy of S�B compared with placebo (plc)�B 

in pts with relapsed/refractory MM after 1�3 prior tx lines, measurable 

disease but no prior B exposure. Methods: 286 pts were randomized 1:1 to 

S�B: B�plc. S 6 mg/kg or plc was given IV q2w. B 1.3 mg/m2 was given IV 

on d 1, 4, 8, 11, 22, 25, 29, 32 for a max of 4 of 42-d cycles and then 

reduced to q1w for 35-d cycles. B was stopped for pts with PD/ 

intolerability, and high dose oral dexamethasone (dex) 40 mg could then be 

started qd on d 1�4, 9�12, 17�20 for a max of 4 of 28-d cycles and on d 

1�4 of subsequent cycles until PD, while S/plc continued. Primary 

endpoint was PFS by EBMT criteria censored at the start of dex/subsequent 

tx. Secondary endpoints included overall response rate (ORR), OS, and 

safety before dex. Results: 142 and 144 pts received S�B and B�plc, 

respectively. Baseline demographics and disease characteristics were well 

balanced across S�B and B�plc, except for age (median 64 vs. 61 yrs) and 

myeloma type (IgG 65 vs. 71%, IgA 27 vs. 20%). Median tx duration was 

5.1 mo in both grps. Median PFS was 8.1 mo in S�B and 7.6 mo in B�plc 

(HR 0.869, p � 0.345). ORR (CR�PR) was 55% in pts on S�B and 47% 

on B�plc (p � 0.213); CR rates were 11 and 7% (p � 0.342), 

respectively. With 24.5 mo median follow up, median OS was 30.8 mo for 

S�B and 36.9 mo for B�plc (HR 1.353 for S�B, p � 0.103). Fewer pts on 

S�B than B�plc moved to dex (23 vs. 31%) and had subsequent SCT (5 

vs. 11%). Gr �3 AEs occurred in 91% on S�B and 74% on B�plc. 

Common gr �3 AEs in S�B were neutropenia (49%), thrombocytopenia 

(48%), leukopenia (14%). SAEs occurred in 29% on S�B and 24% on 

B�plc. Death occurred within 30 d of last study agent administration 

pre-dex in 8% on S�B and 5% on B�plc. Conclusions: The combination of 

S�B had higher response rates but did not prolong survival compared with 

B�plc. A negative survival trend heavily influenced by differences in dex 

and SCT rescue was noted. S�B appears to be generally well tolerated but 

had a higher incidence of hematologic AEs. 


A randomized phase II study of elotuzumab with lenalidomide and low-dose 

dexamethasone in patients with relapsed/refractory multiple myeloma. 

Presenting Author: Philippe Moreau, Hematology Department, University 

Hospital, Nantes, France 

Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody 

targeting CS1, a cell surface glycoprotein. CS1 is highly expressed on 

�95% of multiple myeloma (MM) cells, with lower expression on natural 

killer cells and little to no expression on normal tissues. A phase 1 trial of 

Elo plus lenalidomide and low-dose dexamethasone (Elo/Len/Dex) demonstrated 

an 82% objective response rate (ORR) in patients (pts) with 

relapsed/refractory (RR) MM (Lonial et al. J Clin Oncol, in press). Methods: 

In this phase 2 study, previously treated pts with MM were randomized to 

Elo 10 or 20 mg/kg IV (days 1, 8, 15, and 22 every 28-days in first 2 cycles 

and days 1 and 15 of subsequent cycles), Len 25 mg PO (days 1-21) and 

Dex 40 mg PO weekly. Prophylaxis for infusion-related reactions (IRs) was 

administered prior to each Elo infusion. Treatment continued until disease 

progression or unacceptable toxicity. The primary objective was to assess 

efficacy (ORR �partial response [PR]) according to IMWG criteria. Results: 

Among73 pts (median age 63 years; range, 39-82), 55% had received �2 

prior therapies, 60% had received prior bortezomib, and 62% prior 

thalidomide. ORR was 82% for all pts including 48% � very good PR 

(VGPR). The ORRs were 92% in the 10 mg/kg group (n�36) and 73% in 

the 20 mg/kg group (n�37). Median time to best response was 2.2 months 

(range, 0.7-17.5). After a median follow-up of 14.1 months, median 

progression-free survival (PFS) has not been reached, with PFS rates of 

75% (10 mg/kg) and 65% (20 mg/kg). Elo/Len/Dex also showed encouraging 

activity in pts with high-risk cytogenetics (ORR 80%) and/or Stage 2-3 

MM (ORR 81%). The most common grade 3/4 toxicities were neutropenia 

(16%), lymphopenia (16%), and thrombocytopenia (16%). Investigatordesignated 

IRs were reported in 12% of pts (all grades); 1 pt (1.4%) had 

grade 3 IR (rash). Conclusions: Elo/Len/Dex was generally well tolerated and 

resulted in a high ORR, and PFS not reached after 14.1 months of median 

follow-up in pts with RR MM. Updated results will be presented at the 

meeting. Two phase 3 trials of 10 mg/kg Elo/Len/Dex are ongoing in newly 

diagnosed MM (ELOQUENT1; CA204-006; NCT01335399) and RR MM 

(ELOQUENT2; CA204-004; NCT01239797). 



12:00 PM-1:00 PM 

R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large 

B-cell lymphoma (DLBCL): Final analysis of the LNH03-6B GELA study. 

Presenting Author: Richard Delarue, Hôpital Necker, Paris, France 

Background: In 2000, the GELA established a new standard for elderly 

patients with DLBCL, demonstrating survival advantage of R-CHOP21 over 

CHOP21. Based on RICOVER-60 results, the DSHNHL proposed R- 

CHOP14 as a standard. Comparison between both regimens is lacking. We 

report the results of the final analysis of the randomized phase III trial 

LNH03-6B, with a median follow-up of 56 months. Methods: Pts between 

60 and 80 years old with DLBCL and aaIPI�1 were eligible. They were 

randomized between R-CHOP14 and R-CHOP21 for 8 cycles. G-CSF 

prophylaxis was given according to physician decision. Primary objective 

was to evaluate the efficacy of R-CHOP14 compared to R-CHOP21 as 

measured by the EFS. Results: 602 pts were randomized, 600 were 

evaluable, 304 with R-CHOP14 and 296 with R-CHOP21. Median age was 

70 years. Pts characteristics were similar between the two arms. Percentage 

of pts with baseline IPI3-5 was 72% in R-CHOP14 arm and 78% in 

R-CHOP21 arm. Median interval between 2 cycles was 14 d in R-CHOP14 

arm and 21 d in R-CHOP21 arm. In R-CHOP14 arms, 89% of cycles were 

administered with G-CSF. Median dose-intensity for R-CHOP14 arm was 

88% for cyclophosphamide and doxorubicin. There was no difference in 

median dose-intensity according to G-CSF administration at first cycle. 

Response rate (CR�CRu) was 71% in R-CHOP14 arm and 74% in 

R-CHOP21 arm (p�0.42). The 3-y EFS was 56% in R-CHOP14 arm and 

60% in R-CHOP21 (HR 1.04; CI95% 0.82-1.31; p�0.79). Moreover, 

there is no difference between both arms regarding 3-y PFS (60% vs. 62%; 

HR 0.99; CI95% 0.78-1.26; p�0.90), DFS (72% vs. 67%; HR 0.80; 

CI95% 0.58-1.10; p�0.80) and OS (69% vs. 72%; HR 0.96; CI95% 

0.73-1.26; p�0.75). Finally, percentage of patients with at least one 

serious adverse event (R-CHOP14: 51%; R-CHOP21: 47%) and rate of 

toxic death (4.6% and 4.7% respectively) were similar. Conclusions: 

Results of the final analysis of LNH03-6B demonstrate similar efficacy and 

safety profile between R-CHOP14 and R-CHOP21. 


12:00 PM-1:00 PM 

A multicenter phase II study of bendamustine with rituximab in patients 

with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Presenting 

Author: Michinori Ogura, Department of Hematology and Oncology, 

Nagoya Daini Red Cross Hospital, Aichi, Japan 

Background: Effective salvage therapies are needed in patients (pts) with 

relapsed/refractory DLBCL after R-CHOP. Therapy with bendamustine plus 

rituximab (B-R) was well tolerated and effective in the preceding phase I 

study in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, 

including DLBCL. This phase II study assessed the efficacy and safety of 

B-R in pts with relapsed/refractory DLBCL. Methods: Pts with histologically 

confirmed DLBCL (excluding transformed disease) and 1-3 prior therapies 

received rituximab 375 mg/m2 IV on day 1 and bendamustine 120 mg/m2 IV on days 2 and 3 of each 21-day cycle, for up to 6 cycles. Recovery of 

neutrophil count to �1,000/mm3 and platelet count to �75,000/mm3 were required prior to the start of each cycle; treatment delays �2 weeks 

resulted in discontinuation. The primary endpoint was overall response rate 

(ORR); secondary endpoints included complete response (CR) rate, progression-free 

survival (PFS), and safety. Results: A total of 63 pts were enrolled; 

data from 59 pts were available. Median age was 67 (range, 36-75) years 

with 37 pts over 65 years. The majority of pts (64.4%) had 1 prior therapy; 

57 pts (96.6%) were previously treated with rituximab-containing combination 

chemotherapy and 8 (13.6%) had prior auto-PBSCT. Pts received a 

median of 4 (range, 1-6) treatment cycles. Sixteen (27.1%) pts completed 

6 treatment cycles; most common reasons for early discontinuation were 

disease progression (n�15) and failure to meet criteria to start the next 

cycle (n�13). Among 59 pts evaluable for response, ORR was 62.7% with 

a 37.3% CR rate. The median PFS was 200 days (95% CI, 109-410). Most 

common grade 3/4 adverse events (AEs) included CD4 lymphocytes 

decreased (66.1%), neutropenia (54.2%), and thrombocytopenia (10.2%). 

Four (6.8%) pts discontinued due to serious AEs (cytomegalovirus infection, 

infection, pneumonia, and pneumonia/respiratory failure). Conclusions: 

B-R demonstrated promising activity in pts with relapsed/refractory DL- 

BCL. Toxicity was primarily hematologic and generally manageable. These 

results suggest that B-R is a promising salvage regimen for pts with 

relapsed/refractory DLBCL after R-CHOP. 


515s 


12:00 PM-1:00 PM 

Role of radiotherapy for elderly DLBCL patients in the rituximab (R) era: 

Final results of the RICOVER-60-no-rx study of the DSHNHL. Presenting 

Author: Gerhard Held, Saarland University Hospital, Homburg, Germany 

Background: 117/306 (38%) of the total of 1,222 elderly (61-80 y) DLBCL 

pts. treated in RICOVER-60 with 6xR-CHOP-14�2R were assigned to 

receive additional radiotherapy (Rx) to bulky disease (Pfreundschuh et al., 

Lancet Oncol. 2008). To study the relevance of Rx to bulky disease (Bx), 

166 pts. were prospectively treated without Rx in the R-CHOP-14-noRx 

amendment of RICOVER-60. Methods: The outcome of 166 R-CHOP-14noRx 

patients was compared with the 306 patients who had received 

6xR-CHOP-14�2R plus radiotherapy to Bx (�7.5 cm) in RICOVER-60. 

Methods: The outcome of 166 R-CHOP-14-noRx patients was compared 

with the 306 patients who had received 6xR-CHOP-14�2R plus radiotherapy 

to Bx (�7.5 cm) in RICOVER-60. Results: 164/166 R-CHOP-noRx 

patients are evaluable (median observation: 39 mos). Patients in R-CHOPnoRx 

were older (71 vs. 69 y.; median; p�0.018), more frequently in 

advanced stages (60% vs. 50%; p�0.037), and with extranodal involvement 

(63% vs. 53%; p�0.024), while Bx was more frequent in R-CHOP- 

14-Rx (38% vs. 29%; p�0.038). Overall response to therapy, EFS and OS 

were similar in the two studies adjusting for the prognostic imbalances 

between the cohorts. Patients with Bx who received received additional 

radiotherapy to Bx in R-CHOP-14-Rx had a better 3-year EFS (80% vs. 

54%; p�0.001), a better PFS (88% vs. 62%; p�0.001), and a better OS 

(90% vs. 65%; p�0.001) compared to R-CHOP-14-noRx. This was due 

the worse outcome of pts. with Bx in R-CHOP-14-noRx not achieving CR or 

CRu after 6xR-CHOP, since there was no difference in 3-year EFS in 

patients with Bx in CR or CRu after 6xR-CHOP-14 with and without 

additional radiotherapy (3-year EFS and PFS: 84% vs. 75%; p�0.430); 

OS 87% vs. 79%; p�0.839). Conclusions: In the R era, radiotherapy to 

bulky disease does not improve the outcome of elderly pts. in CR/CRu after 

completion of R-CHOP-14 immunochemotherapy, but appears to be 

beneficial for pts. with Bx not achieving CR/Cru. By restricting Bx 

radiotherapy to patients not achieving a CR/CRu, 43% of the patients with 

Bx could be spared radiotherapy. Supported by Deutsche Krebshilfe. 


12:00 PM-1:00 PM 

Evidence for rituximab (R) underdosing in subpopulations of elderly 

patients with DLBC: Results of the RICOVER-60 study of the DSHNHL. 

Presenting Author: Michael Pfreundschuh, Saarland University Hospital, 

Homburg, Germany 

Background: Gender and weight independently influence R clearance and R 

serum elimination half life (Mueller et al., Blood 2012). To investigate 

whether the differences in R pharmacokinetics translate into different 

outcomes, we analyzed elderly patients (pts) with different R pharmacokinetics 

treated in the RICOVER-60 study. Methods: 1222 elderly pts. 

(61-80 y) were randomized to receive 6 or 8 cycles of CHOP-14 with or 

without R given on days 1, 15, 29, 43, 57, 71, 85, and 99. For this study, 

subgroup analyses were performed for pts with faster R clearance: elderly 

male (vs. female) pts and elderly weighty (upper quartile: �77kg) vs. slim 

(lower quartile: �60 kg) female pts. Results: Elderly females had a slower R 

clearance (8.21 ml/h vs. 12.68 ml/h; p�0.003) and a prolonged R half life 

compared to men (t1/2ß�30.7 vs. t1/2ß�24.7 d; p�0.003). Female pts had 

a higher 3-year PFS (68% vs. 61%; p�0.062) and OS (74% vs. 68% 

p�0.086). The differences in outcome were due to a greater outcome 

improvement by the addition of R in females: the difference in 3-year PFS 

between female and male pts was 5.1% (p�0.448) in pts. receiving 

CHOP-14 only and 7.7% (p�0.053) when R was added. In a multivariate 

analysis the relative risk for progression in male compared to female 

patients was not significantly elevated after CHOP-14 (1.1; p�0.348), but 

was significantly higher after R-CHOP-14 (1.6; p�0.004). With respect to 

weight, addition of R resulted in a significantly improved 3-year PFS (74% 

vs. 49%; p�0.006) in female pts with a body weight within the lower 

quartile (�60 kg) who have an R serum half life of �38.1 days, while there 

was no improvement by the addition of R (72% vs. 71%; p�0.816) in 

female pts. with a body weight within the upper quartile (�77kg), who have 

a serum half life of �29.3 days. Conclusions: The reduced benefit of adding 

R to CHOP in elderly DLBCL pts. with a shorter rituximab serum half life 

(and hence lower serum levels) suggests that the respective subpopulations 

(males and weighty females) are underdosed when R is dosed based on 

body surface area at 375 mg/m2 . Ongoing studies of the DSHNHL 

investigate whether higher R doses for pts with a shorter R serum half life 

can improve the outcome of the respective pts. 




12:00 PM-1:00 PM 

Outcome of elderly DLBCL patients with 6xCHOP-14 and 8 rituximab (R) 

applications given over an extended period (SMARTE-R-CHOP-14 trial of 

the DSHNHL). Presenting Author: Niels Murawski, Saarland University 

Hospital, Homburg, Germany 

Background: 6xCHOP-14 with 8xR given over an extended period improved 

3-year EFS (67% vs. 54%; p�0.030) and OS (80% vs. 67%, p�0.034) of 

poor-prognosis patients (IPI�3-5) in the SMARTE-R trial compared to the 

RICOVER-60 trial where patients received 8xR every 2 weeks. Because we 

had recently shown (Mueller et al., Blood 2012) that elderly male patients 

have a faster R clearance (12.68 ml/h vs. 8.21 ml/h; p�0.003) and shorter 

serum elimination half life (t1/2ß�24.7 vs. t1/2ß�30.7 days; p�0.003) 

than females, we analyzed whether these differences translated into 

different outcomes by comparing the results achieved by elderly female and 

male patients in the RICOVER-60 and SMARTE-R trials. Methods: In 

SMARTE-R, 189 evaluable elderly (61-80 y) pts. with DLBCL received 6 

cycles of 2-weekly CHOP-14 combined with 8xR on days -4, -1, 10, 29, 

57, 99, 155, and 239. The primary endpoint was event-free survival (EFS). 

306 pts treated within the RICOVER-60 trial with 6xCHOP-14 � 8 R given 

on days 1, 15, 29, 43, 57, 71, 85 and 99 served as controls. Results: The 

3-year EFS of 51 poor-prognosis male patients in SMARTE-R was 67% 

compared to 47% of 66 poor-prognosis male patients treated in RI- 

COVER-60 (p�0.037); the respective figures were 71% vs. 53% (p�0.051) 

for PFS and 80% vs. 60% (p�0.027) for OS. In contrast, female poor-risk 

patients had only a small benefit from the extended rituximab exposure in 

SMARTE-R (n�48) compared to RICOVER-60 (n�57): 67% vs. 61% 

(p�0.354) for EFS; 71% vs. 67% (p�0.489) for PFS; and 80% vs. 76% 

(p�0.528) for OS. Conclusions: Elderly male patients with poor-prognosis 

DLBCL who have a faster R clearance and shorter R serum elimination half 

life than female patients, benefit significantly from the longer R exposure in 

SMARTE-R with a gain of 20% in 3-year OS, while the outcome of female 

patients was only slightly improved. Even though R maintenance has failed 

to demonstrate any benefit in the primary treatment of DLBCL to date, 

these results underline the importance of a minimum exposure time of R in 

order to exploit its full therapeutic potential in DLBCL. Supported by 

Deutsche Krebshilfe. 


12:00 PM-1:00 PM 

Retreatment with brentuximab vedotin in CD30-positive hematologic 

malignancies: A phase II study. Presenting Author: Nancy Bartlett, Washington 

University, Siteman Cancer Center, St. Louis, MO 

Background: Brentuximab vedotin comprises an anti-CD30 antibody conjugated 

by a protease-cleavable linker to a microtubule-disrupting agent, 

MMAE. In pivotal phase 2 studies in patients (pts) with relapsed/refractory 

Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma 

(sALCL), objective response rates were 75% and 86% and median 

durations of response were 6.7 and 12.6 mo, respectively. A phase 2 study 

was initiated to investigate if pts who have previously responded to 

brentuximab vedotin could achieve another remission with retreatment 

(ClinicalTrials.gov #NCT00947856). Methods: Pts had a CD30-positive 

hematologic malignancy, achieved an objective response (per Cheson 

2007) with prior brentuximab vedotin treatment, and experienced relapse 

after discontinuing treatment. Brentuximab vedotin was administered IV 

1.8 mg/kg every 21 days; antitumor activity was assessed by the investigator. 

Results: 14 HL pts and 8 sALCL (5 ALK-negative) pts were enrolled 

(median age 34 yr, range 16–72). Pts had received a median of 4 prior 

chemotherapy regimens (range 2–12). Median time since the previous 

brentuximab vedotin treatment was 6.9 mo (range 1–44). Median number 

of retreatment cycles was 7 (range 1� to 32�). Adverse events (AEs) in 

�25% of pts were nausea (41%), fatigue (36%), peripheral sensory 

neuropathy (36%), and diarrhea (27%). The most common Grade 3/4 AEs 

were anemia, fatigue, and hyperglycemia (3 pts each). Of the 11 pts who 

had pre-existing peripheral neuropathy, 3 (27%) had worsening with 

retreatment. Best clinical responses in pts with HL were 3 CR, 5 PR, 3 SD, 

3 PD. Among pts with sALCL, 5 achieved a CR, 1 had PD, and 2 were not 

yet evaluated. Of the 8 pts with CR in retreatment, previous best responses 

to brentuximab vedotin treatment were 4 PR and 4 CR. Median duration of 

retreatment response was 10.8 mo (range 0� to 10.8), and in pts who 

achieved CR, the median duration of response was not reached (range 0� 

to 10.5 mo); 11 pts remain on retreatment. Conclusions: Retreatment with 

brentuximab vedotin was generally well tolerated. Objective responses were 

observed (13 of 20; 65%) in this heavily pretreated population. Enrollment 

to the phase 2 retreatment study is ongoing. 


12:00 PM-1:00 PM 

Multicenter, phase II study of bendamustine in refractory or relapsed T-cell 

lymphoma: The BENTLY trial. Presenting Author: Remy Gressin, University 

Hospital Grenoble, Grenoble, France 

Background: T-cell lymphomas have a poor prognosis with few options of 

effective treatment. This study determined the efficacy and safety of 

bendamustine as a single agent in the treatment of refractory or relapsed 

T-cell lymphomas. Methods: Patients with histologically confirmed peripheral 

T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL), who 

had previously received at least one line of chemotherapy were selected. 

Bendamustine was administered IV at the dosage of 120 mg/m2 on days 1 

and 2 every 3 weeks, for 6 cycles. Treatment response was assessed using 

the IWC for non-Hodgkin’s lymphoma. The primary end point was overall 

response rate (ORR). Secondary end points were duration of response 

(DoR), progression-free survival (PFS), and overall survival (OS), 

NCT00959686. Results: Twenty two female and 38 male were included. 

The median age was 66 years with more 1/4 of them � 75. Histology was 

predominantly angio-immunoblastic lymphadenopathy (n�32) and PTCLnos 

(n�23). The median previous line of chemotherapy was 1 (1-3). Nearly 

one half (45%) of the patients was refractory to the last previous 

chemotherapy and the median duration of the best previous response was 

6.6 (1.5-67) months. The disease was disseminated in the majority of case 

(87%) and the international prognostic index (IPI) was high (3–5) in 68% 

of the patients. Twenty patients (33%) received less than 3 cycles of 

bendamustine. The major reason for early discontinuation was disease 

progression. In the Intent-To-Treat (ITT) population, the best ORR was 

50%, including complete response (CR) in 28% and partial response (PR) 

in 22 %. Bendamustine showed a consistency in the efficacy as a function 

of major disease characteristics. The median values for DoR, PFS and OS 

were 3.5, 4 and 6 months respectively. The most frequent grade 3/4 AEs 

were neutropenia (30%), thrombocytopenia (24%) and infections (20%). 

Conclusions: Bendamustine is active in high risk refractory and relapsed 

T-cell lymphoma with manageable toxicity. 


12:00 PM-1:00 PM 

Everolimus (EVE) for relapsed/refractory classical Hodgkin lymphoma 

(cHL): Open-label, single-arm, phase II study. Presenting Author: Patrick 

B. Johnston, Mayo Clinic, Rochester, MN 

Background: Effective treatment for relapsed/refractory cHL is lacking. The 

oral mammalian target of rapamycin inhibitor EVE showed promising 

efficacy and acceptable toxicity in cHL. We conducted a study to confirm 

EVE safety and efficacy in relapsed/refractory cHL. Methods: In this 

multicenter, open-label, 2-step, phase 2 study, adults with cHL that 

progressed after high-dose chemotherapy with autologous hematopoietic 

stem cell transplant (AHSCT) or a gemcitabine-, vinorelbine-, or vinblastinecontaining 

regimen received EVE 10 mg/d until disease progression or 

unacceptable toxicity. Response was assessed every 12 wk via integrated 

positron emission tomography/computed tomography (CT) with contrast or 

CT with contrast. Primary endpoint was overall response rate (ORR) per 

modified response criteria for malignant lymphoma. Adverse events (AEs) 

were assessed during, and for �4 wk after, EVE treatment. Results: 55 

patients were enrolled. Of the 38 currently evaluable patients, 37% were 

men, median age was 32.5 y, 53% were pretreated with AHSCT, and 95% 

were pretreated with gemcitabine, vinorelbine, or vinblastine; 71% had 

disease progression during previous therapies or discontinued previous 

treatment due to progression. 23 patients discontinued treatment, most 

commonly due to disease progression (n � 11). ORR was 37% (Table). 

Median progression-free survival (PFS) was 7.2 mo. The most common 

hematologic AEs were thrombocytopenia (39%) and anemia (24%); the 

most common nonhematologic AEs were fatigue (47%), cough (29%), 

dyspnea (26%), headache (21%), and rash (21%). Grade 3/4 AEs, most 

commonly thrombocytopenia (18%), were observed in 45% of patients. 

Conclusions: EVE showed a favorable ORR and median PFS in the first 38 

evaluable patients with highly pretreated, relapsed/refractory cHL. The AE 

profile was consistent with that previously observed for EVE. These 

preliminary results confirm those of an earlier study and support further 

evaluation of EVE in cHL. 

Best overall response, n (%) 

EVE 10 mg/d 

N�38 

ORR 14 (36.8) 

Complete response* 1 (2.6) 

Partial response 13 (34.2) 

Stable disease 10 (26.3) 

Progressive disease 5 (13.2) 

Unknown 

*Defined as resolution of all adenopathy. 

9 (23.7) 



12:00 PM-1:00 PM 

A multicenter phase II study of vorinostat in patients (pts) with relapsed or 

refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell 

lymphoma (MCL). Presenting Author: Kiyoshi Ando, Department of Hematology 

and Oncology, Tokai University, Kanagawa, Japan 

Background: Most pts with indolent B-NHL relapse even after rituximabcontaining 

chemotherapy. Vorinostat is an orally active histone deacetylase 

(HDAC) inhibitor, and is under investigation as monotherapy or in combination 

regimens in various hematologic malignancies. It has been reported 

that the histone acetyltransferase genes (EP300 and CREBBP) are frequently 

mutated in NHL, suggesting the potential usefulness of HDAC 

inhibitors in its treatment. Methods: We conducted a phase 2 study to 

investigate the efficacy, safety and tolerability of vorinostat in pts with 

indolent B-NHL or MCL with the overall response rate (ORR) against 

follicular lymphoma (FL) as the primary endpoint. The primary hypothesis 

was to demonstrate the efficacy in FL pts as measured by the ORR. 

Assuming the true ORR with vorinostat of 50% and without vorinostat of 

less than 25%, 39 pts will provide 90% power to demonstrate an 

ORR�25%. Vorinostat was administered at the dose of 200 mg BID for 14 

consecutive days in a 21-day cycle. The ORR and PFS were determined by 

an independent review panel in the Full Analysis Set (FAS) population. 

Results: A total of 56 pts with a median age of 60 years (range: 33 - 75) 

were enrolled, and 50 of them (39 with FL, 11 with other subtypes of 

indolent B-NHL or MCL) were included in the FAS population. The number 

of prior therapeutic regimens was 2 (range: 1 - 4) and 41 pts have 

previously received rituximab-based regimens.. The percentages of pts with 

FLIPI at low risk, intermediate risk and high risk were 41%, 39%, and 

21%, respectively. The ORR in 39 pts with FL was 49% (95% CI: 32, 65), 

and the pre-specified statistical success criterion was met. The median 

PFS in 39 pts with FL was 17.5 months (range: 2, 22�), especially the 

median PFS in 19 responders with FL has not yet been reached. The major 

toxicities were hematologic and gastrointestinal ones, which were reversible 

and manageable. Grade 3/4 infection was observed in 2%. Conclusions: 

This phase 2 study demonstrated that oral vorinostat is an agent with 

sustained antitumor activity in pts with relapsed or refractory indolent 

B-NHL, with acceptable safety profiles, warranting further investigations. 


12:00 PM-1:00 PM 

CNS-directed chemotherapy including high-dose chemotherapy with autologous 

stem cell transplantation (HD-ASCT) for CNS relapse of aggressive 

lymphomas: Final analysis of a phase II study. Presenting Author: Agnieszka 

Korfel, Department of Hematology and Oncology, Charite Campus 

Benjamin Franklin, Berlin, Germany 

Background: The outcome of patients with CNS relapse of aggressive 

lymphoma (secondary CNS lymphoma, SCNSL) is poor with no standard 

therapy established thus far. Here we present the final analysis of a 

prospective multicenter phase II study using an intensive induction 

regimen followed by high-dose chemotherapy and autologous stem-cell 

transplantation. Methods: Adult immunocompetent patients �65 years 

with SCNSL were eligible. Induction chemotherapy consisted of two cycles 

MTX/IFO (methotrexate 4g/m2 iv. d1, ifosfamide 2g/m2 iv. d3-5 and i.th. 

liposomal cytarabine 50mg d6) and one cycle AraC/TT (cytarabine 3g/m2 d1-2, thiotepa 40mg/m2 iv. d2 and i.th. liposomal cytarabine 50mg d3). 

Then, patients without progression received high-dose chemotherapy with 

carmustine 400mg/m2 iv. d -5, thiotepa 2x5mg/kg iv. d -4 to -3 and 

etoposide 150mg/m2 iv. d -5 to -3 followed by ASCT d0. Results: Thirty 

eligible patients (median age 58 years) were enrolled. Three patients had 

T-cell and 27 aggressive B-cell lymphoma. Pre-treatment was CHOP-like in 

29 patients, including rituximab in 26. CNS relapse occurred after a 

median of 8.5 (3-80) months and was intracerebral in 23 and meningeal 

in13 patients (combined in 7); 6 had concomitant systemic lymphoma. 

After induction therapy CNS response was found in 22 (73%) patients 

(8xCR, 14xPR), 3 patients had SD, 4 patients PD and 1 patient no 

response evaluation. HD-ASCT was performed in 24 patients; resulting in 

15 CR (63%), 2 PR (8%) and 7 PD (29%). Myelotoxicity was the most 

frequent WHO grade 3-4 adverse event with infections in 8/30 pts on 

MTX/IFO (27%), 5/23 (22%) on AraC/TT and 11/20(55%) on HD-ASCT. 

One patient died due to septic diverticulitis and one developed persisting 

fecal incontinence. The median follow up was 21 months. The median PFS 

was 12.1 months (95% CI 6.4-17.7) in all patients and 30.4 (95%CI 

2.5-58.3) months after HD-ASCT, the median overall survival was 27.4 

months and not reached, respectively. Conclusions: This first prospective 

study on SCNSL demonstrates that lasting remissions can be achieved with 

CNS-directed HD-ASCT in a large proportion of patients and probably cure 

in some. 


517s 


12:00 PM-1:00 PM 

Interim analysis of the largest prospective trial to date in adult CD20positive 

post-transplant lymphoproliferative disorder (PTLD): Introducing 

risk-stratified sequential treatment (RSST). Presenting Author: Ralf Ulrich 

Trappe, Department of Internal Medicine II: Hematology and Oncology, 

University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany 

Background: The prospective, multicenter international phase II PTLD-1 

trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 

cycles of CHOP-21 � G-CSF) in adult CD20-positive PTLD demonstrated 

excellent efficacy (90% overall response rate, ORR) and safety (11% 

treatment-related mortality, TRM). As the response to rituximab predicted 

overall survival (OS), the trial was amended in 2007 introducing riskstratified 

sequential treatment (RSST) according to the response to 

rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 

and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy 

for patients (pts) in complete remission (CR, low risk) while all others (high 

risk) received 4 cycles of R-CHOP-21 � G-CSF. Key exclusion criteria were 

CNS involvement, HIV infection, severe organ dysfunction not related to 

PTLD, and ECOG � 2. Primary endpoint was ORR. This is an analysis of the 

first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 

12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or 

heart�lung, 3 heart�kidney and 1 kidney�pancreas transplant recipients. 

Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late 

PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of 

treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of 

RSST was 7/90 (8%) including 5 deaths with unknown remission status. 

ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 

pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up 

of �3 years, relapse rate in low risk pts was not increased by rituximab 

consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 

5/14, p�0.104]). In patients in PD after rituximab, R-CHOP was more 

effective than CHOP in achieving CR (15/23 vs. 3/11, p�0.038). OS at 3 

years was higher with RSST (70%, 95% CI: 60-82%) compared to ST 

(61%, 95%CI 49-72%) but this difference was not significant. Conclusions: 

With RSST 27% of pts were classified as low risk and achieved durable 

tumor control without chemotherapy while R-CHOP seems more efficient 

than CHOP in in high risk patients. 


12:00 PM-1:00 PM 

Phase Ib trial of AVL-292, a covalent inhibitor of Bruton’s tyrosine kinase 

(Btk), in chronic lymphocytic leukemia (CLL) and B-non-Hodgkin lymphoma 

(B-NHL). Presenting Author: Jennifer R. Brown, Dana-Farber 


Background: Btk supports activation, survival, and proliferation of malignant 

B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 � 0.5nM), 

selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) 

with previously treated CLL or B-NHL were administered AVL-292 in 

escalating cohorts of 125, 250, or 400 mg po QD using a 3�3 design in 

continuous 28 day cycles until progressive disease (PD) or toxicity. Key 

objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma 

AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 

was assessed by covalent probe assay in peripheral blood mononuclear 

cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 

400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior 

therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with 

both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 

B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 

marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. 

Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD 

after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or 

grade 4 adverse events (AEs) have occurred and MTD has not been reached. 

Most frequent AEs reported include transient diarrhea, rash/skin infection, 

URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug 

related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients 

have stable disease (SD) with median 28% decrease from baseline lymph 

node measurement (range 3-40% decrease). Six of 8 pts with CLL 

experienced increased ALC in cycle 1: median increase 89.5% (range 

50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 

not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose 

levels � 250 mg. Multiple dose PK exposure (AUClast) was linear with no 

accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated 

from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL 

shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was 

achieved with � 250 mg QD and PK was predictable with no accumulation. 

Dose escalation is ongoing and MTD cohort expansion is planned. 




12:00 PM-1:00 PM 

Oral weekly MLN9708, an investigational proteasome inhibitor, in combination 

with lenalidomide and dexamethasone in patients (pts) with previously 

untreated multiple myeloma (MM): A phase I/II study. Presenting 

Author: Paul Gerard Guy Richardson, Dana-Farber Cancer Institute, Boston, 

MA 

Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The 

feasibility of combining a proteasome inhibitor with an immunomodulatory 

drug and a steroid in previously untreated MM has been demonstrated with 

the RVD regimen. This is the first study of MLN9708 in combination with 

lenalidomide and dexamethasone (NCT01217957). Here we report the 

phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with 

previously untreated MM, aged �18 yrs with measurable disease received 

oral MLN9708 (phase 1: 1.68–3.95 mg/m2 ) days 1, 8, and 15, lenalidomide 

25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, 

for up to twelve 28-day cycles. Primary objectives were determination of 

safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and 

CR�VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had 

been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 

69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 

mg/m2 and the RP2D as 2.23 mg/m2 ; for Ph 2, the RP2D was converted to 

a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received 

a median of 6 treatment cycles (range 1–11), 8 received �6 cycles; 6 

stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 

(range 1–2), all are ongoing. Grade �3 hematologic toxicity was reversible 

and included anemia (n�2) and thrombocytopenia (n�1). Grade �3 

nonhematologic toxicity included erythematous rash, syncope, and vomiting 

(2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 

pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the 

MTD). Two pts discontinued due to AE; there were 5 pts who had serious 

drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 � Ph 2), all 

achieved �PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in 

response with duration of confirmed response of up to 9.5 months. Of 4 

response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. 

Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears 

well tolerated with manageable toxicity. These data show antitumor 

activity at the RP2D in pts with previously untreated MM, with �PR in all 

pts to date. 


12:00 PM-1:00 PM 

Response rates to single-agent carfilzomib in patients refractory or intolerant 

to both bortezomib and immunomodulators in trial PX-171-003-A1. 

Presenting Author: David Samuel DiCapua Siegel, John Theurer Cancer 

Center, Hackensack, NJ 

Background: Patients (pts) with relapsed and refractory multiple myeloma 

(RR MM) who are refractory or intolerant to both bortezomib (BTZ) and 

immunomodulators (IMiDs; thalidomide [Thal] or lenalidomide [Len]) (ie, 

“double-refractory/intolerant”), have few therapeutic options and a poor 

prognosis. Carfilzomib (CFZ), a next generation proteasome inhibitor (PI), 

has shown durable single-agent activity in clinical studies including 

003-A1, an open-label, single-arm phase 2b trial in RR MM. The present 

analysis describes clinical activity in pts from 003-A1 with double-refractory/ 

intolerant disease and in other groups of clinical interest including pts with 

disease refractory to all 5 approved classes of anti-MM tx (alkylators, 

anthracyclines, corticosteroids, IMiDs, and PIs) in clinical use (“refractory 

to all approved tx”). Methods: Pts from 003-A1 with double-refractory/ 

intolerant disease were analyzed, as were pts with disease refractory to all 

approved tx. CFZ was given on days 1, 2, 8, 9, 15, 16 of 28-day cycles (C), 

(20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall 

response rate (ORR). Secondary endpoints included duration of response 

(DOR), overall survival, and safety. Results: The study ORR was 22.9% with 

median DOR of 7.8 mo (N�266). 228 pts (86%) with double-refractory/ 

intolerant disease had ORRs of 20.6% and a median DOR of 7.4 mo. 

Conclusions: Single-agent CFZ demonstrated clinically meaningful, durable 

responses in pts with double-refractory/intolerant MM or disease refractory 

to all 5 approved classes of tx. The ORRs across groups of clinical interest 

were generally consistent with results for the entire study population. These 

results are notable for a next-generation PI and demonstrate the activity of 

single-agent CFZ in pts with advanced stage MM. 

Refractory status n ORR (>PR), % DOR, mo 

Refractory/intolerant to BTZ and (>1 IMiD) 228 20.6 7.4 

To BTZ in any prior regimen 194 16.5 7.8 

To Thal in any prior regimen 118 17.8 5.6 

To Len in any prior regimen 221 22.2 7.8 

Refractory to all approved tx 44 20.5 7.8 


12:00 PM-1:00 PM 

Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in 

patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I 

study. Presenting Author: Shaji Kumar, Mayo Clinic, Rochester, MN 

Background: Phase 1 studies are evaluating IV and oral dosing of the 

reversible proteasome inhibitor MLN9708 in multiple tumor types. We 

report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and 

preliminary responses with weekly oral MLN9708 in pts with relapsed/ 

refractory MM (NCT00963820). Methods: Pts aged �18 yrs received 

MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, 

pts required �2 prior therapies (including bortezomib, thalidomide/ 

lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to 

relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor 

(PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have 

been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation 

phase (0.24–3.95 mg/m2 ) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI 

naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation 

cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and 

median number of prior lines of therapy was 3.5 (range 1-13), including 

92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, 

thalidomide, and carfilzomib, respectively. Pts have received a median of 2 

cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable 

pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) 

and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 

mg/m2 . Overall, 69% of pts had drug-related AEs, and 28% had related 

grade �3 AEs, including thrombocytopenia (17%), diarrhea (11%), 

nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had 

drug-related peripheral neuropathy (PN; no grade �3). 2 pts discontinued 

due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2 ,1 

had a PR at 2.97 mg/m2 , and 8 have achieved SD durable for up to 9.5 

mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2 ), Tmax of 

0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active 

hydrolysis product). There was a trend for a dose-dependent increase in 

whole blood 20S proteasome inhibition. Conclusions: Current data suggest 

weekly oral MLN9708 is generally well tolerated with infrequent PN, and 

shows early signs of antitumor activity. 


12:00 PM-1:00 PM 

Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or 

refractory multiple myeloma. Presenting Author: Adriana C. Rossi, Weill 

Cornell Medical College, New York Presbyterian Hospital, New York, NY 

Background: Clarithromycin has been shown to enhance anti-myeloma 

activity of lenalidomide�dexamethasone in the upfront treatment of 

multiple myeloma (MM). Pomalidomide is an immunomodulatory agent 

effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin 

may similarly enhance pomalidomide � dexamethasone in RRMM. 

We now report updated results from a phase 2 trial of ClaPD in RRMM. 

Methods: 73 patients with RRMM were enrolled in a single-institution 

phase 2 study of ClaPD. All subjects had � 3 prior lines of therapy, one of 

which must have included lenalidomide. ClaPD is clarithromycin 500mg 

twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days 

1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin. 

Monthly disease response evaluation included immunoelectrophoresis and 

free light chain analysis; bone marrow biopsy with skeletal imaging was 

used to confirm MM responses. Treatment continued as tolerated until 

disease progression. Results: The 66 patients who completed � 1 cycle of 

ClaPD are reported. Median number of cycles was 6 (range 1-17). 

Responses were progressive disease: 10%, stable disease: 21%, minimal 

response: 12%, partial response: 33%, very good partial response: 18%, 

stringent complete remission: 5%, for an overall response rate (ORR) of 

56% and �VGPR rate of 23%. Median time to PR was 1.25 cycles (range 

1-8). Median PFS was 5 months. Response and PFS were not different in 

patients refractory to lenalidomide (85%), bortezomib (82%), or doublerefractory 

patients (76%). After a median follow up of 12 months,28 pts 

(42%) remain on study without progression and 56pts (85%) are alive. Two 

pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular 

weakness). One patient withdrew consent. Conclusions: ClaPD is highly 

effective for heavily pre-treated RRMM, particularly in lenalidomiderefractory 

disesase and compares favorably to previously published Phase 2 

data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess 

toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7 

months in most subjects. These data support the clinical efficacy of 

pomalidomide based regimens in RRMM. 



12:00 PM-1:00 PM 

Connect MM: The multiple myeloma (MM) disease registry—Incidence of 

second primary malignancies (SPM). Presenting Author: Robert M. Rifkin, 

US Oncology Research, Denver, CO 

Background: Advances in the treatment of MM have greatly improved 

clinical outcomes for patients (pts). SPM occurrence has been observed in 

early and late stage MM as well as with increasing age. US SEER Cancer 

Registry reports a background incidence rate of SPM 2.1/100 person-yrs 

(PY) among persons � 65 yrs of age. However, incidence of SPM in MM pts 

and the relationship to therapy still warrants further exploration. Methods: 

Connect MM is a US-based observational registry designed to characterize 

pts with newly diagnosed MM from 266 US sites. Initiated in Sep 2009, 

patient data were collected at baseline and each subsequent quarter with a 

standardized form. On Dec 14, 2011, Connect MM reached full enrollment 

at 1,500 pts. Results: As of Jan 13, 2012, preliminary retrospective SPM 

data is available for 1015 pts. Median age was 67 yrs, 56.8% male, and 

median follow-up was 10.6 mo (0.03-24.9 mo). 12 pts (7 male) with 

median age of 68.5 yrs developed SPM. Median time to SPM was 8.5 mo 

(0.8-17.7 mo) after treatment initiation. 11 invasive SPM were observed - 

4 hematological (heme): 1 AML, 1 MDS, 1 CMML and 1 DLBCL, and 7 

solid: 2 melanoma skin, 1 bronchus, 1 breast, 1 prostate, 1 tonsil, and 1 

gastric carcinoid. Also, 1 pt had non-melanoma skin cancer (NMSC), and 1 

pt with invasive skin cancer also had NMSC. Of the 4 pts developing heme 

SPM, 3 had bortezomib (BORT), 1 had thalidomide (THAL), 1 had 

lenalidomide (LEN), 2 had melphalan (MEL), and all 4 pts had steroids. Of 

the 7 pts who developed solid tumor SPM, 5 had BORT, 5 had LEN, 2 had 

doxorubicin, 1 had MEL, 5 had steroids, 1 had irradiation, and 1 had not 

received MM treatment. 2 pts with prior history of invasive malignancy 

developed solid tumor SPM (1 pt also developed NMSC).1 pt who received 

irradiation developed NMSC. Early overall incidence of invasive SPM was 

1.21/100 PY (95% CI 0.60, 2.16) for all pts and 1.20/100 PY (95% CI 

0.44,2.62) for pts � 65 yrs of age. Conclusions: This preliminary analysis 

shows that SPM occurred at an expected rate in this disease specific 

registry of patients with NDMM and appeared to occur irrespective of MM 

treatment administered. Incidence rates of SPM may increase over time as 

patients receive transplantation and alkylators. Prospective observation will 

continue. 


12:00 PM-1:00 PM 

Second cancer risk 40 years after cure for Hodgkin lymphoma. Presenting 

Author: Michael Schaapveld, The Netherlands Cancer Institute, Antoni van 

Leeuwenhoek Hospital, Amsterdam, Netherlands 

Background: During the last decades Hodgkin Lymphoma (HL) treatment 

changed towards less toxic chemotherapy schemes and smaller radiation 

fields. The impact of these changes on second cancer (SC) risk is still 

unknown. Methods: We calculated standardized incidence ratios (SIR), 

comparing SC risk after HL treatment with expected risk, based on cancer 

incidence in the general population, and compared SC risk between 

treatment modalities, accounting for competing events, in a large Dutch 

cohort comprising 3,390 5-years HL survivors, aged 15-51 years at HL 

treatment and diagnosed between 1965-2000. Results: The median 

follow-up was 18.2 years; 23% of the patients was followed �25 years. 

During follow-up 734 SCs and 92 third cancers (TC) occurred. The SIR for 

any SC was 4.5 (95% confidence interval (95%CI) 4.1-4.9). SC risk was 

still elevated after 35 years of follow-up (SIR 3.9; 95%CI 2.5-5.8) and 

cumulative incidence (CI) reached 47.1% (95%CI 43.6-50.5) at 40 years 

follow-up. For TCs the SIR was 5.5 (95%CI 4.4-6.9); the 20-year CI was 

22.3% (95%CI 17.8-27.2). Risks of NHL and leukemia strongly decreased 

in more recent treatment periods (P-trend �0.001). The CI of solid tumors 

(ST) between 5-19 years after HL treatment did not differ for patients 

treated between 1965-1979, 1980-1989 or 1990-2000 (P�0.21; 19year 

CI 9.1%, 11.6% and 11.4%, respectively). Radiotherapy (RT) above 

the diaphragm increased risk of STs above the diaphragm (hazard ratio 

(HR) 2.4, P�0.001), while subdiaphragmatic RT was associated with a 

1.7-fold increased HR of a subdiaphragmatic ST (P�0.001). An incomplete 

mantle field was associated with significantly lower breast cancer 

(BC) risk (hazard ratio (HR) 0.4, 95%CI 0.2-0.8). A cumulative procarbazine 

dose �4.2 g/m2 yielded a 1.3-fold increased HR (95%CI 1.0-1.7) for 

non-breast STs and a 2-fold (95%CI 1.2-3.1) increased HR for gastrointestinal 

STs, but was associated with a strongly decreased BC risk (HR 0.3, 

95%CI 0.2-0.6). Conclusions: SC risk after HL has decreased with 

treatment changes over the last decades, due to strongly decreasing risk of 

leukemia and NHL. Smaller radiation fields and procarbazine doses �4.2 

g/m2 are associated with lower breast cancer risk, while high procarbazine 

doses increase risk of gastrointestinal STs. 


519s 


12:00 PM-1:00 PM 

Risk factors for development of second primary malignancies (SPM) after 

autologous stem cell transplant (ASCT) for multiple myeloma. Presenting 

Author: Amrita Y. Krishnan, City of Hope, Duarte, CA 

Background: Studies from the CALGB and IFM have suggested an increased 

incidence of SPM post ASCT in patients on lenalidomide maintenance. 

Patients with MM as well as patients post ASCT are inherently at higher risk 

of SPM. Therefore, assessment of risk factors associated with SPM would 

be useful in therapeutic decisions re preASCT therapy and post ASCTmaintenance. 

Methods: We conducted a retrospective cohort study of 841 

consecutive MM patients who underwent at least one ASCT at City of Hope 

from 1989 to 2009. Sixty cases with 70 SPMs were identified. A nested 

case-control study was also conducted to understand the role of therapeutic 

exposures associated with SPMs. Controls were MM patients post ASCT 

matched by year of HCT (�5 years). Results: The median length of follow up 

was 3.3 yrs. (range 0.3-19.9). Median age at ASCT was 56 yrs (range 

18-77). 62% had received a single autologous HCT, 27% tandem 

autologous HCT, 11% had received multiple HCTs (72 had a second 

allogeneic HCT)). The overall cumulative incidence of any SPM was 7.4% 

at 5 years and 15.9% at 10 years; the cumulative incidence of SPMs for 

patients �55 years approached 21.9% at 10 years. The cumulative 

incidence of MDS/AML was 1.8% and of solid tumors was 13.0%. Factors 

examined included age, race, sex, number and individual therapeutic 

exposures ( pre-ASCT, conditioning, and post-ASCT), disease status at 

ASCT. Multivariate Cox regression analysis revealed non-Hispanic whites 

(RR�2.4, 95% CI, 1.2-4.6, p�0.01) and older age (�55) at diagnosis of 

MM (RR�2.3, 95% CI, 1.3-4.1, p�0.004) to be associated with an 

increased risk of developing SPMs. Only cumulative thalidomide exposure 

(both pre-ASCT and post-ASCT) demonstrated a trend toward a positive 

association (OR�3.5, 95% CI, 0.6-19.4, p�0.15). Six patients (3 cases 

and 3 controls) were exposed to lenalidomide prior to development of SPM 

(OR�1.0, 95% CI, 0.14-7.10). Conclusions: This single institution analysis 

identified non-hispanic whites and older age to be associated with 

increased risk of developing SPM in pts post ASCT for MM. The trend 

towards increased risk with thalidomide exposure may be suggestive of a 

class effect from IMIDs that is not restricted to lenalidomide alone. 


12:00 PM-1:00 PM 

Impact of t (11;14) on the outcome of autologous hematopoietic cell 

transplantation (Auto-HCT) in multiple myeloma. Presenting Author: Koji 

Sasaki, Beth Israel Medical Center, New York, NY 

Background: Approximately 15-20% of patients with multiple myeloma 

(MM) present with t(11;14)(q13;q32) involving IgH and CCND1-XT genes. 

In this study, we report the impact of the t(11;14) on the outcome of 

patients with MM. Methods: We performed a retrospective chart review on 

patients with MM who underwent high-dose chemotherapy followed by 

auto-HCT at the M.D. Anderson Cancer Center between 2/2000 and 

8/2010, and had conventional cytogenetic (CC) or fluorescent in situ 

hybridization (FISH) results available before transplant. The primary 

objective was to compare the progression free survival (PFS) and overall 

survival (OS) of patients with t(11;14) to patients without chromosomal 

abnormalities. Results: CC or FISH studies were available for 1239 

patients: 863 normal, 28 with t(11;14), 348 with other abnormalities. 

Concurrent high-risk abnormalities on CC or FISH were seen in 15/28 

patients with t(11;14): del(13q) in 11 , del(17p) in 3, and t(14;16)(q32; 

q23) in 1. Induction treatment in patients with t(11;14) was: bortezomib � 

dexamethasone �/- thalidomide/lenalidomide : 15 (53%), thalidomide or 

lenalidomide � dexamethasone: 11 (39%), others 2 (8%); they received 

auto-HCT after a median of one line (1-7) of therapy. Median follow up in 

surviving patients was 39 months. There was no significant difference in 

median time from diagnosis to auto-HCT from diagnosis (6.9 vs. 7.7 

months, p�1.0), disease status at auto HCT (�PR1: 82 vs. 76%, �PR1: 7 

vs. 11%, relapsed 10 vs. 13%), complete remission (CR: 21% vs. 32%; 

p�0.30), very good partial remission (VGPR: 29% vs. 21%; p�0.23) or 

overall response (75% vs. 85%; p�0.18) between patients with t(11;14) 

and normal karyotype. Median PFS in patients with t(11;14) and normal 

karyotype was 15.7 months and 35.9 months, respectively (p�0.017). 

Median OS in patients with t(11;14) and normal karyotype was 51.4 

months and 88.4 months, respectively (p�0.03). There was no difference 

in PFS (p�0.25) or OS (p�0.71) in patients with t(11;14), with or without 

other high-risk chromosomal abnormalities. Conclusions: In this large 

single center study with a long follow up, we demonstrated that t(11;14) in 

MM is associated with a shorter PFS and OS in the context of auto-HCT. 




12:00 PM-1:00 PM 

Metronomic therapy for heavily pretreated relapsed/refractory multiple 

myeloma (RRMM). Presenting Author: Xenofon Papanikolaou, Myeloma 

Institute for Research and Therapy, Little Rock, AR 

Background: RRMM represents a true challenge in MM therapy. Based on 

the effectiveness of metronomic therapy in solid tumors, we developed a 

treatment of metronomically scheduled therapy (MT) for RRMM (Hollmig, 

ASH 2004). We are now updating our experience with a median follow up of 

25.6 months. Methods: We identified 187 patients treated with MT from 

03/2004 to 11/2011. Results: The median age was 61 years (range 

36-83); the median number of prior therapies was 14 (range 1-51). 79% of 

patients had prior HDT, 99% had a prior exposure to bortezomib, 98% to an 

IMiD, and 95% to their combination . The median number of completed 

MT cycles was 1 (range 1-5). 63% of patients had a response of MR or 

better (6% CR ,7% VGPR, 36% PR, 16% MR). The median overall (OS) 

and progression free (PFS) survivals were 11.3 and 3.7 months respectively. 

91 of 187 patients had gene expression profiling (GEP) prior to 

initiation of MT, of which 53% were high risk according to the 70-gene 

(GEP70) risk model. OS was affected by elevated CRP (� 8mg/L, 

HR�1.71, p�0.009) and cytogenetic abnormalities within 6 months of 

initiation of MT (HR�2.45, p�0.001). For the 91 patients with GEP data 

available, OS was correlated with elevated CRP � 8mg/L (HR�2.11, 

p�0.009) and GEP70 high-risk (HR�2.65, p�0.001), which also showed 

a trend towards shorter PFS. Hematological toxicity grading was difficult as 

69% of patients presented with grade ��3 thrombocytopenia within 90 

days prior to starting MT. Grade 4 leucopenia , anemia thrombocytopenia 

due to MT occurred in 74%, 17%, 89% of patients respectively. Incidence 

of grade 4 neutropenic fever was 1%. Grade 4 or worse incidence of all 

non-hematological toxicities was below 9%. Most patients were treated in 

the outpatient setting (95%) and secondary admissions due to regimen 

toxicity occurred in 20%. Conclusions: MT is an effective salvage treatment 

in RRMM, with a high ORR and a favorable toxicity profile. 

MT regimen. 

Agent Days Dosage 

Bortezomib 1,4,7,10,13,16 1 mg/m2 Thalidomide 1-16 200 mg 

Dexamethasone 1,4,7,10,13,16 20-40 mg 

Doxorubicin 

1-16 3 mg/m2 IV continuous infusion 

hydrochloride 

Cisplatin 1-16 1.5-3 mg/m 2 IV continuous infusion 

Rapamycin 1-16 3mg on day 1 , 1mg days 2-16 


12:00 PM-1:00 PM 

Long-term results of the phase II trial of the oral mTOR inhibitor everolimus 

(RAD001) in relapsed or refractory Waldenstrom macroglobulinemia. 

Presenting Author: Irene M. Ghobrial, Dana-Farber Cancer Institute, 

Boston, MA 

Background: The mammalian target of rapamycin (mTOR) signal pathway 

controls cell proliferation and survival. The trial’s goal was to determine the 

anti-tumor activity and safety of single-agent everolimus (TORC1 inhibitor) 

in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). 

Methods: Eligible patients had measurable disease (IgM monoclonal 

protein �1000 mg/dL with �10% marrow involvement or nodal masses �2 

cm), a platelet count �75,000 x 106 /L, a neutrophil count �1,000 x 

106 /L. Patients received everolimus 10 mg PO daily. Tumor response was 

assessed after cycles 2 and 6 and then every 3 cycles until progression. 

Results: 60 pts were treated. The median age was 64 years (range, 43-85). 

The median number of prior therapies was 3 (range, 1-11). All but two 

patients (97%) had received prior rituximab based therapy and 64% of 

patients had received prior alkylator based therapies. The overall response 

rate (complete response CR� partial response PR� minimal response MR) 

was 73% (95% CI: 60-84%), with a PR of 50% and 23% MR. The median 

time to progression (TTP), progression-free survival (PFS), and overall 

survival (OS) for the entire study population is 28 months (mos), (95% CI: 

18-not reached (NR)), 22 mos (95% CI: 12 0-NR), and 55 mos (95% CI: 

55-NR), respectively. The estimated PFS at 12 and 24 months is 62% 

(95%CI: 51-75%), and 48% (95%CI: 37-63%), respectively. The 30 

patients who achieved a PR responded after a median of 2 months (range, 

1-26) of treatment. The median duration of response (DR) for these 

patients has not yet been reached and 19 of these patients remain in 

response after a median follow up of 31 months (range, 3-54). All but two 

patients had a decrease in their serum IgM. Grade 3 or higher related 

toxicities were observed in 67% of patients. The most common were 

hematological toxicities with cytopenias. Pulmonary toxicity occurred in 

5% of patients. Dose reductions due to toxicity occurred in 63% of 

patients. Conclusions: Everolimus has high single-agent activity with an 

overall response rate of 73% and manageable toxicity in patients with 

relapsed WM, and offers a potential new therapeutic strategy for this patient 

population. 


12:00 PM-1:00 PM 

Detection of the MYD88 L265P mutation in Waldenström’s macroglobulinemia 

using a highly sensitive allele-specific PCR assay. Presenting Author: 

Lian Xu, Dana-Farber Cancer Institute, Boston, MA 

Background: Waldenström’s macroglobulinemia (WM) is a B-cell malignancy 

characterized by bone marrow (BM) infiltration with lymphoplasmacytic 

cells and production of an IgM paraprotein. By whole genome 

sequencing, we recently identified a somatic mutation (L265P) in the 

MYD88 gene in 27/30 (90%) WM patients (Treon et al, ASH 2011). To 

expand this finding for possible diagnostic testing, we developed an 

allele-specific PCR assay for MYD88 L265P and evaluated this assay in a 

large cohort of WM patients. Methods: An allele-specific PCR assay was 

developed with a threshold of detection of 0.125% for MYD88 L265P. 

DNA from bone marrow aspirates from 99 patients with the clinicopathological 

diagnosis of WM was used for assessment of MYD88 L265P expression 

by both allele-specific PCR and Sanger sequencing. Findings were correlated 

with clinical parameters using ANOVA. Results: We observed that 

85/99 (86%) WM patients were positive for MYD88 L265P using the 

allele-specific PCR assay. Of the 85 allele-specific PCR positive patients, 

81 demonstrated a detectable mutation peak by Sanger sequencing. All 14 

allele-specific PCR negative patients remained negative by Sanger sequencing. 

By the allele-specific PCR assay, MYD88 L265P positive patients 

showed greater bone marrow involvement, higher serum IgM and lower 

serum IgA and IgG levels versus MYD88 L265P negative patients 

(p�0.008). Conclusions: MYD88 L265P is highly expressed in BM samples 

of WM patients using an allele-specific PCR assay, and is associated with 

greater bone marrow disease burden and serum IgM levels. Use of 

allele-specific PCR provides a simple and sensitive diagnostic tool for 

detection of the MYD88 L265P mutation. 


Survival with splenectomy in splenic marginal zone lymphoma: Analysis of 

the Surveillance, Epidemiology and End Results (SEER) database. Presenting 

Author: Adam J. Olszewski, Alpert Medical School of Brown University, 

Providence, RI 

Background: The role of splenectomy as the primary therapy for splenic 

marginal zone lymphoma has been questioned. We studied relative survival 

in SMZL and the impact of splenectomy on lymphoma-specific survival 

(LSS). Methods: SMZL cases (diagnosed in 1993-2008) were derived from 

the SEER database. Age, sex and race-matched actuarial survival data were 

summarized. Factors predictive of splenectomy were studied using logistic 

regression with a subsequent propensity score (PS)-weighted survival 

analysis. Results: 1071 patients were identified with a median age of 69 

years (range, 25-96) and a median follow up of 33 months. 53% were 

women and 92% were white. 70% of the lymphomas were stage III/IV with 

B symptoms recorded in 22.3%. 54% of patients underwent splenectomy. 

The significant factors predictive of surgery included younger age (p�10- 14), stage I/II (p�10-15 ), B-symptoms (p�0.003), no prior malignancy 

(p�0.002), with significantly lower rates in black patients (OR 0.41, 

95%CI 0.21-0.80, p�0.008), on the Pacific Coast (OR 0.62, 95%CI 

0.47-0.81, p�0.0004) and with decreasing rates over time (p�0.0002). 

The actuarial 5-year relative survival was 82.8% (95%CI 77.9-86.7%) 

with no difference by sex (p�0.79), race or stage. 54% of deaths were 

related to SMZL with the estimated LSS of 80.8% (95%CI 78-84%). 

Splenectomy was not associated with improved LSS in propensity scorestratified 

log-rank test (p�0.60) or in the PS-weighted Cox model 

(HR�0.93, 95%CI 0.62-1.38, p�0.70). Advancing age (HR 1.05, 95%CI 

1.03-1.07, p�10-8 ) and presence of B-symptoms (HR�1.98, 95%CI 

1.30-3.01, p�0.002) were significantly predictive of death from SMZL, 

with no evidence of improvement in LSS over the years (HR�0.97, 

95%CI�0.91-1.03, p�0.34). There was also no detectable impact of 

splenectomy on survival in patients who ultimately died of SMZL (p�0.83). 

Conclusions: In this cohort, the largest studied to date, splenectomy did not 

demonstrate a survival benefit in SMZL. Patients continue to have 

decreased survival despite advances in other indolent B-cell lymphomas. 

The role of splenectomy versus chemoimmunotherapy remains to be 

determined. 



Survival outcomes in marginal zone lymphomas in the rituximab era: 

Analysis of the Surveillance, Epidemiology, and End Results (SEER) 

database. Presenting Author: Jorge J. Castillo, The Miriam Hospital, 

Providence, RI 

Background: Despite prognostic models developed for marginal zone 

lymphoma (MZL), the impact of different characteristics and treatments on 

survival in the population is largely unknown. We studied survival of MZL 

patients included in the SEER database. Methods: Records of MZL adult 

cases diagnosed between 1989-2008 were studied using descriptive 

methods and analysis of overall (OS) and lymphoma-specific (LSS) survival 

based on Kaplan-Meier function, stratified log-rank tests and Cox proportional 

hazard models. Results: 13,957 patients with MZL were identified 

and classified as splenic (SMZL; n�1,111, 8%), nodal (NMZL; n�4,101, 

29%) or extranodal MALT-type MZL (MALT; n�8,745, 63%). The median 

age was 68 years, 74% of patients were white and 55% were women. 

Median follow-up was 40 months. MALT was more common in non- 

Caucasians (p�10-27 ). B-symptoms were more common in SMZL (p�10- 5). Both LSS and OS were significantly better for MALT (p�10-60 ) with no 

difference between SMZL and NZML (p�0.30). 10-year LSS estimates 

were 67% for SMZL, 67% for NMZL, 84% for MALT. There was evidence 

for improved LSS since 2000 in MALT (HR 0.69, 95% CI 0.59-0.82, 

p�0.0003) and NMZL (HR 0.64, 95% CI 0.54-0.77, p�10-5 ), but not for 

SMZL (HR 0.85, 95% CI 0.56-1.28, p�0.43). Similar results were found 

for OS. There were differences in survival in MALT subtypes depending on 

primary site (p�10-12 ; Table). Conclusions: In the rituximab era, survival 

has improved for MALT and NMZL, but not for SMZL, possibly due to 

disparate treatment paradigms. The prognosis of MALT is different depending 

on primary site of involvement. 

Site n 5-year OS (%) 95% CI 

Skin 664 87.1 83.5-90.0 

Thyroid 179 85.8 78.0-90.9 

Ocular 1,108 82.4 79.4-85.0 

Salivary 719 82.4 78.7-85.5 

Connective tissue 190 81.7 73.9-87.4 

Breast 277 78.9 72.2-84.2 

Gastric 3,207 72.1 70.3-73.9 

Lung 737 72.1 67.9-75.9 

Bowel 791 71.1 67.2-74.7 

Other 392 72.7 67.0-77.7 


The utility of serum lactate dehydrogenase (LDH) in the follow-up of 

patients with diffuse large B-cell lymphoma (DLBCL). Presenting Author: 

Navneeth Rao Bongu, Nebraska Medical Center, Omaha, NE 

Background: The prognostic significance of high serum LDH is well 

established for both indolent and aggressive lymphomas at diagnosis. The 

performance characteristics of LDH in predicting relapse after treatment in 

patients (pts) with DLBCL has not been well studied. The determination of 

utility of LDH monitoring in pts with DLBCL would have widespread 

practice implications. Methods: We searched the Nebraska Lymphoma 

Study Group database to identify pts with DLBCL who were treated with a 

rituximab-based regimen, from 2000 to 2010, and sustained a complete 

response (CR). For the pts who relapsed (RP), after sustaining a CR, we 

collected the LDH level at relapse and the LDH level 3 months prior 

(considered baseline). For pts who never relapsed (NR), we collected the 

last 2 LDH levels at follow-up; levels had to be at least 3 months apart. The 

relative increase of LDH was compared, to baseline, among RP vs. NR. 

Results: We identified 129 pts, 15 pts were excluded from the analysis as 

their LDH results were not available, 27 relapsed and 87 didn’t. Median 

age of pts was 57 years. Only 9/27 RP (33%) had increase in LDH above 

upper limit of normal (ULN) at relapse. The mean increase in LDH at 

relapse was 1.2 fold above the ULN for RP vs. 0.83 for NR (p�0.59). The 

mean increase in LDH, from baseline, was 1.1 fold in NR vs. 1.3 in RP 

(p�0.3). The likelihood ratio (LR) of relapse was 4.65 for pts who had 1.5 

fold increase in LDH above baseline (1.5xLDH) vs. those who didn’t 

(p�0.03). The sensitivity, specificity, positive and negative predictive 

values of 1.5xLDH for detecting relapse, compared to clinical and imaging 

findings were 0.18, 0.95, 0.55, and 0.79 respectively. Also, 1.5xLDH at 

relapse was significantly associated with the presence of fever (LR�5.74; 

p�0.03) but not with other symptoms including drenching night sweats, 

anemia, or new/progressive lymphadenopathy. Conclusions: A 1.5 fold 

increase in LDH, over a period of 3 months, is associated with increased 

likelihood of relapse from DLBCL. Modest elevations in LDH (�1.5 fold of 

baseline) doesn’t seem to be associated with relapse. LDH, when elevated 

at least 1.5 fold of baseline, is a specific (i.e. 56%), but not a sensitive (i.e. 

19%) marker, for relapse of DLBCL. 


521s 


Early determination of treatment sensitivity in HIV-related Hodgkin lymphoma 

by FDG-PET/CT after two cycles of ABVD chemotherapy: A 

European Cooperative Study Group on AIDS and Tumors (GECAT) study. 

Presenting Author: Nicolas Mounier, CHU l’Archet, Nice, France 

Background: The high prognostic value of FDG-PET/CT performed after 2 

cycles of chemotherapy for HIV negative Hodgkin lymphoma (HL) is well 

known. However, experience with PET in HIV-related HL needs to be further 

studied as nodal FDG uptake can be observed in various opportunistic 

infections and AIDS-related conditions. Methods: A total of 45 consecutive 

HL patients (pts) were enrolled in 10 centers from the GECAT. There were 

42 males and 3 females. Median age was 46 yo, range [26;64]. Median 

CD4 count was 391/mm3 , range [33;1191]. Viral load was negative in 38 

pts (84%) and uncontrolled in 5 pts (11%). Forthy three pts (96%) 

received concomitant HAART. HL was staged III-IV in 25 pts. International 

Prognostic Index scored 3-5 in 24 pts. All PET studies were performed after 

2 ABVD cycles. They were scored, blinded to treatment outcome, according 

to the 5-point Deauville visual scale. It was considered as negative when 

scored 1-3 (i.e tumor FDG uptake less or equal than liver uptake) and 

positive when scored 4-5 (i.e. more than liver uptake or new lesions). 

Chemotherapy was not modified : 4-8 cycles of ABVD, as initially planned. 

Results: Overall, 35 pts (78%) achieved a CR after the end of treatment. 

Three pts received Involved Field Radiation Therapy. At a median follow-up 

of 18 months, 3 pts relapsed and 2 of them died from HL. The 2 yr OS and 

PFS were estimated at 94 and 90%, respectively. PET after 2 cycles of 

ABVD was negative in 40 pts (89%) and positive in 5 pts (11%). Patients 

with negative PET had a significantly better outcome than those with 

positive PET in term of 2 yr PFS (94% vs 60%, P�0.005), and 2 yr OS 

(100% vs 60%, P�0.0002). The negative predictive value was estimated 

at 97% and specificity at 93%. All patients who were PET-negative after 

the 2nd cycle stayed PET-negative after the 4th cycle and entered a 

durable CR. Conclusions: This largest study in HIV-positive HL showed that 

interim PET could play a central role in driving risk-tailored treatment. In 

further studies, de-escalation strategies should be tested for patients 

responding after 2 cycles of ABVD and those not reponding should be 

managed with intensive salvage strategies. 


Association of low expression of VEGF121 soluble isoform with prognostic 

impact and survival in patients with activated B-cell-like (ABC-like) diffuse 

large B-cell lymphoma (DLBCL) from the CORAL trial. Presenting Author: 

Catherine Thieblemont, Saint-Louis Hospital, Paris, France 

Background: Gene expression profiling (GEP) has demonstrated that survival 

of DLBCL is influenced by the origin of the tumor cells (COO), 

germinal center-like (GC-like) vs ABC-like (Alizadeh et al. 2000), but also 

by the tumor microenvironment, particularly the angiogenesis (Lenz et al., 

2008). To further understand the prognostic impact of these tumoral 

characteristics, we analysed the prognostic impact of COO and the 

expression of biomarkers involved in angiogenesis, in a selected population 

of 36 patients with relapsed/refractory DLBCL included in CORAL (Gisselbrecht, 

ASCO 2011). Methods: Expression of 5 biomarkers including VEGF 

(isoforms 121, 165, and 189), and their receptors (VEGFR-1 and R-2) was 

assessed by quantitative qRT-PCR after total RNA extraction and cDNA 

synthesis of tumor samples. COO was determined by GEP, and progression 

free- (PFS) and overall- (OS) survivals were analysed. Results: In the study 

population, VEGF121 expression below the median was associated to a 

better outcome, with 4 year-PFS at 63% vs 33% (p�.053), and a 

4-year-OS at 79% vs 37% (p � 0.032), respectively. VEGF-165 -189, 

VEGF-R1, -R2 did not have any significant impact. Eighteen patients were 

predicted as ABC-like DLBCL and 18 as GCB-like DLBCL. In patients with 

ABC-like DLBCL, low VEGF121 level was associated to a significantly 

better survival than in those with high VEGF121 level: 4-year OS at 100% 

vs 36% (p�.011). The type of induction treatment, R-ICE or R-DHAP, did 

not influence the outcome. The differences in outcome according to VEGF 

isoforms were not significant among CGB patients. Conclusions: Our data 

suggest that angiogenesis plays a central role in ABC-like DLBCL. VEGF121 

seemed to be a key player in this context and should be proposed as a target 

in the treatment of patients with ABC-like DLBCL. 




Transformation of follicular lymphoma in the era of immunochemotherapy: 

A population-based study from British Columbia. Presenting Author: 

Abdulwahab J. Al-Tourah, British Columbia Cancer Agency-Fraser Valley 

Centre and University of British Columbia, Surrey, BC, Canada 

Background: Several published series have established that the risk of 

transformation of follicular lymphoma (FL) to aggressive lymphoma is 

approximately 3% /year (15%-20% at 5 years). The addition of rituximab 

(R) to chemotherapy (immuno-chemotherapy) has significantly improved 

the outcome of patients with FL. The impact of immuno-chemotherapy on 

the risk of transformation remains unknown. We assessed whether the 

introduction of immuno-chemotherapy has altered this risk. Methods: We 

examined the Lymphoid Cancer Database of the British Columbia Cancer 

Agency for FL patients treated with immuno-chemotherapy. Inclusion 

criteria: FL grades 1-3A by WHO criteria; only patients requiring treatment 

at diagnosis were included. Exclusion criteria: FL grade 3B or composite 

histology (FL and DLBCL) at diagnosis; pts who received anthracyclinebased 

chemotherapy; and HIV positivity. The diagnosis of transformation 

was confirmed by biopsy when possible (n�19; 79%) but patients who 

were considered to have transformed based on pre-defined clinical assessment 

(n�5; 21%) were also included in the analysis. Results: We identified 

261 pts with FL grade 1-3A requiring treatment at diagnosis, who received 

immuno-chemotherapy; median f/u 47 months (0.2-116), median age, 61 

y (34-86). Treatment: 243 (93%), R-CVP of which 145 (59%) also 

received maintenance R; 9 (4%), R-Fludarabine combination. 24 pts 

developed transformed aggressive lymphoma. The risk of transformation for 

the entire group was approximately 2% per year or 10% at 5 years. 

However, pts treated with maintenance R (n�151) had a lower risk of 

transformation compared to pts who only received R-chemo at induction 

(n� 110), 8% vs 20% at 5 years respectively, (P� 0.003). The posttransformation 

outcome remains poor with a median survival of 6 months. 

Conclusions: We and other groups have demonstrated that the risk of 

transformation from FL to aggressive lymphoma is approximately 15% to 

20% by 5 years. Our study suggests that the introduction of immunochemotherapy 

has reduced this risk to less than 10%. This effect is 

particularly apparent when patients receive maintenance R. The outcome 

for patients who develop transformation remains poor. 


Efficacy of alemtuzumab (ALZ) in combination with dose-adjusted EPOCH 

(DA-EPOCH) in untreated nodal peripheral T-cell lymphoma (PTCL). 

Presenting Author: Cliona Grant, National Cancer Institute, Bethesda, MD 

Background: The survival of patients (pts) with PTCL (excluding ALCL) is 

disappointing following anthracycline-based therapy and novel approaches 

are needed. In diffuse large B-cell lymphoma, the addition of anti-CD20 

therapy to CHOP has significantly improved outcome and we investigated if 

in PTCL, adding ALZ – which targets CD52, expressed on most PTCLs – was 

feasible and improved outcome. Methods: This was a single-center phase 

I/II trial of ALZ, in combination with DA-EPOCH in patients with treatmentnaïve 

CD52� PTCL. The MTD of 30 mg ALZ was combined with DA-EPOCH 

for phase II evaluation resulting in an intention-to-treat population (ITTP) 

of 30 pts. Results: Patient (n�30) characteristics: median (range) age 50 

(17-77); M:F 1:1; Stage III/IV 27 (90%); IPI �2 22 (73%). Histologies: 

ATLL 11 (37%), PTCL NOS 6 (20%), AITL 5 (16%), Hepatosplenic 3 

(10%), Peripheral T NK cell 2 (7%), Other 3 (10%). At 67 months median 

follow-up, 11 patients were alive, 10 disease-free. Median overall (OS) and 

event-free survivals (EFS) were 15.4 and 6.7 months respectively. Outcome 

was substantially better for pts with ‘nodal’ (AITL, PTCL-NOS, Other) 

compared to ‘non-nodal’ (ATLL and ‘extranodal’ histologies) PTCL subtypes. 

3-year OS for the two groups was 58.3% and 27.8% respectively 

(p�0.082); 3-yrs EFS was 50% (median 27.0 months) and 22.2% 

(median: 5 months) respectively (p�0.041). Half of the ‘nodal’ PTCL pts 

had sustained long-term complete remissions demonstrated by a plateau in 

the EFS curve at 27 months. There were 3 treatment related deaths: 2 from 

neutropenic sepsis; 1 from toxoplasma. Other toxicities included CMV and 

BK virus reactivation in 53% and 30% respectively. Febrile neutropenia 

was seen in 20% and grade 4 thrombocytopenia in 12 % of cycles. 

Conclusions: Although it has significant infectious toxicity, ALZ 30mg and 

DA-EPOCHin untreated PTCL is feasible and associated with a long-term 

favorable outcome in nodal but not extranodal or leukemic PTCL. A phase 

III study of ALZ 30mg with anthracycline-based therapy is ongoing and we 

await the results with interest. 


Long-term follow-up results of a phase I/II study of concurrent chemoradiotherapy 

for localized nasal NK/T-cell lymphoma (NKTCL): JCOG0211. 

Presenting Author: Motoko Yamaguchi, Mie University, Tsu, Japan 

Background: Concurrent chemoradiotherapy has been regarded as one of 

the standard management for localized nasal NKTCL. However, its longterm 

efficacy and toxicity is not known. Methods: The JCOG0211 trial is a 

phase I/II study of concurrent chemoradiotherapy consisting of radiotherapy 

(RT) of 50 Gy and 3 cycles of DeVIC (carboplatin, etoposide, 

ifosfamide, dexamethasone) for newly diagnosed, localized nasal NKTCL 

(JCO 2009). Patients (Pts) with newly diagnosed, localized diseases (IE & 

contiguous IIE with cervical node involvement) who were 20-69 yrs of age 

with PS 0-2 were eligible. 3-D conformal RT planning with a wide margin 

(� 2 cm to the gross tumor, the entire nasal cavity and the nasopharynx) 

and a 2-step cone down were required. 33 pts were enrolled in the study, 

27 of whom were treated with RT and a 2/3-dose of DeVIC, which was 

selected as the recommended phase II dose in the preceding phase I 

portion of the trial. All pts completed RT without any protocol violations. 

Long-term follow-up results on overall survival (OS), progression-free 

survival (PFS) and toxicity were evaluated. Results: The median follow-up 

was 69 months (range, 62-96). The pt (N�33) characteristics were as 

follows: median age 54 yrs (range, 21-68); stage IIE 33%; B symptom (�) 

36%; elevated serum LDH 21%. %5-yr OS and PFS were 73% (95%CI, 

54-85%) and 67% (95%CI, 48-80%), respectively. 11 pts (33%) experienced 

disease recurrence. Two achieved a 2nd CR by salvage chemotherapies 

followed by allogeneic stem cell transplantation, and the remaining 9 

pts died of disease. There was no observed death and disease progression 

after 34 and 31 months, respectively. One pt experienced Grade 3 irregular 

menstruation for 3 years. No other Grade 3 or 4 late non-RT-associated 

adverse events (AEs) were observed. One pt received plastic surgery due to 

Grade 4 RT dermatitis. No other Grade 3 or greater RT-associated late AEs 

were encountered. Conclusions: Both survival benefit and disease control 

from concurrent chemoradiotherapy with RT and DeVIC are maintained 

during a 5-yr follow-up, indicating the excellent efficacy of this approach as 

a first-line therapy for localized nasal NKTCL. Long-term toxicity is 

acceptable. 


Radioimmunotherapy efficiency and safety in consolidation and relapse 

treatment of aggressive B-cell non-Hodgkin lymphoma: An updated analysis 

of 230 patients of the international RIT-network. Presenting Author: 

Karin Hohloch, Hematology and Oncology, Georg August University Göttingen, 

Goettingen, Germany 

Background: In aggressive lymphoma, few reliable clinical data about the 

use of radioimmunotherapy exist. Pts. with DLBCL registered in the 

international RIT-Network (RIT-NT) were analyzed with regard to Indication, 

line of therapy and outcome. Methods: The RIT-NT recruited 1111 pts. 

between Dec. 2006 and 2010. It is a web-based registry that collects 

observational data from RIT-treated patients with malignant lymphoma. 

232 pts. with DLBCL registered in the database were evaluated in the 

analysis. Results: 232 pts with DLBCL are registered, 17 pts were excluded. 

Histologic subtypes: 190 DLBCL, 15 primary mediastinal, 9 large cell 

anaplastic, 1 intravascular. Median age was 62 years (range 17-88), 27% 

of pts �70 years old. Stage I 16pts, II 54 pts, III 60 pts, IV 68 pts; 6 

extranodal involvement, for 11 pts. stage is not documented. 187 pts had 

1-3 previous chemotherapies (Ctx), 21 pts 4-6 previous Ctx, 1 pts had 7 

previous Ctx, for 6 pts. previous Ctx is not documented. 15 pts. had 

previous RIT and 24 pts a stem cell transplantation prior to RIT. 6 pts had 

bone marrow infiltration prior to RIT, 3 with more than 25%. 87 pts had RIT 

as first line (8 pts. conditioning, 68 pts consolidation, 1 primary therapy, 

10 other), and 84 pts received RIT in relapse (2d to 8 th. line therapy) (2 

pts. conditioning, 31 pts consolidation, 26 recurrence, 19 therapy refractory, 

6 other). Grade IV° hematotoxicity occured for neutrophils and 

platelets, grade III° for hemoglobin after RIT. Median time to recovery of 

blood count was 81 days (range 0-600 days). ORR was 63,3 %; CR 54,4%; 

PR 8,8%, SD 0,9%, PD 23,7%, N.D. 12%. CR rate first line was 76,3 %, 

for relapse 44,3%. Mean overall survival (OS) in first line was 26,5 months 

14,3 months for pts. treated in relapse or refractory disease. Conclusions: 

Most pts. with DLBCL in the RIT-N received RIT as consolidation after first 

line therapy with excellent CR rates and OS compared to published data 

from risk groups . In relapsed DLBCL RIT is a safe and feasible treatment 

leading to satisfactory response rates with low toxicity. A prospective 

randomized phase III trial in front line DLBCL is currently planned (ZEST). 



LR-CD: Lenalidomide combination therapy for untreated low-grade B-cell 

NHL. Presenting Author: Craig B. Reeder, Mayo Clinic, Scottsdale, AZ 

Background: Lenalidomide (LEN) is an immunomodulatory agent that has 

shown significant single-agent anti-lymphoma activity in patients with 

relapsed disease and in combination may enhance the efficacy of rituximab 

by various mechanisms. There is limited data on the role of LEN in 

combination regimens for treatment-naïve patients. This phase II single 

arm trial was designed to evaluate tumor response, toxicity (AE) and 

survival with a combination of LEN, rituximab, cyclophosphamide (CTX) 

and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with 

low grade B-cell non-Hodgkin lymphoma. Methods: Eligibility required age 

�18, ECOG PS �2, confirmed diagnosis of low-grade B-cell lymphoma 

(FL1-2, SLL, MZL or LPL/WM), measurable nodes �2cm or IgM �400mg/ 

dL(LPL/WM), ANC �1400/mm3 , platelets �100,000/mm3 , creatinine 

�2mg/dL, signed informed consent and in need of therapy. Treatment 

consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1-21, CTX 

250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 

28 day cycle. Treatment continued 2 cycles beyond best response (max 

12). Toxicity was assessed by NCI CTCAE v3.0. Results: 28 patients have 

enrolled at Mayo Clinic with 25 evaluable for toxicity and 21 for response: 

Median age 65(43-83), 72% male, FL 24%, MZL 28%, LPL/WM 38%, and 

SLL 4%. Median number of cycles given was 5. Overall response in 21 

patients with response data is 95% (95% CI 76-100%) with 19% CR (95% 

CI 5-42%), and 76% PR (confirmed and unconfirmed, 95% CI 53-92%). 

The ORR in 8 patients with LPL/WM with response data was 88%, all PR 

(95% CI 47-100%). At a median f/u of 14.7 months 96% are alive without 

progression. 1 death (unrelated) occurred 7.7 months after completing 12 

cycles of treatment. The most common grade �3 AEs were neutropenia 

(37.5%), leukopenia (16.7%), anemia (12.5%) and fatigue (12.5%). 

Conclusions: The combination LR-CD with the novel agent LEN is feasible, 

well tolerated and produces high response rates in symptomatic patients 

with low grade B-cell NHL. Toxicities are manageable and similar to 

reported data of single agent LEN. 


Association of prior rituximab exposure among patients undergoing autologous 

stem cell transplantation for relapsed/refractory diffuse large B-cell 

lymphoma with inferior outcomes in males compared with females. 

Presenting Author: Aleksandr Lazaryan, Taussig Cancer Institute, Cleveland 

Clinic, Cleveland, OH 

Background: The combination of rituximab with CHOP remains the standard 

upfront therapy of patients (pts) with advanced diffuse large B-cell 

lymphoma (DLBCL). Gender disparity in survival of pts with DLBCL appears 

to be significantly modified by the use of rituximab in both upfront (Ngo, 

2008; Pfreundschuh, 2009; Riihijarvi, 2010) and post-transplant maintenance 

(CORAL trial) settings. The presence of interaction between gender 

and prior rituximab exposure remains unknown in pts with relapsed/ 

refractory DLBCL undergoing autologous stem cell transplantation (ASCT). 

Methods: We conducted a retrospective cohort study of 320 consecutive pts 

who underwent ASCT for relapsed/refractory DLBCL at our center from 

01/1998 to 12/2010. Relapse-free survival (RFS) and overall survival (OS) 

were estimated by Kaplan-Meier method and by Cox proportional hazards 

regression analysis in SAS 9.1 (Cary, NC). Results: Among all pts (median 

age�54 yrs (IQR, 45-61); 92% Caucasians) 210 (66%) were males and 

110 (34%) were females. 85 pts (27%) received more than two prior 

chemotherapy regimens. 174 pts (55%) had pre-ASCT exposure to 

rituximab as a part of induction or salvage regimens. Preparative regimen 

for ASCT uniformly consisted of Bu/Cy/VP-16. In the stratified univariate 

analysis of pts treated with rituximab prior to the ASCT, male pts had 

inferior RFS (p�0.02; hazard ratio [HR]�1.86, 95% CI, 1.09-3.18) and 

OS (p�0.03; HR�1.94, 95% CI, 1.05-3.58). In pts who did not receive 

rituximab prior to the ASCT, no difference in RFS or OS according to gender 

was observed (all p�0.4). Gender disparity among rituximab recipients was 

even more evident for both RFS (p�0.004; HR�2.22, 95% CI, 1.28- 

3.83) and OS (p�0.005; HR�2.42, 95% CI, 1.3-4.5) in the multivariable 

analyses controlling for age at transplant, number of prior chemotherapies, 

and pre-ASCT disease response. Conclusions: Our data support an emerging 

concern that male patients with DLBCL have inferior outcomes when 

treated with rituximab. The present study has extended this observation to 

pts with relapsed/refractory DLBCL treated with ASCT. 


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Final results of phase I/II trial of vorinostat in combination with cyclophosphamide, 

etoposide, prednisone, and rituximab (R-CVEP) for elderly 

patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). 

Presenting Author: David J. Straus, Memorial Sloan-Kettering Cancer 


Background: Standard treatment of relapsed/refractory DLBCL in elderly 

patients who are not candidates for autologous stem cell transplantation 

(auSCT) has not been established. Cyclophosphamide (C), etoposide (E), 

prednisone (P) and procarbazine (CEPP) has been used by many clinicians 

based on limited data (Blood 76: 1293-98, 1990). Vorinostat (V) is a 

histone deacetylase inhibitor that is approved for relapsed cutaneous T-cell 

lymphoma and has activity in B-cell lymphomas. This trial defined the 

maximum tolerated dose (MTD) of V added to standard therapy and 

determined the response rate of this combination. Methods: Patients �age 

60 with relapsed/refractory DLBCL not candidates for auSCT were enrolled 

on R-CVEP (R 375mg/m2 IV, d1; C 600mg/m2 d1 and 8, E 70mg/m2 IV d1, 

140mg/m2 d2 and 3; V PO and Pred 60mg/m2 PO d1-10) every 28 days for 

6 cycles. In the phase I component V was administered at doses of 

300mg/d or 400mg/d for 10 days. The phase I was a 3 � 3 design and the 

phase II a two stage design requiring 8/20 complete responses (CR) for 

expansion. Assessment of response utilized end-of-treatment positron 

emission tomography (PET) (JCO 25: 579-86, 2007). Quality of life (QOL) 

was measured with the FACT-Lym v.4. Results: 27 pts. were enrolled. 1 

died before treatment. For 26 pts: median age 76 yrs. (69-88), 14 females 

and 12 males, baseline PS (ECOG) 1 (0-2). Median follow-up for survivors: 

9.2 mo. Phase I: 6 pts. at 300mg/d (no dose-limiting toxicity-DLT), 6 pts. 

at 400mg/d (2 grade 3 neutropenia � DLT). MTD 300mg/d x 10d. For 20 

pts. at V 300mg/m2 (6 phase I � 14 phase II): 2 off study for toxicity, 1 

withdrew consent, 6 CR (30%), 5 partial response (PR) (25%), 6 

progressed (30%). Phenotypic overall responses (OR): germinal center 

(GC) 4/8 (2 CR), non-GC 6/10 (3 CR), transformed CLL 1/2 (1 CR). Median 

progression-free survival: 10 mo. QOL results will be presented. Conclusions: 

OR rate for V added to conventional chemotherapy and R was 55% (CR 

30%, PR 25%) in relapsed/refractory DLBCL in elderly pts. not candidates 

for auSCT. This could provide a baseline for comparison with future clinical 

trials in this understudied population. 


Effect of short-duration chemoimmunotherapy plus radioimmunotherapy 

on response rates in relapsed follicular lymphoma: A U.K. NCRI Lymphoma 

Group Study, CR UK/07/038. Presenting Author: Timothy M Illidge, 

Manchester Cancer Research Centre, Manchester, United Kingdom 

Background: Radioimmunotherapy (RIT) and rituximab (R) maintenance 

have been investigated after chemotherapy (CT) or R-CT in first line 

treatment of follicular lymphoma (FL), but less is known about the efficacy 

of RIT after R-CT in relapsed FL. This phase II study was conducted to 

examine efficacy and safety of abbreviated R-CT followed by 90Y Ibritumomab 

tiuxetan in patients with recurrent FL. Methods: Patients (pts) had 

FL, at 1st or 2nd relapse after response to R-CT or CT alone. All had 

WHO/ECOG performance status �2, and adequate bone marrow (BM), 

kidney, liver and cardiac function. BM involvement by lymphoma had to be 

�25% prior to infusion of 90Y Ibritumomab tiuxetan, but could be higher at 

study entry. Pts received 3 cycles of either R-CHOP or R-CVP, followed by 

90Y Ibritumomab tiuxetan (15MBq/Kg, maximum 1200 MBq). No maintenance 

R was given. Results: 52 pts were enrolled from 6/2008 to 7/2010. 

Median age was 62 years (range 31-87). 46% had high FLIPI score at 

entry, 31% intermediate. 80% were at 1st recurrence. Median duration of 

best prior remission was 27.7 months. 65% pts had previously received R 

and 25% doxorubicin. 71% pts had R-CHOP and 29% R-CVP, prior to RIT. 

Overall response rate (ORR) after 3 cycles R-CT was 94% (CR/CRu 10%) 

and after RIT ORR 96% (CR/CRu 28%). Grade 3/4 thrombocytopenia 

occurred in 58% pts (median duration 16 days): 3/52 pts after R-CT and 

27/52 after RIT. Grade 3/4 neutropenia occurred in 62% pts: 15/52 pts 

after R-CT and 27/52 after RIT. 5 pts had a total 8 grade 3 infections, only 

1 attributable to RIT. 6 pts required platelets and 4 red cell transfusions. 1 

pt developed myelodysplasia 10 months after 90Y Ibritumomab tiuxetan, 

but no other second malignancy was recorded. PFS was 31.4 months (95% 

CI 15.8 - not reached). There was no difference in PFS according to FLIPI 

score at entry or reinduction CT (R-CHOP vs R-CVP). Pts with CR/CRu 

following RIT showed a trend to improved PFS compared to those with PR 

(12 month PFS 90% versus 63%, p�0.06). Conclusions: Abbreviated R-CT 

and consolidation with 90Y Ibritumomab tiuxetan is an option for pts with 

recurrent FL, with responses of comparable duration to those seen after a 

full course R-CHOP. 




Phase I study cohort evaluating an optimized administration schedule of 

SAR3419, an anti-CD19 DM4-loaded antibody drug conjugate (ADC), in 

patients (pts) with CD19 positive relapsed/refractory b-cell non-Hodgkin’s 

lymphoma (NCT00796731). Presenting Author: Bertrand Coiffier, Hospices 

Civils de Lyon Sud, Pierre-Bénite, France 

Background: The recommended dose (RD) of SAR3419 administered 

intravenously every 3 weeks (q3w) for 6 cycles is 160 mg/m2 and is 55 

mg/m2 when administered weekly (q1w) for 8-12 doses. Reversible corneal 

deposits were dose limiting (DLT) in the q3w schedule. The q1w schedule 

was well tolerated and active. However, based on the occurrence of 

late/cumulative adverse events (AE) at the RD supported by pharmacokinetic 

(PK) analyses showing ADC plasma accumulation after 4 weekly 

doses, an optimized schedule consisting of 4 weekly doses followed by 4 

bi-weekly doses at the RD was tested. Methods: The q1w study was 

extended to treat 25 pts with the optimized schedule for 8 to 12 doses. 

Results: Twenty-one pts were evaluable. Main histologies were diffuse large 

B-cell (DLBCL) (9; 43%) and follicular (6; 29%). Median number of prior 

regimens was 2 [1-8], 6 pts received prior autologous transplantation and 

95% of pts were Ann Arbor stage III-IV at study entry. Median number of 

doses received was 8 as planned with a median relative dose intensity of 

1.0 [0.8-1.0]. Most frequent AEs were asthenia (1 pt with grade 3) and 

gastrointestinal disorders in 7 pts each. No AE fulfilled the defined DLT 

criteria. Reversible grade 1 blurred vision/corneal event occurred in 1 pt. 

Grade 3-4 haematological toxicities were minor consisting of non complicated 

neutropenia in 4 pts, thrombocytopenia in 2 pts and anemia in 1 pt 

with no transfusion support. Six (29%) pts, among them 3 with DLBCL, 

achieved an objective response including 3 CRu (1 in a pt refractory to last 

regimen). In addition, 9 (43%) pts had stable disease. Response duration 

was [8-35�] weeks, 5 pts still responding at the cut-off date. Conclusions: 

The optimized administration schedule shows an improved safety profile 

compared to prior tested schedules. The clinical efficacy is preserved 

essentially in aggressive lymphoma. The optimized schedule is being 

assessed in 2 phase II studies evaluating SAR3419 either as a single agent 

or in combination with rituximab in pts with DLBCL histology. 


High affinity CD3 RECRUIT TandAb for T cell-mediated lysis of CD19� tumor B cells. Presenting Author: Eugene Zhukovsky, Affimed Therapeutics 

AG, Heidelberg, Germany 

Background: CD19 is expressed from early B cell development to the 

differentiation into plasma cells and is an attractive target for B cell 

malignancies either lacking CD20 expression or refractory to anti-CD20 

antibody therapies. T cells are potent tumor killing effector cells that are 

not recruited by native antibodies. The CD3 RECRUIT-TandAb AFM11, a 

human bispecific tetravalent antibody with two binding sites for both CD3 

and CD19, is a novel therapeutic for the treatment of NHL that harnesses 

the cytotoxic nature of T cells. Methods: A bispecific anti-CD19/anti-CD3 

tetravalent TandAb with humanized and affinity matured variable domains 

was constructed. The TandAb’s binding, T-cell mediated cytotoxic activity, 

and cytokine release were characterized in a panel of in vitro assays. In vivo 

efficacy was evaluated in a murine NOD/scid xenograft model reconstituted 

with human PBMC. Results: AFM11 mediates highly potent target tumor 

cell lysis in cytotoxicity assays: EC 50 values are low to sub-picomolar range 

in a panel of CD19 � cell lines and primary B-CLL tumor cells. The cytotoxic 

activity of tetravalent AFM11 is superior to that of alternative bivalent 

antibody formats possessing only a single binding site for both CD19 and 

CD3. High affinity binding of AFM11 to CD19, and more so to CD3 (low to 

sub-nanomolar Kd), is essential for efficacious T cell recruitment. The high 

affinity bivalent binding of AFM11 to CD3 does not trigger T cell activation 

in the absence of CD19 � target cells in functional in vitro assays. AFM11 

activates T cells only in the presence of its targets and mediates lysis while 

sparing antigen-negative bystanders. AFM11 induces down-modulation of 

the CD3/TCR complex in the absence of target cells and at high concentrations. 

Also, AFM11-treated T cells can be re-engaged for target cell lysis. 

These features of AFM11-induced T cell activation may contribute additional 

safety with no compromise of efficacy. Finally, AFM11 demonstrates 

a robust dose-dependent inhibition of subcutaneous Raji tumors in mice. 

Conclusions: AFM11 is a novel highly efficacious drug candidate for the 

treatment of B cell malignancies with an advantageous safety profile. 


Hodgkin’s disease and HIV infection (HD-HIV): Prognostic factors in 596 

patients (pts) within the group of European Cooperation on AIDS and 

Tumors (GECAT). Presenting Author: Michele Spina, National Cancer 

Institute, Aviano, Italy 

Background: Hodgkin’s disease (HD) is the most common non-AIDS 

defining tumour diagnosed in HIV setting. The introduction of highly active 

antiretroviral therapy (HAART) has opened a new prospective in the 

treatment of pts with HD-HIV as the better control of the underlying HIV 

infection allows the use of more aggressive chemotherapy regimens, 

including high dose chemotherapy. However, up to now prognostic factors 

on overall survival (OS) or time to treatment failure (TTF) have not yet been 

identified. Methods: In order to identify prognostic factors, we analyzed data 

on 596 pts with HD-HIV diagnosed and treated in 90 different Institution of 

6 European countries from October 1983 to March 2010. All factors were 

analyzed for OS and TTF. Results: 86% of pts were male and the median 

CD4 cell count was 224/dl (range 3-1274); 52% of pts had mixed 

cellularity subtype, stages III-IV were diagnosed in 72% of cases and 55% 

of pts had extranodal involvement (bone marrow 35%, spleen 21%, liver 

14%). The table summarizes the results of multivariate analysis. 

Conclusions: We identified a new “European Score” for HD-HIV able to 

predict different outcomes in these patients. This score should be considered 

for future prospective studies. 

Factors Overall survival Time to treatment failure 

IPS < 2 1 1 

IPS > 2 2.33 (1.61-3.39) p�0.0001 1.57 (1.09-2.26) p�0.02 

CD4 > 200 1 1 

CD4 < 200 1.63 (1.16-2.29) p�0.005 1.43 (1.02-2.01) p�0.04 

European Score 

0 1 1 

1 2.06 (1.40 - 3.02) 1.64 (1.17 - 2.30) 

2 3.08 (2.13 - 4.45) p�0.001 2.31 (1.66 - 3.20) p�0.001 


Characteristics and outcomes of extranodal NK/t-cell lymphoma (ENKL): A 

North American (NA) multi-institutional experience. Presenting Author: 

Lauren Shizue Maeda, Stanford University Medical Center, Stanford, CA 

Background: ENKL is a rare and aggressive subtype of peripheral T-cell 

lymphoma. Due to its geographic predilection there is a paucity of data on 

clinical experiences from non-Asian countries. The purpose of this study 

was to analyze characteristics and outcomes of patients (pts) with ENKL 

identified from major academic centers in NA. Methods: Pts with newly 

diagnosed CD56� ENKL were retrospectively identified. Analyses included 

disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts 

(63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 

centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n�16; Era 

2: 2000-2005, n�45; Era 3: post-2005, n�54). Median age was 52 years 

(19-88). 75 (65%) had stage I/II disease and were treated with combined 

modality therapy (CMT) n�48, chemotherapy (CT) n�14 or radiotherapy 

(RT) n�14. 40 pts had stage III/IV disease and were treated with CT 

(n�23), CMT (n�12) or RT (n�5). CT regimens used alone or in CMT were 

either anthracycline-based (n�68) or other (n�29). 63% of stage I/II pts 

and 40% with stage III/IV achieved complete remission (CR). 30 pts 

underwent a stem cell transplant (SCT); 14 in first CR and 16 at 

progression/relapse (autologous, n�21; allogeneic, n�9). Pts with stage 

I/II disease had a better progression-free survival (PFS) and overall survival 

(OS) compared with stage III/IV (12 vs 5.2 months (p�0.003) and 41.5 vs 

8.9 months (p�0.0001), respectively). For all stages, treatment with CMT 

compared with CT or RT alone was also associated with better PFS and OS, 

18.0 vs 3.9 months (p�0.0001), and 41.5 vs 10.2 months (p�0.002) 

respectively. Non-anthracycline-based regimens were associated with better 

PFS (p�0.001) and OS (p�0.045). No survival differences were seen 

between Asian and non-Asian pts. Conclusions: This series represents one 

of the largest experiences of ENKL in NA. Our data are consistent with 

Asian studies in: 1) majority of pts present with early stage disease; 2) 

overall poor outcome; 3) superiority of CMT and non-anthracycline regimens. 

Advances in understanding biology and international collaborative 

efforts are required to improve outcome in this rare entity. 



Determinants of and outcomes associated with chemoimmunotherapy dose 

density in elderly subjects with diffuse large B-cell lymphoma (DLBCL). 

Presenting Author: Usha S. Perepu, University of Iowa Hospitals and 

Clinics, Iowa City, IA 

Background: RCHOP is the standard first line therapy for DLBCL but elderly 

patients often receive suboptimal doses. Relative dose intensity (RDI) less 

than 70-90% has previously been associated with inferior survival in CHOP 

treated patients. We now investigate the clinical determinants of immunochemotherapy 

dose delivery and comparative effectiveness of dose intensity 

on lymphoma-specific outcomes in persons over the age of 60. 

Methods: SPORE MER (Molecular Epidemiology Resource) is a prospectively 

accrued observational study in which University of Iowa and Mayo 

Clinic patients with a diagnosis of Non Hodgkins lymphoma have been 

enrolled since 2003. We reviewed data from the Iowa patients along with 

medical records from DLBCL patients over the age of 60 treated with 

anthracycline based chemo immunotherapy consecutively enrolled up 

through to December 2009. Statistical tests of associations between RDI 

and clinicopathologic factors, as well as survival outcomes, were performed. 

Results: We identified 92 patients over the age of 60. The median 

age was 70. 47 subjects experienced at least 1 dose reduction, 26 subjects 

had dose delays, and 20 subjects were unable to complete therapy. RDI 

ranged from 0.30-1.70 (median 0.92) for doxorubicin and from 0.29-1.70 

(median 0.97) for cyclophosphamide. 24 and 19% of subjects received � 

80% of RDI for dox and cy respectively. Age (p� 0.001 for both dox and cy) 

and performance status (p�0.04 for dox) but not number of medications, 

ACE27 co-morbidity score, body surface area, nor need for acute care visits 

were associated with decreased RDI. Adjusted for IPI, RDI did NOT have a 

significant effect on event-free or lymphoma-specific survival. Conclusions: 

Among clinical variables, age is the dominant variable associated with 

delivery dose intensity for chemotherapy in elderly patients treated for 

DLBCL; and among elderly patients receiving chemo immunotherapy, we 

did not find an association between dose intensity and lymphoma-specific 

outcomes. 

Doxorubicin Cyclophosphamide 

Correlation p value Correlation p value 

Age at Rx -0.348 .0007 -0.358 .0006 

BMI 0.097 .359 0.205 .055 

#ofmeds 0.050 .636 -0.007 .942 

LVEF 0.096 .458 0.011 .933 


Progression-free survival for subsequent relapses in patients with peripheral 

T-cell lymphoma (PTCL). Presenting Author: Steven M. Horwitz, Memorial 


Background: In B-cell lymphoma, overall response (ORR) is lower and progression 

free survival (PFS) is often shorter with each subsequent progression. 

However, this has not been described for PTCL. Methods: We undertook a 

retrospective analysis in two U.S. centers (MSKCC and UNMC) and in GELA 

studies. All data for PTCL were reviewed to collect data for each line of therapy: 

treatment, response, PFS, date of next treatment, and survival. When date of 

progression could not be defined we calculated PFS as the time to next 

treatment. Pts who did not progress, died during first line, or were untreated at 

progression 1 were excluded. Data were collected for 4 lines of treatment, front 

line and 3 progressions. Results: 254 pts were identified. 205 were analyzed (49 

excluded for missing data): GELA 116, MSKCC 51, and UNMC 37. Diagnoses 

were PTCL NOS in 34% and 60%, AITL in 49% and 35%, ALCL Alk- in 3% and 

5%, and others in 15% and 18% for GELA and US centers respectively. 67% 

were male, median age was 51 vs 58 y. Advanced stage was more frequent in 

GELA (79% vs. 56% for US); baseline IPI was �2 in 90% vs 71%. Multidrug 

regimens were given in 99% and 80% for front line, 67% and 66% for 2nd line, 

61% and 50% for 3rd line, 53% and 54% for 4th line, for GELA and US. 

Significantly fewer pts received each subsequent line of therapy with 205 pts 

receiving 2nd line, 96 pts 3rd line and 38 pts 4th line. No pt �65 y received 4th 

line treatment. Responses and PFS are listed in the table. Conclusions: For pts 

with PTCL, similar to B-cell lymphomas, ORR and PFS decrease with each line of 

therapy. When evaluating the activity of therapies in relapsed PTCL, line of 

therapy is a consideration and this series provides a benchmark for comparison. 

Based on this dataset, it is possible that better responses will be seen as new 

agents are moved into earlier treatment paradigms. 

GELA data U.S. data All 

1st line (front line) 

- ORR 

-CR 

2nd line 

- ORR 

-CR 

- Median PFS 

- 6-m event-free 

3rd line 

- ORR 

-CR 

- Median PFS 


4th line 

- ORR 

-CR 

- Median PFS 


Abbreviation: NA: not available. 

. 

71% 

57% 

. 

44% 

35% 

13 m 

74% 

. 

23% 

13% 

Not reached 

63% 

. 

6% 

6% 

6m 

38% 

. 

64% 

43% 

. 

52% 

28% 

27 m 

66% 

. 

32% 

18% 

2m 

36% 

. 

38% 

9% 

NA 

NA 


. 

68% 

51% 

. 

47% 

32% 

15 m 

71% 

. 

27% 

15% 

8m 

50% 

. 

24% 

8% 

NA 

NA 

525s 


Biweekly regimen of nonpegylated liposomal doxorubicin with cyclophosphamide, 

vincristine, and prednisone plus rituximab (R-COMP-14) as primary 

treatment for diffuse large B-cell lymphoma (DLBCL): Long-term follow-up 

of a phase II study. Presenting Author: Joaquin Herrero, Hospital General 

de Alicante, Alicante, Spain 

Background: To evaluate the efficacy and toxicity of dose-dense biweekly 

schedule of (R-COMP-14) in patients newly diagnosed of agrressive diffuse 

B cell lymphomas (DLBCL). Methods: In this single-arm, open-label, 

multicenter trial, 60 pts were included between 2004 to 2008. Received 

rituximab (375 mg/m2 ) D1 � cyclophosphamide (750 mg/m2 )D1 � 

vincristine (1.4 mg/m2 ; max. 2 mg)D1 � prednisone (100 mg/d D1 and 

D5) and non-pegylated liposomal doxorubicin (50 mg/m2 ) every two weeks. 

Response was assessed at cycle 3, and patients with complete or partial 

response received 5 additional courses. Granulocyte colony-stimulating 

factor (G-CSF). Pegfilgrastim was administered on day 2. The primary 

efficacy endpoint was (CR) and objective response rate (ORR). Survival 

follow-up data were updated. Results: 59 evaluable patients with a median 

age of 50 years (21-65) were analyzed. Clinical Characteristics: 22 Pts 

stage I-II (aaIPI�1 (37%), 17 (29%) stage III, and 19 (32%) in stage IV. 

aaIPI�1 41(67%), aaIPI2/3� 18(33%).LVEF basal: 65,5[50-93]. Extranodal 

disease: 42%. B symptoms: 44.1%. The mean calculated dose 

intensities of cyclophosphamide, non-pegylated liposomal doxorubicin, 

vincristine and rituximab were 98,7%, 98,7%, 76,1% and 98,3% respectively. 

Among 60 eligible patients (96,7% completed six cycles and 74,4% 

completed all eight cycles. ORR was 81%, and CR rate of 54,2%. IC 95% 

[40,7-67,8]. The main toxicity was neutropenia Gr�III-IV/ and febrile 

neutropenia in 20% of patients. Neurotoxicity Gr�III-IV in 3,4%. No 

cardiac toxicity Gr: III-IV was reported. No toxic deaths. After a median 

follow-up of 25-64m(44m) the 5-year overall survival (OS), event-free 

survival, (EFS) and disease free survival (DFS) were 80%, 67%, and 77% 

respectively. Forty two patients (71%) had (�60 y) and med. OS(p�0,017) 

and med EFS(p�0,014) was 72,3% and 68,1 in aaIPI�1 and 50,4% and 

33,8 in aaIPI�1. Conclusions: Dose dense R-COMP-14 is an effective 

regimen in patients with (DLBCL) comparable o R- CHOP-14. Good 

tolerability profile with no Gr: III-IV cardiac toxicity or reduction of LVEF. 


MLN9708, an investigational proteasome inhibitor, in patients (pts) with 

relapsed/refractory lymphoma: Emerging data from a phase I doseescalation 

study. Presenting Author: Peter Martin, Weill Cornell Medical 

College, New York, NY 

Background: MLN9708 is a reversible, orally bioavailable, specific 20S 

proteasome inhibitor. This study (NCT00893464) studied the safety and 

determined the MTD of IV MLN9708 in pts with relapsed/refractory 

lymphoma, and characterized pharmacokinetics (PK) and pharmacodynamics 

(PD). Methods: Pts aged �18 yrs who had failed �2 chemotherapeutic 

regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until 

disease progression or unacceptable toxicity. One pt was enrolled at the 

0.125 mg/m2 starting dose; dose doubling proceeded with 1 pt at each 

dose up to 1.0 mg/m2 . Dose escalation occurred in �40% increments 

using a standard 3�3 scheme based on DLT occurrence in cycle 1. Blood 

samples were collected at multiple time points after dosing on days 1 and 

15 of cycle 1 for PK/PD analyses. Results: At data cut-off (Dec 1 2011), 21 

pts had been enrolled and treated: 1 each at 0.125, 0.25, 0.5 and 1 

mg/m2 , 4 at 1.4 mg/m2 , 7 at 1.76 mg/m2 , and 6 at 2.34 mg/m2 . Median 

age was 57 yrs (range 23–78); 57% were male. Median number of prior 

therapies was 5; 29% had prior radiation, 24% prior stem cell transplant. 

Histologies included T-cell lymphoma (n�5), Hodgkin lymphoma (n�3), 

follicular lymphoma (n�2), DLBCL (n�1) and other indolent B-cell 

lymphoma (n�7). Pts had received a median of 2 cycles (range 1–22); 2 

DLTs were seen (neutropenia at 1.76 and 2.34 mg/m2 ). All pts experienced 

drug-related AEs, including fatigue (48%), nausea (29%), diarrhea (29%), 

pyrexia, thrombocytopenia, and vomiting (each 24%). 43% had drugrelated 

grade �3 AEs, 1 pt discontinued due to drug-related grade 3 

neutropenia (2.34 mg/m2 ). Three pts had drug-related peripheral neuropathy 

(1 grade 1, 2 grade 2). There were no on-study deaths. Of 18 

response-evaluable pts, 3 achieved PR (including 2 who remain in 

response and on-study for �1 yr) and 4 SD. PK analyses showed linear PK 

(0.5–2.34 mg/m2 ) and a terminal half-life of ~6–9 days. There was a 

dose-dependent increase in maximal whole blood 20S proteasome inhibition. 

Conclusions: These data suggest IV MLN9708 is generally well 

tolerated, with infrequent PN, and is clinically active in pretreated 

lymphoma pts. The trial is ongoing and updated data will be presented. 




Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting 

CD19, in subjects with relapsed or refractory advanced B-cell malignancies. 

Presenting Author: Trishna Goswami, MedImmune, Gaithersburg, MD 

Background: Novel B-cell targeting agents, including monoclonal antibodies 

such as rituximab, are among recent advances in treatment of B-cell malignancies. 

New approaches are needed for patients progressing after rituximab-based 

therapies. MEDI-551 is an afucosylated monoclonal antibody targeting CD-19, a 

B-cell restricted transmembrane protein with enhanced affinity and antibodydependent 

cellular cytotoxicity. Methods: Pts with relapsed or refractory follicular 

lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic 

leukemia, or multiple myeloma received single agent MEDI-551 at dosages 

ranging from 0.5 mg/kg to 12 mg/kg via intravenous infusion over 28-day cycles; 

cohorts 1-6 received 0.5, 1, 2, 4, 8, and 12 mg/kg, respectively. Results: 25 pts 

were enrolled in the phase I portion Jun 2010–Aug 2011. No maximum 

tolerated dose (MTD) was achieved. Most AEs were grade 1/2 with doseindependent 

frequency and severity (Table). Six pts had grade 3 toxicities 

including tumor lysis syndrome, infusion reaction, thrombocytopenia, and 

neutropenia, or grade 4 neutropenia. No grade 5 AEs were seen. All pts 

recovered. Three partial responses (PR) and 2 complete responses (CR) were 

seen in DLBCL and FL pts at 0.5, 4, and 8 mg/kg. Activity included a CR lasting 

9 mo. in a FL pt in cohort 1, who is currently being retreated with MEDI-551 on 

relapse. Conclusions: MEDI-551 demonstrated a safety profile warranting further 

study and showed no MTD reached at the highest dose studied. Anti-tumor 

activity is suggested by the responses achieved across dose levels. Phase II is 

currently enrolling subjects. This study is funded by MedImmune, LLC. 

Frequency of treatment emergent Medi-551-related adverse events. 

Preferred term Total events (N�37) 

Infusion-related reaction 6 (16.2%) 

Anaemia 3 (8.1%) 

Nausea 3 (8.1%) 

Thrombocytopenia 3 (8.1%) 

Aspartate aminotransferase increased 2 (5.4%) 

Blood immunoglobulin M decreased 2 (5.4%) 

Chills 2 (5.4%) 

Fatigue 2 (5.4%) 

Headache 2 (5.4%) 

Hypertension 2 (5.4%) 

Hypotension 2 (5.4%) 

Neutropenia 2 (5.4%) 

Pyrexia 2 (5.4%) 

Alanine aminotransferase increased 1 (2.7%) 


Comparison of the international prognostic factors index (IPI) with the 

absolute monocyte and lymphocyte prognostic index (AMLPI) for patients 

(Pts) with diffuse large b-cell lymphoma (DLBCL) receiving R-CHOP. 

Presenting Author: Nicolas Batty, Roswell Park Cancer Institute, Buffalo, 

NY 

Background: We studied the value of a proposed prognostic index (PI) 

generated by baseline absolute monocyte (AMC) and lymphocyte (ALC) 

counts for pts with DLBCL, using values as previously reported (Leukemia 

25:1502-9, 2011). Methods: From 03/07 to 01/09, 245 consecutive pts 

with untreated DLBCL receiving standard R-CHOP from the MDACC 

database were evaluated. Baseline AMC and ALC were retrospectively 

recorded. High AMC (�610/uL) and a low ALC (�1000/uL) were examined 

as dichotomized variables for progression-free (PFS) and overall survival 

(OS). An AMLPI was generated, stratifying pts into 3 risk groups (RGs): 

low-(AMC �610/uL and ALC �1000/uL), intermediate-(AMC �610/uL or 

ALC �1000/uL), and high-risk(AMC �610/uL and ALC �1000/uL). The 

prognostic effect of the AMLPI and the IPI were examined by multivariate 

analysis (MVA). Results: Ninety (37%) had high AMC and 71 (29%) had low 

ALC. By univariate analysis, a high AMC was associated with inferior PFS 

(p�0.01) and OS (p�0.03). The frequencies of AMLPI RGs were: low-105 

pts (43%), intermediate-119 (48%), and high risk-21 (9%). With a median 

follow-up of 22 months (range �1-42), 3-year PFS and OS rates for these 

RGs were 80%, 61%, and 46% (p�0.007) and 92%, 76%, and 60% 

(p�0.006), respectively. Three-year PFS rates for IPI 0-2 and 3-5 RGs 

were 73% and 58%, respectively (p�0.0004); comparable OS rates were 

88% and 68%(p�0.0001). For pts with IPI 0-2, 1-year PFS rates for 

AMLPI low, intermediate, and high RGs were 92%, 89% and 80% 

(p�0.022); comparable 1-year OS rates were 96%, 95% and 80% 

(p�0.049). By MVA, AMLPI effect (low vs. high RGs) on PFS was 

significant (p�0.046) as was IPI effect (0-2 vs 3-5, p�0.005); similar 

results were observed for OS (p�0.052 and p�0.003, respectively). 

Conclusions: Baseline AMC and AMLPI are significant variables for PFS and 

OS for pts with DLBCL receiving R-CHOP. AMLPI can identify pts with low, 

intermediate, and high-risk disease for PFS and OS, particularly for those 

with IPI 0-2. AMLPI may also add prognostic value beyond that of the IPI. 


Dose- and time-intensified ABVD without radiotherapy (RT) for advancedstage 

Hodgkin lymphoma (HL) with mediastinal bulky disease (MBD). 

Presenting Author: Gaetano Corazzelli, Hematology-Oncology and Stem 

Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione �G.Pascale�, 

Naples, Italy 

Background: The role of consolidation RT on MBD after upfront chemotheraphy 

for advanced HL is debated, also given the supradditive iatrogenic 

risk. We present the results achieved in the subset of patients (pts) with 

MBD (max width � 1/3 of thoracic diameter) accrued in a phase II study of 

an intensified ABVD program without RT. Methods: The current analysis 

derives from the final evaluation of our trial for advanced HL (stage IIXB-IV) 

conducted from 06/2004 to 03/2010 (Russo et al, ASH 2009 abst 715). 

Pts were scheduled to 6 cycles of a ‘time-densified’ ABVD (3-week 

intercycle, drugs on days 1 and 11) with the first 4 cycles being also 

‘dose-intensified’: doxorubicin (ADM) 35 mg/m2 , days 1 and 11 and G-CSF 

on days 6-8 and 17-19. Results: Of 82 accrued pts, 39 had BMD at 

presentation. Median age was 29yrs (r 16-58); male 46%; stage IIB 48%, 

III 8%, IV 43%; B-sympt 87%, E-disease 53%; IP Score �3 51%. All pts 

completed the intensified program. Median actual dose intensities for 

ADM, bleomycin, vinblastine and dacarbazine were 23.12, 6.69, 3.96 and 

245 mg/week, respectively; the increase over conventional ABVD was 85% 

for ADM and averaged 32% for the other agents. PET2 negativity was 

achieved in 36/39 (92%; 95% CI 79-98), complete responses (CR) in 

37/39 [94%; 95% CI 82-99]. At a median f.u. of 54 mo.s (r 20-91) all pts 

are alive with an event-free survival of 89% (95% CI, 80-98). Events were: 

�CR (n�1, CS IVB), progression (n�1, CS IIIA), relapse [n�2; at 10 (CS 

IVA ) and 15 (CS IIB) months after treatment]; all these pts had isolated 

mediastinal recurrence. CTCAE v3.0 toxicity: Grade (G) 2 nail changes 

(31%), G2-G3 hemorrhoids (12%-3%), G3 infection (13%) and constipation 

(5%), G3-G4 stomatitis (7%-2%). No acute or delayed G3-G4 cardiac 

events, nor G3-G4 decline in pulmonary function (FEV1, DLCO,FEF25-75) were seen. Conclusions: Intensified ABVD can achieve PET2 negativity in a 

very high proportion of pts with MBD and ensure a long-term disease-free 

status even without RT. While results need confirmation on a randomized 

basis, the low mediastinal failure rate seems in line with recent suggestions 

that RT could be omitted in MBD when CR is achieved upon intensified 

chemotheraphy. 


Prognostic value of etoposide area under the curve (AUC) in lymphoma 

patients treated with BEAM regimen and ASCT: Multicenter study of 

Groupe d’Etudes des Lymphomes de l’Adulte (GELA). Presenting Author: 

Olivia Bally, Centre Leon Berard, Lyon, France 

Background: The prospective LYMPK study primary objective was to assess 

the impact of etoposide pharmacokinetic (PK) parameters on toxicity and 

efficacy in lymphoma patients receiving the BEAM regimen (carmustine, 

cytarabine, etoposide and melphalan) followed by autologous stem cell 

transplant (ASCT). We previously showed the high inter-individual variability 

in etoposide PKs, defined by area under the curve (AUC) and trough 

concentration (Cmin), among study patients treated with the same doses 

/m2 (You B et al, Proc. ASCO 2008). Methods: Ninety-six patients with 

malignant lymphoma at 1st line (n�52) or relapse (n�44) were enrolled in 

5 centers. All received BEAM regimen, including high-dose etoposide (100 

to 200 mg/m2 bid for 4 days), followed by ASCT. Individual etoposide AUC 

and Cmin were estimated by population PK approach using NONMEM 

program. The impact of PK parameters on toxicity and survival was 

assessed using linear regression and univariate/multivariate analyses. 

Results: Data from 90 patients were assessable after a 4.2-year median 

follow-up. The bi-compartment model previously reported was used to 

characterize PK parameters (You B et al, Proc. ASCO 2008). Etoposide 

AUC and Cmin correlated with mucositis duration, especially for grade 3-4 

toxicity (p� 0.05), but not with other toxicities. Cmin had significant 

prognostic value regarding 5 year progression free survival (p�0.03). Five 

year overall survival (OS) was longer in patients with higher AUC (76% vs 

56%, if AUC � median, p�0.04) as it was in patients with higher Cmin 

(78% vs 54%, if Cmin � median, p�0.02). When assessed with available 

IPI prognostic factors (age; performance status; LDH and stage) using Cox 

analysis, the only independent prognostic factors of OS and disease 

specific survival were etoposide AUC (HR� 0.39, 95% CI � 0.16-0.94) 

and Cmin (HR � 0.32, 95% CI � 0.12-0.80). Conclusions: LYMPK study 

results suggest that individual etoposide systemic exposure has a strong 

impact on survival in lymphoma patient receiving BEAM regimen and 

ASCT. Given the high variability in patient AUCs, plasma concentrationbased 

adjustment of etoposide dose may be considered in future studies. 



Central nervous system involvement in T-cell lymphomas: A single center 

experience. Presenting Author: Ronit Gurion, Rabin Medical Center, 

Petach Tikva, Israel 

Background: Large experiences have reviewed the risk of central nervous 

system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), but 

there are limited data on CNS involvement by peripheral T cell lymphomas 

(PTCL). We characterized the incidence of CNS involvement, risk factors 

and outcome in a large single institution dataset of PTCL. Methods: 

Retrospective review of the T-cell lymphoma database at Memorial Sloan 

Kettering Cancer Center. We identified 232 patients with any subtype of 

PTCL between 1994-2011 with a minimum 6 months of follow-up or an 

event defined as relapse or death. We excluded indolent forms of cutaneous 

T cell lymphoma. Results: Histologies included PTCL-NOS (31%), angioimmunoblastic 

(16.8%), anaplastic (ALCL), ALK negative (12%), ALCL, ALK 

positive (6%), extranodal NK/T cell lymphoma (7.3%), adult T cell 

leukemia/lymphoma (ATLL) (7.3%), and transformed MF (8.6%). Median 

age was 58 years with 59.9% men. CNS disease was found in 17 patients 

(7.32%). 8 (47%) had pathologic confirmation and 7 (41.2%) were 

clinically diagnosed. Two had other diagnoses at biopsy: DLBCL and 

glioblastoma. Median time to CNS involvement was 2.33 months (range, 

0.16 to 103.1). CNS prophylaxis was given to 24 (10.34%), primarily 

intrathecal methotrexate. There was no difference in CNS involvement in 

patients who received prophylaxis vs. those who did not: 3/24 (12.5%) vs. 

12/208 (5.77%) (p�0.192) respectively. Univariate analysis identified: 

stage III-IV (p�0.03), bone marrow involvement (p�0.018), �1 extranodal 

site (p�0.001), and ATLL vs. all other subtypes, 23.5% vs. 6.4% 

(p�0.003) as risk factors for CNS disease. On multivariate analysis, �1 

extranodal site (p�0.004) and high intermediate (H-I) and high (H) IPI (IPI 

3-5 & 4-5) were predictive for CNS involvement (p�0.05). The median 

survival of patients with CNS involvement was 2.628 months. Conclusions: 

Despite high relapse rates, PTCL carries a low risk of CNS involvement 

other than the ATLL subtype. As with other aggressive lymphomas, survival 

of patients with CNS involvement is poor and risk factors include: �1 extra 

nodal site and H-I-H IPI. In this dataset, prophylactic intrathecal chemotherapy 

does not appear to reduce the risk of CNS disease. 


Ocular adnexal lymphoma (OAL)-outcomes for 82 patients (pts) treated at a 

single center. Presenting Author: Craig Anthony Portell, Cleveland Clinic 

Foundation, Cleveland, OH 

Background: OALs comprise 1-2% of NHL and are extranodal marginal zone 

(EMZL) in 80% of cases. We present a retrospective review of 82 pts with OAL 

managed at the Cleveland Clinic between January 2004 and November 2011. 

Methods: 82 pts with NHL of the OA were identified. All biopsies were 

performed/reviewed at the Cleveland Clinic. Survival and relapse were estimated 

using the Kaplan-Meier method. Risk factors for relapse and survival were 

identified using Cox proportional hazards analysis. Risk factors included age at 

diagnosis (dx), gender, prior autoimmune disease, prior lymphoma history (hx), 

hx of other malignancy, bilateral disease, and ocular disease site. Results: The 

table lists pt characteristics. Median follow-up was 25.8 months (range 

0.3-307.4). Age at dx (HR�1.45, CI 1.04-2.02) and prior lymphoma hx 

(HR�3.35, CI 1.33-8.46) were predictive of relapse in a multivariate analysis. 

There was no difference in relapse rates between pts with EMZL and other 

lymphoma types (p�0.82). Relapse occurred in 26 (31.7%) pts with most 

common sites being ipsilateral eye (n�8), contralateral eye (n�3), distant 

lymph node (n�11), and other organs (n�11). Most common organ was breast 

(n�4). Of the 10 pts who had eye-only relapses, 8 received rituximab (R) and 2 

were observed. Of the 16 with extraocular relapse, 9 received radiation (RT), 2 

received R, 3 received other therapies, and 2 were observed. 7 deaths were 

recorded with a 5 year overall survival of 84.2%. Survival was similar to a 

matched healthy population (p�0.69). Causes of death were lymphoma in 4, 

another cancer in 1, and unknown in 2. Conclusions: OAL relapse patterns differ 

depending on initial treatment. Initial RT was more likely to relapse at distant 

sites; where as initial R was more likely to relapse in the OA. RT should be used 

for localized OAL. With bilateral ocular or systemic disease, R results in a high 

rate of long-term disease control. 

Pt characteristics n(%) 

Median age at Dx (range) 64 (24-91) 

Male 45 (54.9) 

Bilateral involvement 22 (26.8) 

Stage IE (n�73) 48 (69.5) 

Pathologic Dx (n�80) 

ENMZ 56 (70.0) 

Follicular 9 (11.3) 

DLBCL 3 (3.8) 

Mantle 2 (2.5) 

Other lymphoma 7 (8.8) 

Non-dx 3 (3.8) 

Initial Rx (n�73) 

RT 43 (58.9) 

R 13 (17.8) 

Chemo 5 (6.8) 

Combination 8 (11.0) 

Observation 4 (5.5) 


527s 


Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: 

Preliminary results from a phase II study. Presenting Author: Ranjana 

Advani, Stanford University Medical Center, Stanford, CA 

Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate 

approved for the treatment of Hodgkin lymphoma and systemic 

anaplastic large cell lymphoma (ALCL) after failure of other therapies. 

Based on the high objective response rate observed in patients with 

systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by 

homogeneous CD30 expression, a study was initiated in other non-Hodgkin 

lymphomas that express the CD30 target. Methods: A phase 2 open-label 

single-arm study is underway in patients with relapsed or refractory 

CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). 

Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until 

disease progression or unacceptable toxicity. The primary endpoint is 

objective response rate assessed by the Revised Response Criteria for 

Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by 

central lab in order to characterize the relationship of CD30 expression with 

antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have 

enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, 

n�2), EBV-positive DLBCL of the elderly (n�3), primary mediastinal B-cell 

lymphoma (n�2), peripheral T-cell lymphoma NOS (n�2), and angioimmunoblastic 

T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy 

regimens; 3 patients had prior stem cell transplants. Of 6 patients 

who have completed the cycle 2 response assessment, 2 attained complete 

remission, 1 with DLBCL (90% CD30�) and 1 with AITL (8% CD30�), 1 

had stable disease, and 3 had progressive disease. Treatment-related 

serious adverse events observed to date were rash, febrile neutropenia, and 

mastoiditis. Conclusions: Preliminary results suggest that brentuximab 

vedotin may have antitumor activity in patients with relapsed or refractory 

CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy 

previously observed in systemic ALCL. Updated study results will be 

presented. 


The impact of race, age, and sex in follicular lymphoma (FL): A comprehensive 

SEER analysis in the pre- and post-rituximab (R) eras. Presenting Author: Chadi 

Nabhan, Advocate Lutheran General Hospital and Oncology Specialists, S.C., 

Park Ridge, IL 

Background: While racial disparity has been well documented in a number of 

cancers, the impact of race in FL outcomes is not well defined. Further, the 

importance of gender in FL has not been fully explored. Methods: We examined 

population-based FL overall survival (OS) data from SEER 13 (1993-2008) 

regarding race, sex, age, and socioeconomic status (SES) over two consecutive 

8-year (yr) periods: Era 1 (1993-2000, n�7,409) and Era 2 (2001–2008, 

n�9,083). Results: We identified16,492 FL patients (pts) (white (W): n�13,441; 

Hispanic (H): n�1,417; Asian/Pacific Islander (A/PI): n�887; and Black (B): 

n�747). Median ages at diagnosis differed significantly according to: (in yrs, W: 

62.1, H: 57.3, A/PI: 60.5, B: 56.6; P�0.01 for each race vs. W). For all pts, OS 

was superior in Era 2 vs. Era 1 (5-yr OS: 77% vs. 68%, respectively, P�0.0001). 

Further, OS was significantly improved for all age groups (�50, 50-59, 60-69, 

and 70-79 yrs) as well as for males (P�0.0019) and females (P�0.0001) 

across eras. Interestingly, females had superior OS compared with males in Era 1 

(P�0.004), but not in Era 2 (P�0.83). We subsequently compared OS within 

and across races (Table). All races, except A/PI, had improved 5-yr OS rates (age 

adjusted) from Era 1 to Era 2 (W: �0.001, H: 0.049, A/PI: 0.15, B: 0.003). 

Notably, A/PIs had the highest OS in Era 1, while H had the poorest OS in Era 2. 

These differences were more evident in males compared with females within 

each race. Finally, pts with higher SES had better OS in both eras, although OS 

was improved across eras for lower and higher SES populations. Conclusions: 

Collectively, we identified improved OS across eras, which was apparent for all 

ages, both sexes, and all races. We did not find superior outcome for females in 

the modern era as has been recently noted. However, several racial disparities 

persist, including inferior OS for H and superior OS A/PIs in the contemporary 

era. The disproportionate improvement in outcomes for some, but not all races, 

warrants continued study of racial disparities in FL. 

OS across eras based on race. 

5-yr OS 

Era 1 

W vs. H 

P values 

W vs. A/PI W vs. B 

W B H A/PI 

68% 

Era 2 

64% 68% 73% 0.20 0.85 0.007 

W B H A/PI 

77% 75% 73% 79% �0.0001 0.019 0.11 




Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic 

malignancies: A California Cancer Consortium study (PhI-42). Presenting 

Author: Ann Mohrbacher, University of Southern California Keck School of 

Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA 

Background: Fenretinide (4-HPR) is a cytotoxic retinoid with broad anticancer 

activity in preclinical studies. Due to limited bioavailability of a capsule 

formulation an intravenous intralipid-like emulsion formulation (4-HPR 

ILE) was developed to increase systemic exposures. Methods: 4-HPR was 

administered as a continuous intravenous infusion for 120 hrs every 21 

days. Systemic toxicities, responses, and pharmacokinetics were assessed. 

Accelerated Simon design proceeded until moderate or dose-limiting 

toxicities (DLT) were scored on Course 1. Doses were 80 mg/m2 /day to 

1810 mg/m2 /day. Patients with asymptomatic hypertriglyceridemia were 

scored separately. All patients were heavily pretreated. Results: Toxicityevaluable 

patients � 25. At 1810 mg/m2 /day, two patients experienced 

DLT hypertriglyceridemia, one with transient Grade 2 pancreatitis; at 1280 

mg/m2 /day (8 pts), two had asymptomatic Grade 4 hypertriglyceridemia, 

one experienced DLT pleural effusions; at 905 mg/m2 /day (6 pts) 2 

experienced asymptomatic Grade 4 hypertriglyceridemia; All 5 pts at 640 

mg/m2/day tolerated treatment. Pharmacokinetics showed a dose-toplasma 

level relationship with mean steady-state 4-HPR levels of ~mid- 

20’s �M (640 mg/m2 ); ~mid-30’s �M (905 mg/m2/day); and ~mid-50’s 

�M (1280 mg/m2 ). Responses to date include a 64% CR�PR�SD 

response rate (36% CR�PR response rate) in 11 relapsed T-cell lymphomas 

which included histone deacetylase inhibitor-refractory patients, and a 

PRu response in a NHL B-cell lymphoma. Reversible hypertriglyceridemia 

related to the intralipid vehicle accounted for 6/7 DLTs. Conclusions: MTD 

� 1280 mg/m2 /day x 5 days, every three weeks. 4-HPR ILE was safely 

administered and obtained 4-HPR plasma levels 6 -7 times higher than 

previously obtained using oral capsules. Durable complete responses were 

observed in T-cell lymphomas from 905 – 1810 mg/m2 /day. An expanded 

cohort is accruing to a dosing schedule modified to decrease asymptomatic 

hypertriglyceridemia of 600 mg/m2 on Day 1 (to allow for induction of 

serum lipases) followed by 1200 mg/m2 Days 2-5. Supported by NCI U01 

CA062505 and CPRIT RP10072. 


Phase I trial of temsirolimus and lenalidomide in pts with rel/ref lymphomas. 

Presenting Author: Sonali M. Smith, The University of Chicago, 

Chicago, IL 

Background: The PI3K/Akt/mTOR axis is deregulated in lymphomas and is 

an emerging therapeutic target. We previously reported activity of temsirolimus 

(TEM) in DLBCL and FL (JCO 2010 28(31); however, the response 

duration was short. Lenalidomide (LEN) is an immunomodulatory agent 

with multiple anti-tumoral and microenvironmental effects, with activity 

across lymphoma subtypes. We are thus conducting a phase I/II study of 

TEM plus escalating doses of LEN. The phase I portion is completed. 

Methods: Patients (pts) had rel/ref lymphoma after �1 cytotoxic regimen. 

Other criteria: ANC � 1000/mL, platelets � 75,000/mL, nl renal and 

hepatic function, no VTE within 3 months, non-pregnant. A standard “3 � 

3” design was used with dose levels (DL) listed (Table). TEM was given IV 

weekly and LEN was dosed orally on D1-D21, q28 days. Dose-limiting 

toxicity (DLT) was defined as cycle 1 grade 3 or 4 non-hematologic toxicity 

not responsive to standard supportive care, grade 4 thrombocytopenia � 7 

days (or associated with bleeding or requiring more than 1 platelet 

transfusion), ANC � 500/mL � 7 days despite growth factors, or any 

thromboembolic event. Results: 18 pts (13M, 5F), med age 64 y (range, 

42-80 y) were enrolled. 3 pts are ineval for DLT evaluation: one withdrew 

consent before starting treatment, 1 withdrew consent after a single dose, 

and 1 died of rapid disease progression after 1 dose. There was 1 DLT at 

DL1 and 2 DLTs at DL3 (Table). Adverse effects that did not meet DLT 

criteria: hypokalemia, hypertriglyceridemia, vomiting, urinary tract infection, 

skin infection, nausea, hypoxia, hyponatremia, diarrhea, and hyperglycemia 

(each occurring in one pt). There are 5 partial responses, 4 stable 

disease, 3 progressive disease, 2 not adequately assessed, and 4 still on 

active treatment. Conclusions: The combination of weekly intravenous TEM 

plus oral LEN is well-tolerated in a heavily pretreated group of pts with 

rel/ref lymphomas. The recommended phase II doses are TEM 25mg 

weekly plus LEN 20mg (D1-D21, q28d). 

Dose level 

TEM 

(flat dose in mg) 

Dose 

LEN 

(flat dose in mg) 

No. Pts DLT 

-1 25 mg 10 mg n/a n/a 

1 25 mg 15 mg 8 (2 ineval for DLT) Grade 4 hypokalemia 

2 25 mg 20 mg 4 (1 ineval for DLT) No DLT 

3 25 mg 25 mg 6 Grade 3 diarrhea, grade 3 

HSV mucositis 


Use of exon-based transcriptome profiling to identify novel signaling 

pathways and survival-associated genes in diffuse large B-cell lymphoma. 

Presenting Author: Sirpa Leppa, Helsinki University Central Hospital, 

Helsinki, Finland 

Background: Identification of biological prognostic factors that could be 

used to define poor risk diffuse large B-cell lymphoma (DLBCL) patients is 

a main concern. Methods: Study population consisted of 38 de novo high 

risk DLBCL patients less than 65 years old. The patients were treated in the 

Nordic phase II protocol with six courses of R-CHOEP14 followed by 

systemic central nervous system prophylaxis with one course of high dose 

methotrexate and one course of high dose cytarabine. Exon array-based 

profiling was used to screen signaling pathways and differentially expressed 

genes between the clinically high risk patients, who had relapsed or 

remained in remission in response to dose dense chemoimmunotherapy. At 

the time of the analysis, median follow up was 34 months, progression free 

survival (PFS) 78% and overall survival (OS) 78%. Results: The screen 

between relapsed patients and the patients in remission using criteria of p 

� 0.05 and fold change � 1.6 revealed 566 differentially expressed genes 

(131 protein coding), of which 24 were likely to be involved in conventional 

signaling pathways, including those regulating antigen processing and 

presentation (CIITA, HLA-DQA2, HLA-DQB1, RFXAP), Jak-STAT signaling 

(SOCS3), Notch signaling (NOTCH1) and Toll-like receptor signalling 

(IRF5). In cox univariate analysis, 12 of 24 genes were found to associate 

with PFS (p�0.05). Of these, high expression of CIITA, DLL4, HLA-DQA2, 

HLA-DQB1, IRF5, NOTCH1, PER1, RFXAP, SEMA4D and ZFP36 had a 

favorable impact on PFS, whereas high levels of ENPP3 and PRKAR2B 

were associated with adverse outcome. Differential expression of four genes 

was confirmed by quantitative PCR, and prognostic value of six genes 

validated using Lymphoma/Leukemia Molecular Profiling Project microarray 

data set. Immunohistochemical validation of the findings in a larger 

patient cohort is ongoing. Germinal centre B-cell signature did not predict 

survival in this cohort. Conclusions: The results provide evidence that 

exon-based transcriptome profiling can identify biologically relevant signaling 

pathways and genes that discriminate the outcome of homogenously 

treated young high risk DLBCL patients. 


Efficacy and safety of bexarotene combined with psoralen/ultraviolet A light 

(PUVA) compared to PUVA treatment alone in stage IB-IIa mycosis 

fungoides (MF): Final results from EORTC cutaneous lymphoma task force 

(CLTF) phase III clinical trial 21011. Presenting Author: Sean Whittaker, 

Guy’s and St. Thomas’ Hospital, London, United Kingdom 

Background: Skin-directed treatment with methoxsalen (PUVA) is the 

current treatment standard in stage IB-IIA MF. A combination of PUVA and 

bexarotene might be of additional clinical benefit for MF stage I/II patients 

(pts). Methods: EORTC 21011 was a randomised, open label phase III 

study comparing combined bexarotene and PUVA versus PUVA alone in pts 

with stage IB and IIA MF. Study primary endpoint was response (complete 

clinical � partial response, CCR�PR) rate; secondary endpoints: cumulative 

dose of UVA and number of PUVA sessions necessary to achieve a CCR, 

duration of CCR, time to relapse, safety and percentage of drop-outs. 

Results: The study recruited stage IB/IIA MF pts and was prematurely 

closed due to low accrual after 93/145 required pts (65%) were randomized; 

45 to PUVA, 48 to PUVA�bexarotene. Median number of PUVA 

weeks were 12 (1-17) in PUVA vs. 10.5 (1-16) in combination arm. Total 

UVA doses were 107J/cm2 (1.4-489.9) in PUVA vs. 101.7J/cm2 (0.2- 

529.9) in combination arm. Few grade 3-4 toxicities were observed in both 

arms (liver enzyme elevation, neutropenia, anemia, increased cholesterol, 

photosensitivity, pruritus, rash, hypertriglyceridemia). Best overall response 

(CCR/PR) rate was 71.1% (33/45) for PUVA alone and 77.1% 

(37/48) for combination arm (p-value�0.57). The median of duration of 

response was 9.6 for PUVA vs 5.8 months for combination arm (p 

value�0.33). CCR was seen in 25 pts, 10 in PUVA (CCR 24%) and 15 in 

combination therapy (CCR 33%) (pvalue�0.45). Similarily, a lower UVA 

dose was required to achieve a CCR in the combination arm (median of 

55.8 J/cm2) compared to the PUVA arm (median of 117.58 J/cm2) (p 

value�0.5). Conclusions: No significant difference in response rate was 

observed in this study. There was a trend towards fewer PUVA sessions and 

lower UVA dose to achieve CCR in the PUVA/bexarotene combination arm 

(median of 27.5 vs. 22,p-value � 0.11) but this did not achieve statistical 

significance due to insufficient power. The safety profile was acceptable, as 

there were only few grade 3-4 toxicities observed in both arms. 



Dual-point FDG-PET: A novel scanning technique in Hodgkin lymphoma 

with bulky disease. Presenting Author: Andrea Gallamini, Hematology 

Department, S. Croce General Hospital, Cuneo, Italy 

Background: Interim 18F-FDG-PET (iPET) is the most important prognosticator 

in advanced-stage ABVD-treated Hodgkin Lymphoma (HL), but in early 

stage w/ or w/o bulky lesion a low PPV of iPET was reported. Dual-point PET 

scan (2P-PET) has been used to discriminate unspecific inflammatory from 

neoplastic FDG uptake. At the Tx end, with a single FDG-avid mass (SFAM), 

the specificity of PET in Tx response evaluation was sub-optimal. We report 

here preliminary results from a cohort of HL patients (p) presenting with 

bulky lesions, scanned with 2P-PET with the aim to increase specificity and 

PPV. Methods: From 12.2008 till 01.2012 24 HL bulky p from Italian, 

French and Polish centers underwent 2P-PET at baseline (2P-PET-0), after 

2 ABVD (2P-PET-2) and at Tx end (2P-PET-end). 2P-PET scanning 

technique consisted in 2 consecutive image acquisitions �60’ (EaS) and 

�120’(LaS) after single, standard-dose FDG injection. Tx was ABVD (x4 or 

x6) � consolidation RxT. No Tx change was done based on iPET results. 

Scans were reviewed by 2 expert readers in a consensus session. Standardized-Uptake 

Value (SUV) MAX was calculated both in EaS and LaS using 

Volume of Interest Regions (VOIs) in sites of residual FDG uptake already 

recorded in PET-0. �SUVMAX and FDG retention index (RI) were calculated 

from SUVs in the same VOIs of both scans. Results: In 24 p (1 stage I,12 II, 

4 III, 7 IV), 34 2P-PET were done.10 p underwent 2P-PET-0: in 10/10 

SUVMAX increased from EaS to LaS (�SUVMAX 1-4.3). 15 p had a 

2P-PET-2: 12 with a mean-follow-up of 18.36 months were evaluable, 3 

too short ( �1, �5, �6 months). 7/12 p showed a RI reduction of 55% 

(200-14): all are in continuous CR (CCR). 5/12 p. showed a 20% (11-26) 

RI increase: all progressed �1 to�9 months after Tx end. Overall 3/12 

cases (1 false �, 2 false- with a Deauville score 4 and 2,3 respectively) 

were correctly classified after 2P-PET. 9 p with a SFAM had a 2P-PET-end: 

in the 5/9 with an increased RI of 23% (9-43) a biopsy proved HL relapse. 

In 4/9 a reduced RI of -29% (9-45) was found: in 2 biopsy disclosed 

presence of residual thymic along with inflammatory tissue and 2 were in 

CCR �2 to�8 after Tx end. Conclusions: DSUV Max increased at baseline 

and in all relapsing patients, and decreased in patients in CCR. The PPV 

and a PNV of 2P-PET were 100%. 


The incorporation of rituximab (R) and liposomal doxorubicin (LD) into 

CODOX-m/IVAC for untreated Burkitt lymphoma (BL): Final results of a 

prospective multicenter phase II study. Presenting Author: Andrew M. 

Evens, The University of Massachusetts Medical School, Worcester, MA 

Background: Two-year survival rates remain �65-70% for adult BL. 

Further, there is a paucity of data examining the addition of R with 

CODOX-M/IVAC. Methods: 25 patients (pts) with classic BL enrolled onto 

this phase II study (3/07-4/11). Pts were classified as low risk (LR) or high 

risk (HR); LR received 3 CODOX-M, while HR had 4 alternating CODOX-M/ 

IVAC (Mead et al, Blood 2008). LD (40 mg/m2 ) was used in lieu of 

doxorubicin, while intravenous R (500 mg/m2 ) was given days 0 � 8of 

CODOX-M and days 0 � 6 of IVAC cycles. Ejection fraction (EF) was 

assessed at baseline, s/p 2 cycles and completion. Results: Median age was 

44 years (yrs) (23-70). There were 20 HR and 5 LR pts; 3 HR and 1 LR pt 

were HIV�. 15% of HR pts had � CNS disease. In addition, 35% of HR pts 

had bulk �10 cm and 40% had bone marrow involvement. 24/25 pts were 

evaluable for toxicity and response. Therapy was completed at a median of 

13 weeks (11-20) for HR pts and 10 weeks for LR (9-12). Myelosuppression 

(62% grade 4 thrombocytopenia, 4% grade 4 anemia) and mucositis 

(33% grade 3, 13% grade 4) appeared comparable with prior CODOX-M/ 

IVAC data. Other grade 3 toxicities were infection (38%), neutropenic fever 

(29%), transaminitis (33%), diarrhea (8%), creatinine (8%), seizure (4%), 

vomiting (4%). Notably, there was no grade 3 or 4 neuropathy. Two grade 2 

and three grade 3 cardiac events occurred (all depressed EF, no clinical 

CHF). Two of the three grade 3 cardiac events occurred in pts age �65 yrs. 

Among all pts, the median change in EF at baseline vs study end was -2% 

(-22% to �11%). The overall response rate (modified Cheson with 

FDG-PET) after 2 cycles was 100% with a 67% complete remission rate. At 

a median follow-up of 2.3 yrs, 2-year PFS and OS rates for all pts were 86% 

and 86%, respectively (LR 2-yr PFS and OS: both 100%; HR 2-yr PFS and 

OS: both 82%). Furthermore, 2-yr PFS and OS for HR, HIV-negative BL 

were 91% and 91%, respectively (disease-specific survival: 100%). 

Conclusions: The integration of R and LD into CODOX-M/IVAC for adult BL 

is feasible and associated with similar tolerability compared with prior 

reports. Moreover, this regimen was associated with excellent survival 

rates, especially for HIV-negative BL. 


529s 


Association of tumor-associated macrophages of M2 subtype with outcome 

in follicular lymphoma. Presenting Author: Clarinda Wei Ling Chua, 

National Cancer Centre Singapore, Singapore, Singapore 

Background: Current methods used to prognosticate patients with follicular 

lymphoma (FL) include the Follicular Lymphoma International Prognostic 

Index (FLIPI) and tumor grade. However, they do not provide information on 

the biological and molecular features of FL. Recent data suggest that high 

tumor-associated macrophages (TAM) content may be an adverse prognostic 

factor in FL. However, TAM consists of two main subtypes, M1 and M2, 

with the former related to pro-inflammatory properties while the latter, 

anti-inflammatory functions. Currently, the prognostic impact of each 

individual subtype has not been elucidated and this may be more important 

than looking at TAM alone. Methods: Tumor specimens of 98 patients with 

FL diagnosed between 2005 and 2009 were investigated using immunohistochemistry 

and fluorescence in-situ hybridization (FISH) using breakapart 

FISH probes targeting BCL2, BCL6, MYC and IgH genes. Tumor 

specimens expressing a higher proportion of CD68�/CD163- in one high 

power field were defined as M1 subtype and those that expressed a greater 

proportion of CD68�/CD163� were denoted as M2 subtype. Results: 

Amongst the 98 patients, 60 (61%) were of the M2 subtype, 59% 

presented with advanced disease, 47% were grade 3 and the median age 

was 59 years (21 – 88 years). Baseline characteristics including grade, 

stage and recurrent translocations did not significantly differ between the 

M1 and M2 groups. Similarly, there was also no difference in terms of 

treatment received (both Rituximab and chemotherapy) between the two 

groups. Despite these similarities, with a median follow-up of 3.2 years, the 

3-year overall survival (OS) was significantly different (M1, 100% vs M2, 

85%; p � 0.01). All 11 patients who died were of the M2 subtype 

(p�0.009). Conclusions: Our findings show that despite similar patient 

characteristics and treatment, there was, however, a statistically significant 

difference in OS, with the M2 subtype demonstrating an inferior outcome. 

The M2 TAM subtype rather than TAM alone may be a more important 

prognostic marker in FL, which could possibly be explained by its known 

biological anti-inflammatory function. 


Efficacy of ocaratuzumab (AME-133v) in relapsed follicular lymphoma 

patients refractory to prior rituximab. Presenting Author: Jennifer L. Wayne, 

Mentrik Biotech, LLC, Dallas, TX 

Background: Ocaratzumab, previously known as AME-133v, is a humanized 

next-generation anti-CD20 monoclonal antibody. It has been optimized 

with a 13 to 20-fold increase in binding affinity to CD20 and improved 

binding to the low-affinity (F/F and F/V) polymorphisms of Fc�RIIIa (CD16), 

which are thought to predict lower response rates and shorter duration of 

responses to rituximab. Methods: In a phase I dose escalation study in 

relapsed follicular lymphoma (FL) patients, ocaratuzumab was welltolerated 

at doses up to 375 mg/m2 (Forero-Torres et al. CCR 2012). In a 

follow-on phase II trial, 44 patients with relapsed FL following prior 

rituximab and the low-affinity Fc�RIIIa polymorphism (F-carriers) received 

375 mg/m2 of ocaratuzumab weekly for 4 doses. In this study, overall 

response rate (ORR) was 36% and median progression free survival (PFS) 

was 91 weeks (Ganjoo et al. Haematologica 2011). Results: Amongst the 

56 patients receiving 100 and 375 mg/m2 of ocaratuzumab, 8 patients had 

a previous time to progression of � 180 days following their last rituximab 

treatment. These patients had a median of 2 prior rituximab treatments, 

(range 1-6 treatments), and median PFS following last treatment of 159 

days. Five of the 8 patients showed a longer PFS after ocaratuzumab 

administration, compared with last rituximab treatment. All 5 patients 

expressed the homozygous low-affinity genotype of Fc�RIIIa (F/F). At the 

time of study closure, 3 of the patients were still in remission (indicated by 

* in the table). Conclusions: This retrospective analysis suggests that 

ocaratuzumab may be non-cross-resistant to rituximab in patients with the 

low-affinity Fc�RIIIa polymorphism. Prolonged PFS in selected patients 

following ocaratuzumab suggests that the increased binding affinity to 

CD16 and improved antibody-dependent cell-mediated cytotoxicity (ADCC) 

of this antibody is clinically relevant. As a single agent, ocaratuzumab may 

provide prolonged clinical benefit in relapsed FL patients and a clinical trial 

comparing ocaratuzumab to rituximab is in preparation. 

No. of prior RTX treatments PFS after RTX (days) PFS after ocaratuzumab (days) 

1 172 826* 

2 159 636 

1 97 434* 

2 163 357* 

3 103 257 

6 180 168 

2 116 119 

2 176 91 




Disruption of the eIF4F translation initiation complex as a determinant of 

diffuse large B-cell lymphoma responsiveness to enzastaurin 

(LY317615.HCl) and its primary metabolite (LY326020). Presenting 

Author: Jeremy Richard Graff, Lilly Research Labs Cancer Biology and 

Patient Tailoring Lilly, Indianapolis, IN 

Background: Enzastaurin (enza) is in ph 3 registration trials for DLBCL 

patients at high risk of relapse following R-CHOP therapy. In a phase 2 

DLBCL study, 4 of 55 treated patients were progression- free after 

prolonged, continuous oral enza therapy with 3 of these 4 confirmed as 

complete responders (Robertson et al., JCO, 2007). The molecular mechanism 

for this differential response is unclear. Methods: In clinical trials, 

Enza yields 2-4 �M total circulating drug, comprised of ~50% enza, ~50% 

primary metabolite, LY326020. We therefore evaluated the sensitivity of a 

DLBCL cell panel representing both Activated B Cell (ABC) and Germinal 

Center (GC) subtypes to enza and LY326020. Gene expression analyses, 

western blotting to explore intracellular signaling and mRNA cap analogue 

co-capture assays were used to identify the critical effectors of drug 

sensitivity. Results: For the first time, we show the profound biological 

activity of LY326020, the primary metabolite that accounts for ~ 50% of 

circulating drug in patients. Like Enza, though more potently, LY326020 

inhibits PKC and PI3K-AKT-TOR pathway signaling and robustly induces 

apoptosis in both ABC and GC DLBCL cells. In both sensitive and resistant 

cells, enza and LY326020 reduced phosphorylation of numerous proteins 

in the PI3K-AKT-TOR pathway (e.g. pGSK3�ser9 ) in a dose and timedependent 

manner. However, only sensitive DLBCL cells showed reduced 

4EBP1ser65 phosphorylation. Accordingly, we show a dose and timedependent 

increase in 4EBP1: eIF4E binding. This increase is most 

pronounced by LY326020. Moreover, cells selected for resistance to enza 

show reduced 4EBP1 expression and cells lacking 4EBP1 are insensitive to 

the pro-apoptotic effects of enza and LY326020. Conclusions: These data 

demonstrate that sensitivity of DLBCL to both enza and LY326020 is 

critically dependent upon 4EBP1 modulation and subsequent disruption of 

the eIF4F translation complex. Moreover, these data are the first to show 

the potent biologic activity of LY326020, the primary metabolite of enza 

that accounts for ~50% of total circulating drug in patients and in 

preclinical models. 


An update on gemcitabine, rituximab, and oxaliplatin in combination for 

relapsed/refractory non-Hodgkin lymphomas. Presenting Author: Robert M. 

Crescentini, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 

Background: Relapsed/refractory non-Hodgkin lymphomas (NHL) have no 

standard of care. A variety of salvage chemotherapy options are available. 

We previously reported results of our phase II trial using gemcitabine, 

rituximab and oxaliplatin (GROC) in the salvage setting for relapsed/ 

refractory NHL in which we observed an overall response rate of 58% with 

an incidence of grade 3-4 thrombocytopenia of 9% and neutropenic fever 

of 3.5%, but no grade 3-4 non-hematologic toxicities. Here we update 

progression free survival (PFS) and overall survival (OS) data. Methods: This 

phase II, single-arm, multicenter study evaluated safety and efficacy of 

GROC in patients with relapsed/refractory NHL. Patients were treated on a 

14 day cycle. On day 1, patients with CD20� NHL received rituximab (375 

mg/m2 ). On day 2, patients received gemcitabine (1000 mg/m2 ) and 

oxaliplatin (100 mg/m2 ). Granulocyte colony stimulating factor was given. 

Stem cell transplant (SCT) was considered after a minimum of 6 cycles. 

Results: A total of 58 patients were enrolled from the H. Lee Moffitt and the 

Auxilio Mutuo Cancer Centers. Ages ranged from 24 to 88 years (median 72 

years). The majority of patients had an ECOG performance status of 0-1 

(89%). Lymphoid neoplasms included large B-cell (79%), follicular (7%), 

lymphoblastic (1.8%), Burkitt (1.8%), primary mediastinal large B-cell 

(3.5%), and peripheral T-cell lymphoma (7%). Eighty-one percent of 

patients had stage III-IV disease, median IPI was 3, 40% had B-symptoms, 

43% had bulky disease and 74% had an elevated LDH. Anthracyclinebased 

therapy had been used in 91% of patients and 66% had received 

rituximab. Median PFS was 134 days (95% CI 115-153) and median OS 

was 296 days (95% CI 164-428). No difference in response was observed 

based on age �60, IPI, LDH or albumin levels. Prior therapy with rituximab 

(p�0.02) and initial response to front-line therapy (p�0.04) appear to 

correlate with improved outcomes. Nine patients went on for SCT. 

Conclusions: GROC is a useful salvage regimen for relapsed/refractory NHL 

with minimal toxicities and good clinical efficacy. Several patients were 

able to be successfully mobilized, collected and transplanted post GROC 

therapy. 


Use of the cumulative amount of serum-free light chains (sFLC) at 

diagnosis and PET2 for the early identification of high risk of treatment 

failure in Hodgkin lymphoma (cHL). Presenting Author: Rosaria De Filippi, 

Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale 

Tumori, Fondazione �G.Pascale�, Naples, Italy 

Background: Since early identification of patients (pts) at risk of failure is 

the mainstay of a risk-adapted therapy, we explored the prognostic impact 

of the sFLC assay in cHL, whose biology involves ongoing activation of 

polyclonal B-cells. Methods: Serum samples from 248 untreated cHL pts 

were tested by the Freelite assay. Median age was 32 yrs (r 15-85), males 

47%, stages: I (5%), II (51%), III (17%), IV (27%); B-sympt. 60%, 

E-disease, 38%; bulky �10 cm, 44%; ESR � 65, 42%; IPS �3, 39%. 

Early unfavorable disease (GHLSG/ EORTC) was respectively found in 33% 

and 42% of cases. ABVD was given to 89% of pts. Results: Absolute FLC 

levels were summed into a sFLC(��) variable and ROC analysis indicated 

57.1 mg/mL as the threshold to discriminate outcomes. CR rates were 96% 

and 67% for pts below and above the cutoff, respectively (p�.0001). Cox 

univariate analysis disclosed a HR of 16.70 (95% CI, 8.5-32.9) of events 

for sFLC(��) � 57.1 mg/mL, by far higher than for PET2 positivity (HR 

10.8), PS �1 (HR 4.2), IPS �3 (HR 2.8) and all other predictors (HR 

0.54-2.4). In a multivariaye model only sFLC(��) and PET2 remained 

independent predictors. A dismal 8-yrs EFS characterized pts with 

sFLC(��) above threshold (20% vs 89%; �2 119, p�.0001). Pts with 

sFLC(��) below cutoff and a negative PET2 had an EFS of 93% as 

compared to 36% of those with sFLC(��) above cutoff or a positive PET2. 

Pts with sFLC(��) above cutoff and positive PET2, had the worse 

outcome with an EFS �10% and a median survival �12 mo.s (�2 65.4; 

p�.0001). sFLC assay was even more valuable in identifying poor risk pts 

within the early unfavorable category (5-yrs EFS �25%, �2 51 p�.0001). 

By immunoistochemistry small B cells and plasmacytoid lymphocytes were 

identified as the main source of sFLC in HL tissues while a strong sFLC 

uptake by mast cells was documented. Conclusions: A cumulative amount 

of sFLC �57.1 mg/mL, is the strongest independent predictor of failure in 

cHL. Combining sFLC(��) and PET2 outcomes can timely discriminate 

poor risk pts subsets, who may benefit from upfront treatment escalation or 

early salvage. Our data also support that sFLC might endorse immunobiologic 

activities relevant to cHL pathobiology. 


Prevention of adverse events during treatment of HIV-associated Hodgkin 

lymphoma with ritonavir and zidovudine. Presenting Author: Sonia Sandhu, 

John H. Stroger Jr. Hospital of Cook County, Chicago, IL 

Background: In response to very high rates of neurologic and hematologic 

adverse events (AE) when ABVD was used in combination with ritonavir 

(RTV) or zidovudine (AZT) in HIV-associated Hodgkin (HL) we instituted a 

policy to use alternative antiretroviral agents during HL therapy in our HIV 

patients. In this study, we examined all AE in HIV-HL since the exclusion of 

RTV and AZT over 2 years ago. We also evaluated the AEs when HAART and 

chemotherapy for NHL were taken together in an expanded cohort of 52 

pts. Methods: A screen of pharmacy and hospital databases between 

1998-2012 identified all HIV-associated HL and NHL patients. Adverse 

events during chemotherapy were assessed by chart review and graded per 

the NCI Common Terminology Criteria for Adverse Events. Statistics: 

Fisher’s exact test was used to examine the differences in AE incidence 

associated with use of specific antiretrovirals. Results: HAART use during 

chemotherapy was identified in 35/36 (96%) pts with HL and 52/108 

(48%) of pts with NHL. Before RTV and AZT were prohibited, G3/4 

neuropathy, neutropenia, and anemia developed in 31, 68, and 57% of 23 

pts with HIV-HL respectively. Since then, 12 patients were treated with 

non-RTV and AZT based HAART. 0% neuropathy and only 20% G3/4 

neutropenia and 10% anemia was observed, each statistically significant 

(p�0.01). Of the 54 patients with NHL, 64% received CHOPR like, 

HYPERCVADR (18%), and daEPOCHR (11%). All AEs for each NHL 

regimen were similar to historical controls and no anti HIV medication was 

found to correlate with any AE, despite 28% of the HAART regimens 

containing RTV. Conclusions: No relationship between any AE and anti HIV 

medications was identified during treatment for NHL. But, excluding RTV 

or AZT-based HIV therapy during HL treatment, decreased neuropathy, 

neutropenia, and anemia by 100%, 38%, and 28% respectively. We 

suggest that exclusion of ritonavir and zidovudine from HAART regimens 

used with ABVD become the standard. 



Hematologic safety data from four phase II studies of single-agent 

carfilzomib in relapsed and/or refractory multiple myeloma Presenting 

Author: Ajay K. Nooka, Emory University Winship Cancer Institute, Atlanta, 

GA 

Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor 

that is currently being evaluated in patients (pts) with multiple myeloma 

(MM). Given that the majority of pts with MM exhibit either disease- or 

therapy-related myelosuppression sometime in the course of their disease, 

detailed evaluation of treatment-emergent hematologic safety data with 

CFZ is of significant interest. In the following analysis, we report the 

hematologic safety profile for single-agent CFZ from 526 pts treated in four 

phase 2 studies. Methods: Pts treated with CFZ in trials 003-A0, 003-A1, 

004, and 005 were included in the analysis. Pts with preexisting hematologic 

abnormalities of Grade (G) 0–2 (G0–3 for 005) were eligible to enroll. 

CFZ was dosed in all studies on Days 1, 2, 8, 9, 15, and 16 of a 28-day 

cycle (C). Doses were 20 mg/m2 in C1 for all studies escalating to 27 mg/m2 in C2 per individual protocol, except 005 (15 mg/m2 in C1, 20 mg/m2 in 

C2, and 27 mg/m2 in C3). Incidence, frequency, and severity of thrombocytopenia, 

lymphopenia, neutropenia, and anemia were analyzed in terms of 

adverse events (AEs) of interest. Laboratory data were analyzed for trends 

over time. Results: See table below for summary of hematologic events. In 

general, platelet counts trended down, reached a nadir by Day 8 of a 28-day 

treatment cycle, and normalized before the start of next cycle. There was no 

evidence of cumulative thrombocytopenia or clinically significant episodes 

of bleeding associated with thrombocytopenia. Febrile neutropenia was 

reported in 1% of pts. No mortality due to hematologic events was reported. 

Conclusions: Hematologic AEs, although common with CFZ treatment, were 

infrequently dose limiting. Clinically significant G3/4 cytopenias were both 

infrequent and transient. In summary, the hematological safety profile of 

CFZ was similar to or better than currently approved MM therapies, 

providing further evidence of its acceptable safety profile in heavily 

pretreated MM pts. Summary of hematologic events. 

Total population 

N�526, n (%) Thrombocytopenia Lymphopenia Neutropenia Anemia 

Any AE 199 (37.8) 136 (25.9) 119 (22.6) 246 (46.8) 

G3/4 AE 131 (24.9) 104 (19.8) 63 (11.9) 118 (22.4) 

Dose reductions 6 (1.1) 0 6 (1.1) 2 (0.4) 

Discontinuations 5 (1.0) 0 1 (0.2) 3 (0.6) 


A prospective clinical study evaluating current models for risk of progression 

from smoldering multiple myeloma (SMM) to multiple myeloma (MM). 

Presenting Author: Benjamin M. Cherry, Multiple Myeloma Section, Metabolism 

Branch, National Cancer Institute, NIH, Bethesda, MD 

Background: The updated (2010) International Myeloma Working Group 

criteria emphasize individual follow-up and development of early treatment 

trials for high risk SMM patients. To facilitate these goals, it is important to 

have reliable models for risk of progression to MM derived from prospective 

clinical studies. Current clinical risk models by the Mayo Clinic and the 

Spanish PETHEMA group stratify SMM patients as low (LR), intermediate 

(IR), or high risk (HR) of progression using bone marrow plasma cell 

fraction and protein levels (Mayo) and abnormal plasma cell fraction on 

flow cytometry with or without immunoparesis (Spanish). We report the first 

comparison of these models in a prospective natural history study. Methods: 

We evaluated 70 patients with SMM and determined the risk classifications 

of each using the Mayo and Spanish models. P values of comparisons 

between risk groups were calculated using Fisher’s exact test. Results: 

Among SMM patients classified as HR by the Spanish model (n�31), 2 

patients (6%) were HR by the Mayo model; the remaining 17 (55%) and 12 

(39%) patients were classified as IR and LR by the Mayo model, 

respectively. Among 2 SMM patients classified as HR by the Mayo model, 

both patients (100%) were HR by the Spanish model. There was significant 

disagreement between the models in identifying HR patients (HR v. 

non-HR, p�0.0001). Similarly, of SMM patients classified as LR by the 

Spanish model (n�17), 11 patients (65%) were LR by the Mayo model; 6 

(35%) were IR and 0 (0%) were HR by the Mayo model. Among SMM 

patients classified as LR by the Mayo model (n�36), 11 (31%) patients 

were classified as LR by the Spanish model; 13 (36%) were IR and 12 

(33%) were HR by the Spanish model. There was significant disagreement 

between the models in identifying LR patients (LR v. non-LR, p�0.0016). 

Conclusions: The significant discordance between the Mayo Clinic and 

Spanish PETHEMA clinical risk models underscores the urgent need for 

biologically derived models that rely on molecular markers to predict 

disease progression. Such models are critical for counseling individual 

patients and for the development of early treatment studies that seek to 

prevent or delay progression to MM. 



Natural killer (NK) cell activation, cytokine production, and cytotoxicity in 

human PBMC/myeloma cell co-culture exposed to elotuzumab (Elo) alone 

or in combination with lenalidomide (Len). Presenting Author: Balaji 

Balasa, Abbott Biotherapeutics, Redwood City, CA 

Background: Elo is a monoclonal IgG1 antibody targeting CS1, a cell surface 

glycoprotein highly expressed on �95% of myeloma cells. In preclinical 

models Elo exerts anti-myeloma activity via NK cell-mediated antibodydependent 

cellular cytotoxicity. Len is an immunomodulatory agent that 

may activate NK cells. The combination of Elo � Len synergistically 

enhanced anti-tumor activity in myeloma xenograft models. We investigated 

the mechanism of enhancing NK cell activation and myeloma cell 

killing with Elo � Len. Methods: Human PBMC/OPM-2 co-cultures were 

treated for 24-72h with Elo, Len, or Elo � Len. Activation markers and 

adhesion receptors were evaluated by flow cytometry. Cytokines were 

measured by Luminex and ELISpot assays. Cytotoxicity was assessed by 

cell counting. Results: Elo � Len increased IFN-� secretion significantly 

more than Elo or Len alone. IFN-� elevates ICAM-1 expression, and ICAM-1 

surface expression on OPM-2 target cells increased synergistically with Elo 

� Len. Elo, Elo � Len but not Len increased expression of CD25 (IL-2R�) 

on NK cells. Len increased the levels of IL-2, but those were decreased in 

the presence of Elo due to increased consumption by CD25 expressing NK 

cells. Blocking uptake of IL-2 with anti-CD25 resulted in higher IL-2 levels 

than with Len. ELISpot assays confirmed that Elo � Len significantly 

increased the number of IL-2-producing cell colonies compared with Elo or 

Len. Elo induced NK dependent myeloma cell killing, and the effect was 

significantly higher with Elo � Len. Conclusions: Elo alone activated NK 

cells and mediated the killing of myeloma cells in PBMC/OPM-2 cocultures. 

Elo � Len synergistically enhanced myeloma cell killing and 

increased expression/production of IFN-�, ICAM-1, IL-2, and CD25. 

Treatment 

No blocking (control mAb) ave n�6 Anti-CD25 blocking mAb ave n�6 

IFN-� (pg/mL) 

ave n�8 

ICAM-1 on 

OPM-2 (MFI) 

n�4 

CD25 on 

NK cells 

(MFI) n�8 

IL-2 (pg/mL) 

(Luminex) 

# IL-2 positive 

colonies 

(ELISpot) n�9 

531s 

OPM-2 

killing (%) 

n�4 

*Control 48 427 155 21 - 30 1 

**Len 94 2040 131 50 - 71 15 

Elo � Len 386 42,259 1546 14 134 191 67 

Elo 65 3068 975 7.8 52 80 39 

*cIgG1 (isotype); **plus cIgG1. 


Costimulatory molecule profiles and NK cell recovery after autologous 

hematopoietic cell transplantation (HCT) in multiple myeloma (MM) 

patients. Presenting Author: Myo Htut, City of Hope, Duarte, CA 

Background: Increased immune responses post autologous HCT may be of 

benefit in long term disease control. Responses may be mediated by NK 

cell function and possibly other alternate pathways, including costimulatory 

molecule pathways. This pilot study assesses the expression of 

inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and 

CD28) molecules on NK cells after auto-HCT in MM patients and evaluates 

the effect of lenalidomide treatment on these pathways. Methods: 17 

patients with MM undergoing HCT, median age 56.7 years (36 – 67), were 

included in the study. Peripheral blood samples were taken 3 days prior to 

HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17 

patients were receiving lenalidomide with d91 as median start date. NK 

cells and their costimulatory molecules were evaluated by flowcytometry 

using 2 six color panels of antibodies. One way ANOVA test and Kruskal- 

Wallis test (non-parametric) were applied to analyze the data using the 

Graphpad Software. Results: See table below. NK cell number was highest 

(median: 26% of total lymphocytes) at d14 (p: � 0.0001) compared to pre 

and post HCT levels. At d180, TNF-R OX40 expression was significantly 

increased in �PR group (n�5) (median: 9.5% of NK cells) compared to 

�VGPR (n�12) (0.8%; p�0.0084). In addition, NK cell number was 

higher in the lenalidomide group (n�13) (median: 15.15 % of total 

lymphocytes) compared to the no lenalidomide group (n�4) (6.74%; 

p�0.0108) at d180 post HCT. Significantly lower level of CTLA-4 

expression was also found in the lenalidomide group (0.33% vs. 2.54%; 

p�0.0362). Conclusions: We observed NK cell recovery to baseline values 

at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was 

higher in �PR group than �VGPR group. Lenalidomide treatment was 

associated with higher NK cells number and decreased expression of 

CTLA-4. This observation could be a possible marker of enhanced host NK 

cell immune response against MM. Future clinical trials will explore 

therapies that increase NK cell responses. 

Pre-HCT d180 

Very good partial response or better (> VGPR) 6 12 

Partial response or worse (< PR) 11 5 




Retrospective analysis of second malignancies in patients with multiple 

myeloma. Presenting Author: Giampaolo Talamo, Penn State Hershey 

Cancer Institute, Hershey, PA 

Background: Recent data from patients with multiple myeloma (MM) 

enrolled in randomized clinical trials have shown an increased incidence of 

second malignancies after treatment with lenalidomide, but the prevalence 

of second malignancies in the overall MM population is uncertain. Methods: 

We retrospectively analyzed the medical records of 320 consecutive MM 

patients followed at the Penn State Hershey Cancer Institute between 

2006 and 2010. We excluded from the analysis basocellular and squamocellular 

carcinomas of the skin. Results: Forty-three patients (13%) were 

found to have second malignancies, and 5 of them had a third cancer. One 

pt had 4 cancers. They included cancers of the prostate (8 pts), breast (8), 

MDS/leukemia (6), colon/rectum (5), melanoma (5), lung (4), uterus (4), 

bladder (3), kidneys (2), pancreas (2), testicle (1), myeloproliferative 

disorders (1), and sarcoma (1). Of 50 cancers, 36 (72%) developed before 

the diagnosis of MM, at a median of 65 months (range, 1-372), and 14 

after that, at a median of 37 months (range, 3-104). Lenalidomide was 

used in 239 (75%) patients, and in 9 of 14 cases of post-MM second 

malignancies. Conclusions: Second malignancies usually develop before 

the diagnosis of MM, i.e., MM is the second malignancy for the majority of 

patients. The use of lenalidomide could not be indicated as a possible 

carcinogenic factor for the majority of MM patients with second malignancies. 


Second autologous stem cell transplantation as a strategy for management 

of relapsed multiple myeloma. Presenting Author: Wilson I. Gonsalves, 


Background: High dose therapy and autologous stem cell transplant (SCT) 

remain an integral part of the treatment of multiple myeloma (MM). Despite 

the introduction of several new drugs, disease relapse remains inevitable 

and a second SCT often allows continued disease control. Methods: We 

examined the outcomes in 105 patients (pts) undergoing a second SCT 

(SCT2) for relapsed MM, from among 1033 pts receiving initial transplant 

between 1994 and 2009. Patients receiving an allogeneic SCT post SCT2 

were not included in the survival analysis. Results: Median (range) age at 

SCT2 was 60 yrs (35-74) and the time between SCTs was 46 mos 

(10-130). The median follow-up was 5 yrs from SCT2. The median (range) 

number of regimens between the two SCTs and from diagnosis was 2 (0-7) 

and 3 (1-11), respectively. Conditioning regimen was Mel 200 in 85 (81%) 

pts. Median (range) CD34 cells infused was 4.6 (2.5-25 million/kg). 

Hospitalization was required for 53 pts (50%), median hospital stay was 7 

days.. Median time to ANC of 500 and platelets of 50,000 were 13 and 16 

days, respectively. Treatment related mortality was seen in 5 (5%) pts. A 

partial response or better was seen in 95 (90%) pts, including a stringent 

CR in 10%, CR in 19%, and VGPR in 21%. Stable disease or progression 

was seen in 7 pts and 3 pts died prior to disease assessment. The median 

(95% CI) PFS and OS after SCT2 were 10.4 (8, 14) and 33 (28, 51) mos, 

respectively. The median OS was not reached and 33 mos respectively, for 

those obtained a CR and those with �CR, P�0.03. FISH pre-SCT2 was 

available for 73 pts; the PFS and OS were not affected by the presence of 

high-risk MM. In multivariate analyses, shorter duration of response to 

SCT1, higher plasma cell (PC) labeling index at SCT2, more regimens used 

prior to SCT2 all predicted shorter PFS and OS post SCT2. Lack of CR to 

SCT2 was also significantly associated with shorter PFS. Conclusions: 

Second SCT is an effective therapy for eligible pts relapsing after other 

treatments. It provides a meaningful duration of response and appears to be 

well tolerated. Pts with longer duration of response to first transplant and 

those achieving a CR appear to have maximum benefit. 


Predictive value of baseline serum MIP-1� and CRP on symptom burden 

and tumor response to induction therapy in patients with multiple myeloma. 

Presenting Author: Charles S. Cleeland, University of Texas M. D. 


Background: Macrophage inflammatory protein-1�(MIP-1�) is a growth 

factor for human multiple myeloma (MM) cells. As an osteoclastic factor, 

its presence provides pathophysiological evidence of the development of 

lytic bone lesions in MM. C-reactive protein (CRP) indicates systemic 

inflammation. The relationship between disease-driven inflammatory markers 

and both patient-experienced symptoms and tumor response to induction 

therapy is unknown. Methods: MM patients (N�39) who were either 

newly diagnosed or had received fewer than 2 cycles of chemotherapy, and 

who also were to receive induction therapy, were enrolled. To test 

concentrations of MIP-1� and CRP, serum samples were collected before 

and after induction and assayed by Luminex. Multiple symptoms were 

measured twice a week via the M. D. Anderson Symptom Inventory MM 

module (MDASI-MM) from -8 to �112 days of induction. The MM-specific 

items of the MDASI-MM are bone aches, constipation, muscle weakness, 

diarrhea, sore mouth or throat, rash, and difficulty paying attention. 

Correlation between symptom severity and inflammatory markers at baseline 

was examined by linear regression modeling. Kruskal-Wallis significance 

test and Wilcoxon test were used to examine association between 

MIP-1� and tumor response. Results: Patients received either bortezomibbased 

(89%) or lenalidomide-based induction therapy. Baseline MIP-1� 

and CRP were significantly inversely related to the mean severity component 

score of the 5 most-severe symptoms (fatigue, pain, bone aches, poor 

sleep, drowsiness) (p�.03; p�.02), and significantly inversely related to 

the severity of a component score of the module-specific symptoms 

(p�0.04; p�.002). Change over time in MIP-1� differed significantly by 

tumor response category (p�.04), with the partial response group having a 

higher median score than the complete response group (1.483 vs. 0.016, 

p�.01). Conclusions: Our data suggest that higher baseline levels of serum 

MIP-1� and CRP predict effective chemotherapy-induced reduction of 

disease-related symptoms in MM patients. Higher serum MIP-1� expression 

after induction therapy was related to less-ideal tumor response. 


Prognostic value of serum lactate dehydrogenase in symptomatic multiple 

myeloma. Presenting Author: Krina K. Patel, University of Texas M. D. 


Background: In patients with symptomatic multiple myeloma, the clinical 

features, responses to treatment, and survival times vary. Well established 

predictors of survival include the International Staging System (ISS), 

cytogenetic abnormalities, and response to therapy. Long recognized has 

been the association of high serum lactate dehydrogenase (LDH) with 

advanced disease and shorter survival. We focused here on the impact of 

high LDH on staging and prognosis in order to guide the role of recent 

advances in therapy. Methods: We evaluated 1,247 patients with newly 

diagnosed, symptomatic myeloma from 10/74 to 7/11. Our goal was to 

determine the prognostic value of high LDH (�300 IU/L) in relation to ISS 

stage. We also compared the frequencies of anemia, hypercalcemia, and 

response to therapy in patients with high LDH with those of patients with 

Stage III disease and normal LDH values. Results: All 1,139 patients with 

normal LDH lived significantly longer than the 108 patients with elevated 

values (47 vs. 16 months, p �.01). LDH was elevated in 9% of all patients, 

but in 2%, 6%, and 18% of patients with ISS-I, II, and III disease, 

respectively. Their survival times were also significantly shorter than those 

of comparable patients in each stage with normal LDH (table). Among the 

108 patients with high LDH, the frequencies of hemoglobin �8.5 g/dl (54 

vs. 41%, p�.03), and serum calcium�11.5 mg/dl (41 vs. 27%, p�.01) 

were significantly higher than those of 292 patients with Stage III disease 

and normal LDH, and the frequency of response to therapy was less (40 vs. 

62%, p�.01). Conclusions: Serum lactate dehydrogenase provides a 

convenient and dependable prognostic indicator in patients with multiple 

myeloma. An elevated LDH value indicates a poor prognosis regardless of 

ISS stage, confirming the report by Gkotzamanidou, Terpos, and Dimopoulos 

et al, and should be included in the definition of stage III disease. Such 

patients require rapid control of disease with sequential combinations of 

effective drugs and intensive therapy in order to improve their outcome. 

Effect of elevated LDH on survival according to ISS stage (median months). 

ISS Stage < 300 IU/L >300 IU/L p 

I 56 16 .09 

II 49 21 �.01 

III 35 16 �.01 



Predicting bortezomib-related severe neurologic adverse events by measuring 

proteasome activity in PBMCs. Presenting Author: Yukiko Cho, Ibaraki 

Prefectural Central Hospital, Ibaraki, Japan 

Background: Although a proteasome inhibitor bortezomib (BOR) is one of 

the backbone drugs for the treatment of multiple myeloma, severe 

neurologic adverse event (sNE) is a major obstacle for continuing the 

treatment. As there is no clinically available biomarker for predicting the 

occurrence of sNAE, we measured the proteasome activity (PrsAtv) in 

peripheral blood mononuclear cells (PBMCs). Methods: Patients (Pts) were 

treated by either standard Q3wks or weekly (BOR 1.3mg/m2 : day 1, 8, 15, 

22; Q5wks) schedule depending on physician’s decision. PBMCs were 

collected from 21 Pts and 99 healthy volunteers. Pts’ samples were 

collected before treatment, 1 hour after the 1st injection of BOR, and at the 

end of the 1st course. PrsAtv in PBMCs was measured by using a specific 

substrate SUC-LLVY-AMC, which becomes fluorescent upon cleavage by 

proteasome. Results: Levels of PrsAtv among volunteers were highly 

variable with no certain correlation with age and sex. Pretreatment levels of 

PrsAtv among Pts were also variable, and didn’t correlate with the 

occurrence of sNAE. After 1 hour of BOR injection, PrsAtv decreased to 

33.2�20.5% (mean � SD) of the pretreatment level, and it generally 

recovered (112.5�77.6%) at the end of the 1st course. However, in 12 out 

of 21 Pts, it didn’t recover to � 100%. Among these Pts, 5 manifested with 

sNAE (�G3) during the 2nd or 3rd course of the chemotherapy. In a sharp 

contrast, no patients whose PrsAtv recovered to �100% manifested with 

sNAE. Pts who manifested with sNAE (5 Pts) showed the lower levels of 

PrsAtv at the end of the 1st course than those without sNAE (16 Pts) 

(67.4�11.8 vs 126.6�83.8%, p�0.075). It should be also strengthened 

that all the Pts who manifested with sNAE were treated by the standard 

Q3wks schedule, although levels of PrsAtv at the end of the 1st course were 

not significantly different between Q3 and Q5wks groups (109.0�68.3 vs 

121.1�96.4 %, p�0.38). Contrary, there was no significant difference of 

the bortezomib response between these two treatment groups. Conclusions: 

Pts whose PrsAtv does not recover to �100% at the end of the 1st course 

are at high risk of manifesting with sNAE, and these Pts should not be 

treated by the standard Q3wks schedule in the subsequent courses. 


Long-term outcome with lenalidomide and dexamethasone therapy for 

newly diagnosed multiple myeloma. Presenting Author: Geetika Srivastava, 


Background: The combination of lenalidomide and dexamethasone (Len- 

Dex) is a commonly used initial therapy for newly diagnosed multiple 

myeloma. While the short-term outcomes with respect to response and 

toxicity is well-known, long-term outcome with this combination as initial 

therapy is not well described. Methods: We studied 286 consecutive 

patients with newly diagnosed MM seen at our institution, who received 

initial therapy with Len-Dex, and who had complete follow up records. Data 

regarding the clinical course was obtained from medical records. Results: 

The median (range) age at diagnosis was 63 (28-92) yrs; 166 (58% were � 

65 yrs and175 (61%) were male. The median estimated follow-up was 3.9 

yrs (95% CI, 3.4, 4.2) and 203 (71%) pts were alive at the time of last 

follow up. The median estimated duration on Len-Dex was 5.3 mos (95% 

CI, 4.6, 6.4). The best overall response (�PR) was 72%, including 26% 

with VGPR or better and 14 (5%) not being evaluable for a response. At last 

follow up, 41 (14%) patients were continuing on therapy. There were 93 

pts (32%) who stayed on therapy for 12 months or more. Among these 

patients, the ORR was 86%, including 45% with VGPR or better. The 

median overall survival (OS) for the entire cohort from diagnosis was 7.4 yrs 

(95% CI; 5.8, NR) and the estimated 5-yr survival was 67%. There were 16 

(5.5%) pts who died within a year of diagnosis. The median time to first 

disease progression, irrespective of transplant status, was 30.2 mos (95% 

CI, 25, 42). Overall, 143 (50%) of the patients have gone to stem cell 

transplant. Censoring those patients who proceeded to SCT prior to relapse 

at the time of BMT, the median TTP was 25.5 mos (95% CI, 22, 29). The 

median OS was 7.4 yrs for those �65 yrs, compared with 6.2 yrs for the 

older patients (P�0.01). The 5-yr OS estimate for patients in ISS stage 1, 

2 and 3 were 82, 65, and 44 months respectively. Conclusions: The current 

study provides long-term estimates of responses and survival in a series of 

patients treated initially with lenalidomide and dexamethasone. The 

median survival of nearly 8 years reflects the efficacy of the novel agents 

both at diagnosis and at relapse and confirms the survival improvements 

seen in MM in the last decade. 


533s 


Regional differences in the treatment approaches for relapsed multiple 

myeloma: An IMF study. Presenting Author: Brian G. Durie, Cedars-Sinai 


Background: Multiple myeloma (MM) remains incurable and invariably 

relapses after initial therapy. There is no uniform approach to management 

of relapsed MM and is dictated by type of initial therapy and the response 

seen, and availability of new drugs. The outcomes associated with current 

approaches have not been systematically examined. Methods: We enrolled 

383 patients (pts) with myeloma who had a documented relapse between 

Jan 2007 and June 2010, including 220 from Europe, 106 from Asia, and 

31 from South America and 26 from North America. Time Zero (T0) was 

defined as date of treatment after first relapse. Results: Across the study, 

61% were male and 49% were over 65 years at T0. ISS stage distribution at 

diagnosis included 26, 40 and 33% of patients in stages 1, 2 and 3, 

respectively. Among regimens used at first relapse; bortezomib (Btz) 

containing regimens were most common (54%), followed by lenalidomide 

(Len, 25%) and cyclophosphamide (21%). The overall response rate 

(��PR) to first therapy after relapse was 58% including 14% with a CR. 

There was a progressive decrease in the response rates with successive 

regimen; 45%, 30% and 15% for regimens 2, 3 and 4 respectively. Len 

use was considerably lower in the Asian cohort, while Btz use was 

comparable across the regions. The median PFS from T0 was 13 mos and 

OS was 35 mos, for the entire cohort. The PFS to first salvage regimen was 

similar across the regions, while OS was shorter for the Asian and South 

American cohorts. In a univariate analysis, ISS stage 3, presence of 

cytogenetic abnormalities, history of plasma cell leukemia or extramedullary 

disease (EMD), bone marrow PC% � 33% and presence of renal 

insufficiency were all associated with a shorter PFS as well as shorter OS 

(P��0.01). In a multivariate model, ISS stage 3 and presence of EMD 

were most associated with short OS. Conclusions: Median PFS for current 

second line regimens, typically containing Btz or Len appear to be 1 yr with 

an OS from first relapse of about 3 yrs. The OS from first relapse is nearly 

double that seen in a cohort of patients in first relapse prior to introduction 

of new drugs. Clear-cut regional differences can be seen in terms of 

patterns of drug use and likely reflect drug availability and healthcare costs. 


Clinical profile of multiple myeloma in Asia: An Asian Myeloma Network 

(AMN) study. Presenting Author: Jae Hoon Lee, Department of Internal 

Medicine, Gachon University Gil Hospital, Incheon, South Korea 

Background: The incidence of multiple myeloma (MM) is known to be 

variable according to ethnicity. However the difference of clinical characteristics 

between ethnic groups is not well-defined. In Asian countries the 

incidence of MM has been lower compared with Western countries. 

However, there are growing evidences that MM is increasing very rapidly in 

this region. Until now, only few data of Asian patients has been reported. 

Asian myeloma network (AMN) decided to analyze the first multinational 

project to explore clinical characteristics of Asian MM patients and clinical 

practice performed in Asian countries. Methods: Data were collected from 

21 centers from 7 countries and regions were collected retrospectively. 

Clinical characteristics of 2969 symptomatic MM patients at diagnosis 

were described. Overall survival (OS) and prognostic factors were analyzed 

for 2273 patients who have survival data. Results: Median OS was 54 

months (95% CI 48.0-60.0). Patients who were diagnosed before 2000 

were shorter survival. Transplantation was performed to 513 patients with 

better survival (84 vs. 45 months, p�0.001). First line treatment of 2339 

evaluable patients was analyzed. Overall response rate was 71% with 30%, 

VGPR or better. New drugs including bortezomib, thalidomide or lenalidomide 

were combined for 32.5% of all 2339 patients without difference in 

response rate or OS according to combination. Conclusions: We successfully 

described clinical characteristics of Asian MM patients and this 

project will be the base for future studies or clinical trials for Asian MM 

patients. Updated analyses and comparison with Western data will be 

presented. AMN, supported by the International Myeloma Foundation 

(IMF) IMWG initiative. 




A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib 

(BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving 

a BTZ-containing combination regimen. Presenting Author: James R. 

Berenson, Institute for Myeloma and Bone Cancer Research, West Hollywood, 

CA 

Background: Recent data has shown that single-agent CFZ can produce 

responses among MM pts refractory to previous treatment regimens 

including those containing BTZ. We conducted an intrapatient Phase 1/2 

trial investigating the safety and efficacy of CFZ as a replacement for BTZ in 

BTZ-containing regimens to which pts have progressed. Methods: Eligible 

pts had to have progressed while receiving their most recent BTZcontaining 

regimen after at least 4 doses of BTZ at � 1.0 mg/m² in � 4 

weeks per cycle. Combination regimens containing an alkylating agent, 

anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in 

each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 

15, and 16 of each cycle. Treatment continued using the same dose(s) and 

schedule(s) of each drug administered in the BTZ-containing regimen. CFZ 

doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 

mg/m² or until a maximum tolerated dose (MTD) was reached for that 

regimen. Results: Of 19 enrolled pts 13 are evaluable to date and 6 have 

recently started treatment. Pts received a median of 7 (range, 1-18) prior 

treatments and 5 (range, 1-5) different BTZ-containing regimens. Pts were 

treated with CFZ and the following different combinations: bendamustine 

(BEND) alone, BEND � methylprednisolone, dexamethasone (DEX) alone, 

DEX � pegylated liposomal doxorubicin, ascorbic acid � cyclophosphamide, 

and melphalan alone. Pts have completed a median of 3 cycles. 

Clinical benefit was seen in 10 (77%) pts (complete response � 8%; very 

good partial response � 8%; partial response � 31%; minor response � 

31%) with another 23% showing stable disease. The median time to 

progression (range: 2-8 months) has not been reached and only 2 pts have 

progressed. The most common grade 3/4 adverse events were thrombocytopenia 

occurring in 5 pts (all � grade 3 except 1 event) and fever occurring 

in two pts (grade 3). Four pts experienced a serious adverse event but no 

regimen has reached a MTD. Conclusions: These early results suggest that 

CFZ is an effective and tolerable replacement for BTZ for pts who are 

refractory to BTZ-containing combination regimens. 


Survival outcomes of early autologous stem cell transplant (ASCT) followed by 

lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients 

with high-risk multiple myeloma (MM). Presenting Author: Jonathan L. Kaufman, 

Winship Cancer Institute, Emory University, Atlanta, GA 

Background: Despite markedly improved survival rates for MM pts in the last 

decade, 15-20% of pts with high risk genetics continue to have dismal outcomes 

with a median PFS of 18.5 months (Kapoor P et al). In this subset of pts, efforts 

are needed to improve response rates and prolong the response duration, but 

doing so without genotoxic therapy as this has been shown not to improve 

outcomes (Barlogie et al). Methods: We evaluated 37 pts with high risk features 

[del17p (n�16), t(4;14) (n�1), t(14;16) (n�4) by FISH/CTG; hypodiploidy 

(n�9), del 13 (n�16); complex karyotype (n�14) by CTG; PCL (n�7) and 

atypical presentation (n�4)]. After completing induction therapy, all pts 

underwent ASCT followed by RVD maintenance. 60 days after ASCT following 

hematological recovery, pts began maintenance [lenalidomide 10 mg/day 

(days1–21), bortezomib 1.3 mg/m2 and dexamethasone 40 mg once a week 

(days 1, 8, 15) every 28 days]. Results: The response rates are summarized in the 

table. 7/36 pts progressed while on RVD maintenance. The median PFS and OS 

for pts on RVD maintenance has not been reached. Pts with �VGPR pre-ASCT 

and with �VGPR on RVD maintenance have median PFS of 28 months and 11 

months, respectively. 4 pts with prior h/o DVT received anticoagulation, while all 

others received ASA for DVT prophylaxis. No thrombotic events were seen. There 

were no grade 3/4 toxicities or treatment-related mortality. The most common 

toxicities during maintenance schedule were: PN-40% (G1: 26%; G2:14%); G1 

rash-10% and G1 fatigue in 78% pts. Cytopenias were seen in 25% pts and dose 

reductions were made in 50% pts. There is no report of secondary malignancies. 

Conclusions: Early ASCT followed by RVD maintenance delivers superior response 

rates in this high risk segment achieving sCR in 47% and �VGPR in 73% 

pts and prevents early relapses. The median PFS and OS have not been reached. 

RVD maintenance regimen is well tolerated and promising. 

Response rates. 

Best response with 

Pre-ASCT response Post-ASCT response RVD maintenance 

n % n % n % 

sCR 3 8 8 22 17 47 

CR 3 8 8 22 5 14 

sCR � CR 6 16 16 44 22 51 

VGPR 13 35 16 43 8 22 

>VGPR 19 51 32 77 30 73 

PR 15 41 5 14 3 8 

>PR 34 92 37 91 33 81 

SD 1 3 

PD 2 6 3 8 


Effect of matrix metallopeptidase 13 (MMP13) on multiple myeloma (MM) 

cells, osteoclast (OCL) activity, and bone resorption. Presenting Author: 

Jing Fu, Columbia University Medical Center, Department of Medicine/ 

Hematology-Oncology, New York, NY 

Background: MM cells produce OCL-activating factors that induce excessive 

bone resorption resulting in lytic lesions. The role of MMPs in invasion/ 

progression of solid tumors is well-known, but its function in MM has not 

been well elucidated. Our group has shown that MMP13 is highly expressed 

in primary MM cells and in sera of MM patients. Levels of MMP13 

significantly correlate with the extent of bone disease. MMP13 is induced 

by IL-6 via AP-1 activation in MM cells and enhances fusion of OCL 

precursors resulting in excessive bone resorption. OCL formation using 

MNCs of mmp-13-/- mice resulted in a fusion defect, significantly decreased 

OCL size and activity, which could be reversed by exogenous 

MMP13 (ASH 2009, IMW 2011). Methods: Methods will be presented in 

the Results section. Results: RT-PCR and western blotting revealed that 

IL-6 treatment of MM cells induced MMP13 transcription (30-fold) and 

secretion (�1000-fold). Protein expression of the AP-1 members c-Jun 

and c-Fos was induced by IL-6, which correlated with MMP13 upregulation. 

Our data further indicate that the catalytic activity of MMP13 is not 

required to enhance OCL formation and bone resorption. To prove this, we 

generated the MMP13 activity-dead mutation MMP13-E223A construct by 

site-directed mutagenesis PCR-based cloning. The mutated protein was 

overexpressed in HEK293 cells and purified from the supernatant to 

confirm whether loss of catalytic activity blocks MMP13 function. To 

further investigate the in vivo role of MMP13 in MM bone disease, MMP13 

expression was knocked down (KD) in murine 5TGM1-MM cells by pKLO. 1 

puro lentiviral infection containing sh-RNA targeting mouse MMP13 

sequence. MMP13-KD 5TGM1-MM cells or WT-5TGM1-MM cells were 

intratibially injected into RAG2-/- mice. Development of lytic bone lesions 

are monitored by micro-QCT and data will be available at the time of 

presentation. Conclusions: Our data suggest that MMP13, secreted by MM 

cells, plays a critical role in the development of lytic lesions. Targeting 

MMP13 represents a promising approach to treat or to prevent bone 

disease in MM. 


Efscalefect of lenalidomide, bortezomib, and dexamethasone (RVD) induction 

therapy in transplant-eligible patients (Pts) with newly diagnosed 

multiple myeloma (MM) on CR rates and survival. Presenting Author: 

Charise Gleason, Winship Cancer Instiute, Emory University, Atlanta, GA 

Background: Addition of lenalidomide to bortezomib and dexamethasone 

(RVD) demonstrated to be an effective and well tolerated regimen in phase 

II trials with overall response rate (ORR) �95% (Richardson P et al). Given 

the lack of phase III data, we have evaluated our institutional experience of 

pts treated with RVD induction therapy, to support this triplet combination. 

Methods: 286 transplant-eligible pts with newly diagnosed MM were 

treated with RVD induction therapy [R - 25 mg/day (days1–14), V-1.3 

mg/m2 (days 1, 4 8, 11) andD-40mgonce/twice weekly as tolerated every 

21 days] from January 2008 until January 2012. 148 pts underwent ASCT 

and 138 pts opted for delayed transplant. Post-ASCT 56% pts are on 

maintenance therapy tailored to their risk (R-40%; RVD-10%; V-6%). 

Demographic and outcomes data for the pts that underwent ASCT were 

collected and responses were evaluated per IMWG Uniform Response 

Criteria. Results: Median age of the pts is 60 years (range 32-77). Other pt 

characteristics include: M/F 55%/45%; ISS I/II/III 40%/30%/30%; Isotype 

IgG/IgA/FLC/IgM 61%/20%/18%/1%; high risk/standard risk 13%/ 

87%. Pts received a median of 4 cycles (2-9) of RVD. Median CD34� stem 

cell collection was 11.24 x 10 6 /kg. 18% pts required dose reductions 

(R/V/D-5%/9%/2%) and discontinuation in 2% pts for progressive disease. 

49%/8% pts had G1-2/G3-4 PN. Median estimated PFS is 47 months and 

median OS has not been reached. Response rates are included in the table. 

Conclusions: RVD is an active induction regimen with superior response 

rates of � 80% �VGPR rates post-ASCT and is well tolerated in newly 

diagnosed MM pts. Incorporation of lenalidomide did not impact the stem 

cell collection. Until phase III data are available, our institutional experience 

could provide a perspective in the choice of RVD as an effective 

induction regimen in improving ORR and prolonging survival. 

Post-induction response Post-ASCT response Best response 

N (148) % N (146) % N (142) % 

sCR 27 18 50 35 81 57 

CR 10 7 18 12 8 6 

nCR 15 10 12 8 10 7 

sCR � CR � nCR 52 35 80 55 99 70 

VGPR 40 27 36 25 26 18 

>VGPR 92 62 116 80 125 88 

PR 48 33 25 17 13 9 

>PR 140 95 141 97 138 97 

MR 3 2 

PD 5 3 5 3 4 3 



Association of bone marrow plasma cell infiltration pre-auto transplant 

with adverse outcomes in multiple myeloma. Presenting Author: Qaiser 

Bashir, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: Auto-stem cell transplantation (SCT) has become the standard 

of care for eligible patients (pts) with multiple myeloma (MM). However, 

the impact of bone marrow (BM) plasma cell (PC) percentage before SCT is 

not yet known. Methods: Retrospective review of 1489 MM pts who 

underwent auto-SCT from 7/8/98 – 12/31/2010 with post-induction, 

pre-SCT BM biopsy information available. Pts were divided into 2 groups: 

�10% PC infiltration (“PC low”) and �10% PC infiltration (“PC high”). 

Progression-free (PFS) and overall (OS) survivals were estimated by the 

Kaplan-Meier method. Log-rank test was performed to test differences in 

survival. Results: 1489 pts were studied. 1174 pts had �10% involvement 

of BM by PCs and 315 had � 10% involvement. For pts in the PC low 

group, 32% had a CR, 20% had a VGPR, 31% had a PR, 13% had �PR 

and 3% had progressive disease (PD) after SCT. For pts in the PC high 

group, 11% had a CR, 14% had a VGPR, 48% had a PR, 21% had �PR 

and 5% had PD after SCT. Median PFS was significantly shorter for the PC 

high group vs the PC low group (24.8 vs 29.5 months, p�0.05), as was 

median OS (52.5 vs 79.4 months respectively, p�0.001). When only pts 

who had a PR to induction were examined, there was a significant 

difference in both PFS (24.4 vs 33.2 months, p�0.04) and OS (58.3 vs 

81.2 months, p �0.002) for the PC high vs PC low groups, respectively. For 

the 1299 (87%) pts treated in the era of novel therapeutics (after 2000), 

the differences between the PC high and PC low groups were maintained for 

both PFS (24.4 vs 29.5 months respectively (p�0.029)) and OS (54.8 vs 

88.4 months respectively, p�0.001). Chemo-mobilization before SCT did 

not improve PFS or OS but this was done in only 44 (14%) of PC high pts. 

Conclusions: PC BM infiltration before auto-SCT is associated with a worse 

outcome. This finding persists in pts with a PR before SCT. Thus BM 

disease burden may further stratify pts with a PR. Though additional 

therapy did not significantly change the outcome for pts with high PC 

burden, this was done only in a minority of pts. Additionally, differences 

between PC high and PC low groups are maintained despite new salvage 

agents over the last 10 years. Further prospective study is warranted to 

determine the true impact of BM PC infiltration. 


Role of immune-related conditions in smoldering myeloma and MGUS. 

Presenting Author: Mary Kwok, Metabolism Branch, National Cancer 

Institute, National Institutes of Health, Bethesda, MD 

Background: Recent guidelines emphasize tailored follow-up and the need 

for clinical trials for high-risk smoldering myeloma (SMM). Emerging 

evidence from epidemiological studies suggests that immune-related 

conditions play a role in the causation of myeloma precursor disease (SMM 

and monoclonal gammopathy of undetermined significance; MGUS) and 

are of clinical importance for the risk of developing multiple myeloma. The 

aim of our study is to assess whether there is an altered biology in 

SMM/MGUS patients with preceding immune-related conditions. Methods: 

From our ongoing prospective SMM/MGUS natural history study, we 

evaluated 56 SMM and 60 MGUS patients. Information on autoimmunity 

was identified at baseline. All patients underwent extensive clinical and 

molecular characterization. At baseline, all patients underwent bone 

marrow biopsy evaluation using immunohistochemistry and multi-color 

flow cytometry of plasma cells. We assessed expression patterns of adverse 

plasma cell markers (CD56 and CD117), and applied risk models based on 

serum immune markers and bone marrow findings. Results: Among enrolled 

SMM and MGUS patients, 7 (12%) and 9 (15%) had a preceding 

autoimmune disorder. We found SMM patients with (vs. without) a 

preceding autoimmune disorder to have a substantially lower rate of CD56 

(28% vs. 61%) and CD117 (28% vs. 61%) expressing plasma cells. When 

we compared the same markers in MGUS patients, CD56 and CD117 

expression patterns were similar among patients with vs. without preceding 

autoimmunity (10% vs. 17%, and 50% vs. 48%). Using the Mayo Clinic 

risk model, none of the SMM patients with a preceding autoimmune 

disorder had high-risk features; in contrast, 3/41 (7%) of those without a 

preceding autoimmune disorder were high-risk SMM. Using the Mayo 

Clinic risk model, none of the MGUS patients were high-risk independent of 

autoimmune status. Conclusions: Our prospective clinical study found 

SMM patients with preceding immune-related conditions to have less 

adverse biology, supportive of epidemiological studies suggesting the risk 

of developing multiple myeloma is substantially lower in these patients. 


535s 


Patterns of nonhematologic malignancies in a population of African 

American veterans with monoclonal gammopathy of unknown significance 

(MGUS). Presenting Author: Hady Ghanem, George Washington University, 

Washington, DC 

Background: Monoclonal Gammopathy of Unknown Significance (MGUS) is 

characterized by the presence of a monoclonal immunoglobulin in the 

serum or the urine with no evidence of hematologic malignancy. A possible 

relationship between MGUS and increased incidence of NHM has been 

suggested in Caucasian populations. However, data in African Americans 

with MGUS are lacking. Methods: Non-MGUS controls were selected 

randomly from patients who did not have a paraprotein detected on 

electrophoresis (NMGUS) and were matched 2-to-1 to MGUS cases. 

Descriptive statistics and comparisons are presented to compare MGUS 

and NMGUS groups. Results: 492 male patients with MGUS patients were 

matched with 984 male NMGUS patients. 451 patients had abnormal 

serum protein studies (91.6%) and 40 had light chain disease (8.4%). 

Median age at diagnosis of MGUS was 68 years (28-81). 144 MGUS 

patients (29.2%) and 296 NMGUS patients (30%) had 1 or more NHM. 

The median age of diagnosis of 1st NHM was 70 (25-94) in the MGUS 

group and 68.4 in the NMGUS group (34.5-94.4). 19 MGUS patients 

(3.8%) and 27 NMGUS patients had 2 different types of NHM (2.7%). 1 

MGUS patient (0.2%) and 3 NMGUS patients (0.3%) had 3 NHM. 57 

patients had MGUS before NHM (11.5%) and 69 patients were diagnosed 

with MGUS after the diagnosis of NHM (14%), and median differences 

between diagnosis of MGUS and 1st NHM were 4 years (1-12 years) and 5 

years (1-38 years) respectively. Types of NHM were comparable, and 

prostate cancer was the most prevalent NHM in both groups (15% of MGUS 

patients and 17% of NMGUS patients). Median time of follow up was 49.3 

months for MGUS patients and 35.2 months for NMGUS patients 140 of 

the MGUS patients (28.4%) and 214 non-MGUS patients (21.75%) had 

died at data cut-off. Conclusions: Based on these observational data, 

prevalence and types of NHM appear to be comparable in MGUS and 

NMGUS African American patients. All cause mortality appears to be 

higher for NHM patients if they had MGUS. This pattern will need to be 

verified prospectively in a larger group of patients. 


Does stage migration exist in active multiple myeloma (MM)? Presenting 

Author: Prashant Kapoor, Mayo Clinc, Rochester, MN 

Background: Tumor stage migration can artifactually inflate cancer survival 

rates and overestimate benefits of newer therapies. We have previously 

shown a favorable impact of widely used novel agents in MM patients. 

However, it is not known whether use of well tolerated and easily 

administrable novel agents results in their introduction at lower levels of 

MM burden (and therefore add to improved outcome). Our goal was to 

assess for stage migration in newly diagnosed active MM patients. Methods: 

We reviewed records of 1,467 patients with active MM at Mayo Clinic, at 

initiation of therapy from 3 consecutive 5-year intervals: 01/1996-12/ 

2000 (Group 1), 01/2001-12/2005 (Group 2), 01/2006- 12/2010 (Group 

3). These intervals reflect the practice changing approaches at our center 

transitioning from the use of alkylator-based to novel agent-based initial 

therapy. Traditional parameters and staging systems were used to estimate 

tumor burden. We performed one way analysis of variance (ANOVA) to 

assess for differences in these parameters among the groups. A p-value of 

�0.05 was considered significant. Results: Group 3 shows an upward trend 

for hemoglobin (Hgb), and lower creatinine and bone marrow plasma cell 

(BMPC) percent. Compared to other groups, a greater proportion of Group 3 

patients are assigned to lower Durie Salmon (DS) stages (Table) suggesting 

reduced tumor burden at therapy initiation. In contrast, the International 

Staging System (ISS) which is not used for decisions regarding therapy 

initiation divides cohorts in similar proportions. Conclusions: Stage migration 

is evident in our cohort of active MM patients presenting in the time 

periods of evolving initial therapeutic strategies. Future studies should take 

into account the bias introduced by this phenomenon in interpreting 

survival analysis of MM patients. 

Group 1 (N�432) Group 2 (N�480) Group 3 (N�555) 

1996-2000 

2001-2005 

2006-2010 

Parameters Median IQ range Median IQ range Median IQ range P value 

Hgb (g/dL) 10.9 9.6-12.1 10.9 9.5-12.1 11 9.8-12.6 0.01 

Creatinine (mg/dL) 1.3 1-1.6 1.2 1-1.6 1 0.8-1.3 �0.0001 

BMPC (%) 37 17-59 32 14-57 29 13-51 0.02 

Calcium (mg/dL) 9.5 9.1-10.2 9.6 9-10.1 9.6 9.1-10.1 NS 

DS stage (%) 

1 10 13 17 0.0003* 

2 06 14 12 

3 84 73 71 

ISS (%) 

1 25 32 24 NS* 

2 45 37 43 

3 

* Chi square. 

30 31 33 




Participation of BTK in MYD88 signaling in malignant cells expressing the 

L265P mutation in Waldenstrom’s macroglobulinemia, and effect on 

tumor cells with BTK-inhibitor PCI-32765 in combination with MYD88 

pathway inhibitors. Presenting Author: Guang Yang, Dana-Farber Cancer 


Background: Bruton’s tyrosine kinase (BTK) promotes B-cell receptor 

signaling along with B-cell expansion and survival through NF-�B and 

MAPK. MYD88 L265P is a widely expressed somatic mutation in tumor 

cells from WM patients. MYD88 L265P promotes enhanced tumor cell 

survival through IRAK 1/4 mediated NF-�B and MAPK signaling. We 

therefore sought to clarify the role of BTK signaling in MYD88 L265P 

expressing WM cells, and the impact of BTK and MYD88/IRAK inhibition 

on WM cell signaling and survival. Methods: Western blot analysis was 

performed using total and phospho-specific BTK antibodies in MYD88 

L265P expressing primary WM patient cells, BCWM.1 and MCWL-1 WM 

cell lines following MYD88 knockdown by lentiviral transduction, and/or 

use of MYD88 or IRAK signal inhibitors. Cells were also treated with the 

BTK inhibitor PCI-32765, in the presence or absence of MYD88 homodimerization 

or IRAK1/4 inhibitors. Annexin V/PIstaining was used to 

assess cell survival, and synergism assessed with CalcuSyn software. 

Results: BTK was phosphorylated in MYD88 L265P expressing WM cells. 

Knockdown of MYD88 by lentiviral transduction, and/or use of MYD88 or 

IRAK 1/4 kinase inhibitors led to decreased BTK phosphorylation. Phosphorylation 

of BTK, TIRAP, a major TLR adapter protein for MYD88 signaling, 

IRAK1, IKB�, ERK1/2 and STAT3 were significantly reduced following 

treatment with PCI-32765. Treatment with PCI-32765 also induced 

apoptosis of MYD88 L265P expressing WM cells, and showed synergistic 

tumor cell killing in the presence of either MYD88 homodimerization or 

IRAK 1/4 kinase inhibitors. Conclusions: BTK activation is facilitated by 

MYD88 pathway signaling in L265P expressing WM cells, and participates 

in MYD88 downstream signaling. Inhibition of BTK by PCI-327625 led to 

robust tumor cell killing of MYD88 L265P expressing WM,cells, which was 

potentiated by MYD88 pathway inhibitors. These studies provide the 

framework for the investigation of BTK inhibitors in WM, as single agents 

and in combination with MYD88 pathway inhibitors. 


miRNA expression profiling of CD20� plasma cell myeloma (PCM): 

Upregulation of miR-155 shedding new insight into disease biology and 

clinicopathologic behavior. Presenting Author: Ravindra Kolhe, Department 

of Pathology, Georgia Health Sciences University, Augusta, GA 

Background: Up to15-20% of patients with PCM have expression of CD20, 

although the significance of this remains unclear. The prognostic significance 

of CD20 expression in PCM is unclear. Recently, a class of 

noncoding RNAs, miRNAs, were identified as critical gene regulators in cell 

growth, disease, and development. Our study investigates importance of 

miRNAs in cases of CD20� PCM and correlates them with clinicopathological 

parameters. Methods: The miRNA expression profile of CD20� PCM 

(n�6), diffuse large B cell lymphoma (DLBCL) (n�6), and CD20 negative 

PCM (n�8) were evaluated using the Affeymertrix miRNA microarray 

platform on GeneChip miRNA 2.0 array in paraffin-embedded samples. 

After hybridization and data acquisition, we used Partek Genomics Suite 

software for RMA normalization and to determine statistically significant 

differences in miRNA expression between experimental groups by ANOVA 

and pairwise comparisons (two-sided ��0.05). Results: miRNA expression 

profiles of CD20� PCM, show upto �4 times upregulation of 7 miRNAs 

and downregulation of 8 miRNAs. miR-155, the miRNA upregulated in 

various B cell lymphomas and plays a key role in the lymphomagenesis, was 

amongst the highest miRNAs that were upregulated. Conclusions: miR-155 

is known to repress SH2-domain containing inositol-5-phosphatase-1 

(SHIP-1), which is a critical phosphatase that negatively down modulates 

AKT pathway and has functions during normal B-cell development. 

Physiologically, miR-155 is upregulated during B-cell activation upon 

antigen stimulation and so plays a role in antibody class switching and 

plasma cell formation. We propose that this overexpression of miR-155 in 

CD20� PCM unblocks AKT activity, inducing cell proliferation and may 

explain some of the immunophenotypic behavior of CD20� PCM. This work 

is intriguing for the new information it provides about the role of miR-155 

in CD20� PCM. Furthermore, the phenotype of miR-155�ve CD20� PCM 

might ultimately provide new insights into regulation of poorly understood 

steps in B cell differentiation and maturation into plasma cell and more 

importantly the clinicopathological behavior of this entity. 


Use of whole genome sequencing to identify highly recurrent somatic 

mutations in Waldenström’s macroglobulinemia. Presenting Author: Zachary 

R Hunter, Dana-Farber Cancer Institute, Boston, MA 

Background: Waldenstrom’s Macroglobulinemia (WM) is an IgM secreting 

lymphoplasmacytic lymphoma. The genetic basis for this disease remains 

to be clarified. Methods: We performed whole genome sequencing (WGS) 

using CD19 � selected bone marrow lymphoplasmacytic cells (LPC) from 

30 WM patients. For 10 of these patients, paired CD19 � depleted 

peripheral blood samples were used for WGS as normal controls. Results: 

The most common somatic variants identified and validated by Sanger 

sequencing included MYD88 L265P, an activating mutation for IRAK/ 

TRAF6/NFKB and MAPK signaling, which was observed in 27/30 (90%) 

patients; the N-terminal domain of CXCR4, which included mutations 

associated with WHIM syndrome and confer constitutive CXCR4 signaling 

resulting from dysfunctional receptor endocytosis, a finding observed in 

8/30 (27%) patients, and ARID1A (5/30; 17%), a tumor suppressor gene. 

Less common somatic variants were also identified in MUC16 (4/30; 13%), 

TRAF2 (3/30; 10%), TRRAP (3/30; 10%) and MYBBP1A (2/30; 7%). 

Conclusions: Using WGS and confirmatory Sanger sequencing, we have 

identified several somatic variants with oncogenic function, the most 

common of which include MYD88 L265P, the N-terminal domain of 

CXCR4, and ARID1A. 


Phase I/II study of investigational agent MLN8237 (alisertib) plus rituximab 

with or without vincristine in patients (pts) with relapsed/refractory 

(rel/ref) aggressive diffuse large B-cell lymphoma (DLBCL)/transformed 

follicular lymphoma (TFL). Presenting Author: Daniel Oscar Persky, University 

of Arizona Cancer Center, Tucson, AZ 

Background: DLBCL and TFL are aggressive subtypes of non-Hodgkin 

lymphoma (NHL), with poor prognosis in the rel/ref setting. Alternatives to 

standard rituximab-based treatments are needed. MLN8237 is an oral, 

selective inhibitor of Aurora A kinase – a key mitotic regulator overexpressed/ 

amplified in various human cancers, including lymphomas (Hamada et al, 

2003; Yakushijin et al, 2004; Qi et al, 2011). Emerging data from a phase 

2 study suggest that MLN8237 has single agent activity in aggressive NHL 

(Friedberg et al, ASH 2011). MLN8237 � rituximab (MR) � vincristine 

(MRV) has also shown activity in preclinical B-cell NHL models (Mahadevan 

et al, ASH 2011). Further clinical evaluation of these regimens in 

rel/ref B-cell NHL is warranted. Methods: This single-arm phase 1/2 study 

(ClinicalTrials.gov #NCT01397825) aims to assess the safety, efficacy, 

and pharmacokinetics of, and determine a recommended phase 2 dose 

(RP2D) and schedule for, MR and MRV in adults with CD20� rel/ref 

DLBCL/TFL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2. 

Pts with other aggressive B-cell lymphomas may also enroll in phase 1. 

~100 pts will be recruited at 22 sites in the US, UK, Italy, and Spain, and 

study duration will be ~2 years. In part 1, a safety lead-in cohort will receive 

MR (table), with the RP2D determined as when �2 dose limiting toxicities 

(DLT) occur in 6 pts in cycle 1. MRV dose escalation (part 2) will then 

follow a 3�3 design. Phase 2 enrollment (part 3) will follow a Simon 

optimal 2-stage design, with pts receiving MRV at the RP2D determined in 

part 2. The primary phase 2 objective is overall response rate by IWG 

criteria. Responders may continue MLN8237 if clinical benefit is seen and 

if the regimen is tolerable. Enrollment as of 20 Jan 2012 is 6 evaluable pts. 

Starting doses: repeating 21-day cycles 

MLN8237 Rituximab Vincristine 

Phase 1 (part 1) 50 mg ECT BID, days 1–7* 375 mg/m 2 IV, day 1 – 

(part 2) ~50% of MR RP2D, days 1–7 † 

as above 1.4 mg/m 2 IV, days 1, 8 † 

Phase 2 (part 3) RP2D from part 2 

ECT, enteric coated tablet; BID, twice daily; *dose reduction permitted; † dose/schedule 

adjustments based on cycle 1 DLT. 



Phase III study of investigational MLN8237 (alisertib) versus investigator’s 

choice in patients (pts) with relapsed/refractory (rel/ref) peripheral T-cell 

lymphoma (PTCL). Presenting Author: Owen O’Connor, Center for Lymphoid 

Malignancies, Columbia University Medical Center, New York, NY 

Background: PTCL is a rare form of aggressive non-Hodgkin lymphoma 

(NHL), accounting for 5–20% of NHL diagnoses. Standard NHL therapies 

developed primarily for B-cell lymphomas are not optimal for PTCL and 

early relapse is common. Current treatments for rel/ref PTCL include 

pralatrexate, romidepsin, and gemcitabine; however, outcomes remain 

poor. The oral, investigational drug, MLN8237, is a selective inhibitor of 

Aurora A kinase (AAK) – a key mitotic regulator that is overexpressed or 

amplified in various human tumors. Emerging clinical data from a phase II 

study of single agent MLN8237 in rel/ref aggressive T-cell lymphoma 

(Friedberg et al, ASH 2011) support further clinical evaluation in this 

indication. Methods: In this open-label, randomized, phase III study, a 

maximum of 354 adults with rel/ref PTCL after �1 prior systemic cytotoxic 

therapies will be enrolled at approximately 140 centers worldwide. Pts will 

be randomized 1:1 to MLN8237 50 mg twice daily as an enteric coated 

tablet on days 1–7 of 21-day cycles, or to investigator’s choice of: 

pralatrexate 30 mg/m2 IV once weekly for 6 weeks in 7-week cycles; 

romidepsin 14 mg/m2 IV on days 1, 8, and 15 of 28-day cycles; or 

gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 of 28-day cycles. Pts 

with disease response/stabilization will be able to continue treatment 

provided that clinical benefit is demonstrated and treatment is tolerable. 

The expected study duration is 44 months. Primary endpoints are overall 

response rate (complete response [CR] � partial response) and progression 

free survival by International Working Group criteria (Cheson et al, 2007). 

Secondary endpoints include CR rate, overall survival, time to progression, 

time to response, duration of response, safety, and quality of life. 

Exploratory endpoints include an evaluation of candidate biomarkers (such 

as AAK protein expression levels and gene amplification, and the tumor 

proliferative marker Ki-67) in tumor biopsies. This study is registered at 

ClinicalTrials.gov: #NCT01482962. 

TPS8112 General Poster Session (Board #40E), Mon, 1:15 PM-5:15 PM 

ELOQUENT-2: A phase III, randomized, open-label trial of lenalidomide/ 

dexamethasone (Len/Dex) with or without elotuzumab (Elo) in relapsed or 

refractory multiple myeloma (RR MM) (CA204-004). Presenting Author: 

Sagar Lonial, Multiple Myeloma Research Consortium, Norwalk, CT/ 

Winship Cancer Institute of Emory University, Atlanta, GA 

Background: MM remains incurable and patients (pts) typically relapse or 

become refractory to current treatments. Novel regimens are needed to 

improve pt outcomes. Elo is a humanized monoclonal IgG1 antibody 

targeting the cell surface glycoprotein CS1, which is highly expressed on 

�95% of MM cells. Len/Dex is approved for treatment of relapsed MM and 

an objective response rate (ORR) of ~60% was reported in phase III trials of 

this combination in RR MM. In a phase II study (N�73) of Elo (10 or 20 

mg/kg) in combination with Len/Dex in pts with RR MM, the 10 mg/kg 

group (n�36) demonstrated an ORR of 92% and median progression-free 

survival (PFS) that was not reached after a median follow-up of 14.1 

months. Encouraging activity was seen in patients with high-risk cytogenetics 

and/or stage 2-3 disease. Based on these data, a randomized, 

open-label phase III trial has been initiated to determine if the addition of 

Elo to Len/Dex will improve PFS in patients with RR MM compared with 

Len/Dex alone. Methods: Pts (N�640) with RR MM and 1-3 prior therapies 

are eligible, including pts with mild or moderate renal impairment. Pts are 

randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days 

1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo 

dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles 

and on days 1 and 15 in subsequent cycles. Dex 8 mg IV � 28 mg PO is 

used during the weeks with Elo. Treatment will continue until disease 

progression, death, or withdrawal of consent. Patients will be followed for 

tumor response every 4 weeks until progressive disease and then survival 

every 12 weeks. The primary endpoint is PFS (90% power for a hazard ratio 

[experimental to control arm] of 0.74) and the secondary endpoints are 

ORR and overall survival. Exploratory endpoints are safety, time to 

response, duration of response, time to subsequent therapy, health-related 

quality of life, and pharmacokinetics and immunogenicity of Elo. Potential 

biomarkers will also be assessed. As of January 10th, 2012, 107 pts were 

enrolled and 68 pts were treated. NCT01239797. 


537s 

TPS8111 General Poster Session (Board #40D), Mon, 1:15 PM-5:15 PM 

Pilot study of MAGE-A3 protein vaccination and autologous stem cell 

transplantation (autoSCT) as consolidation therapy for multiple myeloma 

(MM). Presenting Author: Adam D. Cohen, Fox Chase Cancer Center, 


Background: MAGE-A3 is a cancer-testis antigen (CT Ag) commonly 

expressed in MM but not in normal non-gonadal tissues. MAGE-A3 

inhibited p53-dependent and independent apoptosis in MM cells (Clin 

Cancer Res 2011;17:4309), and spontaneous immunity against CT Ags in 

MM patients was associated with favorable clinical outcomes (Blood 

2007;109:1103; Blood 2008;112:3362), making it a rational target for 

immunotherapy. In this study (NCT01380145), we are examining if a 

recombinant (rec) MAGE-A3 protein vaccine � adjuvant combined with 

vaccine-primed peripheral blood lymphocytes (PBL) can safely stimulate 

antigen-specific immunity in MM patients undergoing autoSCT for consolidation 

therapy. Methods: Patients meeting the following criteria are 

eligible: within 12 months of diagnosis; MAGE-A� MM cells by immunohistochemistry; 

achieving at least a very good partial response with induction 

therapy; and meeting institutional criteria for autoSCT. One patient of a 

planned cohort of sixteen has been enrolled. Six weeks before SCT, 

subjects will receive their first vaccination (300 �g IM) and three weeks 

later undergo leukopheresis to collect vaccine-primed PBL. They then 

undergo stem cell mobilization followed by a standard melphalanconditioned 

autoSCT. On day 3 after stem cell infusion, the unmanipulated, 

primed PBL will be re-infused followed by the second recMAGE-A3 

vaccination on day 10. An additional six vaccinations will be administered 

on days 31, 52, 73, 94, 180, and 270 after autoSCT. The primary 

objectives are safety and tolerability. The secondary objectives of cellular 

and humoral immune responses and lymphocyte reconstitution will be 

assessed by a validated series of quantitative assays using established 

response criteria (PNAS 2008;105:1650). Success criteria based on 

immune response have not been specified for this pilot study, though 

induction of MAGE-A3 immunity in at least 50% of patients would merit 

consideration for further evaluation of clinical efficacy. 

TPS8113 General Poster Session (Board #40F), Mon, 1:15 PM-5:15 PM 

ELOQUENT-1: A phase III, randomized, open-label trial of lenalidomide/ 

dexamethasone with or without elotuzumab in subjects with previously 

untreated multiple myeloma (CA204-006). Presenting Author: Meletios A. 

Dimopoulos, Hellenic Cooperative Oncology Group, Athens, Greece 

Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody 

targeting the cell surface glycoprotein CS1, which is highly expressed on 

�95% of MM cells. In a MM xenograft mouse model, the combination of 

Elo � lenalidomide (Len) significantly reduced tumor volume in a synergistic 

manner compared with either agent alone. In a phase 2 study (N�73) of 

Elo (10 or 20 mg/kg) in combination with Len and low-dose-dexamethasone 

(Dex) in pts with RR MM, the 10 mg/kg dose group (n�36) 

demonstrated objective response rates (ORR) of 92% in all pts, and 100% 

in pts who had received only 1 prior therapy (n�16). The higher response 

rate in pts with fewer prior lines of therapy provides a rationale for 

investigating this combination earlier in the disease course. This randomized, 

open-label, phase 3 trial will determine if the addition of Elo to 

Len/Dex improves progression-free survival (PFS) in pts with newly diagnosed, 

untreated MM. Methods: Pts (N�750) with newly diagnosed 

symptomatic MM ineligible for stem cell transplant will be randomized in a 

1:1 ratio to receive 28-day cycles of Len 25 mg PO (days1-21) and Dex 40 

mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 

10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 

of cycles 3-18 followed by 20 mg/kg on day 1 of cycle 19 onward. Dex 8 mg 

IV � 28 mg PO is used during the weeks with Elo. Treatment will continue 

until disease progression, death, or withdrawal of consent. Pts will be 

followed up for response every 4 weeks until progressive disease and for 

survival every 16 weeks. The primary endpoint is PFS (90% power for a 

hazard ratio [experimental to control arm] of 0.74) and the secondary 

endpoints are ORR and overall survival. Exploratory endpoints are safety, 

time to response, duration of response, time to subsequent therapy, 

health-related quality of life, and pharmacokinetics and immunogenicity of 

Elo. Potential biomarkers will also be assessed. As of January 1, 2012, 13 

pts were enrolled and 9 pts were treated. NCT01335399. 



TPS8114 General Poster Session (Board #40G), Mon, 1:15 PM-5:15 PM 

A phase II randomized study of bortezomib/dexamethasone (Bort/Dex) with 

or without elotuzumab (Elo) in patients (pts) with relapsed/refractory 

multiple myeloma (RR MM) (CA204-009). Presenting Author: Andrzej J. 

Jakubowiak, University of Chicago Medical Center, Chicago, IL 

Background: MM is rarely curable and pts typically relapse or become 

refractory to current treatments. Elo is a humanized monoclonal IgG1 

antibody targeting the cell surface glycoprotein CS1, which is highly 

expressed on �95% of MM cells with little to no expression on normal 

tissues. The mechanism of action of Elo is primarily natural killer (NK) 

cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against 

myeloma cells. Elo � Bort significantly enhanced antimyeloma activity in a 

mouse xenograft model vs either agent alone. The addition of Bort 

enhanced the ADCC activity of Elo in preclinical studies. In a phase I study 

of Elo � Bort in pts with RR MM, objective response rate (ORR) was 48%, 

median progression-free survival (PFS) was 9.5 months, and activity was 

observed in 2/3 patients (67%) refractory to Bort (Jakubowiak et al. J Clin 

Oncol, in press). This study will assess if the addition of Elo to Bort/Dex 

improves PFS and, if so, whether magnitude of the improvement is linked 

to Fc�RIIIa polymorphism. Methods: Pts (N�150) with RR MM after 1 or 2 

prior therapies will be randomized in a 1:1 ratio to receive Bort 1.3 mg/m2 IV or SQ (Cycles 1-8: days 1, 4, 8, and 11; Cycles �9: days 1, 8, and 15) 

and Dex with or without Elo. Elo dose and schedule is 10 mg/kg IV (Cycles 

1-2: days 1, 8, and 15 [21-day cycles]; Cycles 3-8: days 1 and 11 [21-day 

cycles]; Cycles �9: days 1 and 15 [28-day cycles]). In the arm without Elo, 

Dex 20 mg PO is scheduled for Cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, and 

12; and Cycles �9: days 1, 2, 8, 9, 15, 16. In the arm with Elo, Dex 20 mg 

PO is scheduled for Cycles 1-2: days 2, 4, 5, 9, and 11; Cycles 3-8: days 2, 

4, 5, 8, 9, 12; Cycles �9: days 2, 8, 9, and 16) on weeks without Elo, and 

on weeks with Elo, Dex 8 mg PO and 8 mg IV is scheduled on the same day 

as Elo. Treatment will continue until disease progression, unacceptable 

toxicity, or withdrawal of consent. Patients refractory or intolerant to Bort 

will be excluded. Efficacy will be assessed on day 1 of each cycle by IMWG 

criteria. The primary endpoint is PFS. Secondary endpoints include ORR 

and PFS/ORR in pts with �1Fc�RIIIa V allele. As of February 1, 2012, 1 pt 

was enrolled. NCT01478048. 


Phase I/II open-label, multiple-dose, dose-escalation study to evaluate the 

safety and tolerability of SNS01T administered by intravenous infusion in 

patients with relapsed or refractory multiple myeloma. Presenting Author: 

John Anthony Lust, Mayo Clinic, Rochester, MN 

Background: Eukaryotic translation initiation Factor 5A (eIF5A) has been 

implicated in the regulation of apoptosis and is the only known protein to be 

modified by hypusination. Hypusinated eIF5A is the predominant form of 

eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is 

pro-apoptotic. SNS01-T, designed to treat myeloma, consists of two 

components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing 

a lysine to arginine substitution at position 50) which remains 

pro-apoptotic because it cannot be hypusinated, and an siRNA against an 

untranslated region of native eIF5A mRNA. When these two components 

are combined with linear polyethyleneimine (PEI), the nucleic acids are 

condensed into nanoparticles for protection from degradation in the blood 

and enhanced delivery to tissues. The eIF5AK50R transgene is under the 

control of the B29 promoter and enhancer, which restricts expression to B 

cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to 

deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously 

adding pro-apoptotic eIF5AK50R . In vitro cell studies and in vivo 

xenograft studies have demonstrated the efficacy of this approach. Methods: 

Eligible patients are enrolled sequentially into four cohorts of increasingly 

higher doses. Each cohort will receive SNS01-T by intravenous infusion 

twice weekly for 6 consecutive weeks and then be observed every 4 weeks 

during a 24-week follow-up period. Eligible patients must have been 

diagnosed with multiple myeloma according to IMWG criteria, have 

measurable disease, have relapsed disease after two or more prior treatment 

regimens, have a life expectancy of at least 3 months, and not be 

eligible to receive any other standard therapy known to extend life 

expectancy. The primary objective is to evaluate the safety and tolerability 

of multiple escalating doses of SNS01-T. Secondary objectives include 

pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, 

and therapeutic efficacy. Two of the planned 15 patients have 

been enrolled. (Clinical Trials.gov Identifier: NCT01435720.) 

TPS8115 General Poster Session (Board #40H), Mon, 1:15 PM-5:15 PM 

A single-arm, open-label, multicenter phase I/II study of the combination of 

panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/ 

refractory multiple myeloma (RR MM). Presenting Author: Jesus G. 

Berdeja, Tennessee Oncology, PLLC/Sarah Cannon Research Institute, 

Nashville, TN 

Background: Despite novel therapies, MM remains an incurable disease. 

Changes in histone modification are commonly found in human cancers 

including MM. Preclinical studies demonstrate synergistic anti-MM activity 

with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) 

through the dual inhibition of the proteasome and aggresome pathways. 

Pan is an oral pan-HDACi which has shown synergy with bortezomib in 

clinical studies. Cfz is a 2nd generation PI which has shown marked 

anti-MM activity with an improved safety profile. In this trial we evaluate 

the safety and efficacy of the combination of pan and cfz in pts with RR 

MM. Methods: This multi-center US study plans to enroll up to 52 adults 

with RR MM. The phase I study will determine the MTD of the combination 

of cfz and pan and follow a standard dose escalation design. Pan will be 

administered orally three times weekly during weeks 1 and 3 of each 

28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will 

be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 

28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with 

escalation to the corresponding dose level beginning at 27 mg , if well 

tolerated. Dose modifications will not be permitted during cycle 1 unless a 

pt experiences a DLT. A maximum of four dose levels will be evaluated. 

Approximately 24 pts will be enrolled during the phase I portion to 

establish the MTD. In the phase II portion of this study, pts with RR MM will 

receive treatment with the optimal dose of pan and cfz established during 

phase I. Pts will be assessed for response to treatment after each cycle (4 

weeks). Pts with objective response or stable disease will continue 

treatment until disease progression or unacceptable toxicity occurs. The 

primary endpoint is to establish the optimal doses of cfz and pan that can 

be administered to pts with RR MM (phase I) and to evaluate the overall 

response rate (phase II). Secondary endpoints include time-to-progression, 

progression-free survival, overall survival and safety. Approximately 25 pts 

are planned for the phase II portion. Current status: As of 1/27/12 3 

patients have been enrolled. 


Recruitment in a randomized, double-blind, placebo-controlled study to 

assess siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in 

patients with multicentric Castleman’s disease. Presenting Author: Frits 

Van Rhee, University of Arkansas for Medical Sciences, Little Rock, AR 

Background: Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative 

disorder in which dysregulated production of interleukin (IL)-6 

results in lymph node enlargement and debilitating symptoms, including 

systemic inflammatory manifestations (eg, fever, fatigue, weight loss), 

autoimmune phenomena, and markedly abnormal laboratory findings (eg, 

anemia, hyper-�-globulinemia, hypoalbuminemia, thrombocytosis, increases 

in acute-phase proteins such as CRP, ESR, fibrinogen). There is 

currently no approved systemic treatment for MCD in the US or EU. 

Siltuximab (CNTO 328) is a chimeric mAb with high affinity for soluble 

IL-6. In a previous phase 1 study, high objective tumor response rate (64%) 

has been observed in patients with MCD (van Rhee F et al. Blood 

2008;112:1008), and the long-term safety profile looks favourable (Kurzrock 

R et al. Blood 2011;118:3959). These results have prompted a 

randomized, double-blind, placebo-controlled study to definitively assess 

the efficacy and safety of siltuximab in combination with best supportive 

care (BSC) compared with BSC in patients with MCD. Methods: Eligibility 

includes HIV- and HHV-8-negative, symptomatic, measurable MCD patients. 

Patients with prior lymphoma or prior exposure to treatment 

targeting IL-6 or its receptor are excluded. Patients can be enrolled when 

receiving stable doses of corticosteroids (�1 mg/kg/d of prednisone or 

equivalent). Patients will be randomized in a 1:2 ratio to placebo � BSC or 

to 11 mg/kg siltuximab � BSC and will receive siltuximab/placebo in a 

1-hour IV infusion every 3 weeks. The primary objective is to evaluate 

durable tumor and symptomatic response in the intent-to-treat population. 

Secondary objectives include additional efficacy measures, safety, patient 

reported outcomes, and pharmacologic assessment. Status: 67/78 patients 

have been randomly assigned. This is the first randomized, placebocontrolled 

study to be conducted in MCD. The rarity of the disease has 

posed unique challenges, and various enrollment strategies have been 

successfully implemented, with projected completion of enrollment in 

March 2012. 



PILLAR-2: A randomized, double-blind, placebo-controlled, phase III 

study of adjuvant everolimus in poor-risk diffuse large B-cell lymphoma 

(DLBCL). Presenting Author: Tongyu Lin, Department of Medical Oncology, 

Sun Yat-sen University Cancer Center, Guangzhou, China 

Background: Effective DLBCL adjuvant therapy after first-line chemotherapy 

is needed as high-risk DLBCL is associated with a poor 4-year 

overall survival (OS) rate (Sehn et al, Blood 2007;109:1857-61). In a 

phase II study of the oral mammalian target of rapamycin inhibitor 

everolimus in relapsed, aggressive non-Hodgkin lymphoma, DLBCL patients 

(n�47) had a 30% overall response rate (Witzig et al, Leukemia 

2011;25:341-7). Methods: PILLAR-2 is an ongoing international, randomized, 

double-blind, phase 3 study designed to compare everolimus efficacy 

and safety with that of placebo in poor-risk DLBCL patients who achieved 

complete response (CR) with first-line rituximab-based chemotherapy 

(R-chemo) (ClinicalTrials.gov: NCT00790036; sponsor: Novartis Pharmaceuticals). 

Eligibility criteria include age �18 years; confirmed stage II 

bulky, III, or IV DLBCL and International Prognostic Index 3-5 at diagnosis; 

confirmed CR per revised International Workshop Response Criteria for 

malignant lymphoma (Cheson et al, J Clin Oncol 2007;25:579-86) after 

first-line R-chemo regimen completed 6-14 weeks before study drug start; 

Eastern Cooperative Oncology Group performance status �2; no ongoing or 

post–R-chemo radiation; and no myelosuppressive chemotherapy or biologic 

therapy within 3 weeks. Patients are randomized 1:1 to everolimus 10 

mg once daily or matching placebo and treated for 12 months or until 

disease relapse, unacceptable toxicity, or death. Radiologic tumor assessment 

is performed at baseline, every 12 weeks during years 1 and 2, every 

24 weeks during years 3 and 4, and annually thereafter until start of new 

anticancer therapy or 5 years after last patient randomization. The primary 

endpoint is disease-free survival (DFS). Secondary endpoints are OS, 

lymphoma-specific survival, and safety. Expected enrollment is 687 

patients. Final analysis will be performed when 279 DFS events occur; 

survival follow-up will continue until 338 deaths occur and the last 

randomized patient has been followed for �5 years. Currently, 422 

patients are enrolled. The data monitoring committee last reviewed the trial 

in July 2011 and recommended that it continue as planned. 



539s

540s Melanoma/Skin Cancers 

LBA8500^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM 

Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing 

the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine 

(DTIC) in patients with BRAFV600E-mutated melanoma. Presenting Author: 

Axel Hauschild, Universitaetsklinikum Schleswig-Holstein, Kiel Schleswig- 

Holstein, Germany 








Updated overall survival (OS) results for BRIM-3, a phase III randomized, 

open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) 

with dacarbazine (DTIC) in previously untreated patients with BRAFV600E - 

mutated melanoma. Presenting Author: Paul B. Chapman, Memorial 


Background: We previously reported results of the planned OS interim 

analysis for BRIM-3 (50% of the planned 196 deaths required for final 

analysis) at which time the independent Data Safety Monitoring Board 

recommended release of results due to compelling efficacy (hazard ratio 

[HR] for death, 0.37 [95% CI 0.26–0.55]); p�0.0001 and PFS HR 0.26 

[95% CI 0.20–0.33]; p�0.0001) and that DTIC-treated patients be 

permitted to cross over to receive vem. Median follow-up for vem patients 

was 3.75 months, and longer follow-up would estimate median OS more 

reliably. Updated OS with median 6.2 months follow-up and 199 total 

deaths showed HR for death 0.44 (95% CI 0.33–0.59) favoring vem and 

median OS for vem not reached. We report here the results of an updated 

OS analysis performed in Nov 2011 with ~10 months median follow-up on 

vem. Methods: 675 patients with previously untreated, unresectable Stage 

IIIC or IV melanoma that tested positive for BRAFV600E mutation by the 

cobas 4800 BRAF V600 Mutation Test were randomized (1:1) from Jan to 

Dec 2010 to vem (960 mg po bid) or DTIC (1000 mg/m2 IV q3w). 

Co-primary endpoints were OS and PFS. OS data for DTIC patients who 

crossed over to vem were censored at the time of crossover. Results: Median 

lengths of follow-up on vem and DTIC were 10.5 months (range 0.4–18.1) 

and 8.4 months (range �0.1–18.3), respectively. There were 334 deaths. 

Median OS rates with vem and DTIC were 13.2 months (95% CI 

12.0–15.0) and 9.6 months (95% CI 7.9–11.8), respectively. 12-month 

OS rates were 55% for vem and 43% for DTIC. HR for death was 0.62 (95% 

CI 0.49–0.77) in favor of vem. 81 DTIC patients crossed over to vem. 44 

(13%) vem and 65 (19%) DTIC patients received ipilimumab postprogression. 

Conclusions: With longer follow-up, vem treatment continues 

to be associated with improved OS in the BRIM-3 study. An updated 

analysis, with estimated median follow-up of ~13 months and including 

response data, will be conducted in Apr 2012 and presented at the 

meeting. 


BREAK-MB: A phase II study assessing overall intracranial response rate 

(OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k 

mutation-positive melanoma with brain metastases (mets). Presenting 

Author: John M. Kirkwood, University of Pittsburgh Cancer Institute, 

Pittsburgh, PA 

Background: Melanoma brain mets carry a poor prognosis (median survival 

�4 months), for which more effective therapies are needed. Dabrafenib is a 

potent, selective oral inhibitor of mutated BRAF that has demonstrated 

clinical efficacy in pts with BRAF V600E/K mutant melanoma and 

previously untreated brain mets in a phase I study. Therefore, a phase II 

study (BREAK-MB) was initiated. Methods: Stage IV pts with � 1 intracranial 

met (0.5 cm–4 cm assessed by MRI) without prior brain therapy 

(Cohort A) or with progression following prior brain therapy (Cohort B) were 

eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The 

primary endpoint was investigator-assessed OIRR among V600E mutationpositive 

pts. Results: Overall, 172 pts were recruited. At interim analysis, of 

127 pts enrolled (safety population), 41 (Cohort A n�24; Cohort B n�17) 

had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A 

was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% 

CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15 

(53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI: 

1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in 

Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 

(20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR 

was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI: 

1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in 

Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In 

Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In 

Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4 

(5%). The most common AEs were headache (21%), hyperkeratosis and 

rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3 

(19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea 

(22% each) and pyrexia (17%). Conclusions: Dabrafenib shows high 

clinical activity both in pts with intra- and extracranial mets with acceptable 

toxicity. Final data will be presented. 


Analysis of molecular mechanisms of response and resistance to vemurafenib 

(vem) in BRAFV600E melanoma. Presenting Author: Jeffrey Alan 

Sosman, Vanderbilt-Ingram Cancer Center, Nashville, TN 

Background: Vem induces frequent clinical responses (RR �50%) and 

improved survival in patients (pts) with BRAF-mutated metastatic melanoma. 

Multiple mechanisms of escape from vem have been proposed. We 

performed a centralized analysis of pretreatment, cycle 1, day 15 (D15), 

and progression (DP) tumor samples collected during the phase II BRIM-2 

trial (Sosman et al, NEJM 2012). Methods: Of 132 pts enrolled, archival 

tumor samples, biopsies taken at baseline (BL), D15, and DP were 

obtained from 84, 38, 26, and 22 pts, respectively, and analyzed by 

immunohistochemistry (IHC) for signaling molecules in the MAPK, PI3K/ 

AKT, and cell cycle pathways. Genetic analyses of signaling genes were 

performed using Sequenom MASSarray and direct DNA sequencing. 

Results: High levels of ERK phosphorylation were seen at BL indicating 

constitutive MAPK signaling due to the BRAF mutation. In 19/22 paired 

samples, pERK levels were reduced following vem (BL vs D15). Mean 

absolute pERK reduction in pts with clinical response (RECIST criteria) to 

vem (n�14) was significantly greater than in non-responders (n�8; 

p�0.013). Baseline cytoplasmic PTEN H-score was higher in responders 

vs non-responders (H-score�88 vs 68; p�0.042). At progression, upregulation 

of pERK (H-score�181) was frequently, but not uniformly found vs 

D15 tumors (H-score�48.5). At progression, increases in Cyclin D1 and 

Ki67 were seen, without obvious changes in PTEN or pAKT. NRAS 

mutations occurred in 3/13 DP; 2 had paired BL samples without NRAS 

mutations. Only 1/82 pts had a concomitant NRAS and BRAF mutation at 

BL, and did not respond to vem. MAP2K1 (MEK1) codon 124 mutations 

occurred in 7/92 BL and 1/20 DP samples. 2 pts with BL MEK1 mutations 

had partial responses. Conclusions: MAPK signaling was effectively inhibited 

by vem early in treatment, and in the subset of patients with matched 

tumor samples the degree of pathway inhibition correlated with clinical 

response. MAPK signaling is upregulated in many lesions at progression. 

NRAS mutations appear to be a mechanism of acquired resistance in a few 

tumors (3/13), while the role of MEK1 mutations in resistance is less clear. 



Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, 

DTIC plus IL-2 and interferon in patients with high-risk melanoma 

(SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG. 

Presenting Author: Lawrence E. Flaherty, Wayne State University, Detroit, 

MI 

Background: High-dose interferon for one year (HDI) is the FDA approved 

adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts 

to modify IFN dose or schedule have not improved efficacy. A meta-analysis 

demonstrated that biochemotherapy (BCT) produced superior response 

rates compared with chemotherapy in pts with stage IV melanoma (Wheatley 

et al J Clin Oncol 25:5426, 2007). We sought to determine whether a 

short course of BCT would be more effective than HDI as adjuvant 

treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) 

enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and 

randomized them to receive either HDI or BCT consisting of dacarbazine 

800 mg/m2 day 1, cisplatin 20 mg/m2 / days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2 /day continuous IV days 1-4, IFN 5 MU/m2 /day sc 

days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were 

given every 21 days x 3 cycles (9 weeks total). Pts were stratified for 

number of involved nodes (1-3 v �4), micro v macro metastasis, and 

ulceration of the primary. Co-primary endpoints were relapse free survival 

(RFS) and overall survival (OS) using a one-sided log rank test at p� 0.05. 

Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were 

ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 

57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a 

median f/up of 6 yrs, BCT improved RFS (p � 0.02, HR 0.77 [90% CI: 

0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 

yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not 

different between the two arms (p � 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) 

with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for 

HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT 

provides a statistically significant improvement in RFS compared to HDI, 

but no discernable difference in OS and more grade IV toxicity. BCT 

represents a shorter, alternative treatment for pts with HRM, and a 

potential control arm and basis for future combinations in the adjuvant 

setting. 


Phase II randomized study of high-dose interferon alfa-2b (HDI) versus 

chemotherapy as adjuvant therapy in patients with resected mucosal 

melanoma. Presenting Author: Bin Lian, Peking University Cancer Hospital 

and Institute, Beijing, China 

Background: High-dose interferon alfa-2b regimen has been demonstrated 

as the standard of adjuvant therapy for resected melanoma. But the 

subgroup of mucosal melanoma seems more aggressive and insensitive to 

immunotherapy. So we conducted a phase II study (ChiCTR-TRC- 

11001798) to compare Interferon regimen with chemotherapy as adjuvant 

therapy for this particular subgroup pts. Methods: Resected mucosal 

melanoma pts were randomized to observation (Group A) or receive 

postoperative adjuvant Interferon (IFN) alfa2b 15 MU/m2 /day for 5 

days/week X 4 weeks followed by 9 MU/m2 three times each week for 48 

weeks (Group B), or chemotherapy with temozolomide 200 mg/m2 d1-5 � 

cisplatin 25 mg/m2 d1-3, repeated every 3 Weeks X 6 cycles (Group C). 

Results: 189 patients were enrolled and 184 patients were eligible for 

survival analysis. With a median follow-up of 26.8 months, the median RFS 

for Group A, B and C were 5.4, 9.4 and 20.8 months, respectively 

(P�0.001). Estimated median OS for Group A, B and C were 21.2, 41.1 

and 49.6 months (P�0.001), respectively. Toxicities were generally mild 

to moderate. Conclusions: Chemotherapy significantly improved RFS and 

OS as adjuvant therapy for mucosal melanoma pts over HDI regimen or 

observation. This trial suggests that different subgroup of melanoma may 

need different adjuvant therapy. 



Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant 

treatment of stage III malignant melanoma: Final analysis of a 

randomized phase III DeCOG-trial (NCT00226408). Presenting Author: 

Peter Mohr, Elbe-Klinikum Buxtehude, Buxtehude, Germany 

Background: Adjuvant high-dose interferon (HDI) treatment of patients (pts) 

with malignant melanoma (MM) usually consists of 4 weeks initial 

intravenous (iv) infusion of 20 MU/m² IFNa2b followed by 11 months of 10 

MU/m² subcutaneously (sc). It is still unclear, whether both components 

are necessary for the efficacy of HDI in high-risk MM pts. The adjuvant 

phase III DeCOG MM-ADJ-5 trial evaluates efficacy, safety, tolerability and 

quality of life (QoL) of an intermittent (pulsed) high-dose iv IFNa2b 

regimen as compared to standard HDI. Methods: Patients with stage III 

(AJCC 2002) resected intransit or lymph node metastasis from cutaneous 

malignant melanoma were randomly assigned to receive either standard 

HDI regimen (Arm A), or 3 courses of IFNa2b 20 MU/m² iv on 5 days a week 

for 4 weeks repeated every 4 months (Arm B). Distant metastasis free 

survival (DMFS) was the primary endpoint for efficacy analysis. The EORTC 

QLQ C30 questionnaire was used before and during the study in a 

standardized way (weeks 0, 4, 16, 24, 40). In addition, patients completed 

a diary containing global QoL measures every week. Results: Out of 649 

patients who were enrolled, 22 patients had to be excluded from the 

intent-to-treat analysis. The remaining 627 patients were well balanced 

between both arms according to sex, age, and stage. Median follow-up was 

similar in both groups (55.4 vs. 55.3 months). Distant metastasis occurred 

in 138 (Arm A; 44%) vs. 145 (Arm B; 47%) patients without statistical 

significance (p�0.46). Survival was not significantly different for DMFS 

(HR 1.1; p�0.39) or OS (HR�1.0; p�0.85). Termination of treatment due 

to adverse events or QoL related reasons occurred significantly more often 

in arm A than in arm B (26.0% vs. 14.8%; p�0.001). The pulsed schedule 

resulted in less cumulative toxicity as compared to the standard regimen, in 

particular regarding fatigue and neuropsychiatric side effects. Conclusions: 

The final analysis of pulsed adjuvant HDI treatment showed no significant 

DMFS or OS differences in comparison to conventional HDI. There is a 

clearly favorable safety and QoL profile of the pulsed regimen. 


Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in 

patients with advanced melanoma (MEL). Presenting Author: F. Stephen 

Hodi, Dana-Farber Cancer Institute, Boston, MA 

Background: BMS-936558 is a fully human mAb that blocks the programmed 

death-1 (PD-1) co-inhibitory receptor expressed by activated T 

cells. This study describes the activity and safety of BMS-936558 in 

patients (pts) with previously treated advanced MEL and underscores the 

importance of the PD-1/PD-L1 pathway in MEL therapy. Methods: BMS- 

936558 was administered IV Q2WK to pts with various solid tumors at 

doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. 

Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. 

Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as 

of July 1, 2011, 95 MEL pts were treated with BMS-936558 at 0.1 

(n�13), 0.3 (n�17), 1 (n�28), 3 (n�17), or 10 mg/kg (n�20). ECOG 

performance status was 0/1/2 in 56/36/3 pts. The majority of pts (60/95) 

had received prior immunotherapy (IT), primarily interferon-alpha or IL-2 

(prior anti-CTLA-4 excluded). Prior B-raf inhibitor therapy was noted in 

7/95 pts. The number of prior therapies was 1 (n�35), 2 (n�34), or �3 

(n�26). Sites of metastatic disease included lymph node (n�60), liver 

(n�32), lung (n�55), and bone (n�10). Median duration of therapy was 

15 wk (max 120 wk), with 40 pts still receiving treatment. The incidence of 

grade 3-4 related AEs was 19% and included gastrointestinal (4%), 

endocrine (2%), and hepatobiliary disorders (1%). There were no drugrelated 

deaths in MEL pts. Clinical activity was observed at all dose levels 

(Table). Of 20 pts with OR at the time of data lock, 12 had OR duration �1 

yr and 6 pts were on study with OR duration between 1.9 and 11.3 mo. OR 

were seen in pts with visceral or bone metastases. Several pts had 

prolonged SD. Some had a persistent decrease in overall tumor burden in 

the presence of new lesions and were not categorized as responders. 

Conclusions: BMS-936558 had durable clinical benefit in pts with advanced 

MEL, including those who had received prior IT. Further development 

of BMS-936558 in MEL is ongoing. 

Dose 

(mg/kg) n a OR b uPR c RR d (%) 

PFS e rate 

at 24 wk (%) 

0.1 10 2 - 20 TBD f 

0.3 15 0 3 20 TBD 

1 28 7 1 29 TBD 

3 17 7 - 41 55 

10 20 4 - 20 30 

541s 

a Response evaluable pts; b CR or PR; c Unconfirmed PR; d Response rate [(OR � 

uPR) ÷ n]; e Progression-free survival; f To be determined (follow up ongoing). 




Ipilimumab (Ipi) expanded access program (EAP) for patients (pts) with 

stage III/IV melanoma: 10 mg/kg cohort interim results. Presenting Author: 

Omid Hamid, The Angeles Clinic and Research Institute, Santa Monica, CA 

Background: The EAP (CA184-045), begun in 8/07, currently provides the 

largest safety database for Ipi outside of controlled clinical trials (CCTs) 

and included pts with brain metastases (BM) and primary ocular (OM) and 

mucosal (MM) melanoma. The EAP was amended in 10/08 to administer a 

3 mg/kg dose based on the current label (Hodi et al. NEJM 2010). We now 

report interim data from pts treated in the US at 10 mg/kg from 

8/07-10/08. Methods: Pts with unresectable Stage III or IV melanoma who 

progressed on at least 1 systemic therapy or had no alternate treatment 

options were eligible. Pts received 10 mg/kg Ipi i.v. q 3 wks up to 4 doses 

(induction) followed by 10 mg/kg q 12 wks (maintenance) until no longer 

clinically benefiting or unacceptable/unmanageable toxicity occurred. All 

serious adverse events (SAEs) and on-study deaths were collected; overall 

survival (OS) was assessed retrospectively. Results: Of 906 treated pts, 830 

were included in the analysis; 39 from prior Ipi trials � 37 from sites whose 

IRB did not agree to collect OS were excluded. Pts got a median of 4 doses; 

31% got �5 doses. ECOG 0/1/2 was 53%/39%/8% (1 pt was ECOG 3); 

27% had BM, 5% had OM, and 4% MM. Primary reasons for discontinuation 

were disease progression (67%) and drug toxicity (11%). Incidence of 

drug-related SAEs was 27% with diarrhea 10%, colitis 8%, endocrinopathies 

4%, and dermatitis 0.8%. 2 pts (0.24%) had on-study hepatitis 

SAEs, both considered drug-related and resulted in discontinuation. There 

were 3 (0.36%) drug-related intestinal perforations. 2 deaths (0.24%) 

were the outcome of drug-related SAEs; 1 multi-organ failure and 1 acute 

respiratory distress syndrome (both �70 days from last induction dose). 72 

(9%) pts currently remain on treatment (i.e. �3 years). Available OS data 

showed that 138 pts (17%) were still at risk after 3 years. For 27% of pts 

the last known alive date was �30 days before data cutoff (with most �2 

yrs). Conclusions: Data from the US EAP must be interpreted with caution 

compared to CCTs. To date, incidence of SAEs for hepatitis and intestinal 

perforation, and drug-related death at 10 mg/kg Ipi monotherapy is 

consistent with that seen in BMS clinical trials. Durable OS (�3 yrs) was 

observed in at least 17% of pts. 

8510 Clinical Science Symposium, Mon, 3:00 PM-4:30 PM 

Updated safety and efficacy results from a phase I/II study of the oral BRAF 

inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 

inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic 

melanoma. Presenting Author: Jeffrey S. Weber, Comprehensive 

Melanoma Research Center, H. Lee Moffitt Cancer Center, Tampa, FL 

Background: In preclinical models, the BRAFi/MEKi combination has 

demonstrated enhanced activity against BRAF-mutant cancer cells compared 

with either drug alone, delayed emergence of BRAFi resistance, and 

prevented BRAFi-related proliferative skin lesions. A 3-part study investigating 

the dabrafenib/trametinib combination was conducted in patients (pts) 

with V600 BRAF mutant solid tumors. Interim data from the study were 

previously reported (Infante, ASCO 2011); updated safety and efficacy 

data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant 

solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and 

measurable disease according to RECIST 1.1. Pts were treated on 4 

escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 

150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 

melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are 

reported. Results: Among 77 melanoma pts, median age was 52 years, 61% 

male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain 

metastases, and 52% LDH � ULN. Confirmed ORR was 56% (95% CI: 

44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response 

rate for each dose level, respectively, was 67% (n�6), 64% (n�22), 48% 

(n�25), and 54% (n�24). Median PFS (months) for each dose level, 

respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS 

was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 

adverse events (AEs), pneumonia and hyponatraemia. The most common 

G3/4 AEs were pyrexia (n�6, 5%), fatigue (n�6, 5%) and dehydration 

(n�6, 5%). Skin toxicity � G2 occurred in 17 (14%) pts. Cutaneous 

squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 

(2%). Conclusions: The combination of dabrafenib/trametinib has an 

acceptable safety profile, with a lower incidence of MEKi-related rash and 

BRAFi-induced hyperproliferative skin lesions compared with the single 

agents. The clinical activity of dabrafenib/trametinib observed in pts with 

V600 BRAF mutant metastatic melanoma is encouraging and will be 

investigated further in a phase III trial. 

LBA8509 Clinical Science Symposium, Mon, 3:00 PM-4:30 PM 

METRIC phase III study: Efficacy of trametinib (T), a potent and selective 

MEK inhibitor (MEKi), in progression-free survival (PFS) and overall 

survival (OS) compared with chemotherapy (C) in patients (pts) with 

BRAF mutant advanced or metastatic melanoma (MM). Presenting 

V600/k 

Author: Caroline Robert, Institut Gustave Roussy, Villejuif, France 







8511 Clinical Science Symposium, Mon, 3:00 PM-4:30 PM 

Efficacy and safety of oral MEK162 in patients with locally advanced and 

unresectable or metastatic cutaneous melanoma harboring BRAFV600 or 

NRAS mutations. Presenting Author: Paolo Antonio Ascierto, Unit of 

Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori 

Fondazione Pascale, Napoli, Italy 

Background: BRAF and NRAS mutations occur in 50-60% and 15-20% of 

cutaneous melanomas, respectively. MEK162, a selective inhibitor of the 

kinases MEK1 and MEK2, has shown pre-clinical activity in BRAF and 

NRAS mutant (mt) melanoma models. This open label, phase II study 

assessed the antitumor activity of MEK162 in patients (pts) with BRAFV600 

and NRAS mt advanced cutaneous melanoma. Methods: MEK162 was 

administered orally at a starting dose of 45 mg twice daily. Treatment was 

until unacceptable toxicity, disease progression (PD) or investigator or 

patient refusal. Tumor response was assessed by CT imaging every 8 weeks 

(RECIST 1.0) until PD. Results: As of 16 Sept 2011, the full analysis and 

safety populations comprised 66 pts: 42 BRAF mt and 24 NRAS mt. 

Median age 58.0 years; 57.6% male; 72.7% WHO performance status 0. 

All NRAS pts and all but 2 BRAF (1 each stage IIIB and IIIC) pts had stage 

IV disease, and 87.5% of NRAS pts and 66.7% of BRAF pts had received 

prior therapy at study entry. Median time from 1st diagnosis to 1st dose of 

drug was 40.4 months. Median time on study was 10.4 and 8.5 weeks for 

the BRAF and NRAS arms. Relative dose intensities of 80–�100% were 

received by 71.4% and 70.8% of pts, respectively. Among 29 BRAF mt 

and 13 NRAS mt pts evaluable for efficacy, 1 confirmed and 6 unconfirmed 

partial responses (PRs) and 9 pts with stable disease (SD) were recorded in 

the BRAF arm and 2 confirmed PRs, 1 unconfirmed PR and 4 pts with SD 

recorded in the NRAS arm. Common treatment–related adverse events 

(AEs), all grades (Gs) and all pts, were rash (40.9%), diarrhea (33.3%), 

acneiform dermatitis (27.3%), creatine phosphokinase (CK) elevation 

(25.8%), fatigue (18.2%) and peripheral edema (21.2%). Central serous 

retinopathy-like retinal events (G 1/2 only) were reported in 8 (12.1%) pts 

(6 G1, 2 G2). All retinal events were reversible. G3/4 AEs in �1pt were 

diarrhea (4.5%) and CK elevation (15.2%). 5 pts discontinued due to 

toxicity. 34 pts are ongoing with more responses under current review. 

Conclusions: MEK162 showed clinical activity and good tolerability in pts 

with BRAF and NRAS mt advanced melanoma. This is the 1st targeted 

therapy to show activity in pts with NRAS mt melanoma. 



4:45 PM-5:45 PM 

Safety of ipilimumab in patients (pts) with untreated, advanced melanoma 

alive beyond 2 years: Results from a phase III study. Presenting Author: Luc 

Thomas, Lyon 1 University Centre Hospitalier Lyon Sud, Pierre Benite, 

France 

Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks 

cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. 

In a phase 3 study (CA184-024) of previously untreated pts with 

stage III or IV melanoma, IPI � dacarbazine (DTIC) significantly improved 

overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now 

report safety data of IPI in pts from this study alive � 2 yrs from study 

initiation. Methods: Pts with untreated advanced melanoma, were randomized 

to IPI (10 mg/kg) � DTIC (850 mg/m2 ) or placebo � DTIC (850 

mg/m2 ) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. 

Eligible pts (stable disease or better) received IPI or placebo q 12 wks as 

maintenance. In the population of subjects alive �2 yrs, the appearance of 

immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. 

Within this group was a subset of subjects still receiving IPI dosing after 2 

yrs; safety for these pts was evaluated to assess the impact of prolonged IPI 

exposure. Results: In the IPI � DTIC group 68 (28%) pts survived � 2 yrs 

compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI 

dosing for � 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts 

had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade 

events included rash, pruritus (n�2) and elevated ALT / AST (n�1). Overall 

among all 68 pts in the Ipi � DTIC group, there were 5 pts (7.4%) with any 

grade irAEs including grade 3/4 rash, pruritus (n�1) and low grade rash 

(n�3), pruritus (n�2), skin hypopigmentation, and elevated ALT / AST 

(n�1). No gastrointestinal or endocrine events (any grade) were observed. 

Conclusions: In Study 024, IPI � DTIC treatment improved OS pts with 

untreated, advanced melanoma with higher survival rates in the IPI � DTIC 

group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs 

(20.8% vs. 12.2%) (HR 0.72, p�0.001). The safety profile of pts alive 

after 2 yrs suggests that treatment with IPI � DTIC is associated with low 

rates of irAEs in these pts. Furthermore, in pts still receiving active IPI 

treatment beyond � 2 yrs, the safety profile appears to be consistent and 

medically manageable using established safety guidelines (Weber, Oncologist 

2007). 


4:45 PM-5:45 PM 

Phase II study of the frontline combination of ipilimumab and temozolomide 

in patients with metastatic melanoma. Presenting Author: Sapna 

Pradyuman Patel, University of Texas M. D. Anderson Cancer Center, 

Houston, TX 

Background: Ipilimumab (Ipi) alters the immune system balance by 

inhibiting the suppression of T-cell function. In two phase III trials, Ipi has 

shown an overall survival benefit alone and in combination with dacarbazine 

in previously treated and treatment-naïve patients (pts) with metastatic 

melanoma (MM), respectively. We performed a single-institution, 

phase II clinical trial of Ipi plus temozolomide (Tem) in pts with MM. 

Methods: Pts between the ages of 18 and 75 with previously untreated 

unresectable stage III or stage IV MM and an ECOG Performance Status of 

0 to 1 were enrolled in a phase II trial of Ipi plus Tem. Induction phase 

consisted of Ipi 10mg/kg intravenous on Day 1 and oral Tem 200 mg/m2 on 

Days1–4every 3 weeks for 4 doses. Maintenance consisted of Ipi 10 

mg/kg intravenous on Day 1 starting week 12 and repeated every 12 weeks 

and oral Tem 200 mg/m2 onDays1–5starting week 12 and repeated every 

4 weeks until disease progression or unacceptable toxicity occurred. The 

primary endpoint was progression-free survival (PFS) rate at 6 months. 

Responses were evaluated using immune-related response criteria. Results: 

Sixty-four pts were enrolled and received at least one dose of study drug. All 

pts were included in the analysis. With a median follow-up of 8.5 months, 

the PFS rate at 6 months was 43%, exceeding the proposed rate of 30%, 

and the median PFS was 5.1 months. There were 10 (15.6%) confirmed 

complete responses and 8 (12.5%) confirmed partial responses. At the 

time of this analysis, median overall survival has not been reached. 

Immune-related adverse events (irAEs) were experienced by 88% of pts, 

most commonly pruritus (88%), rash (83%), diarrhea (56%), transaminitis 

(45%), and colitis (11%). Grade 3/4 irAEs seen in more than one patient 

were skin rash (11%), diarrhea (9%), pruritus (6%), and transaminitis 

(5%). Constipation occurred in 70% of pts and was the most common 

gastrointestinal (GI) toxicity. There were no GI perforations or deaths on 

study due to treatment. Conclusions: At a median follow-up of 8.5 months, 

the best overall response rate in this study is 28%. Ipi at 10 mg/kg in 

combination with Tem given in an induction followed by maintenance 

fashion is safe, well-tolerated, and efficacious in MM. 


543s 


4:45 PM-5:45 PM 

Phase II multicenter trial of ipilimumab combined with fotemustine in 

patients with metastatic melanoma: The Italian Network for Tumor Biotherapy 

(NIBIT)-M1 trial. Presenting Author: Anna Maria Di Giacomo, 

Medical Oncology and Immunotherapy, University Hospital of Siena, 

Siena, Italy 

Background: Ipilimumab (ipi), an antibody against cytotoxic T-lymphocyteassociated 

antigen-4, improves survival in patients (pts) with metastatic 

melanoma (MM); however, objective tumor responses are limited. NIBIT-M1 

aims to investigate the efficacy and safety of ipi plus fotemustine (FTM), a 

cytotoxic alkylating drug, in pts with MM. Methods: Eligible pts, with or 

without brain metastases, received induction therapy with ipi 10 mg/kg 

every 3 weeks (Q3W) for four doses and FTM 100 mg/m2 weekly for 3 

weeks. Ipi and FTM maintenance therapy was provided Q12W from Week 

24 and Q3W from Week 9, respectively. The primary objective was the 

immune-related (ir) disease control rate (irDCR: pts with complete response 

[CR], partial response [PR] or stable disease [SD] as determined 

using the ir response criteria). Secondary objectives included ir objective 

response rate (ORR), duration of response (DOR) and progression-free 

survival (PFS); overall survival (OS), and safety. Tumor assessments were 

performed Q8W from Week 12 to Week 36 and Q12W thereafter. Results: 

Among 86 pts with unresectable stage III (n�3) or stage IV (n�83) MM 

treated at 7 NIBIT centers, 42 were previously untreated, 44 had 

progressed following first-line treatment and 20 had asymptomatic brain 

metastases. As of December 2011, the irDCR was 46.5% (40/86; 95% CI, 

35.7–57.6%); the irORR was 29.1% (95% CI, 19.8–39.8%; 5 CRs and 

20 PRs) and with a median 8.3 months follow-up, median irPFS was 5.3 

months (95% CI, 3.5–7.1). The 1-year OS rate was 51.8% (95% CI, 

37.5–66.1%); median OS was not yet reached. Among all pts, 58.1% and 

87% completed ipi or FTM induction, respectively. The most common 

grade 3/4 drug-related adverse events (AEs) (reported in 54.6% pts overall) 

were myelotoxicity (43.5%), increased ALT/AST (14.1/10.6%), gastrointestinal 

(4.7%) and skin-related (2.3%). AEs were generally manageable and 

reversible per protocol guidance. Conclusions: The study reached its 

primary objective with 46.5% of pts achieving disease control. The 

combination of ipi plus FTM is safe; the irDCR, 1-year OS rate and median 

irPFS warrant its further investigation in MM pts. 


4:45 PM-5:45 PM 

Hypersensitivity skin reactions in melanoma patients treated with vemurafenib 

after ipilimumab therapy. Presenting Author: James J. Harding, 


Background: Ipilimumab (IPI) and vemurafenib (VEM) each improve overall 

survival for patients (pts) with metastatic melanoma. Both are FDAapproved 

and are being used in pts with BRAFV600E-mutated metastatic 

melanoma. We previously described cases of prominent skin eruptions 

associated with VEM in pts who had previously received IPI. Methods: We 

have updated our experience of BRAFV600E-mutated melanoma pts treated 

with VEM who had previously received IPI. Pts were treated at our center 

from January 2007 to January 2012. Data were collected under an 

approved IRB waiver. Results: Sixteen melanoma pts were treated with VEM 

after having received IPI. The most common drug-related adverse event 

(AE) associated with VEM was rash, occurring in 13/16 patients (81.3%, 

95% CI 56.5-93.2). Four pts developed a severe, Grade 3, maculopapular 

rash within 8 days of starting VEM. Biopsies in 2 pts revealed spongiotic 

and perivascular dermatitis with eosinophils consistent with a drug hypersensitivity 

reaction. Hypersensitivity reactions did not progress to lifethreatening 

reactions such as anaphylaxis or Stevens-Johnson syndrome, 

nor did they result in VEM dose discontinuation. Reactions were managed 

with corticosteroids and dose modifications. Grade 3 rash strongly correlated 

with initiating VEM within one month of IPI (Fisher’s exact test, p � 

0.007) and was not associated with the dose of prior IPI, the number of 

prior doses, or immune-related AEs. The incidence of Grade 3 rash in this 

pt cohort was significantly higher than in pts treated on the phase III trial of 

VEM (4/16, 25% versus 28/336, 8%; �2 � 5.13, Df � 1, p � 0.02). The 

objective overall response for VEM was 50% (95% CI 26.5-73.4), which is 

similar to response rates seen on the phase II and III trials. Conclusions: In 

pts receiving VEM who have previously received IPI, dermatologic AEs 

appear to be more common. This effect seemed most pronounced if VEM 

was given within one month of completing IPI. Although more data are 

necessary to confirm this apparent association, we speculate that the 

release of immune checkpoint inhibition by IPI may predispose pts to 

hypersensitivity skin reactions to VEM. 




4:45 PM-5:45 PM 

Predicting early relapse in patients with BRAFV600E melanoma with a highly 

sensitive blood BRAF assay. Presenting Author: Ryan J. Sullivan, Massachusetts 


Background: Many patients (pts) with metastatic melanoma (MM) who 

progress on BRAF inhibitors (BRAFi) develop rapidly progressive disease 

(PD) which is difficult to manage. Identification of an early marker of PD 

may allow for therapeutic intervention prior to clinical deterioration. We 

have developed a highly sensitive and inexpensive assay in our laboratory 

which can detect as little as 1 BRAFV600E mutant melanoma cell in 

400,000 peripheral blood lymphocytes (PBL). We aimed to determine the 

utility of our assay as a tool to follow pts with BRAF mutant MM who are 

being treated with a BRAFi. Methods: Every pt had a BRAFV600E mutation 

detected from a tumor sample in a CLIA-approved laboratory prior to 

commencing BRAFi therapy. 20 pts with stage IV BRAFV600E MM underwent 

serial venopunctures before and every 4 weeks during treatment with 

a BRAFi. BRAFV600E level was quantified using our proprietary assay (Panka 

et al Melanoma Research 2010). Serial BRAFV600E levels were generated 

for every pt and normalized to the pre-treatment value. BRAFV600E level was 

then correlated with response to therapy and PD. Results: BRAFV600E was 

detected in the PBL of each pt. To date, 10 pts have had BRAFV600E levels 

quantified at 3 or more time points (data for all 20 pts will be available at 

time of presentation). Relative BRAFV600E levels reduced by half following 

the first and second cycles of treatment in 7 pts, which correlated with 

disease regression in each pt. Following the third cycle of treatment, the 

relative BRAFV600E levels varied greatly with a subset of pts having 

continued suppression while others having a rise in their BRAFV600E levels. 

In each pt with PD, the BRAF assay showed an increase � 4 wks in advance 

of clinically or radiographically defined PD. Conclusions: Our assay is able to 

quantify changes in BRAFV600E levels in the blood of pts with BRAF mutant 

MM receiving BRAFi therapy. In these pts, the BRAFV600E levels are 

reduced in the setting of initial disease regression and increase well in 

advance of clinical or radiographic PD. While further development is 

necessary, such a test could be used to identify pts who may be selected to 

receive alternative therapy prior to clinical or radiographic PD. 


4:45 PM-5:45 PM 

Tumor-specific circulating cell-free DNA (cfDNA) BRAF mutations (muts) 

to predict clinical outcome in patients (pts) treated with the BRAF inhibitor 

dabrafenib (GSK2118436). Presenting Author: Georgina V. Long, Melanoma 

Institute Australia, Westmead Institute for Cancer Research and 

Westmead Hospital, The University of Sydney, Sydney, Australia 

Background: Tumor specific cfDNA levels in blood increase with tumor 

burden and decrease following treatment. cfDNA can harbor muts consistent 

with the tumor. Thus cfDNA could be a useful biomarker of therapeutic 

response. BREAK-2, an open label, single arm, Phase II study evaluated 

efficacy, safety and tolerability of dabrafenib in BRAF V600E/K mut� 

metastatic melanoma pts. Exploratory objectives of BREAK-2 were to 

evaluate whether (i) tumor and cfDNA BRAF muts are correlated; (ii) cfDNA 

levels correlate with baseline tumor burden and (iii) cfDNA muts predict 

clinical outcome with dabrafenib. Methods: BRAF mut status was established 

for 92pts using an allele-specific PCR assay in tumor samples. 

Baseline plasma samples were available for 91/92 pts. cfDNA BRAF mut 

status was evaluated by Inostics GmBH using the BEAMing technology. 

Spearman correlation coefficients (R) were used to determine the association 

between cfDNA fraction (mut DNA molecules � 0.01%) and estimated 

baseline tumor burden, calculated by the sum of RECIST measurements of 

target lesions. Logistic regression and Cox proportional hazards models 

were used to assess the association between cfDNA mut status and 

objective response rate (ORR) and progression free survival (PFS), respectively. 

Results: The overall agreement between tumor and cfDNA BRAF 

V600E and V600K mut status was 83%, and 96% respectively. Higher 

cfDNA V600E mut fraction was associated with higher baseline tumor 

burden (R�0.73; p-value � 0.0001; n�60); lower ORR (O.R. � 0.83; 

95% CI � 0.72, 0.96; p-value�0.0134; n�46) and shorter PFS 

(H.R.�1.09; p-value�0.0006; n�46). Median PFS was 27.4 weeks in the 

overall V600E pt population (n�76) and 20.0 weeks in the cfDNA V600E 

pt population (n�46). Otherwise, the response endpoints were comparable 

between the two populations. There was no correlation between V600K mut 

fraction (n�14) and any efficacy endpoints. Conclusions: cfDNA was useful 

for detecting BRAF muts in pts treated with dabrafenib and increasing 

V600E mut fraction was associated with reduced ORR and shorter PFS, 

suggesting higher amounts of mut cfDNA in V600E mut� pts predicts 

poorer clinical outcome. 


4:45 PM-5:45 PM 

An open-label, multicenter safety study of vemurafenib (PLX4032, 

RO5185426) in patients with metastatic melanoma. Presenting Author: 

James M. G. Larkin, Royal Marsden Hospital, London, United Kingdom 

Background: Vemurafenib, a BRAF inhibitor, is associated with improved 

PFS and OS in patients (pts) with BRAFV600-mutant metastatic melanoma 

(mM). We present preliminary safety and efficacy findings from a safety 

study of vemurafenib in pts with unresectable stage IIIC/IV mM with 

BRAFV600 mutations. Methods: Pts with untreated or previously treated 

stage IIIC/IV BRAFV600 mutation-positive (cobas 4800 BRAF V600 Mutation 

Test) melanoma were enrolled. Pts received continuous oral vemurafenib 

960 mg bid. Primary study endpoint was safety; efficacy (RECIST V 

1.1) was a secondary endpoint. Results: Of 1,964 screened pts between 

Mar and Sep 2011, 914 (47%) were enrolled and 834 were evaluable for 

safety. Median age was 53 (21–88 years), 55% males. Median time since 

first mM diagnosis was 7.6 months (0–18 years). At baseline, 80% of pts 

had ECOG PS 0–1, 11% ECOG PS 2 (missing 9%); 27% of pts had brain 

metastases, and 31% had elevated LDH. Most pts had received prior 

systemic therapy (70%) including ipilimumab (14%), MEK and BRAF 

inhibitors (2%). At data cut-off (Sep 30, 2011), median treatment duration 

was 68 days (1–223 days) with 87% of pts still on treatment. Of 834 pts, 

553 (66%) to date have reported AEs. Of 553 pts reporting AEs, 88% were 

related to vemurafenib, 33% Grade 3, and 1.9% Grade 4. The most 

common (�1%) Grade 3/4 AEs were rash (3.6%), arthralgia (3.1%), and 

cutaneous squamous cell carcinoma/keratoacanthoma (4.3%). Most common 

AEs (�10%) of any grade were arthralgia (31%), rash (29%), fatigue 

(22%), photosensitivity (21%), nausea (15%), and were similar irrespective 

of brain metastases and ECOG PS. AEs caused treatment interruption 

in 141 (17%) pts. Of 109 pts who discontinued treatment (13%), main 

reasons for withdrawal were progressive disease (60%), death (20%), AEs 

(6%; most commonly arthritis and abdominal pain). Tumor assessments at 

Week 8 of treatment were available for 302/834 (36%) pts, 61% pts 

achieved CR or PR, and 29% had SD. Conclusions: In a setting representative 

of routine clinical practice, vemurafenib is seen to be well tolerated and 

both safety profile and activity resemble the phase I–III data although this 

analysis is limited by the study duration. 


4:45 PM-5:45 PM 


sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a 

phase I study. Presenting Author: Julie A. Means, Vanderbilt University 

Medical Center, Nashville, TN 

Background: The MET receptor tyrosine kinase is implicated in tumor cell 

proliferation, invasion, and metastasis, and is activated in NRAS mutant 

melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase 

II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor 

activity vs single-agent activity in several tumor models. This phase I 

dose-escalation study assessed the safety of tivantinib plus sorafenib in pts 

with advanced solid tumors. Methods: Endpoints were safety, the recommended 

phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor 

activity. Dose escalation previously established the RP2D as tivantinib 360 

mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts 

enrolled � 20 pts each with melanoma or other tumors. Pts were treated 

until disease progression or unacceptable toxicity. Results: 16 pts with 

melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts 

are still on study. 12 pts received � 1 previous systemic anticancer 

treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK 

inhibitor (1 pt). Common adverse events (� 25%) were rash (50%), 

diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea 

(31% each), and anemia, weight decrease, and hypophosphatemia (25% 

each). Best responses were complete response (CR) in 1 pt, partial 

response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had 

progressive disease and 5 pts were not evaluable (3 pts had not reached 

first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable 

toxicity). The overall response rate and disease control rate were 25% and 

44%, respectively. Median progression-free survival (mPFS) was 5.3 mo 

(95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2 

mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD. 

Conclusions: Tivantinib plus sorafenib combination therapy was well 

tolerated and exhibited preliminary anticancer activity in pts with melanoma. 

Dual inhibition of MET and angiogenesis may be an effective 

treatment strategy in NRAS-mutant melanoma. 



4:45 PM-5:45 PM 

Clinical significance of genomic alterations of the CDK4-pathway and 

sensitivity to the CDK4 inhibitor PD 0332991 in melanoma. Presenting 

Author: Grant A. McArthur, Department of Medical Oncology, Peter 

MacCallum Cancer Centre, Melbourne, Australia 

Background: Activation of CDK4 by amplification, increased expression of 

Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 

(CDKN2A) can contribute to transformation of melanocytes indicating that 

CDK4 can act as an oncogene in melanoma.To explore if CDK4 may be a 

viable target for the treatment of human melanoma we have analyzed the 

frequency and clinico-pathological associations of genomic alterations of 

the CDK4 pathway in primary human melanoma and examined the genomic 

predictors of sensitivity to the highly selective CDK4/6 inhibitor PD 

0332991 (991) in a panel of melanoma cell lines. Methods: A series of 167 

primary melanomas with clinical, molecular and pathological annotation, 

including median follow up of 6.6 years, were analyzed for copy number 

variation (CNV)- gain of CDK4 or CCND1 (average gene copy �2.4) or loss 

of CDKN2A (average gene copy �1.4), by fluorescence in situ hybridization. 

A panel of 39 cell lines were treated with 991 in vitro and GI50s 

calculated. The mean GI50 of the melanoma cell lines was used to define 

sensitivity. Gene expression profiling and mutation or CNV in CDKN2A were 

used to identify predictors of sensitivity. Results: 75% of primary melanomas 

had at least one CNV (75%, 70% and 82% for BRAF, NRAS or 

wild-type BRAF/NRAS mutation status respectively). 55% showed loss of 

CDKN2A. 28% of melanomas had two or more CNVs. Melanomas with two 

or more CNVs involving CCND1 had worse overall survival (HR 5.56, 

p�0.02). Low CDKN2A mRNA expression or mutation or loss of CDKN2A 

predicted sensitivity to 991 with 30/33 mutant/loss lines being sensitive 

compared to only 2/6 wild type lines (p�0.006). Expression of CDK4, 

CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to 991. 

Conclusions: Genomic alterations in the CDK4 pathway are frequent in 

melanoma and are associated with worse survival, particularly when 

melanomas harbor two or more CNVs involving CCND1. Mutation, loss or 

low expression of CDKN2A in melanoma cell lines predicted sensitivity to 

the CDK4 inhibitor 991. Taken together these data support evaluation of 

CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic 

predictor of sensitivity to these agents. 


4:45 PM-5:45 PM 

A phase II trial of dasatinib in patients with unresectable locally advanced 

or stage IV mucosal, acral, and solar melanomas: An Eastern Cooperative 

Oncology Group study (E2607). Presenting Author: Kevin Kalinsky, Columbia 


Background: Pre-clinical studies report a critical role of c-KIT mutations in 

mucosal, acral, and solar melanomas. Clinical trials of KIT-directed therapy 

with imatinib and sunitinib demonstrate activity in these subtypes. Unlike 

other TKIs, dasatinib inhibitory activity is seen in melanoma cell lines with 

the most common KIT mutation at exon 11L576P. E2607 tests the 

efficacy of dasatinib in treatment-naïve or previously treated patients (pts) 

with these unresectable subtypes. Methods: Pts receive dasatinib 70 mg PO 

twice daily for this two-stage phase II trial. The primary objective is 

response rate (RR: RECIST). Stage I was open to KIT mutated (KIT�) and 

wild-type (KIT-) tumors with these subtypes (n�56). Depending upon the 

interim analysis, stage II would pre-select for KIT�. If the overall response 

rate were � 5%, the study would be terminated. Secondary objectives 

include progression-free survival (PFS), overall survival (OS), safety, and 

KIT mutation status. Results: Between May 2009-Dec 2010, 57 pts have 

been accrued to stage I. Of 54 (2 no therapy, 1 ineligible), 26 have mucosal 

(48%), 13 acral (24%), and 15 solar melanomas (28%). As of Jan 2012, 

the median f/u is 15 months (mo, range: 4-24 mo). Best responses (n�52) 

are 1 complete (CR: 2%), 3 partial (PR: 6%), 13 stable disease (25%), 29 

progression (56%), and 6 unevaluable (11%). 51/52 have progressed 

(median PFS: 1.9 mo, 95% CI: 1.5-2.8) and 40/54 died (median OS: 7.4 

mo, 5.7-10.8). KIT status has been assessed in 42 pts: 39 KIT- (93%) and 

3 KIT� (7%). PR is seen in 1/39 KIT-. All KIT- have died: median PFS (1.8 

mo, 95% CI: 1.4-2.9) and OS (6.8 mo, 95% CI: 5.2-10.8). Of the 3 KIT� 

(1 acral, 2 mucosal), 2 have died (PFS 1.4-2.5 mo, OS: 1.4-10.5 mo), and 

1 refused f/u (OS: 13.3� mo). The pt with a CR is alive at 14.4� mo 

(unknown KIT status). Toxicities include 1 grade IV (elevated lipase) and 

grade III dyspnea (n�7), nausea (n�6), and vomiting (n�3). Conclusions: 

Further evaluation of dasatinib should be pursued in pts selected for KIT� 

and subtype, given the lack of promising results in Kit-(�5% RR). The 

current trial is revised to enroll only KIT� acral, mucosal, and vulvovaginal 

melanomas and available via CTSU. 


545s 


4:45 PM-5:45 PM 

SWOG S0826: A phase II trial of SCH 727965 (NSC 747135) in patients 

with stage IV melanoma. Presenting Author: Christopher D. Lao, University 

of Michigan, Ann Arbor, MI 

Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle 

control and agents that can target cdks in malignant progression remain 

viable therapeutic strategies. Selective inhibition of cdk2, in particular, 

may be of therapeutic value in a subset of patients with melanoma. 

Methods: 60 patients with metastatic melanoma of cutaneous or mucosal 

origin were planned to be recruited to a multicenter, single-arm phase II 

trial of the cdk inhibitor, SCH 727965 (NSC747135). Patients were 

potentially eligible if they had 0-1 previous treatments, PS of 0-1, and 

adequate organ function. Ocular melanoma patients and patients with a 

history of brain metastases were excluded. SCH 727965 50 mg IV every 3 

weeks was given until progression with disease assessment occurring every 

2 cycles. Co-primary endpoints were 1-year overall survival (OS) and 

6-month progression free survival (PFS). Results: 72 patients were enrolled 

from July 1, 2009 to November 1, 2010 at 24 institutions. 68% of 

patients had M1c disease and 43% had LDH elevation. 19% had prior 

therapy for metastatic disease. 28 patients (39%) experienced Grade 4 

adverse events, including 20 cases of neutropenia, one case each of 

cardiac ischemia/infarction, cardiac troponin I elevation, dehydration, 

abdominal pain, leukopenia, muscle weakness, headache, syncope, and 

anterior ischemic optic neuropathy. 65 patients are currently evaluable for 

response. The response rate was 0/65 (95% C.I. (0-6%)). Stable disease 

was observed in 22%. The estimated median PFS was 1.5 months (95% 

CI: 1.4 – 1.5); 6-month PFS was 11% (5-20%). Median OS was 8 months 

(95% CI: 5-11 months); 1-year OS was 36% (95% CI: 24-48%). The null 

hypothesis of 1-year overall survival�25% was rejected (p�0.04) but 

6-month PFS�11% was not (p�0.8). Data Analysis will be updated when 

missing data are received. Correlative studies of Rb phosphorylation and 

cyclin expression will be pursued. Conclusions: SCH 727965 appears to be 

reasonably well tolerated although grade 4 events were relatively common, 

particularly near the time of infusion. There were no responses but few 

patients had prolonged disease stabilization that may have resulted in 

improvement in the 1-year OS rate. 


4:45 PM-5:45 PM 

A Cancer Research UK two-stage multicenter phase II study of imatinib in 

the treatment of patients with c-kit positive metastatic uveal melanoma 

(ITEM). Presenting Author: Paul D. Nathan, Mount Vernon Cancer Centre, 

Middlesex, United Kingdom 

Background: The median overall survival (OS) for metastatic uveal melanoma 

is less than 6 months with a median progression free survival(PFS) of 

3 months. No systemic or regional therapy has shown a survival advantage 

over best supportive care. Despite pre-clinical evidence suggesting antitumour 

activity for the KIT tyrosine kinase inhibitor imatinib, there are 

several negative phase II trials in unselected patients. Our primary aim was 

to test the efficacy of imatinib in patients with prospectively-tested c-kit 

immunopositive metastatic uveal melanoma. Secondary aims included 

assessment of toxicity and patient recruitment. Methods: A phase II UK 

multicentre single-arm, two-stage Gehan design recruited 25 evaluable 

patients receiving imatinib 400mg OD until progression/unacceptable 

toxicity. Primary efficacy outcome was PFS at 3 months. Secondary 

outcomes were OS, overall PFS, disease response (RECIST) and toxicity. 

Prospective sample collection for putative biomarkers was included. 

Results: After 16.6 months 37 patients were screened, with 25 were 

registered and included in final efficacy analyses. The sample included PS 

0-1 patients with a median age of 63 yrs and a median 9.3 months from 

diagnosis of metastatic disease. 82% had high LDH levels (�460IU/L), 

65% had no previous treatment for metastatic disease and 8% did not have 

liver involvement by metastasis. Preliminary final results indicate the 

estimated proportion of patients progression free at 3 months is 0.24 (95% 

CI, 0.09 to 0.45). Median PFS and OS were 12.0 weeks (95% CI,11.6 to 

14.3) and 29.6 weeks (95% CI, 19.3 to 61.0) respectively. Two patients 

had confirmed PR with response duration of 93 and 112 weeks, respectively, 

despite the absence of mutations in exons 11, 13, and 17 of the 

c-KIT gene. Conclusions: The trial successfully recruited to target in this 

rare disease area failing to convincingly show improved PFS in a selected 

cohort of c-kit immunopositive patients. Both patients with PR experienced 

long periods of disease control. Response was not dependent upon the 

presence of activating mutations in KIT. Further translational studies are 

ongoing to determine putative biomarkers of response. 




4:45 PM-5:45 PM 

A phase II single arm study of pazopanib and paclitaxel as first-line 

treatment for unresectable stage III and stage IV melanoma: Interim 

analysis. Presenting Author: John P. Fruehauf, UCI Comprehensive Cancer 

Center, Orange, CA 

Background: Metastatic melanoma lacks effective therapy. Pazopanib is a 

small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has 

antiangiogenic activity in renal cell cancer as well as inhibition of 

melanoma tumor xenografts. We designed a phase II single arm, open label 

clinical trial evaluating pazopanib in combination with metronomic paclitaxel 

as first line therapy for subjects with unresectable stage III and stage 

IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax 

design, with a planned interim analysis to confirm �3 responders to move 

to the second stage. To date, 20 eligible patients have been enrolled with 

17 evaluable for response. All subjects were treatment naïve and received 

paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and 

pazopanib at 800mg as a continuous daily oral dose. The primary endpoint 

is 6 month progression free survival. Exploratory endpoints include biomarker 

analysis that may be associated with treatment outcomes (serum 

VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation 

status). An additional exploratory endpoint includes the in vitro activity of 

pazopanib and paclitaxel on patient biopsy material co-cultured with 

vascular endothelial cells. RECIST criteria were used to define treatment 

response. Results: For the 17 evaluable patients treated to date the 

following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall 

RR (CR�PR) was 40%. Total disease control rate was 80% (PR�SD). The 

most common AEs/lab abnormalities were nausea (71%), hypertension 

(57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included 

hypertension (28%), transaminitis (21%) and neutropenia (14%). One 

patient discontinued for grade 4 transaminitis which subsequently resolved 

completely. Dose reductions were required for pazopanib in 5 patients and 

for paclitaxel in one patient. Conclusions: Planned interim analysis of this 

phase II study demonstrated that pazopanib in combination with paclitaxel 

was well tolerated and resulted in a 40% response rate, indicating that this 

combination is of further interest. Accrual will continue to reach a goal of 

60 patients. 


4:45 PM-5:45 PM 

Targeting hyperactivation of the AKT survival pathway to overcome therapy 

resistance of melanoma brain metastases. Presenting Author: Friedegund 

Elke Meier, University of Tuebingen, Tuebingen, Germany 

Background: Brain metastases are a major contributor to mortality in stage 

IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and 

PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor 

progression and therapy resistance. On the basis of significant improvement 

in overall survival, the BRAF inhibitor vemurafenib recently gained 

FDA approval for the treatment of patients with metastatic BRAFV600E 

mutated melanoma. However, ongoing clinical studies suggest short-lived 

responses to BRAF inhibitors in melanoma brain metastases. Methods: We 

observed in several melanoma patients that chemotherapeutics or BRAF 

inhibitors yielded a significant regression of extracerebral metastases while 

brain metastases progressed or newly occurred. We therefore aimed at 

identifying factors that may contribute to treatment resistance of brain 

metastases. Results: Immunohistochemistry of matched brain and extracerebral 

melanoma metastases demonstrated an identical pattern of ERK, 

p-ERK and AKT staining but a different pattern of p-AKT and PTEN 

staining with hyperactivation of AKT and loss of PTEN expression in brain 

metastases. Mutation analysis revealed no difference in BRAF, NRAS or 

KIT mutation status in matched brain and extracerebral metastases. By 

contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and 

PTEN was identical in cell lines derived from brain and extracerebral 

metastases. Furthermore, melanoma cells stimulated by astrocyteconditioned 

medium showed hyperactivation of AKT compared to melanoma 

cells stimulated by fibroblast-conditioned medium. When inhibiting 

the MAPK and AKT signaling pathways at different levels in cells freshly 

isolated from melanoma brain metastases, growth inhibition and apoptosis 

induction was most pronounced with novel PI3K inhibitors such as 

BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation 

of the AKT survival pathway is brain environment-induced and 

relevant for the survival of melanoma cells in the brain parenchyma and 

that 2) inhibition of AKT signaling may be a suitable strategy to enhance 

and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors 

in melanoma brain metastases. 


4:45 PM-5:45 PM 

Phase II trial of RO4929097 Notch gamma-secretase inhibitor in metastatic 

melanoma: SWOG S0933. Presenting Author: Kim Allyson Margolin, 

University of Washington, Seattle, WA 

Background: The Notch pathway regulates expression of genes for cell 

cycle, tissue-specific differentiation, and vasculogenesis. Notch target 

genes affect melanomagenesis, and Notch levels can influence stemlike 

versus differentiated tumor cells. Gamma-secretase, which activates intracellular 

Notch, can be inhibited to kill melanoma cells. We designed this 

trial to test RO4929097 in pts with melanoma and its effects on T 

lymphocytes and tumor gene expression. Methods: To assess 6-month 

progression-free survival (PFS) and 1-year overall survival (OS) in advanced, 

untreated melanoma patients (pts), a 2-stage accrual design was 

used. Correlative studies: markers of Notch pathway activation in archived 

or fresh tumor and T cell functional assays pre-treatment (Rx) and at week 

3. Rx dose was 20 mg orally on 3 consecutive days, weekly. Results: 33 pts 

were Rx’d in stage 1 (median age 61 [range 32-85]; 70% male; 42% 

elevated LDH; 30% unknown primary; 24% bone mets; 36% liver; 55% 

lung; 55% lymph node, skin or soft tissue). The clinical outcomes did not 

meet criteria for stage 2 accrual. One pt had a confirmed PR of 7 months’ 

(mo) duration. The median PFS was 1.4 mo, [95% confidence interval, c.i. 

1.3-2.7], the 6-mo PFS was 11% [95% c.i 3%-33%], and the 1-year OS 

was 45% [95% c.i. 23%-90%]. Treatment was well-tolerated with no grade 

(gr) 4-5 tox. The most common gr 2 drug tox were fatigue and nausea in 4 

patients (12%) each, and only 4 of 7 gr 3 tox were considered drug-related 

(1 increased ALT, 1 QTc prolongation, 1 bradycardia, 1 lymphopenia). Preand 

week 3 on-Rx peripheral T cell samples assayed for IL-2 (23 pts) and 

IFN-� (22 pts) secretion to Staphylococcal enterotoxin A showed no 

significant change, in contrast to in vitro gamma-secretase inhibitors which 

blocked T cell activation. Pre- and on-Rx tumor biopsies in one pt showed 

no decrease in the Notch target Hey1. Conclusions: RO4929097 at this 

dose and schedule has limited activity in molecularly-unselected pts with 

melanoma. Lack of effect on T cell function and tumor Hey1 expression 

suggests that sustained target inhibition might not have been achieved. 

Supported in part by PHS Cooperative Agreements, NCI, DHHS CA32102 

and CA38926. ClinicalTrials.gov identifier: NCT01120275. 


4:45 PM-5:45 PM 

CNS metastases as a site of progression on SWOG intergroup study S0008: 

A phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, 

DTIC plus IL-2 (BCT) versus high-dose interferon (HDI) in patients 

with high-risk melanoma. Presenting Author: Wolfram E. Samlowski, 

Comprehensive Cancer Centers of Nevada, Las Vegas, NV 

Background: Central nervous system (CNS) metastases (mets) are common 

in stage IV melanoma patients (pts). However, the incidence of CNS mets in 

pts with high-risk regional melanoma (HRM; stages IIIA-N2a thru IIIC N3) 

is not well described. A recent large prospective S0008 trial provided an 

opportunity to evaluate the contribution of CNS mets to treatment failure 

and survival. Methods: All pts had HRM treated with wide excision and full 

regional lymphadenectomy. Pts were then randomized to receive treatment 

with either BCT or HDI. All eligible pts were included in the analysis. 

Relapse/progression in the CNS (PCNS) was retrospectively identified only 

if clearly documented in case report forms. The cumulative incidence of 

PCNS in the presence of the competing hazard of death was estimated and 

potential risk factors were explored using the methods of Fine and Gray. 

Survival from PCNS was measured from date of PCNS to date of death. 

Results: 402 patients were evaluated (BCT: 200, HDI: 202), with median 

follow (if alive) of 6 years. The site of progression was identified in 162 (78 

%) of 208 pts relapsing on study. Clearly documented PCNS occurred in 

53/402 pts (13%). PCNS as a component of initial relapse/progression 

occurred in 34 patients (8%) and an additional 19 patients (5%) had 

delayed PCNS following initial systemic relapse. Most PCNS (85%) 

occurred within 3 years of initial surgery. Differences between arms were 

not significant (22 on BCT, and 31 on HDI)(p�0.21). Lymph node 

macromets demonstrated a strong correlation with development of PCNS 

(p�0.01). Neither primary tumor ulceration nor head and neck primary site 

were significant risk factors. Survival from diagnosis of brain mets was short 

(median 6 mo BCS, 5 mo HDI, p�0.93). Conclusions: Although the S0008 

trial was not specifically designed to evaluate PCNS, a retrospective 

analysis identified a high CNS failure rate (at least 13%) in HRM pts, 

including 8% as the initial site of relapse. Further studies are needed to 

evaluate if screening for CNS mets in high-risk pts is useful and whether 

early treatment improves survival. 



4:45 PM-5:45 PM 

Association of high T-cell immune infiltrate and low hemorrhage in 

melanoma brain metastases (MBMs) with prolonged survival. Presenting 

Author: Michal Tadeusz Krauze, University of Pittsburgh Melanoma Program, 

UPCI, Pittsburgh, PA 

Background: Despite the poor prognosis of patients (pts) with MBM several 

pts have prolonged survival. We hypothesized that the heterogeneity of 

BrMM is determined by differences in melanoma biology and its brain 

microenvironment. Methods: We identified pts who have undergone craniotomy 

for MBMs. Evaluation entailed complete clinical information, acquisition 

of archived melanoma brain metastases, histopathologic analysis of 

hematoxylin and eosin-stained sections (n�101), whole genome expression 

profiling (WGEP, Illumina DASL) in 29 archived tissues. Results were 

validated by immunohistochemistry (IHC) or in situ hybridization (ISH). 

Results: In univariate analysis (log-rank) factors significantly associated 

with prolonged survival were high immune infiltrate (HII) plus low hemorrhage 

(hazard ratio, HR, 2.71, p�0.001), present melanin (1.67, p�0.03), 

and recursive partitioning analysis (RPA) class 1 (0.37, p�0.0001). No 

association between HII and use of immunotherapy prior to craniotomy was 

noted. Only RPA class 1 (p�0.029) and HII plus low hemorrhage 

(p�0.002) remained significant in Cox proportional hazards model analysis. 

Gene set analysis of WGEP data confirmed that Encarta pathways 

related with T-cell activation and differentiation were significantly associated 

with prolonged survival whereas Y branching of actin filaments, 

presenilin action in Notch and Wnt signaling, G-protein signaling through 

tubby protein, lissencephaly gene in neuronal migration and development 

are among the gene categories associated with worse survival. IHC and ISH 

analysis of tumor sections for various markers (n�40) showed that high 

peritumoral CD3� (3.31, p�0.009), high peritumoral CD4� (4.41, 

p�0.014), and high peritumoral CD8� (3.02, p�0.030) are associated 

with prolonged survival whereas neither CD14� nor FoxP3� infiltrate, nor 

high melanoma expression of antigen presentation molecules are associated 

with survival. Conclusions: Our study is the first to document that high 

peritumoral T-cell infiltrates are associated with prolonged survival. High 

tumor hemorrhage, an adverse prognostic sign, reflects aggressive melanoma 

cells that migrate and invade in the brain. 


4:45 PM-5:45 PM 

Clinical activity and safety of combination therapy with temsirolimus and 

bevacizumab for advanced melanoma: Phase II trial with correlative 

studies. Presenting Author: Craig L. Slingluff, University of Virginia, 

Charlottesville, VA 

Background: A CTEP-sponsored phase II trial was performed to evaluate 

safety and clinical activity of combination therapy with CCI-779 (temsirolimus) 

and bevacizumab in patients with advanced melanoma. Correlative 

studies assessed mTOR signaling in tumor biopsies and evidence of 

induced immunologic dysfunction systemically. Methods: 17 patients with 

stage III or IV melanoma were enrolled and treated with temsirolimus (25 

mg IV weekly) and bevacizumab (10 mg/kg IV every 14d, starting d.8) for 

up to 13 months. Clinical response was determined by RECIST criteria. 

Adverse events were assessed (CTCAE v3.0). Blood was collected d.1, 2, 

and 23 (to assess immune function), and tumor biopsies were obtained (to 

assess protein kinase activity and melanoma cell proliferation). Results: 

Treatment-related grade 3 or 4 adverse events occurred in 5 and 1 patients, 

respectively; 1 patient developed reversible leukoencephalopathy. In 16 

patients evaluable for clinical response, best overall response was a partial 

response (PR) in 3 patients (19%), stable disease at 8 weeks (SD) in 9 

patients (56%), and progressive disease in 4 patients. Thus, disease 

control rate (DCR � PR � SD) was 75%. Ten of the patients had BRAF 

wild-type (BRAFwt ) melanomas: these accounted for the 3 PRs (30%), and 

a DCR of 100%. Maximal response duration has exceeded 3 years for a 

BRAFwt patient. mTOR signaling was inhibited in melanoma metastases, 

based on decreased phospho-S6 kinase after 24h temsirolimus. Ki67� melanoma cells in tumor biopsies decreased significantly by day 23 (p � 

0.007, F-test), most notably in clinical responders. There was no significant 

alteration of T cell and NK function with combination treatment, by 

ELIspot and cytotoxicity assays. Conclusions: Combination therapy with 

temsirolimus and bevacizumab is well-tolerated in patients with advanced 

melanoma and has intriguing clinical activity. The most notable responses 

were in patients with BRAFwt tumors, a population with no accepted 

effective targeted therapy. Decreases in Ki67� melanoma cells may be 

associated with clinical response. The lack of immunologic dysfunction 

supports future combination with immune therapies. 


547s 


4:45 PM-5:45 PM 

The NIBIT-M1 trial: Activity of ipilimumab plus fotemustine in patients 

with melanoma and brain metastases. Presenting Author: Michele Maio, 

Medical Oncology and Immunotherapy, University Hospital of Siena, 

Siena, Italy 

Background: Patients (pts) with metastatic melanoma (MM) often develop 

treatment-resistant brain metastases (mets). Treatment includes fotemustine 

(FTM), which crosses the blood-brain barrier. Ipilimumab (ipi) has 

shown activity in pts with MM and asymptomatic brain mets (Heller et al. 

ASCO 2011; abs 8581). In the phase II NIBIT-M1 trial, MM pts with 

asymptomatic brain mets were eligible for treatment with ipi plus FTM. 

Here, data from this pt subset are reported. Methods: Eligible pts received 

induction therapy with ipi 10 mg/kg every 3 wks (Q3W) x4 and FTM 100 

mg/m2 weekly for 3 wks, followed by ipi Q12W from Week (W) 24 and FTM 

Q3W from W9. The primary objective was the immune-related (ir) disease 

control rate (irDCR: complete/partial response [CR/PR] or stable disease 

[SD] using the ir response criteria). Secondary objectives included ir 

objective response rate (ORR) and progression-free survival (PFS); overall 

survival (OS), and safety. Tumor assessments were performed Q8W from 

W12 to W36 and Q12W thereafter. Results: Among 86 enrolled pts, 20 had 

brain mets. Of these, 7 had prior whole brain radiotherapy (n�4) or 

radiosurgery (n�3). As of December 2011, the irDCR was 50% (10/20; 

95% CI, 27.2–72.8%) with an irORR of 40% (95% CI, 19.1–63.9%: 2 

CRs and 6 PRs). Pts with irDC also had stability/reduction (n�5) or 

disappearance (n�5) of brain mets. Among pts with progressive disease, all 

but one had progression in the brain. With median follow-up of 8.3 months 

(range: 0.4–16.9), median irPFS was 4.6 months (95% CI, 0.7–12.3). 

The 1-year OS rate was 52.9% (95% CI, 26.6–79.2); median OS was not 

reached. Induction with ipi and FTM was completed by 55% and 85% pts, 

respectively. Grade 3/4 drug-related adverse events (AEs) occurred in 60% 

pts; most commonly myelotoxicity (50%), increased ALT/AST (5%) and 

gastrointestinal (5%). AEs were generally manageable and reversible per 

protocol guidance. CNS AEs of any grade (i.e., haemorrhage, headache and 

seizure) occurred in 25% pts (grade 3/4 in 2 pts) and were attributed to 

disease progression. Conclusions: The combination of ipi plus FTM is active 

and safe in pts with MM and brain mets, regardless of prior treatment, and 

will be further explored in the phase III NIBIT-M2 trial. 


4:45 PM-5:45 PM 

Activity of cabozantinib (XL184) in metastatic melanoma: Results from a 

phase II randomized discontinuation trial (RDT). Presenting Author: 

Michael S. Gordon, Pinnacle Oncology Hematology, Scottsdale, AZ 

Background: MET and VEGF signaling are implicated in angiogenesis, 

invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of 

MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. 

Here we report on the metastatic melanoma cohort, including the ocular 

subtype. Methods: Eligible patients (pts) were required to have progressive 

measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 

wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. 

Treatment � wk 12 was based on response: pts with PR continued 

open-label cabo, pts with SD were randomized to cabo vs placebo, and pts 

with PD discontinued. Primary endpoint in the randomized phase was 

progression free survival (PFS). Results: Enrollment to this cohort is 

complete (n � 77); all pts are unblinded. Baseline characteristics: median 

age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular 

30%; known BRAF mutation 32%; LDH � 1.1 x upper limit normal 35%; 

bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median 

follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the 

open-label Lead-in stage with 25 pts randomized to continue cabo (n�12) 

or to placebo (n�13). Median PFS from randomization was 5.7 months for 

cabo vs. 3 months for placebo (HR�0.3, p �0.055). Median PFS from 

Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is 

44%. Evidence of objective tumor regression was observed in 39/65 pts 

(60%) with � 1 post-baseline tumor assessment including 11/23 pts 

(48%) with ocular melanoma. Two bone scan evaluable pts demonstrated 

partial resolution of bone lesions at wk 6 accompanied by pain relief. Most 

common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%), 

and diarrhea (3%); one related Grade 5 AE of diverticular perforation and 

peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates 

activity in metastatic melanoma pts, regardless of subtypes or BRAF 

mutation status, with improvement in PFS relative to placebo, and high 

rates of PFS6 and objective tumor regression. The safety profile of cabo was 

comparable to that of other VEGFR TKIs. 




4:45 PM-5:45 PM 

Randomized phase III trial of intravenous (IV) versus hepatic intra-arterial 

(HIA) fotemustine in patients with liver metastases from uveal melanoma: 

Final results of the EORTC 18021 study. Presenting Author: Serge Leyvraz, 

Centre Pluridisciplinaire d’Oncologie, Lausanne, Switzerland 

Background: HIA fotemustine has shown promising results in Phase II 

studies that led to the EORTC randomized phase III trial (18021) in 

unpretreated patients (pts) with liver metastases from uveal melanoma. 

Methods: The treatment consisted in an induction cycle of either HIA 

(fotemustine 100 mg/m² over 4 hours, day 1, 8, 15, 22) vs IV control arm 

(fotemustine 100 mg/m² over 1 hour, day 1, 8, 15). After a 5-week break, 

maintenance cycles were given every 3 weeks. Randomization was stratified 

by PS (0 vs 1), LDH (normal vs abnormal) and center. Main endpoint 

was overall survival (OS). Required accrual per protocol was set to 262 pts, 

with final analysis planned after 220 deaths (hazard ratio (HR) �0.67, 

power�85%, 1-sided ��2.5%). Due to poor accrual an interim analysis 

was done after 134 deaths, in order to test futility (power�79%). Results: 

Between Feb-2005- Feb-2011, 171 pts were randomized (HIA: 86, IV: 

85). Characteristics: PS 1: 20%, abnormal LDH: 42%, male: 50%, median 

age: 59 y.; balanced between arms. In the HIA arm 20 (23%) pts never 

started treatment mainly due to catheter problems and 2 pts in the IV arm. 

In those who started the treatment, leucopenia grade 3-4 was 18% and 

thrombopenia grade 3-4: 21% in the HIA arm compared to 32% and 42% 

in the IV arm. Non-hematological grade 3-4 toxicities were minimal (GI 

toxicity, catheter complications). In May 2011, as the OS HR�1.097 was 

� critical value 0.87, the IDMC recommended stopping accrual for futility. 

The final results from Jan-2012 are presented in the table below. 

Treatment comparison adjusted by PS and LDH provided similar results. 

Conclusions: Even if HIA fotemustine administration could not start in 23% 

of pts, it led to a higher ORR and longer PFS compared to IV administration. 

HIA did not translate into an improvement in OS. 

All pts 

(N�171) 

Treatment started 

(N�149) 

Endpoint HIA (N�86) IV (N�85) HIA (N�66) IV (N�83) 

Response 

CR�PR�ORR, N (%) 9 (10.5) 2 (2.4) 9 (13.6) 2 (2.4) 

PFS 

Events, N 84 85 64 83 

Median (months) 4.5 3.7 5.4 3.7 

HR (95% CI), p value 0.62 (0.45 , 0.84), 0.002 0.53 (0.38 , 0.75), 0.0002 

OS 

Deaths, N 79 76 59 74 

Median (months) 14.6 13.0 14.6 13.7 

HR (95% CI), p value 1.09 (0.79 , 1.50), 0.59 1.00 (0.71 , 1.42), 0.98 


4:45 PM-5:45 PM 

Long-term cure after complete resection and adjuvant immunotherapy for 

distant melanoma metastases. Presenting Author: Donald L. Morton, 

Division of Surgical Oncology, John Wayne Cancer Institute, St. John’s 

Health Center, Santa Monica, CA 

Background: In phase II trials, postoperative therapy with Canvaxin allogeneic 

melanoma cell vaccine plus Bacillus Calmette-Guerin (BCG) improved 

the survival of patients with stage IV melanoma. A multicenter, phase III 

placebo-controlled study was undertaken to investigate the vaccine’s 

efficacy. Methods: After complete resection of melanoma involving up to 5 

distant sites, patients were randomized to treatment with BCG plus 

Canvaxin (BCG-Canvaxin) or BCG plus placebo (BCG-placebo). The primary 

endpoint was overall survival (OS); secondary endpoints were disease-free 

survival (DFS) and skin test responsiveness to the study agent. Results: 

Between May 1998 and April 2005, 496 patients were randomized. In 

April 2005, entry to the study was terminated due to low probability of 

demonstrating treatment differences. However, 256 patients from sites 

enrolled in a follow-up study were monitored until March 2010. Median OS 

and 5-year and 10-year rates of OS were 39.1 months, 43.3% and 33.3%, 

respectively, in the BCG-placebo group, versus 34.9 months, 42.5% and 

36.4%, respectively, in the BCG-Canvaxin group (hazard ratio, 1.053; 

95% confidence interval, 0.81 to 1.36; p�0.6964). Median DFS, 5-year 

DFS, and 10-year DFS were 7.6 months, 23.8% and 21.7%, respectively, 

for the BCG-placebo group, versus 8.5 months, 30.0%, and 30.0%, 

respectively, for the BCG-Canvaxin group (hazard ratio, 0.882; 95% 

confidence interval, 0.708 to 1.097; p�0.2595). Positive skin test results 

correlated with improved survival. Conclusions: BCG-Canvaxin was not 

superior to BCG-placebo, but the highly favorable long-term survival for 

combined groups indicates that complete metastasectomy should be 

considered as initial therapy for patients with resectable stage IV melanoma 

(ClinicalTrials.gov identifier: NCT00052156). 


4:45 PM-5:45 PM 

Neoadjuvant ipilimumab in locally/regionally advanced melanoma: Clinical 

outcome and immune monitoring. Presenting Author: Ahmad A. Tarhini, 


Background: Neoadjuvant ipilimumab (ipi) for stage IIIB-C melanoma may 

improve the clinical outcomes and provide access to pre/post ipi blood and 

tumor to gain insight into host effector and suppressor immune response 

mechanisms. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks 

x 4doses total) bracketing definitive surgery. Tissue samples were obtained 

at baseline and at definitive surgery (week � 6) and serum/PBMC collected 

at baseline, 6 weeks, then at 3, 6, 9, 12 months and/or progression. Flow 

cytometry was used to monitor the host effector and suppressor immune 

response in blood and evaluable tumor. Results: Thirty pts (21 male, 9 

female), age 40-87 were enrolled (25 cutaneous primary, 1 unknown, 4 

mucosal). Six had AJCC stage IIIB (N2b, N2c) and 24 IIIC (N3) melanoma. 

Ninety-three cycles have been delivered (median 4). Worst toxicities 

included grade 3 diarrhea/colitis (5 patients; 17%), hepatic enzyme 

elevations (2; 7%), rash (2; 7%), lipase (1; 3%), all manageable. Median 

follow up is 14 months: among 29 evaluable pts 15 (52%) continue 

disease free. Median PFS is 15.5 months, 95% CI � (8.1,-). The 

probability of 6 and 12 month PFS is 82.4% (95% CI�0.63, 0.92) and 

53% (95% CI�0.31, 0.70) respectively. Peripherally, a significant increase 

in frequency of circulating T-regs (CD4�CD25hi� Foxp3�;p�0.02 

CD4�CD25hi�CD39�; p�0.001) from baseline to 6 weeks was observed. 

Greater increases in T-regs were associated with improved PFS 

(p�0.045; HR�0.54). Significant decreases in circulating MDSCs, were 

observed in monocytic HLA-DR� /low/CD14� MDSC subtype (p�0.0001). 

Spontaneous in vivo cross presentation was observed resulting in Th1 CD4 

and CD8 antigen specific T-cell immunity (gp-100, MART-1, NY-ESO-1 

peptides) with increase in frequency after ipi. Activated TIL in tumor 

increased after ipi (CD3�/CD4�/CD69�;p�0.06 and CD3�/CD8�/ 

CD69�) with significant induction/potentiation of T-cell memory (CD8�/ 

CD45RO�/TNF-��;p�0.03). Conclusions: Neoadjuvant ipi exhibits 

promising clinical activity and significantly modulates the host effector and 

suppressor immune response. Full analysis of this completed trial and its 

correlates will be presented. Support: BMS, P30CA047904 and 

P50CA121973. 


4:45 PM-5:45 PM 

Sensitivity rate of ultrasound (US)-guided fine-needle aspiration cytology 

(FNAC) using the Berlin morphology criteria for lymph node metastases to 

reduce the need for surgical sentinel node (SN) staging in melanoma. 

Presenting Author: Christiane A. Voit, Charité, University Medicine Berlin, 


Background: US-guided-FNAC prior to surgical SN staging is emerging as a 

possible cost-effective addition to the staging of melanoma patients (pts). 

Formerly, sensitivity (sens) rates of lymph node US in melanoma were 

disappointing (20–40%). The introduction of the Berlin Morphology 

Criteria has significantly improved sens rates for US-FNAC (J Clin Oncol 

2010;28(5):847-52). The aim of the current study was to report on 1000 

patients the sens, specificity (spec), positive (PPV) and negative (NPV) 

predictive value rates of US-FNAC from our prospective database with 

prolonged follow-up. Methods: Since 2001, �1000 stage I/IIconsecutive 

melanoma pts have undergone US-FNAC prior to SN. All patients underwent 

lymphoscintigraphy. Peripheral Perfusion (PP), Loss of Central 

Echoes (LCE), Balloon Shaped (BS) were the Berlin Morphology Criteria 

which were registered. FNAC was performed in case of presence of any of 

these factors. SN tumor burden was measured according to the Rotterdam 

Criteria. All patients underwent SN or LND in case of positive FNAC. 

Results: Mean/median Breslow thickness was 2.56 / 1.57 mm (0.2 – 44 

mm).Mean/median follow-up was 39 / 32 months (0 – 115). Ulceration was 

present in 24 %. SN positivity rates were 20 % (202 / 1000). Sens was 51 

%. Spec, PPV and NPV were 99%, 91% and 89%. Sensitivity was highest 

for T4 tumors (77%). PP, LCE, BS had sens of 69%, 24%, 25%. SN tumor 

burden � 1 mm in largest diameter according to the Rotterdam Criteria was 

identified by US-FNAC in 86%. Threshold for positive FNAC was 0.4 mm in 

maximum diameter. Conclusions: The new criterion of Periferal Perfusion is 

of key importance to achieve the high sensitivity of US-FNAC according to 

the Berlin Morphology Criteria (J Clin Oncol 2010; 28:847-852) to identify 

lymph node metastases. Especially for T4 patients and in patients with 

advanced SN tumor burden it can reduce significantly the need for surgical 

SN staging. The EORTC Melanoma Group will launch the prospective 

validation study, USE FNAC, in 2012. 



4:45 PM-5:45 PM 

Impact of comorbidities on overall survival of high-risk and advanced 

melanoma. Presenting Author: Prashanth Peddi, University of Texas M. D. 


Background: Comorbidities have been shown to adversely affect survival 

among patients with cancer. Currently, the most important prognostic 

factor in patients with melanoma is AJCC stage. However, little is known 

regarding the impact of comorbidities on melanoma prognosis. The aim of 

our study was to determine the impact of the severity of concurrent 

comorbidities on the overall survival of patients with high-risk and advanced 

melanoma (defined as AJCC stages IIc, III and IV). Methods: We 

conducted a retrospective cohort study of eligible adult melanoma patients 

available in the MelCore prospective database at MD Anderson Cancer 

Center (MDACC) from 01-2003 to 12-2006 who were diagnosed and 

completed staging within 3 months of presentation to MDACC. Patients 

with ocular melanoma were excluded. Demographic, AJCC staging, and 

survival data were collected. The Adult Comorbidity Evaluation-27 (ACE- 

27) was utilized to collect comorbidity information and grade its severity. A 

Cox proportional hazards model was used. Results: Of 444 patients that met 

enrollment criteria, 176 (39.6%) had grade 0 (no comorbidities), 222 

(50%) had grade 1 or 2 (mild or moderate comorbidities) and 46 (10.4%) 

had grade 3 (severe comorbidities). The median age of the entire cohort was 

56.4 years (19.7-98.9), 141 (32%) were female, and 406 (91.4%) were 

white. The median overall survival after presentation to MDACC was 5.0 

years for the entire cohort. Adjusted hazard ratios are shown in the table. 

Comorbidity and AJCC Stage were significantly associated with survival. 

Age, gender and race did not have a significant impact on overall survival. 

Conclusions: In our study, the presence of comorbidities at presentation 

were independent predictors of decreased survival, even when adjusted for 

AJCC stage. Our findings suggest that comorbidity should be incorporated 

into prognostic models and therapeutic decision-making for patients with 

high-risk or advanced melanoma. 

Multivariate Cox model (adjusted for age, sex, gender and stage). 

Grade Hazard ratio 95% CI p value 

ACE-27 0 

1or2 

3 

AJCC stage IIC 

III 

IV 

1.0 

1.5 

1.7 

1.0 

0.7 

3.2 

---- 

1.1-2.0 

1.1-2.7 

--- 

0.4-1.2 

2.0-5.2 

--- 

0.01 

0.02 

--- 

0.27 

�0.001 


A prospective study investigating the impact of definitive chemoradiation in 

locoregionally advanced squamous cell carcinoma of the skin. Presenting 

Author: Michelle K. Nottage, Royal Brisbane Hospital, Brisbane, Australia 

Background: Our state, Queensland, Australia, has the highest rate of 

cutaneous squamous cell cancer (SCC) in the world. Spread to regional 

lymph nodes or more distant sites occurs in 5-10%. A proportion of 

patients can not undergo surgical resection but complete response rates 

with radiotherapy alone are low. This led to the hypothesis that combined 

chemoradiation (CRT) may be of benefit. We decided to document the 

outcomes of concurrent chemoradiation by means of a prospective trial. 

Methods: This was a single arm, phase II study with planned sample size 30 

patients. The primary endpoint was complete response rate (CRR), estimate 

60%. Patients with locally/regionally advanced (non-metastatic) 

cutaneous SCC deemed unresectable or unsuitable for surgery by consensus 

of the multidisciplinary Head and Neck Cancer Clinic, with measurable 

disease, aged over 18, performance status 0-2, received definitive radiotherapy 

(XRT) (70Gy in 35#) and concurrent weekly platinum based 

chemotherapy (CT) (cisplatin 40mg/m2 or carboplatin AUC 2). Results: 14 

patients were enrolled (Feb 2008-June 2011), median age 66 (48-84), 

64% ECOG PS 0, 64% stage IV, 57% nodal disease only. Cisplatin/ 

carboplatin was administered in 64%/36% respectively. 42% received all 

planned CT while 58% had 1 or 2 weeks omitted. 2 patients had dose 

reductions. XRT was completed as planned in 93%. The CRR was 57% 

(8/14) at analysis in December 2011 (median follow-up 13.5m). 2 further 

patients with partial response (PR) achieved CR after undergoing salvage 

surgery. Six (43%) patients had a PR; 4(29%) did not receive surgery and 

later progressed. Median overall survival was not reached, with 3 year 

survival 54%. The most frequent toxicities were dermatitis, mucositis, 

thrombocytopenia, nausea, anaemia, dysphagia. 28% had grade 3/4 

toxicity, mainly cytopenias, infection, dehydration and nausea. Conclusions: 

This is the only prospective series of CRT for cutaneous squamous cell 

cancer. A high complete response rate was documented in patients with 

loco-regionally advanced disease and multiple co-morbidities, with acceptable 

toxicity, making this a reasonable alternative for patients unable to 

undergo surgery. 



Suppression of apoptosis by BRAF inhibitors through off-target inhibition 

of JNK signaling. Presenting Author: Kenneth Yee Tsai, University of Texas 


Background: The advent of targeted therapy has revolutionized the treatment 

of cancer. The mutant BRAFV600E protein is found in over 50% of 

melanomas and thyroid carcinomas, resulting in elevated kinase activity, 

increased mitogen-activated protein kinase (MAPK) pathway signaling, and 

cell proliferation. Vemurafenib and PLX4720 were designed to selectively 

inhibit the BRAF kinase, and clinical trials of vemurafenib in metastatic 

melanoma have demonstrated a response rate of over 50% and an overall 

survival advantage over standard dacarbazine therapy. Approximately 

20-30% of individuals treated with vemurafenib develop cutaneous squamous 

cell carcinoma (cSCC) highlighting the importance of understanding 

toxicities associated with this drug. Paradoxical ERK activation in BRAF 

wild-type, RAS-mutant cells is thought to be the major mechanism by 

which this occurs, as evidenced by the presence of RAS mutations in 60% 

of such lesions. Methods: Using a combination of BRAF-wild-type cSCC cell 

lines, primary human keratinocytes, as well as a UV mouse model of cSCC 

and human cSCC samples, we identified novel effects of BRAFi on 

apoptosis. Results: Here we show an unexpected and novel effect of 

vemurafenib and PLX4720 in suppressing apoptosis through the inhibition 

of multiple off-target kinases. JNK signaling and apoptosis are suppressed 

in cSCC lesions arising in vemurafenib-treated patients as well as in 

irradiated mouse skin. This occurs independently of paradoxical ERK 

signaling and in the presence of MEK inhibitor. Treatment with PLX4720 

greatly accelerates the development of UV-induced cSCC in mice without 

Ras mutations. Kinome screening identified ZAK and MKK4 (MEK4 / 

MAP2K4) kinases as inhibited by vemurafenib, leading to suppression of 

MKK4 and MKK7 (MAP2K7) phosphorylation. Knockdown of inhibited 

off-target kinases recapitulates these anti-apoptotic effects of vemurafenib. 

Conclusions: Our results implicate suppression of JNK signaling, 

independent of ERK activation, as an additional, complementary mechanism 

of adverse effects of vemurafenib. This has broad implications for 

combination therapies with other modalities that induce apoptosis and for 

the long-term use of vemurafenib in the adjuvant setting. 


Outcomes of ipilimumab treatment-related adverse events in patients with 

metastatic melanoma (MM) who received systemic corticosteroids in a 

phase III trial. Presenting Author: Jean-Francois Baurain, Oncologie 

Médicale Cliniques Universitaires Saint-Luc, Brussels, Belgium 

Background: Ipilimumab (ipi) is a fully human monoclonal antibody that 

blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune 

responses. In a phase III trial, ipi at 10 mg/kg plus dacarbazine (DTIC) 

improved overall survival in previously untreated patients (pts) with MM. In 

ipi studies, the most common drug-related adverse events (AEs) were 

immune-related, which were generally reversible using treatment guidelines 

involving prompt recognition, intervention (corticosteroids, and rarely, 

alternative immunosuppressive agents), and possible discontinuation of 

therapy. The purpose of this analysis is to evaluate outcomes of ipi 

treatment-related AEs with use of systemic corticosteroids. Methods: AEs 

were reported from the first ipi dose up to 70 days after the last dose. 

Immune-mediated adverse reactions (imARs) were used to characterize 

inflammatory AEs in previously untreated pts with MM who received ipi plus 

DTIC in a phase III trial. This analysis includes the imAR categories of 

hepatitis, dermatitis, enterocolitis, and endocrinopathies. Results: More 

than 70% of pts who received corticosteroids had complete resolution of 

the imAR, ie, last reported Grade (Gr) of 0 (Table). In pts for whom a 

high-grade imAR had not completely resolved at the last report, �50% had 

improved to Gr 1. Conclusions: In the majority of pts treated with ipi at 10 

mg/kg plus DTIC who received corticosteroids for the management of 

imARs, as recommended per treatment guidelines, the most common 

imARs had completely resolved or improved to Gr 1. 

ImAR 

Resolution or 

last Gr reported 

Outcomes of imARs, N (%) 

Ipi � DTIC, 

worst Gr�2 

549s 

Ipi � DTIC, 

worst Gr >2 

Hepatitis N who received steroids N�10 N�63 

Outcomes Gr 0 8 (80.0) 45 (71.4) 

Gr 1 2 (20.0) 12 (19.0) 

Gr 2 0 (0.0) 2 (3.2) 

Gr 3 0 (0.0) 3 (4.8) 

Gr 4 0 (0.0) 1 (1.6) 

Dermatitis N who received steroids N�29 N�6 

Outcomes Gr 0 24 (82.8) 2 (33.3) 

Gr 1 2 (6.9) 2 (33.3) 

Gr 2 3 (10.3) 1 (16.7) 

Gr 3 0 (0.0) 1 (16.7) 

Enterocolitis N who received steroids N�5 N�10 

Outcomes Gr 0 4 (80.0) 7 (70.0) 

Gr 1 0 (0.0) 2 (20.0) 

Gr 2 1 (20.0) 0 (0.0) 

Gr 3 0 (0.0) 1 (10.0) 

Endocrinopathies N who received steroids N�3 N�0 

Outcomes Gr 0 0 (0.0) 0 (0.0) 

Gr 1 0 (0.0) 0 (0.0) 

Gr 2 3 (100.0) 0 (0.0) 




Prognostic value of BRAFV600 mutations in melanoma patients after 

resection of metastatic lymph nodes. Presenting Author: Philippe Saiag, 

Hospital Ambroise Pare, APHP, University Versailles-SQY, Boulogne- 

Billancourt, France 

Background: Prognosis of AJCC stage III melanoma is heterogeneous. 

BRAF V600 mutations are frequent in melanomas. BRAFV600-targeted therapy 

has dramatic, but often transitory, efficacy in stage IV patients (pts). We 

aimed to determine for the first time the prognostic value of BRAFV600 mutations and other known prognostic criteria in stage III pts with 

sufficient nodal invasion. Methods: We searched all pts with cutaneous 

melanoma who had radical lymphadenectomy in our institution between 

1/1/00 and 15/6/10 and included those with a nodal deposit �2 mm. 

BRAFV600 mutations were detected by DNA sequencing and pyrosequencing 

in formalin-fixed nodal samples containing �60% melanoma cells. 

Samples were considered mutated when �15% of DNA was positive. 

Endpoints were overall survival (OS) and distant metastasis free survival 

(DMFS). 92 patients had to be included to demonstrate a doubling of OS in 

patients without (40 months (m)) and with BRAFV600 mutation (20 m). 

Log-rank test and multivariate Cox proportional hazards regression model 

were used. Results: 105 consecutive pts were included, with 72% prospectively 

followed-up pts. BRAFV600 mutations (E: 83%; K: 14% of pts) were 

detected in 40% of pts. Median follow-up was 19 m (range: 3-139). Death 

occurred in 83% and 60% of pts with and without BRAF mutations, 

respectively, with median OS of 1.4 and 2.8 years. Pts’ age, primary 

melanoma ulceration, number of invaded nodes, AJCC staging, and BRAF 

status influenced OS and DMFS in the univariate analysis. The multivariate 

analysis showed the major prognostic role of BRAF status and of the 

number of invaded nodes (table). Conclusions: Provided our findings are 

independently replicated, BRAFV600 status should be used to stage 

melanoma pts with nodal metastasis. Our results also help to plan adjuvant 

trials with BRAFV600-targeted therapy in such patients, for whom the low 

tumor load may induce longer efficacy of BRAF-targeted therapies. 

OS DMFS 

P HR[IC95%] P HR[IC95%] 

N invaded nodes (1,2-3,4) 0.005 2.2 [1.3-3.9] 0.005 2.4 [1.3-4.3) 

BRAF mutated (Y/N) 0.005 1.9 [1.2-3.1] 0.002 2·1 [1·3-3·4] 

Ulceration of primary (Y/N) NS - 0.04 1.7 [1.0-2.8] 

AJCC staging, extracapsular spread, macro/micrometastasis, Breslow index: NS. 


Role of cytokine-induced plasticity in melanoma on invasive, therapyresistant 

cells that express EMT-related genes and pathways. Presenting 

Author: Jonathan S. Cebon, Ludwig Institute for Cancer Research, Melbourne, 

Australia 

Background: The acquisition of new mutations can explain resistance to 

targeted therapies; however resistance also develops without demonstrable 

new mutations. To better understand potential mechanisms for treatment 

failure we studied subpopulations of chemo-resistant cells that can be 

identified in early passage cell lines and the cellular plasticity that yields 

these. Methods: Melanoma subpopulations were identified and sorted on 

the basis of functional assays. Gene expression was evaluated with Illumina 

HT12 arrays and qPCR to identify potential mechanisms and targets. 

Sorted cells were evaluated in vitro for the induction of phenotype 

switching and effects of target inhibition. Results: A subset of slow 

proliferating label-retaining cells (LRC) was identified using a membrane 

dye. Direct isolation of LRC from a pt showed these were not an in vitro 

artefact. LRC isolated from multiple cell lines comprised the majority of 

cells that resisted cytotoxic drugs and could invade through an artificial 

extracellular membrane. Gene expression profiling identified a network of 

over-expressed genes related to epithelial-to-mesenchymal transition (EMT) 

notable for the expression of Thrombospondin-1 (TSP-1), Transforming- 

Growth Factor, Beta Induced, (TGFBI) and other extracellular matrix 

molecules. Initial studies show that LRC shared gene expression characteristics 

with PLX4032-resistant cells. Although interrogating LRC by qPCR 

showed up-regulation of the putative melanoma stem cell marker ABCB5 

and the lysine specific demethylase Jarid1B, cell sorting and serial 

re-labelling experiments revealed a dynamic and interchangeable phenotype 

for these cells, challenging the hierarchical stem cell model for 

melanoma. The observed slow-cycling and chemo-resistant phenotype 

could be induced in vitro through TGF beta-mediated phenotype switching 

and cellular invasion was blocked using an antibody against TSP-1. 

Conclusions: Cytokine-induced plasticity in melanoma yields invasive, 

therapy-resistant cells which express EMT-related genes and pathways. We 

hypothesize that these cells are a source of treatment resistance in vivo and 

blocking their emergence may prevent treatment failure. 


Characterization of ipilimumab exposure-efficacy/safety response relationships 

in subjects with previously treated or untreated advanced melanoma. 

Presenting Author: Yan Feng, Bristol-Myers Squibb, Princeton, NJ 

Background: Ipilimumab (IPI) is a fully human monoclonal antibody 

directed against CTLA-4 that is being developed as a novel immunotherapeutic 

agent against melanoma and other solid tumors. The objective of 

this analysis was to retrospectively characterize the exposure-response 

(E-R) relationships for efficacy (overall survival, OS) in subjects with 

previously untreated advanced melanoma (pu-MEL), and safety (immune 

related adverse-events, irAEs) in subjects with previously treated advanced 

melanoma (pt-MEL) or pu-MEL. Methods: The E-R analysis of OS included 

498 pu-MEL from a phase III study (CA184024) of IPI administered at 10 

mg/kg � dacarbazine (DTIC) or DTIC � placebo; and the E-R analyses of 

irAE included 1036 subjects from a phase I study (CA184078), 4 phase 

IIstudies (CA184004/007/008/022) and CA184024 of IPI administered 

at doses of 0.3, 3 or 10 mg/kg. The relationship between steady-state IPI 

trough concentration (Cminss) and OS was described using a Cox proportional 

hazards model, and the relationships between Cminss and incidence 

of irAEs were described by ordinal logistic regression models (separate 

models for any irAE, as well as skin, liver and GI irAE). Results: The risk of 

death decreased with increasing Cminss, and is higher for subjects with 

elevated baseline LDH level. The risk of death was higher for subjects with 

baseline ECOG status � 0 and was higher with increasing stage of disease 

(M1C�M1B�M1A�M0). The hazard ratio for OS corresponding to the 

median Cminss of 49.99 �g/mL was 0.745 relative to subjects in DTIC � 

placebo group. The probability of Grade 2� or Grade 3� GI, skin, liver and 

any irAEs also increases with Cminss. Prior anti-cancer therapy (including 

prior DTIC) or concomitant DTIC were the only significant covariates in the 

E-R irAE models. Conclusions: These model-based analyses suggest that 

higher Cminss of IPI appears to be associated with improved survival in 

pu-MEL (based on data from CA184024) and higher Cminss also appears 

to be associated with increased probability of irAEs in pu-MEL or pt-MEL. 


Gene expression profile signature (DecisionDx-Melanoma) to predict visceral 

metastatic risk in patients with stage I and stage II cutaneous 

melanoma. Presenting Author: Navneet Dhillon, Emory University , Atlanta, 

GA 

Background: The current AJCC TNM staging system has poor specificity for 

predicting visceral metastatic risk in patients diagnosed with stage I or 

stage II cutaneous melanoma. We, therefore, developed a gene expression 

profile signature (GEP) following in silico investigation of previously 

published microarray analyses. Methods: 60 formalin fixed paraffin embedded 

primary cutaneous melanoma samples from patients with stage I or II 

cutaneous melanoma with at least a follow up period of at least 6 years were 

macrodissected and analyzed blindly. RNA was isolated, converted to 

cDNA and RT-PCR was performed to assess the expression of the gene set. 

Expression data and biostatistical analysis was performed using GeNorm 

and JMP Genomics (SAS) Predictive modeling included Radial Basis 

Machine (RBM) and Partition Tree Analysis (PTA) Metastasis-free survival 

(MFS) was assessed using Kaplan-Meier analysis. The following clinical 

data was retrieved from medical records: survival, metastases, types of 

metastases. 20 out of 60 patients had developed visceral metastases in the 

follow up period. Results: GEP was developed following multiple analytical 

approaches.Two types of signatures emerged: Low risk (Class 1) and High 

risk (Class 2). Without optimizing for sensitivity, the analyses of the 60 

sample cohort by radial basis machine (RBM) resulted in 92% ROC (met. 

accuracy � 90%, non-met. accuracy � 85%), while partition tree analysis 

(PTA) yielded 99% ROC (met. accuracy � 100%, non-met. accuracy � 

95%). RBM classification showed 6-year MFS rates of 97% for Class 1 and 

19% for predicted Class 2 of metastasis (median MFS � NR and 5.6 yrs, 

resp., P�0.0001 Log-Rank respectively). PTA showed 6-year MFS rates of 

100% for predicted Class 1 and 14% for Class 2 of metastasis (median 

MFS � NR and 5.4 yrs, resp., P�0.0001 Log-Rank respectively). 

Conclusions: This study shows that DecisionDx-Melanoma GEP signature 

can provide excellent accuracy in predicting metastatic risk in stage I and II 

cutaneous melanoma.To our knowledge, the GEP provides the most 

accurate predictor to date for development of visceral metastases in 

patients with Stage I and II cutaneous melanoma. 



Elucidating distinct tumorigenic pathways in nodular versus superficial 

spreading melanoma. Presenting Author: Joshua Andrew Farhadian, New 

York University School of Medicine, New York, NY 

Background: Superficial spreading melanoma (SSM) and nodular melanoma 

(NM), which account for 70% and 20% of all melanoma diagnoses 

respectively, are believed to represent sequential phases of linear progression 

from radial to vertical growth. Recent evidence from several groups 

including ours challenges this linear progression model and suggests that 

SSM and NM are biologically distinct. In this study, we focused on 

identifying tumorigenic pathways that are differentially activated in melanoma 

subtypes and that can be therapeutically exploited. Methods: We 

performed Protein Pathway Array on SSM/radial growth phase (RGP) and 

NM/vertical growth phase (VGP) primary melanoma cell lines to determine 

expression levels of 141 tumorigenic proteins/phospho-proteins. Differential 

protein expression was determined using the Pavlidis Template 

Matching algorithm in TIGR Multi Experiment Viewer. Differentially expressed 

proteins were validated in an expanded panel of RGP, VGP, and 

metastatic melanoma cell lines using western blot. Constitutively active, 

overexpressed proteins in VGP melanoma were down-regulated in cell lines 

using several small molecule inhibitors and the effects on proliferation and 

migration were assessed. Results: 17 (12%) proteins/phospho-proteins are 

significantly overexpressed in VGP versus RGP melanoma (p�0.05). 

Western blot confirmed the results of 5 proteins/phospho-proteins. Each of 

those 5 was equally overexpressed in VGP and metastatic melanoma cell 

lines. Phospho-p90 ribosomal s6 kinase (RSK) was prioritized for functional 

studies based on its role in both the MAPK and AKT signaling 

cascades, two tumorigenic pathways often dysregulated in melanoma. 

Constitutive phosphorylation of p90 RSK in VGP, but not RGP melanoma 

was observed in response to serum starvation. Small molecule inhibition of 

phospho-p90 RSK attenuated proliferation and migration (p�0.05) in VGP 

melanoma. Conclusions: Data demonstrate discrete tumorigenic pathways 

are activated in nodular versus superficial spreading melanoma and 

suggest that phospho-p90 RSK might be a viable target against nodular 

melanoma. 


BEVATEM: Phase II single-center study of bevacizumab in combination 

with temozolomide in patients (pts) with first-line metastatic uveal melanoma 

(MUM): First-step results. Presenting Author: Sophie Piperno- 

Neumann, Institut Curie, Paris, France 

Background: Overall survival (OS) of MUM pts remains poor. In our 

retrospective series of 470 MUM pts, median OS was 13 months, ranging 

from 3 to 12 and 21 months for best supportive care, systemic treatment 

and surgery groups respectively, stressing the lack of effective therapies in 

this rare cancer. Targeting angiogenesis seems to be promising in uveal 

melanoma. Intravitreal application of antiangiogenic agents is used to treat 

neovascular ocular diseases such as age-related macular degeneration or 

proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth 

and in vivo hepatic establishment of micrometastases in experimental 

uveal melanoma. Preclinical data suggest a potential clinical benefit of the 

combination of dacarbazine and bevacizumab. Methods: Phase II study, 

modified 2-step Fleming plan; with expected 6-month progression-free 

survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 

35 pts are to be recruited for a power of 94% (� and � risk 3 and 6%). After 

the first 17 pts, the study will be continued and another 18 pts will be 

enrolled in the second step if �3 evaluable pts show stable disease or 

response. Primary endpoint: 6-month PFS according to RECIST. Secondary 

objectives: response and survival rates, safety; liver perfusion CT for 

functional imaging of response; impact of VEGF-A gene polymorphisms on 

bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 

150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 

IV infusion, 6 cycles (d1�d28) then Bevacizumab maintenance until 

toxicity or progression. Results: From May 2010 to January 2011, 17 pts 

were enrolled according to the first step of the study: 3/17 achieved disease 

control at 6 months, second step is on going with 26/35 pts already 

recruited. One patient with minor response in liver and lung metastases is 

under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as 

good as expected. Liver perfusion CT study showed decrease in blood flow 

and blood volume before lesion size decrease in one stable patient. 

Conclusions: BEVATEM study in first line MUM pts is on going, showing 

promising results in the first step of 17 pts. 


551s 


Serum IL-6 as a prognostic biomarker in patients with stage IIB-III 

melanoma. Presenting Author: Lise Hoejberg, Department of Oncology, 

Odense University Hospital, Odense, Denmark 

Background: Interleukin (IL)-6 is an immunomodulatory cytokine produced 

by cancer cells and different immune cells. The specific function of IL-6 in 

cancer is unknown. Serum IL-6 is elevated in patients with different types 

of cancer. Elevated serum concentration of IL-6 is related to short survival 

in patients with stage IV melanoma. Methods: IL-6 was measured by ELISA 

(R&D) in pretreatment serum samples from 435 patients with stage IIB-III 

melanoma (151 women and 284 men, median age 51 years, range 18-77). 

After surgery patients were treated in a randomized study (The Nordic IFN 

trial) with either adjuvant interferon for 1 or 2 years, or observation. Results: 

Median serum concentration of IL-6 after surgery and before treatment was 

1.8 ng/l, range 0.23-24 ng/l. Patients with serum IL-6 above the median 

had shorter overall survival (OS) compared to patients with serum IL-6 

below the median (p�0.004). Median OS was 4.5 years in patients with 

serum IL-6 above the median (95% confidence interval (CI): 3.05-7.60). 

In patients with serum IL-6 below the median, median OS was not reached 

at the last survival-update. Multivariate Cox analysis including serum IL-6, 

ulceration in primary melanoma, LDH, white blood cells, lymph node 

metastases and Breslow thickness of primary melanoma showed that only 

serum IL-6 (hazard ratio (HR) � 1.48, 95% confidence interval (CI) : 

1.13-1.94, p�0.004) was an independent prognostic factor for OS. In 

subgroup analysis of the control group and the two treatment groups, serum 

IL-6 demonstrated a negative prognostic impact in the control group (HR � 

1.62, 95% CI: 1.02-2.57, p�0.04) and in the group treated with 2 years 

interferon HR � 1.69, 95% CI: 1.06-2.7, p�0.03). In the group treated 

with 1 year interferon this negative impact was not significant (HR � 1.15, 

95% CI: 0.71-1.85, p�0.58). An interaction between IL-6 and treatment 

arm was not significant (p�0.45), suggesting that the negative prognostic 

effect of elevated pretreatment serum IL-6 is independent of treatment. 

Conclusions: Serum IL-6 above the median is an independent prognostic 

biomarker of short OS in patients operated for stage IIB-III melanoma. 


Phase II study of the anti-ganglioside GD3 mouse/human chimeric antibody 

KW2871 combined with high dose interferon-a2b in patients with 

metastatic melanoma. Presenting Author: Stergios J. Moschos, University 

of Pittsburgh Medical Center, Pittsburgh, PA 

Background: Immunotherapy has demonstrated notable effects in metastatic 

melanoma (MM) with durable responses achieved by high-dose IL-2 

and IFN�2b, leading to approval of these therapies for treatment of 

melanoma. However, complete responses occur in only a minority of 

patients. KW2871 is a chimeric monoclonal antibody (mAb) targeting the 

GD3 ganglioside with demonstrated antitumor activity and enhancement of 

antibody-dependent cell-mediated cytotoxicity (ADCC) and complementdependent 

cytotoxicity (CDC). IFN�2b has potent immunoregulatory, antiproliferative, 

differentiation-inducing, pro-apoptotic, and anti-angiogenic 

properties against a variety of malignancies including melanoma. Combining 

high dose IFN�2b (HDI) � KW2871 was hypothesized to have 

synergistic anti-tumor activity due to (1) the ability of HDI to enhance 

KW2871 induced ADCC in vitro (Liu, Cancer Immun 2002); (2) improved 

mAb targeting due to increased GD3 expression and induced inflammatory 

cytokines (TNF-�, IL-4 and IFN-�) (Hoon, Cancer Res, 1991); (3) increased 

tumor-infiltrating immune cells (Kirkwood, Cancer 2002; Moschos, 

J Clin Oncol 2006). Methods: This is an open label, dose-escalation, phase 

II study of KW2871 plus HDI in patients with measurable MM. Primary 

objectives are progression-free survival (PFS) and safety. Secondary objectives 

include assessment for tumor response by RECIST, ADCC, CDC, 

pharmacokinetics, human antichimeric antibodies (HACA), tumor-infiltrating 

immune cells, biomarkers and OS. Patients with measurable disease by 

RECIST, stable brain metastases, and performance status ECOG 0 or 1 are 

eligible. Patients with severe comorbidities or autoimmune disease or prior 

exposure to anti-GD3 antibodies are excluded. Sequential enrollment to 

cohorts of KW2871 at 5, 10 , 20 mg/m2 IV every 2 week in combination 

with HDI 20 MU/m2 IV once daily x 5 Days for 4 weeks, then 10 MU/m2 SC 

three times weekly until disease progression. Results: To date, Cohort 1 (5 

mg/m2 KW2871) and Cohort 2 (10 mg/m2 KW2871) have been completed 

safely. Cohort 3 (20 mg/m2 KW2871) has enrolled of 18 of 27 planned 

patients. Conclusions: Will be presented at study completion. 




Correlations of molecular alterations in clinical stage III cutaneous melanoma 

with clinical-pathological features and patients outcome. Presenting 

Author: Piotr Rutkowski, Maria Sklodowska-Curie Memorial Cancer Center 

and Institute of Oncology, Warsaw, Poland 

Background: To evaluate frequency and type of oncogenic BRAF/NRAS 

mutations in cutaneous melanoma with clinically detected nodal metastases 

(stage IIIB,C) in relation to clinicopathologic features and outcome. 

Methods: We analyzed 221 patients after therapeutic lymphadenectomy- 

LND (1995-2010) not treated with tyrosine kinase inhibitors and performed 

molecular characterization of nodal metastases in terms of BRAF/ 

NRAS genes (analyzed by sequencing of respective coding sequences). 

Median follow-up time was 53 months. Results: BRAF mutations were 

detected in 139 (63%) cases (127–V600E, 8–V600K, 4-others), mutually 

exclusive NRAS mutations in 35(15.8%) cases (mainly Q61R and Q61K). 

BRAF mutation presence correlated with patients’ younger age(median 52 

vs 60 years for BRAF� vs. BRAF-, p�0.05), metastases in axillary basin 

(p�0.05) and less involved nodes (median 3 vs. 4; p�0.05). 5-year overall 

survival (OS) was 35% and 45% (calculated from date of LND and primary 

tumor excision, respectively); 5-year recurrence-free survival RFS (from 

LND) – 29%. We have not found correlation between mutational status and 

RFS or OS (calculated from date of LND and primary tumor excision) – for 

BRAF mutated-melanomas prognosis was the same as wild-type melanoma 

patients(p�0.26) with even trend for better OS for non-V600E mutants. 

Negative prognostic factors (in univariate and multivariate analysis) for OS 

and RFS were: male gender (p�0.01), metastatic lymph nodes�1 

(p�0.001), nodal metastases extracapsular extension (p�0.001). The 

interval from diagnosis of first-ever melanoma to regional nodal metastasis 

(median-10 months) was not significantly different between BRAF-mutant 

and BRAF wild-type patients (p�0.29). Conclusions: BRAF/NRAS mutational 

status is not prognostic marker in stage III melanoma patients with 

macroscopic nodal involvement, what may have implication for potential 

adjuvant therapy. BRAF status had no impact on disease-free interval from 

diagnosis of primary melanoma to nodal metastases. Our first-ever comprehensive 

molecular analysis of clinical stage III melanomas revealed that 

BRAF-mutants show characteristic clinicopathologic features. 


Early alterations of microRNA expression to predict and modulate melanoma 

metastasis. Presenting Author: Eva Hernando, New York University 

School of Medicine, New York, NY 

Background: Melanoma is curable for most patients whose tumors are 

surgically removed early in disease progression; however, many primary 

melanomas recur and progress to metastasis. Clinical staging is insufficient 

to robustly classify patients at highest risk of recurrence, and prognostic 

molecular biomarkers have not yet been identified. Methods: We performed 

miRNA profiling of 92 FFPE primary melanomas to discover metastasis 

relevant miRNAs and develop predictive models of recurrence, which were 

then validated in an independent cohort. We identified miRNAs differentially 

expressed between primary tumors that did and did not recur (3-year 

minimum follow-up) and between thick and thin lesions. We selected 

candidate miRs for screening in a fluorescence-based in vitro invasion 

assay, and prioritized a subset for in vivo testing. Potential downstream 

mediators of these miRNAs were selected by mRNA array analysis and 

tested in a secondary invasion screen. mRNA candidates that mimicked the 

miR’s invasion-suppressive effect were tested in 3’UTR reporter assays to 

confirm them as direct targets. Results: Using the discovery cohort we 

identified a 20 miRNA signature that can distinguish Stage I/II primary 

tumors (n�70) that did from those did not recur with 3-year minimum 

follow-up with an AUC�94%, 95% CI: (0.88, 0.99). Applying this model 

to predict risk for recurrence in the independent validation cohort yielded 

an AUC � 96%, 95% CI: (0.90, 1) in discriminating recurrent versus 

non-recurrent stages I/ II patients (n�45). From the discovery cohort, 40 

candidates were selected for invasion assay screening, of which 5 miRNAs 

robustly inhibit in vitro invasion in 5 melanoma cell lines. Three miRs 

(miR-382, miR-516b, and miR-7) strongly suppressed metastasis in a 

mouse model. Moreover, multiple mRNAs tested as potential mediators 

mimicked the invasion-suppressive effects of candidate miRs. Of those, 

NCAPG2 and CDC42 were identified as miR-516b targets, CTTN as a 

miR-382 target, and PIK3CD as a miR-7 target. These genes have been 

linked to metastasis in melanoma or other tumors. Conclusions: Our data 

demonstrate that aberrant expression of specific miRNAs at diagnosis is 

predictive of and functionally impacts melanoma progression. 


Ipilimumab in the treatment of uveal melanoma: The Memorial Sloan- 

Kettering Cancer Center experience. Presenting Author: Shaheer A. Khan, 


Background: Ipilimumab (ipi) is an antibody that blocks cytotoxic Tlymphocyte 

antigen-4 (CTLA-4) and improves overall survival in patients 

(pts) with metastatic melanoma. Uveal melanoma (UM) is a rare and 

biologically unique disease subtype with no known effective systemic 

therapy. Ipi has proven efficacy in cutaneous melanoma (CM), but limited 

data exists regarding its activity in UM. We reviewed our single-institutional 

experience with ipi in advanced UM. Methods: After IRB approval, the 

MSKCC melanoma database was queried for patients with metastatic UM 

treated with ipi between 03/08-01/12. Radiographic response by RECIST 

and immune-related response criteria (irRC) was assessed by a single 

radiologist blinded to clinical outcomes. Immune-related adverse events 

(irAEs), survival and absolute lymphocyte count (ALC) were also evaluated. 

Results: 20 pts were identified: the median age was 61yrs (range 46-83), 

55% were male, 85% had liver metastases, 60% had elevated LDH, and 

pts reported a median of 1 prior therapies (range 0-5). Pts received a 

median of 4 doses (range 1-16) of ipi. Response rates (RR) by irRC at 12 

and 24 wks are listed below. Among pts with stable disease (SD) at 12 wks, 

the median time to progression was 30.6 wks (range 19.6-83), with one 

partial response (PR) occurring after 24 wks (overall RR 10%). Responses 

were observed in lung, liver and peritoneal metastases. Pts with an ALC � 

1.0 at 7 wks had a trend toward a higher clinical benefit (CB� CR � PR � 

SD) than pts with ALC � 1.0 (5/12 [42%] vs 0/5 [0%]; p� .09), consistent 

with prior studies in CM. To date, median survival for the group is 8.6 mos 

(95% CI, 3.5-NR), with two ongoing PRs (3� yrs and 24� wks). Reported 

irAEs include rash/pruritis (10/20), hepatitis (1/20), colitis (1/20), pancreatitis 

(1/20) and uveitis (1/20). Conclusions: Ipi has potential for benefit in 

pts with advanced UM; RR and irAE rates are similar to those observed in 

pts with advanced CM. Further evaluation of ipi in the treatment of UM, 

including identification of potential biomarkers of CB, is warranted. 

Immune-related response criteria 12 wks 24 wks 

Stable disease 7/20 (35%) 4/20 (20%) 

Partial response 1/20 (5%) 1/20 (5%) 

Complete response 0/20 0/20 

Clinical benefit 8/20 (40%) 5/20 (25%) 


Targeted agents matched with tumor molecular aberrations: Review of 160 

patients with advanced melanoma treated in a phase I clinic. Presenting 

Author: Haby Adel Henary, University of Texas M. D. Anderson Cancer 

Center, and Department of Investigational Cancer Therapeutics, Houston, 

TX 

Background: Identification of activating mutations in melanoma has increased 

the number of novel targeted agents for this disease. Methods: 

Weretrospectively reviewed clinical outcomes of 160 consecutive metastatic 

melanoma patients (pts) treated in the Dept of Investigational Cancer 

Therapeutics (Phase I program) at M. D. Anderson since 2008, and 

compared their median progression free survival (PFS) to their first and last 

standard systemic therapy PFS. In addition, we compared those pts’ 

outcomes tested for tumor molecular aberrations on a phase I trial with a 

matched targeted agent with those of pts who were treated without regard 

for their molecular profiles. Results: Of 160 pts treated on 35 different 

phase 1 clinical trials, 110 pts (69%) had � 1 molecular aberration. Of 

those pts who had adequate tissue for molecular analysis, 63% (85/134) 

pts had BRAF mutation, 20% (22/109) NRAS mutation, 20% (1/5) GNAQ 

mutation, 11% (1/9) P53 mutation, 2.5% (1/39) PIK3CA and 1.3% (1/76) 

had KIT mutation. 77 (48%) pts were treated on a phase I trial with a 

matched targeted agent and 83 (52%) pts were treated on a non-matched 

phase 1 trial. The overall response rate was 39% (complete response [CR], 

9%; partial response [PR], 30%) in the 77 pts treated with matched 

therapy and 9% (all PRs) in the 83 pts treated without matched therapy (P 

� 0.0018). 139 (87%) pts received at least one systemic therapy before 

referral to phase I, median PFS was longer on phase 1 therapy than on last 

line standard therapy prior to referral to phase 1 (4.2 vs. 2.8 months, P � 

0.002). Median PFS was greater for pts on matched vs. non-matched 

therapy (5.3 vs. 3.7 months, log rank P � 0.004). Also, median PFS was 

longer on phase 1 matched trial than on first standard treatment (5.3 vs. 

3.9 months, log rank P � 0.045).PFS did not differ between first standard 

and non-matched phase 1 study. Univariate analyses with the log rank test 

revealed that matched therapy (P � 0.004) was positively associated with 

longer PFS on phase I clinical trials. Conclusions: Matching melanoma pts 

with targeted drugsbased on specific molecular aberrations in the phase I 

setting can be associated with superior outcomes compared to prior 

standard systemic therapies. 



Positron emission tomography/computed tomography to improve staging 

and restaging in Merkel cell carcinoma. Presenting Author: Elena B. 

Hawryluk, Department of Dermatology, Harvard Medical School, Boston, 

MA 

Background: Merkel cell carcinoma (MCC) is a rare (~1,500 cases per year) 

and highly aggressive (33% mortality) cutaneous neuroendocrine carcinoma 

that occurs in older white patients on the UV-exposed skin of the 

head, neck, and extremities. As a patient’s stage at presentation is a strong 

predictor of survival, and there is a high propensity for locoregional 

recurrence and distant progression, imaging remains crucial for initial and 

subsequent management. There is, however, no consensus on the timing or 

method of imaging for MCC. Methods: We retrospectively reviewed 270 

2-fluoro-[ 18F]-deoxy-2-D-glucose (FDG) positron emission tomography/ 

computed tomography (PET/CT) scans performed in 97 patients at the 

Dana-Farber/Brigham and Women’s Cancer Center from August 2003 to 

December 2010. Results: The mean SUVmax was 6.5 for primary tumors, 

6.4 for regional lymph nodes, 7.2 for distant metastases (all sites), 8.0 for 

bone/bone marrow metastases, and 9.4 for non-regional metastases in 

those patients with no identified primary. PET/CT imaging performed for 

initial management tended to upstage patients with more advanced disease 

(50% of stage IIIB patients). Metastases to bone/bone marrow (12 

patients, 38%) was the 2nd most common site of distant spread after 

non-regional lymph nodes (19 patients, 59%), followed by skin (8 patients, 

25%), liver (6 patients, 19%), lung/pleura (5 patients, 16%), adrenal (3 

patients, 9%), muscle (3 patients, 9%), pancreas (2 patients, 6%), and 

peritoneum (1 patient, 3%). In 10 of 12 patients, PET identified bone/bone 

marrow metastases that were not seen on CT imaging, which resulted in 

either upstaging or initiation of more targeted palliative therapy. Conclusions: 

Added value of PET over CT, such as in the detection of bone/bone marrow 

metastases, may lead to more accurate staging, and thus prognostication, 

as well as earlier detection of relapse and initiation of salvage treatment. Its 

use should be considered in the staging and restaging of MCC. 


Randomized, double-blind, and multicenter phase II trial of rh-endostatin 

plus dacarbazine versus dacarbazine alone as first-line therapy for the 

patients with advanced melanoma. Presenting Author: Jun Guo, Peking 

University Cancer Hospital and Institute, Beijing, China 

Background: rh-endostatin (Endostar, water-soluble, rES) is an inhibitor of 

angiogenesis, which is effective as single agent or in combination with 

chemotherapy for non-small cell lung cancer in phase I/II clinical trials. 

This study (NCT00813449) was a randomized, double-blind and placebocontrolled 

phase II trial, aimed to observe the efficacy and safety of rES 

with dacarbazine (DTIC) as the 1st line therapy for patients (pts) with 

advanced melanoma. Methods: Untreated pts with ECOG 0/1 and unresectable 

stage IIIC or IV melanoma (confirmed by histopathology) were 

enrolled, and randomized (1:1) into Arm A (DTIC 250 mg/m2 d1-5 � 

placebo d1-14) or Arm B (DTIC 250 mg/m2 d1-5 � rES 7.5 mg/m2 d1-14). Treatment was continued in 21-day cycle until progression or intolerable 

toxicity occurs. Primary endpoints were progression free survival (PFS) and 

overall survival (OS). Secondary endpoints included objective response rate 

(ORR) and safety, evaluated every 2 cycles. Results: From Dec. 2008, 120 

pts were enrolled and 110 pts evaluable. 30.9% of them were in M1a, 

39.1% in M1b, and 29.1% in M1c. Mean treatment cycles were 3.2 

(range: 1-10) in Arm A and 4.0 (range: 1-12) in Arm B. Until the last 

follow-up in Nov. 2011, 27 pts were still alive. The median PFS was 1.5 

months (95% CI: 1.35-1.65) in Arm A and 5.0 months in Arm B (95% CI: 

2.45-7.55, P�0.004, log-rank test). The median OS was 7.0 months in 

Arm A (95% CI: 4.41-9.59) versus 16.0 months in Arm B (95% CI: 

10.46-21.54, P�0.003, Breslow test). 1-year survival rate was 22.2% 

versus 51.0%, and 2-year survival rate 8.9% vs.10.2%. No statistical 

significance was found for both ORR and toxicities. The most common 

toxicities were increased transaminase (28.9% in Arm A versus 56.1% in 

Arm B) and leucopenia (14.4% versus 13.4%). The incidence of grade 3-4 

toxicity (increased transaminase and thrombocytopenia) was only 1.7% in 

Arm B. Conclusions: rES plus DTIC may obviously improve mPFS and mOS 

versus DTIC alone as the 1st line therapy for advanced melanoma. That 

combining therapy was well tolerated and could be recommended as a new, 

safe and effective regimen for untreated pts with advanced melanoma. 


553s 


Effect of the BH3 mimetic ABT-737 on human melanoma cells to 

apoptosis induced by selective BRAF inhibitors. Presenting Author: Peter 

Hersey, Melanoma Institute Austrailia, Sydney, Australia 

Background: Although the introduction of selective BRAF inhibitors has 

been a major advance in treatment of metastatic melanoma, approximately 

50% of patients have limited responses including stabilisation of disease or 

no response at all. The present study aims to identify a novel means of 

overcoming resistance of melanoma to killing by BRAF inhibitors. Methods: 

We examined the influence of the BH3 mimetic ABT-737 on induction of 

apoptosis by the selective BRAF inhibitor PLX4720 on a panel of 

melanoma cells with BRAF V600E mutations with or without mutations of 

CDK4 and BRAF wildtype cells with or without NRAS mutations. Included 

in the studies were cell lines established from 4 patients before and during 

treatment with selective BRAF inhibitors. Results: Cell lines with no or low 

sensitivity to PLX 4720 underwent synergistic increases and increased 

rates of apoptosis when combined with ABT-737. This degree of synergism 

was not seen in cell lines without BRAF V600E mutations. Apoptosis was 

mediated through the mitochondrial pathway and was due in part to 

upregulation of Bim as shown by inhibition of apoptosis following siRNA 

knockdown of Bim. Similar effects were seen in cell lines established from 

patients prior to treatment but not in lines from patients clinically resistant 

to the selective BRAF inhibitors. Conclusions: These results suggest that 

combination of selective BRAF inhibitors with ABT-737 or the oral form 

ABT-263 may increase the degree and rate of responses in previously 

untreated patients with V600E melanoma but not in those with acquired 

resistance to these agents. 


BRAF mutation as a pejorative marker in metastatic melanoma. Presenting 

Author: Sophie Brissy, Hopital Timone, Aix-Marseille University, Marseille, 

France 

Background: BRAF mutation in melanoma has been shown to be associated 

with a trend in favour of a spontaneous worse outcome after metastases in a 

series of 197 patients in Australia. Objective: To correlate BRAF status in 

metastatic melanoma with clinicopathologic features and outcome. Methods: 

In our department in France 182 patients with metastatic melanoma have 

been tested for BRAF mutation between September 2009 and September 

2011. Survival was assessed by log-rank test. Multivariate analysis was 

performed with Cox model. Results: From 182 patients, 88 (48.3%) were 

B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other 

mutation subtypes. BRAF-mutant patients were younger than BRAF wildtype 

patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 

years, respectively, p�0.003), and at diagnosis of distant metastasis 

(median age 53.6 vs 64.1 years respectively, p�0.002). 34 patients were 

treated by B-RAF inhibitors. There was no significant difference in other 

demographic features of patients with metastatic melanoma by mutation 

status. Features of the primary melanoma significantly associated with a 

BRAF mutation (p�0.05) were histopathologic subtype (SSM), high 

mitotic rate (�1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 

3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, 

p�0.016), truncal location and location on occasionally exposed at sun 

site.The interval from diagnosis of first ever melanoma to first distant 

metastasis was not significantly different in BRAF-mutant and wild-type 

patients. The median overall survival (OS) from diagnosis of primary 

melanoma was 6.5 years for BRAF wild-type patients. Median OS was not 

reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, 

but also in those not treated (p�0.24, and p�0.06 for treated BRAFmutant 

vs BRAF wild-type). The overall survival from diagnosis of first 

distant metastasis was not significantly different (p�0.75). These results 

remained unchanged in a multivariate analysis. Conclusions: Our results 

confirm the characteristics of BRAF-mutant metastatic patients, and the 

efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is 

per se a pejorative predictive marker. 




Everolimus in combination with paclitaxel and carboplatin in patients with 

advanced melanoma: A phase II trial of the Sarah Cannon Research 

Institute (SCRI). Presenting Author: Ralph J. Hauke, Nebraska Cancer 

Specialists, Omaha, NE 

Background: The PI3k/AKT pathway is activated in most metastatic melanomas; 

mTOR is a critical component of this pathway. Everolimus, an mTOR 

inhibitor, has demonstrated single-agent activity in patients with advanced 

melanoma. We evaluated the efficacy and toxicity of everolimus in 

combination with paclitaxel/carboplatin in patients with advanced melanoma. 

Methods: Eligible patients had stage IV or unresectable stage III 

melanoma, unselected for braf status, previously untreated with chemotherapy 

or targeted agents. Previous immunotherapy was allowed. Additional 

eligibility criteria: ECOG PS 0 or 1; measurable disease; no active 

brain metastases; adequate bone marrow, kidney, and liver function; 

informed consent. All patients received paclitaxel 175mg/m2 , 1-3 hour IV 

infusion, and carboplatin AUC 6.0 IV on day 1 of each 21-day cycle. 

Everolimus 5mg PO was given daily. Patients were evaluated for response 

every 6 weeks; treatment continued until progression or undue toxicity. 

Median progression-free survival (PFS) for paclitaxel/carboplatin treatment 

is 4 months; we looked for a median PFS of 6 months with this novel 

combination. Results: Seventy patients were treated between 2/2010 and 

2/2011; median age 63, 90% had stage IV melanoma. 91% of patients 

received at least 2 cycles of therapy; median cycles received: 4 (range: 

1-25�). Twelve patients (17%) had partial responses; an additional 42 

patients (60%) had stable disease at first reevaluation. After a median 13 

months of followup, the median PFS for the entire group was 4 months 

(95% CI: 2.8 – 5.0 months); 96% had progressed during the first 12 

months. Median survival was 10 months (95% CI: 7.3 – 10.9 months). 

Toxicity was as previously described with these agents; neutropenia was the 

most common grade 3/4 toxicity (27%). Only 3 patients stopped treatment 

due to toxicity. Conclusions: The addition of everolimus to paclitaxel/ 

carboplatin was feasible and well-tolerated; however, efficacy results were 

similar to those reported with paclitaxel/carboplatin alone. Further development 

of this combination regimen for treatment of metastatic melanoma is 

not recommended. 


Patterns of progression in patients (pts) with V600 BRAF-mutated melanoma 

metastatic to the brain treated with dabrafenib (GSK2118436). 

Presenting Author: Mary W. F. Azer, The Crown Princess Mary Cancer 

Centre Westmead, Sydney, Australia 

Background: Dabrafenib has shown efficacy in pts with previously untreated 

brain metastases (BM) but most will progress. We report the pattern of 

disease progression (PD) in pts with either previously treated (surgery (Sx), 

SRS, WBRT) or untreated BM on dabrafenib. Methods: Clinicopathologic 

parameters were collected on 23 pts enrolled in the brain cohort of the 

BRF112680 phase I and BRF113929 phase II BM study of dabrafenib at 

Westmead Hospital between Sept 2009 and June 2011. Pts with RECIST 

PD but ongoing clinical benefit were allowed to continue dabrafenib. 

Results: 12 pts (52%) had previously untreated BM and 11 (48%) were 

previously treated with evidence of progression prior to dabrafenib. Median 

OS from study entry (8.4 mo, 95% CI 5.0-11.8), diagnosis of first BM 

(11.0 mo, 95% CI 9.1-13.0), and stage IV diagnosis (17.5 mo, 95% CI 

12.1-23.0) were not different between the two groups. Similarly, PFS did 

not differ between groups. Of the 19 pts who had RECIST PD at datacut, 13 

pts had intracranial (IC) PD with no pts progressing in new brain lesions 

alone (see table). At IC PD, 3/13 underwent SRS/Sx, 5/13 WBRT and 5/13 

had no salvage local therapy to BM. 8 pts continued dabrafenib beyond IC 

PD, median 36 days; range 28-273. All measures of baseline disease 

burden correlated with worse OS; elevated LDH (HR 1.003, 95% CI 

1.0-1.007, P�0.044), increased number (no.) metastatic sites (HR 1.32, 

95% CI 0.97-1.81, P�0.08), increased no. of IC lesions (HR 1.04, 95%CI 

1.00-1.09, P�0.04), increased no. extracranial (EC) lesions (HR 1.07, 

95%CI 1.02-1.12, P�0.01) and increased RECIST sum of diameters 

(SoD) (HR 1.012, 95% CI 1.003-1.021, P�0.007). High baseline SoD 

was the only factor that predicted worse RECIST response. Conclusions: 

Clinical benefit from dabrafenib does not appear to be influenced by prior 

local therapies to BM. There was no dominant pattern of progression in pts 

with BM on dabrafenib, but PD due to new lesions alone is rare. Pts with IC 

PD may benefit from salvage local therapy and continued dabrafenib. 

Extent and burden of disease correlates with reduced OS, but not RECIST 

response. 

Sites of first RECIST PD 

IC only EC only IC and EC Total 

Existing lesions only 1 5 2 8 

New lesions only 0 0 0 0 

Existing and new 4 1 6 11 

Total 5 6 8 19 


The melanoma risk loci as determinants of melanoma prognosis. Presenting 

Author: Justin Rendleman, New York University Cancer Institute, New 

York, NY 

Background: Genetic risk factors of human cancer emerge as promising 

markers of clinical outcome. The recent melanoma genome-wide scans 

(GWAS) have identified loci associated with the disease risk, nevi or 

UV/pigmentation, but the prognostic potential of these variants is yet to be 

determined. In this study, we performed the first-to-date systematic 

evaluation of the association between established melanoma risk loci and 

melanoma progression. Methods: 891 melanoma patients prospectively 

accrued and followed up at NYU Medical Center were studied. We 

examined the association of 108 melanoma susceptibility single nucleotide 

polymorphisms (SNPs), selected or imputed from recent GWASs on 

melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and 

overall survival (OS). The genotyping was performed using Sequenom 

I-plex. Cox PH model was used to test the association between each SNP 

and RFS and OS adjusted by age at diagnosis, gender, tumor stage and 

histological subtype. ROC curves were used to measure predictive utility of 

SNPs in predicting 3-year recurrence. Results: The strong association was 

observed for rs7538876 (RCC2) with RFS (HR�2.445, 95% CI 1.57 – 

3.8, p�0.0006) and rs9960018 (DLGAP1) with both RFS and OS 

(HR�4.7, 95% CI�2.11-10.43, p�0.0061, HR�1.55, 95% CI�1.11- 

2.17, p�0.0094, respectively) using adjusted multivariate analysis. In 

addition, we identified the classifier with rs7538876 and rs9960018, 

stage and histological type at primary tumor diagnosis, achieving a higher 

area under the ROC curve (AUC�84%) compared to the baseline 

(AUC�78%) in predicting 3-year recurrence. Univariate survival analyses 

have identified associations of several SNPs with ulceration and/or tumor 

thickness. Conclusions: Our data revealed an association between specific 

melanoma susceptibility variants and worse clinicopathological variables at 

the time of diagnosis as well as worse disease outcome. The strength of 

associations observed for rs7538876 and rs9960018 suggest biological 

implication of these loci in melanoma recurrence. The observed predictive 

patterns of associated variants with clinical outcome provide for the first 

time evidence for the potential utilization of genetic markers in melanoma 

prognostication. 


MAGE-A3 expression in patients screened for the DERMA trial: A phase III 

trial testing MAGE-A3 immunotherapeutic in the adjuvant setting for stage 

IIIB-C-Tx melanoma. Presenting Author: John F. Thompson, Melanoma 

Institute Australia, Sydney, Australia 

Background: Administration of MAGE-A3 immunotherapeutic involves the 

active immunization of patients (pts) with tumors expressing the MAGE-A3 

protein. This new investigational approach has been previously assessed in 

two phase II trials, one in pts with metastatic melanoma (NCT00086866) 

and another in pts with completely resected non-small cell lung cancer 

(NCT00290355). Based on the positive responses observed in both 

studies, a randomized phase III placebo controlled trial assessing MAGE-A3 

immunotherapeutic as adjuvant treatment in pts with resected, regionally 

advanced melanoma (stage IIIB-C-Tx AJCC/UICC 2010) is currently ongoing 

(DERMA Phase III trial, NCT00796445). Methods: Formalin-fixed, 

paraffin-embedded tumor tissues were prepared from surgically removed 

metastatic lymph nodes and tested for MAGE-A3 expression by qRT-PCR. 

Other baseline patient and tumor characteristics were collected during 

screening to further investigate factors that could potentially influence 

MAGE-A3 expression. Results: Between Dec 1, 2008 and Oct 25, 2011, 

3917 pts were screened. Of the 3,183 valid samples (excluding the 513 

inconclusive tests [66% for poor quality, 27% out-of range, 7% miscellaneous]) 

and the 221 missing samples, 2,092 (65.7%) were positive for 

MAGE-A3 expression. In these stage III melanoma pts, no difference in 

MAGE-A3 expression levels were identified with regard to (1) disease stage 

- IIIB (62.6%), IIIC (66.5%) and IIITx (66.2%); (2) gender - male (64.2%), 

female (68.1%); (3) age group - 18 to 39 years (63.2%), 40 to 49 years 

(65.3%), 50 to 59 years (66.8%), 60 to 69 years (68.1%) and 70 years 

and over (63.4%) and (4) region: Europe (66.1%), North America (63.0%) 

and rest of the world including Argentina, Brazil, Australia, Mexico, Taiwan, 

Japan, Korea (67.9%). Conclusions: Expression of the MAGE-A3 gene in 

the DERMA trial population (stage IIIB-IIIC-IIITx) was 66%. It was not 

correlated with age, gender, disease stage or geographic region. This 

expression frequency is consistent with published data in metastatic 

melanoma (Van den Eynde, 1997; Vourc’h-Jourdain et al, 2009) and has 

potentially important clinical implications. 



Adjuvant sunitinib in high-risk patients with uveal melanoma: A pilot study. 

Presenting Author: Matias Emanuel Valsecchi, Department of Medical 

Oncology, Jefferson Medical College of Thomas Jefferson University, 


Background: Uveal melanoma is the most common primary intraocular 

cancer in adults. Despite the successful treatments for primary tumors, up 

to 50% of the patients later die of distant metastases. Currently no 

effective adjuvant treatment is available for these patients. Our group 

previously reported that sunitinib stabilized systemic metastases in 65% of 

uveal melanoma patients who failed prior treatments. In this pilot study, we 

tested sunitinib in an adjuvant setting in high-risk patients with primary 

uveal melanoma. Methods: Patients with estimated metastatic death rate � 

50% based on the following criteria were eligible: (1) monosomy 3 and 8q 

amplification; (2) large tumor (� 15 mm in diameter and �7 mmin 

thickness); (3) monosomy 3 and other risk factors (large tumor, epithelioid 

dominant cell type, local recurrence, or extra-scleral extension). Sunitinib 

was given at 25 mg PO daily for at least 6 months. Primary endpoint was 

disease-free survival (DFS) and overall survival (OS), estimated with 

Kaplan-Meier analysis (SPSS 17.0). Secondary endpoint was safety. 

Results: A total of 23 Caucasian patients (median, 54 years; range: 25 – 

77) were enrolled. All patients received sunitinib for at least 6 months 

(range: 6 – 12). Eighteen patients had confirmed monosomy 3, from whom 

13 (72%) also showed 8q amplification. The median follow-up was 24 

months (range 12 – 54 months). Only one patient died of unknown cause 

(OS: 30.4 months). A total of seven patients (30%) developed systemic 

metastases, all of which were liver metastases. The DFS and OS rates at 2 

years were 70% (95% CI: 47 – 86%) and 100%, respectively. The OS rate 

at 2 years was better than historical control with monosomy 3 patients 

(51%, 95% CI: 31 – 71%) (Invest Ophthalmol Vis Sci 2003; 44:1008). In 

those patients who relapsed, the median time to progression after finishing 

sunitinib was 2 months (range: 0 – 8). The most common adverse events 

were: diarrhea (47%), fatigue (39%), dermatitis (30%), stomatitis (13%), 

leucopenia (8%), and nausea (4%). Most were grade 1 or 2 (88%) and only 

one was considered grade 4 (diarrhea). Conclusions: In high-risk uveal 

melanoma patients with estimated metastatic death rate of � 50%, 

adjuvant sunitinib showed promising results and deserves further investigation. 


mTOR pathway activation in KIT-mutated melanoma with acquired imatinib 

resistance. Presenting Author: Lu Si, Peking University Cancer 

Hospital and Institute, Beijing, China 

Background: c-Kit mutation is a common genetic abnormality in certain 

melanoma subtypes, and is a target for treatment. However, the mechanisms 

of secondary (acquired) resistance and how to treat patients in the 

second line are unknown. Methods: Tissuesamples were obtained from 

c-Kit-mutated melanoma patients who failed of imatinib after having PR or 

SD for at least 6 months pre- and post-imatinib therapy. Somatic mutations 

in genes in MAP kinase (c-Kit, BRAF, NRAS, etc) and PI3K-AKT-mTOR 

(AKT1, TSC1, PTEN, etc) pathways were detected by DNA sequencing. The 

expression of pS6RP, p4E-BP1, pAKT and pERK1/2 were examined by 

immunohistochemistry (IHC) assays. Results: Four paired samples (formalinfixed, 

paraffin-embedded) were analyzed. 1) Laboratory results: No secondary 

mutations in addition to the c-Kit mutations identified at baseline were 

identified. However, IHC showed increased pS6RP and p4E-BP1 (two 

targets of mTOR activation) as well as increased pAKT and pERK1/2 in 

imatinib-resistant samples, suggested that mTOR signaling pathway was 

selectively activated in these secondary imatinib-resistant melanomas. 2) 

Treatment: Everolimus is an orally administered inhibitor of mTOR. The 

four patients received everolimus (10 mg/day) by continuous daily dosing. 

The tumor response revealed 1 PR and 3 SD (all �3 months) with grade 1-2 

toxicities consisting of myelosupression, hyperglycemia, hypercholesterolemia 

and hypertriglyceridemia, consistent with previously reported toxicities 

for everolimus. Conclusions: The case series provides an important clue 

that activation of the mTOR signal pathway may be one of the mechanisms 

for secondary imatinib resistance in c-Kit-mutated melanomas. The results 

also show that everolimus may be effective and safe for melanoma patients 

who develop resistance to imatinib and could be investigated in combination 

with c-Kit inhibitors in treatment-naive patients. 


555s 


Association of the activation of the mTOR pathway with prognosis in 

Chinese melanoma patients. Presenting Author: Yan Kong, Peking University 

Cancer Hospital and Institute, Beijing, China 

Background: mTOR is a ubiquitously expressed protein kinase and a 

validated target in the treatment of cancer. However, the characterization 

of mTOR pathway in Asian melanoma populations has not been reported. 

Methods: This study involved primary tumor samples from 173 melanoma 

patients (79 acral melanomas, 57 mucosal melanomas, 17 melanomas on 

skin with chronic sun-induced damage, 20 melanomas on skin without 

chronic sun-induced damage) in Peking University Cancer Hospital & 

Institute. Clinical data were collected. Immunohistochemistry assays using 

antibodies against pmTOR, pS6RP, p4E-BP1 and pAKT were performed on 

formalin-fixed, paraffin-embedded specimens. Somatic mutations within 

the hotspot regions of frequently mutated genes in mTOR pathway (AKT1, 

TSC1, PI3K genes, etc) were analyzed by PCR amplification and Sanger 

sequencing. Results: Among the 173 samples, 26% of the cases (45/173) 

demonstrated positive staining with pmTOR. Expression of pS6RP was 

observed in 37% (64/173) of cases. Expression of p4E-BP1 was observed 

in 27% (46/173) of cases. pAKT was expressed by 22% (38/173) of cases. 

Somatic mutations in examined genes were detected. The median survival 

time for patients with expression of pmTOR was significantly shorter than 

patients with absence of pmTOR expression (25.3 vs 62.9 months, P 

�0.048). In addition, statistical differences were found for ulceration rates 

between melanomas with or without pS6RP (64.1%vs 35.9%, P� 0.049). 

Moreover, the median survival time for mucosal melanoma patients with 

pAKT expression was significantly shorter than for patients with absence of 

pAKT expression (20.4 vs 52.1 months, P �0.022). Conclusions: These 

data demonstrate that activation of the mTOR signaling pathway carries 

prognostic significance in Asia patients with melanoma. Targeted therapies 

to mTOR pathway may offer a therapeutic benefit for these melanoma 

patients. 


Analysis of KIT expression and mutations in sinonasal, genital, and 

acrolentiginous melanomas. Presenting Author: Christian R. F. Bull, 

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland 

Background: Melanoma is subdivided into molecular defined groups. One 

major subtype is characterized by a mutation in the BRAF gene. BRAF is 

less commonly mutated in acrolentiginous (ALM) and mucosal (MM) 

melanomas, instead these subtypes predominantly show aberrations in the 

KIT/CD117 gene. KIT aberrations predict the outcome of targeted therapies 

in ALM and MM patients, however the particular role of KIT expression 

in these melanoma subtypes remains controversial. To explore the relationship 

between KIT expression, mutation, and tumor stages, we investigated 

immunohistochemical KIT expression and mutation status in primary 

ALM/MM lesions and their metastases. We also compared the frequency of 

KIT mutations of MM in different anatomic locations. Methods: KIT 

immunoreactivity and mutation status was assessed in 41 ALM and 25 MM 

patients, using polyclonal rabbit anti-human KIT/CD117 antibody, and 

PCR was performed for KIT gene exons 9,11,13,17 and 18. Of these, 19 

ALM and 15 MM patients had matched primary and metastatic lesions. 

Phosphorylated extracellular regulated kinase (P-ERK) was investigated in 

a subset of 8 ALM and 8 MM matched primary/metastatic pairs by 

immunohistochemistry. Results: Heterogeneous KIT immunoreactivity was 

observed in both primary and metastatic lesions. Mutations were present in 

four of 41 ALM (10%) and five of 25 MM (20%) patients. Only vulvar 

mucosal samples carried KIT mutations in contrast to sinonasal lesions (p� 

0.0109). In KIT-mutated tumors, the mutations were present in KIT 

expressing as well as KIT negative cells, as shown by Laser Capture 

Microdissection (LCM). P-ERK expression was preferentially found in 

metastases. Conclusions: KIT expression is heterogeneous and shows no 

relationship with disease progression and mutation status, therefore KIT 

immunoreactivity is not a valuable marker for treatment decisions. In 

mucosal melanoma patients, KIT mutation frequency is significantly 

associated with anatomic location. Vulvar melanoma patients are prone to 

carry activating KIT mutations and thus may be more likely to benefit from 

KIT-targeted therapies than other subtypes. Therefore, especially vulvar 

melanoma patients should be screened for activating KIT mutations. 




High-risk uveal melanoma: A prospective study evaluating the role of 

magnetic resonance imaging of the liver. Presenting Author: Ernie Marshall, 

Clatterbridge Centre for Oncology, Wirral, United Kingdom 

Background: Almost 50% of uveal melanomas are fatal. Metastatic death 

occurs almost exclusively with tumours showing chromosome 3 loss and 8q 

gain. Metastases, which almost always involve the liver, are resectable in 

some patients. They are rarely detectable when the patient presents with 

the primary ocular tumour. Screening is therefore necessary, but there is no 

consensus as to who should be screened, how often, and for how long. 

Methods: Uveal melanoma patients with ECOG performance status 0-2 

were eligible if their risk of metastatic death at 5 years exceeded 50%. 

Survival probability was estimated by multivariate analysis of tumour stage, 

histological grade and genetic tumour type. Patients underwent screening 

6monthly, clinical examination, non-contrast liver MRI and liver function 

tests for at least five years. Results: Between Jan 2000 and November 

2010, 279 high-risk patients were referred for screening. Of these, 188 

(84 male, 104 female) accepted screening and underwent as least 1 MRI. 

The median age was 63 years (IQR 16.5). Median basal tumour diameter 

was 16.5mm (IQR 5.25). Chromosome 3 loss was detected in 175 

tumours. Median follow up time was 28.8 months (IQR 29.1). Median 

relapse-free survival was 33 months (95% CI 28-38) with a 35% 

relapse-free survival at 5 years. After a median of 18 months (IQR 20), 

screening detected metastases in 90/188 (48%), 83 of whom were 

asymptomatic. 12 patients underwent R0 liver resection, which increased 

the median survival from 10 (95% CI 8.1 - 11.9) to 24 (95% CI 20.2- 

27.8) months. The screening programme stimulated a UK NCRI portfolio of 

clinical trials in which 23 of these patients were subsequently treated. 

Conclusions: Six-monthly liver MRI detects metastases from uveal melanoma 

at an early stage, thereby enhancing opportunities for surgical 

metastatectomy, clinical trial participation and prolonging life. 


Biomarker for benefit from ipilimumab: Correlation of breadth of humoral 

tumor-antigen-specific immunity with outcome. Presenting Author: Sarah 

Ellis, University Hospital Southampton NHS Foundation Trust, Southampton, 


Background: Checkpoint blockade through CTLA4 with ipilimumab has for 

the first time improved survival in patients with advanced melanoma. 

Immune-mediated toxicity and increase in humoral and T-cell anti-NY- 

ESO-1 immune responses after treatment are both linked with benefit. 

However there is currently no broadly relevant, immunological biomarker 

for predicting outcome prior to initiation of therapy. Methods: Using a novel 

immunological assay developed by Serametrix Corporation we analysed the 

presence of antibodies to a proprietary panel of tumour associated antigens 

(TAAs) in 34 patients with advanced melanoma, given ipilimumab at 

3mg/kg as second or subsequent line of treatment. Results: 34 patients 

were consented and analysed, 22 females, 13 males. With a median age of 

63 years median overall survival was 24 weeks; 6/34 patients had an 

objective response to ipilimumab (17.6%, median survival not reached). 

Antibody (AB) responses were tested against the panel of 26 TAAs. This 

panel includes BRAF, Cancer/Testis and other described or novel TAAs. We 

observed a wide range in the incidence and levels of antibody response. 12 

patients had no detectable immunity, 6 an AB response to a single antigen, 

5 AB response to 2, and 11 patients to 3 or more TAA. Five patients had 

either pre-existing anti-BRAF antibodies or developed these after CTLA4blockade. 

Survival was significantly longer in those patients with preexisting 

antibodies to 2 or more TAA, compared to those with 0 or 1 

specificities (median survival 39.4 vs 16.4 weeks p�0.02). Conclusions: 

Patients with advanced melanoma had variable levels of humoral immunity 

to a large number of TAA, including to BRAF. The presence of antibody 

response to 2 or more TAA correlated with longer survival following 

treatment with ipilimumab and appears to provide a biomarker for identifying 

those patients that are most likely to respond to checkpoint blockade 

with ipilimumab. 


MicroRNA alterations associated with BRAF status in melanoma. Presenting 

Author: Michelle W. Ma, New York University School of Medicine, New 

York, NY 

Background: We hypothesize that BRAF mutations result in microRNA 

(miRNA) alterations which contribute to orchestrating the mutant BRAF’s 

oncogenic effects in melanoma. Our study is the first to examine the 

association between the BRAF mutation status in primary melanomas and 

the expression of miRNAs that target known tumor suppressors. Methods: 

84 prospectively accrued melanoma patients at New York University 

Langone Medical Center were studied. DNA and total RNA were extracted 

from consecutive sections of formalin-fixed paraffin-embedded primary 

tissues. BRAF mutation status was determined by DNA sequencing. RNA 

was hybridized to miRCURY miRNA microarrays containing 1314 probes. 

Normalized miRNA data were analyzed using the t-test (p�0.05) to 

identify differentially expressed miRNAs between BRAFmut vs. BRAFwt 

cases. Those with an average fold change (FC) � 2 were selected for 

predicted (TargetScan, PicTar) and validated (miRWalk) gene target 

analysis, and overlapping genes targeted by � 2 miRNAs were analyzed 

using pathway-mapping algorithms (KEGG, BioCarta, PANTHER). Results: 

48 (57%) primaries were BRAFwt and 36 (43%) were BRAFmut (26 

V600E, 4 V600K, 1 V600R, 1 V600D, 4 other). 30 miRNAs met the 

criteria for statistically significant differential expression and FC thresholding: 

let-7i, miR-23c, -26a/b, -27b, -34a, -98, -126*, -141, -148a, -181b, 

-195, -199a-3p, -199a/b-5p, -200a/b/c, -203, -205, -455-3p, -491-3p, 

-606, -641, -646, -1297, -4301; miRPlus-C1070, -C1110, -G1246-3p 

(average FC: 2.3-3.5, all increased in BRAFmut vs. BRAFwt). Predicted 

and validated target gene analysis revealed 317 genes, of which 110 (35%) 

were convergent targets of � 2 miRNAs. Pathway analyses of the predicted, 

validated, and convergent target genes pointed to the potential impact of 

BRAFmut-associated miRNAs on known tumor suppressors FAS, PTEN, 

and TNF and the p53 pathway. Conclusions: Differentially expressed 

miRNAs in BRAFmut vs. BRAFwt primaries target genes with known roles 

in melanoma biology and/or treatment response. These miRNAs warrant 

further study as potential effectors of the BRAFmut oncogenic program. 


A single-arm, open-label, U.S. expanded access study of vemurafenib in 

patients with metastatic melanoma. Presenting Author: Lynn Mara Schuchter, 


Background: Vemurafenib (vem) has been FDA approved for the treatment 

of unresectable or metastatic BRAFV600E mutated melanoma since August 

2011 based on results of a randomized phase III study (treatment-naive) 

and a single arm phase II study (previously treated). We report results of an 

expanded access study that allowed appropriate patients (pts) to receive 

vem until the drug was approved. Methods: Eligible pts had metastatic 

melanoma with a BRAFV600E mutation as detected by the cobas 4800 

BRAF V600 

Mutation Test. Enrolled pts received oral vem 960 mg b.i.d. 

Adverse events (AEs) were evaluated for vem-related toxicities; tumor 

responses were assessed using RECIST 1.1. Results: 29 US sites screened 

745 pts and enrolled 374 from December 2010 until October 2011. The 

following results are based on a median follow up time and treatment 

duration of 2 months. At baseline, mean age of pts was 54 y with 22% of 

pts �65 y; 75% had stage M1c disease; 29% had received radiotherapy for 

brain metastases. 19% of pts were ECOG PS 2 or 3; 71% of pts had prior 

systemic therapy for metastatic melanoma (21% 1 regimen; 50% �2 

regimens). 50 pts had prior adjuvant treatment. At data cut-off, 243 pts 

had sufficient follow-up time for tumor assessment. In this group, the 

unconfirmed overall response rate was 52% (95% CI, 46 to 59). The 

median time to response was 1.8 months. Based on 240 pts with available 

ECOG PS status at time of analysis, response rate was 53% for pts with 

ECOG PS 0 or 1 (n�209), and 45% for pts with ECOG PS 2 or 3 (n�31). 

370 pts were evaluable for safety analysis. The most common vem-related 

AEs were rash (36%), arthralgia (33%) and fatigue (21%) with the majority 

(~90%) of grade 1 or 2. 25 vem-related serious AEs were reported in 5.4% 

of pts with a slightly higher rate of pts with ECOG PS 2 or 3 (8.7%) 

compared to ECOG PS 0 or 1 (4.7%). 18% of pts missed at least one dose 

and 11% of pts required dose reduction of at least one level due to AEs. 

Conclusions: This expanded access study, with its limited follow-up time, 

confirms the established rapid and high tumor response rate with vem. No 

new safety signals were detected. Compared to the overall population, pts 

with an ECOG PS 2 or 3 demonstrated a similar benefit. 



Ipilimumab-induced hypophysitis in melanoma patients. Presenting Author: 

Typhanie Carré, Dermatology Department, Timone Hospital, Aix 

Marseille University, Marseille, France 

Background: Ipilimumab (Ipi) is a human monoclonal antibody directed 

against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for 

the treatment of metastatic melanoma (MM) and currently under investigation 

in the adjuvant setting. Methods: Retrospective analysis of patients 

treated with ipi between June 2006 and September 2011 in our department 

in Marseille. As some patients are still blinded in trials, the exact 

number of patient under ipi is unknown. We present a minimal percentage 

(�%) assuming that the 120 patients received ipi. Results: A total of 120 

patients were treated: 76 stages IV MM, from which 16 in the BMS clinical 

trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III 

MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 

or 10mg/kg IV dosage, while stages III MM were randomly assigned to 

receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 

patients (�10%): 2/76 patients with stage IV MM (�2. 6 %) and 10/44 

patients with stage III MM (�22.7). Diagnosis was performed at the 1st ,3rd and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients 

(33.3%). Clinical symptoms included headaches (n�11; 91.6%), asthenia 

(n�7; 58.3%) and decreased libido (n�2; 1.6%). Adrenal, thyroidal 

and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 

patients (58.3%). MRI changes were observed in 7 patients (58.3%): 

pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement 

in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids 

supplementation was required in 11 patients and thyroidian supplementation 

in 4 patients. Clinical symptoms regressed within one week in 8 

patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only 

if clinicians are aware of these unspecific signs. Only MRI can make 

diagnosis in some patients without clinical and/or biological signs. Our data 

suggest that it develops especially for 10mg/kg dosage, after the third 

administration, and that the rate could be higher in patients with a normal 

immune system (adjuvant treatment), than in metastatic ones. Hormonal 

supplementation usually controls the disease. 


Percutaneous hepatic perfusion (PHP or ChemoSat) with melphalan versus 

best alternative care (BAC) in patients (pts) with hepatic metastases from 

melanoma: A post hoc analysis of PHP-randomized versus BAC-to-PHP 

crossover versus BAC-only pts. Presenting Author: H. Richard Alexander, 

University of Maryland School of Medicine, Baltimore, MD 

Background: PHP (Chemosat, Delcath Systems Inc, New York, NY) allows 

repeated delivery of high dose chemotherapy to the liver while limiting 

unwanted systemic exposure by extracorporeal filtration of hepatic venous 

blood. A prospective randomized multicenter study compared melphalan 

PHP versus BAC in pts with unresectable hepatic metastases from ocular or 

cutaneous melanoma and showed a highly significant advantage for PHP in 

terms of the primary endpoint, hepatic PFS, and multiple secondary 

endpoints. We present an exploratory post-hoc analysis of pts assigned to 

BAC who crossed over to PHP after disease progression (BAC-to-PHP 

crossover) versus those who did not (BAC-only) versus PHP-randomized 

pts. Methods: 93 pts were randomized to PHP (n�44) or BAC (n�49). In 

the BAC group, crossover to PHP with melphalan was permitted after 

hepatic disease progression. Up to 6 PHP treatments with melphalan 3.0 

mg/kg ideal body weight were given every 4–8 weeks. Results: In the BAC 

group, 28 of 49 pts crossed over to PHP. Updated efficacy findings 

(investigator) as of 31 March 2011 are shown in the table. Independent 

Review Committee results were similar to investigator-assessed efficacy. 

Safety in BAC-to-PHP crossover pts was similar to that seen in PHPrandomized 

pts. The most common toxicities in BAC-to-PHP crossover pts 

were hematological: peri-procedural thrombocytopenia (71%) and anemia 

(57%), and melphalan-related neutropenia (82%) and thrombocytopenia 

(79%). Conclusions: Efficacy of melphalan PHP in BAC-to-PHP crossover 

pts was consistent with that seen in PHP-randomized pts with hepatic 

metastases from melanoma. Crossover from BAC to PHP after hepatic 

disease progression led to a median 11-month survival advantage vs BAC 

alone. 

Endpoint 

PHP-randomized 

(n�44) 

BAC-only 

(n�21) 

BAC-to-PHP crossover 

(n�28) 

Median hPFS, months 8.0 1.6 8.8 

HR (crossover vs BAC-only) 0.32 

Median overall survival, months 9.8 4.1 15.3 

HR (crossover vs BAC-only) 0.33 

No. alive (f/u 9.7–53.5 mos) 4 3* 7 

*One patient crossed over but never received PHP. BAC-only pts: chemoembolization, HAI 

nab-paclitaxel, temozolomide. 


557s 


Outcomes of patients with malignant melanoma treated with immunotherapy 

prior to or after vemurafenib. Presenting Author: Allison Ackerman, 

Beth Israel Deaconess Medical Center, Boston, MA 

Background: Treatment of patients (pts) with BRAF mutant malignant 

melanoma (MM) with vemurafenib (vem), a BRAF inhibitor (BRAFi), is 

associated with a high response rate (RR) and improvement in progression 

free survival (PFS) and overall survival (OS) compared to standard chemotherapy. 

Responses to vem are typically not durable and most pts require 

additional therapy. However, there is little data to guide sequencing of vem 

with other standard therapies such as ipilimumab (ipi) or interleukin 2 

(IL-2). Methods: 43 pts treated with vem as part of clinical trials from 

2009-2012 were retrospectively identified. RR of vem was calculated for 

all pts as well as for pts treated with immunotherapy (IT) prior to vem. The 

OS from first systemic and vem treatment, duration of vem therapy, OS 

from when pts came off vem, and PFS and OS for post-vem ipi was 

determined using Kaplan-Meier estimates. Results: Of the 43 pts, 11 

remain on vem and 32 are off vem (19 deceased) with a median follow up of 

19 mo. Pre-vem LDH was elevated in 46% (17/37 evaluable pts). The RR 

to vem was 52% (22/42 evaluable pts), the median duration of therapy 5.6 

months (mo), and the median OS 19.3 mo, similar to results in trials. The 

median OS from initiation of any treatment was 27 mo. 16 pts received IT 

(11 IL-2, 4 ipi, 1 IL-2 then ipi) prior to vem with a median OS of 31.2 mo; 

the RR of vem following IT was 75% (12/16). At time of vem discontinuation 

50% of pts (12/24 evaluable) had an elevated LDH, and the median 

OS of the 32 pts who stopped vem was 4 mo from last vem dose. 10 of these 

pts then received single-agent ipi; six of whom had an elevated LDH. Five 

pts died within 3 mo of last vem dose, and all 10 pts had disease 

progression (PD) at 6 months with a median PFS of 0.7 mo and OS of 2.2 

mo. The 3 pts who lived beyond 1 year following vem and then ipi were 

subsequently treated with a BRAFi following PD on ipi. Conclusions: 

Response to vem following IT appears similar to that seen in previously 

untreated pts. Median PFS and OS for pts receiving ipi after discontinuation 

of vem are poor, possibly due to rapid PD at the time of vem 

discontinuation. Prolonged OS is primarily seen with resumption of BRAF 

inhibition. Our data suggests that in appropriately selected pts, IT should 

be considered prior to BRAFi. 


Tim-3 expression and function in natural killer cells from advanced 

melanoma patients. Presenting Author: Ines Esteves Domingues Pires Da 

Silva, New York University Langone Medical Center, New York, NY 

Background: The concept of CD8 � T cell exhaustion in the context of 

metastatic cancer has been reinforced by the recent success of immunotherapies 

targeting the exhaustion markers CTLA-4 and PD-1 in advanced 

melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker, 

is also expressed in natural killer (NK) cells, however its role is still 

unknown. Recent reports have shown that NK cells, innate immune cells 

that eliminate tumors through cytotoxicity and IFN-g production, are 

functionally impaired in advanced melanoma patients, although no receptor 

has been linked with that phenotype so far. In this study, we 

characterize the role of Tim-3 in NK cells, particularly in the presence of its 

natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted 

by some tumor cells including melanoma. Methods: We compared 20 

advanced melanoma donors NK cells with 40 healthy donors NK cells as it 

relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity, 

IFN-� production and proliferation). NK cells cytotoxicity was measured by 

lamp-1 expression, and two different target cells were used: i) K562 cells 

(Gal-9 - ) and ii) Gmel Gal-9 � and Gmel Gal-9 - sorted melanoma cells. 

Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2. 

Recombinant rhGal9 effect was tested in cytotoxicity and IFN-� production. 

Results: Melanoma patients NK cells express higher levels of Tim-3 

compared to healthy donors NK cells (p�0.05). Melanoma patients NK 

cells have a defect in cytotoxicity, proliferation and IFN-� production. 

Tim-3 expression by itself (without engagement of specific ligands) does 

not negatively affect NK cell functions (p�0.05). However, when rhGal9 is 

added to the system, a decrease in NK cell cytotoxicity and IFN-� 

production (p�0.05) was observed. Finally, the expression of Gal-9 by the 

target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9 � vs Gmel 

Gal-9 - ). Conclusions: These data suggest that advanced melanoma patients 

NK cells are exhausted, although it still remains unclear if Tim-3 is involved 

in this phenotype. In addition,the expression/secretion of Galectin-9, 

immunosuppressive for NK cells, may be a possible mechanism for tumors 

to evade immune surveillance. 




Use of Cobas 4800 BRAF mutation test for the analysis of BRAF V600 

mutations in cytological samples (CS) from metastatic melanoma (MM). 

Presenting Author: Salvador Martin-Algarra, Clínica Universidad de Navarra, 

Pamplona, Spain 

Background: Vemurafenib is currently the most active first-line treatment in 

MM patients that harbor BRAF-V600E mutations. The Cobas 4800 BRAF 

V600 Mutation Test is an FDA-approved, CE-marked test that identifies 

formalin-fixed-paraffin-embedded samples (FFPE) carrying the BRAF V600E 

mutation. Fine needle aspirates are frequently the only samples available in 

MM patients, but the use of CS has not been validated in this platform. We 

have evaluated the capability to identify BRAF-V600E mutations in CS of 

MM with the Cobas 4800 BRAF Mutation Test, and results have been 

compared to the conventional Sanger direct sequencing method. Methods: 

BRAF mutations have been studied in 117 samples from 98 MM patients 

with the conventional Sanger method: 37 (32%) FFPE and 80 (68%) CS. 

DNA was extracted from 4-micron sections in FFPE and from stained 

smears in CS. All CS contained �50% of tumor cells. In a second step, 57 

out of the 117 samples have been studied using Cobas (25 CS and 32 

FFPE). In CS, Nucleospin Tissue (Macherey-Nagel) DNA extraction was 

used in 17 cases and the Cobas procedure in 8. FFPE and CS paired 

samples were available in 9 patients. Results were compared using the 

Kappa coefficient. Results: There was 93% (53/57) agreement between 

Cobas and direct sequencing. All V600E� cases were detected with both 

methods. Four V600R� cases were negative using Cobas. Mean DNA 

concentrations using Nucleospin and Cobas procedures were 55.20 ng/�l 

and 11.37 ng/�l respectively. Concordance using Cobas in FFPE and CS 

paired samples was 100%. The table shows the results with Cobas and 

direct sequencing in 25 CS. One V600R� case was not detected with 

Cobas. Conclusions: The Cobas 4800 BRAF Mutation Test results using CS 

containing �50% of tumor cells are identical to those obtained with FFPE. 

In our experience, DNA concentrations from CS with the Cobas method are 

lower than those obtained with Nucleospin procedure. These results 

provide a strong rationale for a larger validation study. 

Direct sequencing results 

WT V600E V600K V600R Total 

COBAS 4800 system results 

MND 4 0 0 1 5 

V600 0 16 4 0 20 

Total 4 16 4 1 25 

MND: Mutation not detected. 


Development of a melanoma risk prediction model incorporating MC1R 

genotype and indoor tanning exposure. Presenting Author: Lauren A. 

Smith, New York University Langone Medical Center, New York, NY 

Background: Invasive melanoma is the second most common cancer in 

young adults, yet they exhibit poor skin-protective behavior. We previously 

demonstrated a significant association between melanoma risk, melanocortin 

receptor (MC1R) polymorphisms, and indoor ultraviolet light (UV) 

exposure. As existing melanoma risk models do not take these factors into 

account, we investigated whether these variables would improve the 

predictive ability of a clinical risk model, especially in a younger population. 

Methods: We determined MC1R genotype and collected self-reported 

phenotypic and UV (indoor and outdoor) exposure variables from 923 

melanoma cases and 813 healthy controls between ages 25 – 59 from the 

Minnesota Skin Health Study. These data were initially used to develop a 

clinical melanoma risk model (Model A) with conventional risk factors (i.e. 

age; gender; hair, skin, and eye color; mole count, freckling, and family 

melanoma history). We then developed a second model (Model B) combining 

outdoor UV, indoor UV, and MC1R genotype variables with those in 

Model A to determine if the model’s predictive ability improved. Finally, we 

assessed the predictive ability of both models when confined to younger 

subjects (ages 25-35). Results: The clinical model, combining conventional 

melanoma risk factors (Model A), yielded an area under the receiver 

operating characteristic curve (AUC) of 0.72 (95% CI 0.70 – 0.75). 

Incorporating outdoor UV, indoor UV, and MC1R genotype variables (Model 

B) increased the AUC to 0.75 (p�0.001, 0.72 – 0.77). Confining the 

analyses to younger subjects substantially increased the AUC of Model A to 

0.78 (0.72 – 0.84) and Model B to 0.83 (p�0.007, 0.78-0.88). 

Conclusions: This preliminary risk model is the first in melanoma to 

demonstrate that the addition of genotypic data and indoor UV exposure 

results in a measurable increase in predictive ability when compared to 

models comprised only of clinical and outdoor UV exposure variables. The 

enhanced predictive ability of the model (AUC�0.80) when limited to 

younger individuals suggests the potential for developing tools to facilitate 

targeted screening and prevention strategies in melanoma. 


Immunological and biological changes during ipilimumab (Ipi) treatment 

and their correlation with clinical response and survival. Presenting Author: 

Ester Simeone, Unit of Medical Oncology and Innovative Therapy, Istituto 

Nazionale Tumori Fondazione Pascale, Napoli, Italy 

Background: Ipilimumab (Ipi) is approved in the US as first and second line 

therapy in patients with metastatic melanoma (MM) and in MM patients 

with previous therapy in the EU, based on an overall survival benefit shown 

in a phase III study (Hodi, NEJM 2010). To date, no clinical parameter has 

been found to be predictive for response to treatment and only few 

immunologic changes have been identified as potential candidates. Methods: 

From June 2010 to November 2011 we treated in the Expanded Access 

Program with Ipi at 3 mg/kg, 95 pre-treated metastatic melanoma patients. 

The median age was 58 yrs (range 17-84); 10 pts (10,5%) were stage IIIc 

inoperable, 2 pts (2,1%) stage M1a, 4 pts (4,2%) stage M1b, and 79 pts 

(83,2%) stage M1c. 30/95 pts had brain metastases and 1/95 spinal cord 

metastases. All 95 patients were evaluable for response (DCR � 

CR�PR�SD according the irRC), overall survival, safety, including changes 

in LDH, CRP (C-reactive protein) and lymphocyte populations 

(CD4�,CD4CD25�,FOXP3/T-Reg cells). PBMC and sera were collected at 

week 0, 4, 7, 10 and 12. Results: We found a statistical significant 

decrease of LDH, CRP and FOXP3/T-Reg cells (p�0.0001; �2 and 

Mann-Whitney), and an increase of lymphocyte count (p�.0001) in the 

responders group. These differences were also correlated to survival 

(log-rank test). No differences were observed for CD4� and CD4�CD25� 

between responders and non-responders (p�0.39;p�0.83; Mann-Whitney). 

An ORR of 22.1% (1CR�20PR; 95% CI 13.8-30.4) and a DCR at 

week 24 of 37.9% (36/95; 28.1-47.6, 95% CI) were observed. Median 

overall survival was estimated of 7.8 months (95%CI:5.0-10.6), with a p 

value not evaluable at the moment of the analysis due to insufficient 

follow-up because of long-term survival. Adverse events were registered in 

40% (38/95) of patients and the most frequent were of grade 1 and 2 

(pruritus 57.9%; rash 5.3%; thyroditis 5.3%). Conclusions: The decrease 

of LDH, CRP and T-Reg cells during Ipi treatment suggest these parameters 

should be further explored as potential predictive markers for response and 

survival. Given the potential clinical utility of these findings, these data 

warrants further prospective validation in a randomized trial. 


Evaluation of the absolute lymphocyte count as a biomarker for melanoma 

patients treated with the commercially available dose of ipilimumab 

(3mg/kg). Presenting Author: Michael Andrew Postow, Memorial Sloan- 


Background: Ipilimumab (ipi) has demonstrated an overall survival (OS) 

benefit in 2 phase III trials. Only ~30% of patients (pts) achieve clinical 

benefit, and factors that determine which pts benefit are unclear. For pts 

treated with 10mg/kg of ipi, we previously reported that an absolute 

lymphocyte count (ALC) �1000/�L prior to dose 3 [week (wk) 7] was 

associated with improved OS. Since the mean increase in ALC during ipi 

treatment correlates with dose, we investigated if ALC is also associated 

with improved OS at 3mg/kg, the currently FDA approved, commercially 

available dose. Methods: In an IRB-approved analysis, we evaluated 

landmark survival data from 137 pts treated with 3mg/kg of ipi at Memorial 

Sloan-Kettering Cancer Center. 67 pts were treated on an expanded access 

protocol (CA 184-045). 70 pts were treated per FDA approval (commercial 

ipi) with 4 standard induction doses. These 2 groups were analyzed 

separately because some pts in CA 184-045 received re-induction ipi. ALC 

was determined at first ipi dose (baseline, wk 1) and at subsequent doses 

(wks 4, 7, and 10). Results: Pts treated with 3mg/kg on CA 184-045 with a 

wk 7 (prior to dose 3) ALC �1000/�L had significantly improved OS 

compared to pts with an ALC at wk 7 �1000/�L (Median OS: not reached 

vs. 4.24 mos, p�0.001). This OS difference was also seen for pts treated 

with commercial ipi (Median OS: not reached vs. 4.44 mos, p�0.01). This 

difference remained significant in a multivariable model accounting for 

Karnofsky performance score, LDH, M-stage, and number of prior therapies 

for pts in the CA 184-045 group and commercial ipi group (p�0.01 and 

p�0.05, respectively). Baseline ALC �1000/�L was associated with 

improved OS (p�0.02) for pts in the commercial ipi group, though 

follow-up is limited. Conclusions: At the FDA approved dose of ipi, 3mg/kg, 

ALC at wk 7 remains significantly associated with improved OS. Our 

preliminary finding of improved OS for pts treated with commercial ipi 

whose pre-treatment baseline ALC �1000/�L deserves confirmation with 

longer follow-up and prospective validation. Baseline or on treatment ALC 

may be a marker of overall prognosis, regardless of therapy. 



Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies 

as predictive biomarker of response to adoptive therapy in metastatic 

melanoma patients. Presenting Author: Davide Bedognetti, National Institutes 

of Health, Bethesda, MD 

Background: Adoptive therapy with tumor infiltrating lymphocytes (TILs) 

induces objective responses (OR) in approximately 50% of patients with 

metastatic melanoma. The recruitment of TILs through CXCR3/CCR5ligand 

chemokines is believed critical for immune-mediated rejection. 

Here, we investigated the predictive role of a gene-signature based on 

CXCR3/CCR5-ligand chemokine transcripts in pre-treatment melanoma 

biopsies, its biological role and its relation with CCR5-�32 polymorphism, 

which encodes a protein not expressed on cell surface. Methods: Expression 

of CXCR3/CXCR3-ligand transcripts (i.e CXCL9, 10, 11) and CCR5/CCR5ligand 

transcripts (i.e. CCL3, 4, 5) were assessed in 113 pre-treatment 

tumor biopsies from patients enrolled in adoptive therapy trials: 24 

patients achieved a complete remission (CR), 34 a partial remission (PR), 

and 55 did not respond (NR). Copy number variation and gene expression 

profile of these target genes were assessed in 15 biopsy-derived cell lines. 

CCR5-�32 was assessed by sequencing germinal DNA. Results: CXCL9, 10 

and 11 and CCL5 clustered together and were selected for hierarchical 

clustering analysis based on the mean-centered gene expression values. A 

signature characterized by the over-expression of these genes was associated 

with the likelihood to achieve a clinical response (OR rate: PR�CR: 

65% vs 38%, High vs Low, respectively, P�0.015). Neither correlation 

between the copy number variation and the gene-expression of the 

corresponding genes, nor correlation between the transcripts of the 

investigated genes between tumor biopsies and the matched cell lines was 

detected. Transcript expression of the target genes did not differ between 

CCR5-�32 (n �20) and wild type patients (n�93). Conclusions: Coordinate 

over-expression of CXCR3/CCR5 ligands in pre-treatment tumor 

samples was associated with responsiveness to treatment. However, the 

lack of correlation between in vivo and ex vivo data suggest the inflammatory 

status characterized by the up-regulation of these inflammatory 

chemokine genes is an in vivo multifactorial phenomenon. 


Diagnosis of melanoma: Importance of comparative analysis and “ugly 

duckling” sign. Presenting Author: Jean Jacques Grob, Dermatology Department, 

Timone Hospital, Aix-Marseille University, Marseille, France 

Background: “Ugly duckling” (UD) sign is widely admitted as a major sign 

for melanoma (MM) detection. UD is based on the concept of intraindividual 

comparative analysis, which has never been validated. It is 

assumed that, in a given individual, variability of nevi is limited and 

represented by a few similarity clusters (SC) grouping all nevi sharing the 

same pattern, and that a nevus is suspicious when it does not fit with the 

SCs of this individual (UD). Objective: To validate the concept of UD and 

SC. Methods: 9 international experts (dermatologists) and 9 novices 

(untrained individuals) were blindly tested, using digital images of the nevi 

at clinical and dermoscospic scale successively in 80 patients, (2,089 nevi 

and 7 MM). Concordance was assessed by kappa statistics for UDs, and 

B-cubed metrics for SCs. Results: At clinical scale, experts had a better 

concordance for UDs (kappa� 0.53, [0.33 - 0.87]) and SCs (B-cubed � 

0.65, [0.55, 0.73]), than novices (0.31, [0.03, 0.51] and 0.56 [0.49, 

0.64], respectively). Experts identified a mean number of 1 UD and 2.7 

SCs per patient, and agreed on consensual UD and SCs, whatever their 

natural propensity to see a high or a low number of UDs and SCs: among the 

254 nevi considered as UDs by at least 1 expert, 54 were considered as 

such by at least 5, and from them, 20 by all 9 experts. The 20 consensual 

UDs included all the MMs (7/7) (sensitivity for MM: 100%). At dermoscopic 

scale, concordance tended to be lower for SCs than at clinical scale. 

Conclusions: We demonstrated the limited variability of nevi patterns in 

each patient, the consistency in the recognition of UD, and its clinical 

relevance, supporting evidence that it is useful for experts and to a lesser 

degree to general population to spot the skin lesions with the highest 

probability of being MM. 



Rapid rational drug targeting of Merkel cell polyomavirus (MCV)-positive 

Merkel cell carcinoma (MCC) using the survivin inhibitor YM155. Presenting 

Author: Reety Arora, Cancer Virology Program, University of Pittsburgh 

Cancer Institute, Pittsburgh, PA 

Background: MCC is an aggressive, chemoresistant skin cancer causing 

more deaths each year than chronic myelogenous leukemia. We discovered 

a new virus, Merkel cell polyomavirus (MCV), clonally integrated into ~80% 

of primary and metastatic MCC in 2008. To find therapeutic targets for this 

cancer, we examined cellular genes perturbed by MCV infection. Methods: 

Digital transcriptome subtraction was used to discover MCV and also to 

reveal survivin gene (BIRC5) upregulation in virus-positive tumors. MCV T 

antigen knockdown studies in seven MCC lines and large T (LT) transduction 

into BJ fibroblasts were used to confirm this. Drug screening was 

performed in vitro using Cell-Titer Glo assays in a two stage analysis. In vivo 

screening used an MKL-1 (MCV�) MCC NOD-SCIDg mouse xenograft 

model with a single three-week treatment round. Results: MCV large T 

oncoprotein induces survivin transcription through retinoblastoma protein 

sequestration by the LT LXCXE motif. MCV T antigen knockdown results in 

nonapoptotic MCC cell death and loss of survivin expression. YM155, a 

phase II survivin transcription inhibitor, causes MCV� MCC cell necroptosis 

associated with autophagy at 1-12 nM EC50. Of 1359 other drugs from 

LOPAC and NCI Oncology Set II libraries, only bortezomib had in vitro 

potency comparable to YM155. In MKL-1 xenograft studies, mice were 

treated with saline, bortezomib or YM155 for three weeks using standard 

dosings. Bortezomib did not significantly improve mouse survival (33%) 

over saline (24%) during treatment. In contrast, all YM155-treated mice 

survived (100%, p�0.001) the 3 week treatment period. Tumors resumed 

growth once YM155 treatment was stopped suggesting that YM155 is 

cytostatic in vivo rather than cytotoxic. Conclusions: Survivin expression is 

induced by MCV LT and is critical to MCV� MCC survival. A survivin 

inhibitor, YM155 was nontoxic to mice and cytostatic for MCV� MCC 

xenografts. Using genomic technologies, in less than four years, the 

primary viral cause for most MCC was discovered, new diagnostic tests 

developed and a promising rational drug candidate identified. A cooperative 

group trial (E1611) for YM155 and bortezomib in MCC patients is 

currently planned. 


Efficacy and safety of the hedgehog pathway inhibitor vismodegib in 

patients with advanced basal cell carcinoma (BCC): ERIVANCE BCC study 

update. Presenting Author: Aleksandar Sekulic, Mayo Clinic, Scottsdale, 

AZ 

Background: The ERIVANCE BCC study is the pivotal trial of vismodegib 

(GDC-0449), a first-in-class small-molecule inhibitor of Hedgehog signaling, 

for treatment of locally advanced (laBCC) and metastatic BCC (mBCC), 

for whom there are no other effective therapy options. The study met the 

primary endpoint of overall response rate by independent review (Sekulic, 

Melanoma Res 2011). Here we report a 6-mo update of investigatorassessed 

(I-A) efficacy and safety endpoints as of May 26, 2011. Methods: 

This multicenter, international, nonrandomized 2-cohort study enrolled 

patients (pts) with laBCC (deemed inoperable or for whom surgery would be 

significantly disfiguring), and mBCC pts with RECIST-measurable disease. 

Pts received 150 mg oral vismodegib daily. Results: 104 pts (71 laBCC/33 

mBCC) enrolled at 31 sites in the US, Europe, and Australia. I-A efficacy 

endpoints are shown in the table. One-year survival rate was 77.3% (95% 

CI 62.48–92.09%) for mBCC and 93.1% (95% CI 86.49–99.63%) for 

laBCC. Adverse events (AEs) in �30% of pts were muscle spasms, 

alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea 

(33.3%; 2/6 pts). Serious AEs were reported in 32 pts (31%). No 

additional fatal AEs were reported since the prior data cut (n�7, 7%; none 

considered related to vismodegib). Conclusions: This 6-mo update of I-A 

efficacy and safety endpoints from the ERIVANCE BCC study supports the 

significant clinical benefit of vismodegib in both laBCC and mBCC reported 

at the primary analysis. Median DOR and PFS increased numerically with 

follow-up. The AE profile was consistent with the prior data cut. These 

results further support the efficacy of vismodegib for treatment of advanced 

BCC. 

Parameter 

Overall response rate 

(ORR), n (%) (95% CI) 

Median duration of response 

(DOR), mo (95% CI) 

Median progression-free survival 

(PFS), mo (95% CI) 

26 Nov 2010 data cut 26 May 2011 data cut 

mBCC 

(n�33) 

15 (45.5) 

(28.1–62.2) 

(n�15) 

12.9 

(5.55–12.91) 

9.2 

(7.39–NE) 

laBCC 

(n�63) 

38 (60.3) 

(47.2–71.7) 

(n�38) 

7.6 

(7.43–NE) 

11.3 

(9.46–16.82) 

mBCC 

(n�33) 

16 (48.5) 

(30.8–66.2) 

(n�16) 

12.9 

(5.55–NE) 

9.3 

(7.39–16.59) 

559s 

laBCC 

(n�63) 

38 (60.3) 

(47.2–71.7) 

(n�38) 

NE 

(7.62–NE) 

12.9 

(10.22–NE) 




A clinical and translational phase II trial of sequential axitinib and 

carboplatin/paclitaxel in advanced melanoma. Presenting Author: Alain 

Patrick Algazi, University of California, San Francisco, San Francisco, CA 

Background: Several clinical trials adding VEGF signaling inhibitors to 

chemotherapy have not demonstrated any benefit over chemotherapy alone 

in advanced melanoma potentially due to decreased tumor cell proliferation 

induced by VEGF blockade. We tested the hypothesis that sequential 

administration of axitinib followed by carboplatin and paclitaxel may be 

more effective than chemotherapy alone in metastatic melanoma. Methods: 

We conducted a prospective phase II trial of this combination in previously 

treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and 

normal organ function. Axitinib 5 mg PO bid was taken on days 1 through 

14 of each 21-day treatment cycle, and carboplatin (AUC�5) with 

paclitaxel (175 mg/m2 ) was administered on day 1 starting with cycle 2. 

FLT-PET scans were performed on 6 patients to assess tumor cell 

proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has 

been well tolerated. The most common grade 3 AEs have been neutropenia, 

hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs 

have not been observed. 4 of 5 patients completing FLT-PET scans to date 

showed increases (23% to 92%) in SUV values during the axitinib holiday. 

The fifth patient had a single, minimally FLT avid lesion at baseline 

(SUV�1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2 

unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in 

tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD 

as the best response. With a median follow-up of 8.3 months and 17 

patients still active, the median PFS is 6.9 months, and 23 patients (77%) 

are still alive. 26 of 30 evaluable patients have been wild type for 

BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin 

and paclitaxel has been well tolerated and effective in a largely BRAF 

wild-type metastatic melanoma population. Given the urgent need for 

effective therapies in this population, this regimen warrants phase III 

testing. 


Phase I trial of extended-dose anti-PD-1 antibody BMS-936558 with a 

multipeptide vaccine for previously treated stage IV melanoma. Presenting 

Author: Ragini Reiney Kudchadkar, H. Lee Moffitt Cancer Center & 


Background: BMS-936558, a fully human IgG4 anti-PD-1 antibody, has 

shown clinical activity in melanoma and renal cancer. Methods: 30 HLA 

A*0201 positive patients with unresectable, previously treated stage IV 

melanoma received MART-1/gp100/NY-ESO-1 peptides with adjuvant 

Montanide ISA 51 injected subcutaneously with BMS-936558 at 1, 3 or 

10 mg/kg intravenously every 2 weeks for 24 weeks, followed by BMS- 

936558 alone every 3 months. No patient had prior ipilimumab. Endpoints 

were toxicity, correlative studies of immunity measured by ELISPOT and 

T-cell phenotype assays, and response by RECIST. Results: Median age was 

62, with 14 men and 16 women. 73% of patients had M1c disease. One 

patient had dose limiting optic neuritis; one patient had dose limiting grade 

3 interstitial pneumonitis. Of 10 patients at 1 mg/kg, 2 had confirmed 

partial responses (PR), both one year from initiation of study. 13 patients 

were treated at the 3 mg/kg cohort; 3 patients did not complete more than 3 

doses secondary to progressive disease and one withdrew consent. Of 12 

evaluable patients, 3 had confirmed PRs and 2 unconfirmed PRs. In the 10 

mg/kg cohort, thus far 6 patients completed one cycle with 2 unconfirmed 

PRs and one patient stable. Only 2 of the 9 responders after one cycle have 

progressed with a median follow-up of 7 months. 2/6 patients failing 

BMS-936558 responded to ipilimumab. At week 12, patients in all cohorts 

had decreased PD-1 on CD4 and CD8 T-cells (p�0.0001), increased CD4 

CTLA-4 levels (p�0.01) and dose related decreases in CD8 T-cells whereas 

CD4 T-cells increased (both p�0.05). ELISPOT assays showed that 

patients at all doses had no increased responses in fresh PBMC to 

MART-1/gp100, but showed dose related decreased responses to viral 

(CMV, EBV, FLU) peptides over time (p�0.04). Conclusions: BMS-936558 

in combination with a peptide vaccine is well tolerated at 1 and 3mg/kg. 

Accural to the 10mg/kg cohort is on-going. Responses have been observed 

at all dose levels. PD-1 levels on T-cells decreased, and CTLA-4 levels 

increased in CD4 T cells in all cohorts. There was a dose-related decrease in 

CD8 T-cells and in viral-specific T-cells. Further study of BM-936558 is 

warranted to determine its optimal dose. 


Assessment of germ-line and somatic alterations in main candidate genes 

among patients with multiple primary melanoma. Presenting Author: 

Giuseppe Palmieri, Istituto di Chimica Biomolecolare, CNR, Sassari, Italy 

Background: We have studied a series of patients with multiple primary 

melanoma (MPM) for the involvement of the key-regulator genes in 

susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such 

a disease. Methods: Genomic DNA from peripheral blood of 63 MPM 

patients (54 cases with two primary melanomas, 8 with three, and 1 with 

four) were screened for germline mutations in p16CDKN2A and p14CDKN2A genes by automated DNA sequencing. Melanoma families were identified 

according to standardized criteria: 9 (14%) patients were classified as 

familial cases. Paired synchronous and/or asynchronous MPM tissues 

(N�100) from same patients (N�46) were analyzed for somatic mutations 

in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes. 

Results: Overall, 6 (10%) different CDKN2A germline mutations were 

identified: 5 in p16CDKN2A and1inp14CDKN2A . The age of onset was 

significantly lower and the number of primary melanomas higher in patients 

with mutations. CDKN2A mutations were significantly more frequent in 

patients with familial history of melanoma (5/9; 56%) compared with 

patients without (1/54; 2%) (P�0.001), and in patients with more than 

two melanomas (3/9; 33%) compared with patients with only two melanomas 

(3/54; 6%) (P�0.012). The debated A148T polymorphism was found 

at low level (2/54; 4%) in our series. Regarding genetic alterations at 

somatic level, BRAF mutations were identified in 36/100 (36%) primary 

melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was 

observed in 2/88 (2%) and 10/88 (11%) analyzed tissue samples, 

respectively. Considering all types of genetic events, paired samples 

presented a poorly consistent distribution of somatic alterations in same 

patients (52% consistency). Conclusions: Coexistence of MPM and familial 

recurrence of melanoma as well as the presence of more than two 

melanomas seem to be strong indications to address patients to CDKN2A 

mutational screening. The low consistency in genetic patterns of primary 

tumors from the same patients provide additional evidence that pathogenetic 

mechanisms of melanomagenesis are heterogeneous and molecularly 

different cell types may be generated in multiple primary melanoma. 


Surgery for patients receiving ipilimumab: Safety profile and immunological 

insights. Presenting Author: David E. Gyorki, Memorial Sloan-Kettering 


Background: Ipilimumab (ipi), a monoclonal antibody blocking CTLA-4, 

demonstrated survival benefit in metastatic melanoma in two randomized 

controlled trials. With its approval by the FDA, the use of this immunotherapy 

is increasing. The surgical safety of ipi has not been reported. 

Methods: From our prospective database, we identified patients undergoing 

surgery within 30 days of receiving a dose of ipi or on maintenance ipi 

between October 2007 and August 2011. Surgical toxicity was graded 1-5 

by the Clavien classification. In 10 patients matched blood and tumor 

infiltrating lymphocytes were harvested. Phenotype of T cell subsets were 

analyzed by flow cytometry. Results: 23 patients were identified who 

underwent 34 operations a median of 27 weeks after initiation of ipi 

(1-123 weeks). Indications for surgery were symptomatic, progressive, or 

isolated persistent disease in 52%, 39% and 9% respectively. Subcutaneous 

resections were the most frequent, followed by intra-abdominal and 

nodal procedures (Table). Grade 1 wound complications were seen in 17% 

of patients. One patient had a Grade 2 wound complication. No Grade 3-5 

complications were seen. With a median follow up from starting ipi of 86 

weeks, 3 patients have no evidence of disease, 10 are alive with disease 

and 10 have died of disease. Analysis of the T cell infiltrate and peripheral 

blood from 10 patients with progressive or symptomatic disease shows an 

elevated % of CD4 � FOXP3 � T regulatory cells and a 2.8 fold reduction in 

CD8 � / CD4 � FOXP3 � T regulatory ratio in the tumor compared to blood 

(p�0.02). Conclusions: Results from this single-center experience suggest 

that surgery is safe in patients receiving ipi. Immune modulation caused by 

CTLA-4 blockade does not appear to impact wound healing, even in the 

bowel. In carefully selected patients metastectomy may be appropriate for 

breakthrough metastases. The high percentage of T regulatory cells and low 

T effector cells in the progressive tumors suggests a mechanism of immune 

escape. 

Surgical indications. 

Metastectomy site n (%) 

Isolated 

disease 

Progressive 

disease 

Symptomatic 

disease 

Subcutaneous 12 (35%) 2 5 5 

Intra abdominal 11 (32%) 0 7 4 

Brain 5 (15%) 0 0 5 

Nodal 3 (9%) 1 2 0 

Other 3 (9%) 0 0 3 



Correlation of BRAF and NRAS mutation status with tumor characteristics 

and treatment outcomes in melanoma patients with brain metastasis. 

Presenting Author: Eugene J. Koay, University of Texas M. D. Anderson 


Background: The management of melanoma has evolved rapidly with the 

identification of activating mutations in the majority of patients (pts). We 

reviewed characteristics and outcomes of molecularly characterized melanoma 

pts with brain metastasis (BM) to help design and interpret future 

clinical trials. Methods: We reviewed clinical and pathologic features of 

melanoma pts with known BRAF and NRAS mutation status and BM. Pt 

demographics, intra- (IC) and extra-cranial (EC) tumor characteristics, and 

IC/EC disease treatments were correlated to BM treatment outcomes (local 

and distant brain control [LC, DC]) and overall survival (OS). Univariate and 

multivariate analyses were performed to identify significant associations 

between mutation status and outcome. Results: We identified 296 pts with 

melanoma BM and known BRAF/NRAS mutation status diagnosed from 

2005 to 2011. Mutation prevalence was BRAF 57%, NRAS 17%, and 

wild-type for both genes (WT) 26%. The initial treatments given for BM 

were surgery/radiosurgery (SRS) 60%, surgery/SRS � whole brain radiation 

(WBRT) 7%, WBRT alone 19%, systemic therapy alone 9%, and no 

treatment 5%. Mutation status was not significantly associated with sex, 

performance status, EC disease status, number of brain lesions, or BM 

treatment. Pts with mutations were younger (p�0.0001) and more likely to 

have symptomatic BM (p�0.0003) than WT pts. In univariate analysis, BM 

treatment strategy (p�0.001) and mutation status predicted for poor LC, 

with 6 month LC rates of 70% for any mutation and 88% for WT 

(HR�1.86, p�0.048). Compared to systemic agents alone, use of radiation 

(SRS or WBRT) improved LC for pts with a mutation (HR 0.23, 

p�0.0006). Subsequent multivariate analysis identified mutation status 

and radiation treatment as independent predictors of LC (HR 2.5 and 0.25, 

respectively). Mutation status did not predict for DC or OS. Conclusions: 

The presence of BRAF and NRAS mutations predicts worse LC following 

conventional treatments for melanoma BM. Radiation may improve LC in 

pts with a mutation. This data suggest a role for combining radiation with 

targeted therapies in melanoma pts with activating BRAF or NRAS 

mutations in the treatment of BM. 


Clinical experience with atypical spitzoid tumors in patients younger than 

age 18: Does fluorescence in situ hybridization predict lymph node 

metastasis? Presenting Author: Eric J. Stanelle, Memorial Sloan-Kettering 


Background: Determining the malignant potential of atypical spitzoid 

melanocytic proliferations can be diagnostically challenging, and many 

patients are therefore managed as if they had melanoma. However, few 

studies focus specifically on atypical spitzoid tumors (AST). Further, 

cytogenetic analysis using fluorescence in situ hybridization (FISH) has 

been used to determine malignant potential. We reviewed our institutional 

experience to determine staging and clinical outcomes, and the correlation 

between FISH findings and regional nodal positivity in patients with AST. 

Methods: With IRB approval, we retrospectively reviewed all patients aged 

�18 years treated for AST from 1981-2011 to determine staging variables, 

outcome, and the results of 4-probe FISH assay. A total of 44 patients with 

a median age of 11.5 years were identified. All pathology was re-reviewed 

by a single dermatopathologist. Staging was based on 2010 AJCC criteria. 

Correlations were determined using either the Pearson or Spearman 

correlation coefficient. Results: Median lesion thickness was 2.8 mm 

(range: 0.55-12) and eight (18%) lesions met spitzoid melanoma criteria. 

Median followup was 4.1 years for all patients (5.5 years for spitzoid 

melanomas). Thirty-nine patients (89%) underwent sentinel lymph node 

biopsies (SLNB) and 15 (38%) were positive. Lymph node (LN) positivity 

correlated with tumor thickness (p�0.002), stage (p�0.001), and mitotic 

rate (p�0.05). FISH was available for 17/39 patients who had SLNB; 

sensitivity and specificity for LN metastases were 50% and 54%, respectively. 

Of 15 patients with a positive SLNB, 12 underwent completion LN 

dissection, three of which were positive for 1, 2, and 3 additional nodes, 

respectively. There were no recurrences or disease-related deaths. 

Conclusions: Traditional indicators of thickness and stage predicted nodal 

involvement in pediatric patients with AST. However, FISH results did not 

predict nodal status and should not be used to guide management. With 

100% disease specific survival and no recurrences, AST should be 

considered a separate entity from melanoma and complete excision may be 

sufficient therapy. 


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Metastatic basal cell carcinoma: Differences in survival by site of spread. 

Presenting Author: Margaret Elizabeth McCusker, Genentech, South San 

Francisco, CA 

Background: Basal cell carcinoma (BCC), the most common skin cancer, 

rarely metastasizes. Consequently, the epidemiology of metastatic BCC 

(mBCC) is poorly characterized. The largest published mBCC review 

includes 170 cases reported from 1894–1980 (von Domarus H, Stevens P. 

J Am Acad Dermatol 1984;10:1043-60). Targeted therapies with hedgehog 

signaling pathway inhibitors, such as vismodegib, are currently being 

developed to treat this rare disease. The objective of the current analysis 

was to provide an updated description of the epidemiology and survival 

outcomes for mBCC. Methods: A PubMed literature search was conducted 

for mBCC case reports published in English during 1981–2011. mBCC 

cases that met the following criteria were evaluated: primary BCC located 

on skin; primary tumor and metastasis confirmed by pathology, and 

metastasis was not the result of direct tumor spread. Only cases with 

survival data giving dates (month and year) or durations were included in 

the analysis. Differences between groups were assessed with t tests and �2 tests as appropriate. Survival was assessed with Kaplan–Meier (K-M) 

methods. Results: We identified 101 mBCC cases that met the selection 

criteria; 38 patients (38%) had lymph node-only disease (LD) and 63 

(62%) had distant metastases (DM). In both groups, males predominated. 

DM patients were younger at mBCC diagnosis (mean 59 vs 66 y for LD). 

Among 96 cases with treatment data for metastatic disease, more DM 

patients received chemotherapy (25% vs 9% for LD), but more LD patients 

underwent surgery (85% vs 52% for DM). Survival duration ranged from 0 

to 120� months in all patients. The overall 1-y probability of survival after 

mBCC diagnosis was 75.7% (95% CI 67.2–84.2%), with lower survival in 

DM patients (69.1%; 95% CI 57.5–80.7%) vs LD patients (86.5%; 95% 

CI 75.5–97.5%). Conclusions: Patients with LD and DM mBCC may have 

different clinical courses and outcomes. Based on published case reports, 

DM patients were younger at mBCC diagnosis and had a lower 1-y survival 

probability vs LD patients. To our knowledge, these are the first K-M 

survival estimates reported for an mBCC case series of this size. These data 

help to provide a historical context for novel mBCC therapies under 

development, such as vismodegib. 


A phase II, multicenter, open-label study of YM155 plus docetaxel in 

subjects with stage III (unresectable) or stage IV melanoma. Presenting 

Author: Joyce Leta Steinberg, Astellas Pharma Global Development, 

Deerfield, IL 

Background: Survivin is a microtubule-associated protein implicated in 

both preservation of cell viability and regulation of mitosis in tumor cells. It 

is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma. 

YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts: 

Part 1 established the dose of docetaxel that was tolerable in combination 

withYM155 at 5 mg/m2 /day continuous infusion over 168 hours q 3 weeks. 

Part 2 utilized the dose of docetaxel established in Part 1 to further 

evaluate the tolerability and activity of the combination. The primary 

endpoint was 6-month progression-free survival (PFS). Secondary endpoints 

were overall response rate, 1-year overall survival (OS), time from 

first response to progression, clinical benefit rate, time to response, and 

safety. Results: 64 patients with metastatic melanoma were treated with 

docetaxel followed by continuous infusion YM155. 7 patients were treated 

with 100mg/m2 of docetaxel and 57 patients were treated with 75mg/m2 of 

docetaxel. Median age was 59, with 44 men and 20 women treated. 

6-month PFS per Independent Review Committee (IRC) was 34.8% (95% 

CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with 

no complete responses (CR) and 8 patients with partial responses (PR). The 

Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR � 

PR � SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of 

patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to 

either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities 

occurring in greater than 5% of patients treated included neutropenia 

(59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%), 

diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all 

attributable to disease progression. Conclusions: YM155 is a novel agent 

that shows modest activity when combined with docetaxel in patients with 

melanoma. YM155 was generally well tolerated, but the pre-determined 

primary endpoint for efficacy was not achieved. 




KIT, NRAS, BRAF, and PTEN alterations in acral lentiginous melanomas. 

Presenting Author: Abdlsattar Zebary, Department of Oncology-Pathology, 

Karolinska Institute, Stockholm, Sweden 

Background: Acral lentiginous melanoma (ALM) accounts for ~5% of all 

melanomas. ALMs are often located on palms, soles and under nails. 

Patients with ALM are significantly older at diagnosis and have a poorer 

prognosis than patients with other types of cutaneous melanoma. We 

analyzed a large series of ALMs from Swedish patients to better define the 

frequency of KIT, BRAF, NRAS, and PTEN mutations in ALM. The effect of 

mutation status on tumor and patients characteristics was also studied. 

Methods: A total of 77 primary ALMs and 8 paired metastases were 

analyzed. Laser capture microdissection was used to dissect tumor cells 

from formalin-fixed paraffin-embedded tissue. Tumors were screened for 

mutations in the KIT (exons 11, 13, 17 and 18), NRAS (exons 1 and 2), 

BRAF (exons 11 and 15) and PTEN (exons 1, 3-6, 10, 11 and 12) genes by 

direct sequencing. Results: There were 42 females and 35 males with a 

median age at diagnosis of 71 years. The most common location was the 

feet (60.5%), followed by subungual sites (34.2%). Overall, mutations in 

KIT, NRAS and BRAF were detected in 11.8%, 14.5% and 16.0% of the 

ALMs, respectively. In no case were KIT, NRAS and BRAF mutations 

detected in the same tumor. For 8 primary ALMs the corresponding 

metastases were available for analysis. In five metastases the same KIT 

(n�3) or BRAF (n�2) mutation was detected as in the primary ALMs, 

suggesting that the KIT and BRAF mutations had occurred before metastasis. 

BRAF and NRAS mutations were significantly more common in females 

(P�0.044). ALMs with NRAS and BRAF mutations were more commonly 

located on the feet compared with KIT mutated ALMs which were more 

frequent on subungual sites (P�0.041). Other clinicopathological features 

such as age at diagnosis, thickness, ulceration, histological subtype and 

Clark’s level showed no significant correlation with the mutation status. A 

subset of 25 tumors was evaluated for mutations in the PTEN tumor 

suppressor gene. One tumor was found to carry a nonsense mutation 

(W111X). To our knowledge, this is the first description of a PTEN mutation 

in ALM. Conclusions: Our results confirm the presence of KIT, NRAS and 

BRAF mutations in ALM. KIT, NRAS and BRAF mutation status associated 

significantly with anatomical site. PTEN mutations seem to be rare in 

ALMs. 


The impact of immune status on clinical outcomes in patients with Merkel 

cell carcinoma. Presenting Author: Sean Donovan, Mayo Clinic, Jacksonville, 

FL 

Background: Merkel Cell Carcinoma (MCC) is an aggressive cutaneous 

malignancy of neuroendocrine origin associated with immunosuppression 

presumably through infection with Merkel Cell Polyomavirus present in 

�80% of patients (pts). The impact of immune status on clinical outcomes 

in pts with MCC is unknown. The primary objective of this study was to 

compare clinical characteristics and outcomes of pts with MCC who are 

immunosuppressed (ISP) versus non-immunosuppressed (non-ISP). 

Methods: We performed a retrospective chart review on pts with MCC 

diagnosed at the Mayo Clinic between 1981 and 2009. A dermatopathologist 

confirmed all cases. ISP was defined as pts diagnosed with chronic 

lymphocytic leukemia, HIV, solid organ transplant recipients, or chronic 

immunosuppressive medication. The association between ISP status and 

overall survival was summarized using the hazard ratio (HR) and 95% 

confidence interval (CI) estimated from a Cox regression model. Results: Of 

the 268 pts identified and included in the study, 38 (14%) were ISP. We 

found no differences in age, tumor size, tumor location, stage of disease, or 

recurrence rate in ISP vs Non-ISP. Among pts who had Stage 3-4 disease, 

there was no difference in the size of the primary between groups. Among 

pts with Stage 1-2 disease, ISP status was not significantly associated with 

poorer survival (HR 1.5, 95% CI 0.7-3.3). However, among pts with Stage 

3-4 disease, ISP pts had significantly poorer survival compared to non-ISP 

pts (HR 2.7, 95% CI 1.2 - 6.2). Conclusions: Baseline clinical characteristics 

of pts with MCC do not differ based on immunosuppression, and 

outcomes do not differ in pts in regards to immunosuppression in early 

stage MCC (Stage 1-2). However, in pts with Stage III-IV MCC, ISP pts have 

a worse clinical outcome suggesting that metastatic MCC either behaves 

more aggressively in ISP pts either through intrinsic differences in the 

biology of the tumor or improved immune evasion in ISP pts. These results 

should be cautiously interpreted given the small number (n�12) of 

immunosuppressed pts with advanced stage MCC. The authors will update 

their data with an additional 58 patients by the date of presentation. 


TILs in metastatic melanoma tumors: A biomarker for immunotherapy? 

Presenting Author: Sunandana Chandra, New York University School of 

Medicine, New York, NY 

Background: Increased tumor infiltrating lymphocytes (TILs) in primary (P) 

and locoregional melanoma tissue correlate with improved clinical outcome. 

Our recent data have suggested that matrix metalloproteinase 23 

(MMP 23) expression (exp) in P result in lower prevalence of TILs and 

correlate with poor clinical outcome. On this basis, we examined P and 

metastatic (M) melanoma tissues to assess for concordance between the 

presence of TILs, MMP 23 protein levels and clinical response(resp) to 

anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) therapy (tx). Methods: 21 

melanoma patients (pts) with M specimens were analyzed. 17 matched P 

specimens were also evaluated. Immunohistochemical (IHC) staining for 

TILs of the pre-anti-CTLA4 specimens were conducted and confirmed by 2 

pathologists. IHC TILs were graded- 2�: �10% TILs present in multiple 

foci in both peri- and through the tumor; 1�: 1-10% TILs present in one or 

more foci in the tumor and predominantly peri-tumor; 0: no TILs were 

present or if the lymphocytes did not infiltrate the tumor. TILs in P and M 

were analyzed for concordance and potential for predictability of resp to 

anti-CTLA4 tx. Staining to identify lymphocyte subtypes and MMP 23 exp 

in M is being completed. Results: 20 pts received anti-CTLA4 tx. M 

analysis- 6 pts with 0 TILs in M (5 no response [NR], 1 partial response[PR]); 

8 pts with 1-2� TILs in M (1 complete response [CR], 5 PR, 2 

progressive disease [PD]); 6 pts with 2� TILs inM(3CR,2PR,1PD). 1 pt 

with 2� TILs in M resected, no tx and 4 years disease free. TILs present in 

13 P, absent in 4 P and not evaluable in 4 pts with unknown P melanoma. 

MMP 23 protein scores in P (range 2-4) correlated with melanoma 

recurrence. MMP 23 exp in M will be reported. Conclusions: TILs in P do not 

appear to correlate with TILs in M or predict for resp to anti-CTLA4 tx. TILs 

in M may be an indicator of responsiveness to anti-CTLA4 tx. Identification 

of the type of M TIL subsets may further refine tx recommendations. 


Vemurafenib (V) in BRAF V600E metastatic melanoma (mM): Analysis of 507 

patients (pts) enrolled in the French temporary authorization for use (ATU). 

Presenting Author: Celeste Lebbe, Saint-Louis Hospital, Paris, France 

Background: V, a selective BRAF inhibitor, significantly improves OS in BRAF 

mutated mM. ATU is an exceptional measure making available drugs that have 

not yet been granted a Marketing Authorisation. We provide demographic data of 

pts treated by V in the ATU. Methods: V 960 mg BID was given to pts with 

unresectable stage IIIC or IV BRAF V600E mM. Genotyping was done on the 

national network of molecular genetics platforms funded by the Institut National 

du Cancer. Data were prospectively collected. Results: From Apr 2011 to Jan 

2012, 83 sites enrolled 507 pts. 80% were treated by oncodermatologists. Pts 

characteristics at baseline are summarized below. Safety and efficacy data are 

being evaluated. Conclusions: Around 2 out of 3 patients with a BRAF mutated 

mM were enrolled in France in the ATU highlighting a large access to BRAF 

genotyping and to V. Demographic data differs from literature and clinical trials 

for: site of primary melanoma (reverse trunk/extremity ratio) and inclusion of pts 

with brain metastasis or PS�2 (excluded in CT). A high number of pts had risk 

factors for NMSC emphasizing the importance of the communication between 

oncologists and dermatologists for managing V therapy. 

n� 507 

Males (%) 54.8 

Median age (years), range 57 (22-92) 

ECOG PS (%) 

0-1 

2-3 

4 

Site on primary melanoma (%) 

Extremity 

Trunk 

Head /neck 

Occult 

Others 

Mucosal 

86.4 

9.7 

4 

44 

34.7 

11.5 

8.5 

1 

0.2 

Current AJCC stage IV (%) 97 

Mean time from diagnosis of stage IV or unresectable stage III C (months) (range) 4 (0-261) 

Median number of metastatic sites, (range) 3 (1-7) 

Brain metastasis (%) 31.9 

Number of previous therapies for mM ( %) 

0 

1 

>2 

Main previous therapies (%) 

Dacarbazine 

Fotemustine 

Ipilimumab 

Temozolamide 

Previous tyrosine kinase inhibitors (n) 

BRAF inh 

MEK inh 

Epithelial proliferations at baseline (%) 

Actinic keratosis 

Basal cell carcinoma 

Squamous cell carcinoma 

Risk factors for nonmelanoma skin cancer (NMSC) (%) 

Previous radiation 

Past history of NMSC 

BRAF V600E identification method (%) 

Sanger sequencing 

Pyrosequencing 

Allele-specific oligonucleotide PCR 

High-resolution melt 


31.7 

61.8 

6.5 

45.1 

17.9 

10.6 

6.7 

4 

7 

13.8 

3.1 

1.5 

12.4 

14.4 

43.4 

14.8 

12.8 

12.4


Molecular profiling and comparative genomic hybridization analysis in 

human melanoma cell lines and identification of BRAF amplification in a 

PLX4032 acquired resistance cell line. Presenting Author: Erika Maria Von 

Euw, University of California, Los Angeles School of Medicine/Translational 

Oncology Research Laboratory, Los Angeles, CA 

Background: Melanoma is the most aggressive form of skin cancer. Its 

management is evolving rapidly due to an improved understanding of the 

molecular heterogeneity and the development of effective, personalized 

targeted therapies. PLX4032 is a BRAF inhibitor that induces tumor 

response in patients with BRAF mutation whose response is limited due to 

acquired resistance. We used comprehensive microarray and genomic 

analysis to molecularly characterize a panel of melanoma cell lines with the 

goal of identifying new molecular subgroups. To better understand the 

mechanisms of acquired resistance to PLX4032, we included two cell lines 

that were conditioned in vitro to acquire resistance. Methods: Using 

microarray, we studied 52 melanoma cell lines for mRNA expression and 

performed array CGH using genome microarrays. Data analysis was done 

using Rosetta Resolver and Agilent Analytics 4.0 software. Results: Microarray 

analysis suggests melanoma is comprised of at least two distinct 

molecular groups. One group has a differentiated melanocyte phenotype 

and the other has an expression signature characteristic of progenitor-like 

cells. The progenitor-like group expresses SOX9, WNT5A and WNT5B and 

also has the lowest relative expression of MITF. The most differentiated 

group had the highest MITF and SOX5 levels, while the progenitor-like cell 

lines have decreased expression. MITF appears to be a strong candidate 

marker for this group. Positive correlation exists between MITF expression 

levels and gene copy number, as almost all of the MITF samples amplified 

by CHG analysis are also overexpressed. A third group shows strong 

expression of SOX5, SOX10 and Nestin. One of the most important findings 

is M14-R cell line, conditioned to acquire PLX4032 resistance, has a focal, 

high level amplification of BRAF (Log2 ratio � 3, 8-fold amplification) 

when compared with the parental cell line, which is extremely sensitive to 

PLX4032. Conclusions: These results afford new insight into the potential 

pathogenesis and classification and provide a greater understanding of 

melanoma. BRAF amplification could be a novel mechanism of resistance 

to PLX4032. 


A phase IB study of lenvatinib (E7080) in combination with temozolomide 

for treatment of advanced melanoma. Presenting Author: David S. Hong, 



VEGFR1-3, FGFR1-4, RET, KIT and PDGFR�. In phase I studies of 

lenvatinib partial responses were observed in melanoma as well as thyroid, 

endometrial, and renal cancers. Methods: Patients (pts) with stage 4 or 

unresectable stage 3 melanoma were treated in sequential cohorts of 

escalating doses of lenvatinib by continuous once daily dosing and 

temozolomide (TMZ) days 1-5 every 28 days. Cohort 1: lenvatinib 20mg, 

TMZ 100 mg; cohort 2: lenvatinib 24 mg, TMZ 100 mg; cohort 3: 

lenvatinib 24 mg, TMZ 150 mg. Adverse events were recorded according to 

CTCAE v3.0 and tumor response assessed according to RECIST 1.0. 

Results: 32 pts were treated: cohort 1: 6 pts, cohort 2: 4 pts, cohort 3: 22 

pts. Demographics: median age: 58; males: 63%. Dose limiting toxicities 

occurred in 0/6 pts in cohort 3 leading to cohort expansion to a total of 22 

pts to enable more extensive assessment of toxicity and a preliminary 

estimate of efficacy. The most common treatment related adverse events in 

the cohort 3 were fatigue: 50% (gr3: 9%), hypertension: 50% (gr3: 9%), 

proteinuria: 50% (no gr3), vomiting: 46% (no gr3), hypothyroidism: 46% 

(no gr3), anorexia: 41% (no gr3), nausea: 41% (no gr3), diarrhea: 36% 

(gr3: 5%), thrombocytopenia: 32% (no gr3). No treatment-related gr4 

events were reported in these categories. The best overall responses per 

RECIST were partial responses: 5/22 (23%) for cohort 3 pts and 6/32 

(19%) for all pts treated at all dose levels. Six-month progression free 

survival (PFS) rate was 37% and median PFS was 5.4 months. PK/PD 

analysis and correlation of response with genetic mutational status (BRAF 

mutations in 31% pts; NRAS mutations in 19% pts) will be presented. 

Conclusions: Lenvatinib 24 mg once daily in combination with TMZ 150 mg 

days1-5 every 28 days was given without apparent worsening of either 

lenvatinib or TMZ related toxicities. Modest clinical efficacy for this 

combination was observed. 


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Gene expression profiling of whole blood in ipilimumab-treated patients for 

identification of potential biomarkers of immune-mediate gastrointestinal 

adverse events. Presenting Author: Vafa Shahabi, Bristol-Myers Squibb, 

Princeton, NJ 

Background: Treatment with ipilimumab, a fully human anti-CTLA-4 

antibody approved for treatment of metastatic melanoma (MM), is associated 

with a number of immune-mediated Adverse Events (imAEs) such as 

colitis and skin rash. Predictive biomarkers that can help identify patients 

(pts) who might experience these imAEs could enhance the management of 

these toxicities. Methods: Gene expression profiling (using Affymetrix gene 

chip HT-HG-U133A) was performed on the whole blood samples from 162 

MM pts at baseline, 3 and 11 weeks after the start of ipilimumab treatment 

in two phase II clinical trials (CA184004 and -007). Overall, 49 pts 

experienced Grade 2 or higher GI-imAE (G2�) during the course of 

treatment. A repeated measures ANOVA was used to evaluate the differences 

in mean expression levels between the two groups and at the three 

time points. Uncorrected p-value of 0.05 was used as a cutoff for this 

analysis. Results: In baseline samples, 27 probe sets showed differential 

mean expression (� 1.5 fold, p � 0.05) between G2� pts and others. Most 

of these genes belonged to three functional categories: immune system, 

cell cycle or intracellular trafficking. Changes in gene expression over time 

were also characterized. In the G2� pts, 58 and 247 genes had a � 1.5 

fold (p � 0.05) change in expression from baseline to week 3 and 11 

post-treatment, respectively, compared to 17 and 73 in other pts. In 

particular, the on-treatment increases of the expression of CD177 and 

CEACAM1, two neutrophil activation markers, were closely associated with 

G2� GI-imAE, suggesting a possible role of neutrophils in ipilimumab 

associated GI-imAEs. In addition, the expression of several Ig genes 

increased over time, with higher increases in the G2� pts. These observations 

were reproduced in another ipilimumab monotherapy study in MM 

(CA184078). Conclusions: Gene expression profiling of peripheral blood 

resulted in the identification of a set of potential biomarkers that may be 

predictive of severe GI-imAEs before, or early in the course of treatment 

with ipilimumab. Further validation of these biomarkers in a larger patient 

cohort is warranted. 


Patterns of care in adjuvant systemic therapy of patients with stage III 

melanoma: A U.S. population-based study. Presenting Author: Boyu Hu, 

Case Western Reserve University School of Medicine, Cleveland, OH 

Background: Use of adjuvant systemic therapy in patients with stage III 

melanoma is widely known to be variable based upon multiple factors such 

as patient age and comorbidities as well as the preference and even 

geographic location of the oncologist and patient. The purpose of this study 

was to compare the use of adjuvant therapy among patients treated in 

teaching hospitals and community hospitals. Methods: The study population 

consisted of patients with stage III melanoma enrolled into the 

National Cancer Database (NCDB) between 2000-2008. Patients were 

selected based upon surgery as the first course of therapy which resulted in 

a total of 27,353 eligible for analysis. The study population was then 

categorized into those who were treated at Teaching Hospitals (TH) 

including National Cancer Institute-designated cancer centers or Community 

Hospitals (CH). Multiple variables including age, median household 

income, insurance status, race and overall survival were compared between 

patients in the two hospital groups. Results: The overall proportion of stage 

III patients who received adjuvant systemic therapy was approximately 

30%. There was no difference in the proportion of patients receiving 

adjuvant systemic therapy between patients treated in TH as compared to 

CH, and there was no obvious trend towards increased use over time. Of 

interest was that the cohort of patients designated as being treated at TH 

had a higher proportion of patients less than 70 years old as compared to 

CH. Median household income was found to be higher in patients treated at 

TH. Finally, despite the observation that the proportion of patients who 

received adjuvant therapy was not different, there a significantly higher 

5-year overall survival in patients treated at TH as compared to CH. 

Conclusions: Although the proportion of patients who received adjuvant 

systemic therapy was comparable in TH and CH, there was a significant 

increase in 5-year overall survival within TH. Additional factors such as age, 

lesser comorbidities, more favorable socioeconomic factors or other unmeasured 

factors such as type of adjuvant therapy or whether adjuvant therapy 

was completed may have contributed to the improved survival in patients 

treated at TH. 




Detection of BRAF mutations in melanoma: Rate of mutation detection at 

codon 600 using Sanger sequencing as compared to the cobas 4800 

method. Presenting Author: Kevin Z. Qu, Nichols Institute, San Juan 

Capistrano, CA 

Background: Detection of BRAF V600 mutations is currently a prerequisite 

for approved use of vemurafenib in patients with metastatic melanoma. The 

cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics), a 

PCR-based assay approved to aid in selecting patients for vemurafenib 

therapy, primarily detects V600E. It is also reported to detect V600K, 

which has been associated with vemurafenib response as well. We 

compared the mutation detection rate of the cobas assay with that of 

Sanger sequencing. Methods: 125 de-identified FFPE tissues submitted for 

BRAF mutation analysis that all showed histologically-confirmed melanoma 

were tested. BRAF mutations were detected using both the cobas kit 

and bidirectional Sanger sequencing using BigDye kits (Applied Biosystems). 

DNA was extracted from 5-um sections without macrodissection 

using the cobas DNA extraction kit (for the cobas test) or from 5-10-um 

sections using Agencourt extraction kits (Beckman Coulter) following 

macrodissection. Results: The two methods showed agreement in 104/125 

(83.2%) of cases (Table). Sanger sequencing detected V600 dinucleotide 

mutations in 9 samples that were negative by the cobas assay. Sanger 

sequencing produced no results in 10 cases owing to suboptimal PCR, 

including 2 that were positive by the cobas assay. The cobas assay 

produced 2 invalid results, including 1 that was positive for V600E by 

Sanger.The cobas assay detected 7/11 V600K mutations. Conclusions: 

Overall agreement between cobas and Sanger sequencing was 83.2%. The 

Sanger method had higher analytic sensitivity, resulting in nine additional 

V600 mutations not called by cobas compared to the two seen by cobas but 

not Sanger sequencing. Thus, 16% (9/57) more patients would be 

identified as candidates for vemurafenib therapy using the Sanger method. 

Sanger 

sequencing 

Not detected V600E V600K V600R Non-600 No result Total 

Not detected 56 3 a 

4 b 

2 c 

2 d 

7 74 

cobas detected 40 7 2 49 

Invalid 1 1 2 

Total 56 44 11 2 2 10 125 

a 2/3 had dinucleotide mutations (GTG�GAA) and 1 had V600_K601del. b All had 

dinucleotide mutations (GTG�AAG). c Both had GTG�AGG dinucleotide mutations. d 1) 

G469R; 2) E501G. 


Pharmacodynamic activity of selumetinib to predict radiographic response 

in advanced uveal melanoma. Presenting Author: Richard D. Carvajal, 


Background: Functionally activating mutations (mut) in Gnaq or Gna11, 

genes that encode for widely expressed G-protein alpha subunits, are early 

oncogenic events in uveal melanoma (UM) development and result in 

activation of the MAPK pathway. We previously demonstrated effective 

pathway inhibition with selumetinib (AZD6244, ARRY-142866) in UM cell 

lines, with decreased viability associated with pERK and cyclinD1 suppression 

(Ambrosini, AACR 2010). Methods: Using paired metastatic tumor 

biopsies from patients (pts) with radiographically progressing UM treated 

with selumetinib 75 mg BID on a phase II trial (NCT01143402), we 

correlated MAPK pathway inhibition with radiographic tumor regression 

and clinical benefit. Biopsies were performed at baseline and after 14 �/-1 

days of treatment. Western blotting was performed for pERK and cyclinD1, 

and quantitated by densitometry. Response (RECIST 1.1) was assessed at 

baseline, week (wk) 4, wk 8, and q8wks subsequently. Radiographic 

regression was defined as greatest percentage shrinkage from baseline. 

Clinical benefit was defined as RECIST response or stable disease �16wks. 

Results: Paired tumor biopsies were assayed from 18 pts: median age 60 

(range 47-81), M:F 11:7, median 1 prior therapy (range 0-2), 17 with liver 

involvement, Gnaq mut:Gna11 mut:wild-type 8:9:1. Radiographic regression 

was observed in 5 pts, with 2 achieving partial responses. 4 pts were 

on study �16wks (16�, 20, 25, 31 wks), with one currently on study at 

11� wks. Median pERK and cyclinD1 as measured by densitometry 

decreased by 48% (p�.03) and 76% (p�.03), respectively. Radiographic 

regression correlated with suppression of pERK (Spearmen’s rank correlation; 

p�0.04) but not cyclinD1 (p�0.38). A trend towards pERK suppression 

correlating with clinical benefit was observed (p�.07) with each of the 

5 pts achieving PR or SD �16wks having a decrease of �30% in pERK 

from baseline. Conclusions: Selumetinib can inhibit pERK and cyclinD1 in 

UM and can result in tumor shrinkage. Sustained inhibition of pERK 

inhibition at day 14 may be predictive of benefit. Further evaluation of MEK 

inhibition in this disease is warranted. 


MicroRNAs induced in melanoma treated with combination targeted 

therapy of temsirolimus and bevacizumab. Presenting Author: Aubrey G. 

Wagenseller, University of Virginia, Charlottesville, VA 

Background: Targeted therapies directed at commonly overexpressed pathways 

in melanoma have clinical activity in numerous trials. Little is known 

about how these therapies influence microRNA expression, particularly 

with combination regimens. A better understanding of how microRNAs are 

altered with treatment may contribute to understanding mechanisms of 

therapeutic effects as well as mechanisms of tumor escape from therapy. 

Methods: Using microRNA arrays, we analyzed microRNA expression levels 

in melanoma samples from a Cancer Therapy Evaluation Programsponsored 

phase II trial of combination temsirolimus and bevacizumab in 

stage III or IV melanoma, which elicited clinical benefit in a subset of 

patients. Seventeen patients were treated with temsirolimus for one week, 

then combination of both temsirolimus and bevacizumab. Metastatic 

melanoma biopsies were evaluated days 1, 2, and 23. Tumor samples were 

evaluated from 12 patients. Results: microRNA expression remained 

unchanged with temsirolimus alone; however, expression of 15 microRNAs 

was significantly upregulated (1.4 to 2.5-fold) with combination treatment, 

compared to pre-treatment levels. Interestingly, twelve of these fifteen 

microRNAs have been reported to possess tumor suppressor capabilities in 

various cancer types, including melanoma. We identified 15 putative 

oncogenes and B7-H3, IGF-1, and IGF-1R as potential targets of the 12 

tumor suppressor microRNAs, based on published experimental evidence. 

For 18 of 25 pairings of microRNA and target-mRNA, changes in gene 

expression from pretreatment to post-combination treatment samples were 

inversely correlated with changes in microRNA expression, suggesting a 

functional effect of the microRNA changes induced by combination 

therapy. Clustering analysis based on selected microRNAs revealed signatures 

characteristic of clinical response to combination treatment and of 

tumor BRAF mutational status. Conclusions: We have identified microRNAs 

that may be involved in the mechanism of action of combination temsirolimus 

and bevacizumab in metastatic melanoma, possibly through inhibition 

of oncogenic pathways. 


Exhibition of a stem-cell like phenotype with the expression of CD271 in 

drug-resistant melanoma cells. Presenting Author: Elizabeth Ann Teresa 

Lieser, Mayo Clinic, Rochester, MN 

Background: Chemotherapy resistance is a common, difficult problem for 

melanoma patients needing long term care and those suffering from 

recurrence. Neural growth factor receptor (NGFR), also known as CD271, is 

commonly expressed on mesenchymal stem cells and is important for 

development, survival and differentiation of cells. This has previously 

shown to be expressed on melanoma stem cells. We hypothesized that 

treatment with carboplatin enriches the population of tumor cells for 

cancer stem cells (CSC) as a mechanism of chemotherapy resistance. 

Methods: Core tumor samples from 118 patients with metastatic melanoma 

were obtained from formalin-fixed paraffin embedded specimens. Slides 

were stained using an anti-CD271 antibody for IHC. A375 melanoma cells 

were treated with increasing concentrations of carboplatin for approximately 

1 year. WT, 6 mg/mL and 10 mg/mL resistant cells were tagged with 

CD271-PE antibody and run on a flow cytometer. These cells were then 

tested for gene expression by microarray using an Affymetrix human 133 

plus 2.0 chip, and analyzed on Partek software. Pathway analysis of these 

carboplatin resistant cells was preformed using Ingenuity. Results: Virtually 

all melanoma tumor samples stained positively for CD271 by IHC, with a 

median of 50% cells within tumor samples expressing the cytoplasmic 

marker. Flow cytometry demonstrated an increase in the percentage of cells 

expressing CD271 as resistance to carboplatin increased. Wild type A375 

cells contained 30% positive CD271, A375 6mg/mL resistant contained 

42% positive and A375 10mg/mL resistant showed 66% positive. Microarray 

also exhibited a direct correlation between CD271 gene expression with 

increasing carboplatin resistance. Functional ontology enrichment revealed 

development and regulation of the EMT pathway as an important 

process impacted by our resistant cell line. Conclusions: The data suggests 

that as melanoma cells become resistant to certain chemotherapy drugs 

they essentially loose their differentiated phenotype and become more 

stem cell-like. Monitoring melanoma expression of CD271 could help 

individualize therapy and anticipate chemotherapeutic resistance in this 

high-risk group of patients. 



Preoperative peripheral blood lymphocyte/monocyte ratio and survival in 

patients with resected stage IV melanoma. Presenting Author: Nicole M. 

Rochet, Mayo Clinic College of Medicine, Rochester, MN 

Background: The prognosis of stage IV melanoma patients remains poor. 

Published results have suggested that components of the complete blood 

count have significant prognostic value in several malignancies. Among the 

most studied were the absolute lymphocyte count (ALC), and absolute 

monocyte count (AMC) on clinical outcomes of patients with lymphoid 

malignancies. Thus, we sought to investigate if the pre-operative ALC 

(ALC-PO), AMC (AMC-PO) and ALC/AMC ratio (ALC/AMC-PO) affects the 

risk of disease recurrence and survival after complete surgical resection of 

metastatic melanoma. Methods: We studied 66 stage IV, resected melanoma 

patients followed at Mayo Clinic from 2000 to 2010. Log rank 

chi-square analysis was used to determine the best cut-off values for each 

pre-operative variable, while proportional hazards models were used to 

compared survival. Results: The median follow-up of the cohort was 24 

months (range: 2.3 – 117 months). ALC-PO, AMC-PO and ALC/AMC-PO, as 

continuous variables, were all identified as prognostic factors for both 

relapse-free survival (RFS) and overall survival (OS). The best cut-off values 

for ALC-PO, AMC-PO and ALC/AMC-PO were 1.9; 0.62; and 2.05, 

respectively. Using Kaplan-Meier analysis, patients with an ALC-PO � 1.9 

x109 /L experienced superior OS and RFS compared with ALC-PO � 1.9 x 

109 /L patients [median OS of 58 months vs. 34 months, p � 0.04; median 

RFS of 14 months vs. 5 months, p � 0.009]. Conversely, a low AMC-PO 

(�0.62 x 109 /L) was associated with better OS and RFS compared with 

higher AMC-PO (� 0.62 x 109 /L): [median OS of 47 months vs. 14 months, 

p � 0.007; median RFS of 9 months vs. 5 months, p � 0.02]. When the 

ALC-PO and AMC-PO were combined as an ALC/AMC ratio, the group with 

an ALC/AMC-PO � 2.05 experienced a superior OS and RFS compared to 

patients with ALC/AMC-PO � 2.05: [median OS of 49 months vs. 12 

months, p � 0.0001; median RFS of 10 months vs. 4 months, p � 

0.0001]. Multivariate analysis showed ALC/AMC-PO to be an independent 

prognostic factor for RFS and OS (HR � 0.32, p � 0.003; HR � 0.23, p � 

0.002). Conclusions: Our study showed, that ALC/AMC-PO ratio is an 

independent prognostic factor for RFS and OS in patients undergoing 

resection of metastatic (stage IV) melanoma. 


A phase I/II trial of BKM120 combined with vemurafenib (PLX4032) in 

BRAFV600E/k mutant advanced melanoma. Presenting Author: Andrea 

Kantor, University of California, San Francisco, San Francisco, CA 

Background: Vemurafenib induces transient objective responses in half of 

BRAFV600E mutant melanoma patients and a median PFS of 5.3 months 

(NEJM. 2011;364:2507-2516). BRAF mutations are not sufficient to 

cause melanoma, but the combination of BRAFV600E mutation and PTEN 

loss is sufficient to recapitulate the malignant melanoma phenotype in vivo 

(Nat. Genet. 2009;41:544-552). PTEN loss and PI3K activation are 

common in BRAF mutant metastatic melanoma, and PI3K activation has 

been implicated as a cause acquired resistance to BRAF inhibitors (Cancer 

Cell. 2010;18:683-695). This phase I/II study is the first trial to test the 

safety and efficacy of combining a potent BRAF inhibitor, vemurafenib, 

with a potent PI3K inhibitor, BKM120, in patients with metastatic BRAF 

mutant melanoma. Methods: Design: Phase I patients receive a single dose 

of oral BKM120 (d -7) then vemurafenib twice daily with BKM120 daily 

(starting on c1d1). PK analysis is performed for BKM120 alone and for 

both drugs in combination. Doses of both drugs will be escalated in 3�3 

scheme. Phase II patients receive continuous dosing of vemurafenib twice 

daily and BKM120 daily. Serial biopsies for PD and mRNA expression 

analyses are required for patients with visible or palpable tumors. Reimaging 

will be performed every 8 weeks.Eligibility: This study is enrolling 

BRAFV600E/K mutant metastatic melanoma patients with no prior exposure 

to BRAF inhibitors or PI3K inhibitors, ECOG PS � 2 and adequate organ 

function. Endpoints: The primary endpoint for phase 1 is the recommended 

phase 2 dose of the combination. The primary endpoint for phase II is the 6 

month PFS rate. Secondary endpoints include median PFS and OS. 

Baseline PTEN expression and changes is pS6 protein levels will be 

examined as predictors of efficacy, and changes in gene expression profiles 

will be assessed. Summary: This is the first trial examining the safety and 

efficacy of combined BRAF/PI3K inhibition in BRAF mutant melanoma 

patients. 


565s 


Comparison of sun protection modalities in parents and children. Presenting 

Author: Laurent Mortier, Clinique de Dermatologie, CHRU de Lille, 

Lille, France 

Background: Routine sun protection is recommended to prevent skin 

cancer. Our aims were to examine and compare, in an observational survey, 

modalities of sun protection in parents and their children. Methods: This 

French nationwide observational survey, EDIFICE melanoma, was conducted 

through phone interviews among a representative sample of 1502 

subjects aged � 18 years old, using the quota method. The survey took 

place shortly after summer, from 28 Sep 2011 to 20 Oct 2011. Results: 

1502 subjects were interviewed. Among them 1067 reported that they 

were sun-exposed (SE) at least ten days per year, 748 were parents, and 

319 had no children. Sun protection measures seemed well done both in 

“parents” and “nonparents” groups: 74% used clothing; 43% used 

sunscreen, which was regularly renewed in 57% of cases. Sun protection 

measures used by SE parents for SE children were superior, both qualitatively 

and quantitatively to those used for themselves, ie 50% of parents 

reported using clothing, sunglasses and hat for their children vs 23% for 

themselves. In 87% of cases, parents reported regular re-application of 

sunscreen for their children vs 44% for themselves. The sunscreen SPF 

(Sun Protection Factor) was significantly lower for parents than for their 

children. Such data are in accordance with Buller et al. (Oncol Nurs Forum 

1995), but contrast with the findings of Riordan et al. (J Pediatr 2003) with 

children being significantly less likely to wear sunglasses and to adopt sun 

avoidance habits than their parents. Conclusions: Sun protection awareness 

seems globally satisfying in the French population, with no difference 

between adult parents and nonparents, and is similar to that reported in 

Germany (Gambicher JEADV 2010), but seems better than in the US 

(Buller et al. JAAD 2011). Furthermore, French parents use sun protective 

measures qualitatively and quantitatively more efficiently for their children 

than for themselves. 


CA184-161: A phase I/II trial of vemurafenib and ipilimumab in patients 

with BRAF V600 mutation-positive metastatic melanoma. Presenting 

Author: Antoni Ribas, University of California, Los Angeles, Los Angeles, 

CA 

Background: Ipilimumab (ipi) is a fully human monoclonal antibody that 

blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor 

immune responses. Ipi significantly improved overall survival (OS) in two 

separate phase III trials of metastatic melanoma (MM): (1) at 3 mg/kg as 

monotherapy in previously treated patients and (2) at 10 mg/kg combined 

with dacarbazine in previously untreated patients. The most common 

drug-related adverse events with ipi were immune-related, and were 

generally reversible using treatment guidelines. Vemurafenib (vem) is a 

potent inhibitor of BRAF V600E-mutated kinase, which occurs in ~50% of 

MM. In clinical studies, vem produced objective response rates of ~50% 

with a significant improvement in the rate of OS in patients with previously 

untreated BRAF V600-positive MM. The purpose of this phase I/II study is 

to determine the safety and feasibility of ipi plus vem in patients with BRAF 

V600-positive MM, and to evaluate the efficacy of the combination in 

comparison to historical results observed with each agent alone. Methods: 

In phase I, an escalating dose design is used to assess safety/tolerability 

and to determine the maximum tolerated dose (MTD) of each agent. Vem 

will initially be given alone for 28 days at 960 mg p.o. BID, followed by vem 

in combination with ipi i.v. at 3 mg/kg [induction (q3w x 4) and 

maintenance (q12w)]. The next cohort will receive vem at 960 mg plus ipi 

increased to a dose of 10 mg/kg. Phase I will enroll an estimated 20 

patients who have not previously received a CTLA-4 antagonist or BRAF 

inhibitor. If new or heightened frequency or severity of toxicities is not 

observed, a phase II single-arm extension at the MTD of each agent will be 

conducted in patients with previously untreated MM. The primary objectives 

of phase II (estimated enrollment of 30 patients) are to obtain 

preliminary evidence of efficacy (OS, 1- and 2-year survival rates) and to 

evaluate safety of the combination. Major inclusion criteria are � 18 years 

of age, BRAF V600-positive MM, measurable tumor, no active brain 

metastasis, and an ECOG PS of 0-1. The first patient was enrolled in 

November 2011 and enrollment is ongoing (ClinicalTrials.gov identifier: 

NCT01400451). 




OPTiM: A randomized phase III trial to evaluate the efficacy and safety of 

talimogene laherparepvec (T-VEC) compared with subcutaneously (sc) 

administered GM-CSF for the treatment (tx) of unresectable stage IIIb, IIIc, 

and IV melanoma. Presenting Author: Howard Kaufman, Rush University 


Background: T-VEC (formerly OncoVEXGM-CSF ) is an oncolytic HSV1 that 

selectively replicates in tumors. The proposed MOA includes lytic destruction 

of injected tumors and induction of a systemic anti-tumor immune 

response enhanced by local GM-CSF expression. Intratumoral T-VEC tx in a 

50-patient (pt) ph II study in advanced melanoma (Stage IIIc-IVM1c) was 

well tolerated and achieved a high rate and duration of response, including 

20% CR (Senzer et al., JCO 2009; 27: 5763-71). As immune effects may 

be delayed, progressive disease (PD) often occurred before response. 

Based on the ph II data, a randomized ph III trial of T-VEC in unresectable 

melanoma (the OPTiM study; clinical trials registry NCT00769704) was 

designed taking into account the response patterns seen with T-VEC and 

other immunotherapeutic agents. T-VEC is the first �armed� oncolytic agent 

to enter pivotal testing worldwide. Methods: OPTiM compares the efficacy 

and safety of intratumoral T-VEC to sc GM-CSF in 430 pts with treated or 

untreated unresectable Stage IIIb-IVM1c melanoma stratified by typical 

prognostic factors. Pts are randomized 2:1 to T-VEC (priming dose of up to 

4x106pfu intratumorally then 3 wks later by up to 4x108pfu Q2W) or 

GM-CSF 125 �g/m2 qd sc x 14 days every 28 days. Key eligibility criteria 

are � 18 yrs old, ECOG 0-1, and at least 1 injectable cutaneous, sc, or 

nodal tumor. The primary endpoint is durable response rate (DRR: CR or PR 

continuously maintained for � 6 mo initiating within 12 mo of starting tx; 

secondary endpoints include OS. Responses are subject to independent 

review. Pts are treated until wk 24, even with PD. Thereafter pts are treated 

until clinically significant PD, CR, or for 1 yr. The study has 90% power to 

show a 10% difference in DRR with 2-sided Fisher Exact Test (� � 5%). 

Enrollment closed in July 2011 with 439 pts randomized in the US, UK, S 

Africa, and Canada. Interim analysis in Dec 2010 on 75 pts on study � 9 

mo concluded that the study should continue. Results are expected during 

2012. Conclusions: T-VEC provides a novel potential tx for melanoma. This 

pivotal ph III study is expected to report during 2012. 


Pilot evaluation of sulforaphane in melanoma patients with multiple 

atypical nevi: Tissue STAT1 and STAT3 as risk markers. Presenting Author: 

David Lobur, University of Pittsburgh Medical Center, Pittsburgh, PA 

Background: Increasing incidence and the poor prognosis of advanced 

melanoma argue for prevention efforts. Primary prevention and ultraviolet 

radiation (UVR) reduction have failed to gain traction in the population, 

making chemoprevention increasingly attractive. Sulforaphanes (SFN) are 

bioactive cruciferous compounds rich in the Brassica family, especially 

broccoli sprouts. Topical broccoli sprout extracts (BSE) decrease UVR 

erythema response in human skin, and may protect against UVR DNA 

damage. We have shown SFN inhibition of STAT3, which is constitutively 

activated in melanoma. We have therefore initiated a pilot study to evaluate 

BSE SFN in relation to melanoma progression biomarkers, and expression 

of STAT proteins of atypical melanocytic nevi. Methods: Melanoma patients 

with �2 atypical nevi are eligible for this trial, which aims to define the 

safety and clinico-pathological response to oral BSE-SFN. Secondary 

objectives are documentation of pharmacokinetics and pharmacodynamics 

of BSE-SFN, and the modulation of STAT 1/3 expression in atypical nevi 

and normal skin. Baseline photo-documentation and atypical nevus biopsy 

is performed to assess histopathological atypia and STAT 1/3 expression. 

Adjacent normal skin biopsies will establish baseline skin SFN levels. Six 

subjects per group will be accrued at daily dosages of 50, 100, and 200 

�M. Subjects must abstain from dietary glucosinolates and isothiocyanates 

for the study duration and maintain food diaries. Following 27 days of 

BSE-SFN, blood samples, photography of index atypical nevi, and biopsies 

of selected atypical nevi and normal skin will be obtained. The three dosage 

groups will be analyzed for changes in atypia, SFN localization histopathology, 

and STAT 1/3 expression in the nevi and skin harvested at baseline and 

at study completion. This trial, UPCI 10-114, has received an IND and is 

IRB-approved. Accrual is planned to be completed during 2012-13. 


A randomized phase II study of sunitinib versus dacarbazine in the 

treatment of patients with metastatic uveal melanoma. Presenting Author: 

Ernie Marshall, Clatterbridge Centre for Oncology, Wirral, United Kingdom 

Background: Metastatic uveal melanoma represents an orphan disease area 

with a median survival of less than 6 months. There is currently no effective 

systemic therapy for metastatic uveal melanoma and few clinical trials have 

been conducted. In the absence of phase III data, many patients in the UK 

continue to receive single agent dacarbazine or best supportive care outside 

of the context of clinical trials. Uveal melanoma is characterized by 

activation of the MAP kinase pathway via functionally activating mutations 

in Gnaq/11. Evidence also suggests that dysfunctional c-Kit signalling and 

angiogenesis may both play a role in disease progression and a small 

single-arm phase II trial recently reported preliminary activity using the 

multi-targeted receptor tyrosine kinase inhibitor, sunitinib (Tijani et al, 

ASCO 2010). Methods: The SUAVE trial aims to evaluate the Progression 

Free Survival (PFS) of good performance status patients treated with 

sunitinib or dacarbazine. Secondary objectives include: Overall Survival 

(OS), Overall Response Rate (ORR), safety, crossover PFS and response 

and biomarker analyses. SUAVE is a CR-UK-funded, open-label, randomised, 

phase II trial that will include 124 patients. Patients will be 

stratified according to their Helsinki Prognostic Index (ALP, largest 

diameter of largest metastasis, ECOG). Inclusion Criteria: good performance 

status patients with confirmed unresectable metastatic uveal 

melanoma, with at least one target lesion measurable by RECIST 1.1. 

Patients must not have received previous systemic therapy. At confirmed 

progression, good performance status patients may crossover to the other 

study treatment. The trial opened in Oct 2010 and as of 23 January 2012, 

had randomized 49 patients with at least 1 recruited from each of the 12 

recruiting sites. There will be a total of 13 sites. Completion of the 

recruitment phase is expected within 36 months. Prospective tissue and 

blood sample collection for translational biomarker analyses is also 

ongoing. The SUAVE trial represents one of the largest randomised trials in 

this rare disease area (Clinical trial registry number: 2008-008794-55). 



Randomized trial of vitamin D3 to prevent worsening of musculoskeletal 

symptoms and fatigue in women with breast cancer starting adjuvant 

letrozole: The VITAL trial. Presenting Author: Qamar J. Khan, University of 

Kansas Medical Center, Kansas City, KS 

Background: Musculoskeletal (MS) pain and fatigue are common in women 

on adjuvant Aromatase Inhibitors (AIs) and lead to reduced compliance. 

Pilot studies suggest a positive impact of vit D on MS pain and disability 

from AIs. We conducted a bi-institutional, double blind, placebo controlled 

randomized trial to study the impact of 30,000 I.U of vit D3 in preventing 

worsening of MS pain and fatigue in women starting letrozole. Methods: 

Women with stage I-III breast cancer starting adjuvant AI and a 25(OH)D 

level of 40 ng/ml or less were eligible. Women with prior renal stones or 

hypercalcemia were excluded. All subjects received letrozole, plus standard 

dose vitD3 (600 IU) and calcium (1200 mg) daily, all provided by the 

study. Women were randomly assigned to 30,000 IU of oral vitD3 wkly (vitD 

arm) or matched placebos (PL arm) for 24 weeks. The following were 

assessed at baseline, 12 wks, and 24 wks (end of study): 1) 25OHD levels, 

2) symptoms tools (BFI – Brief Fatigue Inventory, HAQII - Health Assessment 

Questionnaire II, Qualitative Joint Pain (none, mild, moderate, 

severe), BPI – Brief Pain Inventory) and 3) hand grip strength with a 

dynamometer. Results: 160 women (80/arm) were enrolled from 4/09 to 

7/10. There were no differences between the two arms in demographics/ 

tumor characteristics. Median age was 61, median BMI was 29.8 kg/m2. 

43% had adjuvant chemotherapy. Median 25OHD (ng/ml) was 25 at 

baseline, 32 at 12 wks and 31 at 24 wks in the PL arm and 22, 53 and 57 

in vitD arm. One patient in the PL arm developed mild hypercalcemia. 

There were no SAEs. 147 subjects were evaluable for efficacy. 3 subjects, 

all in the PL arm discontinued early due to a MS adverse event. At wk 24, a 

higher proportion of women in PL (51%) vs vitD arm (37%) had a protocol 

defined MS event (worsening of joint pain, disability from joint pain or 

discontinuation of Letrozole due to MS symptoms) (p�0.069). A significantly 

higher proportion of women in PL (72%) vs vitD arm (42%) had an 

adverse QOL event (worsening of pain, disability or fatigue) (p��0.001). 

Conclusions: 30,000 IU/week of vitamin D3 is safe and results in decreased 

adverse QOL events from adjuvant aromatase inhibitors in women with 

breast cancer. 


Dexamethasone (DM) for cancer-related fatigue: A double-blinded, randomized, 

placebo-controlled trial. Presenting Author: Sriram Yennurajalingam, 


Background: Cancer-related-fatigue (CRF) is the most common and distressing 

symptoms in patients with advanced cancer. Currently, there is no 

standard treatment for CRF. Although corticosteroids have been used in the 

treatment of CRF, there are no well-powered placebo-controlled trials that 

used a validated CRF outcome measure. The primary objective of this 

prospective, randomized, double-blind, placebo-controlled study is to 

compare the effect of DM versus placebo on CRF. Methods: Advanced 

cancer patients with fatigue � 4/10 on the Edmonton Symptom Assessment 

Scale (ESAS) and at least 2 other CRF-related symptoms (pain, 

nausea, appetite, depression, anxiety or sleep disturbance � 4/10), normal 

cognition, no infections and hemoglobin � 9 g/L were eligible for 

enrollment. Patients were randomized to either receive dexamethasone 4 

mg orally twice a day for 15 days (primary end point) or matching placebo. 

The primary outcome was the day 15 change in Functional Assessment of 

Chronic Illness-Fatigue (FACIT-F) subscale scores. Differences in the group 

means (normal distribution) were analyzed using the two-sample t-test. 

Results: In 83 evaluable patients (43 DM and 40 placebo), median age was 

60 years, 61% were white, and 53% were female. There was no difference 

in the demographics and fatigue (FACIT-F subscale) between DM and 

placebo groups except for sex (p�0.02). The mean (SD) FACIT-F subscores 

at baseline and at day 15 for DM were 18 (11) and 27 (11) (p�0.001) and 

for placebo were 21 (9) and 24 (12) (p�0.06), respectively. Mean 

improvement in FACIT-F subscale was significantly higher in the DM group 

compared to placebo (9.6 (11) vs. 3.1 (9.7), p�0.005). We found a 

significant difference in ESAS physical distress (p�0.02), but no differences 

in ESAS overall symptom distress (p�0.11) and ESAS psychological 

distress (P�0.88) between DM and placebo. There were insignificantly 

higher numbers of grade �3 toxicities in patients who received DM than in 

patients who received placebo (20/42 vs. 18/47, p�0.37). Conclusions: 

Dexamethasone was more effective than placebo in reducing CRF in 

patients with advanced cancer. Long-term safety studies are needed. 



Phase III evaluation of American ginseng (panax quinquefolius) to improve 

cancer-related fatigue: NCCTG trial N07C2. Presenting Author: Debra L. 

Barton, Mayo Clinic, Rochester, MN 

Background: Ginseng is popularly used as a treatment for fatigue, one of the 

most common and disabling symptoms in people diagnosed with cancer. It 

is termed an “adaptogen”, thought to help the body combat negative 

effects of stress. This trial was to evaluate 2,000 mg American Ginseng 

versus placebo for cancer-related fatigue (CRF). Methods: Patients with 

cancer undergoing or having completed curative intent treatment and 

experiencing fatigue, rated at least 4 on a numeric analogue fatigue scale 

(1-10) for �1 month, were eligible. Exclusion criteria included CNS 

lymphoma, brain malignancies, or prior use of ginseng or chronic systemic 

steroids. Other etiologies for fatigue, such as pain and sleep, were also 

excluded. Patients were randomized to receive, in a double blind manner, 

2,000 mg/d of American Ginseng or placebo in BID dosing for 8 weeks. The 

primary endpoint was change from baseline in the general subscale of the 

Multidimensional Fatigue Symptom Inventory (MFSI) at 4 weeks. Other 

MFSI subscales and the fatigue-inertia subscale of the Profile of Mood 

States (POMS) were also analyzed. Data were transformed to a 0-100 scale. 

Results: 364 patients were enrolled from 10/2008 to 07/2011. Data at 4 

and 8 weeks are provided for several fatigue endpoints in the table below; 

higher numbers are better. Mental, emotional and vigor subscales of the 

MFSI were not significantly different between arms. There were no 

statistically significant differences in any grade of toxicity or self reported 

side effects between ginseng and placebo. Conclusions: This trial provides 

data to support that American Ginseng reduces general and physical CRF 

over 8 weeks without side effects. The treatment did not provide significant 

reductions in fatigue at 4 weeks and did not impact mental, emotional, and 

vigor dimensions of fatigue. 

Fatigue measure Weeks 

Change scores (SD) 

Ginseng 

n�147 

567s 

Placebo 

n�152 p value 

MFSI - general 4 14.4 (27.1) 8.2 (24.8) 0.0737 

8 20.0 (27.0) 10.3 (26.1) 0.0029 

MFSI - physical 4 1.6 (15.9) -0.4 (14.7) 0.3942 

8 3.0 (17.9) -1.7 (18.2) 0.0043 

MFSI – total 4 4.1 (13.4) 2.1 (12.9) 0.2061 

8 6.7 (14.0) 3.7 (14.6) 0.0193 

POMS – fatigue/inertia 4 14.5 (25.0) 7.7 (23.6) 0.0795 

8 18.6 (24.8) 10.2 (26.1) 0.0083 


Cluster-randomized trial of early palliative care for patients with metastatic 

cancer. Presenting Author: Camilla Zimmermann, Princess Margaret Hospital, 

University Health Network, Toronto, ON, Canada 

Background: Patients with metastatic cancer have compromised quality of 

life (QOL), which tends to worsen towards the end of life. We conducted a 

cluster-randomized trial of early versus routine palliative care in patients 

with metastatic cancer, to assess impact on QOL, symptom control and 

satisfaction with care. Methods: Twenty-four medical oncology clinics were 

randomized, stratified by tumour site (4 lung clinics, 8 gastrointestinal, 4 

genito-urinary, 6 breast, 2 gynecological), to intervention and follow-up (at 

least monthly) by a palliative care team, or to routine cancer care. Eligible 

patients had ECOG performance status 0-2 and a clinical prognosis of 6 

months to 2 years. Patients completed measures of QOL (FACIT-Sp, 

including physical, social, emotional, functional and spiritual well-being; 

range 0-156, with higher scores indicating better QOL), symptom severity 

(Edmonton Symptom Assessment System; range 0-90, with higher scores 

indicating worse symptom severity), and satisfaction with care (FAMCARE- 

P16; score range 16-80) at baseline and monthly for 4 months. The 

primary outcome was the change in FACIT-Sp at 3 months. The planned 

sample size was 225 patients per arm, assuming 80% power and a 2-sided 

significance level of 0.05. Results: From December 2006 to September 

2010, 461 patients completed baseline measures (228 intervention, 233 

control); 442 patients completed at least one follow-up assessment (mean 

patients/cluster 18.8�11.6 control, 18.1�12.6 intervention). At 3 months, 

patients in the intervention group had marginally improved QOL (mean 

change in intervention vs. control, 1.6�14.5 vs. -2.0�13.6, p�0.07) but 

not symptom severity (0.1�16.9 vs. 2.1�13.9, p�0.34). At 4 months the 

change in QOL was more marked (2.5�15.5 vs. -4.0�14.2, p�0.008) 

and symptom severity was marginally better (-1.3�16.0 vs. 3.2�13.9, 

p�0.05). Improvement in satisfaction with care was evident at one month 

(p�0.001) and remained significant at both 3 months (2.3�9.1 vs.- 

1.8�8.2, p�0.001) and 4 months (3.7�8.6 vs. -2.4�8.3, p�0.001). 

Conclusions: In patients with metastatic cancer, early palliative care 

intervention immediately improved satisfaction with care, while QOL and 

symptom control improved later. 


568s Patient and Survivor Care 


A video decision support tool for CPR in advanced cancer: A randomized 

controlled trial. Presenting Author: Angelo E. Volandes, Massachusetts 


Background: End-of-life decision-making is important to patients, including 

whether or not to attempt cardiopulmonary resuscitation (CPR). Doctors 

often rely solely on verbal descriptions to communicate information 

regarding CPR. Video decision support tools have the potential to improve 

patients’ understanding of CPR by providing visual images of what this 

intervention entails. The objective of this study was to examine the effect of 

a CPR video among patients with advanced cancer on their preferences and 

knowledge of CPR. Methods: A randomized controlled trial of 150 subjects 

with diverse advanced cancers (� 1-year prognosis) recruited from 4 

cancer centers in the United States. Subjects were randomized to either a 

verbal narrative describing CPR, or to a video with verbal narrative. The 

video depicts CPR and reviews the success rate in advanced cancer. Study 

endpoints were subjects’ CPR preferences, knowledge of CPR (knowledge 

scores ranged from 0-4, higher score indicating more knowledge), and 

perceived value of the video. Chi-square tests were used to compare the 

distributions of categorical outcomes and two-sample t-tests were used to 

compare the means between the two groups. Results: A total of 150 

subjects were randomized to a verbal narrative (n�80) or video with verbal 

narrative (n�70). Mean age was 62, 49% were women, 47% White, 34% 

Black, and 47% had lung or colon cancer. Among subjects receiving the 

verbal narrative, 38 (47.5%) preferred to have CPR attempted; 41 (51.2%) 

chose not to have CPR; and 1 (1.3%) was uncertain. In the video group, 14 

(20%) preferred to have CPR attempted; 55 (78.6%) chose not to have 

CPR; and 1 (1.4%) was uncertain (P�0.001). The mean knowledge score 

was higher in the video group than in the verbal group (3.3 vs. 2.6 

respectively; P�0.001). Of the subjects who viewed the video, 94.1% 

stated they were comfortable watching the video, 97.1% found the video 

helpful, and 100% would recommend the video. Conclusions: Compared to 

subjects who only heard a verbal description, subjects with advanced 

cancer who viewed a CPR video were more likely to prefer not having CPR, 

and were more knowledgeable about CPR. The majority of subjects found 

the video helpful, comfortable to view, and would recommend it to others. 


Long-term protective effects of the angiotensin receptor blocker telmisartan 

on epirubicin-induced inflammation, oxidative stress, and myocardial 

dysfunction. Presenting Author: Giovanni Mantovani, Department of Internal 

Medical Sciences, Service of Medical Oncology, University of Cagliari, 

Cagliari, Italy 

Background: Chronic inflammation, oxidative stress and renin-angiotensin 

system (RAS) play a significant role in chemotherapy-induced cardiotoxicity 

(CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 

receptor, reduces anthracycline (ANT)-induced CTX. Methods: A phase II 

placebo (PLA)-controlled randomized trial was carried out to assess the role 

of TEL in the prevention of cardiac subclinical damage induced by 

epirubicin (EPI). Forty-nine patients (mean age � SD, 53.0�8 years), 

cardiovascular disease-free with cancer at different sites and eligible for 

EPI-based treatment, were randomized to one of two arms: TEL n�25; PLA 

n�24. A conventional echocardiography equipped with Tissue Doppler 

imaging, strain and strain rate (SR) was performed, and serum levels of 

proinflammatory cytokines, IL-6 and TNF-�, and oxidative stress parameters, 

reactive oxygen species (ROS) and glutathione peroxidase were 

assessed. All assessments were carried out at baseline, after every 100 

mg/m2 EPI dose and at 6, 12 and 18-month follow-up (FU). Results: A 

significant reduction in the SR peak in both arms was observed at t2 (cumulative dose of 200 mg/m2 EPI) in comparison to t0. Conversely, at t3, t4 (300, 400 mg/m2 EPI), 6, 12 and 18-month FU, the SR increased 

reaching the normal range only in TEL arm, while in PLA arm SR remained 

significantly lower as compared to t0. The differences between SR changes 

in PLA and TEL arms were significant from 300 mg/m2 EPI (t3)upto18 month-FU. IL-6 increased significantly in PLA arm at t2 compared to t0, but 

remained unchanged in the TEL arm. ROS levels also increased significantly 

at t2 vs. baseline in PLA arm, while remained unchanged in TEL arm. 

The mean change in ROS and IL-6 at t2 was significantly different between 

the two arms. At 3, 6, 12 and 18 month-FU, ROS and IL-6 decreased in 

comparison to t2 in PLA arm, while remained low in TEL arm. Conclusions: 

Our results suggest that TEL is able to reverse acute EPI-induced 

myocardial dysfunction and maintain a normal systolic function up to 18 

month-FU. These effects are likely due to two different mechanisms, RAS 

blockade and prevention of chronic inflammation/oxidative stress. 


ZOOM: A prospective, randomized trial of zoledronic acid (ZOL;q4wkvsq 

12 wk) for long-term treatment in patients with bone-metastatic breast 

cancer (BC) after 1 yr of standard ZOL treatment. Presenting Author: Dino 

Amadori, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, 

Meldola, Italy 

Background: ZOL (4 mg q 4 wk) is an established therapy for reducing the 

risk of debilitating skeletal-related events (SREs) in patients (pts) with 

bone metastases (mets) from BC. As BC treatments continue to improve pt 

survival, long-term SRE-reduction is increasingly important, and evaluation 

of modified ZOL dosing to retain efficacy with reduced adverse events (AEs) 

is warranted. Methods: ZOOM, a phase III prospective, randomized, 

open-label, multicenter study, assessed the safety and efficacy of quarterly 

(4 mg q 12 wk; Arm 1) vs monthly (4 mg q 4 wk; Arm 2) ZOL for ~1 yr in pts 

with BC who have � 1 bone met, and have received ~1 yr of prior ZOL 

treatment (9 to 12 doses over � 15 months; last dose � 3 months prior). 

The primary endpoint was skeletal morbidity rate (SMR; number of 

SREs/pt/yr). Sample size to detect non-inferiority with 80% power (1-sided 

a � 0.025) was 420 pts. Secondary endpoints included time to first SRE, 

bone pain, bone marker (N-telopeptide of type I collagen; NTX) levels, and 

safety. Results: 425 pts were enrolled (209 in Arm 1; 216 in Arm 2); arms 

were well balanced for pt and disease characteristics, and anticancer 

therapies. SMR was similar between arms: 0.26 (95% confidence interval 

[CI] � 0.15, 0.37) in Arm 1 vs 0.22 (95% CI � 0.14, 0.29) in Arm 2; 

between-arms difference � 0.04 (upper limit of 1-tailed 97.5% CI � 

0.17). Despite the proximity of 0.17 to the adjusted non-inferiority margin 

(0.19), the non-inferiority of Arm 1 vs 2 remains statistically significant. 

Safety analyses showed that ZOL was well tolerated. Renal AEs were 

reported in similar proportions of pts in both arms; 7 cases of osteonecrosis 

of the jaw were reported (1.65% overall; 4 cases in Arm 1 vs 3 in Arm 2). 

Conclusions: ZOOM is the first randomized trial to compare ZOL q 12 wk vs 

ZOLq4wkinBCptsafter 1 yr of standard ZOL therapy. SMR was similar 

between arms. Limitations in study design suggest the need to confirm 

non-inferiority of ZOL q 12 wk in other ongoing phase III trials. 


Post diagnosis weight gain and the role of exercise in breast cancer 

survivors. Presenting Author: Tara Beth Sanft, Yale University, New Haven, 

CT 

Background: Obesity is linked to poor breast cancer (Br Ca) outcomes 

including higher risk of recurrence and death. No study has examined if 

post-diagnosis weight (wt) gain modifies the effect of exercise interventions 

on body composition. We examined wt change from diagnosis (diag) to 

enrollment (enroll) into a 6-mo randomized trial of exercise v. usual care to 

explore if post-diagnosis wt gain modified the effect of exercise on body wt, 

body fat, lean body mass (LBM) and bone mineral density (BMD) in breast 

cancer survivors. Methods: 75 inactive Br Ca survivors were recruited and 

randomized to exercise (n � 37) or usual care (UC) (n � 38). At baseline, 

women completed a questionnaire assessing self-report wt at diag and at 

the time of enroll into the study (~3 yr). The exercise group participated in 

150 min/wk of supervised exercise. The UC group maintained their 

physical activity level. Body composition was assessed at enroll and 6-mo 

via dual-energy X-ray absorptiometry (DXA) by one radiologist blinded to 

intervention group. Results: Wt and DXA data were available for 68 / 75 

participants. On average, women gained 3.3�8.2 kg from diag to enroll, 

with 53% gaining wt (mean � 8.9 � 6.8 kg) and 47% maintaining or losing 

wt (mean change � -2.9 �3.9 kg). The majority of wt gain occurred among 

women who were non-obese at diag (BMI � 30), with 60% of non-obese 

women gaining wt (mean � 8.0 � 6.8 kg) compared with 38% of obese 

women gaining wt (mean � 12.2 � 6.4 kg). Those randomized to exercise 

lost body fat including women who gained wt since diag (mean % fat loss 

for exercisers (-0.92 � 0.31) vs. UC (0.36 �0.30), p � .0063) and women 

who did not gain wt since diag (mean % fat loss for exercisers (-0.65 � 

0.39) vs. UC (0.45�0.47), p � .08) even after adjusting for obesity status 

at diag. Similar improvements in LBM and BMD were observed with 

exercise in women who did or did not gain wt since diag. Conclusions: Wt 

gain in Br Ca survivors is common, the majority of weight gain in this study 

occurred among women who were not obese at diag. Exercise led to body fat 

loss and other favorable body composition changes among both non-obese 

and obese women. Exercise and other wt management programs should be 

offered to all Br Ca survivors regardless of BMI at diagnosis as a strategy 

towards prevention of wt gain. 



Electronic self-report assessment for cancer: Results of a multisite randomized 

trial. Presenting Author: Donna Lynn Berry, Dana-Farber Cancer 


Background: Attending to symptoms and side effects promotes safe and 

effective delivery of cancer therapies. Providing focus to the patient’s 

report in the clinic can efficiently address the most important concerns, 

without extending visit times. The web-based electronic self report assessment 

for cancer (ESRA-C) and clinician summary has been shown to 

improve patient-clinician communication about symptoms and quality of 

life issues (SQI). The purpose of this trial was to evaluate the impact of an 

enhanced ESRA-C intervention (ESRA-C INT) on symptom outcomes. 

Methods: Patients (planned N�702) with all cancer types treated in stem 

cell transplant, medical oncology and radiation oncology at two comprehensive 

cancer centers used ESRA-C to self-report SQI during and after new 

anti-cancer therapy, with summary reports delivered to clinicians. Patients 

were randomized to standard ESRA-C (control) or ESRA-C INT adding the 

opportunity to self-monitor SQI between clinic visits and receive self-care 

SQI management education, plus custom coaching on how to report SQI to 

clinicians, all delivered via a secure web sites. We analyzed the intervention 

effect on Symptom Distress Scale (SDS) scores using a two-sided t-test and 

multivariate linear regression, adjusting for pre-selected covariates, including 

baseline SDS, age, service, and work status. Results: Among 757 

patients (increased N due to involuntary attrition), demographic variables 

were balanced between groups except age (t�2.13; p�.03) with a younger 

INT group (mean 1.97 year difference). Of the 562 patients who completed 

final reports, the control group reported significantly higher SDS scores (t� 

1.98; p � .048). A significant interaction between study group and age was 

observed; significantly lower SDS scores were found in the ESRA-C INT 

group among patients � 50 years (-1.95; p�.002), and no significant 

difference among patients � 50. Conclusions: Adding self-care and 

communication coaching to ESRA-C, a system to allow self-report and 

clinician notification of SQI, reduced symptom distress in a large sample of 

patients during and after active cancer treatment compared with ESRA-C 

alone. Patients over the age of 50, in particular, may benefit from the 

intervention. 


EXCAP exercise to improve fatigue, cardiopulmonary function, and strength: 

A phase II RCT among older prostate cancer patients receiving radiation 

and androgen deprivation therapy. Presenting Author: Karen Michelle 

Mustian, University of Rochester Medical Center, Rochester, NY 

Background: Radiation therapy (RT) and androgen deprivation therapy 

(ADT) result in cancer-related fatigue (CRF), decreased cardiopulmonary 

function (CPF) and decreased strength. Research suggests exercise can 

improve CRF during RT and ADT, through physical conditioning responses 

that improve CPF and strength. We explored the influence of an individuallytailored, 

home-based exercise intervention (EXCAP), including progressive 

resistance and aerobic training, on CRF, CPF and strength. Methods: Older 

prostate cancer patients (N�58; mean age�67), receiving RT (47%) or 

ADT (53%), were randomized to 6 wks of EXCAP (7 days/wk) or standard 

care (RT or ADT with no exercise). CPF (VO2 max) was assessed via graded 

exercise testing (GXT) or a 6-minute walk test when GXT was contraindicated. 

Muscular strength was assessed using multiple repetition maximum 

testing (chest press and leg extension). CRF was assessed via valid 

self-report questionnaires (BFI, POMS-FI, MFSI). All assessments were 

pre- and post-intervention. Results: ANCOVAs, controlling for baseline, 

revealed significant differences between groups in mean levels of CRF on 

the BFI and POMS-FI (all p�0.05), and a trend toward differences on the 

MFSI (p�0.10) with significant baseline interactions (all p�0.05) postintervention: 

exercisers decreased CRF while controls increased. ANCOVAs 

revealed a trend toward differences between groups in mean levels of CPF 

(VO2 max) and strength (all p�0.10): exercisers improved while controls 

declined in performance. Pearson correlations revealed significant inverse 

associations between changes in CRF (BFI) and CPF (p�0.05;r�-0.0.36), 

and CRF and strength (p�0.05;r�-0.0.31). MANOVA revealed that changes 

in CPF and strength significantly predicted changes in CRF (p�0.05, 

r�0.67) and accounted for 45% of the variance. Conclusions: Exercise 

improves CRF and these improvements may be mediated, in part, by 

improvements in CPF and strength. Future phase III RCTs with prostate 

cancer patients receiving RT and ADT are needed to confirm these 

relationships. Funding: DOD W81XWH-07-1-0341, NCI K07CA120025, 

NCI 1R25CA102618. 


569s 


Physical activity participation and functional limitations in geriatric cancer 

survivors. Presenting Author: Lisa Sprod, University of Rochester Medical 

Center, Rochester, NY 

Background: Functional limitations (FL) increase with age, as does cancer 

incidence. Treatments for cancer may exacerbate age-related FL. Physical 

activity (PA) reduces the risk of recurrence of some cancers and may 

improve survival. FL may reduce PA participation in geriatric cancer 

survivors (�65 yrs.) which could increase the risk of recurrence and reduce 

survival. This investigation describes and compares patterns of PA and FL 

in geriatric cancer survivors versus those without a cancer history. Methods: 

Using a national sample of community-dwelling elders (� 65 yrs.) from the 

2003 Medicare Current Beneficiary Survey (N�14,887), we characterized 

the differences between cancer survivors and those without a cancer history 

in FL, current amount of PA, and current amount of PA compared to PA one 

year prior. Respondents rated FL on a 1-5 scale (1�no difficulty, 5�can’t 

do): stooping, crouching, or kneeling (stoop), carrying objects up to 10 lbs 

(lift), extending arms above shoulder level (reach), grasping small objects 

(grasp), and walking ¼ of a mile (walk). Frequency of walking for a least 10 

minutes (1-5 rating scale; 1�daily, 5�never), weekly participation in PA, 

exercise, or sports (yes/no), and time spent doing moderate or vigorous PA 

(hrs/wk) were reported. Multivariate logistic regression was used to determine 

associations. Results: Of the 14,887 participants, 2,603 (6%) 

reported a history of cancer. Compared to those without a cancer history, a 

greater proportion of cancer survivors reported having difficulty or being 

unable to stoop, lift, reach, grasp or walk (all p�0.01). Cancer survivors 

who had more FL were less likely to engage in PA (all p�0.01). Cancer 

survivors reported a lower frequency of walking at least 10 minutes at a 

time (p�0.01). Cancer survivors were more likely to decrease PA from the 

previous year (p�0.01) and spent less time doing moderate (p�0.01) or 

vigorous activity (p�0.01) than those without a cancer history. Conclusions: 

Older cancer survivors engage in less PA and are at greater risk of FL than 

those without a history of cancer. This may lead to reduced independence, 

a greater risk of cancer recurrence, and reduced survival. Therefore, PA 

interventions are important in this population. 


Correlation of short telomeres (ST) with vulnerability, toxicity, and early 

death in elderly AOC patients receiving carboplatin: A multicenter GINECO 

trial. Presenting Author: Claire Falandry, Centre Hospitalier Lyon Sud, 

Lyon, France 

Background: Age induces a progressive decline in the functional reserve and 

interferes with cancer treatments. As aging is heterogeneous, this decline 

has to be assessed individually. Telomere attrition leads to tissue senescence. 

We tested the hypothesis that telomere lenght (TL) could predict pts 

vulnerability and outcome during cancer treatment. Methods: This study 

was performed in the “Elderly women” GINECO trial designed to evaluate 

the impact of geriatric covariates on survival in AOC pts over 70 receiving 6 

courses of carboplatin. TL was estimated in duplicate using standard 

Terminal Restriction Fragment analysis from peripheral blood cells at 

inclusion and tested for its correlation with geriatric covariates and pts 

outcomes (TC and tolerance, overall survival: OS). Results: TL (in base pair) 

was estimated for 109/111 pts (median 5997; extremes [4517-8333]). 

No significant correlation was found with any pts characteristics. With a 

cutoff of 5770 bp, TL discriminated two groups with significantly different 

Treatment Completion (TC) rates: 0.80 (95CI[0.71-0.89]) and 0.59 

(95CI[0.41-0.76]), OR�2.8, p�0.02 for long telomere (LT) and short 

telomere groups, respectively . ST pts were at higher risk of severe adverse 

events (SAE, OR�2.7; p�0.02) and tended to have more unplanned 

hospital admissions (OR�2.1; p�0.08). Considering OS, after adjustment 

on FIGO stage, TL shorter than the median was a nearly significant risk 

factor of premature death (HR�1.57; p�0.06. Finally, we addressed if TL 

correlated with our previously validated geriatric vulnerability score (GVS)c 

including ADL score�6, IADL score�25, albuminemia�35g/l, 

lymphopenia�1G/L, HADS score£15 as risk factors of poorer survival. 

Despite no significant correlation with any of these factors, GVS³3) and ST 

tended to be correlated (OR�2.1; p�0.08). Conclusions: This exploratory 

study identifies TL as predictive factor of decreased TC, SAE risk, 

unplanned hospital admissions and OS after adjustment on FIGO stage. 




Prognostic factors of the loss of autonomy (LoA) in older patients with 

cancer receiving first-line chemotherapy. Presenting Author: Pierre-Louis 

Soubeyran, Institut Bergonie, Bordeaux, France 

Background: Actual data on prognostic geriatric factors of health outcomes 

are lacking. We aimed to examine whether a decrease in autonomy for 

activities of daily living (ADL) after a first cycle of chemotherapy influences 

elderly cancer pts prognosis, and to determine prognostic factors of this 

LoA from a range of biological and geriatric evaluation factors. Methods: 

Pts� 70 years receiving 1st-line chemotherapy for a range of cancers were 

included in this multicentre prospective study. A LoA was defined as a 

decrease of 0.5 or more points on the ADL scale between the beginning of 

treatment and the 2nd cycle (ADL scored 6 to 0). The association between 

a LoA and OS was examined and prognostic factors were sought from the 

pre-treatment Geriatric Assessment data (CIRS-G, IADL, MNA, MMSE, 

GDS et Get up and Go) and from baseline biological and clinical information 

(age, sex, tumor extension and localization, performance status, BMI, 

weight loss, albumin, CRP, haemoglobin levels, leucocyte and platelet 

count, creatinine clearance). Pts completely dependent at baseline (ADL 

score 0) were excluded as a LoA was not possible. Results: Among 364 pts 

included, 299 pts were evaluable and 50 experienced a LoA. A LoA was 

significantly associated with an increased risk of death (RR 1.518, 

95%CI[1.079-2.135]). Biological and clinical factors were not associated 

with LoA but pre-treatment low GDS15, dependencies on the IADL, low 

MMS, slow Get Up and Go, low ECOG-PS and poor MNA were found to be 

prognostic of a LoA in univariate analyses. In the multivariate model, low 

GDS (OR 2.4, p�0.01, 95%CI [1.23-4.66]) and dependencies on the 

IADL (OR 3.0, p� 0.027, 95%CI � [1.13-9.09]) were independently 

associated with an increased risk of LoA. Conclusions: Our study underlines 

the close link between LoA during treatment and poorer prognosis of elderly 

pts with cancer. Pts with a pre-treatment low GDS15 and IADL-dependent 

were the most likely to experience LoA after the 1st chemotherapy cycle. 

This research suggests that the GDS15 and IADL should be included as 

part of any screening for elderly pts before treatment. 

9014 Clinical Science Symposium, Tue, 9:45 AM-11:15 AM 

Falls, physical performance deficits, and functional losses in cancer 

survivors with chemotherapy-induced neuropathy (CIPN): A University of 

Rochester CCOP study. Presenting Author: Supriya Gupta Mohile, University 

of Rochester Medical Center, Rochester, NY 

Background: CIPN impairs quality of life in cancer survivors. Little is known 

about the prevalence of falls, physical performance (PP) deficits, and 

functional losses or their association with CIPN toxicities in cancer 

survivors. Methods: We conducted an analysis of baseline assessments from 

a phase III randomized clinical trial in cancer survivors with CIPN self 

reported pain scores of � 4 reflecting leg and foot pain from neuropathy 

over the past 24 hours on a scale from 0 (“no pain”) to 10 (“pain as bad as 

you can imagine”). Patients also completed EORTC QLQ-CIPN-20 sensory 

and motor scales for neuropathy toxicities and self reported falls in the 

previous 3 months. A PP deficit was defined as “a lot of difficulty” or 

“unable to do” any of 6 physical tasks (e.g., lifting objects, walking a 

quarter of a mile). Functional losses were defined as “a lot of difficulty” or 

“unable to do” any of 5 functional tasks (e.g., managing money, bathing). 

We examined the association of baseline characteristics and CIPN toxicities 

with falls, PP deficits and functional losses using logistic regression. 

Results: Of 421 patients, 11.9% experienced recent falls, 58.6% reported 

a PP deficit, and 26.6% reported a functional loss. Patients with falls 

and/or PP deficits were more likely to be older (mean age 60.9 vs 58.9, 

p�0.02), female (75.3% vs 65.2%, p�0.03) and have less education 

(�high school: 7.1% vs 0.6%, p�.01). Cancer and chemotherapy history 

were not different between groups. Patients with falls and/or PP deficits 

reported higher severity of CIPN toxicities: pain (6.82 vs 6.05, p�0.01), 

sensory (23.3 vs 19.6, p�0.01), and motor (17.4 vs 12.7, p�0.01). In 

multivariable analysis, factors associated with having a fall and/or PP 

deficit included: older age (OR 1.03, p�0.04), low education (OR 9.34, 

p�0.04), and motor toxicity (OR 1.21, p�0.01). Factors associated with 

functional losses included: non-white race (OR 3.16, p�0.01), Hispanic 

ethnicity (OR 5.32, p�0.05), motor toxicity (OR 1.19, p�0.01), and PP 

deficit (OR 4.94, p�.01). Conclusions: CIPN toxicities, primarily motor, are 

significantly associated with falls, physical performance deficits, and 

functional losses. 

CRA9013 Clinical Science Symposium, Tue, 9:45 AM-11:15 AM 

CALGB 170601: A phase III double blind trial of duloxetine to treat painful 

chemotherapy-induced peripheral neuropathy (CIPN). Presenting Author: 

Ellen M. Lavoie Smith, University of Michigan, Ann Arbor, MI 








Rates and risks of suicidality in young adults (YAs) with advanced cancer. 

Presenting Author: Kelly Marie Trevino, Dana-Farber Cancer Institute, 

Boston, MA 

Background: Suicide rates in YA cancer patients are higher than in the 

general population. Although cancer is associated with a four-fold increase 

in the likelihood of a suicide attempt, little is known about suicidality in 

YAs with cancer. This study examined rates and clinical risk factors 

associated with suicidality in a sample of YAs with advanced cancer. 

Methods: Structured interviews were conducted between 4/2010 and 

9/2011 with 70 YA advanced cancer patients (range 20-40 yrs, M�33.97, 

SD�5.61) receiving care at the Dana-Farber Cancer Institute. Validated 

measures assessed suicidality (i.e., Yale Evaluation of Suicidality), quality 

of life, major depressive disorder, grief over cancer-related losses, and 

social support. Scores on the suicidality measure were dichotomized into 

positive screen � 1 and negative screen � 0. Chi-square, t-test, and 

logistic regression analyses evaluated the relationship between suicidality 

and participant characteristics and psychosocial variables, controlling for 

confounding variables. Results: Over one-fifth (21.4%) of the sample 

screened positive for suicidality. Female gender �2 (1, N � 70) � 4.95, p � 

.026), breast compared with other cancer diagnosis �2 (1, N � 70) � 5.66, 

p � .017), and better performance status (t(68) � 3.13, p � .01) were 

associated with lower rates of suicidality. Participants who met criteria for 

current (OR [95% CI] 8.67 [1.78, 42.22]) or lifetime major depressive 

disorder (5.38 [1.60, 18.12]) endorsed higher rates of suicidality. Better 

overall (.97 [.94, .99]), psychological (.93 [.87, .94]), and existential 

quality of life (.91 [.85, .98]) were associated with reduced suicidality risk. 

More severe grief was associated with greater risk (1.15 [1.04, 1.28]) 

whereas greater social support was associated with lower suicidality risk 

(.85 [.74, .97]). Conclusions: YAs with advanced cancer reported higher 

rates of suicidality than observed in other age groups. Developmentally 

targeted interventions that promote physical function, effectively treat 

depression, improve quality of life and reduce grief, and provide opportunities 

for social support may reduce rates of and risk for suicidality in this 

population. 



Patterns of antidepressant use in cancer patients (pts): An analysis from 

SOAPP (ECOG E2Z02: Symptom Outcomes and Practice Patterns). Presenting 

Author: Judith Manola, Dana-Farber Cancer Institute, Boston, MA 

Background: Antidepressant (AD) use is common in outpatient oncology, 

but the pattern and determinants of prescribing for commonly used AD are 

unknown. Methods: 3106 pts with cancer of the breast, prostate, colon/ 

rectum, or lung were enrolled from multiple sites in a study of symptoms. 

Five depression case-finding methods were explored : 3 based on MDASI 

items reported by patients (1) sadness/ depression��4, (2) distress��4, 

(3) interference with mood��7 or enjoyment��7; 2 based on clinician’s 

report (4) presence of psychological distress, (5) depression being listed as 

one of top 3 symptoms. AD use (excluding tricyclic antidepressants and 

psychostimulants) was examined by depression status. Logistic regression 

models were used to examine the effect of demographic and clinical 

characteristics on AD use. Results: Rates of depressive symptoms varied by 

casefinding method (1�29%, 2�28%, 3�14%, 4�24%, 5�11%); 47% 

(1457) pts were defined as having depressive symptoms by at least one 

method. AD were prescribed in 25% of depressed pts compared to 14% of 

non-depressed pts. After adjusting for other covariates, factors associated 

with greater use of AD included depression (OR�1.7, P�0.01), family 

history of depression (OR�2.2, P�0.01), female sex (OR�1.8, P�0.01), 

younger age (OR�1.2, P�0.04), non-Hispanic White race (OR�2.0, 

P�0.01), prior chemo/immune/ hormonal treatment (OR�1.5, P�0.01), 

more concurrent medication use (OR�3.3, P�0.01), anxiolytics use 

(OR�2.0, P�0.01), sedative use (OR�2.1, P�0.01), receiving counseling 

(OR�1.6, P�0.04), patient’s perception of poor QOL (OR�1.3, 

P�0.02), duration of current treatment �1 year (OR�1.6, P�0.01), and 

being enrolled by a CCOP (OR�1.8, P�0.01). These significant associations 

remained regardless of the case-finding method used for depression, 

with only slight changes in the magnitude of ORs. Conclusions: Depressive 

symptoms are common in outpatients with cancer. One-fourth of solid 

tumor pts with depressive symptoms are taking an AD. Antidepressant 

prescribing varies by type of institution, race/ethnicity, age, concomitant 

medication exposure and several other clinical factors. 


4:45 PM-5:45 PM 

SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine 

for the prevention of taxane-induced neuropathy during adjuvant breast 

cancer therapy. Presenting Author: Dawn L. Hershman, Columbia University 

Medical Center, New York, NY 

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a 

common, disabling side effect of taxanes that leads to suboptimal 

treatment and diminished quality of life. Acetyl-L-Carnitine (ALC) is a 

natural compound involved in tubulin acetylation and neuronal protection. 

Pre-clinical and phase II studies suggest ALC may be effective for the 

prevention and treatment of CIPN. Methods: A randomized, double-blind, 

multi-center, phase III trial comparing ALC (1000 mg TID) vs placebo for 

24 wks in women with stage I-III breast cancer undergoing adjuvant taxane 

therapy was conducted. The primary objective was to determine if ALC 

prevents CIPN as measured by the 11-item neurotoxicity (NTX) component 

of the FACT-Taxane scale (low score � worse NTX) at 12 wks. Secondary 

objectives included change at 24 wks, change in the Trial Outcome Index 

(TOI), fatigue (FACIT Fatigue) and NTX grade. Patients were stratified by 

planned treatment, and age (�60, �60). Results: 409 patients were 

evaluable (208 ALC, 201 placebo). No imbalances were observed by age, 

ethnicity, race, planned taxane treatment, performance status, or stage. 

The mean FACT-NTX score was 5.2 points lower at 12 wks on ALC and 4.5 

points lower on placebo. In a linear regression adjusting for baseline score, 

planned treatment and age, wk 12 scores were 0.9 points lower on ALC 

than placebo (95% CI: -2.2 to 0.4, p�.17). At 24 wks, the mean observed 

FACT-NTX score was lower for ALC (5.3 vs. 3.6). In the multivariate model, 

wk 24 scores were 1.8 points lower on ALC (95% CI: -3.2 to -0.4, p�.01), 

representing more self-reported NTX. Grade 3/4 NTX was more frequent in 

the ALC arm (p�.04). Also at 24 wks, 38% on ALC had �5 point decrease 

score compared to 28% on placebo (OR�1.57, p�.05), and FACT-TOI 

scores were 3.5 points lower on ALC (95% CI: -6.5 to -0.4, p�.03). No 

differences between arms were observed for the FACIT-Fatigue scale or for 

other toxicities. Conclusions: There is no evidence that ALC has a positive 

impact on CIPN at 12 wks. However, ALC increases CIPN by 24 wks. 

Correlative studies are ongoing to explain this unexpected finding. Patients 

should be discouraged from using ALC and other supplements without 

proven efficacy. 


571s 


4:45 PM-5:45 PM 

A prospective study to evaluate the efficacy and safety of oral acetyl-Lcarnitine 

(ALC) in treatment of chemotherapy-induced peripheral neuropathy 

(CPIN). Presenting Author: Yuanjue Sun, Sixth Affiliated Hospital of 

Shanghai Jiaotong University, Shanghai, China 


major side effect of many commonly used chemotherapeutic. This side 

effect of chemotherapy can be debilitating and effective treatment for CIPN 

remains elusive. Previous studies demonstrated that Acetyl-L-Carnitine 

(ALC) is effective in attenuating CIPN, controlled study is needed to 

substantiate ALC’s effect in treatment of CIPN. Methods: This study was 

designed to evaluate the efficacy and safety of Acetyl-L-Carnitine (ALC) 

Hydrochloride Enteric-coated Tablet (oral administration) in the treatment 

of CIPN. It was a prospective, randomized, double-blinded, placebocontrolled 

and paralleled clinical study (registration No. 2007L03540). Of 

239 subjects enrolled in the study (NCI grade 2 or above), 118 subjects 

received 3g/day ALC orally for 8 weeks and 121 received placebo. Primary 

endpoint was set as improvement of peripheral neuropathy at least 1 grade 

and assessment was made in week 4, 8 and 12 after enrollment. Results: In 

full analyses set (FAS) and per-proposal set (PPS), the peripheral sensory 

neuropathy was significantly ameliorated in ALC group with 50.5% and 

51.6% patients meeting the primary endpoint at week 8 and 12 respectively 

while only 24.1% and 23.1% of patients in the placebo group at week 

8 and 12 respectively (p�0.001 in both sets). Secondary endpoint such as 

nerve electrophysiological test and Physical Condition Score (Karnofsky 

performance status, KPS) were also significantly improved in patients with 

ALC treatment (in FAS, P�0.0463 and P�0.022; in PPS, P�0.0076and 

P�0.0064, respectively). Cancer-related fatigue was significantly alleviated 

after ALC treatment in PPS (P�0.0135). Safety: 236 subjects were 

included in safety assessment and 41 patients experienced 62 adverse 

events during the course of study. There was no significant difference in 

AE/SAE incidence between the two groups (P�0.3903). Conclusions: Oral 

administration of ALC is effective in attenuating CIPN as well as in 

reducing cancer-related fatigue and improving physical conditions in 

cancer patients. The treatment of oral ALC is safe and well tolerated. 


4:45 PM-5:45 PM 

Low-level laser therapy for chemotherapy-induced peripheral neuropathy. 

Presenting Author: John Muzi Lee, Legacy Health Systems, Portland, OR 

Background: Chemotherapy induced peripheral neuropathy (CIPN) is a 

common and serious side effect from chemotherapy agents. Low-level laser 

light therapy (LLLT) devices were approved in 2002 for pain management. 

Studies suggest a local release of serotonin, increased mitochondrial ATP 

production, or anti-inflammatory effects as a mechanism of action. We then 

questioned whether LLLT would show efficacy in mitigating symptoms 

caused by CIPN. Methods: In a single center prospective randomized trial, 

participants were randomized to receive either treatment with LLLT twice a 

week for 8 weeks or placebo LLLT twice a week for 4 weeks followed by 

actual treatment twice a week for 4 weeks. FACT/GOG-NTX, Brief Pain 

Inventory (BPI -Severity and Interference), SF-36 Quality of Life (Physical 

and Mental Score), monofilament and function testing (buttoning, coin use 

and walking) were conducted prior to initiation of therapy, during, at 

completion, and 2 months after treatment. 20 participants, 16 women and 

4 men (average age 58 and 63 respectively), were enrolled between 

October 2009 and June 2010. 10 patients were randomized to each group. 

Average time from end of chemotherapy to enrollment was 32.6 months 

(range 2 - 120 mo). All patients had neuropathic involvement of the feet. 

14 patients had additional involvement of the hands. Results: Compared to 

baseline, patients receiving any amount of active treatment showed 

significant improvement at 8 weeks in NTX, BPI, function testing, and 

SF36 Mental score. Those receiving 4 weeks of placebo treatment showed 

improvement in only BPI, NTX and SF36 Mental score. At 2-month follow 

up, all 20 patients showed a significant improvement in walking and SF 36 

mental score, suggesting 4 weeks of active treatment improved function. 

No significant difference in monofilament testing was observed throughout 

the study in either group. Direct comparison between 4 or 8 weeks of 

treatment vs. placebo showed a statistically significant difference in 

walking function at 2-months. All patients tolerated therapy well without 

side effects. Conclusions: Low-level laser light therapy improved functional 

test over placebo and may be a viable option for non-medical management 

of CIPN. Further study of LLLT in CIPN is warranted. 




4:45 PM-5:45 PM 

Patient-reported cognitive impairments among women with breast cancer 

randomly assigned to hormonal therapy (HT) alone versus chemotherapy 

followed by hormonal therapy (C�HT): Results from the Trial Assigning 

Individualized Options for Treatment (TAILORx). Presenting Author: Lynne 

I. Wagner, The Robert H. Lurie Comprehensive Cancer Center of Northwestern 

University, Chicago, IL 

Background: Cognitive impairment is a complication of chemotherapy. 

Perceived cognitive impairments (PCI) were prospectively assessed among 

TAILORx participants randomized to HT alone versus chemotherapy followed 

by HT (C�HT). Methods: TAILORx participants with an OncoType DX 

Recurrence Score 11-25 were randomly assigned to HT or C�HT. PCI, 

fatigue, endocrine symptoms and health-related quality of life (HRQL) were 

assessed at baseline, 3, 6, 12, 24, and 36 months, using the Functional 

Assessment of Cancer Therapy (FACT) in 455 patients enrolled after 

1/15/10. PCI change scores � 4.5 from baseline were defined a priori as 

clinically meaningful. Linear regression (LR) was used to model PCI scores 

on baseline PCI, treatment and other factors. Results: PCI scores were 

significantly worse at 3, 6, and 12 months compared to baseline for both 

groups (Table). The decline was greater for C�HT than HT at 3 months, but 

scores were similar at 12 months. Tests of an interaction between 

menopausal status and treatment were non-significant. PCI correlated with 

fatigue (r � 0.57-0.64) but not FACT Emotional well-being (EWB; r � 

0.28-0.38); controlling for EWB did not account for differences in PCI 

change scores between treatment arms. Conclusions: Our study is the first 

to examine PCI among breast cancer patients randomized to receive C�HT 

vs. HT alone. C�HT was associated with greater declines in PCI at 3 

months, but at 12 months PCI was similar in the C�HT and HT groups. PCI 

was associated with fatigue but not EWB. Pre- and post-menopausal groups 

demonstrated the same pattern of change. Since this study did not include 

a control group of patients not treated with HT, further study is required to 

determine if and to what extent HT contributes to PCI. 

Mean change in PCI score from baseline. 

3 months 6 months 12 months 

Change 

scores Difference 

(LR) P value Change 


(LR) P value Change 


(LR) P value 

HT -2.78 -3.61 � 0.001 -3.27 -2.28 � 0.05 -4.67 1.20 n.s. 

C�HT -6.40 -5.66 -6.08 


4:45 PM-5:45 PM 

Subjective cognitive complaints one year after ceasing adjuvant endocrine 

therapy for early-stage breast cancer: Findings from the Breast International 

Group (BIG) 1-98 trial. Presenting Author: Kelly-Anne Phillips, Peter 

MacCallum Cancer Centre, Melbourne, Australia 

Background: We have previously reported that, in the BIG 1-98 trial, 

objective cognitive function improved in postmenopausal women one year 

after cessation of adjuvant endocrine therapy for breast cancer. Here we 

evaluate changes in subjective cognitive function (SCF). Methods: One 

hundred postmenopausal women, randomized to receive five years of 

adjuvant tamoxifen, letrozole, or sequences of both, completed selfreported 

measures on SCF, psychological distress, fatigue and quality of 

life during the fifth year of trial treatment (year 5) and one year after 

treatment completion (year 6). Changes between years 5 and 6 were 

evaluated using the Wilcoxon signed-rank test. SCF and its correlates were 

explored. Results: Mean age of participants was 63.9 years [SD�7.1 years]. 

SCF and the other patient-reported outcomes did not change significantly 

after cessation of endocrine therapy with the exception of improvement in 

hot flushes (p�0.0005). No difference in changes was found between 

women who were taking tamoxifen or letrozole at year 5. SCF was the only 

psychosocial outcome with a substantial correlation between year 5 and 6 

(Spearman’s R�0.80). Correlations between SCF and the other patientreported 

outcomes were generally low. Conclusions: Although objective 

cognitive function improved after cessation of adjuvant endocrine therapy 

in the BIG 1-98 trial, improvement in SCF was not evident. The underlying 

reason for the clear disconnect between objective and subjective cognitive 

function seen in this and most other studies, is a crucial issue. It should be 

a research priority in order to effectively tackle the concerns of women 

about their cognition during and after breast cancer treatment. 


4:45 PM-5:45 PM 

Cognitive function and fatigue in colorectal cancer (CRC) patients: A 

prospective longitudinal controlled study. Presenting Author: Janette L. 

Vardy, Sydney Cancer Centre, University of Sydney, Sydney, Australia 

Background: A subset of cancer patients has cognitive impairment and 

fatigue after chemotherapy (CTh). We evaluated these symptoms and 

potential mechanisms in CRC patients and healthy controls (HC). Methods: 

Cognitive function was evaluated in CRC patients and HC at baseline 

(pre-CTh), 6 and 12 months. Group 1A (Stage II/III) received CTh and Gr 

1B (Stage I/II) no CTh. Gr 2 had limited metastatic CRC. All subjects 

completed cognitive assessment and questionnaires for fatigue, QOL, 

anxiety/depression, and perceived cognitive function. Blood tests evaluated: 

10 cytokines, clotting factors, sex hormones, CEA, CBC and apolipoprotein 

genotyping as potential causal factors. Primary endpoints: cognitive 

function and fatigue (Gr. 1A & 1B) at 12 months. Associations between 

results and demographic and disease-related factors were sought. Results: 

359 CRC patients (173 Gr 1A, 116 Gr 1B, 70 Gr. 2) and 72 HC were 

assessed. Median age 58 (23-75 years); 58% male. Cognitive impairment: 

baseline Gr 1A 34% vs 1B 32.5% (p�.9), Gr 1 33% vs HC 10% 

(p�0.001); 12 months Gr 1A 21% vs 1B 16% (p�0.43), Gr 1 19% vs HC 

2% (p�0.001). Cognitive domains most affected: verbal & visual memory, 

processing speed. Men had greater impairment than women (p�0.009). 

Cognitive decline from 0-12 months: Gr 1A 30%, Gr 1B 19%, Gr 2 24%, 

and HC 16%. Perceived cognitive impairment at 12 months: Gr 1A 19% vs 

1B 7% (p�.04), Gr 1 14% vs HC 0% (p�.009). Fatigue was greatest in Gr 

1A (70%) at 6 months; at 12 months Gr. 1A 46% vs 1B 31% (p�0.056), 

Gr 2 60%, HC 36%. Cytokines were elevated in CRC patients compared to 

HC. No association was found with cognitive function and: fatigue, QOL, 

anxiety/depression, cytokines, sex hormones, clotting factors, CEA or apoE 

genotype. Objective cognitive function was associated with perceived 

cognitive function at baseline only. Fatigue at baseline was associated with 

hemoglobin and at 12 months with neutrophil count. Conclusions: Compared 

to HC, CRC patients had more cognitive impairment at baseline, 6 

and 12 months; but impairment was not significantly different between 

those who did and did not receive CTh. The mechanisms of cognitive 

impairment remain unknown. Fatigue improved with time. 


4:45 PM-5:45 PM 

Methylphenidate (MP) and nursing telephone intervention (NTI) for cancerrelated 

fatigue (CRF) in advanced cancer patients: A double-blind randomized 

phase II trial. Presenting Author: Eduardo Bruera, University of Texas 


Background: CRF is the most common and distressing symptom in advanced 

cancer patients. Preliminary studies support MP and NTI for CRF 

(Bruera et al. JCO 2006). The primary objective of our study was to 

determine the effect of MP as compared to placebo (P). A secondary 

objective was to investigate the role of NTI as compared to control 

telephone intervention (CTI). Methods: Advanced cancer patients with 

fatigue �4/10 on the Edmonton Symptom Assessment Scale (ESAS), 

normal cognition, no evidence of major depression and hemoglobin �8 

were eligible. Patients were randomized to 4 groups in a 2x2 factorial 

design (MP�NTI, P�NTI, MP�CTI and P�CTI). Primary endpoint was 

Functional Assessment of Chronic Illness-Fatigue (FACIT-F) subscale 

scores between day 15 and baseline. The dose and duration of methylphenidate 

was 5 mg every two hours, as needed, up to 20 mg/day. We tested the 

median difference in FACIT-F subscale scores between the groups using 

the Kruskal Wallis test and Wilcoxon signed rank test. Longitudinal 

regression analysis was conducted with a mixed model. Results: Total 

accrual was 197. Mean (SD) age was 58 (12), female 67% (N�148), white 

72% (N�136), gastrointestinal cancers were the most common 22% 

(N�41). Baseline FACIT-F subscores were similar among the 4 groups. The 

median FACIT-F subscores showed significant improvement between Day 

15 and baseline for all four groups except for P�CTI (Table): MP�NTI 

(4.5, P�0.004), P�NTI (8, P�0.001), MP�CTI (7, P�0.001), and 

P�CTI (5, P�0.06), with no statistically significant difference between MP 

and P (6 vs. 6, P�0.89). Longitudinal regression analysis showed a time 

effect (P�0.001) and group differences for NTI vs. CTI with FACIT-F 

(P�0.13) and ESAS (P�0.03). Grade 3 toxicities were similar between the 

MP and P arms (34/93 vs. 24/97, P�0.09). Conclusions: MP was not 

effective as compared to P for CRF in advanced cancer patients. NTI may 

be effective and should be further studied. 

FACIT-F at baseline, day 8 and day 15 group. 

Median (interquartile range) 

Group Baseline Day 8 Day 15 

MP�NTI 21 (12) 31 (14) 25 (16) 

P�NTI 20 (13) 32 (14) 28 (13) 

MP�CTI 20 (14) 27 (14) 27 (14) 

P�CTI 22 (14) 31 (18) 28 (23) 



4:45 PM-5:45 PM 

Phase Ib, multicenter, single-blinded, placebo-controlled, sequential doseescalation 

study to assess the safety and tolerability of topically applied 

AG013 in subjects with locally advanced head and neck cancer (LAHNC) 

receiving induction chemotherapy (ICT). Presenting Author: Sewanti Atul 

Limaye, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA 

Background: Oral mucositis (OM) is a significant toxicity of ICT in LAHNC. 

AG013, a mouth rinse composed of a recombinant Lactococcus lactis 

(sAGX0085) engineered to secrete human Trefoil Factor 1 (hTFF1) and 

deficient in the gene encoding thymidylate synthase, was investigated in 

patients receiving ICT (cisplatin, 5-fluorouracil �/-docetaxel:PF�/-T). 

TFFs have wound-healing properties and are protective of mucosal tissues. 

Methods: To evaluate the safety, tolerability, PK profile and efficacy of 

AG013 in attenuating ICT-associated OM, 52 patients (pts) with newly 

diagnosed LAHNC receiving ICT (24TPF, 1PF) were screened in ICT cycle 

(Cy) 1 for symptomatic OM (SOM). 25 pts who developed SOM in Cy1 were 

enrolled into 3 successive groups of at least 7 pts each in the active phase 

and randomly assigned at the Baseline visit (d1 of ICT Cy2) in a 5:2 ratio to 

receive AG013 or placebo during ICT Cy2. Dose was escalated in successive 

groups from 1 x/day (qd) to 3 x/day (tid) and to 6 x/day, resulting in 

doses of2x1011 ,6x1011 , and 1.2 x 1012 colony-forming units (CFU)/day 

respectively. Pts were assessed daily from Cy 2 d1 to d14 for OM using 

WHO criteria. Safety endpoints and PK (mucosal, salivary and blood 

samples) were assessed. Results: AG013-sAGX0085 could not be detected 

in blood. Recovered oral live bacterial levels were high immediately after 

dosing, decreased by 90 minutes post dose, and undetectable at study end. 

No differences in hTFF1 serum levels were seen. Pts in the placebo group 

had ulcerative OM (UOM) on nearly 60% of the days vs. 35-40% days in the 

AG013 group. 29 % pts who received AG013 had 0 or 1 day of UOM vs. at 

least 2 days of UOM in the placebo group. Pts who received AG013 on any 

dosing schedule had a lower % of days with OM, fewer unplanned office and 

emergency room visits compared to pts who received placebo. No differences 

were noted in mouth and throat soreness, opioid use, or gastrostomy 

tube placement. Conclusions: Topical administration of AG013 appears 

safe, well tolerated and effective in reducing the severity and course of OM 

in patients receiving ICT for HNC. 

9026^ Poster Discussion Session (Board #10), Mon, 1:15 PM-5:15 PM and 

4:45 PM-5:45 PM 

Effect of cancer cachexia on treatment toxicity in metastatic colorectal 

cancer patients: Results of a prospective multicenter study. Presenting 

Author: Maximilien Barret, Hôpital Européen Georges Pompidou, Department 

of Gastroenterology, Paris, France 

Background: Malnutrition reduces tolerance to treatment and survival in 

numerous cancers, including metastatic colorectal cancer (mCRC). Previous 

studies have shown that chemotherapy toxicity may be linked to 

sarcopenia. We evaluated the effect of sarcopenia on chemotherapy toxicity 

among mCRC patients. Methods: In this prospective, cross-sectional, 

multicenter study, oncological and nutritional data were collected in all 

consecutive mCRC patients between March 7th and March 20th 2005 in 

three hospitals. Computed tomography (CT) images were analysed using 

Slice-O-Matic software V4.3 (Tomovision) to evaluate cross-sectional areas 

(cm2) of muscle tissue (MT), visceral and subcutaneous adipose tissue 

(VAT and SAT). The 3rd lumbar vertebra (L3) was chosen as a reference, 

since L3 and whole-body measurements are linearly related. Indexed on 

height, MT, VAT and SAT (cm2/m2), were computed and described, after 

stratification on sex. In accord with the literature, sarcopenia was defined 

as MT �55 cm2/m2 for men and �39 cm2/m2 for women. Images were 

obtained within one month of clinical evaluation. Toxicities were evaluated 

according to the NCI-CTC, version 3.0, in the two months following clinical 

evaluation. Results: 53 mCRC patients (72% men (M)), participated in the 

study. According to body mass index (BMI) only 7% of female patients (F) 

and 3% M were malnourished (BMI�17 kg/m²), and 93% F and 97% M 

were of normal weight or overweight (BMI� 25kg/m²). These results are to 

be compared to the 38% (F) and 82% (M) of patients with sarcopenia. 

Grade 3-4 toxicities were observed in 28% of the cases, with neurotoxicity 

in 6%, diarrhea 2%, anemia 2%, neutropenia 9%, and nausea and 

vomiting 6%. In multivariate analysis including age, sex, BMI, sarcopenia, 

SAT and VAT, the only factor associated with grade 3-4 toxicity was 

sarcopenia (OR� 13.55 95% CI [1.08;169.31], p�0.043). Conclusions: 

In mCRC patients undergoing chemotherapy, low muscle tissue was much 

more frequently observed (68%) than “visible” malnutrition (4%). Despite 

the small number of patients included in our study, we showed that 

sarcopenia was associated with severe chemotherapy toxicity in mCRC. 


573s 


4:45 PM-5:45 PM 

Parenteral hydration (PH) in advanced cancer patients: A multi-center, 

double-blind, placebo-controlled randomized trial. Presenting Author: 

Shalini Dalal, University of Texas M. D. Anderson Cancer Center, Houston, 

TX 

Background: The vast majority of cancer patients at the end of life receive 

PH in hospitals and no PH in hospice. There is limited evidence supporting 

either practice. Our preliminary study suggested that PH (1L/day) improved 

dehydration symptoms (Bruera et al. JCO 2005). In this randomized 

controlled trial, we determined the effect of PH on symptoms associated 

with dehydration, quality of life and survival for patients with advanced 

cancer. Methods: We randomly assigned 129 cancer patients from 6 

hospices to receive subcutaneous PH (normal saline 1 L/day) or placebo 

(normal saline 100 mL/day) daily over 4 hours. The primary outcome was 

change in the sum of 4 dehydration symptoms (fatigue, myoclonus, 

sedation and hallucinations, 0�best and 40�worst possible) between day 

4 and baseline. Secondary outcomes included Edmonton Symptom Assessment 

Scale (ESAS), Memorial delirium assessment scale [MDAS], Nursing 

delirium screening scale [NuDESC], unified myoclonus rating scale [UMRS], 

FACIT-F, creatinine, urea, and overall survival. Intention-to-treat analysis 

was conducted to examine the change in each variable between baseline 

and day 4 or day 7. Log rank test was used for survival analysis. Results: 

Mean age was 67 (range 43-92), female 61%, Caucasians 60%, gastrointestinal, 

genitourinary and lung cancers 70%, performance status 3-4 113 

(88%), with no baseline differences between the hydration (N�63) and 

placebo (N�66) groups. No significant differences were found between the 

hydration and placebo groups for the sum of 4 dehydration symptoms (-3.3 

v. -2.8, p�0.77), ESAS (all non-significant), MDAS (1 vs. 3.5, p�0.084), 

NuDESC (0 v. 0, p�0.13) and UMRS (0 vs. 0, p�0.54). We also did not 

identify any group differences for day 7, except for a decrease in urea level 

in the hydration group (-2 vs. 2, P�0.02). Median overall survival was 21 

days for PH and 15 days for placebo (p�0.83). Conclusions: PH at 1 L/day 

did not improve symptoms, quality of life or survival compared to placebo. 

Further studies are required to determine if any subgroups would benefit 

from PH. 


4:45 PM-5:45 PM 

Curcumin for radiation dermatitis: A randomized, double-blind, placebocontrolled 

clinical trial of 30 breast cancer patients. Presenting Author: 

Julie L. Ryan, University of Rochester Medical Center, Rochester, NY 

Background: Radiation dermatitis occurs in approximately 95% of patients 

receiving radiation therapy for cancer and often leads to pain and treatment 

delays. There is no standard treatment with demonstrated effectiveness for 

the prevention of radiation dermatitis. We conducted a randomized, 

double-blind, placebo-control clinical trial to assess the efficacy of curcumin, 

a potent antioxidant and anti-inflammatory component of turmeric, 

to reduce radiation dermatitis in 30 breast cancer patients. Methods: 

Eligible patients included adult females with non-inflammatory breast 

cancer or carcinoma in situ prescribed radiation therapy without concurrent 

chemotherapy. After randomization, patients took four 500 mg capsules of 

curcumin or placebo three times daily throughout their course of radiation 

therapy (total daily dose � 6.0 g). Weekly assessments included Radiation 

Dermatitis Severity (RDS) Score, presence/absence of moist desquamation, 

erythema measure, and McGill Pain and Symptom Inventory (SI) 

questionnaires. Results: The 30 evaluable patients were white (90%; mean 

age � 58.1 years) with ER�PR� breast cancer (76.7%) who did not have 

total mastectomy (90%) or chemotherapy prior to start of radiation therapy 

(56.7%). No significant differences were observed between arms for 

demographics, compliance, erythema, pain, symptoms, or radiation skin 

dose. Standard pooled variances t-test showed that curcumin reduced RDS 

at end of treatment compared to placebo (mean RDS � 2.6 vs 3.4; 

p�0.008). Fisher’s exact test showed that curcumin significantly reduced 

the presence of moist desquamation at the end of radiation therapy (28.6% 

vs. 87.5 %; p�0.002). Repeated measures analysis confirmed divergence 

of RDS between curcumin and placebo arms at Week 5. Conclusions: Oral 

curcumin, 6.0 g daily during radiation therapy, reduced radiation dermatitis 

severity and moist desquamation in breast cancer patients. A multisite 

CCOP trial (N�700) is underway to confirm the effectiveness of curcumin 

to reduce radiation dermatitis severity during various radiation therapy 

regimens for breast cancer. Support: IND 75,444, Dermatology Foundation, 

KL2 RR024136, NCI PHS 1R25CA10618. 




4:45 PM-5:45 PM 

YOCAS yoga for musculoskeletal symptoms in breast cancer patients 

receiving aromatase inhibitors: A URCC CCOP randomized, controlled 

clinical trial. Presenting Author: Luke Joseph Peppone, University of 

Rochester Medical Center, Rochester, NY 

Background: Up to 50% of breast cancer patients on aromatase inhibitor 

therapy report significant musculoskeletal symptoms such as joint and 

muscle pain, which decreases treatment adherence. We conducted a 

secondary data analysis of a multi-site, phase III randomized, controlled, 

clinical trial examining the efficacy of yoga for improving musculoskeletal 

symptoms among breast cancer patients currently receiving hormone 

therapy (aromatase inhibitors [AI] or tamoxifen [TAM]) through the University 

of Rochester Cancer Center Community Clinical Oncology Program 

(CCOP). Methods: The original RCT randomized patients with any type of 

non-metastatic cancer without previous yoga participation into 2 arms: 1) 

standard care monitoring [controls] or 2) 4-week yoga intervention (2x/wk; 

75 min/session) plus standard care. The yoga intervention utilized the UR 

Yoga for Cancer Survivors (YOCAS) program consisting of breathing 

exercises, 18 Hatha and Restorative yoga postures, and meditation. Only 

breast cancer patients currently receiving AI (N�95) or TAM (N�72) were 

included in this secondary analysis. Changes in musculoskeletal symptoms 

were assessed using ANCOVA with baseline values as covariates between 

the yoga and control groups. Results: Compared to TAM users at baseline, 

AI users reported higher levels of general pain (1-5 score: AI�2.65 vs. 

TAM�2.17; p�0.01), muscle aches (0-4 score: AI�2.14 vs. TAM�1.65; 

p�0.01), and total physical discomfort (0-24: AI�8.03 vs. TAM�5.92; 

p�0.01). Among AI users only, participants in the yoga group demonstrated 

greater reductions in general pain (CS�change score; Yoga CS� 

-0.37 vs. Control CS� �0.02; p�0.02), muscle aches (Yoga CS� -0.58 

vs. Control CS� -0.15; p�0.03) and total physical discomfort (Yoga CS� 

-2.07 vs. Control CS� -0.58; p�0.04) from pre- to post-intervention than 

the control group. Conclusions: The severity of musculoskeletal symptoms 

was higher for AI users than for TAM users. Among breast cancer patients 

on AI therapy, the community-based YOCAS intervention significantly 

reduced general pain, muscle aches, and physical discomfort. Funding: 

NCI U10CA37420, KL2RR024136-05, K07CA120025. 


4:45 PM-5:45 PM 

Association of screening for psychosocial distress in patients with newly 

diagnosed stage IV NSCLC and survival. Presenting Author: William F. Pirl, 


Background: While screening for psychosocial distress has become an 

ASCO QOPI indicator of quality cancer care, data has yet to show an 

association with improved cancer outcomes. We examined the relationship 

between adherence to the QOPI measure for assessment of emotional 

well-being and survival in a sample of patients with newly diagnosed stage 

IV NSCLC. Methods: From 8/07 to 9/10, we recruited consecutive new 

patients in a multidisciplinary thoracic oncology clinic to participate in a 

research database for which patients completed self-report instruments for 

depression (PHQ-9) and anxiety (GAD-7) at their first oncology visit. We 

then performed a QOPI chart audit for patients with stage IV NSCLC who 

received care at our institution. To adhere to the QOPI measure, oncologists 

were required to document their own assessment of patient emotional 

well-being (without access to patient self-report data) within one month of 

the first office visit. Survival was calculated from first oncology visit to 

death. Cox proportional hazards models were used to test associations with 

survival. Results: 243 patients completed baseline assessments and had 

follow up. Emotional well-being was assessed in 90 (37%). Median survival 

of those with an emotional assessment was 12 months vs. 10 months for 

those without (p�.03). Yet, emotional assessment was associated with 

younger age (p�.01) and higher depression (p�.05) and anxiety scores 

(p�.03). Controlling for age, sex, performance status, smoking, primary 

oncology provider, PHQ-9, and GAD-7, having an assessment of emotional 

well-being was associated with improved survival (HR .68, 95% CI 

.49-.93, p�.02). Although higher PHQ-9 scores were independently 

associated with worse survival (HR 1.05, 95% CI 1.02-1.08, p�.004), 

neither depression nor anxiety moderated the relationship between clinician 

screening and survival. Conclusions: In this large prospective study of 

patients with newly diagnosed stage IV NSCLC, adherence to the QOPI 

measure for assessment of emotional well-being was associated with a 

survival benefit. This benefit appears to extend to all patients, not just those 

with depression and anxiety. Randomized trials are needed to confirm these 

findings. 


4:45 PM-5:45 PM 

A randomized controlled trial of expressive writing for patients with renal 

cell carcinoma (RCC). Presenting Author: Timothy Burnight, University of 


Background: Most previous research examining the efficacy of brief expressive 

writing interventions have used small sample sizes and followed people 

for no more than 3 months. We conducted a large randomized trial to 

examine an expressive writing intervention for patients with renal cell 

carcinoma and followed them for 10 months after the end of the writing 

sessions. Methods: Two hundred patients with RCC were randomly assigned 

to either write their deepest thoughts and feelings about their cancer (EW) 

or to write about neutral topics (NW) on four separate occasions over 10 

days for a maximum of 20 minutes at each writing session. Patients 

completed the MD Anderson Symptom Inventory (MDASI), Brief Fatigue 

Inventory, SF-36, IES, CES-D, and PSQI at baseline and then again 1, 4, 

and 10 months after the writing sessions. Results: The mean age of the 

participants was 58 (range 34-82 years), 41% were women, and staging 

data were 39% stage I, 15% stage II, 19% stage III, and 27% stage IV. The 

groups were well balanced on all demographic and medical characteristics. 

Examination of group differences 1 month after the writing sessions, 

controlling for the respective baseline measure, revealed decreased IES 

scores for the EW group (intrusive thoughts: EW, 5.0 v NW, 7.2; p�.02; 

avoidance behaviors: EW, 6.3 v NW, 8.7; p�.07). By 4 months after the 

intervention, the EW group reported higher levels of SF-36 Social Functioning 

scores (EW: 52.6 v NW: 49.7; p�.04). At the 10 month time point, the 

EW group reported fewer cancer-related symptoms (EW: 20.8 v NW: 30.8; 

p�.04), higher levels of SF-36 Role Physical scores (EW: 69.6 v NW: 54.0; 

p�.02), and fewer sleep disturbances (subscale of the PSQI; EW: 1.4 v 

NW: 1.6; p�.05). Means for the other SF-36 subscales at 10 months were 

in the expected, but did not reach statistical significance. There were no 

group differences for CES-D or fatigue scores at any time point. Mediation 

analyses revealed that IES scores at 1 month mediated the effects of EW on 

cancer-related symptoms (F� 1.85, p�.06) at the 10 month follow up. 

Conclusions: These findings indicate expressive writing leads to short-term 

reduction in intrusive thoughts about the cancer experience and results in 

long-term improvement in aspects of quality of life. 


4:45 PM-5:45 PM 

The effect of pretreatment psychosocial factors on immune function and 

quality of life after brief presurgical stress management. Presenting Author: 

Chelsea D. Gilts, University of Houston, Houston, TX 

Background: It is important to identify factors that predict who will benefit 

the most from psychosocial interventions in cancer populations. Methods: 

We examined the association between pretreatment psychosocial factors 

and subjective and objective outcomes from a brief cognitive-behavioral 

stress management program. This three-arm randomized clinical trial 

investigated the effects of a presurgical stress management (SM; n�53) 

compared to supportive attention (SA; n�54) and standard care (SC; 

n�52) on quality of life (QOL) and immune outcomes in men with prostate 

cancer scheduled for radical prostatectomy. We previously reported improved 

QOL 1 year after surgery in the SM and SA groups compared to the 

SC group and higher pro-inflammatory cytokines 48h after surgery in the 

SM group. We investigated the moderating effects of baseline psychosocial 

factors (social support (SS), dyadic adjustment (DA), distress (BSIGSI), 

and impact of event (IES)), on QOL (SF-36 physical (PCS) and mental 

(MCS) component scores) 1 year after surgery and immune response 48h 

after surgery. Results: Baseline SS and BSIGSI interacted with group in 

predicting PCS 1 year after surgery (p’s �.05). Men who reported low 

baseline SS and were in SM had increased PCS 1 year after surgery 

compared to men with low SS in the SC group (b�.36, p�.01). Conversely, 

men who reported high BSIGSI at baseline and were in SA had increased 

PCS 1 year after surgery compared to those in SM (b�11.14, p�.03), with 

SC having an intermediate nonsignificant effect. All four psychosocial 

factors (SS, DA, BSIGSI, IES) interacted with group in predicting changes 

in pro-inflammatory cytokines (interleukin (IL)-1, IL-6, IL-8, IL-10, tumor 

necrosis factor, and interferon) 48h post-surgery (all p’s �.04). In all 

significant interactions, men who reported greater psychosocial vulnerability 

at baseline and were in SM had increased immune response 48h after 

surgery compared to psychosocially vulnerable men in either SC (all p’s 

�.02) or SA (all p’s �.02). Conclusions: These findings suggest that 

baseline psychosocial factors are important indicators of who may benefit 

most from a SM intervention on both subjective and objective outcomes. 



4:45 PM-5:45 PM 

Social environment as a predictor of smoking cessation and recidivism in 

lung cancer survivors. Presenting Author: Lawson Eng, Princess Margaret 

Hospital, University of Toronto, Toronto, ON, Canada 

Background: Smoking during cancer treatment negatively impacts treatment, 

survival and quality of life. Lung cancer patients with a smoking 

history often continue to smoke; some ex-smokers re-start after diagnosis. 

Social environment impacts cessation and recidivism rates in non-cancer 

patients. We assessed whether the same influences occur among lung 

cancer patients. Methods: Lung cancer patients, recruited from Princess 

Margaret Hospital, completed a baseline questionnaire about their demographics 

and smoking history (at diagnosis). A follow-up questionnaire was 

administered at a median of two years, assessing changes in smoking 

habits, exposure at home/work/among friends, healthcare use, social 

support and alcohol use since diagnosis. The relationship between each 

variable with cessation/recidivism was analyzed. Odds ratios (OR) and 95% 

confidence intervals (95% CI) were calculated. Results: 478 patients 

completed both questionnaires. Of the 100 current smokers at diagnosis; 

52 quit by the time of the follow-up questionnaire. Among 294 ex-smokers, 

15 started to smoke after diagnosis. None of the 84 never smokers at 

baseline started to smoke after diagnosis. Exposure to smoking at home was 

associated with continued smoking and relapse (OR�5.1, 95% CI: 

1.8–14.3, p�0.001; and OR�3.9, 95% CI: 0.8–14.4, p�0.04, respectively). 

Specifically, spousal smoking was associated with both continued 

smoking (OR�7.3, 95% CI: 2.4–21.7, p�2.0E-04) and recidivism 

(OR�3.7, 95% CI: 0.6–16.6, p�0.08). Having more than a few friends 

who smoke is associated with continued smoking (OR�3.5, 95% CI: 

1.4–8.7, p�0.005) and relapse (OR�4.8, 95% CI: 1.5–15.0, p�0.004). 

Not completing high school was also associated with continued smoking 

(OR�3.0, 95% CI: 1.2–7.6, p�0.02). Multivariate analysis identified 

spousal smoking as the major single predictor of continued smoking 

(OR�8.8, 95% CI: 2.2–34.8, p�0.002). Conclusions: Smoking cessation 

programs for lung cancer patients should not only target the patient but 

also include the immediate family, consider a patient’s peers and be 

tailored to the patient’s education level. Involvement of the immediate 

family and consideration of peers may help prevent smoking relapse. 


4:45 PM-5:45 PM 

Factors associated with life expectancy (LE) < 3 months (mo) among older 

adults receiving palliative chemotherapy (chemo). Presenting Author: Arti 

Hurria, City of Hope, Duarte, CA 

Background: Optimal treatment decision-making for older adults with 

advanced cancer requires a better understanding of risk factors associated 

with limited LE. Our objective was to evaluate the factors associated with 

LE� 3mo among patients (pts) age � 65 who were beginning a new chemo 

regimen. Methods: We conducted a secondary analysis of a multi-site cohort 

study of pts �65 years receiving chemo (Hurria et al, JCO 2011). This 

analysis included only pts receiving palliative chemo. Bivariate analysis 

and multivariate logistic regression were utilized to identify factors associated 

with LE � 3 mo including: sociodemographics, labs [hemoglobin 

(Hb), albumin, liver function, creatinine clearance], and geriatric assessment 

(GA) variables (functional status, social support, comorbidity, psychological, 

cognitive, and nutritional status). Results: Among 290 pts (median 

age 72 [range 65-91], 52% female) with advanced cancer (gastrointestinal 

28%, lung 31%, breast/gyn 22%, other 19%), 13.4% died within 3 mo of 

chemo initiation. In bivariate analysis, pts with LE � 3mo were more likely 

(p�0.05 for each variable) to have lower albumin and Hb, unintentional 

weight loss, and poorer physical function [defined as need for assistance 

with instrumental activities of daily living (IADL), lower score on Medical 

Outcomes Survey (MOS) Physical Health, MD-rated and patient-rated 

Karnofsky performance status (KPS), and MOS Social Activity score]. 

Measures of functional status were highly correlated with one another and 

therefore one functional status measure (in addition to measures significant 

in bivariate analysis) was included in each multivariate logistic 

regression. In multivariate analyses, (controlling for age, comorbidity, and 

line of chemo) poorer physical function (as evaluated by need for assistance 

with IADLs, MOS Physical �70, or MD-rated KPS �70) and unintentional 

weight loss were independently associated with LE�3mo (p�0.05). 

Conclusions: Among older pts with advanced cancer who were prescribed a 

new chemo regimen for palliative intent, physical function measures (as 

evaluated by geriatric assessment and MD report) and unintentional weight 

loss were associated with LE � 3months. 


575s 


4:45 PM-5:45 PM 

Strength and endurance training in the treatment of lung cancer patients 

staged IIIA/IIIB/IV. Presenting Author: Corinna C. Henke, Department of 

Oncology and Hematology, Vivantes Klinikum Neukölln, Berlin, Germany 

Background: This RCT tested the effect of a specially designed strength and 

endurance training on the independence in activities of daily living and 

quality of life in lung cancer patients staged IIIA/IIIB/IV while receiving 

palliative chemotherapy. The aim was to break the vicious circle created 

through the connection of physical inactivity and the worsening of symptoms 

and side effects. Methods: Between August 2010 and December 

2011 lung cancer patients staged IIIA/IIIB/IV with a good performance 

status receiving an inpatient palliative chemotherapy treatment at the 

Vivantes Hospital Neukölln/Berlin, were randomized into an intervention 

and control group. The Barthel Index and the EORTC QLQ-C30/ LC13 

questionnaire were used for evaluation. The Six-Minute-Walk-Test and stair 

walking in combination with the Modified Borg Scale have been used to test 

the patient´s endurance capacity. Furthermore muscle strength was examined. 

Non-parametrical data were statistically analyzed with the Wilcoxon 

and Mann-Whitney-U test. For parametric data student t- tests were used. A 

significance level of p� .05 was accepted. Results: Out of 46 patients, who 

signed the informed consent, 29 patients completed the trial (18� 

Intervention group, 11� Control group). Significant differences between 

the groups were detectable in the Barthel Index (IGmean(SD)�92.08 

(15.15); CGmean�81.67 (14.98); p�.041), and in single scores of the 

EORTC QLQ C-30/LC-13 questionnaire (Physical Functioning p�.025; 

Haemoptysis p�.019, Pain in Arms or Shoulder p�.048, Peripheral 

Neuropathy p�.050, Cognitive functioning p�.050). Significant differences 

were found between the groups concerning the 6MWT, stair walking 

and strength capacity (IG�CG). Additionally the level of dyspnoea decreased 

significantly in the IG while performing submaximal walking 

activities. Conclusions: The training program has a positive impact on the 

patient´s independence in carrying out activities of daily living. Although it 

does not have a significant impact on the patient´s quality of life, single 

factors can be significantly improved. Moreover it has a positive effect on 

the patient´s endurance and strength capacity. The dyspnoea perception is 

improved. 


4:45 PM-5:45 PM 

The influence of age plus standard clinical approach with or without 

comprehensive geriatric assessment (CGA) on treatment decisions in older 

cancer patients: Final results. Presenting Author: Lore Decoster, Department 

of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis 

Brussel, Brussel, Belgium 

Background: The aim of this prospective study was to examine how age and 

standard clinical approach with and without CGA results determine 

treatment decisions in older cancer patients (pts). Methods: This study,conducted 

in 2 Belgian university hospitals, included pts � 70 years with a 

malignant tumor (breast, colorectal, ovarian, lung, prostate and hematological) 

if a new cancer therapy was considered. All pts underwent a uniform 

CGA. Results were communicated to the treating physician. After the 

treatment decision, an interview with the treating physician was performed, 

using a predefined questionnaire: 1/ What would be your oncological 

treatment proposal in case the pt was 55y without other comorbidity? 2/ Is 

this different from your treatment proposal for this pt according to age and 

standard clinical approach without CGA results? 3/ Is this different from 

your treatment proposal for this pt with CGA results? Results: From October 

2009 till July 2011, 937 pts were included in the study. Median age was 

76y (range 70-95) and 63.5% was female. A total of 902 (96.3%) 

questionnaires were completed and 56.2% of the physicians were aware of 

the CGA results at treatment decision. In 381 pts (42.2%; 95%CI 

39.0-45.5) age and standard clinical approach led to a different treatment 

decision compared to younger pts without comorbidity. This influence was 

most prominent for chemotherapy decisions: 309 patients did not receive 

standard chemotherapy (reduced dose (13), less toxic regimen (163), less 

toxic regimen at reduced dose (5) or no chemotherapy (128)). When the 

physician was aware of the CGA, these results influenced their treatment in 

6.7% (95%CI: 4.5-8.9), mostly concerning chemotherapy. In 8 pts CGA 

results encouraged the treating physician to choose a more aggressive 

chemotherapy regimen and in 11 pts CGA results led to a decision of 

palliative care. Conclusions: Based on this prospective trial, we conclude 

that physicians use adapted treatment regimens in older versus younger 

pts, only based on age and standard clinical approach. CGA results change 

the treatment decision in 6.7% and sometimes trigger the use of a more 

aggressive treatment. 




4:45 PM-5:45 PM 

Patient information desire in actual decision making for advanced cancer 

treatment: Do doctors know their patients? Presenting Author: Linda J. M. 

Oostendorp, Radboud University Nijmegen Medical Center, Nijmegen, 

Netherlands 

Background: Providing information is an important element of cancer care. 

While several studies have investigated patients’ information desire, to our 

knowledge, this study is the first to involve patients facing an actual 

decision. We examined the information desire of patients at the point of 

decision making, the ability of doctors to judge this desire, and the 

information provided by the doctor. Methods: This prospective multicenter 

study included patients with advanced colorectal or breast cancer faced 

with the decision whether or not to pursue second-line chemotherapy. 

Patients received the usual treatment-related information from the doctor 

plus a decision aid from a nurse. The aid contained information on adverse 

events, tumor response, and survival. For each item, the nurse asked the 

patient whether the information was desired and whether it had been 

disclosed by the doctor and the doctor made a substitute judgment of the 

patient’s information desire on the inclusion form. The match between 

patient’s desire and doctor’s judgment was expressed in percentage 

agreement and agreement corrected for chance (�). Results: By 01/2012, 

71 patients had received the decision aid. Median age was 62 years (range 

39-80), 38% were male, and 28% had college education or higher. 

Information on adverse events, tumor response, and survival was desired by 

94%, 90%, and 73% of patients. The doctors judged that information 

desire would be 100%, 97%, and 81%, respectively. There was a poor 

match between doctor’s judgment and actual information desire for 

adverse events (94%, � not applicable), tumor response (87%, � � 

-0.049), and survival (61%, � � -0.104). When asked whether the 

information was previously disclosed by the doctor, 73%, 57%, and 30% of 

patients answered affirmatively. Conclusions: Patients expressed a high 

information desire, which was accurately judged by the doctors. However, 

doctors were unable to judge an individual patient’s information desire 

beyond chance. According to the patients, doctors did not disclose all 

desired information, especially on survival. Decision aids, similar to those 

used here, have been shown to help doctors provide safe, effective, and 

timely information to patients. 


Difficult conversations with terminal patients: Palliative care and death at 

home. Presenting Author: Eduardo L. Morgenfeld, Instituto Oncológico 

Henry Moore, Buenos Aires, Argentina 

Background: More than half the total number of oncological patients may 

die due to the disease’s progression, and at some point in time the 

oncologist must communicate that the disease is terminal. This is the 

hardest conversation (HC) of a clinical oncologist. The following paper’s 

objective is to determine whether or not the treatments applied to patients, 

and their evolution, are affected by having had the HC. Methods: All 

patients who died due to progression of the disease in 2011 were selected 

for this study. Both medical histories and applied treatments were 

evaluated. All doctors were interviewed to establish when the HC had taken 

place. The distribution of variables was analyzed and both populations 

compared. Results: Between January 2011 and December 2011, 110 

patients who met the previous criteria were studied. Population characteristics: 

Sex (Female: 52 pts; Male: 58 pts). Median age at the time of death: 

61 years (Range: 27-88). Patients were divided in two groups: A (terminal 

status of the disease had been discussed; 70 pts) and B (terminal status of 

the disease had not been discussed; 40 pts). Both groups were similar in 

diagnosis, age and previous treatments. During the post HC evolution, three 

elements were categorized according to the table below. Conclusions: 1– 

The conviction, ethical sense and strength of will of the doctor are 

determining factors when related to his or her capacity to talk with the 

patient about the terminal aspect of the disease. 2 – The chemotherapy 

treatments applied during the last two months of life are similar in both 

groups. 3 – The percentage of patients that died at their homes under 

palliative care was remarkably higher amongst those who had been 

informed than those who had not been informed. 

Group A 

N�70 (%) 

Group B 

N�40 (%) p value 

Condition 

Recieved chemotherapy in the 

two months prior to death 

24 (34%) 17 (42%) 0.391 

Received palliative care 55 (79% 15 (37%) 0.0001 

Died at home 44 (63%) 6 (15%) 0.0001 


4:45 PM-5:45 PM 

Women know, and men wish they knew, prognostic information in advanced 

cancer. Presenting Author: Kalen M. Fletcher, Dana-Farber Cancer Institute, 

Boston, MA 

Background: Little is known about gender differences in advanced cancer 

patient communication with oncologists. The few studies conducted have 

explored differences in preferences for prognostic disclosure. Our data 

allow us to test for gender differences in actual rates of audio-recorded, 

patient and oncologist reported, prognostic disclosures. We studied a group 

of advanced cancer patients to determine whether gender disparities exist 

in: a.) reported rates of prognostic disclosures from physicians and b.) 

willingness to estimate (versus not) one’s prognosis (i.e., amount of time 

left to live). Among patients who report never receiving a prognosis from 

their physician, we also tested for gender difference in wishing that this had 

been discussed. Methods: Coping with Cancer II is an NCI -funded 

multi-site, prospective longitudinal study of advanced cancer patients. 

Patients were interviewed after receiving scan results and asked if they 

have received a prognosis from their oncologist either at their most recent 

visit or at any time in the course of their disease. They are also asked if they 

would be willing to estimate their prognosis. Patients who state that they 

have not received a prognosis are asked if they wish that they had. Results: 

Among the advanced cancer patients studied (N�51; men�23, 

women�28), male cancer patients were significantly more likely to state 

never receiving a prognosis from their physician than female patients 

(OR�3.5; �2�4.49, df�1, p�0.034). Male cancer patients were also 

significantly less willing to provide a life-expectancy estimate (OR�5.6; 

�2�5.06, df�1, p�0.025). Among patients who stated never receiving a 

prognosis (N�27; men�16, women�11), male patients tended to be more 

likely than female patients to wish that their prognosis had been discussed 

(OR�7.8; �2�3.11, df�1, p�0.078). Conclusions: Male advanced cancer 

patients are less likely than female cancer patients to state that they have 

received prognostic information and less willing to provide a lifeexpectancy 

estimate. Although male patients receive less open prognostic 

disclosure than female patients, male patients tend to be more likely than 

female patients to want prognostic information. 


In-hospital cancer care: Are we missing an opportunity for end of life care? 

Presenting Author: Gabrielle Betty Rocque, University of Wisconsin Carbone 

Cancer Center, Madison, WI 

Background: Little data exists on the estimated survival of patients with 

metastatic cancer after hospitalization. As part of a prospective quality 

improvement project, we characterized the population of patients admitted 

to an inpatient oncology service in an academic medical center with 

emphasis on the disposition at discharge and overall survival. Methods: We 

collected data over a 4 month period (9/1/10-12/23/10) representing 149 

admissions of 119 unique patients. We measured patient characteristics, 

disease evaluation, procedures, consults, imaging studies performed, 

disposition, length of stay, and overall survival. These data were compared 

to a similar study conducted in our center in 2000. Results: Uncontrolled 

symptoms were the most common reason for admission (pain 28%, 

dyspnea 9%, nausea 9%). Imaging studies were more common than in 

2000 (415 vs. 196 total procedures). Eighty-five percent of patients had 

progressive disease. Seventy percent of patients were discharged home 

without additional services such as home health or hospice. The overall 

median survival was poor in 2000 and in 2010, 100 days and 60 days from 

discharge, respectively. Despite an overall poor prognosis, palliative care 

consultation was obtained only 13 times (8% of admissions) and 18% of 

patients were enrolled in hospice at discharge. Conclusions: An unscheduled 

hospital admission portends a poor prognosis. Cancer patients in the 

hospital are nearing the end-of-life with a median life expectancy of 

approximately 3 months and could be considered hospice-eligible and 

appropriate for a palliative care consult. We believe that hospital admission 

represents a missed opportunity to provide palliative care services and 

end-of-life counseling to this patient population. 



Palliative cancer therapy during end of life at a regional cancer center in 

Norway in 2005 and 2009. Presenting Author: Mari Aas Gynnild, Department 

of Cancer Research and Molecular Medicine, Norwegian University of 

Science and Technology and The Cancer Clinic, St. Olavs Hospital, 

Trondheim University Hospital, Trondheim, Norway 

Background: With increasing number of available therapies, there is a risk 

that patients (pts) are overtreated. Palliative cancer therapy is mostly 

recommended for pts with good Performance Status (PS). In one study, 42 

% of pts received chemotherapy (CTx) during the last 30 days of life – 

suggesting that this may not always be the case. Methods: All pts who, 

according to the national registry, died from cancer in our region in 2005 

and 2009 were analyzed. Data were collected from individual medical 

records. Endpoints: Time from the end of palliative cancer therapy until 

death. Whether there were differences depending on age; type of cancer; 

year of death or if they were seen at a palliative care unit (PCU). PS when 

the last cancer therapy was initiated. Results: 616 pts died in 2005; 599 in 

2009. We excluded 495 pts: No cancer therapy (n�260); no information 

of cancer (n�101); last therapy with curative intention (n�83); hematological 

malignancy (n�51). Median age 71 (6 - 99); 49 % men; median overall 

survival from diagnosis: 16.9 mos. Last therapy was radiotherapy (RT): 31 

%; CTx: 40 %; hormonal: 15 %; surgery: 11 %. 4 % died from treatment 

complications. Median time from start of last CTx or RT until death: 100 

days; from end of last CTx or RT: 63 days. Younger pts received more CTx 

and RT in the last 30 days: Age � 60: 28 %; 60-70: 23 % and 70�:12% 

(p�.001). The table shows the use of CTx and RT the last 30 and 14 days 

for the most common cancers. Among those who got CTx in the last 30 days 

(n�74); 54 % had PS 2; 14 % PS 3-4. Among those who got RT in the last 

30 days (n�61), 31 % had PS 2; 54 % PS 3-4. Of the 49 % referred to the 

PCU, fewer received CTx or RT in the last 30 days (PCU: 14 %, no PCU: 22 

%; p�.002) and 14 days (PCU: 5 %, no PCU: 12 %; p�.001). Conclusions: 

Many pts received cancer therapy the last month of life. The percentage 

varies with age, cancer type and was lower in 2009 than in 2005. Pts seen 

at the PCU received less CTx and RT. Many pts had a poorer PS at the start 

of last cancer therapy than recommended. 

(n in 2005/2009) 

Lung 

(n�74/81) 

Colon 

(n�57/52) 

Breast 

(n�34/33) 

Prostate 

(n�45/46) 

All 

(n�352/369) 

CTx last 30 d 19%/20% 4%/10% 18%/6% 0%/0% 11%/10% 

CTx last 14 d 12%/4% 0%/4% 12%/3% 0%/0% 6%/3% 

RT last 30 d 22%/11% 11%/4% 9%/6% 0%/11% 10%/7% 

RT last 14 d 12%/6% 5%/0% 6%/3% 0%/7% 5%/3% 


Feasibility and acceptability of patient-reported outcomes data collection 

for clinical care following breast reconstruction. Presenting Author: Andrea 

Pusic, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: To date, systematic measurement of patient-reported outcomes 

(PROs) has played an important role in cancer research, but not in 

routine clinical care. Our objective was to evaluate the feasibility of 

developing and piloting an electronic PRO data collection in clinical care 

among breast reconstruction patients using the BREAST-Q, a previously 

developed condition-specific PRO measure for breast surgery patients that 

measures quality of life (e.g. psychosocial, physical and sexual well-being) 

as well as patient satisfaction (e.g. satisfaction with breasts, with information, 

with surgeon). Methods: The BREAST-Q was loaded to the MSKCC 

WebCore, a generic electronic patient-reporting platform adhering to strict 

privacy and security standards. Patients attending visits at the MSKCC 

Breast Reconstruction Clinic were asked to complete the BREAST-Q 

electronically prior to scheduled visits. For patients with email addresses, a 

reminder with web-link to the questionnaire was emailed automatically 

prior to the visit. Results: Over a 9 month start-up period, BREAST-Q 

surveys were completed by 1442 patients. Patients completed the questionnaire 

at set time points before and after surgery. A total of 2340 BREAST-Q 

surveys were completed overall. Mean completion time was 5:53 minutes. 

Acceptability was high with both patients and clinical staff contributing 

positive comments along with suggestions for improvement via email. 

Conclusions: This pilot experience suggests that ePRO data can be 

efficiently collected among outpatient breast surgery patients with high 

acceptability. In the next phase of this project, we will introduce real-time 

individual patient reports to the clinical team and evaluate the impact of 

this information on clinical care and quality improvement. 


577s 


Effect of chemotherapy and psychosocial distress parameters on perceived 

cognitive disturbances in Asian breast cancer patients. Presenting Author: 

Yin Ting Cheung, National University of Singapore, Singapore 

Background: A qualitative study has revealed that Asian breast cancer 

patients attributed their post-chemotherapy cognitive disturbances to 

psychosocial distress. To validate this claim, we aim to examine perceived 

cognitive disturbances, anxiety and quality of life (QoL) in Asian breast 

cancer patients and to identify clinical and psychosocial factors associated 

with perceived cognitive disturbances. Methods: A prospective, observational 

study was held at the largest cancer center in Singapore. Chemotherapy 

(CT) and non-chemotherapy (non-CT) receiving breast cancer 

patients completed self- reported questionnaires to assess the following 

domains: patients’ perceived impact of chemotherapy on cognitive disturbances 

(FACT-Cog), health-related QoL (EORTC QLQ-C30) and anxiety 

(Beck Anxiety Inventory). Multiple regression was conducted to delineate 

factors associated with perceived cognitive impairment. Results: A total of 

166 (1:1 CT/non-CT) patients were recruited (age: 54.1�10.2 years; 

78.9% Chinese; 53.6% post-menopausal). Most of the CT patients 

received anthracycline-based chemotherapy (93.1%) and anti-hormonal 

therapy (69.4%). Comparing to non-CT patients, CT patients experienced 

more fatigue (QLQ-C30 fatigue scores: 22.2 vs 33.3 points; p�0.005), 

more significant anxiety (8.6% vs 21.9%; p�0.002), and more cognitive 

disturbances (FACT-Cog scores: 110 vs 124 points; p�0.0001). Regression 

model identified chemotherapy, anti-hormonal therapy, emotional 

functioning and global health status to be strongly associated with 

cognitive disturbances in Asian breast cancer patients. The interacting 

effect between anxiety and fatigue, comparing to fatigue alone, was more 

associated with cognitive disturbances (��-0.212; p�0.032 vs ��-0.07; 

p�0.25, respectively). Conclusions: This is the first study to demonstrate 

that Asian breast cancer patients experiencing both fatigue and anxiety are 

more predisposed to cognitive disturbances. Post-chemotherapy cognitive 

changes are observed in our patients, and our results suggest that 

psychosocial factors are impactful to identify cancer patients who are more 

susceptible to cognitive disturbances. 


Patient-reported satisfaction with reconstructed breasts in the long-term 

survivorship period: Comparison of autologous and nonautologous breast 

reconstruction. Presenting Author: Amie Scott, Memorial Sloan-Kettering 


Background: Breast cancer patients undergoing mastectomy may choose to 

have reconstruction performed using either their own tissue or an implant. 

As many patients are candidates for both, valid and reliable patientcentered 

outcomes data are crucial to shared medical decision-making. 

The objective of this study is to determine whether patient-reported 

satisfaction with their reconstructed breasts is dependent on type of 

reconstructive surgery and length of time from reconstruction. Methods: 

Participants were recruited from Memorial Sloan-Kettering Cancer, NY and 

the University of British Columbia, Canada. Patients completed the 

BREAST-Q, a new patient-reported outcome measure for breast surgery 

patients. The dependent variable was the BREAST-Q Satisfaction with 

Breast score, a 16-item scale scored from 0-100. Procedure type, time 

since surgery, and patient characteristics were independent variables. 

Univariate analysis and clinical judgment were used to identify variables 

included in the model, and multivariate linear regression models were 

constructed to control for confounders. Results: The study sample consisted 

of 510 women (response rate 62%). The sample was on average aged 54.3 

� 9.3 (range 21-81), surveyed 3.71 years � 1.55 (range 1-9) after 

surgery, 66% were reconstructed using an implant. Type of surgery and 

laterality were found to be variables that predicted higher patient satisfaction 

with their breasts after controlling for radiation therapy, follow-up time, 

timing of surgery, age, body mass index, and major complications (surgery 

type p�0.001; laterality p�0.001, R-square�0.17). Conclusions: As there 

is a growing population of breast cancer survivors, understanding how a 

woman’s satisfaction with her reconstructed breasts changes over time is 

essential. This study suggests that patient satisfaction with breast reconstruction 

depends on the type of reconstruction a woman undergoes. This 

patient-centered outcome data can be used to enhance shared medical 

decision-making by providing patients with information about realistic 

expectations for satisfaction with breasts related to type of surgery chosen. 




Predictors of resilience in women treated for breast cancer: A prospective 

study. Presenting Author: Barbara Kaye Bennett, University of New South 

Wales, Sydney, Australia 

Background: Because a cancer diagnosis may be regarded as a potentially 

traumatic event with untoward consequences, much research has focussed 

on negative aspects of cancer diagnosis and treatment, emphasising 

psychological outcomes. A recent paradigm shift recognises that such a 

psycho-pathological approach discounts the human capacity for resilience 

�the ability to maintain relatively stable functioning following an aversive 

life event� (Bonanno GA Curr Direct in Psychol Science 2005 14(3) 135). 

Predictors of resilience in women who recovered uneventfully from surgical 

and adjuvant treatment for early stage breast cancer were investigated in a 

prospective study. Methods: Validated self-report measures of mood, 

somatic symptoms, temperament, illness attitudes, and social support 

were completed post-surgery. Clinical, tumor and treatment details were 

recorded. At end treatment and subsequently at 1, 3, 6, 9 and 12 months, 

self-report measures of mood and somatic symptoms were completed. 

Resilience was defined as: no evidence of protracted psychological or 

somatic distress in the 12 months following treatment completion. Identified 

resilient and non-resilient groups were compared and predictors sought 

by logistic regression. Results: Of 218 women evaluated, 106 (49%) were 

classified as �resilient.� They either reported no clinically significant 

psychological or other distress post-surgery (34%) and 12months following 

adjuvant treatment or recovered promptly (15%) and remained well. There 

were no significant differences in age (52 years); marital status; tumor size; 

treatment; treatment toxicity (nadir hemoglobin and neutrophil count) or 

mortality at 5 years post treatment (8 confirmed deaths in each group). 

Logistic regression identified low neuroticism (temperament or personality 

trait) as the most significant predictor of resilience. Conclusions: These 

findings suggest that without any intervention almost half the women 

treated for breast cancer adapt well to diagnosis and treatment. These 

outcomes warrant further research, to provide further insight into how 

individuals cope with major illness and to facilitate development of 

programs to aid those in whom outcomes are protracted. 


Patient-related factors influencing time between first signs of breast cancer 

(BC) and appointment for medical visit (AMV): An international survey. 

Presenting Author: Jacek Jassem, Klinika Onkologii i Radioterapii Gdanski 

Uniwersytet Medyczny, Gdansk, Poland 

Background: Reducing diagnostic delays may improve treatment outcomes 

in BC. We investigated in various countries patient-related factors influencing 

time to seeking medical advice for signs of BC. Methods: A total of 

4,816 female BC patients from 10 countries were surveyed using a uniform 

questionnaire translated into local languages. Time between first patientdetected 

signs of BC and AMV was measured using categorized time scales. 

Out of 14 original items on a multiple scale measuring BC-related attitudes 

and behaviors, 5 factors were extracted and used for further analysis: 

distrust in medical system and success of therapy, disregard of signs, fear 

of BC, practicing regular breast self-examination and support from friends 

and family. Results: In the subset of 2,870 patients with self-detected BC 

who provided complete answers to relevant variables, the mean time to 

AMV varied in particular countries from 3.4 to 6.2 weeks (grand mean of 

4.7 weeks), with 39% of cases with a delay of �4 weeks. Overall, patient 

attributes that significantly influenced time to AMV were: distrust (p�1E- 

36), disregard (p�1.26E-30), fear (p�2.65E-16), self-examination 

(p�1.31E-21), place of living (p�3.5E-3) and education (p�2.73E-3). 

Multilevel analysis indicated that significant differences among particular 

countries were only due to slopes of distrust and disregard included in 

general regression model. The model enhanced with the two abovementioned 

random effects provided significant improvement in predicting time 

to AMV. Re-estimation of the model based solely on data from individual 

countries produced 10 significant equations with varied coefficients for 

distrust and disregard (see table). Conclusions: Patient-related factors 

contribute considerably to delay in the diagnosis of BC. Differences 

between particular countries call for country-specific approaches. 

Country Distrust Country Disregard 

Romania 2.3 Turkey 1.5 

Serbia 1.7 Serbia 1.5 

Slovakia 1.5 Latvia 1.4 

Hungary 1.4 Slovakia 1.1 

Latvia 1.2 Poland 1.0 

Poland 1.1 Russian Fed. 1.0 

Russian Fed. 0.9 Bulgaria 1.0 

Lithuania 0.9 Lithuania 0.6 

Bulgaria 0.7 Hungary 0.4 

Turkey 0.03 Romania -0.9 


Predictors of satisfaction with decision in patients with advanced cancer. 

Presenting Author: Felicitas Hitz, Department of Medical Oncology, Kantonsspital 

St.Gallen, St. Gallen, Switzerland 

Background: Treatment decisions in palliative cancer care depend on 

various patient-, treatment, and disease-related factors. This study investigated 

patients’ satisfaction with decision and decision-making preferences 

in a Swiss oncology network and evaluated factors that predict satisfaction 

with decision (SWD). Methods: Patients receiving a new line of palliative 

cancer treatment completed a multi-dimensional questionnaire 4-6 weeks 

after treatment decision. Patient-reports comprised socio-demographic 

information, satisfaction with decision (primary endpoint), subjective 

treatment goal, preferences for decision-making, health, locus of control, 

and several quality of life (QoL) domains. Information on diagnosis, line of 

therapy, metastases, prognosis, performance status and duration of consultation 

were provided by the attending physician. Predictors of SWD (range: 

0�worst; 30�best) were evaluated by uni- and multivariate (primary 

analysis, 80% power, 5% significance level) regression models. We 

consider �24 points as high SWD. Results: 445 out of 480 patients treated 

in 8 hospitals and 2 private practices completed all questions regarding the 

primary endpoint. 44% of patients preferred shared-, 42% physiciancentered 

decision making. Median duration of consultation was 30 minutes 

(range 10-200 minutes). Overall, 326 (73%) patients reported high SWD. 

In univariate analyses various factors (e.g. global and physical QoL, 

performance status, treatment goal, locus of control, prognosis and 

duration of consultation) were significant predictors of SWD. The only 

significant predictor in the multivariate analysis was duration of consultation, 

which was positively associated with SWD (p�0.01). Conclusions: 

SWD is generally high in patients with advanced cancer treated in an 

oncology network in Switzerland. Our results indicate that duration of 

consultation is a very important factor among many others in predicting 

SWD. In busy clinical practice, taking your time with patients may be a 

simple measure to enhance patients’ SWD. 


Validity and reliability of the patient-reported outcomes version of the 

common terminology criteria for adverse events (PRO-CTCAE). Presenting 

Author: Amylou C. Dueck, Mayo Clinic, Scottsdale, AZ 

Background: Symptomatic adverse events (AE) in cancer trials are reported 

by clinicians using the National Cancer Institute’s (NCI) Common Terminology 

Criteria for Adverse Events (CTCAE). To integrate the patient perspective 

into AE reporting, NCI contracted (HHSN261201000043C) to create 

a patient-reported outcomes companion tool (PRO-CTCAE). We report the 

validity and reliability of PRO-CTCAE’s 124 items reflecting 78 symptomatic 

AEs. Methods: English-speaking subjects (n�869; 44% male; median 

[mdn] age 59; 32% racial/ethnic minority; 34% high school or less; 17% 

ECOG Performance Status [PS] 2-4) receiving treatment for a range of 

cancers at 4 NCI-designated cancer centers and 5 sites in NCI’s Community 

Cancer Centers Program completed a web-based survey in clinic 

including PRO-CTCAE and EORTC QLQ-C30. Pearson correlations were 

computed between PRO-CTCAE items and QLQ-C30 scales. Differences in 

PRO-CTCAE item scores between clinician-reported ECOG PS (0-1 vs 2-4) 

groups were computed. Test-retest reliability of 48 prespecified items was 

evaluated in a subset (n�79). Results: Correlations in the expected 

direction were observed for 116/124 PRO-CTCAE items with the QLQ-C30 

global health scale (mdn r�-.21; range .08 to -.57). Stronger correlations 

were seen for PRO-CTCAE items with conceptually related QLQ-C30 

domains: fatigue with physical, role and social functioning (-.54 to -.66); 

anxiety and depression with emotional functioning (-.54 to -.70); and 

concentration and memory problems with cognitive functioning (-.62 to 

-.72) [all p �0.001]. Fatigue, nausea, vomiting, pain, dyspnea, insomnia, 

appetite loss, constipation and diarrhea items strongly correlated with 

corresponding QLQ-C30 symptom scales (.69 to .79, all p �0.001). 

Scores for 98/124 PRO-CTCAE items were higher in the ECOG PS 2-4 vs 

0-1 group (mdn effect size .3). Test-retest reliability was observed across 

all tested items (mdn intraclass correlation coeff .77; range .53 to .96). 

Conclusions: Results demonstrate favorable validity and reliability of 

PRO-CTCAE in a large, heterogeneous sample of patients undergoing 

cancer treatment. Further testing in multicenter treatment trials is underway. 



Patient-physician communication about code status preferences: A randomized 

controlled trial. Presenting Author: Wadih Rhondali, University of 


Background: Code status discussions are important in cancer care. The best 

modality for such discussions has not been established. Our objective was 

to determine the impact of a physician ending a code status discussion with 

a question (autonomy approach) versus a recommendation (beneficence 

approach) on patients’ do-not-resuscitate (DNR) preference. Methods: 

Patients in a supportive care clinic watched two videos showing a 

physician-patient discussion regarding code status. Both videos were 

identical except for the ending: one ended with the physician asking for the 

patient’s code status preference and the other with the physician recommending 

DNR. Patients were randomly assigned to watch the videos in 

different sequences. The main outcome was the proportion of patients 

choosing DNR for the video patient. Results: 78 patients completed the 

study. 74% chose DNR after the question video, 73% after the recommendation 

video (p�NS). Median physician compassion score was very high 

and not different for both videos (p�0.73). 30/30 patients who had chosen 

DNR for themselves and 30/48 patients who had not chosen DNR for 

themselves chose DNR for the video patient (100% v/s 62%, p�0.001). 

Age (OR�1.1/year, p�0.01) and white ethnicity (OR�9.43, p�0.004) 

predicted DNR choice for the video patient. Conclusions: Ending DNR 

discussions with a question or a recommendation did not impact DNR 

choice or perception of physician compassion. Therefore, both approaches 

are clinically appropriate. All patients who chose DNR for themselves and 

most patients who did not choose DNR for themselves chose DNR for the 

video patient. Age and race predicted DNR choice. 


Psychosocial correlates of sleep architecture in women with advanced 

breast cancer. Presenting Author: Arianna Aldridge Gerry, Stanford University 

School of Medicine, Stanford, CA 

Background: Sleep disturbance is prevalent among metastatic breast 

cancer (MBC) patients and few studies have objectively evaluated this 

problem using polysomnography (PSG). Disturbed sleep negatively affects 

quality of life. The current study examines the relationship of mood and 

family structure with sleep parameters assessed over three nights of PSG (2 

at-home, 1 in-lab). Methods: MBC patients (n � 103) and healthy controls 

(n � 27) were recruited. Patients were 57.8 years (SD � 7.7), non- 

Hispanic white (86.3%), and had Karnofsky ratings of at least 70%. 

Multiple regression analyses assessed relationships among depression, 

cohabitation, and sleep parameters. Results: Among patients, sleep architecture 

was significantly related to depression and marital status/ 

cohabitation. Women reporting more depressive symptoms had less deep 

sleep: lower percentage (B � -.26, p � .01) and fewer minutes of REM (B 

� -.23, p � .02), lower % (B � -.25, p � .02) and fewer minutes of stage 2 

sleep (B � -.28, p � .01), and more % stage 1 sleep (B � .28, p � .01). 

Marriage/cohabitation was positively related to sleep quality indicators: 

less wake time after sleep onset (B � -.20, p � .05), better sleep efficiency 

(B � .28, p � .01), more total sleep time (B � .30, p � .01), more minutes 

of REM (B � .23, p � .02), more stage 2 sleep (B � .27, p � .01), and less 

% stage 1 sleep (B � -.27, p � .01). Relative to healthy women, patients 

had more sleep stage transitions/hour (B � .21, p � .03), more awakenings 

(B � .18, p � .04), and more time awake after sleep onset (B � .21, p � 

.02). Slow wave (deep, non-REM) sleep was shorter for patients as 

measured by both minutes (B � -.20, p � .04) and % of stage 4 sleep (B � 

-.23, p � .02). Conclusions: Depressed patients or those living alone have 

greater reductions in deep sleep. Relative to healthy women, patients’ sleep 

disturbance and quality was worse. These findings demonstrate that the 

architecture of deep sleep is linked to depression and family structure. 


579s 


Smoking habits of relatives of patients (pts) with cancer. Presenting 

Author: Mutlu Hayran, Hacettepe University Institute of Oncology, Ankara, 

Turkey 

Background: We aimed to determine the rate and habitual patterns of 

smoking, intentions of cessation, dependence levels and sociodemographic 

characteristics of relatives of cancer patients. Methods: The 

smoking habits of relatives of cancer pts were evaluated with a questionnaire 

and Fagerstrom test (FT) of nicotine dependence. FT and a questionnaire 

form were filled in by the volunteers. The quit rate of the relatives of 

the cancer pts was compared with the rates declared in the literature. 

Results: A total of 560 subjects who have relatives of pts with cancer. The 

median age of those with lower and higher Fagerstrom scores (FS) were 40 

years and 42 years, respectively (p�0.001). We found no association 

between FS and sociodemographic variables, such as the subject’s medical 

status, gender, living in the same house, educational status, family income, 

closeness and time spent with the cancer pts. Only 2% of the subjects 

started smoking after cancer was diagnosed in their relative and almost 

20% of subjects had quit smoking within the year. Spontaneous quit rates 

of these subgroup of smokers (20%) was significantly higher than reported 

self-quit rates (max. ~10%) in the literature (p�0.001). Conclusions: The 

FS is known to be helpful in determining who would benefit from a cigarette 

smoking cessation program. We also show here that the cancer diagnosis in 

a smoker’s family motivates this individual to quit smoking and may create 

a time window for any involved health staff to intervene for help. This study 

was designed by the Turkish Oncology Group, Epidemiology and Prevention 

Subgroup. 

Individual characteristics by Fagerstrom score. 

Low FS High FS 

n % n % p 

Sex F 33 27 18 21 0.358 

M 89 73 66 79 

Education Literate 4 3 4 5 0.183 

Primary 45 37 33 39 

High 34 28 30 35 

University 39 32 18 21 

Income �1000 TL 58 49 31 39 0.266 

1001-3000 TL 43 36 38 47 

�3000 TL 18 15 11 14 

Finds smoking bans effective No 44 36 44 48 0.028 

Yes 77 64 41 52 

Wants professional help No 55 46 37 45 0.860 

Yes 65 54 46 55 

Obeys smoking bans No 10 8 17 20 0.012 

Yes 112 92 67 80 

Contemplates quitting No 38 31 31 36 0.001 

Indecisive 6 5 5 6 

Yes 77 64 49 58 


Mistletoe as complementary treatment in patients with advanced non-small 

cell lung cancer treated with carboplatin-based combinations: A randomized 

phase II study. Presenting Author: Gil Bar-Sela, Division of Oncology, 

Rambam Health Care Campus, Haifa, Israel 

Background: The mistletoe preparation, iscador, is commonly used in 

complementary medicine for improving the quality of life (QoL) of cancer 

patients, but its efficacy needs to be further proved. This randomized phase 

II study was aimed at assessing the value of iscador as a modifier of 

chemotherapy-induced toxicity in chemotherapy-naïve non-small-cell lung 

cancer (NSCLC) patients treated with carboplatin containing regimens. 

Methods: Patients with stage IIIA or IIIB/IV NSCLC, ECOG performance 

status 0-2, and no history of brain metastasis were randomized to receive 

either chemotherapy alone (arm-1) or chemotherapy plus iscador Q 10mg 

SC injections 3 times weekly until tumor progression (arm-2). Chemotherapy 

consisted of 21-day cycles of IV carboplatin area under curve 5.0, 

day 1, combined with IV gemcitabine 1000mg/m2 , days 1, 8, or with IV 

pemetrexed 500mg/m2 , day 1. Results: Seventy-two patients were enrolled, 

39 to arm-1 and 33 to arm-2. The arms were well balanced except that 

more patients with PS-0 were in arm-1 (p�0.041). Most patients (65%) 

were in stage IV and 62% had squamous histology. Median overall survival 

was 11 months in both arms. Median TTP was 4.8 months (arm-1) and 6 

months (arm-2) (p�0.07). Carboplatin dose reductions and delays in 

gemcitabine on day 8 were more frequent in arm-1 (44% vs. 13% in arm-2, 

p�0.005; 31% vs. 13% in arm-2, p� 0.013). The difference in grade 3-4 

hematological toxicity was not significant. More non-hematological toxicity 

was observed in arm-1 (41% compared to 16% in arm-2, p�0.043). The 

number of hospitalizations was higher in arm-1, 54%, compared to 24% in 

arm-2 (p�0.016). No significant difference was seen in QoL using the 

EORTC QLQ-C30 questionnaire; However, significant improvement in 

arm-2 was seen in coughing (p�0.013) and peripheral neuropathy 

(p�0.019). Conclusions: Chemotherapy dose reductions, severe nonhematological 

side effects, and hospitalizations were less frequent in 

patients treated with iscador. Further investigation of iscador as a modifier 

of chemotherapy-related toxicity is warranted. 




3D index calculated from duration and severity of neutropenia and a degree 

of fever as prognostic factors predicting mortality of chemotherapy-induced 

febrile neutropenia in hematologic malignancies. Presenting Author: Ryosuke 

Shirasaki, Department of Hematology/Oncology, Teikyo University 

School of Medicine, Tokyo, Japan 

Background: Risk stratification of patients with febrile neutropenia (FN) is 

important to select the suitable therapeutic option. Although the MASCC 

scoring system is used as a reliable risk-discriminator, the objective 

evaluation of “burden of illness” has been difficult to be pointed-out. The 

latest IDSA Guidelines on FN proposes a set of risk factors based on the 

expert’s recommendations. The present study demonstrates usefulness of 

newly proposed 3D-index on predicting mortality of chemotherapy-induced 

FN in hematologic malignancies (HM). Methods: Patients with HM admitted 

to our hospital between Jan 2008 and Dec 2011 were enrolled, and 

data from 282 FN episodes in 129 FN patients including 20 infectionassociated 

deaths were retrospectively analyzed to determine useful 

prognostic factors on the mortality of FN. Correlation between mortality and 

59 characteristics including 3D-index were examined by univariate analysis 

and receiver operating characteristic curve analysis. 3D-index is a 

duration and severity of neutropenia and degree of fever. Total duration of 

days during neutropenia was not calculate at the time of risk evaluation. 

3D-indexes after three and five days from the start of FN were also 

analyzed. Results: 32 out of 59 characteristics were significantly correlated 

with mortality by univariate analysis. Among them, 3D-index and 3Dindexes 

after three and five days were demonstrated as more useful factors 

(3D-index, p�0.0015; 3D-index after three days, p�0.0030; 3D-index 

after five days, p�0.0044). And 3D-index after three days over 4000 

indicates patients’ mortality above 20%, index 2600-4000 15-20% , 

index 900-2600 10-15%, and index below 900 below 10%, respectively. 

Conclusions: 3D-indexes after three days were suggested as useful predictors 

for infection-related mortality during FN. It was suggested that FN 

patients were categorized into four risk groups according to the value. 


Comparison of three different radiation fractionation schedules in the 

palliation of painful bone metastasis. Presenting Author: Monica Malik, 

Nizam’s Institute of Medical Sciences, Hyderabad, India 

Background: The purpose of this study was to compare the efficacy of a 

single fraction versus two multifractionated regimens in the palliation of 

painful bone metastases. Methods: Patients with painful bone metastases 

were randomized into three groups. Group I received a dose of 8 Gy in a 

single fraction, Group II received 20 Gy in five fractions and Group III 

patients received 30 Gy in 10 fractions. Pain score, ECOG performance 

status and analgesic requirement were recorded at baseline and at 1, 4, 8 

and 12 weeks following treatment. Pain score was recorded on a 5-point 

verbal rating scale from 0 (no pain) to 4 (extremely severe pain). Overall 

response was defined as decrease in pain score by at least one point. 

Complete response was defined as achieving a pain score of zero at any 

point during follow-up. Duration of overall response was defined as the time 

from initial response till return of pain to its baseline value. Results: 45 

patients were included with 15 in each group. Median age was 55 years 

(range 29-78 years). 17(37.7%) had metastasis in pelvic bones; 17(37.7%) 

in the spine while the remainder in the appendicular bones. Overall 

response rates in Groups I, II and III at week 1 were 60%, 53.3% and 60% 

respectively (p�0.71). At 1 month, overall response rates were 71.4%, 

73.3% and 73.3% (p�0.84) and at 3 months; 78.5%, 80% and 80% 

respectively (p�0.86). The rate of complete response in all the three 

groups was 20%. Improvement in performance status in Groups I, II and III 

was seen in 60%, 66% and 80% respectively (p�0.69). Analgesic usage 

decreased in 86%, 87% and 80% patients in groups I, II and III 

respectively (p�0.66). Out of the nine complete responders, two sustained 

the response for less than four weeks, four patients up to eight weeks and 

remaining three till the end of follow-up. There was no statistically 

significant difference in between the three arms among all the variables 

compared. Conclusions: All three groups showed equal efficacy in pain 

palliation, analgesic requirement, improvement in performance status and 

duration of response. In patients with very advanced disease and short life 

expectancy, where the treatment goal is to decrease pain, 8 Gy in single 

fraction is a convenient and cost effective schedule. 


A positron emission tomography (PET) study to assess the degree of 

neurokinin-1 (NK1) receptor occupancy in the human brain after single 

doses of netupitant to healthy male subjects. Presenting Author: Giorgia 

Rossi, Helsinn Healthcare SA, Lugano, Switzerland 

Background: Netupitant (NETU) is a highly selective neurokinin 1 (NK1) receptor antagonist for the prevention of nausea and vomiting associated 

with emetogenic chemotherapy. In this study, PET imaging with the NK1 receptor-binding–selective tracer 11C-GR205171 was used to determine 

the levels and the duration of central NK1 receptor occupancy (RO) 

achieved by therapeutic doses of NETU. Methods: This was a single dose, 

randomized, open-label, PET study investigating the degree of NK1 RO in 

human brain after single oral doses of NETU (100, 300 or 450 mg) in 6 

healthy male subjects. PET scans and blood samples for NETU determination 

were obtained up to 96 hrs post dose. The Patlak model was used to 

define the net uptake rate of 11C-GR205171 in the brain regions of interest 

while the percent of NK1 RO was calculated as the relative difference 

between the uptake rate at baseline and post-treatment administration. 

Results: NETU plasma concentrations over the 100 mg to 450 mg dose 

range were comparable with those obtained in previous single dose studies. 

ANK1RO of 90% or higher was achieved with all tested single oral doses in 

the majority of the outlined brain regions 6 hrs after dosing (corresponding 

to netupitant Cmax). All doses had a long duration of blockade of NK1 receptors with the 300 mg dose showing moderate (62%) to high (94%) 

NK1 RO for all investigated brain regions at 96 hrs post dose. The 

relationship between NETU concentration and NK1 RO, assessed using a 

sigmoid Emax model, indicated that in the striatum, the reference brain 

area with the highest NK1 receptor expression, a concentration of 225 �g/L 

of NETU corresponded to an NK1 RO of 90%. This data suggests that a 

single oral dose between 100 and 300 mg NETU would be needed to reach 

90% NK1 RO levels in human brain. Conclusions: PET results demonstrate 

that NETU is a potent agent targeting NK1 receptors with a high degree of 

occupancy for a long duration. NETU, given as single doses of 100 to 450 

mg was well tolerated. 


Pulmonary symptoms and their importance to patients with non-small cell 

lung cancer undergoing second- and third-line chemotherapy. Presenting 

Author: Susan Magasi, Northwestern University Feinberg School of Medicine, 

Chicago, IL 

Background: As new cancer therapies are developed, it is important to 

evaluate their efficacy based not only on survival outcomes but also 

meaningful patient benefit in terms of symptoms and concerns that are 

important to patients. The purpose of this study of patients undergoing 

2nd /3rd line chemotherapy for non-small cell lung cancer (NSCLC) was to 

characterize pulmonary symptoms and the importance patients place on 

these symptoms, as a part of assessing the content validity of the 

Pulmonary Symptom Index (PSI) of the Functional Assessment of Cancer 

Therapy – Lung (FACT-L). Methods: We conducted semi-structured thematic 

interviews with 20 stage III/IV NSCLC patients undergoing 2nd or 3rd line treatment. Interviews included open elicitation of NSCLC symptoms 

and their functional impact, and participant ratings of the relative importance 

of pulmonary symptoms. Results: Mean age was 62 years (range 

30-79); 80% had non-squamous histology, and 30% had co-morbid COPD. 

While participants described a range of symptom experiences and severity, 

a core set of pulmonary symptoms emerged - shortness of breath (reported 

by 16/20, 13/20 rated as very important), cough (reported by 14/20, 10/20 

rated as very important), and chest tightness (reported by 15/20, 9/20 

rated as very important); these matched key symptoms in the PSI. 

Symptom importance ratings were influenced by the functional impact they 

had upon patient ability to perform valued roles and responsibilities. 

Patients described diverse coping strategies including breaking down 

activities into manageable tasks, priority setting, physical assistance, 

emotional support, and health promoting changes in diet and exercise. 

Ninety percent (18/20) of participants reported tiredness or fatigue; most 

said it was “very important.” A quarter (5/20) of the participants reported 

having no pulmonary symptoms. Conclusions: These results in NSCLC 

patients undergoing 2nd /3rd line treatment support the importance, relevance, 

and impact of core pulmonary symptoms included in the PSI and 

offer initial evidence that its content may constitute a key element of 

patient benefit in evaluating the efficacy of new cancer therapies. 



Widespread use of complementary and alternative medicine (CAM) among 

non-Hodgkin lymphoma (NHL) survivors. Presenting Author: Alexis D. Leal, 


Background: The incidence of CAM use among patients with cancer is 

higher when compared to the general population. However, there are few 

studies examining CAM use in NHL survivors, and limited data are available 

regarding beliefs in CAM. This study was conducted to examine the 

prevalence of CAM use in NHL, define CAM beliefs among NHL survivors, 

and explore differences between patients with indolent and aggressive 

lymphoma. Methods: Newly diagnosed lymphoma patients were prospectively 

enrolled within 9 months of diagnosis in the University of Iowa/Mayo 

Clinic SPORE Molecular Epidemiology Resource from 2002-2008. NHL 

patients who completed the 3-year post diagnosis questionnaire, which 

includes questions regarding CAM use and beliefs, were included in this 

study. Chi-squared tests and Wilcoxon rank-sum tests were used to assess 

the association of CAM use with prognostic and demographic factors. 

Results: 719 patients were included with a median age of 63 years (range 

22-92). 53% were male. Overall, 636 (89%) reported ever using CAM. 

78% of patients used vitamins and 54% alternative therapies (chiropractic 

(36%) and massage therapy (24%)). Among CAM users, 141 (22%) 

believe CAM can assist the body to heal, 123 (19%) believe CAM can 

relieve cancer symptoms, 115 (18%) believe CAM use gives a feeling of 

control, 106 (17%) believe CAM can boost immunity, 24 (4%) believe 

CAM can cure cancer, and 35 (6%) believe CAM can prevent the spread of 

cancer. Female gender was associated with increased overall CAM use 

(p�0.0001) as well as use of vitamins (p�0.0001), herbal supplements 

(p�0.006) and alternative therapy (p�0.0002) specifically for cancer. 

Older age was also associated with increased vitamin use (p�0.005) and 

decreased herbal supplements use (p�0.008). There was no significant 

difference in overall CAM use between those with follicular lymphoma 

grades I-II (n�195, 91%) and non-relapsed diffuse large B-cell lymphoma 

(n�151, 87%), although massage therapy was utilized more often by FL 

survivors (29% versus 18%, p�0.005). Conclusions: CAM modalities are 

used by the majority of NHL survivors (89%). The assessment of CAM use 

and education regarding potential harms is imperative for the NHL survivor. 


Prevention of palmoplantar erythrodysesthesia (PPE) with an antiperspirant 

in breast cancer patients treated with pegylated liposomal doxorubicin 

(PLD), a placebo-controlled, double blinded, phase lll trial (SAKK 92/08). 

Presenting Author: Thomas Ruhstaller, Swiss Group for Clinical Research, 

Berne, Switzerland 

Background: PPE, also known as hand-foot syndrome, is a distinctive 

adverse drug reaction of PLD treatment. PLD has been detected in elevated 

concentrations in eccrine sweat glands in palms and soles. We postulated 

that prophylactic administration of an antiperspirant (F511 cream) prior 

and during treatment with PLD could decrease the incidence of PPE. 

Methods: Patients (pts) with metastatic breast cancer treated with PLD 

monotherapy �10mg/m2 per week applied an antiperspirant to the left or 

right hand and foot and a corresponding placebo to the opposite site with 

double-blinding for the content of the cream applied to either side 

(intra-patient randomization). The creams were applied once daily during 

the first week, then three times per week. The primary endpoint was the rate 

of PPE grade (G) � 2 in the antiperspirant or placebo treated side. Pts were 

evaluable if they developed PPE G � 2 or had received cumulatively at least 

160mg/m2 PLD. Patient-reported extent of symptom burden was a secondary 

endpoint. Using McNemar’s matched pairs design 53 pts were needed 

to detect a difference of 20% between the sides with a significance level of 

5% and power of 90%. Results: 52 of 90 pts from 11 Swiss centers 

included were evaluable. Median age was 64.5 years; median duration of 

PLD treatment was 12 weeks. 30 pts developed PPE G � 2. In 3 pts PPE G 

� 2 occurred on the placebo side but not on the antiperspirant side 

(p�0.097; table). PPE G � 2 was borderline significantly more frequent in 

placebo foot than antiperspirant foot (p�0.048). Patient-reported extent of 

symptom burden showed a trend in favor of the antiperspirant side for skin 

problems (peeling, blistering, bleeding) in the group of pts with PPE G � 2 

(p�0.051). Conclusions: In this double-blind trial with intra-patient randomization 

we observed a trend towards less PPE G � 2 with application of the 

antiperspirant cream F511 in pts treated with PLD as determined by the 

treating physician and reported by the pts. 

Antiperspirant side 

PPE grade > 2 toxicity 

No Yes Total 

Placebo side 

No 22 (42%) 0 (0%) 22 (42%) 

Yes 3 (6%) 27 (52%) 30 (58%) 

Total 25 (48%) 27 (52%) 52 (100%) 


581s 


Prospective survey study regarding the implementation of new communication 

skills curriculum for medical oncology trainees. Presenting Author: 

Nathan M. Shumway, San Antonio Military Medical Center, Ft. Sam 

Houston, TX 

Background: After a diagnosis of cancer, many patients suffer from anxiety 

and distress from uncertainty of symptoms, treatments, and prognosis. 

Clinicians must recognize opportunities to explore concerns. This study 

assesses oncology trainees’ views about communication with cancer 

patients before (PRE) and after (POST) a 12 month curriculum. Methods: 

Medical oncology fellows were surveyed PRE and POST a communication 

curriculum consisting of case studies and 6 core lectures which included 

fundamentals, breaking bad news, transitions to palliative care, advanced 

care planning, conducting family conferences, and discussing treatment 

options and informed consent. A 5 point Likert-scale was used to measure 

fellows’ attitudes and comfort regarding communication PRE and POST 

with questions grouped according to core topics. (�2 � trainee disagreement, 

3�neutral opinion, and � 4 indicated agreement). Results: PRE and 

POST surveys were completed by 11 and 8 trainees respectively. In PRE 

100% felt communication skills were important and 63% believed these 

skills could be taught. 82% felt there was not enough time during most 

visits to address emotion. This decreased to 27% in POST. 18% PRE 

agreed they were comfortable recognizing coping mechanisms versus 

100% POST. 45% felt comfortable eliciting values in PRE versus 87.5% 

POST. Only 1 fellow (9%) felt comfortable addressing futility in PRE versus 

25% in POST. The median grouped score for fundamentals increased from 

15 to 17 (p�0.016) and median grouped score for advance care plans and 

DNR increased from 11 to 13(p�0.026). Conclusions: There is a need to 

improve oncology communication skills. Our curriculum is just one approach. 

After intervention, the majority of fellows agreed there was enough 

time to address emotion and felt more comfortable recognizing coping 

mechanisms and eliciting values. Discussing futility remains difficult for 

our fellows. All fellows were more comfortable with fundamental communication 

skills and advance care plans after the curriculum. The extent the 

curriculum contributed to the change in survey results is unclear. Further 

research is needed to guide communication education of oncologists. 


Pharmacokinetics, pharmacodynamics, and tolerability of BCD-017, a 

novel pegylated filgrastim: Results of open-label controlled phase I study 

with dose escalation in healthy volunteers. Presenting Author: Kirill D. 

Nikitin, BIOCAD, Moscow, Russia 

Background: Pegfilgrastim (conjugate of filgrastim and 20 kDa PEG) is 

approved for treatment of chemotherapy-associated neutropenia. BCD-017 

is a covalent conjugate of filgrastim with 30 kDa PEG. Increased molecular 

weight of PEG molecule may provide additional benefits compared to 

pegfilgrastim. We have conducted this open-label phase I study to assess 

the PK, PD and tolerability of BCD-017. Methods: 24 healthy male 

volunteers signed the informed consent and were sequentially assigned to 

receive 1, 3 or 9 mg of BCD-017 or 5 mcg/kg/day of filgrastim for 7 days, 6 

volunteers per group. Outcome measures included absolute neutrophil 

count (ANC) and �D34� cell count, PK parameters and adverse events 

(AEs). Results: BCD-017 induced a fast and significant increase of ANC. 

Median maximum ANC (ANCmax) for BCD-017 1, 3, 9 mg and filgrastim 

was 18.68 (10.62-21.02), 25.92 (15.43-28.07), 32.22 (18.22-45.79), 

and 28.21 (21-31.95) �103 cells/mm3 , respectively; median time to 

ANCmax was 24 (12-24); 48 (24-72); 72 (48-72); and 132,5 (12-169) h, 

respectively; median increase in �D34� cells number 96 h post dose was 

4.7 (1.2-6.5), 6.5 (1.7-12.3), 40.9 (24.5-102), and 17.8 (3.3-35.2) 

times, respectively. Filgrastim serum concentration was analyzed using 

ELISA. Median Cmax for BCD-017 3 and 9 mg and filgrastim was 45 

(31-65), 446 (191-649), and 40 (20-54) ng/mL, respectively; median 

Tmax was 48 (24-72), 36 (24-48), and 8 (6-8) h respectively; median T1/2 was 65 (51-70), 46 (41-57), and 6.7 (6.2-7.6) h, respectively. BCD-017 

was well tolerated. No dose-limiting AEs were observed. AEs included 

headache, back pain, myalgia, arthralgia, thrombocytopenia, hyperuricemia, 

alkaline phosphatase/LDH increased. All AEs were of grade 1-2. 

Compared to filgrastim, the best tolerability was observed in 3 mg group. 

Conclusions: BCD-017 is shown to be a potent stimulator of granulopoiesis. 

BCD-017 3 mg did not differ from filgrastim in terms of ANC increase and 

its safety was shown in healthy volunteers. Further phase II study of 

BCD-017 for treatment and prophylaxis of neutropenia in patients receiving 

cytotoxic chemotherapy is necessary. 




Randomized double-blind evaluation of dronabinol for the prevention of 

chemotherapy-induced nausea. Presenting Author: Steven M. Grunberg, 

Fletcher Allen Health Care, Burlington, VT 

Background: Although great progress has been made in the control of 

chemotherapy-induced vomiting (CIV), prevention of chemotherapyinduced 

nausea (CIN) has been less successful. Preliminary data suggests 

that some families of lesser used antiemetic agents, such as the cannabinoids, 

may have greater efficacy against nausea than against vomiting. 

Methods: Adult solid tumor patients (pts) receiving cyclophosphamide 

� 1500 mg/m2 (C) and/or doxorubicin � 40 mg/m2 (A) were eligible. Pts 

could have received prior mildly emetogenic chemotherapy (EC). Pts were 

not eligible who were receiving other moderately or highly EC, were 

receiving cranial, abdominal or pelvic radiotherapy, had CIV/CIN with 

previous chemotherapy, had other causes for nausea/vomiting besides 

chemotherapy, or were scheduled to receive other antiemetics. Pts with 

habitual cannabinoid use were not eligible. All pts received palonosetron 

0.25 mg (PALO) and dexamethasone 10 mg (DXM) IV before chemotherapy. 

Patients were randomized double-blind to receive dronabinol 5 mg 

(D) or matching placebo (P) 3 times a day for 5 days. Nausea, vomiting and 

toxicity data was collected daily for 5 days. Results: 62 pts were entered on 

study – female/male 61/1, White/Black/Hispanic/Other 45/14/2/1, median 

age (range) 58 (29-76). No significant difference was noted in CIVdependent 

endpoints (including No Vomiting, Complete Response, or 

Complete Protection) or in rescue medication use. However pts receiving D 

had a shorter duration of nausea – Mean number of days of nausea (D vs P) 

1.86 days vs 3.10 days (p�0.027) – and a trend toward greater frequency 

of No Nausea (D vs P) 37% vs 17% (p�0.143). Common toxicities 

included fatigue (D/P 17/11), headache (D/P 16/16), dizziness (D/P 14/7), 

constipation (D/P 14/11), and diarrhea (D/P 13/6) No pt discontinued 

therapy due to mood changes. Conclusions: Low-dose D decreased the 

duration of CIN and increased the frequency of No Nausea in pts receiving 

C and/or A. Agents to prevent CIV (such as PALO and DXM) and to prevent 

CIN (such as D) have complementary activity and result in improved overall 

control when used together. 


Decision-making preferences of advanced cancer Hispanic patients from the 

United States and Latin America. Presenting Author: Henrique Afonseca 

Parsons, University of Texas M. D. Anderson Cancer Center, Houston, TX 

Background: To determine whether preferences in frequency of passive decision 

making differ between Hispanic patients from Latin America (HLA) and 

Hispanic-American (HA) patients. Methods: We conducted a survey of advanced 

cancer Hispanic patients referred to outpatient palliative care clinics in the U.S, 

Chile, Argentina, and Guatemala. Information on demographic variables, PS,and- 

Marin Acculturation Assessment Tool (only U.S. patients) was collected. 

Decision-making preference was evaluated by the decision-making assessment 

tool. Results: A total of 387 patients with advanced cancer were surveyed: 91 

(24%) in the US, 100 (26%) in Chile, 94 (25%) in Guatemala, and 99 (26%) in 

Argentina. Median age was 59 years, and 61% were female. HLA preferred 

passive decision-making strategies significantly more frequently with regard to 

involvement of the family (24% versus 10%, p�0.009) or the physician (35% 

versus 26%, p�0.001), even after controlling for age and education (OR 3.8, 

p�0.001 for physician and 2.4, p�0.03 for family) (Table 1). 76/91 HA 

(83.5%), and 242/293 HLA (82%) preferred family involvement in decisionmaking 

(p�NS). No differences were found in decision-making preferences 

between low- and highly acculturated U.S. Hispanics. Conclusions: HA prefer 

more active decision-making as compared to HLA. Among HA, acculturation did 

not seem to play a role in decision-making preference determination. Our 

findings in this study confirm the importance of family participation in decision 

making in both HA and HLA. However, HA patients were much less likely to want 

family members or physicians to make decisions on their behalf. 

Distribution of decision-making preferences according to the dyadic independent 

relationships between patient and family. 

USA 

(N�90) 

Latin America 

(N�296) 

n (%) n (%) p 

Passive 9 (10%) 69 (24%) �0.001 

Shared 45 (50%) 144 (49%) 

Active 32 (36%) 64 (22%) 

Didn’t know/preferred not to answer 4 (4%) 17 (6%) 

Distribution of decision-making preferences according to the triadic simultaneous 

relationships between patient, physician, and family. 

USA 

(N�91) 

Latin America 

(N�293) 

n (%) n (%) 

p 

Passive 13 (14%) 69 (23.5%) �0.001 

Shared 31 (34%) 151 (51.5%) 

Active 47 (52%) 73 (25%) 


The effect of melatonin on appetite and other symptoms in patients with 

advanced cancer and cachexia: A double-blind placebo-controlled trial. 

Presenting Author: Egidio Del Fabbro, University of Texas M. D. Anderson 


Background: Patients with advanced cancer experience anorexia and weight 

loss which impairs their quality of life. Prior studies suggest melatonin, a 

frequently used integrative medicine may attenuate weight loss, anorexia, 

fatigue, and depression. These studies were limited by a lack of blinding 

and absence of placebo controls. The primary objective of this study was to 

compare melatonin to placebo for appetite in patients with cachexia. 

Methods: A randomized, double-blind, 28 day trial of melatonin 20mg vs. 

placebo in patients with advanced lung or gastrointestinal cancer, appetite 

scores �3 ona0to10scale (10 � worst appetite) and a history of weight 

loss � 5% within 6 months. Patients unable to maintain oral intake, thyroid 

or adrenal dysfunction, or with a karnofsky �40 were excluded from the 

study. The assessments included weight, symptom severity by Edmonton 

Symptom Assessment Scale (ESAS) and quality of life by the Functional 

Assessment of Anorexia/Cachexia Therapy (FAACT).Differences between 

groups from baseline to day 28 were analyzed using one-sided two sample t 

tests (appetite, pain and well-being) or Wilcoxon two-sample tests for the 

other variables. Interim analysis at half point had a Lan-DeMets monitoring 

boundary with an O’Brien-Fleming stopping rule. The decision boundaries 

for the interim test was to accept the null hypothesis of no treatment 

difference (futility) if the test statistic Z � 0.39 (p � 0.348). Results: After 

interim analysis of 48 patients, the study was closed by the Data Safety 

Monitoring Board for futility. There were no significant differences between 

groups in appetite (p�0.78), weight (p� 0.17), FAACT score (p�0.95), 

insomnia (p�0.62) or other symptoms measured by the ESAS from 

baseline to day 28.No significant toxicities were observed. Conclusions: In 

cachectic patients with advanced cancer, 20mg oral Melatonin at night 

does not improve appetite, weight or quality of life compared to placebo. 


The use of olanzapine versus metoclopramide for the treatment of breakthrough 

chemotherapy-induced nausea and vomiting (CINV) in patients 

receiving highly emetogenic chemotherapy. Presenting Author: Rudolph M. 

Navari, Indiana University School of Medicine South Bend, South Bend, IN 

Background: Olanzapine (OLN) has been shown to be a safe and effective 

agent for the prevention of CINV. OLN may also be an effective rescue 

medication for patients who develop breakthrough CINV despite having 

received guideline directed CINV prophylaxis. Methods: A double blind, 

randomized phase III trial was performed for the treatment of breakthrough 

CINV in chemotherapy naïve patients receiving highly emetogenic chemotherapy 

(HEC) (cisplatin, �70 mg/m2 , or doxorubicin, �50 mg/m2 and 

cyclophosphamide, � 600mg/m2 ) comparing OLN to Metoclopramide 

(METO). Patients who developed breakthrough emesis or nausea despite 

prophylactic dexamethasone (12 mg IV), palonosetron (0.25 mg IV), and 

fosaprepitant (150 mg IV) pre chemotherapy and dexamethasone (8 mg 

p.o. daily, days 2-4) post chemotherapy were randomized to receive OLN, 

10 mg orally daily for three days or METO, 10 mg orally TID for three days. 

Patients were monitored for emesis and nausea for the 72 hours after taking 

OLN or METO. Eighty patients (median age 56 yrs, range 38-79; 43 

females; ECOG PS 0,1) consented to the protocol and all were evaluable. 

Results: During the 72 hour observation period, 30 of 42 (71%) patients 

receiving OLN had no emesis compared to 12 of 38 (32%) patients with no 

emesis for patients receiving METO (p�0.01). Patients without nausea (0, 

scale 0-10, M.D. Anderson Symptom Inventory) during the 72 hour 

observation period was: OLN: 67% (28 of 42); METO 24% (9 of 38) 

(p�0.01). There were no Grade 3 or 4 toxicities. Conclusions: OLN was 

significantly better than METO in the control of breakthrough emesis and 

nausea in patients receiving HEC. 



Clinical needs of patients referred early to supportive and palliative care. 

Presenting Author: Jung Hye Kwon, Department of Internal Medicine, 

Hallym University Medical Center, Hallym University College of Medicine, 


Background: Palliative care is evolving from delivering care to patients at 

the end-of-life to those earlier in the disease trajectory. We evaluated the 

differences in clinical characteristics, symptoms burdens, and service 

utilization between traditional palliative care patients (late referrals, LR) 

and the new patients group who are in earlier in their course of disease 

(early referrals, ER). Methods: We reviewed consecutive cancer patients 

referred to the Supportive Care Clinic with follow up visit within 30 days 

between August 2008 and October 2010. Patients were divided into two 

groups: ER (defined as patients with expected survival � 2 years or 

receiving treatment for curative intent) and LR (all others). We compared 

clinical characteristics, symptoms and service utilization between both 

groups using chi-square test and Wilcoxon rank sum test. Results: 58% 

(695/1208) patients had a 2nd visit within 30 days. Among them, 100 

patients were classified as ER (14.4%) and 100/595 LR were randomly 

selected as the comparison group. ER patients were younger (median age 

54 years vs 60 years, p�0.009), more likely to have head and neck cancer 

(67% vs 6%, p�0.001) and to have a shorter interval between cancer 

diagnosis and palliative care consultation (3.8 m vs 16.2 m, �0.001). ER 

patients were also more likely to be CAGE positive (15% vs 4%, p�.014), 

referred from radiation oncology (49% vs 3%, p�0.001), referred for 

treatment related side effects (70% vs 9%, p�0.001), and receiving active 

anti-cancer treatment at the time of consultation (74% vs 48%, p�0.0002). 

Baseline symptoms (Edmonton Symptom Assessment Scale) were similar 

between ER and LR except for insomnia (1.8 vs 2, p�0.004). LR patients 

experienced greater improvement in the symptom distress score (-5.5 vs -3, 

p�0.007). Overall median number of medical visits was 24 for ER vs 10.5 

for LR (p�0.001); however, median visit per month was 4.3 for LR and 2.1 

for ER (p�0.001). Conclusions: ER was associated with different patient 

characteristics; patients have similar distress but different needs and 

outcomes as compared to traditional LR patients. 


Clostridium difficile-associated diarrhea in cancer patients treated with 

fidaxomicin or vancomycin. Presenting Author: Oliver A. Cornely, 1st 

Department of Internal Medicine, and Zentrum für Klinische Studien–ZKS 

Köln (BMBF 01KN070), University Hospital of Cologne, Koeln, Germany 

Background: Oncology patients are at risk for infections, including C 

difficile infection (CDI). Fidaxomicin (FDX) is a novel antibiotic highly 

specific for C difficile with improved sustained response compared with 

vancomycin (VAN). Another important clinical outcome of CDI is time to 

resolution of diarrhea (TTROD), corresponding to the duration of passing 

unformed bowel movements. Methods: 183 patients with a current diagnosis 

of cancer were compared to non-cancer patients from a combined 

population of 1105 subjects with CDI in two phase 3 trials comparing 10 

days of treatment with FDX (400 mg/day) or VAN (500 mg/day). Number of 

unformed bowel movements (UBM) per 24 h was monitored. Response was 

considered as �3 UBM/24 h. Time to resolution of diarrhea was defined as 

time in hours from the first dose of study drug to the last UBM on the day 

preceding two days of �3 UBM/24 h. Kaplan-Meier survival analysis (K-M) 

used the log rank test for significance (p�0.05). Results: The response rate 

at end of treatment was 79.2% for 183 patients with cancer, compared to 

88.6% for 922 patients without cancer (p�0.001). Median TTROD was 

longer by 45 h in patients with cancer than those without. In the VAN 

treatment group, median TTROD was 65 h longer in patients with cancer vs 

those without and significant by K-M. In the FDX group, although median 

TTROD was longer by 20 h in patients with cancer vs those without, the 

difference was not significant by K-M. For patients with cancer, TTROD was 

significantly shorter during treatment with FDX than with VAN. Conclusions: 

Patients with cancer responded more slowly to treatment for CDI than did 

non-cancer patients; however, resolution of diarrhea was more rapid by 49 

h during treatment with FDX than with VAN. 

Median TTROD, h (95% CI) 

Subgroup 

No cancer Cancer K-M log rank p 

All patients (N�1105) 55 (53-58) 100 (71-119) �0.001 

Treated with FDX (N�539) 54 (48-58) 74 (54-103) 0.145 

Treated with VAN (N�566) 58 (54-72) 123 (78-142) �0.001 

Fidaxomicin Vancomycin 

Patients with cancer (N�183) 74 (54-103) 123 (78-142) 0.045 


583s 


Effect of complementary and alternative medicine on the survival and 

health-related quality of life among terminally ill cancer patients: A 

prospective cohort study. Presenting Author: Young Ho Yun, Seoul National 

University College of Medicine, Seoul, South Korea 

Background: Few have examined the effect of complementary and alternative 

medicine (CAM) use on survival and health-related quality of life 

(HRQOL) in cancer patients. Methods: From July 2005 to October 2006, we 

conducted a prospective cohort study of 481 terminally ill cancer patients 

at 11 university hospitals and the National Cancer Center in Korea. We 

assessed how the use of CAM affected HRQOL and survival. Results: In a 

follow-up of 481 patients and 163.8 person-years, we identified 466 

deceased cases. On multivariate analyses, CAM users did not have better 

survival than nonusers (adjusted hazard ratio (aHR), 0.91; 95% confidence 

interval (CI), 0.74-1.10). Among biologically based therapies, dietary 

supplements (aHR, 0.70; 95% CI, 0.48–1.01) and ginseng (aHR, 0.73; 

95% CI, 0.52–1.04) did not show significantly better survival. Among 

mind-body interventions, prayer showed significantly worse survival 

(aHR,1.56; 95% CI, 1.00–2.43). Clinically, CAM users reported significantly 

worse cognitive functioning (-11.6 v -1.3; p � 0.05) and fatigue 

(9.9 v -1.0; p � 0.05) than non-users. Compared with non-users in 

subgroup analysis, users of alternative medical treatments, prayer, vitamin 

supplements, mushrooms, or rice and cereal reported clinically significant 

worse changes in some HRQOL subscales. Conclusions: While CAM did not 

provide any definite survival benefit, CAM users reported clinically significant 

worse HRQOLs. 


Interdisciplinary palliative care in metastatic non-small-cell lung cancer. 

Presenting Author: Marianna Koczywas, City of Hope, Duarte, CA 

Background: Palliative cancer care is the integration into cancer care of 

therapies that address multiple issues that cause suffering for patients and 

their families and impact their life quality. Challenges and barriers 

continue to hinder the integration of palliative care into comprehensive, 

ambulatory oncology care. This paper aims to describe how symptoms, 

distress, and quality of life (QOL) data from the usual care phase of a 

NCI-supported Program Project (P01) informed the development of an 

interdisciplinary palliative care intervention for patients with metastatic 

non-small-cell lung cancer (NSCLC). Methods: Patients receiving usual 

care for metastatic NSCLC were recruited into this prospective longitudinal 

study. A total of 130 patients with stage IV NSCLC were accrued, and 114 

patients had evaluable data. Upon informed consent, patients completed 

outcome measures that assessed physical function/cognitive status, social 

activities and support, symptom characteristics, psychological distress, 

and overall QOL. Patient-reported outcomes were completed at baseline, 6, 

12, and 24 weeks post-accrual. Results: Subjects were primarily female 

(64%), ranged in age from 40-84 years, and 39% were ethnic minorities. 

The majority were former smokers (66%). KPS, IADL, and Cognitive scores 

deteriorated significantly over time (p�.001, .009, and .042, respectively). 

Patients reported higher severity scores with symptoms such as 

dyspnea, fatigue, insomnia, lack of appetite, peripheral neuropathy, pain, 

dry skin, nail changes, and problems with sexual interest in all four time 

periods. Global Symptom Distress Index and Total Symptom score both 

significantly worsened at 24 weeks (p�.003 and .017, respectively). 

Physical Well-Being worsened significantly (p�.036), while overall QOL, 

spiritual well-being, and psychological distress scores remained statistically 

stable over time. Conclusions: Patients with metastatic NSCLC 

continue to experience high symptom burden and diminished physical 

well-being over time while receiving treatments. An interdisciplinary 

palliative care intervention is currently being tested to improve symptom 

burden and overall QOL. 




Attrition rates, reasons, and predictive factors in supportive/palliative 

oncology clinical trials at a comprehensive cancer center. Presenting 

Author: Isabella Claudia Glitza, University of Texas M. D. Anderson Cancer 


Background: Attrition is common among supportive/palliative oncology 

clinical trials. Few studies have documented the reasons and predictors for 

dropout. We aimed to determine the rate, reasons and factors associated 

with attrition both before reaching the primary endpoint (PE) and the end of 

study (EOS). Methods: We conducted a review of all prospective interventional 

supportive/palliative oncology trials by our department between 

1999-2010. Patient and study characteristics and attrition data were 

extracted. We determined factors associated with attrition using multivariate 

logistic regression analysis. Results: 15 blinded randomized trials and 3 

single arm trials were included. 16 of 18 studies did not reach accrual 

target. Baseline demographics for the 1214 patients were: median age 60 

(range 23-93 years), female 56%, Caucasians 69%, ECOG performance 

status �3 41%, gastrointestinal malignancies (23%), median fatigue 

7/10, appetite 5/10 and pain 4/10. Attrition rate was 26% (N�311) for PE 

and 44% (N�535) for EOS. Common reasons for EOS dropout were patient 

preference (N�93, 17%), symptom burden (N�87, 16%), death (N�45, 

8%) and hospital admission (N�43, 8%), and were similar for PE 

dropouts. No predictors were identified for PE attrition. The Table shows 

poor performance status, anorexia and dyspnea are associated with EOS 

attrition in multivariate analysis. Conclusions: We found that attrition rate 

was high amongsupportive/palliative oncology clinical trials, and was 

associated with poor function and high baseline symptom burden. These 

findings have implications for future study designs including eligibility 

criteria and sample size calculation. 

Factors associated with EOS attrition in multivariate analysis. 

Characteristics Odds ratio (95% confidence interval) p value 

ECOG performance status �0.001 

0 0.35 (0.11-1.16) 0.09 

1 0.26 (0.12-0.58) �0.001 

2 0.34 (0.16-0.72) 0.01 

3 0.56 (0.26-1.2) 0.14 

4 1.0 Ref 

Median ESAS (interquartile range) 

Appetite (per point) 1.08 (1.01-1.14) 0.02 

Dyspnea (per point) 1.1 (1.03-1.18) �0.001 


Biomarkers of amenorrhea and ovarian function in breast cancer survivors. 

Presenting Author: Kathryn Jean Ruddy, Dana-Farber Cancer Institute, 

Boston, MA 

Background: Ovarian function after treatment of early breast cancer may 

affect fertility, menopausal symptoms, endocrine therapy decision-making, 

and subsequent health and psychosocial concerns among young survivors. 

We aim to improve understanding of ovarian reserve in women with a history 

of breast cancer by comparing anti-mullerian hormone (AMH), estradiol 

(E2), and follicle-stimulating hormone (FSH) levels in survivors with and 

without amenorrhea, a surrogate for ovarian dysfunction and menopause. 

Methods: As part of an ongoing prospective multi-center cohort study, 

women diagnosed with breast cancer at age �41 have blood and surveys 

collected one year after diagnosis. Women who reported that they were 

receiving ovarian suppression or had undergone hysterectomy or bilateral 

oophorectomy/ovarian ablation were excluded. Amenorrhea was defined as 

�6 months between blood draw and last menstrual period. AMH, E2, and 

FSH levels were compared between those with and without amenorrhea 

using a Wilcoxon rank sum test with 2-sided p-values. Results: The first 199 

eligible women with blood and survey data at one year were included in this 

analysis. Median age was 37 years (range 22-40). Seventy-two(36%) had 

received chemotherapy alone, 75 (38%) had received chemotherapy 

followed by tamoxifen (TAM), 25 (13%) had received TAM alone, and 10 

(5%) reported TAM use but did not respond to chemotherapy items. Median 

AMH and E2 were lower and FSH was higher in women with amenorrhea, 

and these differences remained significant when those on and off TAM were 

analyzed separately (Table). Conclusions: AMH, E2, and FSH all are 

promising biomarkers for amenorrhea and residual ovarian function in 

young breast cancer survivors. Future research will evaluate whether AMH, 

E2, and FSH at baseline and early in the survivorship period predict ovarian 

function later. 

N 

Median 

AMH 

AMH 

p value 

Median 

E2 

E2 

p value 

Median 

FSH 

FSH 

p value 

Total patients 199 0.06 85.0 7.91 

No amenorrhea 134 0.22 �0.0001 111.5 �0.0001 5.94 �0.0001 

Amenorrhea 65 0.01* 25.0 31.48 

No TAM 0.001 0.02 0.001 

No amenorrhea 66 0.09 81.5 5.61 

Amenorrhea 23 0.01* 30.0 47.09 

TAM �0.0001 0.001 �0.0001 

No amenorrhea 68 0.48 183.0 6.18 

Amenorrhea 42 0.01* 16.5 29.04 

* Values reported to be �0.02 were analyzed as 0.01 


Humoral and cellular immune response after influenza vaccination in 

patients with postcancer fatigue and patients with chronic fatigue syndrome. 

Presenting Author: Hetty Prinsen, Department of Medical Oncology, 

Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands 

Background: Postcancer fatigue (PCF) is a frequently occurring problem, 

impairing quality of life. Patients with chronic fatigue syndrome (CFS) also 

suffer from severe fatigue symptoms. We hypothesized that in fatigued 

patients (PCF and CFS) alterations in immune response could explain 

fatigue symptoms. Therefore, we examined whether the humoral and/or 

cellular immune response after influenza vaccination differed between 

fatigued patients and non-fatigued individuals and between PCF and CFS 

patients. Methods: PCF (n�15) and CFS patients (n�22) were vaccinated 

against influenza. Age and gender matched non-fatigued cancer survivors 

(n�12) and healthy controls (n�23) were included for comparison. 

Antibody responses were measured at baseline and at day 21 by a 

hemagglutination inhibition test. T cell responses were measured at 

baseline and at day 7 by a lymphocyte proliferation and activation assay. 

Results: Both patient groups developed seroprotection rates comparable to 

the accompanying control groups. Functional T cell reactivity was observed 

in all groups. Proliferation at baseline was significantly lower in fatigued 

patients compared to non-fatigued individuals. A significant increase in 

proliferation from baseline to day 7 was observed in fatigued patients, but 

not in controls. At day 7, proliferation was not significantly different 

between fatigued patients and non-fatigued individuals. CD4�CD127- 

FoxP3� expression was significantly higher in PCF patients compared to 

non-fatigued cancer survivors. Conclusions: We observed a lower T cell 

proliferation at baseline in fatigued patients compared to non-fatigued 

individuals, suggesting a difference in the baseline state of the immune 

system between fatigued patients and non-fatigued individuals. Furthermore, 

the difference in CD4�CD127-FoxP3� expression between PCF and 

CFS patients suggests subtle differences in immune state between these 

two fatigued patient groups. However, since humoral and cellular immune 

responses after vaccination did not differ significantly between fatigued 

patients and non-fatigued individuals, vaccination of fatigued patients 

(PCF and CFS) can be effective. 


A randomized, double blind, placebo-controlled crossover trial of a sustained 

release methylphenidate in cancer-related fatigue. Presenting 

Author: Carmelita P. Escalante, University of Texas M. D. Anderson Cancer 


Background: Cancer-related fatigue (CRF) is common and distressing. This 

study assessed the efficacy of OROS methylphenidate 18 mg daily (OM) vs. 

placebo (P) for CRF reduction. Other objectives were to compare the effects 

of OM vs. P on other symptoms, cognitive function, work yield, patient (pt) 

perceptions and preferences, and an exploratory analysis of cytokines. 

Methods: Initially, pts were randomly assigned (1:1) to receive OM-P or 

P-OM for 4 weeks (wks). Pts were crossed to the other treatment after 2 

wks. Assessments were done at baseline, 2 and 4 wks. Continuous and 

categorical variables were assessed using Wilcoxon signed rank tests and 

McNemar tests, respectively. The primary efficacy end point was the 

change of “fatigue worst” on the Brief Fatigue Inventory (BFI) at the end of 

each 2 wk period. Results: 42 female breast cancer pts were enrolled (3 

ineligible, 6 unevaluable); 33 pts were studied. The mean age was 58 

(range, 32-79), 30% had metastasis, 82% were receiving chemotherapy 

(ctx), 9% hormonal therapy (ht), and 9% both ctx and ht. 94% were ECOG 

�1 and 52% were employed. 45% were on pain medicines and none on 

antidepressants. The mean baseline BFI was 5.7 (range 4.1-8.6). Fatigue 

worst did not differ between OM and P (p� 0.54) or in other symptoms. 

There was significance in WAIS-III Digit Symbol between OM and P 

(p�0.01), and Hopkins Verbal Learning Test with BFI interfere and BFI 

active (p�0.04, p�0.03, respectively). Hours (hrs) missed due to health 

(p�0.03) and hrs worked (p�0.04) differed in OM vs. P. At study end, pts 

were asked if OM improved CRF and if they wanted to stay on OM. 64% felt 

improved. Of these, 58% wanted to continue. There were no serious 

adverse events due to OM. There were differences in serum IL6 (p�0.03), 

IL10 (p�0.0004), and TNF� (p�0.02) among OM and P. Conclusions: Low 

dose OM did not show improvement in CRF on fatigue worst of BFI. Pts 

taking OM had better cognition and less work absences. Pts tolerated OM 

well and a majority felt better and wanted to continue OM. Future studies 

examining higher doses or longer treatment duration with OM, pt preferences 

and impact on productivity are necessary. Changes in serum cytokine 

levels should be further explored. 



Genetic polymorphisms of SCNA9 as predictive markers of oxaliplatininduced 

neuropathy. Presenting Author: Maria Sereno, Oncology Department, 

Hospital Infanta Sofía, Madrid, Spain 

Background: Oxaliplatin (OXL) is an active drug in digestive tumors. 

Oxaliplatin induced peripheral neuropathy (OIN) is the main dose limiting 

toxicity. Around 60-80% of patients developed a mild cold-induced 

neurotoxicity that used to disappear few days after but in 15% became a 

persistent neuropathy. The pathophysiology of oxaliplatin-induced neuropathy 

(OIN) remains unclear, preclinical studies suggest involvement of 

voltage Na channels. SCN9A gene codifies to Na channels � subunit highly 

expressed in nociceptive neurons. Mutations in SCN9A are involved in 

alterations in neuropatic pain perception. This study tried to identify if 

variants in SCN9A could be associated to a higher risk to OIN. Methods: 

Serum were obtained from 100 patients with digestive cancer (colorectal, 

gastric, pancreatic and bile duct) treated with OXL (adjuvant or advanced 

setting) in Infanta Sofía University Hospital. No diabetes or hypotiroidism 

were detected. Patients were divided in two groups according to the 

development of OIN: Arm A 50 patients diagnosed of grade 2-3 OIN after 6 

courses and Arm B 50 with no OIN. The evaluation of severity of the OIN by 

a neurologist included a classification according to NCI-CTC and OSNS 

scales and conduction studies. Genomic DNA was isolated from serum and 

variants of SCN9A were analyzed by PCR-RFLP. The relation between 

SCN9A genotype and the development of severe OIN was the primary aim 

Results: One hundred patients were enrolled between May 2010-November 

2011. 56 (56%) females and 44 (44%) males; mean age was 62; mean 

ECOG was 1; primary tumor were colorectal 81 pts (81%), gastric 10 

(10%); 8 (8%) pancreto-biliar and anus 1(1%). Stage were classified in 

localized 65 (65%) and advanced (35%). The chemotherapy regimen 

included: 94 (94%) XELOX, 1 (1%) XELOX-Herceptin and 5 (5%) EOX 

regimen. The mean of cycles were 7 (1-14). Mean OXL dose intensity was 

100mg/m2.The mean PFS was 23 months. High expression of SCN9A 

variants were detected in patients 26/50, 52% arm A and in 5/50, 10% 

arm B patients, suggesting a possible relationship beetwen the development 

of OIN and SCN9A genotype (p�0.04). Conclusions: SCN9A polimorphysms 

may help to identify those patients with a higher risk to develop 

oxaliplatin induced neuropathy. 


Pilot study of Scrambler therapy for the treatment of chemotherapyinduced 

peripheral neuropathy. Presenting Author: Deirdre R. Pachman, 


Background: Chemotherapy-induced peripheral neuropathy (CIPN), a common 

dose-limiting side effect of chemotherapy, remains without known 

effective interventions. Preliminary data support that Scrambler therapy, a 

device which treats pain via non-invasive cutaneous electrostimulation, is 

beneficial for the treatment of CIPN. This pilot trial was performed to 

investigate the effect of Scrambler therapy for the treatment of CIPN. 

Methods: Eligible patients included those age �18 years, ECOG PS �2, life 

expectancy �3 months, with pain or CIPN symptoms of �1 month duration 

and tingling or pain �4/10 during the prior week. Patients were treated 

with Scrambler therapy to the affected area for up to 10 daily 30 minute 

sessions. Symptoms were monitored daily during therapy using a questionnaire 

to measure symptoms of neuropathy with a numerical analogue scale. 

Results: We report on the first 11 CIPN patients, enrolled between 

7/18/2011 and 12/12/2011, 3 men and 8 women; mean age 57 years. 

Patients had history of exposure to various chemotherapeutic agents and 

the majority had symptoms �2 years. The table portrays data at baseline, at 

the end of the 10 planned days of therapy, and the percent changes from 

baseline to the end of treatment, regarding patient reported pain, tingling, 

and numbness over the preceding 24 hours. There were no adverse events. 

Persistent benefit out to 5 weeks was seen in some patients; maturing data 

will be available by May 2012. Descriptive summary statistics formed the 

basis of data analysis. Further patients are being entered on this trial. 

Conclusions: Scrambler therapy appears to be beneficial in the treatment of 

CIPN. A prospective placebo-controlled clinical trial should be performed 

to confirm these preliminary findings. 

Effect of Scrambler therapy on CIPN score. 

Mean baseline score Mean final score Percent change 

Symptom Mean Worst Mean Worst Mean Worst 

Pain 5.7 (2.20) 6.0 (2.10) 3.0 (2.65) 3.8 (3.06) -48% (2.65) -36% (3.54) 

Tingling 6.5 (1.81) 7.0 (1.84) 3.8 (2.82) 4.0 (2.65) -41% (2.34) -43% (1.95) 

Numbness 6.5 (1.57) 7.2 (1.78) 5.1 (2.43) 5.2 (2.48) -21% (1.75) -28% (2.14) 

Numbers in parentheses represent standard deviations. 


585s 


Psychological impact of exercise in women with breast cancer receiving 

adjuvant therapy: What is the optimal dose needed? Presenting Author: 

Marion Carayol, Laboratory Epsylon EA 4556 Dynamics of Human Abilities 

and Health Behaviors, Department of Medicine, Human, Society and Sport 

Sciences, University of Montpellier and St-Etienne, Montpellier, France 

Background: Several meta-analyses have examined the role of exercise 

interventions in improving psychological outcomes in cancer survivors but 

most did not focus on adjuvant therapy period and did not investigate the 

optimal dose of exercise needed. Methods: The present meta-analysis 

examines the impact of exercise interventions delivered at this particular 

period on fatigue, anxiety, depression and quality-of-life (QoL) as well as 

dose-response relationships between volume of prescribed exercise and 

these psychological outcomes. Randomized controlled trials that proposed 

an exercise intervention to breast cancer patients undergoing chemotherapy 

and/or radiotherapy were systematically identified and coded. 

Standardized mean differences (SMDs) of psychological outcomes were 

weighted by the inverse of their variances to obtain a pooled estimate using 

random effects model. Linear and quadratic regressions were carried out to 

explore dose-response relationships. Results: In total, 17 studies involving 

1380 participants and 20 exercise interventions were included. Intervention 

subjects significantly reduced their fatigue and depression levels 

showing pooled effect sizes (EF) and their associated 95% confidence 

interval (95%CI) of -0.28 [95%CI: -0.54; -0.03] and -0.28 [95%CI: 

-0.46; -0.09] respectively. Levels of anxiety also appeared to be reduced 

but pooled estimate did not reach significance (p�0.06). Significantly 

increased QoL was observed: EF�0.34 [95%CI: 0.07; 0.62] favouring 

intervention. Consistent and significant inverse associations of weekly and 

total volume of prescribed exercise were observed with fatigue (F test: 

p�0.04, R²�0.19 and p�0.009, R²�0.26 respectively) and QoL (F test: 

p�0.01, R²�0.14 and p�0.02, R²�0.29 respectively), implying that 

SMDs magnitude decreased as exercise dose increased. Conclusions: 

Exercise intervention enhanced fatigue, depression and QoL in breast 

cancer patients undergoing adjuvant therapy. Prescription of relatively low 

doses of exercise (�12 MET.h per week) consisting in approximately 

90-120 min of weekly moderate physical exercise seems more efficacious 

in improving fatigue and QoL than higher doses. 


Paucity of core palliative care elements available to children with cancer at 

end-of-life: Perspectives of bereaved parents and clinicians. Presenting 

Author: Alisha Kassam, The Hospital for Sick Children, Toronto, ON, 

Canada 

Background: Recognition of serious deficits in palliative care for children 

has prompted hospitals to develop specialized pediatric palliative care 

programs. However, only a minority of children who die from advanced 

cancer receive services from these dedicated programs. We aimed to 

determine which elements of palliative care are considered important 

according to bereaved parents and pediatric oncology clinicians and to 

determine availability of these elements. Methods: We administered questionnaires 

to 75 bereaved parents (response rate 53%) and 48 pediatric 

oncology clinicians (response rate 91%) at the Hospital for Sick Children in 

Toronto, Canada. The main outcome measures were importance ratings and 

availability of core elements of palliative care delivery based on the 

National Quality Forum clinical practice guidelines for quality palliative 

care. Results: Fifteen of the twenty-one core elements were highly valued by 

both parents and clinicians (defined as � 60% of parents and clinicians 

reporting the item as important). When compared to clinicians, parents 

gave higher importance ratings to receiving cancer-directed therapy during 

the last month of life (p � 0.007) and involvement of a religious or spiritual 

mentor (p � 0.03). Clinicians gave higher importance ratings to involvement 

of a social worker (p � 0.0001). Notably, of the valued elements, only 

three of them were available greater than 60% of the time according to 

clinicians and parents. Valued elements least likely to be available 

included a direct admission policy to hospital, involvement of a religious or 

spiritual mentor, sibling support and parent preparation for medical 

aspects surrounding death. Conclusions: Children with advanced cancer are 

not receiving key elements of palliative care despite both parents and 

clinicians recognizing them as important. Evaluation of barriers to provision 

of quality palliative care and strategies for overcoming them is critical. 




Efficacy and safety of rolapitant, a novel NK-1 receptor antagonist, for the 

prevention of chemotherapy-induced nausea and vomiting in subjects 

receiving highly emetogenic chemotherapy. Presenting Author: Luis Enrique 

Fein, Centro Oncologico de Rosario, Rosario, Argentina 

Background: Management of chemotherapy-induced nausea and vomiting 

(CINV) improves quality of life and increases the likelihood that patients 

will continue to receive appropriate treatment. The objective of this dose 

finding study was to evaluate rolapitant for the prevention of CINV in 

subjects receiving highly emetogenic chemotherapy (HEC). Methods: A 

phase II, double blind study in which 454 subjects receiving HEC 

(�70mg/m2 cisplatin-based chemotherapy) were randomized in equal 

fashion prior to chemotherapy to receive ondansetron � dexamethasone � 

either placebo or 10, 25, 100 or 200mg of rolapitant. Subjects recorded 

episodes of emesis, severity of nausea, and use of rescue medication(s) 

daily within a subject diary from Days 1 through 6 of Cycle 1. Results: The 

rolapitant 200mg group had significantly greater complete response rates 

(no emesis and no use of rescue medication) in the overall (0 to 120 hours), 

acute (0 to �24 hours) and delayed (�24 to 120 hours) phases compared 

to the placebo group (62.5% vs. 46.7%, p�0.032; 87.6% vs. 66.7%, 

p�0.001 and 63.6% vs. 48.9%, p�0.045, respectively). Moreover, the 

200mg group had significantly greater rates of no emesis and no significant 

nausea in the overall, acute, and delayed phases and achieved statistically 

significant better QoL scores (FLIE questionnaire) compared to the placebo 

group. Rates for no emesis and no significant nausea for the 200mg dose 

group in Cycles 2 to 6 continued to demonstrate superior treatment effect 

vs. placebo. Treatment-related adverse events were mild and included 

constipation, headache, fatigue and dizziness. Overall, serious adverse 

events (SAEs) occurred with similar incidences across all treatment groups 

(9% - 14%). Most common SAEs were febrile neutropenia, neutropenia, 

vomiting, dehydration, nausea and pneumonia and were considered related 

to chemotherapy or underlying cancer and not to rolapitant. Conclusions: 

Administration of rolapitant 200mg with ondansetron and dexamethasone 

is safe and effective at preventing CINV in subjects receiving HEC. 


Development of a geriatric vulnerability score (GVS) in elderly advanced 

ovarian cancer (AOC) patients (pts) treated in first line: A prospective 

GINECO trial. Presenting Author: Gilles Freyer, Oncologie Médicale, Centre 

Hospitalier Lyon-Sud, Lyon, France 

Background: Two previous prospective GINECO studies in elderly patients 

have underlined the prognostic value of geriatric covariates (Co) on overall 

survival (OS) (Freyer G., et al. Ann Oncol. 2005 and Tredan O, et al Ann 

Oncol 2007). Methods: This open prospective trial was designed to confirm 

the impact of geriatric Co including psycho-geriatric Co on OS of elderly pts 

(�70) with stage III-IV AOC treated in first line with 6 courses of 

carboplatin AUC5/3weeks. Geriatric Co were tested for their impact on OS 

in uni- and multivariate analyses. The best fitting proportional hazard 

model (GVS) was developed with the inclusion of major (MaC) and minor Co 

(miC). Results: From 08/2007 to 01/2010, 111 pts were included in 21 

centres. A majority of pts displayed characteristics of vulnerability: age 

(median:78, range: 70-93, �80:41%), PS�2: 43%, �3 major comorbidities: 

27%, �4 comedications: 69%, ADL score�6: 55%, IADL score�25: 

75%, HADS�15:37%. A total of 74% of pts, however, completed planned 

chemotherapy. Gr3-4 haematological toxicity was observed in 50% of pts 

(thrombocytopenia [27%], anaemia [19%], and neutropenia [30%]) and 

gr3-4 non-haematological toxicity was fatigue (16%), anorexia (13%) and 

infection (10%). Median OS was 16.2 months (95%CI[14-21]). MaC were: 

albuminemia�35g/L; ADL score �6; IADL score �25 and miC: 

lymphopenia�1G/L; HADS£14. The survival score�exp(0.320*Number 

[MaC] �0.354*Number[miC]) was validated upon a bootstrap analysis. 

Using a cutoff of 3, the simplified GVS score � Number[MaC] � 

Number[miC] discriminated two groups with significantly different OS 

:11.5 vs 21.7 months; HR�2.94; p�10-4 , but also treatment completion 

rates: 65.4% vs 82.1%; OR�0.41; p�0.04; severe adverse events (SAE): 

52.7% vs 28.6%; OR�2.8; p�0.009 and unplanned hospital admissions: 

52.8% vs 30.3% OR�2.6; p�0.02. Conclusions: The GVS identified a 

group of pts at high risk of severe toxicity, early treatment stopping, 

unplanned hospitalization and poor outcome. GVS provides a useful tool to 

identify vulnerable pts in future elderly AOC trials. 


Effect of aprepitant on adherence to high-dose cisplatin-based chemotherapy. 

Presenting Author: Serge Makarenko, British Columbia Cancer 


Background: Treatment of locally advanced head and neck cancers (HNC) 

and gastroesophageal cancers (GEC) frequently consists of high-dose 

cisplatin, which is highly emetogenic. Our aims were to 1) explore the 

impact of aprepitant for improving adherence to cisplatin-based chemotherapy 

in HNC and GEC, 2) examine its effect on reducing chemotherapyinduced 

nausea and vomiting (CINV) and 3) determine if use of aprepitant 

changed after introduction of insurance coverage for this drug. Methods: 

Patients diagnosed with HNC or GEC in British Columbia, Canada from Jan 

2008 and June 2011 and prescribed high-dose cisplatin were reviewed. 

Using regression models that adjusted for confounders, we evaluated the 

relationship between aprepitant use and treatment and outcome characteristics, 

such as number of chemotherapy cycles, prevalence of CINV, and 

recurrence and survival. Results: A total of 333 patients were identified: 

162 HNC and 171 GEC patients of whom 80% were men, 44% were aged 

�/�60 years, 35% were smokers, and 42% were alcohol users. Aprepitant 

was prescribed in 49%, nausea and vomiting occurred in 64 and 24%, 

respectively, and completion of all planned cisplatin was 52%. Younger 

patients (55 vs 41%, p�0.01) and those with less tumor burden (64 vs 

38%, p�0.01) were more likely to be given aprepitant. Individuals who 

received aprepitant were significantly less likely to experience CINV 

(p�0.01). Use of aprepitant differed between HNC and GEC patients 

(p�0.01); however, its use did not increase when insurance coverage of 

this agent was introduced (p�0.16). In multivariate analyses, aprepitant 

use was significantly associated with adherence to all planned cisplatin 

treatments (OR 2.33, 95% CI 1.27-4.25, p�0.01). In Cox regression, 

completion of all cisplatin cycles was significantly correlated with a lower 

risk of recurrence (HR 0.56, 95%CI 0.32-0.97 p�0.04) and a trend 

towards decreased death (HR 0.56, 95%CI 0.31-1.10, p�0.10). 

Conclusions: Aprepitant was associated with a reduction in CINV in both 

HNC and GEC patients and correlated with better adherence to high-dose 

cisplatin-based chemotherapy. Individuals who completed all planned 

cisplatin had improved outcomes, specifically a lower risk of recurrence 

from HNC and GEC. 


Correlations between depression according DSM-IV-TR (DSM) criteria, 

three validated scales, oncologist assessment, and clinical psychiatric 

interview in elderly advanced ovarian cancer (AOC) patients (pts): A 

GINECO study. Presenting Author: Marilène Filbet, Hospices Civils de Lyon 

Lyon, France 

Background: Depression is a major outcome in cancer pts. Clinicians 

typically rely on their clinical impression of depression rather than pts 

self-reports. Our aim was to explore the association between patientreported 

depression, oncologist assessment (OA) and a clinical psychiatric 

interview (CPI) in elderly AOC pts. Methods: This analysis was a secondary 

endpoint of theElderly Women AOC trial, designed to assess the impact of 

geriatric covariates, notably depression, on survival in pts over 70 receiving 

6 courses of carboplatin. Depression was assessed using the Geriatric 

Depression Scale-30 (GDS; cut off score of 10/30), the Hospital Anxiety 

Depression Scale (HADS; cut off score of 15/42), the distress thermometer 

(DT; cut off score of 4/10) and OA (yes/no). CPI was conducted by 

psychologists within 10 days after inclusion. The interview guide for CPI 

(yes/no) was constructed and adapted from three validated scale: GDS, 

Hamilton Depression Rating Scale Hamilton (HDRS), Montgomery Asberg 

Depression Rating Scale (MADRS) and the DSM criteria. DSM was 

considered as the gold standard. Results: Out of 111 pts, 100 (90.1 %) 

completed all the assessment (OA, GDS, HADS, DT, CPI). Patients 

characteristics were: mean age 78, performance status �2: 48 (55%). 

Thirty six pts (36%) were identified as depressed by the CPI versus 17 

(17%) by OA, 32 (32%) by the GDS, 36 (36%) by the HADS, 58 (58%) by 

the DT and 16 (16%) according to DSM. We found a significant correlation 

between DSM and GDS (r�0.58; p�0.001), DSM and CPI (r�0.53; 

p�0.001). We did not find any significant correlation between DSM and OA 

(r�-0.05;p�0.733), DSM and DT (r�-0.07;p�0.583), and between DSM 

and HADS (r�0.127;p�0.258). Identification according to OA (yes/no) 

resulted in 87% false negatives and 18% false positives rates. The best 

sensitivity and specificity as a screening tool was found for GDS, 94% and 

80% respectively. Conclusions: The use of validated tools such as GDS and 

a collaboration between psychologists and oncologists are warranted to 

better identify emotional disorders in elderly women with AOC. 



Inflammatory markers and symptom burden in patients with multiple 

myeloma undergoing autologous stem cell transplantation. Presenting 

Author: Loretta A. Williams, University of Texas M. D. Anderson Cancer 


Background: We explored the association between activation of inflammatory 

networks and development of severe symptoms during mobilization 

and the acute phase of autologous hematopoietic stem cell transplantation 

(ASCT) for multiple myeloma (MM). Methods: From mobilization through 

the first 3 months after ASCT, multiple symptoms were measured repeatedly 

via the myeloma module of the M. D. Anderson Symptom Inventory 

(MDASI-MM). Serum levels of interleukin (IL)-6, IL-10, tumor necrosis 

factor (TNF)-a, soluble TNF receptors 1 and 2 (sTNF-R1, sTNF-R2), IL-1 

receptor antagonist (IL-1RA), vascular endothelial growth factor (VEGF), 

macrophage inflammatory protein-1 (MIP-1a), monocyte chemoattractant 

protein (MCP)-1 and C-reactive protein (CRP) were collected up to 11 times 

per patient and assayed by Luminex. Ordinal regression modeling was used 

to analyze repeated-measures data. Results: Among50 MM patients, the 

most severe symptoms reported by werefatigue, pain, muscle weakness, 

disturbed sleep, drowsiness, numbness, poor appetite, and bone aches. 

Symptoms worsened rapidly from conditioning therapy and peaked at WBC 

nadir. Over time, controlling for age, sex, and MM stage, increased serum 

IL-6 (P�.0007) and MCP-1 (P�.0005) were significantly associated with 

worsening of the most severe symptoms; MIP-1a (P�.005) and VEGF 

(P�.002) were inversely associated with these symptoms. Increased CRP 

was significantly associated with worsening pain (P�.01), fatigue (P�.007), 

and bone aches (P�.006). Conclusions: This longitudinal study indicates a 

strong association between dynamic changes in circulating inflammatory 

molecules and the most severe symptoms in MM patients during the acute 

phase of ASCT. This observation, similar to IL-6-related multisymptom 

development around WBC nadir of allogeneic SCT (Wang et al, 2008), 

provides evidence of potential inflammation-induced behavioral changes in 

humans. Testing of anti-inflammatory interventions is warranted to further 

confirm the role of inflammation in the development of symptoms and 

identify effective mechanism-driven symptom management during ASCT. 


Longitudinal relationship between inflammatory markers and patientreported 

symptom severity during induction therapy for multiple myeloma. 

Presenting Author: Mary H. Sailors, University of Texas M. D. Anderson 


Background: Multiple myeloma (MM) patients undergoing induction therapy 

experience both disease- and therapy-related symptoms. We investigated 

the association between the trajectory of symptom severity and changes in 

levels of inflammatory markers. Methods: MM patients (N�62) rated 

symptoms via the M. D. Anderson Symptom Inventory (MDASI) twice a 

week during induction therapy. Patients contributed serum samples before 

the start of every chemotherapy cycle. A panel of pro- and antiinflammatory 

cytokines and markers was evaluated by Luminex. Ordinal 

regression analyses were used to describe the relationship between 

cytokines and symptom outcomes across time. These analyses were 

adjusted for patient and clinical factors (age, sex, diabetes diagnosis, 

anemia, BMI, comorbidity, staging, ECOG PS, prior treatment status, 

tumor response, opioid use, and chemo regimen). Results: Bortezomibbased 

induction therapy was received by 89% of the sample. Fatigue was 

persistently the most severe symptom during induction therapy, followed by 

disturbed sleep, muscle weakness, pain, drowsiness, and bone aches. 

Numbness, which is representative of chemotherapy-induced peripheral 

neuropathy, significantly worsened from baseline (p�0.01). We observed 

significant longitudinal associations between sIL-1R1 and distress and 

sadness (both p�0.02); between sIL-6R and disturbed sleep (p�0.001), 

poor appetite (p�0.04), and sore mouth (p�0.006). IL-6 was significantly 

associated with pain, fatigue, nausea, and sore mouth (all p�.05). A 

negative association between sTNF-RII and pain, sleep, distress, remembering, 

poor appetite, and nausea (all p�0.05) was also observed. MCP-1 was 

positively associated with numbness (p�0.04); while MIP-1� was negatively 

associated with sleep, numbness, constipation, poor attention (all 

p�0.01), and bone aches (p�0.0006). IL-10 was negatively associated 

with mood interference (p�0.04). Conclusions: Frequent assessment can 

document the longitudinal course of multiple symptoms during induction 

and provides opportunity to evaluate systemic inflammation as a potential 

source of symptom burden during induction therapy for MM. 


587s 


Baseline subclinical sensory deficits and the development of pain and 

numbness in patients with multiple myeloma (MM) being treated with 

chemotherapy. Presenting Author: Elisabeth G. Vichaya, University of 



dose-limiting toxicity experienced by patients with MM. Patients may 

develop painful and non-painful (e.g., numbness) symptoms that impair 

function and often persist after therapy is terminated. This study examined 

the predictive value of baseline subclinical sensory deficits on the development 

of treatment-related pain and numbness. Methods: Patients (N�56) 

who had two or fewer cycles of induction therapy and no obvious 

neuropathy were assessed for sensory deficits using quantitative sensory 

testing (QST). Patients reported the severity of pain and numbness (on a 

0-10 scale) at least weekly via the MD Anderson Symptom Inventory during 

induction (up to 16 weeks); 15 of 56 patients provided data for up to 16 

additional weeks of maintenance therapy. These values correlate to patient 

reported pain and numbness in the hands/feet. Based on data collected 

from healthy controls, patients were classified as being with or without a 

sensory deficit at baseline on each QST domain. We fit linear mixed models 

for pain and numbness with each sensory deficit and time, controlling for 

cumulative cycles, diabetes, age, and treatment agent. Data is shown as 

mean � standard deviation. Results: Patients who showed baseline deficits 

in sharpness detection (20%) reported significantly lower levels of pain 

(1.2�1.9 vs 3.1�2.9, p�.004) and numbness (0.4�0.8 vs 2.4�2.6, 

p�.001) during induction therapy and less numbness (0.0 vs 3.5�2.8, 

p�.001) during maintenance therapy. Further, those who showed deficits 

in warmth detection (40%) reported higher levels of pain (5.2�2.8 vs 

1.7�2.3, p�.001) and numbness (5.8�2.2 vs 1.6�1.8, p�.001) during 

maintenance therapy. Finally, those with lower skin temperature (47%) 

reported higher levels of pain (4.5�2.3 vs 1.7�2.9, p�.005) during 

maintenance therapy. Conclusions: Our results suggest that subclinical 

sensory deficits may be useful in determining a patient’s risk for developing 

CIPN prior to initiation of induction therapy. This information could be used 

to provide patients with more-personalized chemotherapy plans that take 

into account their neuropathy risk. 


Randomized trial of a physical activity intervention in patients with 

metastatic breast cancer. Presenting Author: Jennifer A. Ligibel, Dana- 

Farber Cancer Institute, Boston, MA 

Background: Physical activity (PA) interventions improve fitness, functional 

capacity, and quality of life in patients with early-stage breast cancer. 

There are almost no data regarding the feasibility or potential benefits of PA 

in women with metastatic breast cancer (MBC). Our study evaluated the 

impact of a moderate-intensity PA intervention upon functional measures 

in patients with MBC. Methods: Participants were randomized 1:1 to a 

16-week PA intervention or usual care control group. Eligibility included 

diagnosis of MBC, ECOG 0-1, and no active brain metastases. The 

intervention consisted of 4 weekly meetings with an exercise physiologist, 

followed by monthly in-person and weekly telephone-based meetings. The 

PA goal was 150 minutes per week. Baseline and 16-week evaluation 

included: modified Bruce treadmill test, 7-Day Physical Activity Recall 

Interview, and EORTC QLQ C-30 questionnaire. Results: 101 women 

enrolled between 9/06 and 3/11. Median age was 49 years, median time 

since diagnosis of MBC was 1.1 years, 48% of participants were on 

hormonal therapy and 42% on chemotherapy/biologic therapy. 69% 

completed all study measures (an additional 9% all but the final treadmill 

test). Attrition was higher in the intervention arm (30% vs. 16%, p�0.15). 

Outcome measures are shown in table below. Both groups experienced 

improvements in treadmill times. Intervention participants also reported 

improvements in physical functioning and increased minutes of weekly PA, 

with a trend toward significant differences between groups. Conclusions: 

Women with MBC participating in a PA intervention experienced consistent, 

but non-significant, trends toward improvements in functional measures. 

Our sample size was small, limiting power to evaluate the potential 

benefits of PA in women with MBC. Additional work is warranted, 

particularly since PA interventions appear feasible in this patient population. 

Baseline Change over 16 weeks 

Exercise Control Exercise Control p value 

Treadmill (min)* 5.6 � 1.8 5.3 � 1.7 .61 � .19** .37 � .16** .35 

Physical functioning* 84.2 � 14.4 83.9 � 13.2 4.79 � 2.40** .93 � 2.07 .23 

Exercise min/wk* 86.3 � 217.8 74.7 � 80.6 71.8 � 185.6** 53.8 � 183.7 .14 

*Data presented as means � SD. **Within-group comparison �0.05. 




A randomized trial to determine if vitamin B6 can prevent hand and foot 

syndrome in cancer patients treated with capecitabine chemotherapy. 

Presenting Author: Tareq Braik, John H. Stroger Jr. Hospital of Cook 

County, Chicago, IL 

Background: Capecitabine is an oral fluoropyrimidine that is used to treat 

various malignancies. Hand and Foot Syndrome (HFS) is a dose limiting 

toxicity of capecitabine and can limit the use of this agent in some patients. 

Some investigators have observed that pyridoxine (vitamin B6) can ameliorate 

HFS caused by capecitabine. We designed a prospective trial to 

determine if pyridoxine can prevent HFS in patients receiving capecitabine. 

Methods: In our double-blind, placebo controlled trial, we randomly 

assigned eligible patients treated with capecitabine to receive either daily 

pyridoxine 100 mg or placebo along with their capecitabine-containing 

chemotherapy regimen. Patients were observed during the first four cycles 

of capecitabine treatment. The primary end point was the incidence and 

grade of HFS that occurred in both arms. Results: Between 2008 and 

2011, 77 patients were randomly assigned to receive either pyridoxine 

(n�38) or placebo (n�39). Both arms were matched in baseline characteristics. 

The median age was 53.5 years. The ethnic composition of the study 

population was African American 53%, Caucasian 22%, Hispanic 18%, 

and Asian 7%. The daily doses of capecitabine were: 2000 mg/m2 (69 

pts), 1650 mg/m2 (5 pts), 1400 mg/m2 (2 pts) and 1000 mg/m2 (1 pt). 

Dosages of capecitabine were equally matched between the two arms of the 

study. HFS occurred after a median of 2 chemotherapy cycles in both 

groups. HFS developed in 10/38 (26%) patients in the pyridoxine group 

and in 8/39 (20%) patients in the placebo group (p�0.547). Therefore, the 

risk of HFS was 6 percentage points higher in pyridoxine group (95% CI for 

difference: -13 percentage points to �25 percentage points). Given our 

study results, we can be confident of excluding a true benefit from 

pyridoxine larger than 13 percentage points. No difference in HFS grades 

was observed. Conclusions: Prophylactic pyridoxine (vitamin B6), given 

concomitantly with capecitabine-containing chemotherapy, was not effective 

for the prevention of HFS. 

Grades HFS I HFS II HFS III No HFS 

Pyridoxine 4 (11%) 2 (5%) 4 (11%) 28 (73%) 

Placebo 2 (5%) 3 (8%) 3 (8%) 31 (79%) 


Usefulness of medical oncologists’ estimates of survival time in people with 

advanced cancer. Presenting Author: Belinda E. Kiely, NHMRC Clinical 

Trials Centre, University of Sydney, Sydney, Australia 

Background: We sought to determine the calibration, precision, prognostic 

significance and suitability of estimated survival time (EST) as a basis for 

estimating and explaining prognosis in advanced cancer. Methods: Medical 

oncologists recorded their EST as the “median survival of a group of 

identical patients” in patients with advanced cancer and a life expectancy 

�3 months recruited to a randomized trial of sertraline (Lancet Oncol 

2007; 8: 603). Calibration, precision and suitability were defined by the 

proportions of patients whose observed survival times (OST) were bounded 

by simple multiples of their EST (based on our previous studies), i.e. 50% 

expected to live longer (or shorter) than their EST; 30% expected to live 

from 0.75 to 1.33 times their EST (arbitrary criterion for precision); 50% 

expected to live from half to double their EST (range for typical scenario); 

10% expected to live �3 times their EST (best case scenario), or �¼ of 

their EST (worst case scenario). Results: Characteristics of the 114 patients 

were: median age 63 years, Karnofsky performance status (KPS) �70 in 

25%, and a median of 8.5 months since diagnosis of advanced cancer. 

Primary cancer sites included breast (18%), colorectal (16%), lung (15%), 

prostate (12%) and ovary (10%). Median survival was 10.6 months after a 

median follow-up of 14 months and 68 deaths. EST were well-calibrated: 

54% of patients lived longer than their EST and 46% lived shorter than 

their EST. EST were imprecise (21% within 0.75 to 1.33 times OST) but 

equally likely to be over-optimistic (34% �1.33 x OST) or over-pessimistic 

(39% �0.75 x OST). 6% of patients lived �¼ of their EST; 62% lived from 

half to double their EST and 9% lived �3 times their EST. Independently 

significant predictors of OST in a multivariable Cox model included EST 

(HR�0.92, p�0.004), dry mouth (HR�5.07, p�0.0001), alkaline phosphatase 

�101U/L (HR�2.80, p�0.0002), KPS �70 (HR�2.30, 

p�0.007), prostate primary (HR�0.23, p�0.002), and steroid use 

(HR�2.35, p�0.02). Conclusions: Medicaloncologists’ EST were wellcalibrated, 

imprecise, independently associated with OST, and useful for 

estimating and explaining best case, worse case, and typical scenarios for 

survival time in patients with advanced cancer. 


In-hospital and long-term outcomes in patients with malignancy undergoing 

percutaneous endoscopic gastrostomy (PEG). Presenting Author: Emily 

Keung, Department of Surgery, Brigham and Women’s Hospital, Boston, 

MA 

Background: PEG is widely performed in cancer patients as a means of 

providing nutrition or palliation. Although considered safe, PEG-associated 

outcomes in these patients remain poorly described. We examined the 

safety and benefits of PEG placement in this patient population. Methods: A 

five year retrospective review of all patients with malignancy (excluding 

head/neck, thoracic) who underwent attempted PEG at our institution was 

performed. Results: PEG was placed in 187 of 189 patients; 64 with 

hematologic malignancy (H-M), 125 non-hematologic malignancy (NH-M). 

Median age at time of PEG was 60.8 years. Indication was nutritional 

support (100%) in H-M, enteral access (59.2%) and management of 

obstructive symptoms (38.4%) in NH-M. A minority were able to return 

home (27.5%), discontinue parenteral nutrition (22%), advance diet for 

nutrition (24.6%) or comfort (17.1%) with the rest remaining NPO. Overall 

rates of PEG-related major (aspiration, tube dislodgement/leakage, bleeding, 

visceral injury, respiratory failure after procedure, cardiac arrest) and 

minor (superficial infection, ileus) complications were 21.4% and 11.3%, 

respectively, with higher rates in H-M (34.4% and 20.3% vs 14.4% and 

6.4%). All cause in-hospital mortality was high: 31.3% H-M, 13.6% 

NH-M. Median time from PEG placement to death was 54 days. Leading 

cause of death differed by malignancy: respiratory failure and sepsis in H-M 

(31% and 21%), primary malignancy in NH-M (75%). Overall one year 

mortality was 56%. Code status was changed in 21% of patients after PEG 

(“Full Code” to “Do Not Resuscitate/Do No Intubate” or “Comfort Measures 

Only”). Multivariate/subgroup analyses will be presented at time of meeting. 

Conclusions: PEG placement in this study population was associated 

with significant procedure-related complications and failed to achieve TPN 

independence or advancement of diet. Nearly 25% of patients declined 

aggressive resuscitation strategies after undergoing surgery for PEG. Thus, 

higher burden of counseling is needed to carefully weigh the risk and 

benefit of PEG placement in these patients. Further studies are needed to 

elucidate the factors affecting the decision process and patient selection. 


Risk of rash with nilotinib: A systematic review of the literature and 

meta-analysis. Presenting Author: Aaron Mark Drucker, University of 


Background: Nilotinib is indicated for the treatment of chronic myelogenous 

leukemia (CML). The reported incidence and risk of rash from this 

medication vary widely and have been inconsistently reported in published 

trials. Therefore we conducted a systematic review and meta-analysis of the 

literature to determine the incidence and risk of developing rash. Methods: 

Relevant studies were identified from the PubMed database (1998-2012), 

abstracts presented at ASCO and ASH Conferences (2004-2011) and Web 

of Science database (1998-2012). Eligible studies were limited to prospective 

Phase II-III clinical trials in which patients received nilotinib at doses 

of either 300 mg or 400 mg twice daily. Incidence, relative risk (RR), and 

95% confidence intervals (CI) were calculated using random-effects or 

fixed-effects models based on heterogeneity of included studies. Results: 

Data from a total of 3,186 patients receiving nilotinib in 16 clinical trials 

were available for analysis. The overall incidence of all-grade and highgrade 

(grade �3) rash were 33.1% (95% CI: 27.7-39.1) and 2.6% (95% 

CI: 2.1-3.4), respectively. Incidence of all-grade rash for patients with 

CML, gastrointestinal stromal tumor (GIST) and systemic mastocytosis 

were 33.2% (95% CI: 27.2-39.9), 25.7% (95% CI: 14.0-42.5) and 

25.0% (95% CI: 15.7-37.4), respectively. Nilotinib was associated with 

increased risk of all-grade rash (RR�2.891, 95% CI: 2.079-4.020; 

P�0.001) when compared to patients treated with imatinib. Risk of 

high-grade rash was increased compared to imatinib (RR�1.823, 95% CI: 

0.670-4.957), but this was not statistically significant (P�0.24). 

Conclusions: Patients with hematologic malignancies and GIST who are 

treated with nilotinib are at significant risk for developing a rash. Further 

studies for characterization, prevention and treatment of this untoward 

toxicity are needed in order to maintain patients’ quality of life and 

minimize the need for dose modification, which may impact clinical 

outcome. 



The chemotherapy-induced peripheral neuropathy (CIPN) outcome measure 

standardization (CI-PeriNomS) study: From consensus to validity and 

reliability in CIPN assessment. Presenting Author: Guido Cavaletti, University 

of Milan-Bicocca, Monza, Italy 

Background: Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a 

debilitating and dose limiting complication of cancer treatment. However, 

the impact of CIPN has never been studied in a clinimetric manner, in its 

impact on quality of life. This study was performed to select appropriate 

outcome measures and to establish, for the first time with a clinimetric 

approach, their validity and reproducibility. Methods: After literature review 

and a consensus meeting, face/content validity were obtained for the 

following scales: the National Cancer Institute Common-Toxicity-Criteria 

(NCI-CTC), the Total Neuropathy Score (TNSc), the modified INCAT 

sensory sumscore (mISS), the European Organization for Research and 

Treatment of Cancer (EORTC) QLQ-C30 and CIPN20 quality of life 

measures. 281 patients with stable CIPN were examined through an EU/US 

collaboration involving 20 oncology/neurology centers. For each scale the 

inter- and intra-rater agreement was evaluated by means of weighted 

K-Cohen coefficients and 95% confidence intervals, when analyzing 

qualitative ordinal scales and by means of Spearman’s rank correlation 

coefficient and t-test when analyzing quantitative ordinal scales. The 

adopted weights for the estimate of K-Cohen coefficients were the Fleiss- 

Cohen weights. For validity purposes, the Kruskal-Wallis equality-ofpopulations 

rank test was performed relating the mISS and TNSc to the 

NCI-CTC grades. Results: Proper, although slightly different, inter-/intraobserver 

scores (i.e. r � 0.7) were obtained for the TNSc, mISS, and 

NCI-CTC sensory/motor subscales. Test-retest values were also high for the 

EORTC QLQ-C30 and for the recently developed and never formally tested 

CIPN20. Acceptable validity scores were obtained through correlation 

between the the mISS and TNSc to the NCI-CTC scores (p values ranging 

from 0.04 to � 0.001). Conclusions: Proper validity and reliability scores 

were demonstrated for the set of selected outcome measures in CIPN. 

These results will allow to base new trials on a solid methodological 

background, although future studies are warranted to investigate the 

responsiveness issues. 


Gender difference in vulnerability and geriatric syndromes among elderly 

cancer survivors. Presenting Author: Lin Fan, University of Rochester 

Medical Center, Rochester, NY 

Background: Few studies have evaluated the gender difference of vulnerability 

and geriatric syndromes (GS) among cancer survivors. Methods: Using 

2003 Medicare Current Beneficiary Survey, we applied multivariable 

logistic regression to evaluate the association of gender with vulnerability 

and GS among cancer survivors. Vulnerability is measured by Vulnerable 

Elders Survey-13 (VES-13), which is calculated from age, self-rated health 

status, difficulty with physical activities and functional activities. Vulnerability 

is defined by a VES-13 score of 3 or higher. 8 common geriatric 

syndromes were assessed: sight trouble, hearing trouble, nutrition problem, 

incontinence, falls, depression, memory loss and osteoporosis. Cancer 

survivors are defined as patients with cancer diagnosed more than one year 

ago. Results: Among the 1,883 cancer survivors, 749 (40.0%) were male; 

1,134 (60.0%) were female. Female survivors had a higher prevalence of 

vulnerability (47.8% vs 35.7%), and GS (65.5% vs 44.6%) than male 

survivors. Mean GS number was 1.19 for female survivors, while 0.77 for 

male survivors (p�0.001). More specifically, female survivors had significantly 

higher prevalence of sight trouble (7.73% vs 5.0%), incontinence 

(14.3% vs 7.1%), falls (28.9% vs 22.1%), depression (13.8% vs 7.7%) 

and osteoporosis (38.2% vs 6.7%). After adjusting for confounders, female 

survivors were more likely to be vulnerable (adjusted OR (AOR): 1.62; CI: 

1.21-2.17; p�0.001); have a geriatric syndrome (AOR: 2.39; CI: 1.91- 

3.00; p�0.001); have sight trouble (AOR: 1.70; CI: 1.00-2.87; p�0.049); 

have incontinence (AOR: 2.48; CI: 1.67-3.69; p�0.001); have depression 

(AOR: 1.87; CI: 1.29-2.71; p�0.001); and have osteoporosis (AOR: 8.48; 

CI: 6.07-11.84; p�0.001). Conclusions: Female cancer survivors experience 

a higher prevalence of vulnerability and overall geriatric syndromes. 


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Incidence, characteristics, and associations of oxaliplatin-induced peripheral 

neuropathy in colorectal cancer patients: Results of a prospective, 

multicenter, international study. Presenting Author: Andreas Argyriou, 

Department of Neurology, “Saint Andrew’s” State General Hospital of 

Patras, Patras, Greece 

Background: We sought to trace the incidence and severity of oxaliplatininduced 

peripheral neuropathy (OXLIPN) and to determine its clinical 

pattern. Among other associations, we also specifically aimed at testing 

whether the degree of acute neuropathy is clinically related to the 

development and severity of chronic OXLIPN. Methods: 170 patients (mean 

age 64y), scheduled to be treated with either FOLFOX or XELOX for 

metastatic colorectal cancer were studied. Patients were prospectively 

monitored at baseline and followed-up during chemotherapy in four 

European sites. The motor/neurosensory NCI-CTCv3 criteria and the 

clinical version of the Total Neuropathy Score were applied to clinically 

grade the severity of OXLIPN. Nerve conduction studies were also longitudinally 

performed. Results: Evidence of acute OXLIPN was disclosed in 

146/170 patients (85.9%). The vast majority of patients manifested 

cold-induced perioral (95.2%) or pharyngolaryngeal dysesthesias (91.8%). 

Other uncommon symptoms, such as jaw spasm were also present. Severe 

acute OXLIPN, requiring prolongation of OXL infusion from 2 to 4-6 hours 

was evident in 32/146 patients (21.9%). Overall, 123/170 patients 

(72.4%) experienced chronic OXLIPN. Severities were grade I: 39 (22.9%); 

grade II: 52 (30.6%); grade III: 33 patients (19.4%). Worst severities were 

related to cumulative oxaliplatin dose (r:0.269;p�0.001). Follow-up 

assessments revealed significant decrease in all sensory action potentials 

examined. The severity of the acute OXLIPN was significantly correlated 

with both the development (r:0.450;p�0.001) and degree of the chronic 

form (r:0.703;p�0.001). Conclusions: Most patients treated with oxaliplatin-based 

chemotherapy would manifest OXLIPN, mainly of moderate 

degree. The severity of the acute syndrome appears to clinically correlate 

with the degree of the chronic form of OXLIPN. Our data suggest that acute 

phenomena, related to axonal hyperexcitability, could contribute to the 

development of peripheral neuropathy; thus it could be advisable to test 

agents against acute OXLIPN in order to verify their effects on the chronic 

form. 


Risk of skin rash with the proteasome inhibitor bortezomib: Updated 

systematic review and meta-analysis. Presenting Author: Emily Christine 

Case, Columbia University, College of Physicians and Surgeons, New York, 

NY 

Background: Rash is a common, adverse event to the novel proteasome 

inhibitor bortezomib (Velcade). Indicated for the treatment of multiple 

myeloma and mantle cell lymphoma, bortezomib is the first proteasome 

inhibitor approved by regulatory agencies. Because the incidence of 

bortezomib-induced skin rash varies widely in published manuscripts, we 

performed a systematic literature review and meta-analysis to determine 

the incidence and overall risk. Methods: We searched PubMed and Web of 

Science databases and abstracts presented at the American Society of 

Clinical Oncology and The American Society of Hematology annual meetings 

(1998 to July 2011) to identify relevant clinical studies. Eligible 

studies included prospective clinical phase II and phase III trials, with data 

on the incidence of rash in patients taking 1.3mg/m2 , 1.5mg/m2 ,or1.6 

mg/m2 of bortezomib intravenously either weekly or twice weekly. The 

incidence of rash and relative risk (RR) were calculated using randomeffects 

or fixed-effects model, depending on the heterogeneity of included 

studies. Results: A total of 2,616 patients with various hematologic and 

solid malignancies from 35 clinical trials were included for analysis. 

Among patients receiving twice weekly bortezomib, the summary incidence 

of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) 

and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant 

increase in all grade rash incidence with higher doses of bortezomib: 19.3 

% (95% CI: 15% to 24.5%) and 20.8% (95% CI: 11.6% to 34.4%) for 

doses of 1.3 mg/m2 and 1.5 mg/m2 , respectively. In addition, bortezomib 

was associated with an increased risk in both all grade (RR: 19.70, 95% CI: 

8.73 to 44.44, p�0.001) and high-grade rash (RR: 5.35, 95% CI: 2.16 to 

13.29, p�0.001), compared to controls. Weekly bortezomib is associated 

with lower risk of rash compared to twice weekly dosing (incidence 3.9% 

versus 18.8%, p�0.001). Conclusions: Bortezomib is associated with a 

significant risk of developing rash with a higher risk among patients 

receiving twice weekly dosage. Management of rash to bortezomib is 

critical to prevent a negative effect on quality of life and dose modifications, 

both of which affect clinical outcome. 




Feasibility of screening hospitalized cancer patients for palliative care. 

Presenting Author: Paul A. Glare, Memorial Sloan-Kettering Cancer Center, 

New York, NY 

Background: The National Comprehensive Cancer Network Palliative Care 

(PC) Guideline recommends screening all oncology patients for PC needs, 

and to call a PC consult when referral criteria are met. There are no data on 

the feasibility or impact of this approach. The aim of this pilot study was to 

assess the feasibility of PC screening in patients admitted to a comprehensive 

cancer center (CCC). Methods: Design: Observational study. From 

11/1/10 to 1/31/11, floor nurses screened all patients the day after 

admission under the two teams (“Team A” and “Team B”) of the 

Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer 

Center. Team A patients were also evaluated by the referral criteria. 

Endpoints: Patients screened ‘positive’ if they had advanced disease and 

any of the clinical situations nominated in the Guideline. The referral 

criteria triggered PC consults in Team A patients; clinical judgment 

triggered Team B consults. Outcomes: Screening rates, nursing satisfaction 

survey, clinical and operational metrics. Results: Ninety percent (229 

of 254) of admissions were screened. Both Teams’ patients were seriously 

ill (see Table), and it was no surprise that 63% (145 of 229) screened 

positive. Survey respondents (response rate 50%) rated screening as 

simple, quick and helpful, although nurses scored the extent of disease 

wrong in 16%. Sixty eight percent (55 of 780) of Team A patients who 

screened positive met the referral criteria. This generated more consults on 

Team A, but the effect on key outcomes was not significant (n.s.). 

Conclusions: Screening for PC was feasible in this setting, but is a 

challenging concept in terms of reliability, validity and timing. The value to 

a CCC of increasing PC access via referral criteria needs evaluation in 

well-designed trials. 

Screened patients Team A (n�113) Team B (n�116) p value 

Status on admission 

Time since diagnosis (months) 13 15 n.s. 

Advanced disease 92% 97% n.s. 

Best supportive care 36% 39% n.s. 

Died within next 3 months 33% 45% n.s. 

Pain score > 7/10 33% 34% n.s. 

Screen positive 71% 56% 0.028 

Outcomes 

Consults 42% 15% �0.0001 

Pain score > 7/10, day 4* 13% 38% n.s 

Median length of stay (days) 4 4 n.s. 

Died in hospital 4% 7% n.s. 

Hospice referral 19% 21% n.s. 


Medical oncologist’s commitment in the end of life (EoL) care of cancer 

patients: The caregiver’s perspective. Presenting Author: Romeo Bascioni, 

Ospedale Murri, Fermo, Italy 

Background: Optimizing the impact of EoL care on cancer patients (pts) and 

their caregivers should be a primary goal of an oncology unit. In this study 

we evaluated satisfaction of family caregivers when the medical oncology 

team assisted pts until death. Methods: Two oncology units were reorganized 

to ensure continuity of care; oncologists trained in palliative care 

medicine assisted pts until EoL. The model assumes that the medical 

oncologist (MO) is the physician in charge throughout the entire disease 

trajectory. Relatives of pts assisted at home or at an inpatient hospice 

underwent a semistructured phone interview conducted by a psychologist 

or a social worker � 1 month after pts’ death. Satisfaction was evaluated for 

symptoms control, communication, psychological support, overall quality 

of care and continuity of therapeutic relationship with the MO. A final 

open-ended question was included for any additional comment. Satisfaction 

was measured using a five-point Likert scale ranging from very 

dissatisfied to very satisfied and converted to a 0-to-100 scale. Results: 

Relatives of 65 pts were contacted, 55 accepted the interview (27 spouses, 

22 sons, 5 in-laws, 1 parent); 50/55 were the leader caregiver. Patients 

were followed at home (41) or at an inpatient hospice (14), for 1-24 wks. 

Satisfaction mean scores were: symptoms control 76/100, communication 

85, psychological support 82 and overall quality of care 87; a specific 

question on the relevance of the MO in EoL care produced a score of 87, 

with no negative or neutral responses recorded for this item. Of note, a 

common perception among caregivers was the appreciation of the MO’s 

commitment during EoL in addition to the technical quality of the 

intervention. The overall satisfaction score was higher than in our previous 

study in which a continuity of care model was not formally adopted, with a 

score improvement from 55 to 87/100. Conclusions: A care pathway where 

the MO is involved in EoL management of cancer pts improved satisfaction 

of caregivers.When a longstanding and trusting relationship has been 

established, the pts-MO connection should not be lost to prevent feelings of 

abandonment. 


Sexual functioning in young women with breast cancer. Presenting Author: 

Shoshana Rosenberg, Harvard School of Public Health, Boston, MA 

Background: Sexual dysfunction is a known complication of adjuvant 

therapy for breast cancer and an important determinant of quality of life. 

Little is known about the frequency and magnitude of this problem among 

very young women with breast cancer during the year following diagnosis. 

Methods: 298 sexually-active women enrolled in an ongoing multi-center 

cohort study with Stage 0-III breast cancer at or before age 40 were 

included in this analysis. Treatment data was self-reported on a survey 

mailed to participants at enrollment. Sexual functioning was assessed 

using the sexual interest and dysfunction subscales from the Cancer 

Rehabilitation Evaluation System (CARES). Scores range from 0-4, with 

higher scores indicative of poorer function. The survey included a measure 

of anxiety and depression (Hospital Anxiety and Depression Scale), of body 

image (CARES) and of physical and menopausal symptoms (Breast Cancer 

Prevention Trial Symptom Checklist). Mean differences in CARES scores 

between treatment groups (chemotherapy vs. none; hormone therapy vs. 

none; lumpectomy vs. mastectomy vs. mastectomy � reconstruction vs. no 

surgery; radiation vs. none) were compared using T-tests and ANOVA. 

Multiple regression models were fit to assess symptoms thought to be 

mediators of the treatment-sexual functioning association. Results: Mean 

age at diagnosis was 36 (range: 22-40) years and mean time from diagnosis 

to survey completion was 5 months (range: 1-16). Mean CARES sexual 

interest and dysfunction scores were higher in women who received 

chemotherapy compared to those who did not (p�0.0001). In the 

multivariate analysis, chemotherapy was no longer associated with decreased 

sexual interest or function. Anxiety, depression, musculoskeletal 

pain, and poorer body image were predictive of both decreased sexual 

interest and function. Vaginal pain symptoms were associated with greater 

dysfunction, while unhappiness with appearance was associated with 

decreased interest. Conclusions: Young women who receive chemotherapy 

are at risk for problems related to sexual functioning early in the survivorship 

period. This effect appears to be mediated through several physiologic 

and psychologic mechanisms, underscoring the need for interventions that 

target both. 


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Defining mild, moderate, and severe fatigue in cancer patients and 

survivors: E2Z02, a trial of the Eastern Cooperative Oncology Group. 

Presenting Author: Xin Shelley Wang, University of Texas M. D. Anderson 


Background: Although mild, moderate and severe categories have been 

used in clinical guidelines for fatigue management in cancer patients, the 

optimal cutpoints on a 0-10 scale for delineating these categories have not 

been replicated. Methods: A multicenter ECOG study (E2Z02) enrolled 

breast, lung, prostate, or colorectal cancer patients with any treatment 

status. Fatigue and symptom interference were measured on the 0-10 

numerical rating scale of the M. D. Anderson Symptom Inventory (MDASI). 

The optimal boundaries for categorizing fatigue severity were determined 

by the largest F ratios from MANOVA (Serlin’s criteria, 1995). Logistic 

regression with robust standard errors was used to identify risk factors for 

moderate/severe fatigue for cancer survivors (defined as patients with no 

evidence of disease and receiving no cancer treatment). Results: The 

optimal cutpoints that identified 3 distinct levels of fatigue severity for the 

2341 patients were: ratings of 1-3 as mild, 4-6 as moderate, and 7-10 as 

severe. Known-group validity for these cutpoints was established by 

significant differences of fatigue severity by ECOG performance status and 

patient-reported quality of life (all P�0.001). Using these cutpoints, 45% 

(983/2177) of patients undergoing active therapy had moderate/severe 

fatigue, with significant more mild fatigue in breast and colorectal cancer 

patients, while more severe fatigue in lung cancer patients (p�.001). 

Among cancer survivors, 29% (150/515) had moderate/severe fatigue 

(breast 31%, colorectal 27%, prostate 22%, lung 33%). Younger age 

(OR�0.97, 95% CI�0.95-0.99) and poor performance status (OR�4.21, 

95% CI�2.36-7.51) were associated with more moderate/severe fatigue in 

cancer survivors. Survivor time was also associated with moderate/severe 

fatigue in breast and colorectal cancer survivors (��5yrs vs. �5yrs: 

OR�0.23, P�0.01 for breast, OR�9.3, P�0.03 for colorectal). 

Conclusions: This multicenter study confirmed the standard cutpoints for 

fatigue severity used in NCCN fatigue management guidelines. It also 

provides a profile of moderate to severe fatigue prevalence for actively 

treated cancer patients and for cancer survivors. 


Early outpatient palliative care in patients with metastatic NSCLC: A 

qualitative study. Presenting Author: Jaclyn Yoong, Massachusetts General 

Hospital Cancer Center, Boston, MA 

Background: Early outpatient palliative care (PC) is an emerging practice 

and its key components have not been defined. We conducted a qualitative 

analysis of data from a randomized controlled trial which demonstrated 

improved quality of life, mood and survival in outpatients who received 

early PC integrated with standard oncologic care versus standard oncologic 

care alone. Our objectives were to 1) identify the content and key 

components of early PC clinic visits, 2) explore timing of key components, 

and 3) compare the content of PC and oncology visit notes at the critical 

time points of clinical deterioration and radiographic disease progression. 

Methods: We chose a random selection of 20 patients with newly diagnosed 

metastatic NSCLC who received early PC who survived within 4 time 

frames: less than 3 months (n�5), 3 to 6 months (n�5), 6 to 12 months 

(n�5) and 12 to 24 months (n�5). We performed content analysis on PC 

and oncology electronic health record notes of these patients using NVivo 9 

software. Results: Addressing symptoms and coping ability were the most 

prevalent components of the PC clinic visits. The content of initial visits 

focused on building relationships and rapport with patients and their 

families and illness understanding. Discussions about prognostic awareness 

occurred during earlier visits while goals of care and hospice 

discussions occurred in later visits. The frequency of addressing these 

components was similar regardless of patients’ length of life. Comparing PC 

and oncology visits around critical time points, both included discussions 

about current illness status and goals of care; however PC visits emphasized 

symptoms, coping, and implications of anti-cancer treatments, while 

oncology visits focused on medical discussions about treatment plans. 

Conclusions: Early PC clinic visits emphasize managing symptoms, strengthening 

coping, and cultivating illness understanding and prognostic awareness 

in a structured, responsive and time-sensitive model. Around critical 

clinical time points PC and oncology visits have distinct features that 

suggest a key role for PC involvement while enabling oncologists to focus on 

anti-cancer management. 




Clinical trial participation as part of end-of-life (EOL) cancer care: 

Associations with medical care near death and bereaved caregivers’ mental 

health. Presenting Author: Andrea Catherine Phelps, Dana-Farber Cancer 


Background: Clinical trial participation is necessary to improve existing 

therapies, encouraged by national guidelines, and common among advanced 

cancer patients. The relationships between trial participation and 

important EOL outcomes such as aggressive care are unknown. Methods: 

Coping with Cancer Study, an NCI-funded multicenter prospective cohort 

study of advanced cancer patients and their caregivers, enrolled September 

2002 – February 2008. Patients were interviewed at baseline, and clinical 

trial participation was documented by chart review. Patients were followed 

to death, (median 4.4 months from baseline). Medical care and quality of 

life (QOL) in the last week of life was assessed by caregiver interview and 

chart review. Caregiver interview 6 months post-bereavement assessed 

QOL and mental health (Structured Clinical Interview for the DSM-IV). The 

primary outcome was aggressive EOL care (ventilation, resuscitation, or 

chemotherapy in the last week of life). Secondary outcomes were bereaved 

caregivers’ mental health and QOL. Propensity-score weighting balanced 

patient characteristics (e.g. clinical variables, EOL preferences) that 

differed by trial participation. Propensity-score weighted regression models 

estimated the effect of trial participation on outcomes. Results: Of 246 

patients followed to death with non-missing propensity scores, 27 were 

clinical trial participants. In propensity-score weighted analyses, trial 

participation was significantly associated with aggressive EOL care [29.6% 

v 9.1%; adjusted OR (AOR), 12.14; 95% CI, 3.65-40.36], ICU admission, 

mechanical ventilation, chemotherapy, and a trend toward inferior QOL 

near death (p � 0.069). Of 180 matched caregivers, trial participation 

predicted less mental illness [AOR, 0.15; 95% CI 0.04-0.57], major 

depression [AOR, 0.25; 95% CI, 0.08-0.80], but was unassociated with 

QOL (p � 0.15) in adjusted analyses. Conclusions: Clinical trial participation 

is associated with increased risk of aggressive EOL care for advanced 

cancer patients, but better mental health for bereaved caregivers. 


Comparative patient-centered outcomes (health state and adverse sexual 

symptoms) between adjuvant brachytherapy versus no adjuvant brachytherapy 

in early-stage endometrial cancer. Presenting Author: Shari Damast, 

Yale University School of Medicine, New Haven, CT 

Background: We performed a cross-sectional analysis of survivors of stage I 

endometrial cancer (EC) to examine the relationship between receipt of 

adjuvant intra-vaginal radiation therapy (IVRT), health state (HS), and 

sexual functioning (SF). Methods: Survivors were administered anonymous 

questionnaires containing demographic and treatment-related items, the 

EQ5D to measure current HS, and the Female Sexual Function Index (FSFI) 

to measure current SF. All were disease-free and had undergone simple 

hysterectomy (SH) with or without adjuvant IVRT at least one year prior to 

questionnaire completion. None had received chemotherapy or hormonal 

therapy. The study was IRB-approved under a waiver of consent. The 

primary endpoint was a comparison of EQ5D-health states and FSFI scores 

between survivors who had received SH alone and those who had received 

SH and adjuvant IVRT. Fisher’s exact test was used to compare IVRT and 

no-IVRT groups and multivariate regression was applied to find associations 

between factors and the outcome measures. Results: 136 (66.3%) participants 

had undergone SH alone and 69 (33.7%) had undergone SH and 

adjuvant IVRT. The SH alone group was younger; otherwise, the two groups 

were balanced with respect to ethnicity, marital status, education level, 

medical co-morbidities (diabetes, hypertension, anxiety), type of SH 

(laparotomy vs minimally invasive surgery-MIS), and baseline sexual 

activity. In the IVRT and no-IVRT groups, the median EQ5D-health states 

were 88 (range 40-100) and 85 (range 10-100) respectively, and the 

median FSFI scores were 14.1 (range 1.2-35.4) and 16.5 (range 1.2-34.8) 

respectively. Controlling for age and type of SH, receipt of IVRT was 

associated with better HS (p�0.018) and not associated with poorer SF 

(p�0.1399). Receipt of laparotomy (vs MIS) was associated with poorer 

HS and worse SF (p�0.0156 and p�0.0115, respectively), and its 

detrimental effect on FSFI score was more pronounced in the IVRT 

compared to no-IVRT group (p�0.0486). Conclusions: Compared to SH 

alone, receipt of adjuvant IVRT was generally not associated with poorer SF 

or HS. 


Changes in patient-reported outcomes in women with breast cancer in a 

multicenter double-blind randomized controlled trial assessing the effect 

of acupuncture in reducing aromatase inhibitor-induced musculoskeletal 

symptoms (AIMSS). Presenting Author: Ting Bao, University of Maryland 

Greenebaum Cancer Center, Baltimore, MD 

Background: Aromatase Inhibitors (AIs) have been associated with worsening 

of patient related outcomes (PROs) such as AIMSS, menopausal 

symptoms and depression. Acupuncture has been reported to alleviate 

such symptoms. We hypothesized that real acupuncture (RA) would 

improve PROs more than sham acupuncture (SA). Methods: We collected 

PROs at baseline, 4, 8, and 12 weeks (wks), from women enrolled in a 

multi-center double blind RCT designed to assess the effect of acupuncture 

in reducing PROs. Patients were randomized to 8 wkly RA or SA. PROs were 

measured by the revised National Surgical Adjuvant Breast and Bowel 

Project (NSABP) menopausal symptoms questionnaire, Center for Epidemiological 

Studies Depression Scale (CESD), Hospital Anxiety and Depression 

Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), Hot Flash Daily 

Diary, Hot Flash Related Daily Interference Scale (HFRDI) and EuroQoL 

survey. We measured estrogen and cytokines concentrations at baseline 

and wk 8. We used Wilcoxon rank sum and signed-rank tests to make 

comparisons between and within group, respectively. Results: We included 

23 patients from RA and 24 from SA arms in the intent-to-treat analysis. 

We have previously reported no significant difference in reduction of AIMSS 

between two arms. RA caused reduction of CESD scores compared to SA 

(median: -2 vs 0, p � 0.057). When compared to baseline, there were 

statistically significant improvements at wk 8 in hot flash severity score 

(p�0.006), hot flash frequency (p�0.011), HFRDI (p�0.014) and NSABP 

menopausal symptoms (p�0.022) scores in RA arm; for EuroQoL 

(p�0.022), HFRDI (p�0.043) and NSABP menopausal symptoms 

(p�0.005) scores in SA arm. The majority of patients’ estradiol concentrations 

were undetectable at baseline and wk 8. Changes in other time points, 

data and analysis of cytokines changes will be presented at the meeting. 

Conclusions: Real and sham acupuncture were both associated with 

improvement in PROs in breast cancer patients taking AIs. We detected no 

significant difference in the change of PROs between real and sham 

acupuncture, except for CESD. 


A randomized trial of a cardiopulmonary resuscitation (CPR) video (V) in 

advance care planning (ACP) for progressive hepatopancreaticobiliary 

cancer patients. Presenting Author: Andrew S. Epstein, Mount Sinai, New 

York, NY 

Background: CPR is an important advance directive topic in patients with 

progressive cancer; however such discussions are challenging. Previous 

work by Volandes et al suggests that V images help, however whether V 

educational information about CPR engenders broader ACP discourse is 

unknown. Methods: A randomized trial of an educational V or narrative (N) 

in patients with progressive hepatopancreaticobiliary cancers was conducted. 

The V and N were 3 minutes long and contained an identical 

description of CPR. Primary endpoint: ACP documentation 1-month 

post-test (either a formal advance directive or a documented ACP discussion), 

80% powered with 0.01 type-I error rate for estimated advance 

directive completion rates of 70% V arm vs. 25% N arm with a sample of 

56 subjects. Secondary endpoints (exploratory): impressions of the study 

information; pre and post knowledge of and preferences for CPR and 

mechanical ventilation; and follow-up longitudinally (to death or 6 months 

post-test). Results: 56 subjects consented and analyzed. 1-month post-test 

ACP documentation was not significantly higher in the V arm (12/30, 

40.0%) vs. the N arm (4/26, 15.4%); Fisher’s exact test, OR � 3.583 

[95% CI: 0.886 – 17.937], p � 0.07. Knowledge increased in both arms 

after the intervention. Preferences for CPR changed in V arm but not in N 

arm; for mechanical ventilation, there was no change in either arm. The 

majority of subjects in both arms reported the information as helpful, 

comfortable to discuss, and recommended to others. Longitudinally, 

outcomes were similar between V & N arms, respectively: % advance 

directives completed (63% & 58%); median days from test to advance 

directive (60 & 72) and advance directive to death (21 & 20); median ACP 

documentation after 1 month (0 & 1); median hospital admissions (1 & 1), 

days of stay (5 & 7), ICU stays (0 & 3) and CPR/mechanical ventilation (1 & 

3). 52% of all subjects died by study end, the majority in hospice care. 

Conclusions: This first randomized trial addressing downstream ACP effects 

of V vs. N decision tools demonstrated a trend towards more ACP 

documentation in V patients. Further research into these types of educational 

media is needed. 



Understanding the symptom experience of breast cancer outpatients: The 

validity and utility of the M.D. Anderson Symptom Inventory (MDASI). 

Presenting Author: Tito R. Mendoza, University of Texas M. D. Anderson 


Background: Breast cancer and its treatments can produce multiple 

symptoms that cause distress and impair function. The MDASI, a patientreported 

outcome measure of symptoms (sxs) and functional interference 

has been validated in general oncology and has the potential to inform 

symptom experience and guide treatment specific to breast cancer patients 

(pts). Methods: The Eastern Cooperative Oncology Group (ECOG) conducted 

the Symptom Outcomes and Practice Patterns (SOAPP) study at academic 

and community medical oncology clinics and included pts with breast 

cancer of all stages and phases of care. At baseline and 4 weeks, pts 

completed the MDASI. Symptom experiences and psychometric properties 

of the MDASI in breast cancer pts (n � 1544) were analyzed. Results: The 

median age was 58 years, and the race/ethnicity included 11% black and 

8% hispanic. 5% had ECOG performance status (PS) �2. The 5 most 

prevalent moderate/severe sxs reported at baseline were fatigue (31%), 

disturbed sleep (27%), drowsiness (21%), hair loss (22%) and dry mouth 

(19%); moderate/severe skin rash (6%) and vomiting (4%) were the least 

prevalent. At follow-up, about 1/3 of patients had moderate/severe fatigue 

and 19% had moderate/severe pain and distress. Internal consistency and 

test-retest reliability were good, with Cronbach alphas of �0.85 and 

intraclass correlations of �0.76 for all subscales. Among those whose PS 

was stable or improving, the change scores in sx severity improved most for 

sleep disturbance, numbness/tingling, and difficulty remembering things. 

Significantly higher scores and moderately large effects for the severity 

scale were reported by pts with poorer PS (ES�.61) and those with 

local/regional/metastatic disease (ES�.67). Results were similar for the 

interference scale. Pts whose quality of life (QOL) declined showed greater 

increase in severity (1.1 vs .07, p�.001) from baseline to follow-up than 

pts whose QOL was unchanged, demonstrating sensitivity to change. 

Conclusions: Breast cancer pts have significant sx burden despite wellpreserved 

PS. The MDASI is a valid, reliable, and sensitive sx assessment 

method for research and patient care in breast cancer outpatients. 


Comparing three validated methods of patient self-reported fatigue in a 

prospective randomized clinical trial. Presenting Author: Katherine Sams, 

Wake Forest University, Winston Salem, NC 

Background: Fatigue can be measured with different validated assessment 

instruments in symptom management trials. Methods: Between 2004- 

2009, the Wake Forest CCOP Research Base protocol 97202 randomized 

236 women receiving adjuvant chemotherapy for newly diagnosed breast 

cancer to Coenzyme Q10 supplementation vs placebo. The primary 

endpoint was change in self-reported fatigue. Patients (pt) were assessed at 

baseline, 8, 16, and 24 weeks (wk) with 3 instruments: 1) Profile of Mood 

States – Fatigue (POMS; 7 questions; scored 0-4); 2) Functional Assessment 

of Cancer Treatment – Fatigue (FACIT; 13 questions; scored 0-4); 

and 3) Visual Analog Scale (VAS; one scale; scored 0-10). For comparison, 

each instrument was rescaled from 0 to 100; higher numbers indicate 

worse fatigue. Results: CoQ10 did not significantly affect fatigue (Lesser G 

et al, ASCO Proc., 2010). All 3 measures demonstrated an increase in 

fatigue after chemotherapy initiation at 8&16wkswith trend towards 

baseline levels at 24 wks. The fatigue measures were highly correlated: r � 

0.8 for all pairwise associations at all times. However, their scores varied. 

The Table shows mean rescaled scores for pt below/above the median 

fatigue level, calculated by taking mean of the three scores averaged across 

the four time periods. In general, POMS tended to give the lowest and VAS 

the highest scores, but differences between POMS and FACIT and FACIT 

and VAS depended on mean fatigue level. For pt experiencing lower 

(�median) fatigue, FACIT and VAS scores were similar, while POMS scores 

were significantly lower. For higher (�median) fatigue, POMS and FACIT 

scores were similar, while VAS was significantly higher. Conclusions: While 

POMS, FACIT, and VAS scores were highly correlated, their scale scores 

varied depending on the level of fatigue experienced by the pt. Fatigue 

assessment methods in clinical trials should be selected carefully as they 

do not always give equivalent results. Supported by NCI/DCP grant U10 

CA81851. 

Means (standard deviations) by average level of fatigue across all time 

points. 

Instrument < Median fatigue (N�116) > Median fatigue (N�116) 

POMS 10.8 (7.6) 41.6 (17.9) 

FACIT 14.1 (9.0) 41.4 (14.3) 

VAS-F 15.3 (9.8) 48.2 (14.9) 


593s 


A randomized trial evaluating the integration of online questionnaires into 

follow-up (FU) care for early-stage breast cancer (ESBC). Presenting 

Author: Alyse Wheelock, University of California, San Francisco Helen 

Diller Family Comprehensive Cancer Center, San Francisco, CA 

Background: Large numbers of cancer survivors have led to the need for FU 

care addressing lasting effects of BC and its treatment. We conducted a 

trial evaluating formats of FU care to determine if integration of remote 

electronic questionnaire FU provides for timely symptom management and 

more efficient care than routine clinic visits alone. Methods: Patients (pts) 

with ESBC were randomized to either usual care (UC, frequency of visits 

determined by oncology providers) with completion of an optional online 

health and symptom questionnaire (Q) before each clinic visit, or to 

SIS.NET FU care, in which pts were scheduled for up to 3 routine oncology 

related clinic visits over 18 mos and completed the online Q every 3 mos. 

Qs were reviewed by a survivorship nurse practitioner (NP) with pt phone 

contact for symptoms requiring urgent attention. We recorded the time 

between electronic symptom reporting and FU for pts in the SIS.NET arm. 

Data included the number of oncology related clinic visits, total number of 

physician visits, and number of medical tests including labs and imaging 

studies ordered. Kolmogorov-Smirnov tests for equal distributions were 

used to determine if there were any significant differences between 

SIS.NET and UC. Results: 100 pts were enrolled, 75 completed the 18 

month study and 25 pts remain in FU. For the 75 pts, 85% received 

chemotherapy and 77% received hormone therapy. Pts in the SIS.NET arm 

completed an average of 3.8 out of 7.2 emailed surveys (52.6%), and pts in 

the UC arm completed an average of 2.2 out of 3.4 (69.1%) routine 

pre-clinic surveys. For pts in the SIS.NET arm, 75% of reported symptoms 

were reviewed by a NP in � 3 days. There was no significant difference 

between SIS.NET and UC FU for oncology related clinic appointments, 

total number of physician visits, or number of medical tests performed. 

Conclusions: Use of on-line health and symptom surveys with remote NP 

review provided timely symptom FU but did not reduce clinic visits or 

medical testing in pts with ESBC. Further analyses of these data as well as 

additional studies are necessary to understand the barriers to integration of 

web-based tools to achieve more efficient FU care for BC survivors. 


Anemia and functional disability in older adults with cancer. Presenting 

Author: Cynthia Owusu, Case Western Reserve University, Cleveland, OH 

Background: While anemia is associated with functional disability in older 

adults in general, this relationship has not been well characterized in older 

adults with cancer. We sought to examine the association between anemia 

and functional disability and to identify other factors associated with 

functional disability in patients (pts) age �65 with cancer. Methods: We 

conducted a secondary analysis of a multi-center prospective study of 500 

pts � age 65 that identified predictors of chemotherapy (chemo) toxicity 

(Hurria et al, JCO, 2011). The primary outcome of this analysis was 

functional disability, defined as need for assistance with �1 instrumental 

activities of daily living. Data collected prior to initiation of a new chemo 

regimen included: age, tumor/treatment variables, labs [including hemoglobin 

(Hb)], and geriatric assessment (functional status, comorbidity, social 

support, psychological, cognitive, and nutritional status). Anemia (World 

Health Organization criteria) was defined as Hb �12g/dl (women) and Hb 

�13g/dl (men). Bivariate analysis and logistic regression were used to 

examine the association between functional disability, anemia, and other 

pre-treatment variables. Results: Among 500 pts [median age 72 years 

(range 65-91), 56% female, 61% stage IV], the prevalence of functional 

disability and anemia was 43% and 51%, respectively. The mean Hb was 

11.7g/dl and 12.6g/dl among pts with and without functional disability. 

Pts with anemia were more likely to report functional disability (53% vs. 

46%, p�0.01). On multivariate analysis, factors associated with functional 

disability included anemia [Odds Ratio (OR)� 2.06, 95% confidence 

interval (CI)� 1.39-3.05], increased age (OR� 1.04, 95% CI � 

1.00-1.07), increased comorbidity (OR� 1.23, 95% CI � 1.09-1.39), 

advanced stage (OR� 1.85, 95% CI � 1.22-2.80), and unintentional 

weight loss (OR� 2.02, 95% CI � 1.37-3.00). Conclusions: Anemia was 

highly prevalent and was associated with functional disability. Prospective 

studies that further examine the relationship between anemia and functional 

disability and randomized-controlled trials that evaluate the correction 

of anemia as a modifiable strategy to improve functional status in older 

pts with cancer are warranted. 




Efficacy and safety of half-dose pegfilgrastim in cancer patients receiving 

cytotoxic chemotherapy. Presenting Author: Ryan C. Ramaekers, Saint 

Francis Cancer Treatment Center, Grand Island, NE 

Background: Pegfilgrastim reduces neutropenia risk in patients (pts) on 

cytotoxic chemotherapy. A single 6 mg dose per chemotherapy cycle 

commonly causes bone pain and leukocytosis. While half-dose pegfilgrastim 

has been shown to be safe and effective in breast cancer pts, there is no 

data on half-dose pegfilgrastim in general oncology pts. Methods: We 

evaluated the efficacy and safety of half-dose pegfilgrastim in general 

oncology pts on cytotoxic chemotherapy at St Francis Cancer Center. Pts 

who received at least one dose of 6 mg pegfilgrastim and developed 

NCI-CTCAE grade 2 or more bone pain and/or leukocytosis (WBC�10,000/ 

ml) were given 3 mg dose pegfilgrastim on their following chemotherapy 

cycles. Pt demographics, type/number of chemotherapy regimens, efficacy, 

side effects and complications were evaluated. McNemar’s test, logistic 

regression analysis and ANOVA were used for statistical analysis. Results: 

Twenty-six pts (3 males, 23 females, all Caucasian) with median age 55 

(range 34-86) received a total of eighty-three 3 mg doses of pegfilgrastim. 

Cancers treated were breast (N�16), colorectal (N�7), head and neck 

(N�1), non-Hodgkin lymphoma (N�1) and non-small cell lung cancer 

(N�1). Chemotherapy received was anthracycline (N�9), taxane (N�7), 

5-FU/oxaliplatin (N�7), 5-FU/cisplatin (N�1), gemcitabine/oxaliplatin 

(N�1), pemetrexed/carboplatin (N�1). No neutropenia or chemotherapy 

dose modifications occurred on half-dose pegfilgrastim. In the 26 pts we 

report, bone pain occurred in 23 pts at 6 mg and 14 pts at 3 mg dose. 

Leukocytosis occurred in 23 pts at 6 mg and only 2 pts at 3 mg dose 

(McNemar’s test, P�0.01). While older age and full-dose pegfilgrastim 

were predictive of bone pain, more than one line of chemotherapy and 

half-dose pegfilgrastim were predictive of lack of leukocytosis (logistic 

regression analysis/ANOVA, P�0.01). Conclusions: Half-dose pegfilgrastim 

in general oncology pts receiving cytotoxic chemotherapy seems to be safe 

and effective with less bone pain and leukocytosis without resultant 

neutropenia or need for chemo modification. Larger prospective studies of 

half-dose pegfilgrastim in this setting are needed to further understand the 

feasibility of this approach. 


Determinants of fatigue improvement in outpatient oncology according to 

baseline categories of fatigue severity. Presenting Author: Michael Fisch, 


Background: Understanding the determinants of fatigue response may help 

distinguish between different fatigue phenotypes and inform trial designs. 

Methods: Patients with invasive cancer of the breast, prostate, colon/ 

rectum, or lung were enrolled from multiple sites. At baseline and 4-5 

weeks later patients rated their symptoms on a 0-10 numerical rating scale. 

A 2-point change was considered clinically significant for fatigue change. 

Logistic regression models and ordinal logistic regression models were used 

to examine the effects of demographic and clinical factors on fatigue 

change. Separate models were constructed for fatigue deterioration in 

patients with mild fatigue at baseline and lack of improvement for those 

with severe fatigue at baseline or any significant change for those with 

moderate baseline fatigue. Results: 3,106 pts were enrolled at baseline and 

3,032 were analyzable for fatigue change. At baseline, 23% had no 

fatigue, 35% mild, 25% moderate, and 17% severe. Improvement varied 

by baseline fatigue score with response in 54% with severe fatigue, 31% 

with moderate, and 9% with mild. Overall, 13 different parameters were 

significant in these 3 models of fatigue change, but no single parameter 

was common to all 3 categories of fatigue. Exposure to anxiolytics and 

duration of current treatment were significant in models of mild and severe 

fatigue; antidepressant exposure was significant for mild and moderate 

fatigue, and baseline fatigue level was a significant parameter in moderate 

and severe fatigue. In colorectal and lung cancer patients, gender was not 

significant for fatigue change in patients with mild or moderate fatigue, but 

gender was the strongest predictor fatigue improvement in patients with 

severe fatigue with men most likely to significantly improve (OR�2.49, 

95% CI 1.15-5.41, p�0.021). Conclusions: Clinically significant improvement 

in fatigue varies between 9% and 54%. Predictors of fatigue change 

vary depending on categories of baseline fatigue severity. Gender is the 

strongest predictor for fatigue improvement among lung and colorectal 

outpatients with severe baseline fatigue. Future trial designs should 

account for gender and baseline fatigue severity. 


Continued suppression of bone turnover following a single dose of zoledronic 

acid: Time to re-think dosing intervals in the management of bone 

metastases? Presenting Author: Christine E. Simmons, St. Michael’s 

Hospital, University of Toronto, Toronto, ON, Canada 

Background: The management of patients (pts) with bone metastases has 

changed significantly over the past decade, with the advent of newer, more 

potent anti-osteoclastic agents. However, the dosing interval in which these 

agents are given has not changed; pts are still dosed at a frequency of 

monthly or q3weekly injections. It is not known if this is the optimal dosing 

frequency or due to convention. The purpose of this study was to determine 

the duration of suppression of bone turnover by Zoledronic Acid (ZA) in a 

population of bisphosphonate naive metastatic breast cancer (MBC) pts. 

Methods: This prospective single arm phase II study enrolled 26 pts with 

MBC to bone who had not received bisphosphonates in the metastatic 

setting. A single dose of ZA was given at week 0, and biomarkers of bone 

turnover (serum CTX) were collected every 2 weeks subsequently. Pain 

scores and quality of life data were collected every 4 weeks. Pts remained 

on study if their biomarkers remained suppressed, but came off study as 

soon as escape from suppression was noted, (defined as a rise � 50% of 

baseline value). Results: At 12 weeks, 73% (95% CI 56%-90%) of pts had 

continued suppression of bone turnover demonstrated by serum CTX. The 

pts that escaped suppression did so at a median of 8 weeks after first 

infusion of ZA (range 8-10 weeks). The magnitude of suppression (proportion 

decrease from baseline) of serum CTX at week 4 was significantly 

greater in those who had continued suppression compared to those who 

escaped suppression before 12 weeks (75% vs 58%, p � 0.02). The 

absolute baseline value of CTX was significantly lower in pts who maintained 

suppression (507 vs. 745 ng/L, p � 0.04). Quality of life scores and 

pain medication use did not change appreciably during this period. 

Conclusions: This study suggests that ZA may not need to be given at 

conventional intervals in the majority of pts, and may safely be withheld 

without increased risk to morbidity or decline in quality of life over a 12 

week period. Baseline CTX and the magnitude of suppression of bone 

turnover at 4 weeks may predict for the optimal dosing frequency. 

Confirmation in a randomized trial is needed. 


Pain, sleep disturbance, and fatigue symptom cluster in patients suffering 

from chronic chemotherapy-induced neuropathic pain (CINP). Presenting 

Author: Jennifer S. Gewandter, University of Rochester Medical Center, 

Rochester, NY 

Background: Various symptom cluster combinations of pain, fatigue, sleep 

disturbance (SD), and depression have been identified in cancer patients. 

The presence of symptom clusters has not been assessed in patients with 

persistent CINP. This exploratory analysis aimed to determine which 

symptoms statistically clustered with pain in cancer survivors with CINP. 

Methods: The University of Rochester Cancer Center Community Clinical 

Oncology Program recruited 461 patients with CINP � 4 (on a 0-10 scale) 

who had completed chemotherapy (median 7 months ago) for a pain 

intervention trial. At baseline, groups of highly associated symptoms that 

included pain were identified empirically using factor and cluster analyses 

of the 11 symptoms in the University of Rochester Symptom Inventory plus 

the Hospital Anxiety and Depression Scale (HADS) scores. To investigate if 

associated symptoms track together over time, multiple linear regression 

(MLR) analysis was performed using changes in symptom severity between 

baseline and week 6, controlling for gender, age, education, race, and 

marital status. Results: Subjects were 88% white and 71% female, and on 

average 61 years old. Mean (standard deviation) baseline pain, fatigue, and 

SD were 5.7 (2.8), 5.0 (2.7), and 4.2 (3.1), respectively; 26% of subjects 

had borderline or abnormal HADS scores. Factor analysis identified 3 

factors that accounted for 88% of the variance. One factor included pain, 

fatigue, SD, but not HADS, and accounted for 37% of the variance. 

Variable clustering also identified pain, SD, and fatigue as 1 symptom 

cluster. Changes in severity of SD and fatigue (p � 0.0001), but not HADS, 

were associated with changes in pain (adjusted R2 � 0.168) in MLR 

analysis. Conclusions: Pain, fatigue, and SD were identified as a symptom 

cluster by factor and cluster analyses, and were found to track together over 

time by MLR. Since these data suggest that pain is associated with sleep 

quality and fatigue in patients with persistent CINP, targeting one of these 

symptoms may lead to reductions in the others. Future research should 

investigate interventions that target pain, fatigue, and SD concurrently in 

cancer survivors suffering from CINP. 



Treatment and mortality rates of older cancer patients with a body mass 

index Grade 3 2 (50) 3 (30) 2 (67) 6 (67) 

Liver AEs 0 1 (10) 0 2 (22) 

Renal AEs 

Thromboembolic events 

2 (50) 0 0 3 (33) 

b 

0 1 (10) 0 2 (22) 

SAEs 1 (25) 2 (20) 1 (33) 5 (56) 

Deaths, n (%) c 

595s 

2 (50) 4 (40)� 1 (33) 3 (33) 

Plts: Cycles 2-6, mean (n) 

Pre ctx Day 1 309 (4) 443 (9) 314 (3) 442 (9) 

Pre ctx Day 8 204 (4) 355 (10) 239 (2) 270 (9) 

Pre ctx Day 15 75 (3) 164 (10) - - 

Nadir 103 (4) 143 (10) 53 (2) 113 (9) 

Grade 3/4 thrombocytopenia: Cycle 2-6, n (%) 1 (25) 0 2 (67) 3 (33) 

a 7/33 randomized pts never received epag/pbo. b None were considered related to epag and all 

resolved. One event occurred after stopping epag and following disease progression (PD). c All 

deaths were from PD; three additional patients died prior to receiving epag or pbo. 




Disease-driven symptoms and response to chemotherapy in treatmentnaive 

patients with advanced non-small cell lung cancer (NSCLC). Presenting 

Author: Desiree Jones, University of Texas M. D. Anderson Cancer 


Background: The disease-driven symptoms of treatment-naïve patients with 

advanced NSCLC have not been the primary focus of previous studies. One 

reason for this gap in the literature is that randomized trials typically lack 

an opportunity to capture the symptom profiles of patients who are truly 

treatment-naïve. To address this need, this study sought to: (i) characterize 

the symptom profile of treatment-naïve patients with advanced NSCLC, and 

(ii) describe patients’ response to chemotherapy. Methods: The study 

sampleconsisted of43 treatment-naïve patients (no prior treatment by 

surgery, radiation, or chemotherapy) with a primary diagnosis of advanced 

NSCLC from the MD Anderson Cancer Center, and was derived from a larger 

study (Cleeland et al. J Clin Oncol 29:2859-65, 2011). Patients’ symptoms 

were assessed pre-chemotherapy, and then prospectively at 6, 12, 

and 18 weeks from initiation of chemotherapy using the MD Anderson 

Symptom Inventory Lung Cancer module. Results: The top symptoms 

reported by patients, in order of severity, were shortness of breath, fatigue, 

distress, sadness, drowsiness, and pain. Chemotherapy did not significantly 

improve shortness of breath, drowsiness, pain, disturbed sleep, lack 

of appetite, coughing, and constipation in this sample of patients, and was 

associated with a significant increase in levels of fatigue and numbness 

(mean difference in fatigue at 12 weeks from baseline � 2.8; 95% CI, 

0.5–2.9; p � .01; and in numbness from baseline � 1.1; 95% CI, 

0.2–2.0; p � .02). Conclusions: This study characterizes the disease-driven 

symptoms of truly treatment-naïve patients with advanced NSCLC. Knowledge 

of these symptoms is of intrinsic value in the clinical management of 

advanced NSCLC as it provides the critical reference point against which 

symptom palliation must be measured. Patients’ lack of symptomatic 

improvement from chemotherapy in this study suggests that this sub-set of 

patients may have had rapidly progressing disease and that chemotherapy 

may have prevented symptoms levels from worsening. Consistent with 

literature, transient but significant increase in both fatigue and numbness 

are chemotherapy-related toxicities. 


Final results of a large collaborative, hospital-based quality improvement 

study aimed at the implementation of interventions for the psychosocial 

care of adult cancer patients (HUCARE project). Presenting Author: 

Rodolfo Passalacqua, Istituti Ospitalieri di Cremona, Cremona, Italy 

Background: Incorporating psychosocial research into practice is challenging. 

Aim of this study is to assess the feasibility and effectiveness in real life 

of interventions which have been tested in RCTs and have demonstrated to 

improve pts psychosocial conditions Methods: This is an implementation 

study of five EBM interventions conducted in 28 centers. We adopted the 

model of Pronovost (BMJ 2008), which includes context analysis to 

identify local barriers; introduction of the interventions, and evaluation of 

how many pts receive the recommended interventions. Primary EPs: degree 

of implementation detected in a blinded fashion by external personnel. 

Interventions included: 1) EBM communication courses for doctors and 

nurses; 2) use of a question prompt list (QPL) for all pts; 3) creation of the 

Point of Information and Support (PIS) in the ward (J Clin Oncol 

27:1794-99,2009); 4) identification of a referring nurse (RN) for informing 

and educating pts; 5) screening of distress and social needs. Results: In 

December 2008, 28 eligible centers applied to participate. 27 are 

evaluable and 1 is too early. 156 oncologists and 401 nurses attended the 

3 days training course. A QPL was subjected to cross-cultural adaptation, 

yielding the first validated Italian QPL (BMC Health Serv Res 2010). 24 

centers (89%) have successfully implemented the intervention; 3 centers 

failed for various reasons: internal conflicts of the staff, poor motivation, 

etc. Main results for each intervention are shown in the table. Conclusions: 

A successful implementation of EBM measure was obtained in the vast 

majority of oncology centers and yields to significant changes in the 

delivery of psychosocial care. Project funded by the Italian Ministry of 

Health and Lombardia Region. 

EBM training 

courses 

(No. of 

attendee, oncologists 

plus nurses) 

Referring 

nurse (RN) 

(% of pts 

withaRN) 

PIS 

(No. of 

centers 

with a PIS) 

Use of 

the QPL 

(% of pts 

who receive 

the QPL) 

Psychosocial 

evalutaion 

(% of screened 

patients) 

Pre-implementation 0/598 0% 5 0% 0% 

Post-implementation 557/598 (93%) 86% 22 73% 83% 


Evaluation of a non-peptidic mimic of host defense proteins, PMX30063, 

in an animal model of oral mucositis. Presenting Author: Richard W Scott, 

PolyMedix, Inc., Radnor, PA 

Background: Oral ulcerative mucositis (OM) is a common, painful, doselimiting 

toxicity of cancer therapy. The care for OM is largely palliative and 

there is an urgent need for new and effective therapies. Host defense 

proteins (HDPs) are amphiphilic components of the innate immune system 

that serve as a primary response to infection. Exclusive of their direct 

antimicrobial activity, HDPs have been shown to possess immune modulatory 

and anti-inflammatory activities. We are developing non-peptidic 

mimics of HDPs, capturing the structural and biological properties of HDPs 

within a framework of smaller fully synthetic oligomers. The lead compound, 

PMX30063, is in Phase 2 clinical trials for iv treatment of systemic 

staphylococcal infections. Recently, we observed that HDP mimics attenuate 

anti-inflammatory pathways and reasoned that these activities could be 

leveraged into a mucositis intervention. Methods: In an acute radiation 

hamster model, PMX30063 was applied as a topical rinse, 3 times daily at 

1, 3 or 10 mg/ml over a 28 day treatment regimen ( n � 10), following a 

single radiation dose to the buccal cheek pouch (40 Gy). In a fractionated 

radiation model, radiation (7.5 Gy/dose) was administered on days 0, 1, 2, 

3, 6, 7, 8 and 9, targeting the left buccal pouch mucosa. PMX30063 was 

given topically 3 times daily at 3 mg/ml over a 35 day regimen beginning on 

day0(n�10). OM was scored using an established blinded method. 

Results: In the acute model, PMX30063 reduced the number of animal 

days with ulceration from 43% in vehicle-treated hamsters to � 5% in all 3 

PMX30063 dose groups (�2 test; p�0.001). In the fractionated model, 

PMX30063 significantly reduced the daily mucositis scores prior to peak 

mucositis and throughout the remaining course of treatment (Mann- 

Whitney Rank-sum analysis; p�0.001). PMX30063 reduced the number 

of animal days with ulceration from 55% in vehicle-treated hamsters to 

3.3% (�2 test; p�0.001). The time courses of efficacy argue that direct 

antimicrobial action is not the primary driver of efficacy. Conclusions: The 

safe and highly efficacious activity of PMX30063 in animals supports its 

further development as a topical therapeutic to prevent OM in cancer 

patients. 


Clinical ethics consultation in oncology. Presenting Author: Andrew G. 

Shuman, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: There is limited empirical research exploring the nature of 

clinical ethical consultations within the oncology population. Our objective 

is to review, describe and compare clinical ethics consultations at two 

NCI-designated comprehensive cancer centers, in order to identify opportunities 

for systems improvement in clinical care. Methods: This case series is 

derived from prospectively-maintained clinical ethics consultation databases 

at each institution. All adult oncology patients receiving ethics 

consultation from 2007 through 2011 were included as eligible cases. 

Both qualitative and quantitative analyses were undertaken. Demographic 

and clinical information were obtained from the databases for all patients, 

and verified via chart abstraction. Additional variables studied included the 

reason for and context of the ethical consultation, the patient’s code status 

before and after consultation, and involvement of palliative care or other 

adjuvant services. Opportunities for systems-level improvements and/or 

educational initiatives were identified. Results: A total of 207 eligible cases 

were identified. The most common primary issues leading to ethics 

consultation were code status and advance directives (25%), surrogate 

decision-making (17%), and medical futility (13%). Communication lapses 

were identified in 41%, and interpersonal conflict arose in 51%. Prior to 

ethics consultation, 26% of patients were DNR; 60% were DNR after 

ethics consultation. Palliative care consultation occurred in 41% of cases. 

Opportunities for systems improvement and professional education related 

to goals of care at the end of life, the role of palliative care involvement, and 

improved communication. Conclusions: Ethics consultations among cancer 

patients reflect the realities inherent to their clinical management. Appropriately 

addressing advance directives within the context of overall goals of 

care is crucial. Thoughtful consideration of communication barriers, 

sources of interpersonal conflict, symptom control, and end-of-life care are 

paramount to optimal management strategies in this patient population. 



A prospective longitudinal study of cancer-related fatigue in patients undergoing 

breast-conserving surgery and radiation with or without chemotherapy 

for breast cancer. Presenting Author: Mylin Ann Torres, Department 

of Radiation Oncology, Emory University, Atlanta, GA 

Background: We prospectively evaluated risk factors for persistent cancerrelated 

fatigue in women with breast cancer undergoing lumpectomy with 

or without chemotherapy (CTX) prior to whole breast radiotherapy (XRT). 

We assessed the potential role of inflammatory mediators, demographic 

characteristics, and treatment history including CTX. Methods: Following 

lumpectomy, 60 women received a definitive course of whole breast XRT 

(50 Gy plus a 10 Gy boost). Prior to XRT, at week 6 of XRT, and 6 weeks 

post XRT, subjects completed the Multidimensional Fatigue Inventory 

(MFI) and underwent blood draws for inflammatory mediators (protein and 

mRNA). Results: Independent multivariate analyses of clinical and demographic 

factors revealed that CTX (p�.001) , given neoadjuvantly or 

adjuvantly, and age �50 (p�.03) were significant predictors of higher 

fatigue scores post XRT. Mean MFI scores in patients treated with CTX 

(n�24) were 20 points higher than patients not treated with CTX (p�.001) 

with a clinically meaningful difference in scores being 10 points on the 

MFI. Gene ontology analysis of differentially expressed genes indicated 

increased activation of genes involved in immune and inflammatory 

responses in fatigued vs. non-fatigued patients (p�.001). Of the inflammatory 

mediators, plasma IL-6 prior to XRT was the strongest predictor of post 

XRT fatigue (p�.02). Moreover, plasma IL-6 concentrations prior to XRT 

were significantly higher in patients who received CTX (mean 4.96 vs. 

2.53, p�.01). Patients who received CTX also had significantly higher 

levels of NF Kappa B DNA binding 6 weeks post XRT (p�.001), and 

transcription factor binding analysis revealed a greater representation of 

genes with the NF Kappa B DNA binding motif in fatigued vs. non-fatigued 

patients (p �.05). Conclusions: Collectively, these data suggest an interaction 

between CTX and XRT leading to inflammation and fatigue several 

weeks post XRT. This relationship was independent of whether CTX was 

given pre or post-operatively. Treatments targeting inflammation before 

XRT may reduce fatigue post therapy, particularly in patients previously 

treated with CTX. 


A national survey of support and information needs of Australian women 

living with advanced breast cancer. Presenting Author: Linda R. Mileshkin, 

Peter MacCallum Cancer Centre, Melbourne, Australia 

Background: Improved treatments mean women with advanced breast 

cancer (ABC) are living longer, sometimes for many years. As a result, these 

women may experience chronic needs that are different from those with 

early breast cancer. We aimed to assess the support and information needs 

of women living with ABC. Methods: A national postal survey was sent to 

2,345 women with ABC registered as members of the consumer organizations 

BCNA and/or BreaCan. Women were asked about their disease, 

treatment, experiences of care, and to complete the Supportive Care Needs 

Survey. Results: The response rate was 34% (792 valid responses). Mean 

age was 57 (range 25-99) with 21% living alone and 27% working. 18% 

reported living with ABC for �7 years. 656 (85%) were having current 

treatment: chemotherapy (43%), hormonal therapy (46%), bisphosphonates 

(49%), and/or trastuzumab (Herceptin) (19%) respectively. 49% of 

women reported having access to a Breast Care Nurse (BCN) since 

diagnosis of ABC but only 3% cited a BCN or cancer nurse as their main 

contact. The majority (76%) cited their medical oncologist as their main 

contact, 8% cited their family doctor. Women wanted information about: 

treatment options (84.2%), new treatments (79.2%), symptoms/side 

effects (78.9%), clinical trials (60.8%), managing pain (57.2%) and 

financial assistance (38%). Women � 65 had significantly higher levels of 

unmet needs than those �65 for the 7 items below, including all items 

from the sexual domain. Conclusions: Women with ABC have many unmet 

needs with younger women particularly needing more support with sexual 

needs and anxiety. Women are heavily reliant on their medical oncologist, 

who may not be equipped or best placed to meet these needs. Models of 

care need to be developed to address the unmet supportive care needs of 

women living with ABC. 

Moderate-high Moderate-high 

Item 

need < 65 

need > 65 P value 

Uncertainty about the future 50% 39% 0.009 

Concerns about the worries of 

those close to you 

48% 35% 0.002 

Worry that the results of 

treatment are beyond your control 

37% 27% 0.026 

Changes in sexual relationships 28% 15% 0.001 

Changes in sexual feelings 27% 15% 0.001 

Being given information about 

sexual relationships 

21% 9% �0.0001 

More choice about cancer specialists 17% 8% 0.002 


597s 


The relationship among age, anxiety, and depression in older adults with 

cancer. Presenting Author: Talia Weiss, Memorial Sloan-Kettering Cancer 


Background: Depression and anxiety are common psychological sequelae of 

cancer, resulting in decreased adherence to treatment regimens and longer 

hospital stays. In men with prostate cancer, aging is associated with 

reduced anxiety and increased depression. The overall goal of this study 

was to examine the association among age, anxiety, and depression in a 

cohort of older adults receiving chemotherapy (chemo). Methods: This is a 

secondary analysis of a prospective longitudinal study investigating chemotherapy 

toxicity in older adults with cancer. Eligibility included: age � 65, 

diagnosis of cancer, and scheduled to receive a new chemo regimen. 

Baseline data (pre-chemotherapy) included: age, sociodemographics, tumor 

and treatment factors (including tumor type and stage), geriatric 

assessment parameters (functional status, comorbidities, psychological 

state, nutritional status, social support). Anxiety and depression were 

measured by the Hospital Anxiety and Depression Scale (HADS). Univariate 

and multiple regression analyses were conducted to test the relationship 

between age, anxiety, and depression. Results: The average age of the 500 

patients (56% females) was 73.1 (range 65-91, SD�6.18) with 5% Stage 

I, 12% Stage II, 22% Stage III and 61% stage IV. Mean depression and 

anxiety scores were: 3.6�3.17; 4.7�3.60. Clinically significant depression 

was reported in 12.6% (n�62). Clinically significant anxiety was 

reported in 20.9% (n�103). In univariate analyses, there was no association 

between anxiety and age, or depression and age. In multivariable 

analyses, older age (beta� -0.07, p � 0.05) was associated with decreased 

anxiety, as well as lack of social support (p � 0.01) and increased number 

of comorbidities (p � 0.01). In multivariable analysis, depression was 

associated with lack of social support (p � 0.01), increased number of 

comorbidities (p � 0.01), and advanced stage (p � 0.01). Conclusions: 

This study supports previous research that anxiety decreases with age in 

older adults with cancer. However, depression remained constant with 

increasing age. Greater resources and attention to identifying and treating 

the psychological sequelae of cancer in older adults are warranted. 


Efficacy and safety of balugrastim compared with pegfilgrastim in patients 

with breast cancer who are receiving chemotherapy. Presenting Author: 

Constantin D. Volovat, Centrul de Oncologie Medicala, Iasi, Romania 

Background: Patients receiving cancer chemotherapy are at an increased 

risk of neutropenia. Recombinant granulocyte colony stimulating factors 

(G-CSFs) have been developed to stimulate proliferation and differentiation 

of neutrophils. Pegfilgrastim is a pegylated recombinant G-CSF that allows 

for once-per-cycle dosing. Balugrastim is a long-acting G-CSF composed of 

a genetic fusion between recombinant human serum albumin and G-CSF. 

The objective of this study was to compare the efficacy and safety of 

balugrastim and pegfilgrastim in patients with histologically or cytologically 

confirmed breast cancer who were scheduled to receive doxorubicin and 

docetaxel. Methods: In this double-blind, randomized, active-comparator, 

noninferiority trial, patients with �1.5x109 neutrophils/L, and �100x109 platelets/L were randomly assigned to subcutaneous injections of balugrastim 

40 mg (n�153) or pegfilgrastim 6 mg (n�151) with stratifications for 

weight, prior chemotherapy exposure, and global location. The primary 

efficacy endpoint was the duration of severe neutropenia (days with an 

absolute neutrophil count �0.5x109 cells/L) during the cycle 1 for the 

population of patients who did not have major protocol violations. Results: 

Mean duration of severe neutropenia in cycle 1 was 1.1 days in the 

balugrastim group and 1.0 days in the pegfilgrastim group (95% CI for 

difference between groups -0.13 to 0.37). Fifty-eight percent of patients in 

the balugrastim group and 59% in the pegfilgrastim group had severe 

neutropenia during cycle 1 (95% CI for difference between groups 

-11.98% to 10.41%). Two and 4 patients, respectively, had febrile 

neutropenia during cycle 1; no patients in either group had febrile 

neutropenia during cycles 2-4. Twenty percent of patients in the balugrastim 

group and 19% in the pegfilgrastim group had adverse events that the 

investigator considered to be related to study medication. Six and 7 

patients, respectively, had serious adverse events. Conclusions: The results 

of this study support the noninferiority of balugrastim versus pegfilgrastim, 

demonstrating that both compounds have comparable efficacy. There were 

no unexpected safety events. 




Using scenarios to explain survival time: Attitudes of people with a cancer 

experience. Presenting Author: Martin R. Stockler, NHMRC Clinical Trials 

Centre, University of Sydney, Sydney, Australia 

Background: Most people with advanced cancer want some information on 

their life expectancy. We sought the attitudes of people with a cancer 

experience to using three scenarios for survival (best-case, worst-case, and 

typical) to explain life expectancy to people with advanced cancer. 

Methods: Oncology clinic attendees and Breast Cancer Network Australia 

(BCNA) members completed a survey describing two formats for explaining 

life expectancy to a hypothetical patient with incurable cancer - providing 

either three scenarios for survival or just the median survival time. 

Associations between respondent attitudes and their demographic and 

tumour characteristics were explored. Results: Characteristics of the505 

respondents from outpatient clinics (n�251) and BCNA (n�254) were: 

median age 58 years; female 74%; completed high school education 80%; 

breast primary 64%; self-report of cancer spread to other body parts 23% 

and; a median of 4 years since diagnosis of cancer. More respondents 

agreed that explaining three scenarios (vs. just the median survival time) 

would: make sense (93% vs. 75%), be helpful (93% vs. 69%), convey hope 

(68% vs. 44%), reassure (60% vs. 40%) and help family members (91% 

vs. 71%); all p-values �0.001. Fewer respondents agreed that explaining 

three scenarios (vs. median survival) would upset people (24% v 36%); 

p�0.001. The proportions of respondents agreeing that each of the 3 

scenarios should be presented were: best-case 89%, worst-case 82%, and 

typical 92%. Most respondents (85%) agreed it would be helpful to receive 

a printed summary of the scenarios for survival. For information about their 

own prognosis, 88% preferred all three scenarios and 5% a single estimate 

of the median. Respondents with higher education were more likely to agree 

that presenting three scenarios would be helpful (95% v 90%, p�0.05). 

Respondents with breast cancer were more likely to agree that explaining 

three scenarios would upset people (31% v 13%, p�0.001). Conclusions: 

Most respondents judged presentation of best-case, worst-case and typical 

scenarios preferable and more helpful and reassuring than presentation of 

just the median survival time when explaining life expectancy to patients 

with advanced cancer. 


Caring for people at the end of life: How do cancer caregivers differ from 

other caregivers? Presenting Author: Afaf Girgis, University of New South 

Wales, Sydney, Australia 

Background: The size of the population in receipt of cancer care is growing 

as the population ages and grows, with many receiving outpatient care, 

living for longer and wishing to be cared for at home. Hence, cancer is now 

one of the most common health conditions in receipt of informal care 

giving. Methods: The South Australian Health Omnibus is an annual, 

face-to-face, cross-sectional, whole-of-population, multi-stage, systematic 

area sampling survey which seeks a minimum of 3,000 respondents each 

year state-wide. From 2000-2007, questions about end of life were asked. 

This study compares people who cared for someone with cancer until death 

(cancer caregivers) with caregivers of people with other life limiting 

illnesses (non-cancer caregivers). Results: 4,665/14,624 (31.9%; participation 

rate 71.6%) had someone close to them die from an “expected” 

death in the 5 years prior to being surveyed. One in 10 (10%; 1,504/ 

14,624) provided hands-on (day-to-day or intermittent) care; the majority 

(79.5%) having cared for someone with cancer. Compared to non-cancer 

caregivers, cancer caregivers cared for someone who was significantly 

younger (mean age 66 vs 74 years; p�0.0001), and to have had a palliative 

care service involved in the care of that person (64.9% vs 39%; p�0.000). 

Whilst not statistically significant, cancer caregivers were somewhat less 

likely to be the spouse of the person they cared for (11.8% vs 16.8%); more 

likely to be of non-English speaking background (11% vs 7.5%); more 

likely to report that the deceased was comfortable in the last 2 weeks of life 

(44.1% vs 31.7%); and prepared to care again for someone with a 

life-limiting illness (81.3% vs 71.4%). Conclusions: Caring for someone 

with cancer at the end of life appears to be fundamentally different to other 

caregiver populations, particularly in relation to age of, and relationship to, 

the patient, which may contribute to their substantially greater utilisation 

of palliative care services. Being a younger caregiver increases the 

likelihood of them caring again in the future. 


A prospective study of family conferences (FCs) in a palliative care unit 

(PCU) at a comprehensive cancer center. Presenting Author: Rony Dev, 


Background: TheFC provides the family information and emotional support 

in the transition to end-of-life care. There are a few, mainly qualitative, 

studies of FCs in a palliative care setting. A retrospective report suggested 

increased emotional expression by family members when patients were not 

present in the FC. The purpose of our study was to determine the 

characteristics of FCs and the effect of patient participation on emotional 

expression by family members. Methods: A prospective study was conducted 

during 18-month period with140 consecutive FCs conducted by an 

interdisciplinary team (palliative care physician, social worker, and others). 

Data collected included demographics, discharge disposition, number of 

participants, caregiver characteristics, expressions of emotional distress, 

conflict with healthcare providers, and topics discussed. Descriptive 

statistics and frequencies were calculated. Analysis was performed using a 

chi-square test. Results: 70 patients (50%) were female, 64 (46%) white, 

127 (91%) with solid tumors and a median age of 59. In 68/140 family 

meetings (49%), patients actively participated. The primary caregivers 

were predominantly female (66%), white (49%), and either the spouse or 

partner (59%). A median number of 4 family members and 4 healthcare 

providers attended the FCs with median duration of 1 hour and median of 2 

days prior to discharge. Questions concerning advanced directives, symptoms 

anticipated at death and caregiver well-being were infrequent. 

Patients verbalized distress frequently, (73.1%). Primary caregivers emotional 

expression of verbal distress were high but not significantly affected 

by patient presence (82% vs 82%, P:NS); however, verbal expressions of 

emotional distress by family were more common when patients were absent 

(87%) than when present (73%), p � 0.037. Conclusions: There was a high 

frequency of expression of emotional distress by patients and family 

members. Patient participation was associated with decreased verbal 

emotional expression by family members but not the primary caregiver. 

Further studies are needed on the benefits of allocating additional time to 

meet with family members without patient presence during a FC. 


Polymorphisms in genes OPRM1, �-arrestin 2, STAT6, and COMT and 

clinical outcome to opioid therapy. Presenting Author: Sara Cros, Catalan 

Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain 

Background: Morphine sulfate is the most widely used opioid in oncologic 

pain. There is a high variability in response between individuals. The 

objectives are to correlate the variability in response (R) and tolerability 

with polymorphisms within OPRM1, �-arrestin 2, STAT6 and COMT gene 

sequences. Methods: DNA from 44 oncologic patients (pts) with an EVA 

score � 6 was prospectively analyzed using allelic discrimination techniques 

and automatic sequencing. Pts (never treated with opioids) received 

morphine sulfate 10 mg per day. Pain was assessed by EVA score and 

toxicity was evaluated according to the most common opioid side effects. 

Symptomatology was reassessed after 72 hours. Chi-squared and Fisher’s 

tests where used to analyze data. Results: 17 pts (38.6%) responded with 

an EVA � 3. 6 pts (13.6%) did not experience toxicity, 36 pts (81.8%) had 

mild side effects and 2 pts (4.5%) had severe side effects. There was no 

relation between R rate (RR) and tolerance. 76.5% of pts responding to 

treatment had a CC/CT �-arrestin 2 genotype and this was associated with a 

better RR (CC/CT R � 46.4% vs. TT R � 25% p � 0.16). The 2 pts having 

severe side effects belonged to CC/CT group. COMT genotypes AA/GA were 

associated with a higher RR (83.3%pts) and better tolerance (100% pts 

with no toxicities). OPRM1 genotype GG was associated with both treatment 

failure (0% responded) and worse tolerance (any toxicity � 100%; 

severe side effects � 33%). Only 2,4% pts in the AA/GA genotype 

experienced some toxicity (p � 0.041). Although STAT6 genotypes were 

not associated with RR, tolerance was better in those pts with an AA or GA 

genotype with 97.5% pts showing either mild or no side effects (p � 

0.007). Conclusions: Common variants in �-arrestin 2, COMT, OPRM1 and 

STAT6 genes have shown to predict for opioid-associated response and side 

effects in oncologic patients. Further studies are needed to assess factors 

determining the variability in response and tolerance to opioid treatment. 



Cognitive symptoms in non-Hodgkin lymphoma survivors: Prevalence and 

discussion with doctors. Presenting Author: Neeraj K Arora, National 

Cancer Institute, Bethesda, MD 

Background: Several studies have documented the negative impact of 

chemotherapy on patients’ cognitive functioning. However, this concern 

has been understudied among non-Hodgkin Lymphoma (NHL) survivors. 

Methods: We analyzed survey data from a population-based study of 

survivors diagnosed with aggressive NHL in Los Angeles County 2-5 years 

prior to the study; data were collected between 2003-2005. We assessed 

prevalence of cognitive symptoms (CS) by a single item screener that asked 

if in the past 6 months survivors experienced problems with memory, 

attention, or concentration; if yes, we asked if they discussed the problem 

with a doctor. Frequency of CS was assessed by a 4 item scale that 

measured how often survivors experienced different CS in the past 4 weeks 

(none, a little, some, most, all the time). Logistic regression analyses 

identified correlates of reporting CS (yes/no) as well as discussion with a 

doctor (yes/no). Analyses were based on data from 358 survivors who had 

received chemotherapy and saw a doctor for follow-up care in the past year. 

Results: 134/358 survivors (37%) reported CS, many reporting difficulty 

some, most, or all the time with memory (64%), attention (58%), 

concentration (57%), and problem solving (46%). Survivors with higher 

education, who were not married/partnered, and who had more comorbidities 

were more likely to report CS (p�0.05 for all). Report of CS was not 

associated with age, NHL grade, time since completion of chemotherapy, 

or having been treated with radiation or bone marrow/stem cell transplant. 

Of the 134 survivors who reported CS, only 43% discussed them with a 

doctor. Survivors who reported being given information about late effects of 

treatment were more likely to discuss CS than those who were not (OR: 3.4, 

95% CI 1.4-8.5, p�0.01). Conclusions: One in three NHL survivors 

reported CS following chemotherapy; however, a majority did not discuss 

these with a doctor. Periodic screening for CS in NHL survivors may be 

needed and would provide an opportunity to improve patient-clinician 

communication about this issue. Additionally, research that identifies 

mechanisms that cause CS in this population is warranted in order to 

develop targeted behavioral and medical interventions. 


Addressing spirituality within the care of patients at the end of life: 

Perspectives of advanced cancer patients, oncologists, and oncology 

nurses. Presenting Author: Andrea C. Phelps, Dana-Farber Cancer Institute, 

Department of Medical Oncology, Boston, MA 

Background: Attention to patients’ religious and spiritual needs is included 

in national guidelines for quality end-of-life care, but little data exists to 

guide spiritual care. Methods: The Religion and Spirituality in Cancer Care 

Study is a multi-institution, quantitative-qualitative study of 75 advanced 

cancer patients and 339 cancer doctors and nurses. Patients underwent 

semi-structured interviews and providers completed a web-based survey 

exploring their perspectives on the routine provision of spiritual care by 

doctors and nurses. Theme extraction was performed following triangulated 

procedures of interdisciplinary analysis. Multivariable ordinal logistic 

regression models assessed relationships between participant characteristics 

and attitudes toward spiritual care. Results: The majority of patients 

(77.9%), physicians (71.6%), and nurses (85.1%) believed that routine 

spiritual care would positively impact patients. Only 25% of patients had 

previously received spiritual care. Among patients, prior spiritual care 

(adjusted odds ratio [AOR], 14.65; 95% CI, 1.51-142.23), increasing 

education (AOR, 1.26; 95% CI, 1.06-1.49) and religious coping (AOR, 

4.79; 95% CI, 1.40-16.42) were associated with favorable perceptions of 

spiritual care. Physicians held more negative perceptions of spiritual care 

than patients (p � 0.001) and nurses (p � 0.008). Qualitative analysis 

identified benefits of spiritual care, including supporting patients’ emotional 

wellbeing and strengthening patient-provider relationships. Objections 

to spiritual care frequently related to professional role conflicts. 

Participants described ideal spiritual care to be individualized, voluntary, 

inclusive of chaplains/clergy, and based upon assessing and supporting 

patient spirituality. Conclusions: Most advanced cancer patients, oncologists, 

and oncology nurses value spiritual care. Themes described provide 

an empiric basis for engaging spiritual issues within clinical care. 


599s 


Prevalence of cancer-related fatigue in a population-based sample of 

colorectal, breast, and prostate cancer survivors. Presenting Author: 

Jennifer M. Jones, University Health Network, Princess Margaret Hospital, 


Background: Cancer-related fatigue (CRF) is the most prevalent and 

distressing cancer-related symptom and has a greater negative impact on 

patients’ daily activities and quality of life than other cancer-related 

symptoms, including pain and depression. However, the prevalence and 

severity of persistent CRF and related disability in the post-treatment 

survivorship period has seldom been examined in populations other than 

breast cancer. The primary objective of the study was to describe the 

prevalence of significant CRF and associated levels of disability in a mixed 

cancer population sample at 3 time points in the post-treatment survivorship 

trajectory. Methods: Based on cancer registry data, a self-administered 

mail based questionnaire using Dillman’s Tailored Design Method was sent 

to 3 cohorts of disease-free cancer survivors (6-18 months; 2-3 years; and 

5-6 years post-treatment) previously treated for non-metastatic breast, 

prostate or colorectal cancer. Fatigue was measured using the FACT-F and 

disability was measured with the WHO-Disability Assessment Schedule. 

Clinical information was extracted from chart review. Frequencies of 

significant fatigue by disease sites and time points were studied and 

compared using chi-square test. Disability between those with and without 

CRF was also compared using Cochran-Armitage trend test. Results: 1294 

questionnaire packages were completed (63% response rate). The FACT-F 

score was 39.1�10.9; 29% (95% CI: [27%, 32%]) of the sample reported 

significant fatigue (FACT-F�34) and this was associated with much higher 

levels of disability (p�0.0001). Breast (40% [35%, 44%]) and colorectal 

(33% [27%, 38%]) survivors had significantly higher rates of fatigue (�34) 

compared to the prostate group (17% [14%, 21%]) (p�0.0001). Fatigue 

levels remained relatively stable across the 3 time points. Conclusions: CRF 

was a significant and debilitating symptom for a substantial minority of the 

respondents across all 3 time points. Effective CRF management strategies 

are needed and have the potential to significantly reduce morbidity 

associated with cancer and its treatments and to improve quality of life for 

the growing population of cancer survivors. 


Palonosetron (PALO) plus 1-day versus 3-day dexamethasone (DEX) with or 

without aprepitant against delayed nausea (DN): Pooled analysis for 554 

women receiving highly emetogenic chemotherapy (HEC). Presenting 

Author: Luigi Celio, Department of Medical Oncology, Fondazione IRCCS 

Istituto Nazionale Tumori, Milan, Italy 

Background: Nausea is more difficult to control than vomiting, because the 

incidence of the symptom continues to rise over the days after chemotherapy. 

This post-hoc analysis addressed two questions: 1) Does PALO 

plus single-dose DEX result in suboptimal control of DN when compared to 

the same regimen with additional DEX doses? 2) Is the combination of 

PALO, DEX, and aprepitant a more effective coverage against DN? Methods: 

The analysis was based upon outcomes in chemo-naïve women (median age 

�52) with solid tumors (89% breast) enrolled in two Phase III and two 

Phase II trials of HEC (AC combination or cisplatin). Patients received the 

following regimens: 1) PALO 0.25 mg plus DEX 8 mg IV on day 1 of 

chemotherapy (1-day regimen, n�243); 2) the same regimen on the day 1 

followed by DEX 8 mg orally on days 2 and 3 (3-day regimen, n�207); or 

PALO plus DEX plus aprepitant 125 mg on day 1 followed by aprepitant 80 

mg on days 2 and 3 (triple regimen, n�104). The pre-specified primary 

endpoint was the proportion of patients with no DN (days 2-5 after the first 

cycle of chemotherapy). The two primary comparisons were 1-day vs. 3-day 

regimen, and triple vs. 3-day regimen, with statistical significance set to 

the 0.025 level. Results: The 1-day to 3-day regimen comparison was not 

statistically significant (44% vs. 47.8%; risk difference (RD) � -3.8%, 

95% CI (-5.4 to 12.9%), P�0.421 (two-sided chi-square test). The triple 

to 3-day regimen comparison was also not significant (57.7% vs. 47.8%), 

RD��9.9%, 95% CI (-1.9 to 21.3%), P�0.101. More patients receiving 

triple regimen experienced no acute-onset nausea compared with those 

administered only DEX (97.1% vs. 51.2%, P�0.0001). Conclusions: This 

analysis provides evidence that PALO plus 1-day or 3-day DEX yield similar 

prevention of DN. The addition of aprepitant does not improve the control of 

DN. Complete results utilizing a multivariable model accounting for risk 

factors and trial heterogeneity will also be presented. 




Longitudinal study of hope, meaning/peace (M/P), and quality of life (QOL) 

in patients (pts) with ovarian cancer (OC). Presenting Author: Lois M. 

Ramondetta, University of Texas M. D. Anderson Cancer Center, Houston, 

TX 

Background: M/P may be the most valued end point of life. How hope, faith, 

physical and psychological factors impact M/P is unknown. We evaluated 

factors affecting M/P in pts with OC. Methods: OC pts at a cancer center 

(CC), academic hospital (AH) and county hospital (CH for primarily 

uninsured) participated. Surveys completed at initiation of chemotherapy 

(CTX); completion of CTX; and 1 yr later. Surveys included FACT-O, -SP, 

Herth Hope Index, Hospital Anxiety and Depression Scale (HADS), ESAS, 

and Locus of Control (LOC). Results: N�115. Median age�55 yrs, married 

64%, Christian 96%. CH had more AA/Hispanics pts (p�.001) and 

unmarried pts (p�.001). QOL and symptoms improved for all sites over 

time (p �.03); CH pts had the worst scores (p� �.001). CC pts expressed 

more hope, less anxiety and depression (A/D) compared to CH and AC pts 

for all time points (p�.03). CH pts had higher and increasing A/D over time 

while CC pts had the least (p�.02). LOC scores differed by site (p�.01). 

CH pts held strongest belief that life was controlled by chance and 

“others”; CC pts had the least. There was no association between site/time 

for belief of internal control over one’s life. CH pts consistently had the 

lowest M/P scores (p�004). Adjusting for site, disease status and time, 

higher M/P associated with higher hope, better QOL, symptoms and faith 

(p� �.0001). Lower M/P associated with increased A/D (p�.003) and 

symptoms (p�.0001). Poorer M/P over time correlated with belief that life 

was controlled by chance (p�.01) and �powerful others�(p�.02). Level of 

M/P did not correlate with belief of internal control over one’s life. 

Conclusions: M/P did not change over time. CC pts had highest M/P. Higher 

M/P associated with higher hope and faith, better QOL, less symptoms and 

A/D. Lower M/P associated with sense that life is controlled by chance and 

powerful others. Data show medically underserved pts have poorer QOL, 

more symptoms and A/D and may believe the future is determined by 

luck/chance and by “others”. Triaging for spiritual crisis may be important 

in these pts. Interventions to decrease A/D and symptoms may improve pts’ 

sense of M/P over the cancer journey. 


Associations between receipt of a treatment summary, emotional concerns, 

and patterns of care among post-treatment cancer survivors. Presenting 

Author: Ruth Rechis, LIVESTRONG, Austin, TX 

Background: Treatment summaries (TS), a critical component of survivorship 

care plans, were identified as a tool to improve long-term outcomes for 

the 12 million cancer survivors alive in the US. Methods: In 2010, the 

Lance Armstrong Foundation fielded the LIVESTRONG Survey for People 

Affected by Cancer. Respondents were recruited through several channels 

including partnerships with national organizations such as ASCO. Over a 9 

month period, more than people completed the survey, including 3,682 

post-treatment cancer survivors (PTCS). The survey addressed posttreatment 

concerns including receipt of TS. Full survey results were 

presented at the 2011 ASCO Conference. Results: Receipt of TS data was 

available for 3042 PTCS: average age (50); female (65%); average time 

since diagnosis (6 years); received a TS (34%). PTCS who received TS 

reported that they were: Closer to time since diagnosis or since treatment 

ended (p�0.01); more likely to have received chemotherapy (p�0.01); 

more often receiving the majority of their health care from a medical 

oncologist (p�0.05); experiencing significantly fewer (p�0.05) posttreatment 

emotional concerns (including emotional distress; fears of 

recurrence; concerns about family risk; and appearance concerns) and 

were more likely to have received care; significantly less likely to say that 

they had “learned to live with” their concerns (p�0.05) – the most 

common reason among participants for not receiving care. Finally, receipt 

of a TS was related to higher information efficacy (p�0.01; which appeared 

to mediate the relationship between receipt of a TS and fewer emotional 

concerns). PTCS who received a TS more often reported that their needs 

were met including information received about possible late-effects; care 

they got during treatment; and care they received after treatment. 

Conclusions: These results support the provision of TS to PTCS. Receipt of 

TS was associated with a variety of positive outcomes; however, only about 

one-third of PTCS received one. Future studies focused on patient 

perspectives on care planning tools, such as treatment summaries and care 

plans, can help to improve optimal survivorship care delivery. 


Prospective cohort study of chemotherapy-associated toxicity and supportive 

care in oncology practice. Presenting Author: Eva Culakova, Duke 

University, Durham, NC 

Background: Neutropenic complications remain important dose-limiting 

toxicities of cancer chemotherapy associated with considerable morbidity, 

mortality and cost. The risk of the initial neutropenic event is greatest in the 

first cycle when most patients are receiving full dose chemotherapy. 

Methods: A prospective cohort study of adult patients with solid tumors or 

lymphoma receiving a new chemotherapy regimen was conducted at 115 

U.S. practice sites between 2002 and 2006. Chemotherapy-associated 

toxicities were captured in up to 4 cycles including severe neutropenia 

(SN), febrile neutropenia (FN), and infection. Documented interventions 

included colony-stimulating factor (CSF) and antibiotics use and reductions 

in chemotherapy relative dose intensity (RDI). Results: Results are 

available on 3,638 patients starting chemotherapy of which 3,301, 2,937, 

and 2,199 went on to cycles 2, 3, and 4, respectively. The majority of 

neutropenic and infection events occurred in cycle 1. A significant inverse 

relationship was observed between subsequent reductions in neutropenic 

and infectious events and efforts to reduce these complications (Table). 

Most patients with stage 4 solid tumors underwent reductions in chemotherapy 

RDI. Patients with lymphoma and stage 1-3 solid tumors were less 

likely to undergo dose reductions with half or more receiving prophylactic 

CSFs during treatment. Approximately 15% of patients also received 

prophylactic antibiotics. Conclusions: While the risk of neutropenic complications 

remains greatest during the initial cycle of chemotherapy, clinician 

efforts to reduce the risk of these events vary with cancer type and stage. 

Reduced dose intensity is evident in two-thirds of patients with advanced 

solid tumors whereas the CSFs are employed in half to two-thirds of 

patients with early stage solid tumors or lymphoma. 

Percent of patients (%) 

Cycle-specific events Cumulative events 

Solid tumor Solid tumor 

Measure 

1 2 3 4 Lymphoma stage 1-3 stage 4 

FN 6.4 3.8 2.9 0.8 13.7 11.9 7.8 

SN or FN 20.0 14.4 13.5 14.3 37.3 33.4 20.6 

Infection 12.6 9.4 8.6 1.7 27.5 23.6 21.1 

Proph CSF 21.2 38.9 47.9 53.7 63.5 49.5 35.2 

Proph antibiotics 4.8 9.5 12.7 15.6 18.2 14.4 11.7 

RDI < 85% 25.0 34.6 34.3 36.8 48.4 43.3 60.3 


Outpatient chemotherapy supportive care: Trial of an IT-integrated, NPdelivered 

system for unrelieved symptoms. Presenting Author: Kathi 

Mooney, University of Utah, Salt Lake City, UT 

Background: We tested an automated computer based remote monitoring 

system paired with nurse practitioner (NP) follow up using a case 

management system to address unrelieved symptoms. Methods: Prospectively 

336 patients beginning a course of chemotherapy were randomized 

to the Telephone Care NP (TC) intervention (n 174) or usual care (UC) (n 

162). All called daily reporting presence, severity, and distress (0-10 scale) 

for 11 common symptoms. Those in the TC intervention also received 

automated tailored symptom self-care messages and, based on automated 

alerts for unrelieved symptoms at moderate or higher levels, NP calls to 

further treat symptoms utilizing national guidelines. Results: There were no 

differences between groups on any demographics: 84% White, 56 years 

old, female (77%), breast (45%) or lung (17%) cancer. Average study days 

were 73 with 87% call completion. Prevalence of participants reporting 

moderate to severe symptoms were fatigue (86%), pain (80%), sleep 

(78%), nausea (60%), depressed mood (52%), anxious (49%), trouble 

thinking (48%), numbness (43%), sore mouth (38%), diarrhea (38%), and 

appearance concerns (35%). Mixed modeling with intention to treat was 

used to compare overall symptom scores by treatment condition (TC/UC) 

while accounting for individuals. Results indicate the TC group mean 

symptom score was significantly lower than UC (mean difference � .30, p 

� .001). Also, each symptom was significantly lower for the TC group 

except for diarrhea. Poisson regression showed TC had lower Severe days 

than UC (est. means and SE) 3.16 (0.44) vs 10.24 (1.84), p � .001; and 

lower Moderate days 8.91 (1.04) vs 19.06 (2.22), p � .001. TC had 

somewhat higher Mild days than UC 19.85 (2.81) vs 13.75 (1.85), p � 

.06; and more No symptom days 66.06 (3.82) vs 52.02 (4.15), p � .01. 

Mixed modeling was used to explore TC intervention impact following NP 

calls for alerts. TC reduced symptom scores compared to UC over a4day 

period (mean difference � 1.28, p� .001). Conclusions: Remote telephone 

monitoring of symptoms after chemotherapy with nurse practitioner follow 

up on moderate and severe symptoms results in decreased symptom 

severity, distress, fewer severe and moderate days and more no symptom 

days. 



Prospective cohort study of chemotherapy-induced alopecia with or without 

scalp cooling. Presenting Author: Julie Lemieux, URESP, Centre de 

Recherche FRSQ du CHA Universitaire de Québec, Quebec City, QC, 

Canada 

Background: Scalp cooling can prevent chemotherapy-induced alopecia. 

Success varies according to the type of chemotherapy. A controversy exists 

regarding the use of scalp cooling because of the lack of efficacy data with 

modern chemotherapy regimen and safety data. We present a prospective 

cohort study design to measure alopecia. Methods: The prospective study 

was conducted at the Centre des Maladies du Sein Deschênes-Fabia (CMS) 

in Quebec City (where scalp cooling is offered routinely and 85% of women 

use it) and at the Centre Hospitalier Universitaire de Montreal (CHUM), in 

Montreal (where scalp cooling is not available). Women were eligible if they 

were going to receive neoadjuvant or adjuvant chemotherapy for breast 

cancer. The study involved completion of questionnaires (on degree of 

alopecia, hair type, hair care, use of head accessories, tolerance to scalp 

cooling and questions related to sick leave from work) and having pictures 

taken at baseline, cycle 3 and at the last cycle of chemotherapy. For the last 

43 patients, the EORTC QLQ-C30/BR23 and an adaptation for Hairdex 

were added. Results: A total of 136 patients were recruited (110 at CMS 

over 2 years and 26 at the CHUM over a 9-month period). Preliminary 

efficacy results are shown in the Table (data on quality of life have not yet 

been analyzed). Hair preservation was defined as a SUCCESS for hair loss 

(since the beginning of chemotherapy) characterized as “not at all”, “a 

little” or “moderate” and “FAILURE” when characterized as “a lot” or “all” 

or “hair shaved”. Overall, in the scalp cooling group, 34% were considered 

a “success” using hairdresser evaluation and 49% using patient evaluation; 

for the non scalp-cooling group, these rates were 9% and 4% 

respectively. Conclusions: Scalp cooling appears to be efficacious for 

preventing chemotherapy-induced alopecia in this exploratory cohort study. 

Success of scalp cooling as assessed at last cycle of chemotherapy. 

CMS 

CHUM 

(n�99 evaluable) 

(n�23 evaluable) 

Hairdresser evaluation 

AC 7 (32%) 1 (25%) 

TC 14 (45%) 0 (0%) 

FEC-D 6 (20%) 0 (0%) 

Other 7 (44%) 1 (9%) 

Total 34 (34%) 2 (9%) 

Patient evaluation N(%) N(%) 

AC 8 (36%) 0 

TC 19 (61%) 0 

FEC-D 12 (40%) 0 

Other 9 (56%) 1 (9%) 

Total 48 (49%) 1 (4%) 


Validation of the chemotherapy-induced neuropathy assessment scale. 

Presenting Author: Sheeba K. Thomas, University of Texas M. D. Anderson 


Background: Many of the assessment tools used to assess peripheral 

neuropathy in clinical trials focus on painful neuropathy. However, some 

chemotherapy agents cause both painful and non-painful peripheral 

neuropathy. The Chemotherapy-Induced Neuropathy Assessment Scale 

(CINAS) was designed to evaluate the multi-dimensional nature of chemotherapy-induced 

neuropathy, including non-painful sensory and motor 

deficits. This study evaluated the psychometric properties of the CINAS in 

patients with multiple myeloma (MM) receiving induction chemotherapy 

and/or autologous hematopoietic stem cell transplantation. Methods: We 

collected demographic and clinical data and administered 2 items measuring 

pain and numbness/tingling at its worst (0-10 scale), and the CINAS. A 

total CINAS score was computed by summing all 11 CINAS items. For 

reliability and validity analyses, we used the highest total CINAS score for 

each patient. Validity was assessed by factor analysis and by correlating 

CINAS subscales with the pain and numbness/tingling items. Cronbach 

alpha reliability coefficients were computed. To test sensitivity, we compared 

change in total CINAS score during induction from baseline to last 

total CINAS score in a subset of patients (N�20) receiving bortezomib or 

thalidomide. We hypothesized that such patients would develop neuropathy. 

Results: Ninety patients were enrolled. Participants were primarily 

white (90%) and male (63%). Factor analysis revealed 3 underlying 

constructs for the CINAS - sensory, motor functioning, and allodynia - 

explaining 74% of the common variance. Cronbach alphas were 0.84, 

0.85, and 0.83 for the sensory, motor functioning, and allodynia subscales, 

respectively, while subscale correlations with the numbness/ 

tingling item were 0.74, 0.56, and 0.52, respectively. Pain was only 

modestly correlated with these subscales (0.21, 0.36, 0.29). Total CINAS 

scores of patients receiving bortezomib or thalidomide induction worsened 

significantly (from 3.4 to 11.9, effect size�0.55, p�.02). Conclusions: 

The CINAS demonstrated validity, reliability and sensitivity in patients with 

MM during and after chemotherapy and can be used to assess the 

multidimensional aspects of chemotherapy-induced neuropathy. 


601s 


Advance care planning (ACP) among hematopoietic cell transplant (HCT) 

patients and bereaved caregivers. Presenting Author: Elizabeth T. Loggers, 

Fred Hutchinson Cancer Research Center, Seattle, WA 

Background: HCT remains a high risk, potentially curative treatment 

typically offered to young, otherwise healthy patients with hematologic 

malignancies. Given this, patients and caregivers may not have considered 

end-of-life ACP. This study investigated the effect of pre-transplant ACP in 

surviving patients or bereaved caregivers. Methods: A retrospective, mixedmethods, 

audio-taped telephone survey adapted from validated instruments 

was conducted by a trained interviewer with English-speaking HCT 

survivors (n�18) and bereaved caregivers (n�11), 6-12 months post-HCT. 

Subjects were identified via HCT databases at two high-volume, tertiary 

centers between 2001-2003. Analysis included percentages from quantitative 

sections and qualitative transcripts coding by 2 investigators, with 

differences resolved by consensus. Results: HCT survivors [median age 47 

years (range 33-67); 50% college-educated; all white] were interviewed a 

median of 13 months after HCT for acute leukemia (7), lymphoma (5), or 

other (6). Twelve (67%) had discussed mortality risk pre-HCT with the 

medical team; of these, 83% felt hope was increased or unchanged (I/U) 

and 100% felt clinician commitment to transplant was I/U by the 

conversation. Regardless of whether mortality was discussed, 50% had 

living wills and �75% had a formal proxy, yet 67% didn’t discuss mortality 

with family members pre-HCT. “Ignorance is bliss” was expressed by 6 

survivors while 2 survivors regretted not discussing mortality risk. Bereaved 

caregivers [73% spouses; all W] were interviewed a median of 10 months 

after their loved one’s death, which occurred a median of 31 days (range 

13-152) post-HCT. 100% were the patient’s proxy. Nine (82%) had 

discussed mortality risk pre-HCT with the medical team; of these, 78% felt 

hope was I/U, 100% felt clinician commitment to transplant was I/U, and 

78% discussed EOL preferences with the patient pre-HCT, with 67% 

feeling ACP reduced burden. Four expressed appreciation for “the straight 

story.” Conclusions: Discussions of potential mortality with patients and 

caregivers before HCT did not affect hope, and supported confidence in 

medical teams. 


Physical and functional well-being in women with breast cancer taking 

gabapentin for hot flashes. Presenting Author: Kavita Dayal Chandwani, 

University of Rochester Medical Center, Rochester, NY 

Background: Hot flashes reduce quality of life (QOL) in women with breast 

cancer. In a randomized, double-blind, placebo-controlled trial of gabapentin 

for hot flashes, 900 mg of the drug was found to reduce hot flashes in 

women with breast cancer; however, their QOL of has not been studied. We 

conducted secondary analyses to study two domains of QOL: physical 

(PWB) and functional well-being (FWB) in women in this trial. Methods: A 

nationwide sample of women with breast cancer and hot flashes � 2/day 

was studied at baseline (T1), 4 weeks (T2), and 8 weeks (T3) of treatment 

with gabapentin 300mg/day (G300) and 900mg/day (G900) in divided 

doses, and a matching placebo (PL). PWB and FWB were assessed via 

subscales of the Functional Assessment of Cancer Therapy-Breast. Linear 

mixed model analyses of PWB and FWB were conducted, adjusted for 

demographic and treatment variables. Results: The mean age of women 

(N�384) was 54.9 years � 8.07 (range: 31-81, 72% �50 years); 76% 

were married; 71% had more than high school education; 95% were 

Caucasian and 3% African-American; 10% were undergoing chemotherapy, 

and 9% radiotherapy (RT). PWB showed significant time effect 

(p�.0001) and interaction of time and treatment (p�.0001). There was an 

improvement in PWB in the G300 by T2 with no change at T3, while the 

improvement in PL and G900 was more modest at T2 and continued at T3 

(PL - T1 20.7, T2 21.2, T3 21.6; G300 - T1 20.9, T2 22.2, T3 22.2; and 

G900 - T1 21.2, T2 21.5, T3 21.7). FWB also showed a significant time 

effect (p�.001) and interaction of time and treatment (p�.002). FWB in 

G300 improved by T2, with no additional improvement at T3; it was 

unchanged in G900 at T2 with a slight reduction at T3; PL showed a 

modest improvement at T2 followed by a modest worsening at T3 (PL - T1 

17.8, T2 18.1, T3 17.9; G300 - T1 17.9, T2 18.6, T3 18.6; G900 - T1 

18.6, T2 18.6, T3 18.5). Conclusions: As reported previously, G900 is 

effective in reducing hot flashes. In this analysis, however, PWB and FWB 

showed different patterns of change over time between the two gabapentin 

and placebo groups with G900 showing minimal effects on PWB and FWB. 

Future trials to further study the changes in physical and functional 

well-being of women with breast cancer taking gabapentin for hot flashes 

are needed. 




YOCAS yoga, fatigue, memory difficulty, and quality of life: Results from a 

URCC CCOP randomized, controlled clinical trial among 358 cancer 

survivors. Presenting Author: Michelle Christine Janelsins, University of 

Rochester Medical Center, Rochester, NY 

Background: Memory difficulty is a serious problem for many cancer 

survivors and can negatively affect quality of life (QOL). Little evidence 

exists on the effects of physical activity (PA) interventions, such as yoga, on 

memory in cancer survivors. We previously reported in a nationwide, Phase 

III RCT that YOCAS Yoga, implemented over 4 weeks (2 x/wk; 75 

min/session), significantly improved fatigue and QOL in cancer survivors. 

The purpose of this study was to assess the effects of YOCAS on memory 

and to identify moderating and possible mediating effects of memory in 

YOCAS improvements of fatigue and QOL. Methods: Cancer survivors 

between 2-24 months post adjuvant therapy with no participation in yoga 

during the previous 3 months were randomized to standard care (SC) or SC 

with YOCAS. YOCAS consists of breathing exercises, gentle Hatha and 

Restorative yoga postures and meditation. This secondary analysis included 

participants (N�358, mean age � 54, 96% female, 75% breast 

cancer) who provided pre- and post-intervention data on Difficulty Remembering 

Things (modified MD Anderson Symptom Inventory with 0 � “Did 

not Interfere” to 10 � “Interfered Completely”), fatigue and QOL (FACIT- 

F). ANCOVA was used to assess the effects of YOCAS on memory at 

post-intervention incorporating baseline memory score. Path Modeling was 

conducted to assess the moderating and mediating effects of memory on 

YOCAS changes in fatigue and QOL. Results: ANCOVA revealed a significant 

group effect of YOCAS on memory at post intervention (mean change: Yoga 

- Control � -0.44; Cohen’s D� -0.24; p �0.05). Moderation analyses 

revealed that baseline memory difficulty did not affect how much YOCAS 

would improve fatigue (p�0.05) or QOL (p�0.05). Mediation analyses 

identified changes in memory as a significant partial mediator for improved 

fatigue (p�0.05) and improved QOL (p�0.05). Conclusions: YOCAS yoga 

significantly reduces perceived memory difficulty in cancer survivors. 

Improvements in memory due to YOCAS may be a possible mediator for 

improving fatigue and QOL. More elaborate PA RCTs are needed to confirm 

these results. Funding: NCIR25CA10618, K07CA120025, and 

U10CA37420. 


Validation of the NCI patient-reported outcomes version of the common 

terminology criteria for adverse events (PRO-CTCAE) in women receiving 

treatment for metastatic breast cancer. Presenting Author: Sandra A. 

Mitchell, National Cancer Institute, Bethesda, MD 

Background: NCI PRO-CTCAE is designed to enhance adverse event 

reporting by integrating patients’ self-report of the frequency (F), severity 

(S) and interference (I) with usual activities of 78 symptomatic treatment 

toxicities. This study examined the construct validity of a subset of 

PRO-CTCAE items in women with metastatic breast cancer (MBC). Methods: 

207 women (70% aged 45-59 years; 94% White;71% college-educated) 

with HER2� MBC who had received treatment in the past month were 

recruited from 6 U.S. breast cancer support groups and completed a web 

survey that collected 18 PRO-CTCAE symptoms, and the Rotterdam 

Symptom Checklist (RSC). Pairwise concordance among PRO-CTCAE 

symptom dimensions was examined using weighted Kappa and Bowker’s 

test for symmetry. Results: Respondents were a median of 47 months since 

MBC diagnosis and 61% rated their health-related quality of life (HRQL) as 

good to excellent. Symptom prevalence was similar for PRO-CTCAE and 

RSC, with respondents more likely to endorse mood disturbance on 

PRO-CTCAE (Anxiety/Worry 90%; Sad/Unhappy Feelings 86%) vs. RSC 

(Anxiety 63%; Depressed Mood 61%). There was parallel rank-ordering of 

fatigue, anxiety, insomnia, depression, difficulty concentrating and neuropathy 

as the symptoms that were most severe, interfered most and caused 

the greatest bother. Within PRO-CTCAE, pairwise agreement among F, S 

and I was moderate for most symptoms (�w�.42 to .54). Agreement 

between F and S was highest for pain, nausea and arm/leg swelling 

(�w�.61 to .80), and lowest for anxiety/worry and sad/unhappy feelings 

(�w� .27-.37). Except for arm/leg swelling, endorsement patterns by the 

dimensions of F, S and I were distinct (Bowker’s p all �.002). Across 

PRO-CTCAE symptoms, S was consistently higher than I (mean differences 

.12 to .72, all p�.01]). Means for S were consistently and significantly 

higher for those with impaired versus preserved HRQL, providing evidence 

of construct validity. Conclusions: This study supports the construct validity 

of PRO-CTCAE, and suggests that F, S and I dimensions offer nonoverlapping 

information relative to 17 /18 PRO-CTCAE symptomatic 

toxicities. 


Changes in the use of eythropoetin-stimulating agents (ESAs) in cancer 

patients: Before and after FDA safety advisories. Presenting Author: Dana 

Stafkey-Mailey, South Carolina College of Pharmacy, Columbia, SC 

Background: Benefits of ESAs in the treatment of cancer-induced anemia 

have been well documented, most importantly reducing the likelihood of 

patients needing red blood cell transfusions. However, in early 2007, the 

FDA issued a series of cautions and Black Box Warning (BBW), that ESAs 

may enhance tumor progression, increase likelihood of a VTE and decrease 

patient survival. The objective of this study is to elucidate population 

patterns and trends in ESA use for cancer patients pre- and post- the BBW 

and examine their associated outcomes. Methods: Data for this analysis was 

derived from South Carolina Medicaid claims. Patients with a diagnosis of 

Lung Cancer (162.x), Breast Cancer (174.x) or Non-Hodgkin’s Lymphoma 

(200.x or 202.x) receiving chemotherapy between January 1, 1994 and 

December 31, 2010 were eligible for inclusion. The main outcome 

measures were ESA utilization, blood transfusion, and venous thromboembolism. 

The percentage of patients experiencing these outcomes were 

plotted over time to allow for visual examination of changes due to the 

BBW. In addition, we used multivariable logistic regression models to 

analyze each of the associated outcomes with clinical and demographic 

variables. Results: Among the 9,280 patients with one of the study cancers, 

an average of 25.4% received an ESA. The proportion of patients receiving 

an ESA increased from 6.2% in 1994 to a high of 47.1% in 2005 at which 

time utilization began to decline. In 2010, only 7.8% of these patients 

received an ESA. Use was associated with older age, female sex, and 

receipt of radiation therapy. The rate of blood transfusion varied sporadically 

throughout the study period from 5.2% (2008) to 11.7% (1994) 

(p�0.0001). Venous thromboembolisms developed in 12.3% and 8.5% of 

patients receiving and not receiving an ESA, respectively (OR� 1.31; 

p�0.001). Conclusions: As the FDA advisory cautioned, we find an 

increased risk of venous thromboembolisms associated with ESA use. In 

contrast to our a priori beliefs initial decline in utilization of ESAs began, in 

2005, prior to the BBW and was likely due to changes in reimbursement 

rates. However, the BBW resulted in the largest decline in ESA use, 19.1 

percentage points, between 2007 and 2008. 


Health behaviors among testicular cancer survivors. Presenting Author: 

Steven C. Palmer, University of Pennsylvania, Philadelphia, PA 

Background: Testicular cancer survivors (TCS) experience elevated risk for 

cardiovascular issues including coronary artery disease that present a 

greater threat to their long-term health than recurrence of cancer. These 

risks may be moderated by health behaviors (HBs), yet little is known about 

HBs or their barriers in this population. This is unfortunate, as these 

barriers may serve as intervention targets. This study examined HBs and 

their barriers in a population-based sample of TCS. Methods: TCS were 

recruited through the PA Cancer Registry. Eligible individuals were diagnosed 

with testicular cancer between 1990 - 2007 and provided informed 

consent. Participants completed measures of tobacco use, alcohol use, 

dietary habits, physical activity, BMI, quality of life (QOL), and barriers to 

performing HBs, as well as self-reported disease and treatment information. 

Results: 189 participants provided data. Participants were middleaged 

(M�44 yrs. R�19-59), predominately white (95%), married (72%), 

parents (69%), 6.8 years post-diagnosis (R�1-19), and at normative levels 

for physical and psychosocial QOL. A substantial minority (31%) was 

unaware of their disease stage or histopathological type (27%), although 

89% reported surgery, 32% chemotherapy, and 53% XRT. Almost 25% 

reported current tobacco use, and 35% reported “risky” alcohol use. 

Adequate aerobic activity was reported by half, but only 28% reported 

adequate strength and flexibility activities. 84% reported above normal 

BMI, with 35% in the obese range. Barriers to HBs included cancer-related 

problems (e.g., neuropathy, pain, hernia risk) and competing demands 

(e.g., work responsibility, time constraints). Cancer-related barriers were 

related to worse physical QOL and higher BMI. Competing demands 

predicted worse psychosocial QOL, unhealthy eating, and inadequate 

physical activities. Conclusions: Given the negative HBs in this sample and 

their potential cardiovascular risk, interventions aimed at reducing tobacco 

and risky alcohol use, as well as improving dietary and physical activity 

levels are needed. These interventions will likely need to overcome 

perceived barriers to adoption of HBs in order to be successful. 



Lifetime traumas and their influence on advanced cancer patients’ illness 

understanding and likelihood of end-of-life discussions. Presenting Author: 

Elizabeth L. Kacel, Dana-Farber Cancer Institute, Boston, MA 

Background: Research on posttraumatic stress in cancer patients has 

focused on patient reactions to their cancer diagnosis. Few studies have 

examined the impact of lifetime traumatic events prior to diagnosis on how 

advanced cancer patients understand the life-threatening nature of their 

illness and how likely they are to discuss their end-of-life (EOL) wishes with 

their oncology providers. Methods: The Coping with Cancer (CwC) is an 

NCI-funded prospective, multi-institutional cohort study of advanced 

cancer patients and their caregivers. Participants were recruited from 

September 2002 to February 2008 from six comprehensive cancer centers 

across the United States. Lifetime traumas were captured by the number of 

events reported in response to the Structured Clinical Interview for the 

DSM-IV (SCID) Lifetime Posttraumatic Stress Disorder question that 

probed for “extremely upsetting” life events. Associations between patient 

characteristics and number of lifetime traumas were estimated as odds 

ratios using ordinal logistic regression. Associations between number of 

lifetime traumatic exposures, controlling for confounding patient characteristics, 

and patient Terminal Illness Acknowledgement (TIA) and reports of 

EOL discussions were estimated as odds ratios using multiple logistic 

regression. Results: After adjusting for race, education, and recruitment 

site, the number of lifetime traumas patients reported remained significantly 

associated with TIA (OR � 1.25, p � .034) and discussion of EOL 

wishes (OR � 1.29, p � .013). Conclusions: The greater the number of 

traumatic experiences reported by cancer patients the more likely they are 

to acknowledge that they are terminally ill and discuss their end-of-life 

wishes with their oncology providers. The impact of witnessing or experiencing 

serious or life-threatening events in the past appears to improve 

advanced cancer patients’ abilities to understand the seriousness of their 

condition and increases the likelihood that they will discuss their preferences 

for care at the end of life with their doctors. 


Prospective and working memory decline as a result of impaired sleep 

and/or impared blood glucose in breast cancer patients during chemotherapy 

treatment. Presenting Author: Liliana Moyers-Ruiz, Bournemouth 

University/ Royal Bournemouth Hospital, Bournemouth, United Kingdom 

Background: Breast cancer patients might develop impaired sleep patterns 

during chemotherapy, and impaired cognitive function has been associated 

with sleep patterns disruption. It has been suggested that sleepiness (sleep 

tendency) in cancer patients is prevalent and causes distress in the 

patient’s quality of life, that and their cognitive abilities are also affected. 

Furthermore, increased blood glucose levels among women undergoing 

chemotherapy may contrubute to memory deficits in breast cancer patients. 

It is proposed that Prospective and Working Memory are being 

affected by the disturbance of these biological factors over the course of 

chemotherapy. Methods: Ninety participants will be invited to take part in 

the study. Thirty will be breast cancer patients receiving chemotherapy 

treatment, thirty breast cancer patients receiving treatment other than 

chemotheray, and thirty healthy controls. Measures of sleep and sleepiness, 

will be administered at 4 testing sessions during a 9-month period, 

along with a neuropsychological battery. Additionally, blood samples will 

be analysed. Eight of planned 60 cancer patients have been enrolled, and 

four of them have completed the second testing session. For the assessment 

of sleep/wake activity, participants will be required to wear a sleeping 

monitor (sensewear armband) for 7 days. Pupil dilatation to observe 

sleepiness will be meassured by using a Pupillometry developed at Poole 

hospital in the UK. Prospective Memory will be assessed using CAMPROMT 

test to analyse if this is a more sensitive measure for mild cognitive 

impairment. Discussion: Impairment on variables such as sleep, sleepiness 

and glucose have not been studied within the context of Chemo-Brain on 

breast cancer patients.Therefore we want to observe whether impaired 

sleep and sleepiness, and impaired glucose levels are at the core of 

Prospective and Working Memory decline in Chemo-Brain patients in order 

to find a cause-and-effect relationship as a consequence of chemotherapy. 


603s 


Using cancer patient stories to “power” communication modules. Presenting 

Author: Forrest Lang, East Tennessee State University, Johnson City, 

TN 

Background: Caring for patients with cancer poses great challenges to 

doctors’ communication skills. This project, funded by NIH-NCI, represents 

an innovative collaboration between ETSU faculty in medical oncology, 

family medicine, and storytelling. The team secures patients’ and 

caregivers’ cooperation in recording stories of their journeys with illness. 

These are the focus of a set of cancer communication modules, to be 

offered as educational experiences for medical students, residents, and 

oncology fellows. The modules in development address 1) breaking bad 

news, 2) living through treatment, 3) transitioning from curative to 

palliative care, 4) communicating with family, and 5) sensitivity to issues of 

religion and spirituality. Methods: A collaborative inter-professional team 

developed an interview protocol to facilitate sharing of cancer-themed 

narratives. Video records are transcribed and coded using N-Vivo 8. The 

rating team meets to identify video clips that speak powerfully to positive, 

negative, or ambivalent aspects of cancer communication. Selected patients 

are brought together into “story circles,” where additional narratives 

are gathered. The module development team uses these stories to create 

empathic involvement in viewers, and to sensitize them to effective and 

ineffective communication strategies and challenges surrounding critical 

moments in patients’ lived experience of cancer. Modules effectiveness is 

tested with 1) Family Medicine and Internal Medicine residents, 2) medical 

oncology fellows and 3) multi-professionals health students just completing 

a communication courses. Assessment includes a pre-test and post-test 

OSCE addressing a number of the challenging cancer communication 

moments. Eighty-four of a projected 100 patient interviews and twelve 

physician//faculty interviews have been recorded, and all have agreed to the 

use of their interview materials. Representative examples of recorded 

cancer stories will be presented to demonstrate their evocative and 

pedagogical value. Opportunities will be discussed for further uses of these 

and similar stories in collaborations between medicine and the arts and 

humanities. 

TPS9149^ General Poster Session (Board #51G), Sat, 8:00 AM-12:00 PM 

CATCH: A randomized trial comparing tinzaparin versus warfarin for 

treatment of acute venous thromboembolism (VTE) in cancer patients. 

Presenting Author: Agnes Y. Lee, University of British Columbia, Vancouver, 

BC, Canada 

Background: VTE is a major cause of morbidity and mortality in cancer 

patients. LMWHs have been shown to be superior to warfarin in one 

randomized study, but adequately powered confirmatory studies have not 

been conducted and warfarin continues to be widely used for treatment of 

cancer-associated VTE. Methods: We are conducting an open-label, randomized 

trial of tinzaparin versus warfarin in 900 patients with active cancer 

and symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary 

embolism (PE). Tinzaparin is given at full treatment doses (175 IU/kg once 

daily) for 6 months in the experimental arm and initial tinzaparin treatment 

for 5-10 days followed by dose-adjusted warfarin (target INR 2.0-3.0) is 

given for 6 months in the control arm. The primary composite outcome is 

time to recurrent VTE event, including incidentally diagnosed VTE and fatal 

PE. Baseline characteristics will be analysed for their ability to predict the 

risk for recurrent VTE or bleeding. In particular, the parameters of the 

Khorana scale and Wells rule will be tested for their usefulness in 

predicting recurrent VTE. Predictive biomarkers will be tested including 

D-dimer and Tissue Factor. Assessment of post-thrombotic syndrome 

(PTS), quality of life and healthcare resource utilization will also be 

performed. The trial is recruiting in � 160 sites in �25 countries in 4 

continents (NCT01130025). As of Jan 2012, 135 sites were activated for 

study enrolment and 228 patients have been enrolled. We anticipate 

completion of enrolment in Jan 2013. The results obtained from this study 

will add significantly to the knowledge on the efficacy, safety and 

cost-effectiveness of LMWH to prevent recurrent VTE. Important prospective 

data on the clinical significance of incidental VTE in patients with 

active cancer will be generated, and analyses of risk stratification parameters 

will add important information that may help to further tailor therapy. 

The study of PTS, which has not previously been done in this selected 

patient population, will add to the evidence that tinzaparin significantly 

reduces the incidence of PTS and leg ulcers (Hull et al, Am J Med 

2009;122:762-9). 




Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic 

acid in the palliation of osteoblastic metastases from lung, breast, 

and prostate cancer: Report of RTOG 0517. Presenting Author: Michael J. 

Seider, Akron City Hospital, Akron, OH 

Background: Skeletal related events (SREs) diminish quality of life (QOL) as 

well as overall survival (OS) in patients with bone metastases, a common 

event in breast, lung and prostate cancer. SREs can be reduced or delayed 

by the use of bisphosphonates. It is postulated that the radiopharmaceuticals, 

Strontium-89 (Sr89) and Samarium-153 (Sm153), when added to a 

bisphosphonate can decrease the incidence of SREs. Methods: RTOG 0517 

randomized patients with breast, lung and prostate cancer and blastic bone 

metastases to either Zoledronic acid (ZA) alone or ZA plus a single standard 

dose of either Sr89 or Sm153. No limitations were placed on additional 

therapy such as chemotherapy or hormonal treatment. The projected 

median time to SRE [pathological bone fracture, spinal cord compression, 

surgery to bone, or radiation to bone] for the ZA arm was 10.4 months 

requiring 257 SRE events to detect a 33% relative reduction for the 

radiopharmaceutical arm in the time to development of an SRE with 90% 

power. Other study objectives included quality of life, pain control, OS and 

toxicity. Results: 261 patients (median age 68; 62% male; 55% prostate, 

35% breast, 10% lung) were accrued from July 2006 through February 

2011 (4.6 patients/month). Due to a lower than expected rate of SREs in 

the control (ZA) arm, the study was closed early and therefore did not reach 

the targeted accrual. 28 (17.4%) patients in the ZA arm and 27 (16.8%) in 

the radiopharmaceutical arm experienced an SRE. Median time to development 

of an SRE in the ZA and radiopharmaceutical arms was 11.60 and 

16.74 months, respectively (p�.47). Median OS in the ZA arm and 

radiopharmaceutical arm was 15.95 and 11.18 months, respectively 

(p�0.12). Cox proportional hazards regression model showed that baseline 

characteristics, including gender, race, ethnicity, primary disease site or 

number of bone metastases, had no significant impact on OS. There was no 

difference in QOL parameters or toxicities between the two arms. Conclusion: 

Patients receiving ZA only experienced a much lower SRE rate than 

was hypothesized. The addition of Sr89 or Sm153 did not result in a 

difference in SREs, OS, or QOL 


Radioprotection study of topical norepinephrine in postsurgical breast 

cancer patients. Presenting Author: James F. Cleary, University of Wisconsin, 

Madison, WI 

Background: This study derives from radiodermatitis studies in a rat model 

evaluating radioprotection from topical norepinephrine application. In the 

model, increasing radiation doses induce dermatitis of increasing severity, 

ranging from mild erythema to wet desquamation. The model was initially 

designed to identify topical radioprotectants that function as oxygen free 

radical scavengers. In an experiment designed to test the hypothesis that 

the co-application of a topical vasoconstrictor and an aminothiol scavenger 

would limit the systemic uptake of the scavenger, it was observed that the 

combination was synergistic and that the topical vasoconstrictor was active 

when administered alone as a control. Subsequent experiments demonstrated 

that topical a-adrenergic receptor agonists are active in preventing 

radiodermatitis. The data are consistent with a mechanism based on local 

and transient vasoconstriction within the skin, which reduces local tissue 

oxygenation. This subsequently limits the formation of radiation-induced 

reactive oxygen species and protects skin stem cells from radiation 

damage. Methods: Two Phase 1 safety studies have been conducted, one in 

normal volunteers and one in cancer patients receiving palliative radiation 

therapy for bone metastases. This study is a nonrandomized, open-label 

safety and exploratory study in post-surgical breast cancer patients treated 

with 45 to 50 Gy to the whole breast and axilla. A 10-16 Gy boost to the 

lumpectomy region is permitted. Eligible patients are age 18 years or older 

with a diagnosis of Stage Ia (T1, N0, M0), Stage Ib (T0 or 1, N1mic, M0) or 

Stage IIa (T�3cm, N0, M0) infiltrating ductal or lobular carcinoma of the 

breast or ductal carcinoma in situ (DCIS). The dose is a single daily topical 

application of 3.0 mL of norepinephrine HCl (82.3 mg/mL in 70% ethanol) 

applied to the same 50 cm2 treatment site in the axilla about 20 minutes 

prior to each radiotherapy fraction. The radiodermatitis severity at the 

treatment site will be compared to surrounding (untreated) control areas. 5 

of planned 12 patients have been enrolled. Clinical trial registry number 

NCT01263366. 


Do we need to perform pulmonary function tests in non-small cell lung 

cancer patients never diagnosed as COPD? Presenting Author: Narongwit 

Nakwan, Prince of Songkla University, Hatyai, Thailand 

Background: Although chronic obstructive pulmonary disease (COPD) and 

lung cancer share a common risk factor, namely smoking, health care 

providers usually overlook the symptom of COPD in the management of 

lung cancer. Should, then, lung cancer patients undergo pulmonary 

function tests (PFT) to identify the presence of COPD? Our study was 

performed to describe the results of pulmonary function tests and define 

risk factors for COPD in non-small cell lung cancer (NSCLC) patients. 

Methods: A total of 31 eligible patients with NSCLC but no obvious 

symptoms of COPD participated. We collected baseline characteristics and 

conducted a detailed assessment of pulmonary function, particularly 

spirometry, lung volume measurement, and diffusing capacity of carbon 

monoxide (DLCO). Dyspnea was assessed using modified Borg (mBorg) and 

modified Medical Research Council (mMRC) scores. Results: Twelve 

patients had airflow limitation (FEV1/FVC�0.7). These patients had mean 

percent predicted FEV1, RV and DLCO of 52%, 143% and 66% respectively, 

and a mean RV/TLC of 0.55. Being male, and having a smoking 

history, low body mass index and squamous cell carcinoma were significantly 

associated with obstruction in univariate analysis. However, obstruction 

was not more common in advanced stage than in locally advanced 

NSCLC. Neither mBorg nor mMRC differed between obstructive and 

non-obstructive groups. Discussion: COPD was found in patients with 

NSCLC who had never been diagnosed as, or showed symptoms of, COPD. 

Male, smoking history, low BMI and squamous cell carcinoma were 

significantly associated with obstruction. 


A multi-site, fixed dose, parallel arm, double-blind, placebo controlled, 

block randomised trial of the addition of infusional octreotide or placebo to 

regular ranitidine and dexamethasone for the evaluation of vomiting 

associated with bowel obstruction at the end of life. Presenting Author: 

David C. Currow, Flinders University, Adelaide, Australia 

Background: Bowel obstruction due to advanced cancer that is surgically 

inoperable is a major management problem. Studies to date have either 

been underpowered or have used comparators that may not draw on the 

best available evidence. Methods: This double-blind, block randomised, 

placebo controlled, set dose, parallel arm study was conducted across 12 

sites in Australia. Eligibility included inoperable bowel obstruction secondary 

to cancer or its treatments. The intervention was the addition of 

infusional octreotide or placebo in addition to 200mg ranitidine per 24 

hours parenterally and 4mg per 24 hours parenterally of dexamethasone. 

The primary outcome measure was the numbers of days free of vomiting up 

to 72 hours after all medications were administered the first time. 

Participants were also administered between 10-20mls per hour of 

subcutaneous isotonic fluid over the 72 hour period. Results: This study 

will close to recruitment in March 2012. To date 89 of 92 required 

participants have been randomised. Conclusions: This adequately powered 

study will define the additional net clinical benefit derived from octreotide 

over placebo in people who have an anti-secretary agent (ranitidine) and 

glucocorticoids (dexamethasone). 



The European InCASA telecare-telehealth electronic platform (ICT-FP7) for 

the daily assessment of symptoms, weight, and activity in cancer patients 

on chronotherapy at home. Presenting Author: Francis Levi, INSERM 

U776, Paul Brousse Hospital, Villejuif, France 

Background: Self-rated symptoms contribute to the Quality of Life (QoL) of 

cancer patients (pts) and impact on prognosis. Behavioural functions are 

controlled by the circadian timing system (CTS), through a network of 

molecular clocks that time cellular proliferation and drug metabolism (Lévi 

et al. ARPT 2010). Chronotherapy aims at the reduction of treatmentrelated 

symptoms through the adjustment of chemotherapy delivery to the 

CTS. Cancer chronotherapy is delivered at home using programmable 

pumps, and avoids familial and social disruption. Telemedicine tools can 

provide continuous information on symptoms, behavior, QoL and CTS from 

non hospitalized pts. Methods: The inCASA platform enables telemonitoring 

of multiple functions in order to help physicians to detect early warning 

signals in pt condition at home, and prompt adequate and timely interventions. 

Our pilot site investigates the clinical relevance of daily teletransmitted 

self assessed symptoms, body weight and rest-activity circadian rhythm 

in cancer pts. This system was first well understood and accepted by 14 pts 

(9 male, 5 female, 43-77 years) at the outpt clinic, then used by 5 pts (4 

male, 1 female, 61�13 years) at home daily for 6� weeks, while receiving 

chronotherapy. The pilot phase will accrue 30 pts receiving chronotherapy 

at home from 03/01/2012. Pts will fill in the M.D. Anderson Symptom 

Inventory scale on a touch-screen device, measure their body weight using 

a Bluetooth scale and record their circadian rest-activity rhythm using an 

infrared wrist-watch accelerometer over 6-weeks. The data are transmitted 

to the platform, then to a web portal with secured access to be daily 

inspected by the oncology nursing and medical team. The modelling of 

these continuous records will define alert thresholds for nurse-controlled 

graded intervention decisions. Conclusion: The assessment criteria set 

forth for the inCASA solution will address the issues of pt autonomy, CTS 

entrainment in the pt usual environment, safety of chronotherapy delivery 

at home and treatment costs. Its use should induce important organisational 

changes and perception in healthcare professionals. 


605s 


Assessing clinical appropriateness on a population basis within a regional 

cancer network. Presenting Author: Paolo Giovanni Casali, Fondazione 

IRCCS Istituto Nazionale dei Tumori, Milan, Italy 

Background: The Lombardia Cancer Network (ROL: “Rete Oncologica 

Lombarda”) connects all cancer resources of the Lombardia region, with 

9,000,000-plus citizens, to improve quality of cancer care and patient 

data sharing. Assessment of appropriateness of cancer care on a population 

basis is an aim. Implementation of electronic records is partial and 

heterogeneous. However, clinical discharge reports for both inpatients and 

oupatients are released as “pdf” files onto a secure regional health care 

information system, accessible by physicians. Methods: ROL includes 58 

oncology premises. Clinical practice guidelines are annually updated 

within this oncology community. For each solid cancer, guidelines enlist all 

main clinical presentations (“disease phases”), along with their “treatment 

options” (either “standard”, “individualized”, or “investigational”). ROL 

upgraded the existing non-structured electronic clinical discharge report 

into a field-based resource, with both free-text (17) and codified (25) fields. 

Two codified fields enlist, respectively, disease phases as per guidelines, 

and the corresponding treatment options. If they match, the strategic 

medical decision is considered tentatively “appropriate”. Even the report of 

a single encounter within a disease phase is enough to make this work. 

Results: Currently, the instrument is being incorporated stepwisely within 

the information systems of all oncology facilities, though a central 

web-based tool is also available. More than 36,000 reports were released in 

2011. Appropriateness assessment proved feasible on a pilot set of 

patients. A research project is underway to detect causes of mistakes and 

mismatches, by automatically analyzing free-text fields. A training effort is 

ongoing to improve clinicians’ learning curve on semantics. Conclusions: 

To assess clinical appropriateness on a population basis in a large region, 

we exploited two key bottlenecks: 1) the electronic discharge report, within 

patient information flows, to cope with a variety of local information 

systems; 2) the disease phase, within the cancer-specific clinical decisionmaking 

process, to cope with a likely lack of reports from a substantial 

proportion of encounters. 


606s Pediatric Oncology 


Efficacy of crizotinib in children with relapsed/refractory ALK-driven 

tumors including anaplastic large cell lymphoma and neuroblastoma: A 

Children’s Oncology Group phase I consortium study. Presenting Author: 

Yael P. Mosse, The Children’s Hospital of Philadelphia, Philadelphia, PA 

Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) 

gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma 

(NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and 

c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK 

translocation. We performed a phase 1 dose-escalation and pharmacokinetic 

(PK) trial of crizotinib in patients (pts) with refractory solid tumors 

and ALCL. Methods: Crizotinib was administered bid without interruption in 

28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 

215, 280, 365 mg/m2 /dose) have been evaluated (A1). Pts with confirmed 

ALK fusion proteins, mutations or amplification (A2) could enroll at one 

dose level lower than part A1 and those with NB could enroll on a separate 

stratum (A3). PK studies were performed on day 1 and at steady state (SS). 

ALK genomic status in tumor tissue was evaluated and qPCR was used to 

measure NPM-ALK fusion transcript in bone marrow and blood samples of 

ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, 

[median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on 

A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral 

hemorrhage) at 215 mg/m2 and 1/6 pts developed DLT (grade 4 liver 

enzyme elevation) at 365 mg/m2 . In A2, 1 grade 4 DLT (neutropenia) 

occurred at 165 mg/m2 ; in A3, no DLTs occurred. Mean (�SD) Cave (�AUC0-12h/12h) of crizotinib at SS was 466�114 ng/mL at 215 mg/m2 / 

dose (n�5), 443�121 ng/mL at 280 mg/m2 /dose (n�8), and 720�230 

ng/mL at 365mg/m2 /dose (n�4). Response data for pts with ALCL (six at 

165 mg/m2 , two at 280 mg/m2 ) approved for release by the Data Safety 

Monitoring Committee demonstrates 7/8 (88%) complete response (CR) 

rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained 

and will be described. In addition, 2 pts with NB have had CRs, one with a 

documented ALK mutation. One patient with an inflammatory myofibroblastic 

tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in 

pediatric pts with ALK-driven tumors occurs with minimal toxicity and is 

associated with objective anti-tumor activity. 


Stanford V chemotherapy and involved field radiotherapy for children and 

adolescents with unfavorable risk Hodgkin lymphoma: Results of a multiinstitutional 

prospective clinical trial. Presenting Author: Monika Metzger, 

University of Tennessee Health Science Center, Memphis, TN 

Background: To evaluate the efficacy of 12 weeks of Stanford V chemotherapy 

(prednisone, vinblastine, doxorubicine, nitrogen mustard, etoposide, 

vincristine, and bleomycin) without routine growth factor support plus 

response-adapted low-dose, involved-field radiotherapy (IFRT) in children 

and adolescents with unfavorable risk Hodgkin lymphoma (HL). Methods: 

Multi-institutional (St. Jude Children’s Research Hospital, Stanford University, 

Children’s Hospital Boston, Massachusetts General Hospital and 

Maine Children’s Hospital) clinical trial. One hundred forty-one patients 

with clinical stages IIB (n�43), IIIB (n�19), IVA (n�27), and IVB (n�52) 

HL were treated with 12 weeks of Stanford V chemotherapy and low dose 

IFRT between June 2002 and May 2011. Involved nodal sites in complete 

remission (CR, defined as � 75% shrinkage of the original tumor and PET 

negative) after 8 weeks of Stanford V received 15 Gy IFRT; those sites that 

achieved only partial response received 25.5 Gy IFRT after completion of 

all 12 weeks of chemotherapy. Results: With a median follow-up of 4.6 

years, the 3-year overall and event-free survival (EFS) are 97% (SE�2%) 

and 79% (SE�4%) respectively. There was no significant difference in EFS 

by stage (IIB vs. IIIB vs. IV; P�0.84). Ten patients developed progessive 

disease and 18 relapsed, while 5 have died (1 after relapse in an accident 

and 4 of refractory disease). Most common toxicities were grade 3 

hematologic with 234 episodes of neutropenia in 101 patients (72%) and 

85 episodes of anemia in 52 patients (37%); Fever and neutropenia 

occurred 13 times in 12 patients (9%). Conclusions: Risk-adapted, 

combined-modality therapy using 12 weeks of Stanford V chemotherapy 

plus IFRT is well tolerated in this population with manageable acute 

toxicities. Overall survival is comparable to other more intense chemotherapy 

regimens. Future high-risk front line therapies may consider a 

Stanford V backbone with targeted intensification and further tailoring of 

radiation therapy. 


Efficacy of rituximab plus FAB group C chemotherapy without CNS 

radiation in CNS-positive pediatric Burkitt lymphoma/leukemia: A report 

from the Children’s Oncology Group. Presenting Author: J. Kimble Frazer, 

University of Utah, Salt Lake City, UT 

Background: Historically, CNS-positive (CNS�) mature B-NHL in children 

and adolescents has been associated with a dismal outcome (Miles/Cairo, 

Br J Haematol, 2012). Adding CNS radiation and high-dose MTX and 

cytarabine to group C therapy for children with CNS� B-NHL yielded a 

77% 5-yr EFS in LMB89 (Patte et al., Blood, 2001). An ensuing 

FAB/LMB96 trial replaced cranial radiation with further HD-MTX and 

intrathecal therapy with similar results (75% 4-yr EFS) (Cairo et al., Blood, 

2007). Here, patients with marrow and CNS� disease fared worse than 

isolated CNS� (61% vs. 83% 4-yr EFS, p�0.001), with �50% of CNS� 

patients who progressed or recurred having systemic, but not CNS, relapse. 

Rituximab, a chimeric anti-CD20 antibody, improved EFS, PFS, and OS 

when added to chemotherapy for adults with DLBCL (Coiffier et al., N Engl J 

Med, 2002; Pfreundschuh et al., Lancet Oncol, 2006). We tested whether 

adding rituximab to FAB group C chemotherapy in pediatric patients with 

CNS� B-NHL was safe and efficacious. Methods: Children and adolescents 

(�21 yrs.) with CNS� B-NHL received FAB group C1 therapy (Cairo et al., 

Blood, 2007). Rituximab (375 mg/m2 /dose) was given twice in COPADM 

courses 1&2andonce in CYVE courses (Cairo et al., ASCO, 2010). CSF 

blasts (�1), cranial nerve palsy (CNP), intra-cerebral mass (ICM), and/or 

parameningeal extension (PME) defined cases as CNS�. Results: Of 40 

eligible Group C patients,15 (38%) were CNS�; all 15 had Burkitt 

morphology. Eight CNS� patients were CSF� [WBC median 35 (range 

1-1104)] with 6 cases CNP�, 4 PME�, and 1 ICM�. No adverse events 

were attributed to rituximab. Fourteen of 15 CNS� patients (93%) are alive 

and disease-free. Of 7 BM- /CNS� patients, 100% are NED. In BM�/CNS� 

cases, 7/8 (88%) are NED, with one patient progressing with systemic and 

CNS disease. Conclusions: Addition of rituximab to group C FAB therapy 

was well tolerated. Outcomes in this small cohort of 15 children and 

adolescents with CNS� BL (93%) suggest that adding rituximab to FAB 

group C therapy without CNS radiation may reduce systemic relapse. Large 

randomized studies are warranted to test this hypothesis in this previously 

high-risk clinical subgroup. 


The effects of dexrazoxane on cardiac status and second malignant 

neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS). 

Presenting Author: Lisa M. Kopp, The University of Arizona, Tucson, AZ 

Background: Anthracyclines are highly efficacious in OS but associated with 

risk of cardiotoxicity. We conducted two studies using dexrazoxane as a 

cardioprotectant: i) AOST0121, a phase II study for metastatic OS and ii) 

P9754, a series of pilot studies including doxorubicin dose intensification 

in patients with localized OS. Methods: Patients on AOST0121 received 

methotrexate, doxorubicin (375 mg/m2 ), cisplatin, ifosfamide and etoposide 

(MAPIE). Those with HER2-positive tumors also received trastuzumab 

(4 mg/kg loading dose, 2 mg/kg weekly). On P9754, patients received MAP 

in Pilot 1, MAPI or MAPIE in Pilots 2 and 3. Total doxorubicin was 450 

mg/m2 or 600 mg/m2 with each dose preceded by dexrazoxane (10:1 ratio). 

Etoposide was never given simultaneously with dexrazoxane. Measurements 

of left ventricular systolic function by echocardiography, serum 

troponin-T (cTnT, a myocardial injury marker) and N-terminal pro-brain 

natriuretic peptide (NT-proBNP, a cardiomyopathy marker) were obtained 

at baseline and repeated during therapy. Secondary malignancies were 

reported to the NCI. Results: None of the 47 patients (17 receiving 

trastuzumab) evaluated for cardiac toxicity on AOST0121 had significant 

changes in left ventricular fractional shortening, measurable cTnT, elevation 

of NT-proBNP or clinical evidence of cardiotoxicity (CTCv2.0). In 

P9754, 242 patients were evaluated for cardiotoxicity. Only 1 patient had 

CTCv2.0 grade 3 toxicity and 1 patient had a measurable cTnT. Three of 96 

patients treated on AOST0121 and two of 272 patients on P9754 

developed AML. Combining both studies: 5/398 or 1.4%. Conclusions: This 

large group of OS patients demonstrates that dexrazoxane is an effective 

cardioprotectant for doxorubicin alone (375-600 mg/m2 ), and in combination 

with trastuzumab. Dexrazoxane did not lead to an increase in 

secondary malignancies in OS patients treated with these regimens as 

compared to historical rates of 1-2%. Our results do not support the 

findings of a recent European Medicines Agency safety review that 

concluded dexrazoxane was unsafe for use in children and adolescents due 

to risk of SMN. 



Cardioprotection and safety of dexrazoxane (DRZ) in children treated for 

newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced 

stage lymphoblastic leukemia (T-LL). Presenting Author: Barbara Asselin, 

University of Rochester, Rochester, NY 

Background: POG 9404 evaluated the efficacy of DRZ as a cardioprotectant 

and its side effects in children receiving doxorubicin (DOX) as part of 

chemotherapy for T-ALL/T-LL. Methods: Between 6/1996 and 9/2001, 537 

T-ALL/T-LL patients were treated with multi-agent chemotherapy that 

included 12 DOX doses of 30 mg/m2 . Patients were randomized at 

diagnosis to treatment with or without DRZ (300 mg/m2 IV immediately 

prior to each DOX dose). Cardiac effects were assessed by serial echocardiograph 

measurements of left ventricular (LV) function (fractional shortening) 

and structure (end-diastolic dimension, wall thickness, and mass). Adverse 

events, grades 3-5 were recorded using CTCAE version 2.0. Results: 

Five-year EFS was similar for the DRZ (0.77�0.03%) and no-DRZ 

(0.76�0.03%) groups (p�0.9). Acute cardiac toxicity occurred in 1 

patient (arrhythmia) on DRZ and 4 patients treated without DRZ (1arrhythmia, 

3-decreased LV fractional shortening). At each of the three 

time-points post-baseline (end-induction, after the last DOX dose and two 

years post study entry) LV dimensions were larger from baseline for patients 

who did not receive DRZ. In univariate analyses, change in LV end-diastolic 

dimension from baseline was the only variable that was significantly 

different between DRZ and no-DRZ arms. This was true at each of the three 

time points (p�0.005-0.02). The frequencies of grade 3 or 4 toxicity 

(hematologic, infection, CNS events, mucositis) or death were similar in 

groups with or without DRZ (p�0.24). There were 13 second malignancies, 

10 patients had received DRZ and 3 had not (p�0.07). Conclusions: Our LV 

dimension measurements suggest that DRZ may protect against the early 

LV remodeling and enlargement that is seen with DOX cardiotoxicity. 

Addition of DRZ did not interfere with the anti-tumor efficacy of this 

DOX-containing, multi-agent regimen, and there was no significant increase 

in toxicities. An increased rate of second malignancies with DRZ did 

not reach conventional levels of statistical significance. The study was not 

powered to assess second malignancy rates and this trend is of unknown 

clinical significance. 


In vivo monitoring of JAK/STAT and PI3K/mTOR signal transduction 

inhibition in pediatric CRLF2-rearranged acute lymphoblastic leukemia 

(ALL). Presenting Author: Sarah Kathleen Tasian, The Children’s Hospital 

of Philadelphia, Philadelphia, PA 

Background: Therapy intensification for children with B-precursor ALL with 

high-risk genetic lesions has improved relapse-free survival. CRLF2 rearrangements 

and JAK2 and IL7RA mutations occur in 10-15% of adult and 

pediatric ALL patients, most of whom relapse. We and others identified 

aberrant kinase signatures and perturbed JAK/STAT and PI3K/mTOR signal 

transduction via in vitro studies of CRLF2-rearranged (CRLF2r) ALLs, 

suggesting the therapeutic relevance of signal transduction inhibitors 

(STIs). Our creation of CRLF2r ALL xenograft models has enabled rapid 

preclinical testing of STIs and measurement of in vivo target inhibition. We 

hypothesized that inhibition of JAK/STAT and PI3K/mTOR phosphosignaling 

correlates with therapeutic responses in these models. Methods: 

NOD/SCID/�c-null (NSG) mice well-engrafted with pediatric ALL samples 

were treated with the JAK inhibitor ruxolitinib, the mTOR inhibitor 

sirolimus, or vehicle for 72 hours (for signaling response) or 4 weeks (for 

therapeutic response). Splenocytes were briefly stimulated ex vivo with 

thymic stromal lymphopoietin (ligand for CRLF2) and stained with humanspecific 

surface and intracellular phosphoantibodies for multi-parameter 

phosphoflow cytometry analysis. Results: Ruxolitinib-induced inhibition of 

phospho (p)-JAK2 and pSTAT5 was most pronounced in non-CRLF2r ALLs 

with novel JAK2-activating BCR-JAK2 and IL7RA/LNK mutations. Sirolimus 

potently inhibited pS6 and other PI3K/mTOR pathway phosphoproteins 

in the CRLF2r r ALLs. PSTAT5 and pS6 inhibition correlated with 

longer-term ruxolitinib- and sirolimus-induced decreases in ALL cell 

burden, demonstrating therapeutic responses to STIs. Conclusions: Ruxolitinib 

inhibited JAK/STAT phosphosignaling and markedly decreased 

leukemic burden in the JAK2-activating BCR-JAK2 and IL7RA/LNK mutant 

ALL xenografts. Sirolimus potently inhibited PI3K/mTOR (as well as some 

JAK/STAT) phosphosignaling and had greater therapeutic efficacy than 

ruxolitinib in the CRLF2r ALLs. The safety of ruxolitinib and of temsirolimus 

with cytotoxic chemotherapy are currently being established in Children’s 

Oncology Group Phase I trials. 



Efficacy of the Children’s Oncology Group (COG) long-term followup 

(LTFU) guidelines in reducing risk of congestive heart failure 

(CHF) in childhood cancer survivors (CCS). Presenting Author: F. 

Lennie Wong, City of Hope, Duarte, CA 

Background: CCS are at risk for left ventricular dysfunction (LVD) and 

subsequent CHF due to exposure to anthracyclines and chest radiation 

(RT). COG LTFU guidelines recommend screening for LVD using echocardiograms 

(ECHOs) every 1-5y depending on anthracycline dose, RT, and 

age at cancer diagnosis. The relevance and cost-effectiveness of these 

consensus-based guidelines are unknown. Methods: Life expectancy and 

age at onset of CHF were projected in a simulated cohort (�1 million) of 

CCS undergoing screening ECHO per COG guidelines. Intervention for LVD 

was modeled to reduce annual CHF risk by 30%. Quality-adjusted life-years 

(QALYs) and lifetime costs with and without ECHO screening were 

calculated. Non-CHF mortality was estimated from the Childhood Cancer 

Survivor Study and US population rates. Costs and QOL adjustments were 

obtained from the Healthcare Cost and Utilization Project and medical 

literature. Screening was considered cost-effective if it resulted in a �6 

month delay in onset of CHF and �$50,000/QALY gained. Results: 

Recommended screening strategies (Table) were cost-effective in: i) CCS 

exposed to �300mg/m² of anthracycline regardless of RT or age; and ii) 

CCS diagnosed at age 1-4y, exposed to RT and �300mg/m² of anthracycline. 

Screening was most cost-effective for CCS diagnosed at age 1-4y 

exposed to RT � �300 mg/m² of anthracycline (1.4y delay in CHF onset; 

$15,821/QALY gained). Screening as currently proposed was not costeffective 

for other age/anthracycline/RT combinations. Conclusions: Recommended 

ECHO screening strategies are cost-effective for all CCS exposed to 

�300 mg/m² of anthracycline; screening was also cost-effective for those 

1-4y at diagnosis, exposed to anthracycline �300 mg/m² � RT. Alternate 

screening strategies are needed for CCS with other exposure conditions. 

Age Dx 

(years) RT 

Anthracycline 

dose 

(mg/m²) 

Recommended 

ECHO 

interval 

(years) 

Delay in 

CHF onset age 

(years) 

607s 

Cost / QALY 

gained 

(US$) 

1-4 Yes �300 1 0.8 $49,750 

�300 1 1.4 $15,821 

No �100 5 0.3 $17,798 

100-299 2 0.4 $29,415 

�300 1 1.2 $25,065 

>5 Yes �300 2 0.4 $36,874 

�300 1 0.8 $28,093 

No � 200 5 0.1 $50,750 

200-299 2 0.2 $86,867 

�300 1 0.7 $36,401 


Relapse-specific mutations in cytosolic 5’-nucleotidase II in childhood 

acute lymphoblastic leukemia. Presenting Author: Julia Meyer, New York 

University Langone Medical Center, New York, NY 

Background: Relapsed childhood acute lymphoblastic leukemia (ALL) 

carries a very poor prognosis despite intensive retreatment that often 

includes allogeneic stem cell transplantation, due to intrinsic drug resistance. 

Novel therapeutic approaches are urgently needed and identification 

of the biological pathways that mediate resistance might provide targets for 

the effective prevention and treatment of relapsed ALL. However, the 

spectrum of somatic mutations responsible for ALL relapse is not yet 

known. Methods: We profiled the transcriptome of matched diagnosis and 

relapse bone marrow specimens from 10 pediatric B lymphoblastic 

leukemia patients using massively parallel sequencing technology (RNAseq) 

to identify novel mutations specific at disease recurrence. Results: 

Transcriptome sequencing identified 20 newly acquired novel nonsynonymous 

mutations in 10 relapse specimens not present at initial 

diagnosis. Two patients harbored relapsed specific mutations in the same 

gene, NT5C2, which codes for the Cytosolic 5’-nucleotidase II protein at 

different sites in the protein sequence. Mutations were validated as relapse 

specific after Sanger resequencing of germline, diagnosis and relapse DNA. 

RNA-seq coverage of each mutation was �100X, indicating that if a 

relapsed clone were present at diagnosis it made up � 1% of the bulk 

leukemia. Full exon sequencing of NT5C2 was completed in 61 additional 

relapse specimens, identifying 5 additional mutations which were also 

confirmed as relapse specific. Structural modeling of the relapseassociated 

mutations in the encoded protein Cytosolic 5’-nucleotidase II 

suggests alteration of enzyme subunit association/dissociation. Clinically, 

patients who harbored NT5C2 mutations were more likely to relapse earlier 

following initial diagnosis than those patients without mutations (p�0.03). 

Conclusions: Mutations in NT5C2 are associated with the outgrowth of drug 

resistant cells in childhood ALL. 



CRA9508 Oral Abstract Session, Sat, 1:15 PM-4:15 PM 

Outcome in adolescent and young adult (AYA) patients compared with 

younger patients treated for high-risk B-precursor acute lymphoblastic 

leukemia (HR-ALL): A report from the Children’s Oncology Group study 

AALL0232. Presenting Author: Eric Larsen, Maine Children’s Cancer 

Program, Scarborough, ME 








Development of prognostic molecular markers in pediatric rhabdomyosarcoma 

based on gene expression and copy number variations. Presenting 

Author: Edoardo Missiaglia, Swiss Institute of Bioinformatics, Lausanne, 

Switzerland 

Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft 

tissue sarcoma and comprises two major histological subtypes: alveolar and 

embryonal. The majority of alveolar tumors harbor PAX/FOXO1 fusion 

genes. Current patient risk stratification, unlike other pediatric embryonal 

tumors, does not utilize any molecular data. Therefore, we aimed to 

improve the risk stratification of RMS patients through the use of molecular 

biological data. Methods: Two independent data sets of gene expression 

profiling for 124 and 101 RMS were used to derive prognostic gene 

signatures by meta-analysis. Genomic array CGH data for 109 RMS was 

also evaluated to develop a prognostic marker based on copy number 

variations (CNVs). The performance and usefulness of these derived 

metagenes and CNVs as well as a previously published metagene signature 

were evaluated using rigorous leave-one-out cross-validation analyses. 

Results: The new prognostic gene expression signature, MG15, and one 

previously published (MG34) (Davicioni. JCO. 2010) performed well with 

reproducible and significant effects (HR 3.2 [1.7-5.9] p � 0.001 and HR 

2.5 [1.5-4.3] p � 0.001, respectively). However, they did not significantly 

add new prognostic information over the fusion gene status (PAX3/FOXO1, 

PAX7/FOXO1 and Negative). Similarly, a prognostic CNV marker, although 

showing HR 2.9 [1.5-5.6] p � 0.01, was also not improving models with 

fusion gene status. Within fusion negative RMS, the analysis identified 

prognostic markers based on either gene expression or CNVs and showed 

significant association with patients outcome (HR 6.3 [1.5-26.3] p � 

0.016 and HR 11.2 [2.5-50.7] p � 0.010, respectively). Moreover, these 

were able to identify distinct risk groups within the COG (Children’s 

Oncology Group) risk categories, which is currently used to guide treatment. 

Conclusions: Molecular signatures derived using all RMS effectively 

stratify patients by their risk, but most of their prognostic information is 

contained in the PAX/FOXO1 fusion gene status which is simpler to assay. 

New markers developed within the fusion negative population seem 

improving current RMS risk classifier and should be tested in follow-up 

studies. 


Vincristine (V), dactinomycin (A), and lower doses of cyclophosphamide (C) 

with or without radiation therapy for patients with newly diagnosed low-risk 

embryonal rhabdomyosarcoma (ERMS): A report from the Children’s 

Oncology Group (COG). Presenting Author: David Walterhouse, Children’s 

Memorial Hospital, Chicago, IL 

Background: Intergroup Rhabdomyosarcoma Study (IRS) trials showed 

improved survival with VAC compared with VA for patients with Stage 1 

Group III (non-orbit) or Stage 3 Group I/II ERMS (see table). In COG 

ARST0331, we hypothesized that VA in combination with lower doses of C 

(total cumulative dose�4.8 g/m2 ) would produce the benefit of IRS-IV VAC 

with less toxicity for patients with Stage 1 Group III (non-orbit) or Stage 3 

Group I/II low-risk ERMS. Methods: This single arm, non-inferiority, phase 

III study enrolled newly diagnosed patients with Stage 1 Group III 

(non-orbit) ERMS or Stage 3 Group I/II ERMS onto Subset 2. Therapy was 4 

cycles of VAC followed by 12 cycles of VA over 46 weeks (total cumulative 

doses: V�54 mg/m2 ,A�21.6 mg/m2 ,C�4.8 g/m2 ). The radiation therapy 

dose was 36 Gy for Group IIA patients, 41.4 Gy for Group IIB/C patients, 

and 50.4 Gy for Group III patients. From 2004–2008 girls with Group III 

vaginal RMS did not receive radiotherapy if a complete response was 

achieved with chemotherapy with or without delayed resection. The primary 

endpoint was failure-free survival (FFS), and results were compared with a 

fixed expected outcome. Results: With a median follow-up of 3.0 yrs, we 

observed 16 failures vs. 7.8 expected failures. Estimated 3-yr FFS was 

63% (95% CI: 46%, 75%) (n�60), and overall survival (OS) was 84% 

(95% CI: 68%, 93%). Estimated 3-yr FFS was 46% (95% CI: 23%, 67%) 

for girls with non-bladder genitourinary tract ERMS (n�21) and 75% (95% 

CI: 53%, 88%) for all other Subset 2 patients (n�39). Conclusions: We 

observed suboptimal FFS of patients with Subset 2 low-risk RMS using 

reduced total cyclophosphamide (4.8 g/m2 ). Results were complicated by 

the choice of no radiation therapy for girls with vaginal tumors. Future 

studies for low-risk RMS Subset 2 patients could investigate a dose of C 

between 4.8 and 26.4 g/m2 with VA and local radiotherapy. 

Chemotherapy cumulative dose 

Study 

Duration 

(weeks) V (mg/m 

FFS 

(5-yr) 

OS 

(5-yr) 

2 ) A (mg/m2 ) C (g/m2 ) 

IRS-III 45 72 13.5 - 70% 79% 

IRS-IV 45 48 22.5 26.4 84% 

98% 

p�0.008 p�0.004 


Identification of TNK2 as a critical kinase in rhabdomyosarcoma through a 

loss of function shRNA screen. Presenting Author: Fernanda Irene Arnaldez, 

Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 

Background: Rhabdomyosarcoma is the most common pediatric soft tissue 

sarcoma. Embryonal rhabdomyosarcomas (ERMS) are characterized by 

11p15 LOH while alveolar rhabdomyosarcomas harbor a translocation 

between PAX3 or PAX7 and FOXO1. Relapsed or metastatic disease has a 

5-year survival rate of 25%. Methods: We sought to identify critical genes 

for rhabdomyosarcoma cell growth and survival. We performed a loss-offunction 

shRNA screen where a library of 15,000 shRNAs was introduced 

in RH30 (ARMS) and RD (ERMS) cells engineered to express the bacterial 

tetracycline repressor in a tet-on system. Relative abundance of cells 

containing a certain shRNA was determined using specific barcodes. We 

subtracted “hits” that are common to 4 lymphoma cell-lines to eliminate 

common survival pathways. Forty genes were associated with rhabdomyosaroma 

cell growth, of which 15 cause greater suppression in ARMS. We 

performed a subsequent validation of these 15 genes in multiple ARMS 

and ERMS cell lines using three different shRNA sequences using lentiviral 

constructs. In addition, we validated our results in an independent siRNA 

screen of the protein kinome in RMS cells. Results: TNK2 (tyrosine kinase, 

non-receptor 2) was identified as tyrosine kinase involved in rhabdomyosarcoma 

cell growth independently in the inducible shRNA screen and in the 

non-inducible siRNA platform. This molecule has been involved in downstream 

signaling from EGFR and integrins. Amplification of the TNK2 gene, 

located at 3q29, has been described in breast, prostate and lung cancer. 

More recently, a siRNA screen identified it as a potential therapeutic target 

in Ewing’s sarcoma. We confirmed TNK2 expression across patient tumor 

samples in a publically available database; where patients with high TNK2 

expression showed lower overall survival. TNK2 knock down resulted in 

decreased rhabdomyosarcoma cell growth in vitro and in orthotopic 

xenografts. We confirmed specificity of our findings with a rescue experiment. 

Conclusions: We identified TNK2 as a potential therapeutic target in 

rhabdomyosarcoma using a loss-of-function shRNA screen and subsequent 

validation. Further work is ongoing to fully characterize the molecular 

mechanisms involved in these findings. 



Evaluation of the effect of care at NCI comprehensive cancer centers 

(NCICCCs) on disparities in outcome within adolescents and young adults 

(AYAs) with cancer. Presenting Author: Julie Anna Wolfson, City of Hope, 

Duarte, CA 

Background: AYAs (15-39y at diagnosis) with cancer have not seen the 

survival improvement evidenced by younger and older age groups with 

similar diagnoses, leaving an AYA Gap. While treatment on pediatric 

protocols is associated with superior survival in 15-21 year-olds, the 

impact of site of care on survival for vulnerable AYA subpopulations (age at 

diagnosis or race/ ethnicity) between 22-and 39y at diagnosis remains 

unstudied. Methods: We constructed a cohort of 10,727 patients newly 

diagnosed between the ages of 22- and 39y with lymphoma, leukemia, 

brain tumors, melanoma, thyroid and GU cancers, and reported to the LA 

County cancer registry between 1998 and 2008. Multivariable Cox 

regression analysis was conducted, and included race/ethnicity, age at 

diagnosis, SES, insurance status, primary cancer diagnosis and diagnosis 

year in the model; the analysis was stratified by site of care (NCICCC vs. 

non-NCICCC). Results: A total of 928 (9%) patients received treatment at 

the 3 NCICCCs (City of Hope, Jonsson Cancer Center and Norris Cancer 

Center) in LA County, and 9,799 received care elsewhere. Five-year overall 

survival (5y OS) was significantly worse for patients treated at non-NCICCC 

(87%) when compared with those treated at NCICCC (84%, p�0.02). In 

addition, 5y OS was worse for African Americans (71%) vs. non-Hispanic 

whites (89%, p�0.0001) and for older patients (31-39yo: 84%, vs. 

22-30yo: 86%, p�0.0004). Multivariable analysis adjusting for SES, 

insurance status, diagnosis and diagnosis year revealed that African 

Americans (HR�1.4, p�0.0002) and older AYAs (31-39y: HR�1.24, 

p�0.0001) were at an increased risk of death. Among patients treated at 

NCICCC, the difference in risk of death due to race (African Americans: 

HR�0.8, p�0.7) and age (31-39yo: HR�1.1, p�0.6) was abrogated. On 

the other hand, among patients treated at non-NCICCC, these differences 

in outcome persisted (African Americans: HR�1.45, p �0.0002; 31- 

39yo: HR�1.25, p�.0001). Conclusions: Population-based data reveal 

that receipt of care at an NCICCC abrogates the effects of race and older 

age on mortality in AYAs with cancer. Barriers to accessing care at NCICCCs 

are being explored. 


Increasing risk of chronic health conditions in aging survivors of childhood 

cancer: A report from the Childhood Cancer Survivor Study. Presenting 

Author: Gregory T. Armstrong, St. Jude Children’s Research Hospital, 

Memphis, TN 

Background: Survivors of childhood cancer are at an increased risk for 

treatment-related chronic health conditions during early adulthood. However, 

the incidence, severity, and spectrum of chronic health conditions in 

the fourth and fifth decades of life have not been well studied. Methods: 

Analyses included 14,358 � 5 yr survivors of childhood cancer (median 

age at last follow-up 32.3 yrs, range 8.0-58.0; 21.4% � 40 years) and a 

sibling comparison group (n � 4,031). Self-reported health conditions 

were classified using NCI CTCAE 4.0 grading system. Analyses focused on 

two primary outcomes: severe/life-threatening/fatal conditions (grades 

3-5), and multiple (� 2) conditions. Cumulative incidence of a new chronic 

health condition was calculated from age 26 yrs. Cox proportional hazards 

models adjusted for gender and race, were evaluated using age as the time 

scale. Results: Among survivors with no previous health conditions through 

age 25, the cumulative incidence for a new grade 3-5 condition by age 50 

compared to siblings was 45.9% (95% CI 45.9-45.9) vs. 13.9%, (95% CI 

13.9-14.0) and for new onset of � 2 conditions 33.0% (95% CI 

33.0-33.1) vs. 24.9% (95% CI 24.8-24.9) . Survivors � 40 yrs of age had 

a 5.8-fold (95% CI 5.3 – 6.5) increased risk of a grade 3-5 condition 

compared to same age siblings, in contrast to those � 40 years of age (HR 

2.7, 95% CI 2.5-3.0). A similar magnitude of difference was present for 

risk of �2 conditions (HR 2.7 vs. 1.2). In comparison to siblings, survivors 

� 40 years of age had a significantly increased risk for: congestive heart 

failure (HR 15.7, 95% CI 9.2-26.7), myocardial infarction (HR 8.8, 95% 

CI 6.0-12.9), stroke (HR 8.6, 95% CI 5.6-13.2),joint replacement (HR 

6.8, 95% CI 4.1-11.4), renal failure (HR 5.1, 95% CI 2.2-11.9) among 

other serious conditions. Conclusions: As they age, adult survivors of 

childhood cancer continue to develop new and serious health conditions at 

substantially higher rates than siblings. These data emphasize the importance 

of placing a greater focus on investigations of premature aging and 

organ senescence in this high risk population. 


609s 

CRA9513 Oral Abstract Session, Mon, 8:00 AM-11:00 AM 

New insights into the risk of breast cancer in childhood cancer survivors 

treated with chest radiation: A report from the Childhood Cancer Survivor 

Study (CCSS) and the Women’s Environmental Cancer and Radiation 

Epidemiology (WECARE) Study. Presenting Author: Chaya S. Moskowitz, 









A large prospective trial of children with unilateral retinoblastoma with and 

without histopathologic high-risk features and the role of adjuvant chemotherapy: 

A Children’s Oncology Group (COG) study. Presenting Author: 

Murali M. Chintagumpala, Baylor College of Medicine, Houston, TX 

Background: The definition of histopathologic high-risk features (HRF) in 

enucleated eyes of children with unilateral retinoblastoma and their 

contribution to metastases is controversial. The COG completed a large, 

prospective international study to determine the prevalence of strictly 

defined histopathologic HRF that are predictors of recurrence and the role 

of chemotherapy to prevent recurrences. Methods: All patients who underwent 

enucleation for unilateral retinoblastoma were eligible for the study. 

Pathology slides were submitted for central review within 21 days of 

enucleation. Patients with evidence of one or more high-risk features 

(posterior uveal invasion grades IIC and D, concurrent optic nerve and 

choroid involvement and post-lamina optic nerve involvement) as determined 

by central review, received 6 cycles of chemotherapy consisting of 

carboplatin, vincristine and etoposide. All others were observed. All 

patients were followed for extraocular recurrences. Results: Patients were 

enrolled from February of 2005 until May 2010. As of July 2011, the 

median follow-up from enrollment was 1.9 years (max�5.3 years). Of 312 

patients with central histopathology review, 49 patients had their risk 

classification changed (13% with no HRF had HRF, 24% with HRF had no 

HRF). Two patients developed extraocular disease and one patient died of 

unknown cause. The death and one of the extraocular relapses occurred 

among the 93 (2/93�2.2%, upper 95% CI 3.4%) patients assigned by the 

central review to receive chemotherapy, while one patient experienced 

extraocular relapse among the 209 (1/209�0.5%, upper 95% CI 0.6%) 

assigned to observation only. There is no evidence of a difference in the 

EFS and OS in these two groups. Conclusions: Preliminary results strongly 

suggest that a central review of pathology can spare a significant number of 

patients from exposure to chemotherapy. Chemotherapy may have contributed 

to fewer relapses in patients with high-risk features as defined in this 

study. The preliminary results from this study indicate an excellent 

outcome with this approach. 




Relationship of divergent ancestral genetic variation on chromosome 6p22 

and racial disparities in survival in neuroblastoma. Presenting Author: 

Navin R. Pinto, The University of Chicago, Chicago, IL 

Background: An increased prevalence of high-risk disease and worse 

outcome are observed in children with neuroblastoma who self-report as 

black versus white. We sought to determine whether genetic variation 

would explain this racial disparity. Methods: After quality control, we 

analyzed 511,836 germline genetic variants in 2,709 ethnically diverse 

children with neuroblastoma enrolled on Children’s Oncology Group study 

ANBL00B1 from 2001 to 2009. Genetic variation was summarized by 

conducting principal components analysis. The first principal component 

(PC1) separated patients with African ancestry from all others. PC1 was 

used as a continuous variable for ordinal regression with risk group and a 

Cox proportional hazard model of EFS. To identify genetic mechanisms for 

the observed disparities, we developed a method using genome-wide 

variation data applied to high-risk versus non-high risk samples. We 

identified a comprehensive list of loci with significant divergence between 

the ancestral populations. We then tested each such locus for association 

with high-risk phenotype using logistic regression with the proportion of 

African ancestry estimated by ADMIXTURE as covariate. Finally, top SNPs 

were added to multivariate models of both risk and event-free survival to 

determine if any top associations could abrogate observed disparities. 

Results: PC1 was associated with both risk (p � 0.007) and EFS (p � 

0.037). We identified 72 population-divergent SNPs nominally associated 

with high-risk disease (p � 0.001). The risk allele for one of the top SNPs: 

rs9295536 (p � 9.2x10-8 ) was more common in the African ancestral 

population, was associated with high-risk phenotype and poor outcome in 

all patients and validated in a Caucasian-only subanalysis. In multivariate 

testing, this SNP abrogated the PC1 association with EFS (p � 0.18). 

Conclusions: A SNP with high divergence between ancestral populations on 

chromosome 6p22 accounts for the observed racial disparity in survival and 

is also a common genetic variant associated with survival in patients 

derived from either European or African ancestry (Bonferroni adjusted p � 

0.05). Studies to elucidate the function of this SNP are underway. 


Use of whole genome sequencing to identify novel mutations in distinct 

subgroups of medulloblastoma. Presenting Author: Giles W. Robinson, St. 

Jude Children’s Research Hospital, Memphis, TN 

Background: Medulloblastoma is a malignant childhood brain tumor comprising 

four discrete subgroups (SHH-subgroup, WNT-subgroup, subgroup-3 

and subgroup-4). The genetic alterations that drive these subgroups 

and that might serve as treatment targets are largely unknown. Methods: We 

sequenced entire genomes of 37 tumors and matched normal blood. 136 

somatically mutated genes identified in this discovery cohort were sequenced 

in an additional 56 medulloblastomas. All tumors were classified 

into the 4 subgroups by expression profiling and immunohistochemistry. All 

mutations were validated by custom capture, 454, or Sanger sequencing. 

Results: Recurrent mutations were detected in 49 genes: 41 are not yet 

implicated in medulloblastoma. Several target distinct components of the 

epigenetic machinery in different disease subgroups, e.g., regulators of 

H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and 

ZMYM3), and CTNNB1-associated chromatin remodellers in WNTsubgroup 

tumors (e.g., SMARCA4 and CREBBP). Modelling of mutations in 

mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, 

identified genes that maintain this cell lineage (DDX3X) as well as mutated 

genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. 

Conclusions: We have identified several new recurrent somatic mutations 

that are enriched in specific subgroups of medulloblastoma. Alterations 

affecting subgroup-3 and 4 tumors appear to disrupt chromatin marking, 

most notably H3K27me3 , potentially preserving a stem cell-like state in 

tumor cells. Mutations in WNT subgroup tumors affect binding partners of 

CTNNB1 that regulate WNT-response gene transcription. These data 

provide important new insights into the pathogenesis of medulloblastoma 

subgroups and highlight targets for therapeutic development. 


Phase II study of temozolomide in combination with topotecan (TOTEM) in 

relapsed or refractory neuroblastoma and other pediatric solid malignancies: 

A European ITCC study. Presenting Author: Angela Di Giannatale, 

Institute Gustave Roussy, Villejuif, France 

Background: Temozolomide and topotecan have shown activity in several 

pediatric cancers, including neuroblastoma. Resistance to alkylating agents 

due to MGMT expression, MMR deficiency or microsatellite instability may 

be overcome through the combination with topoisomerase I inhibitors. The 

combination of temozolomide and topotecan (TOTEM) was well tolerated 

and showed preliminary activity in children with neuroblastoma and glioma 

(Rubie et al, 2010). Methods: This multicenter, non-randomized, multicohort 

Phase II study included children with neuroblastoma according to a 

2-stage Simon design, and patients with central nervous system (CNS) and 

extra-cranial solid tumors in a descriptive design. Temozolomide was 

administered orally at 150 mg/m2 followed by topotecan at 0.75 mg/m2 

intravenously for 5 consecutive days every 28 days. The main endpoint was 

objective response (OR), i.e., Complete or Partial Response (CR�PR), 

evaluated after 2 cycles according to WHO criteria, or INRC criteria for 

neuroblastoma patients with mIBG-positive lesions, by an independent 

radiological review. Independent review of mIBG imaging is pending. 

Results: 103 patients, median age 9.4 years (range 1-21), were treated 

between June 2009 and May 2011 in 18 centers: 38 neuroblastoma, 33 

CNS tumors and 32 other solid tumors. Overall 420 cycles were administered 

(median 3 per patient; range 1-12). Grade 3 or 4 neutropenia was 

frequent (55% courses), though only 6% of patients developed febrile 

neutropenia. In the neuroblastoma cohort, 1 CR and 7 PR were observed, 

leading to an estimated OR rate of 21% (95%CI, 10-37%). Additionally 22 

patients had disease stabilization (SD), leading to an overall tumor control 

(CR�PR�SD) of 79% (63-90%), and a 12-month progression-free survival 

rate of 47% (31-64%). Overall, 17/102 evaluable patients achieved 

an OR (17%, 10-25%), with 1 CR and 3 PR in 9 medulloblastoma (44%, 

14-79%), 2 PR in 4 PNET, 1 PR in 12 malignant glioma, and 2 PR in 9 

RMS. Conclusions: Temozolomide-topotecan combination results in significant 

tumor control in children with neuroblastoma and medulloblastoma/ 

PNET with favorable toxicity profile. 


A phase I/II study of LDE225, a smoothened (Smo) antagonist, in pediatric 

patients with recurrent medulloblastoma (MB) or other solid tumors. 

Presenting Author: Birgit Geoerger, Institut Gustave Roussy, Villejuif, 

France 

Background: Hedgehog (Hh) signaling is crucial in the development and 

homeostasis of many human organs and tissues. Aberrant Hh signaling is 

involved in tumorigenesis through promotion of cell proliferation, survival, 

and differentiation in wide range of human cancers, including approximately 

30% of MBs. LDE225 is a potent and selective inhibitor of Smo, a 

key positive regulator of Hh signaling. The phase I is exploring the safety 

and pharmacokinetics of LDE225 in pediatric patients with advanced solid 

tumors that are potentially dependent on Hh signaling. Preliminary data 

from the ongoing phase I are presented. Methods: Dose-escalation was 

performed according to a Bayesian design starting at 372 mg/m2 of 

continuous once daily oral LDE225. Safety and preliminary efficacy of 

LDE225 at the maximum tolerated dose will be assessed in pediatric and 

adult patients with recurrent MB in a phase II expansion part. Pharmacokinetic 

profiles were performed at Day 1 and 21. Tumor samples were 

analyzed for Hh pathway activation status using a 5-gene Hh signature 

assay. Results: Thirty-three patients (24 MB, 3 rhabdomyoscarcoma [RMS], 

3 osteosarcoma, and 1 each of neuroblastoma, gliomatosis and oligoastrocytoma) 

with a median age of 13 years (range, 4–17 y) have enrolled. 

Dose-limiting toxicity of Grade 4 creatine phosphokinase elevation occurred 

in 1 RMS patient out of 7 patients treated at 372 mg/m2 .No 

dose-limiting toxicity was observed at 233 and 425 mg /m2 . LDE225 at 

233 and 372 mg/m2 was absorbed with a median Tmax of 2 h (range, 1–24 

h). Systemic exposures were comparable with adults. Two MB patients 

achieved a confirmed complete response (CR) at doses of 372 and 425 

mg/m2 . Analysis of 14 available MB tumor samples using the 5-gene Hh 

signature assay showed that the 2 CR patients have Hh-activated tumor. 

The remaining 12 tumor samples were from patients who did not achieve 

response and were determined to be Hh pathway non-activated. Conclusions: 

LDE225 is well tolerated in pediatric patients with advanced malignancies. 

Preliminary data show promising efficacy in medulloblastoma patients and 

support the use of the 5-gene Hh signature assay as a pre-selection tool in 

future trials. 



Real-time dynamic and sequential tracking of tumor propagation and 

associated immune responses in the CNS microenvironment. Presenting 

Author: Alex Yee-Chen Huang, Case Western Reserve University, Cleveland, 

OH 

Background: Ex vivo experimental systems are often unable to fully capture 

complex intercellular communication between tumor cells and surrounding 

tissues - a critical feature in understanding cancer development and 

immune evasion. Imaging modality such as bioluminescence lacks the 

resolution necessary to discern subtle structural differences and heterogeneity 

in the tumor niche. Microscopic examination of fixed specimens is 

devoid of the 3-dimensional context or evolution of tumor progression 

within the same host. Methods: New insights have come from studies 

involving the use of intravital 2-photon laser scanning microscopy (2P- 

LSM), which allows deep visualization (�300um) with single-cell resolution 

(�1um), thus enables direct observation of cellular behavior in intact 

tissues at a suitable dynamic spatial-time resolution. We study the role of 

tumor niche in shaping immune repertoire and develop strategies to modify 

tumor niche to enhance anti-tumor immunity. Results: One example is our 

study of glioblastoma multiforme (GBM), which contains a cellular hierarchy 

with a CD133� sub-population representing self-renewing and tumorigenic 

GBM stem cells (GSCs). In a xeno-transplant model, GSC was 

capable of tumor initiation in the mouse brain. To directly test the relative 

tumorigenic potential of GSCs (CD133�) and non-GSCs (CD133- ), we 

inoculated paired tumor populations from the same primary GBM tumor 

cells and monitored tumor competition by serial 2P-LSM through implanted 

cranial windows. Serial 2P-LSM imaging shows that after 35 days, 

GBM formation was driven exclusively by GSCs but not non-GSCs. To 

interrogate tumor-associated immune responses, we inoculated syngeneic 

mouse glioma tumors into C57BL/6 mice. Using this and CNS-inflammatory 

models, we have begun to undercover the role of perivascular 

antigen-presenting cells and microglia in guiding the recruitment of 

CNS-bound lymphocytes. Conclusions: Our data provide the first direct 

functional evidence that CSCs are responsible for tumor propagation in 

GBM, and represent an in vivo experimental platform to monitor immunotherapeutic 

interventions. 


11:30 AM-12:30 PM 

Outcome of 116 cases of pleuropulmonary blastoma type I and type Ir 

(regressed): A report from the International PPB Registry (IPPBR). Presenting 

Author: Yoav H. Messinger, Children’s Hospitals and Clinics of 

Minnesota, Minneapolis, MN 

Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung 

neoplasm of early childhood with progression from a purely cystic Type I 

(T-I) lesion to cystic solid and solid high grade sarcoma (Type II and Type 

III). A regressed form of PPB (T-Ir) has been recognized pathologically. The 

outcome of both T-I and T-Ir has been only partially described. Methods: 

Retrospective analysis of 345 IPPBR cases showed 116 T-I or T-Ir. In all 

cases the PPB diagnosis was made on surgically removed cysts. The 

treating physician decided whether to use chemotherapy after surgery. 

Results: The pathologic diagnosis of the 91 PPB T-I and 25 T-Ir is now 

confirmed by central review (LPD and DAH). Patients with T-I were younger 

than T-Ir (median: 8 months vs. 48 months).Diagnosis after age 6 years 

included only one T-I compared to 10 T-Ir patients. Therapy is not known 

for 28 T-I and 2 T-Ir. Surgery was followed by chemotherapy in 31 T-I and 2 

T-Ir. Six (5%) recurred with the same type, all were alive at last follow-up: 5 

(5.5%) T-I, 1 (4%) T-Ir. Progression to high-grade Type II or III occurred in 

9/91 (10%) T-I and 2/25 (8%) T-Ir. The addition of chemotherapy did not 

significantly reduce progressions (Fisher’s exact test). All of the tumor 

progressions were seen by 75 months of age; this finding is similar to 

broader IPPBR data: � 95% of patients are diagnosed with Type II/III by 

72 months of age. Of the 9 patients with T-I who progressed, 5 ultimately 

died, whereas the 2 T-Ir who progressed were alive. At last follow-up 

111/116 (95.6%) were alive. Conclusions: A cyst in an older individual 

most likely will be Type Ir. Type I and Type Ir are clinically similar with a 

small risk of progression to the advanced Type II/III up to 6 years of age. 

Outcome for those whose cystic PPBs progressed is poor. The role of 

chemotherapy remains uncertain for the prevention of progression in the 

pure cystic PPB Type I or Ir. 

Upfront chemotherapy and progression. 

Progression No progression Total 

Type I: 

Surgery � chemotherapy 2 29 31* 

Surgery only 6 25 31 

Unknown 

Type Ir: 

1 27 28 

Surgery � chemotherapy 1 1 2** 

Surgery only 1 19 20 

Unknown 0 2 2 

Excluding 2 chemotherapy treated patients: for 2nd malignancy*, and for concurrent rhabdomyosarcoma** 


611s 


11:30 AM-12:30 PM 

Effect of radiation on outcome of types II and III PPB: A report from the 

International Pleuropulmonary Blastoma Registry. Presenting Author: 

Gretchen M. Williams, Children’s Hospitals and Clinics of Minnesota, 

Minneapolis, MN 

Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung 

neoplasm of early childhood with progression from a purely cystic (Type I) 

lesion to a solid high-grade sarcoma Type III (T-III), or a mixed solid/cystic 

stage Type II (T-II). Surgery and chemotherapy are required for T-II and 

T-III PPB, but the benefit of radiation therapy for T-II and T-III PPB is 

debated and is being evaluated in this study. Methods: This is a retrospective 

analysis of central pathology-reviewed Types II and III PPB from the 

IPPBR. Treatments were chosen by physician, were not randomized, and 

included surgery and chemotherapy. The outcome of patients treated with 

upfront radiation (before progression or relapse) was compared to patients 

who did not receive radiation. Event-free survival (EFS) and overall survival 

(OS) were determined to last follow-up, using the Kaplan-Meier analysis, 

with log-rank test. Results: Outcome for 212 patients (117 Type-II and 95 

Type III) was significantly better for T-II than T-III: EFS for T-II was 68.1% 

vs. T-III 45.7% (P�0.002), and OS for T-II was 75.2% vs. T-III 57.9% 

(p�0.01). Excluding patients with incomplete therapy information, 174 

were treated with surgery and chemotherapy. Of these 44 (25%) also 

received radiation therapy; 130 patients did not. The table below shows 

comparison of radiated vs. non-radiated. Radiation provided no additional 

survival benefit, overall or by tumor Type. Multivariate analysis showed that 

gender and extent of primary tumor resection (biopsy vs. gross total 

resection) had no effect on outcome, however T-II vs. T-III retained 

prognostic significance. Conclusions: For this collection of advanced-type 

PPB, outcome is significantly better for T-II than T-III. For patients treated 

initially with surgery and chemotherapy, adding radiation therapy offered 

no improvement in event-free or overall survival. Limitations of this study 

include its retrospective nature and non-uniform treatment regimens. 

Non-radiated Radiated P (log-rank) 

All patients (n�174) EFS 55.5% 46.1% 0.312 

OS 63.1% 63.6% 0.952 

Type II (n�90) EFS 65.8% 46.7% 0.096 

OS 70.7% 66.7% 0.651 

Type III (n�84) EFS 41.8% 46.4% 0.452 

OS 52.7% 62.1% 0.405 


11:30 AM-12:30 PM 

Increase in the incidence of differentiated thyroid carcinoma in children, 

adolescents, and young adults (AYA): A population-based study. Presenting 

Author: Lucas B. Vergamini, Faculdade de Ciencias Medicas da Santa Casa 

de Sao Paulo, Sao Paulo, Brazil 

Background: Studies have shown an increase in thyroid cancer incidence 

among adults since the 1990s. However, few studies have evaluated this 

occurrence among children and AYA. Increases resulting from enhanced 

detection are most likely to involve small tumors. The objective of this study 

is to investigate trends in incidence of differentiated thyroid carcinomas in 

children and AYA by size and sex. Methods: This is an ecological time-trend 

study. Cases of differentiated thyroid cancer (1984-2008) in patients 

younger than 30 years old were selected from SEER 9 cancer registries 

using International Classification of Diseases for Oncology 3rd edition 

(ICD-O-3) codes for papillary and follicular cancers (codes 8050/3, 

8052/3, 8130/3, 8260/3, 8290/3, 8330-8332/3, 8335/3, 8340- 

8344/3, 8450/3 and 8452/3). Patients who had multiple primary tumors 

were excluded from the study. SEER*Stat software was used to calculate 

age-standardized rates (estimated per 1,000,000 persons; World Standard 

Population) and annual percentage changes (APC) were calculated using 

Joinpoint model. Results: Rates ranged from 2.77 (1990) to 7.45 (2002) 

for males and from 17.19 (1987) to 41.3 (2008) for females. Overall, a 

significant increasing trend in incidence was observed for females 

(APC�3.20, 95%CI 2.80, 3.60). When a stratified analysis based on 

tumor size was performed, significant increasing trends were noted for the 

following categories: 0.5-0.9 cm (Males: APC�3.50, 95%CI 1.50, 5.40; 

Females: APC�7.30, 95%CI 5.90, 8.80), 1.0-1.9 cm (Males: APC�3.20, 

95%CI 1.00, 5.40; Females: APC�2.90, 95%CI 2.20, 3.70), and � 2cm 

(Males: APC�1.30, 95%CI 0.30, 2.40; Females: APC�2.50, 95%CI 

1.70, 3.20). However, no statistically significant trends were noted for 

tumors �0.5 cm (Males: APC�2.50, 95%CI -0.30, 5.40; Females: 

APC�2.0, 95%CI -6.90, 11.80). Conclusions: Incidence rates for differentiated 

thyroid carcinoma are also increasing among children and AYA in the 

United States. The absence of increasing trends for small tumors (� 0.5cm) 

rules out diagnostic scrutiny as the only explanation for the observed 

results. Environmental, dietary and genetic factors should be investigated. 




11:30 AM-12:30 PM 

Treatment of pediatric stage IA lymphocyte-predominant Hodgkin lymphoma 

with surgical resection alone: A report from the Children’s Oncology 

Group. Presenting Author: Burton Appel, Hackensack University Medical 

Center, Hackensack, NJ 

Background: Lymphocyte-predominant Hodgkin lymphoma (LPHL) is an 

uncommon histologic subtype comprising up to 10% of cases in pediatric 

series. Patients with LPHL typically present with low stage disease and are 

responsive to regimens used for classical HL. Recurrence is uncommon; 

secondary malignant neoplasms or evolution to non-Hodgkin lymphoma are 

more common events. Small retrospective studies have suggested that 

some patients with stage I LPHL can be cured with surgery alone. We report 

the results of a large prospective study using a treatment algorithm in which 

a selected subset of patients received surgery alone. Methods: Patients ages 

0-21 years with newly-diagnosed, low risk LPHL were eligible for 

AHOD03P1. Low risk was defined as clinical Stage IA and IIA in the 

absence of bulk disease (a mediastinal mass � 1/3 of the thoracic diameter 

or a nodal aggregate � 6 cm). Central pathology review was performed to 

confirm LPHL histology. Baseline evaluations included CT and FDG-PET. 

Patients with Stage IA disease in a single node that was completely 

resected were observed without further therapy. Total resection (TR) was 

confirmed by rapid central review of CT and FDG-PET. In some cases the 

extent of resection was equivocal; repeat imaging 6-7 weeks after initial 

evaluation was used to allocate such patients to either observation or 

chemotherapy. Patients who recurred were assigned to treatment with 3 

cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). 

Results: Between January 2006 and November 2010, 52 patients with 

Stage IA, single node LPHL were enrolled with a confirmed TR. Nine 

patients have experienced a relapse; 8 were Stage I and 1 was Stage II at 

relapse. The median time to relapse was 10 (range 1-17) months. The 

median follow up among the 43 remaining patients is 26 (range 4-60) 

months. The current 2 year EFS estimate among these patients is 80.3% 

(95% CI: 65.3% -89.3%). Overall survival for the 52 patients is 100%. 

Conclusions: With this strategy of surgical resection followed by observation 

in a highly select cohort of pediatric LPHL, up to 80% of patients may be 

spared chemotherapy. Follow up is limited but overall survival to date is 

excellent. 


11:30 AM-12:30 PM 

Dietary intake and metabolic syndrome in adult survivors of childhood 

cancer. Presenting Author: Webb A. Smith, St. Jude Children’s Research 

Hospital, Memphis, TN 

Background: Childhood cancer survivors (CCS) are at increased risk for 

metabolic syndrome (MetSyn) and increased morbidity and mortality from 

cardiovascular disease. Following a heart healthy diet may decrease this 

risk. The purpose of this investigation was to characterize dietary patterns 

and to evaluate the association between diet and MetSyn among CCS. 

Methods: CCS who were 10� year survivors of childhood cancer, who were 

older than 18 years of age, and participating in the St. Jude Lifetime Cohort 

Study (SJLIFE). They completed a medical assessment based on Children’s 

Oncology Group screening guidelines, and a food frequency questionnaire 

(FFQ). Laboratory and physical measures were obtained to determine 

MetSyn status using the NCEP-ATPIII criteria. Participants were classified 

as having MetSyn if they met the criteria for �3 components of MetSyn. 

Data from the FFQ were used to score dietary patterns according to 

WCRF/AICR recommendations. Those who met �4 of the 7 recommendations 

were classified as following a “healthy diet.” A stratified analysis by 

sex using log-binomial regression models was undertaken to evaluate 

associations between diet and MetSyn, adjusted for age, age at diagnosis, 

cranial radiation, education, household income, and smoking status. 

Results: Among 1421 participating CCS (49.3% male, median age 33.0 

years, range, 18.9-60.0 years), 31.5% met the criteria for MetSyn and 

25.8 % followed a healthy diet according to the WCRF/AICR recommendations. 

In multiple regression models stratified by sex, females who followed 

a “healthy diet” were 2.1 (95% CI 1.5-2.9) times less likely and males who 

followed a “healthy diet” were 2.2 (95% CI 1.5-3.1) times less likely to 

have MetSyn than those who reported following a “healthy diet”. Conclusions: 

Heart healthy diets in CCS are associated with decreased risk for MetSyn. 

Dietary interventions may be warranted in CCS with MetSyn. 


11:30 AM-12:30 PM 

Family history of cancer and clinical outcome in pediatric oncology. 

Presenting Author: Joshua David Schiffman, Huntsman Cancer Institute, 

University of Utah, Salt Lake City, UT 

Background: We previously reported in a small study (n�363) that children 

diagnosed with cancer who have a family history of cancer (FHC) may have 

worse prognosis than those without FHC, specifically children diagnosed 

with Hodgkin Disease (HD) and acute lymphoblastic leukemia (ALL) 

(Eichstadt et al., ASCO 2009). The Utah Population Database (UPDB), a 

unique resource, includes a Surveillance Epidemiology and End Results 

(SEER) registry (the Utah Cancer Registry) record-linked to extensive 

genealogies for 6.5 million people in which most Utah families are 

represented. A majority of pedigrees include �3 generations and several 

span 7� generations. The UPDB provides an accurate, objective assessment 

of FHC. We expanded our original study by examining cancer 

mortality of 4,482 pediatric cases (age �18) diagnosed from 1966-2009 

with adequate follow-up (median 9.5 years) and family information. 

Methods: We compared survival from cancer-caused mortality for pediatric 

cases diagnosed from 1966-2009 with FHC of any cancer diagnosed �80 

yo in 1st-degree, 2nd-degree, or 3rd-degree relatives to pediatric cases 

without FHC. Nonparametric estimates of survivor function were determined 

by the life-table method and a log-rank test of homogeneity was used 

to test for differences between pediatric probands with FHC compared to no 

FHC. Results: Overall survival was significantly lower in children with 

positive FHC (n�1,128) than in children with no FHC (n�3,354) independent 

of stage (p�0.0001; 10yr survival, 69% with FHC vs.78% with no 

FHC). We observed lower survival in children with any leukemia and FHC 

(n�279) compared to children with leukemia and no FHC (n�871; 

p�0.0001). In particular, cases with ALL and FHC had lower survival 

(p�0.0001; 10yr survival, 61% vs. 75%). Pediatric lymphoma cases had 

lower survival when positive for FHC (n�150) vs. no FHC (n�428; 

p�0.0001), specifically for an HD diagnosis (p�0.0004; 10yr survival, 

83% vs. 94%). Conclusions: Pediatric cancer cases with FHC of any cancer 

(children or adults) have decreased survival compared to cases with no 

FHC, specifically in children diagnosed with ALL or HD, thus validating our 

earlier findings. Familial factors likely contribute to increased pediatric 

cancer mortality. 


11:30 AM-12:30 PM 

Association of bone mineral density with incidental renal stone in long-term 

survivors of childhood acute lymphoblastic leukemia. Presenting Author: 

Prasad Laxman Gewade, St. Jude Children’s Research Hospital, Memphis, 

TN 

Background: With 5-year survival of childhood acute lymphoblastic leukemia 

(ALL) now exceeding 90%, long term morbidities are of growing 

concern. Both low bone mineral density (BMD) and renal dysfunction have 

been reported in ALL survivors. Our objective was to evaluate the association 

between low BMD and incidental renal stones, a known predictor of 

renal dysfunction. Methods: Adult participants who were 10� year survivors 

of childhood ALL and members of St. Jude Lifetime Cohort study were 

recruited between 12/2007 and 3/2011. During their risk-based medical 

evaluations they underwent quantitative computed tomography (QCT) to 

evaluate BMD. Incidental renal stones were identified by radiologists’ 

review of axial QCT source images. Demographic information was abstracted 

from responses to health surveys and dietary intake from a Block 

food frequency questionnaire. Association between BMD and renal stones 

was evaluated in a multivariable logistic regression model. Confounding 

variables were selected using directed acyclic graphs and change in effect 

estimates strategy. Results: At a median of 26.1 years from diagnosis, BMD 

Z score of � 1 standard deviation (SD) was detected in 77/662 (11.6%) 

and renal stones in 73/662 (11%) participants. In a multivariable model 

adjusted for age, dietary vitamin D and renal radiation, when compared to 

BMD Z score � 1 SD, the risk of renal stones increased with a decrease in 

BMD Z-score; 1 to 0 SD (Odds Ratio (OR), 1.93; 95% confidence interval 

(CI), 0.69 to 5.41), 0 to -1 SD (OR, 1.46; 95% CI, 0.52 to 4.05), -1 to -2 

SD (OR, 2.72; 95% CI, 0.81 to 6.41), and � -2 SD (OR, 4.96; 95% CI, 

1.43 to 17.13). Older age (45-54 vs.18-24 y; OR, 3.66; 95% CI, 1.10 to 

12.15), renal radiation (OR, 1.97; 95% CI, 0.59 to 6.50) and � 141.5 IU 

intake of vitamin D (OR, 1.65; 95% CI, 0.98 to 2.77) were also associated 

with renal stone formation. Conclusions: Our results not only help us 

recognize survivors at risk, but also informs radiologists to be vigilant of 

incidental renal stones among older ALL survivors with low BMD. 



11:30 AM-12:30 PM 

Renal carcinoma following therapy for cancer in childhood: A report from 

the Childhood Cancer Survivor Study. Presenting Author: Carmen Louise 

Wilson, St. Jude Children’s Research Hospital, Memphis, TN 

Background: Limited data exists describing the incidence of and risk factors 

for subsequent renal carcinoma among long-term survivors of childhood 

cancer. Methods: The study included 14,351 five-year survivors of childhood 

cancer diagnosed between 1970 and 1986 who participated in the 

Childhood Cancer Survivor Study. Chemotherapy and radiotherapy exposures 

were abstracted from medical records; total dose of radiation to the 

renal beds was estimated by a radiation physicist. Standardized incidence 

ratios (SIRs) were calculated using age-, sex-, and calendar-specific 

incidence data from the Surveillance, Epidemiology and End Results 

(SEER) program. Cumulative incidence was calculated treating death as a 

competing risk. Poisson regression analyses were used to assess associations 

between diagnosis and treatment characteristics and the risk of 

subsequent renal carcinoma while adjusting for changes in risk due to age. 

Results: Twenty-six survivors were diagnosed with a renal carcinoma at a 

median follow-up of 19.3 years (range: 1 month to 34.3 years) from study 

entry at 5 years post diagnosis. Eight patients received �5Gy radiotherapy 

to a renal bed, 16 received chemotherapy, seven of whom seven received 

both radiotherapy �5Gy and chemotherapy. Cumulative incidence of renal 

carcinoma at 20 years was 0.16% (95% CI 0.12-0.20). The SIR was 8.1 

(95% CI 5.3-11.8) comparing survivors to the general population. Highest 

risk for renal carcinoma was observed among survivors of neuroblastoma 

(SIR 87.1, 95% CI 38.4-175.2), non-Hodgkin lymphoma (SIR 9.3, 95% 

CI 1.9-27.4), and bone tumors (SIR 7.0, 95% CI 1.4-20.4). In multivariable 

analyses, the risk of subsequent renal carcinoma was elevated among 

survivors exposed to platinum-based chemotherapy (Rate Ratio 3.1, 95% 

CI 0.9-10.6) or renal bed radiotherapy �5Gy (RR 3.6, 95% CI 1.5-8.4). 

Conclusions: While cumulative incidence is low, survivors of childhood 

cancer are at an eight-fold increased risk for subsequent renal carcinoma 

compared to the general population. In addition to a primary diagnosis of 

neuroblastoma, radiotherapy directed to the renal bed increased the risk for 

renal carcinoma. 


11:30 AM-12:30 PM 

Effect of dexraoxane on impaired mitochondrial structure and function in 

doxorubicin-treated childhood ALL survivors. Presenting Author: Steven E. 

Lipshultz, Department of Pediatrics, University of Miami Miller School of 

Medicine, Miami, FL 

Background: Cardiotoxicity in doxorubicin (DOX)-treated long-term childhood 

cancer survivors is characterized by impaired cardiac function which 

is partly mediated by mitochondrial (mt) energy production. Preclinical 

studies show irreversible DOX-associated cardiac mt dysfunction. A response 

to impaired mt function is to increase the mtDNA copies/cell 

(mtDNA). We examined mtDNA and function in peripheral blood mononuclear 

cells (PBMCs) in childhood survivors of high-risk ALL who received 

DOX alone or DOX plus dexrazoxane (DOX/DEX). Methods: Patients with HR 

ALL treated on DFCI Childhood ALL protocols from 1987-2005 were 

eligible for this study. PBMCs mtDNA and oxidative phosphorylation 

(OXPHOS) NADH dehydrogenase (CI) and cytochrome c oxidase (CIV) 

activities were measured by RT-PCR and immunoassays respectively. A 

Wilcoxon rank-sum test was used to compare continuous measures between 

groups. Models for mitochondrial parameters were based on maximum 

likelihood variance component estimation and were adjusted for 

patient characteristics. Results: 64 patients provided samples at a median 

follow-up of 7.8 (2.9-30.2) years. 58% received DOX/DEX. Median 

cumulative DOX dose was 300 mg/m2 . A significant difference was 

detected between groups for mtDNA (p�0.001, adjusted p�0.015). 

MtDNA medians for the DOX and DOX/DEX groups were 1106.3 and 310.5. 

No significant differences were found between groups for CI or CIV 

activities. Conclusions: DOX-treated survivors have increased mtDNA consistent 

with impaired mt function, which is abrogated by concurrent use of 

DEX. The use of DOX/DEX is associated with lower mtDNA. Due to a 

compensatory increase in mtDNA to augment mt function, overall mt 

function is not different between groups. This compensatory mechanism in 

7.8-year survivors at risk for cardiac dysfunction is concerning over their 

subsequent lifespan. 

N 

DOX 

Median (range) N 

DOX/DEX 

Median (range) P 

mtDNA 27 1106.3 (144.2-6746.8) 35 310.5 (15.3-1859.2) 0.001 

CI activity (OD/mg x 10 3 ) 25 10.5 (5.0-31.3) 33 11.7 (5.0-41.4) 0.97 

CIV activity (OD/mg x 10 3 ) 25 9.8 (5.0-20.1) 34 8.1 (4.7-23.4) 0.40 


613s 


11:30 AM-12:30 PM 

A longitudinal study of anthracycline cardiotoxicity in pediatric Ewing 

sarcoma. Presenting Author: Tanya Renae Brown, British Columbia Children’s 

Hospital, Vancouver, BC, Canada 

Background: Trends in cardiac function over time have not been previously 

described in Ewing sarcoma. Our cohort is unique as all the cardiac 

evaluations occurred systematically in one tertiary cardiology unit during a 

28 year period. Objectives: 1.To evaluate the cardiac functional trends in 

the cohort at baseline, during treatment and in surveillance. 2.To evaluate 

the risk factors associated with cardiac toxicity. Design: Received ethics 

approval for a retrospective chart review of all patients less than 17 years, 

diagnosed with Ewing sarcoma from 1978-2006, treated initially at British 

Columbia Children’s Hospital . Methods: There was complete data on 71/79 

eligible patients. Echocardiograms were recorded at 5 time points: pre 

treatment, worst function during treatment, on therapy completion, worst 

function during surveillance and the most recent echocardiogram. Cardiac 

toxicity was graded using CTCAE v 4.0. The statistical analysis with SAS 

software v 9.2 calculated the chi square and odds ratios to explore a 

possible association between exposure and outcome. Results: Median age 

at diagnosis 11.1 yrs (2.2-16.1 yrs), 52% female, metastatic in 17, overall 

survival 74% at 10yrs. A total of 397 echocardiograms were performed with 

244 (61%) being normal and 153 (39%) being abnormal. The median 

cumulative dose of anthracyclines was 365mg/m2 . Grade 1-5 cardiomyopathy 

occurred in 42 (59%) patients. Grade 3-5 toxicity occurred in 11 

(15%) patients on chemotherapy completion increasing to 23 (32%) 120 

months post diagnosis. The median time to the worst cardiac function was 

51months (2-183). Four of 19 (20%) deaths were cardiac related 

including 2/3 cardiac transplants. Conclusions: Symptomatic cardiac 

toxicity increased from 20% noted in our earlier Ewings cohort (Kakader et 

al. 1997) to 32% with longitudinal evaluation assessments. Significant 

and progressive cardiac toxicity occurred after completion of chemotherapy. 


11:30 AM-12:30 PM 

Tumor location and neurocognitive impairment in adult survivors of 

pediatric brain tumors: A report from the St. Jude Lifetime Cohort (SJLIFE). 

Presenting Author: Tara M. Brinkman, St. Jude Children’s Research 

Hospital, Memphis, TN 

Background: Follow-up guidelines identify supratentorial tumor location as 

a risk factor for poor neurocognitive outcomes during childhood; yet few 

studies have systematically compared long-term cognitive outcomes between 

adult survivors of childhood infratentorial and supratentorial brain 

tumors. Methods: Neurocognitive functions were evaluated in 130 adult 

survivors of pediatric brain tumors (58 supratentorial and 72 infratentorial, 

mean [SD] current age � 27.4 years [5.2], age at diagnosis � 8.6 years 

[4.6], and time since diagnosis � 18.8 years [4.8]) participating in the 

SJLIFE long-term follow-up protocol. Age-adjusted standard scores for 

measures of intelligence, attention, memory, processing speed, and executive 

functioning were calculated, with clinical impairment defined as scores 

�10th percentile. Odds ratios (OR) and 95% confidence intervals (CI) were 

calculated using multivariable logistic regression models to examine 

associations between neurocognitive functions and tumor location. Results: 

As a group, survivors performed below average across multiple neurocognitive 

domains, including full scale IQ (mean�88.1; SD�18.2), with 34% 

demonstrating impaired IQ. Survivors of infratentorial tumors were more 

likely to be impaired on measures of focused attention (OR�2.19, 95% 

CI�1.03-4.65) and fine motor dexterity (OR�2.62, 95% CI�1.21-5.66) 

compared to survivors of supratentorial tumors. After adjusting for sex, age 

at diagnosis, shunt placement and cranial radiation (yes/no), infratentorial 

tumor location was only associated with reduced performance on a task of 

visual abstract reasoning (OR�3.76, 95% CI�1.40-10.1). Cranial radiation 

therapy was independently associated with impaired short-term 

memory (OR�15.6, 95% CI�1.64-147.8) and processing speed 

(OR�3.86, 95% CI�1.15-13.0). Conclusions: Tumor location was not 

associated with neurocognitive impairment after adjusting for treatment 

exposures. To further delineate potential differences associated with tumor 

location, future studies will examine factors including radiation dose/ 

volume, extent of surgical resection, and medical complications. 




11:30 AM-12:30 PM 

Parent-reported cognition and its clinical applications in pediatric oncology. 

Presenting Author: Jin-Shei Lai, Northwestern University, Chicago, IL 

Background: Parent-reported cognitive function (PCF) of their child’s 

cognitive abilities is often used to trigger referral for comprehensive 

neuropsychological evaluation. The purpose of this study was to evaluate 

the clinical utility of PCF to predict impairment as measured by neuropsychological 

assessment and to identify factors associated with PCF. Methods: 

565 patients (53% brain tumor, BT; 47% other types of cancer, non-BT) 

aged 7-21 (mean�14 yrs; 56% males) and their parents were recruited. 

34% received radiation therapy, 72% chemotherapy and 71% surgery. 

Mean years since diagnosis� 5.7 yrs. PCF was measured using a 43-item 

pediatric perceived cognitive function item bank (pedsPCF). Parents 

completed the pedsPCF and a single item to rate their child’s quality of life 

(QOL). Patients completed NINDS-NeuroQOL Depression, PedsQL Fatigue 

scales and neuropsychological tests (NPT) of psychomotor function, 

attention, learning and working memory using the CogState. K-Means 

clustering was used to group patients based on scores of depression, 

fatigue and pedsPCF. Results: PedsPCF significantly differentiated BT from 

non-BT, t�5.65, p�.01. Correlations between pedsPCF and NPT ranged 

from 0-0.66 (BT, � 1 yr diagnosis, psychomotor), depending on BT (vs 

non-BT), yrs since diagnosis and treatment, and NPT. Three clusters were 

identified with its own unique characteristics. Specifically, pedsPCF was 

significantly correlated w/ depression & fatigue for cluster 1; correlated w/ 

NPT scores for non-BT for cluster 2; and correlated w/ NPT for BT for 

cluster 3. Cluster membership of patients were significantly differentiated 

by Karnofsky rating, surgery (yes/no), QOL, parent education, child age, 

and child gender, but not types of treatment, and grade repetition (yes/no). 

Conclusions: This is one of the first studies to report an association between 

perceived cognitive function, using parent ratings, and neuropsychological 

performance. PedsPCF demonstrated clinical utility in differentiating 

between children with a brain tumor from children with other cancer types. 

PedsPCF has the potential to serve as a screening tool to facilitate efficient 

referral for comprehensive neurocognitive assessment. 


11:30 AM-12:30 PM 

Genome-based outcome prediction in MYCN nonamplified high-risk neuroblastoma. 

Presenting Author: Andres Eduardo Morales La Madrid, University 

of Chicago, Chicago, IL 

Background: Less than 40% of children with high-risk neuroblastoma 

achieve long-term survival, and at diagnosis, it is not possible to identify 

patients who will be cured. Microarray studies have proposed expression 

signatures associated with outcome within high-risk cohorts. However, 

integrating this technology as a clinical test has been difficult, in part due 

to the lack of available frozen tissue and high quality RNA. The nCounter 

overcomes this obstacle, using formalin-fixed paraffin embedded tissue 

(FFPE). Our objective is to test the correlation of a previously published 

“ultra high-risk” microarray gene signature developed in the MYCN 

nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 

2006) with the gene expression signature obtained with the nCounter 

(NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified 

high-risk neuroblastoma samples. Methods: FFPE tumor samples 

linked to clinical outcome data were obtained from 6 collaborative 

institutions. Tumor content of each sample was assessed morphologically. 

RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding 

to the candidate genes were designed by NanoString. Hybridization 

reactions were performed in duplicate using 100 ng of RNA. Positive 

and negative control probes and housekeeping probes were included in 

every reaction and were used to normalize data for differences in purification, 

hybridization, and capture efficiencies Results: Forty-two MYCN 

nonamplified high-risk neuroblastoma samples were analyzed by the 

nCounter. The cohort 5-year event-free survival and overall survival were 

44.6 �/- 8.0% and 53.8 �/- 8.4% respectively. Highly degraded RNA 

(RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle 

components analysis on normalized expression data showed differential 

expression of most of the genes with clustering of cases depending upon 

outcome (FDR � 0.05). Conclusions: Our results demonstrate that the 

nCounter can yield gene expression profiles that are similar to microarray 

gene signatures. Further investigation of the clinical utility the nCounter 

technology to prognosticate outcome in patients with high-risk neuroblastoma 

is warranted. 


11:30 AM-12:30 PM 

Outcome analysis of non-high-risk neuroblastoma patients enrolled on 

Children’s Oncology Group trials P9641 and A3961. Presenting Author: 

Holly Jane Meany, Children’s National Medical Center, Washington, DC 

Background: Patients with non-high-risk neuroblastoma (low- and intermediate-risk) 

generally have an excellent event free (EFS) and overall (OS) 

survival with current therapy. However, within this heterogeneous patient 

population, there are patients that may benefit from further therapy 

reduction and patients that may benefit from augmented therapy. Methods: 

Survival tree regression analysis was performed in patients enrolled on 

P9641 and A3961 with OS the primary endpoint. Univariate Cox proportional 

hazards models determined statistically significant prognostic factors. 

Secondary analysis of cases with MYCN non-amplified, non-high-risk 

neuroblastoma classified patients by age, INSS stage, Shimada histology 

and genomic features to determine 5-year EFS and OS. Favorable genomics 

were defined as hyperdiploid tumors without 1p or 11q loss of heterozygosity 

(LOH). Those with LOH at 1p or 11q or with a diploid DNA index were 

considered unfavorable. Patients without genomic data were excluded. 

Results: In the survival tree analysis, ploidy and genomic features were 

found to be statistically significant. In the secondary analysis, patients 

�18 months of age with stage 2 or 3, favorable histology tumors with 

favorable genomic profile had 5-year EFS and OS rates of 92.9�3.9% and 

100% respectively. Patients with stage 2 and 3 tumors, unfavorable 

histology and unfavorable genomic features had EFS of 68.4�8.0% and 

OS of 78.4�7.0%. Patients �12 months of age with stage 4 disease and 

either unfavorable histologic or genomic features had EFS of 69.1�5.4% 

and OS of 88.5�3.8%. Conclusions: Excellent outcomes in non-high-risk 

neuroblastoma patients with favorable histologic and genomic features 

suggest further reduction in therapy is possible in this cohort while 

maintaining survival and decreasing side effects. Select patients with 

unfavorable features have suboptimal OS and would benefit from modifications 

in therapy. Histologic and genomic criteria can be used to identify 

patients with non-high-risk neuroblastoma that may benefit from modifications 

in therapy. These data support the conduct of a cooperative group 

clinical trial to refine therapy for patients with non-high-risk disease. 


11:30 AM-12:30 PM 

Relationship of fusion protein status and outcome for children with 

intermediate-risk rhabdomyosarcoma: A Children’s Oncology Group report. 

Presenting Author: Stephen Skapek, University of Texas Southwestern 

Medical Center, Dallas, TX 

Background: Rhabdomyosarcoma (RMS) includes both alveolar (ARMS) 

and embryonal (ERMS) subtypes, with ARMS generally having a worse 

prognosis. Most ARMS express one of two fusion genes generated by 

balanced translocations fusing DNA binding domains of PAX3 or PAX7 with 

FOXO1 (P3F and P7F, respectively). The prognostic value of fusion gene 

versus histological subtype is not clear. We carried out a multi-institutional 

clinical trial through the Children’s Oncology Group (COG) to evaluate this 

molecular feature. Methods: All participants were enrolled on COG D9803 

from 1999-2005 for children and young adults with intermediate risk 

ARMS or ERMS, and were treated with vincristine, dactinomycin, and 

cyclophosphamide (�/- topotecan), radiotherapy, and surgery. Diagnostic 

specimens were reviewed centrally and fusion gene was assessed by 

fluorescence in situ hybridization (FISH), RT-PCR, or both. Event-free 

(EFS) and overall survival (OAS) at 5 years (yr) was correlated with histology 

and fusion gene status. Results: Of 327 cases included in a re-review of the 

pathology, 295 could be classified biologically. Cases with ARMS but 

unknown trans status (N�23) and those with mixed or RMS-NOS histology 

without trans (N�17) and 12 with inadequate clinical data were excluded. 

ARMS cases with detectable fusion gene were defined as ARMS P3F�, 

ARMS P7F�, while ARMSn was reserved for those without detectable 

fusion. P3F and P7F were not observed in ERMS. An additional 189 pts 

with ERMS tumors not re-reviewed were also included in the survival 

analysis. There was a trend toward better EFS for those with ARMSn than 

for ERMS (p�0.15); EFS for ARMS P3F� and P7F� were worse than that 

for ERMS (p�0.001). Only ALV P3F� cases had poorer OAS (p�0.004). 

Conclusions: ARMSn has an outcome similar to ERMS and a superior EFS 

compared to ARMS with P3F or P7F, when given therapy designed for 

intermediate risk RMS. This analysis, from a single, prospective trial 

restricted to those with non-metastatic disease and with near universal 

molecular evaluation, supports incorporating fusion status into treatment 

allocation. 

ERMS ARMSn ARMS P3F� ARMS P7F� 

N of patients 305 21 85 23 

5-yr EFS 77% 90% 54% 65% 

5-yr OAS 82% 89% 64% 87% 



11:30 AM-12:30 PM 

Association of chromosome complexity with age and metastasis in synovial 

sarcomas: Validation of expression and genomic prognostic signatures. 

Presenting Author: Fred Chibon, Bergonie Cancer Institute, Bordeaux, 

France 

Background: Synovial sarcoma (SS) is one of the rare sarcomas that occurs 

in adolescents as well as in adults. Nevertheless, metastasis occurs with a 

lowest frequency in the former, 10 vs 50% respectively. In almost all cases, 

a characteristic translocation t(X;18)(p11.2;q11.2) exists and the importance 

of this translocation in SS oncogenesis is well established, but the 

genetic basis of SS metastasis is still poorly understood. We recently 

published expression (CINSARC) and genomic (GI) signatures related to 

chromosome integrity control that predict outcome in undifferentiated 

sarcomas and GIST and ask whether these signatures could also predict 

outcome in SS. Methods: To asses this issue we selected in the European 

sarcoma database CONTICABASE 92 primary untreated SS for expression 

and genomic profiling. Results: As demonstrated by metastasis-free survival, 

CINSARC and GI have strong and independent prognostic values (p � 

1.6x10-5 and p � 4x10-6 , respectively). Comparing expression profiles of 

tumors with or without metastasis in a training series of 58 SS, a 52-genes 

signature was identified and validated in an independent series of 34 SS. 

Fourteen of these genes are common with CINSARC and these 52 genes are 

involved the same pathways than CINSARC, mitosis checkpoints and 

chromosome integrity. Comparing genomic profiles of adult versus pediatric 

SS we show that in both situations metastasis is associated to genome 

complexity and that the adult genome is highly more frequently rearranged. 

In line with this, the pediatric good-prognosis patients, according to GI, do 

not develop metastasis. Conclusions: Results clearly indicate that SS 

metastasis development is strongly associated with chromosome complexity 

and that CINSARC and GI are powerful prognostic factors. Data also 

mean that the metastasis frequency difference between adult and children 

likely is associated to the genome instability which is highly more frequent 

in adults. Finally, among these tree signatures, GI is potentially the best 

overall and clearly the most clinically relevant considering that CGH from 

FFPE samples is already used in the daily practice of pathology. 


11:30 AM-12:30 PM 

Conservative treatment of intraocular retinoblastoma: A prospective phase 

II randomized trial of neoadjuvant chemotherapy followed by local treatments 

and chemothermotherapy. Presenting Author: Isabelle Aerts, Institut 

Curie, Pediatric Oncology Department, Paris, France 

Background: intraocular retinoblastoma treatments often associate chemotherapy 

and focal treatments. The protocols vary and may combine two or 

three drugs, and different number of cycles associated to the local adjuvant 

treatments. A first prospective protocol of conservative treatments in our 

institution showed the efficacy of the use of two courses of chemoreduction 

with etoposide and carboplatin, followed by chemothermotherapy using 

carboplatin, as a single agent. In order to decrease the possible long term 

toxicity of chemotherapy due to etoposide, a prospective randomized phase 

II chemo reduction protocol was conducted, using vincristine and carboplatin 

vs. etoposide carboplatin. Methods: the study was proposed when initial 

tumour size or location did not allow the use of front-line local treatments. 

The phase II randomized study of reduction chemotherapy used vincristin 

carboplatin or etoposide carboplatin, followed by local treatment including 

chemothermotherapy using the combination carboplatin and laser diode 

hyperthermia. Primary endpoint was the need for secondary enucleation or 

EBRT not exceeding 40% at 2 years. The new treatment was considered 

sufficiently effective if 10 events or less were observed among 33 eyes. 

Results: 55 children, 65 eyes were included in the study (May 2004- 

August 2009).32 eyes (27 children) were treated conservatively in the arm 

etoposide-carboplatin and 33 (28 children) eyes in the arm vincristin 

carboplatin.At two years after treatment 23/33 (69.7%) eyes were treated 

and salvaged without EBRT or enucleation in the arm vincristin-carboplatin 

and 26/32 (81.3%) in the arm etoposide and carboplatin. Conclusions: 

neoadjuvant chemotherapy by two cycles of vincristine and carboplatin 

followed by chemothermotherapy (using the combination carboplatin, as a 

single drug, and laser diode hyperthermia) does not seem to offer an 

optimal local control. 


615s 


11:30 AM-12:30 PM 

Evaluation of local control strategies in patients with localized Ewing 

sarcoma of bone: A report from the Children’s Oncology Group. Presenting 

Author: Steven G. DuBois, University of California, San Francisco, San 

Francisco, CA 

Background: Patients (pts) with Ewing sarcoma (EWS) require local control, 

either with surgery alone (S), radiation alone (R), or a combination of 

surgery � radiation (S�R). Optimal choice of local control for disease 

control remains unclear. Our primary aim was to determine the mode of 

local control associated with the highest event-free survival (EFS). Methods: 

Pts with localized EWS of bone treated on INT0091, INT0154, or 

AEWS0031 phase III trials were included if they had complete local control 

data, did not have cranial tumors, received local control starting 2-6 

months after enrollment, and were randomized to receive standard dose 

5-drug chemotherapy every 3 weeks. We used propensity scores to control 

for differences in age, tumor site, and year of diagnosis between local 

control groups. We constructed Cox models controlling for local control 

propensity scores to assess the impact of local control type on EFS and 

overall survival (OS) from the start of local control. Results: 465 pts were 

included. Pts selected for S were treated more recently (p � 0.001), more 

likely to have appendicular tumors (p � 0.001), and younger (p � 0.02). 

Pts treated with R, compared to S, had higher unadjusted risk of any event 

(HR 1.70; 95% CI 1.18 - 2.44; p � 0.004) or death (HR 1.84; 95% CI 

1.18 – 2.85; p � 0.006). Pts treated with S�R, compared to S, had higher 

unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p � 0.02). After 

adjusting for propensity scores, there was a trend of higher risk of any event 

for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p � 0.10) compared 

to S, though this was not statistically significant. No other differences in 

adjusted risk of event or death between local control groups were statistically 

significant. We confirmed these results with standard Cox models 

using age, tumor site, and year of diagnosis as covariates. Conclusions: In 

this large group of uniformly treated pts, investigator choice of local control 

approach was not significantly related to EFS. These data support current 

practice of surgical resection when feasible, while validating radiotherapy 

as a reasonable alternative in selected pts. 


11:30 AM-12:30 PM 

Carboplatin (CBP) versus cisplatin (CP) within prognostic groups in 

pediatric extracranial malignant germ cell tumors (MGCTs). Presenting 

Author: Juliet Hale, Newcastle upon Tyne Hospitals Trust, Newcastle upon 

Tyne, United Kingdom 

Background: It is established that CBP is inferior to CP in adult MGCTs 

when used at AUC 5 or 400mg/m2 . There are no randomised data for 

paediatric MGCTs, so conclusions from adult MGCTs have been generalised 

despite differences in site, histology and biology. A database, pooling 

patients from US and UK paediatric MGCT studies, was established to 

determine prognostic factors in paediatric MGCTs. We examined the effect 

of CBP and CP in identified prognostic groups. Methods: A dataset of 1110 

paediatric MGCTs was created, treated 1983 to 2009. Treatment was CBP 

(JEB, AUC 7.9) in the UK and CP (PEB) in the US. After excluding patients 

with surgery only, pure germinoma or immature teratoma , 697 patients 

remained. The cure model was used to assess the prognostic significance of 

chemotherapy regimen after adjustment for patient characteristics. Results: 

Analysis stratified prognosis according to age (0-10 v 11�yrs) and stage 

(1-3 v 4) at diagnosis by site (testis: ovary: extragonadal). Outcome for CBP 

and CP in these prognostic groups is shown in the table. Conclusions: 

Interpretation of the results of this nonrandomised comparison requires 

caution. However, after adjustment for other prognostic factors, the risks of 

failure for JEB and PEB were not statistically different . This is particularly 

true for 0-10yrs. At AUC7.9 CBP is tolerable in paediatric patients, with 

potentially fewer late toxicities than CP. 

Prognostic group 4-year EFS JEB (95% CI) 4-year EFS PEB (95% CI) P value 

Testis 0-10 stage 1-3 0.94 (0.63-0.99) 0.92 (0.83-0.96) 0.79 

Testis 0 –10 stage 4 0.82 (0.45-0.95) 0.94 (0.67-0.99) 0.31 

Ovary 0-10 stage 1-3 1.00 (0.80-1.00) 1.00 (0.92-1.00) n/a 

Ovary 0 -10 stage 4 0.67 (0.05-0.95) 0.80 (0.20-0.97) 0.78 

Extragonadal 0-10 stage 1-3 0.92 (0.81-0.97) 0.90 (0.82-0.94) 0.90 

Extragonadal 0-10 Stage 4 0.76 (0.60-0.86) 0.83 (0.74-0.90) 0.38 

Testis 11� stage 1-3 1.00 (0.54-1.00) 0.95 (0.68-0.99) 0.57 

Testis 11� stage 4 1.00 (0.16-1.00) 0.81 (0.59-0.91) 0.52 

Ovary 11� stage 1-3 0.82 (0.62-0.92) 0.90 (0.80-0.95) 0.25 

Ovary 11� stage 4 0.71 (0.26-0.92) 1.00 (0.29-1.00) 0.85 

Extragonadal 11� stage 1-3 0.50 (0.01-0.91) 0.68 (0.44-0.83) 0.55 

Extragonadal 11� stage 4 Not assessable 0.45 (0.17-0.71) 0.45 




11:30 AM-12:30 PM 

Phase I trial of temsirolimus (TEM), irinotecan (IRN), and temozolomide 

(TMZ) in children with refractory solid tumors: A Children’s Oncology 

Group study. Presenting Author: Rochelle Bagatell, The Children’s Hospital 

of Philadelphia, Philadelphia, PA 

Background: Inhibitors of mTOR have demonstrated activity in preclinical 

pediatric solid tumor models. A phase I trial to define the dose limiting 

toxicities (DLTs) associated with the mTOR inhibitor TEM in combination 

with IRN and TMZ was conducted in patients (pts) with refractory solid 

tumors. Methods: Escalating doses of TEM were administered intravenously 

on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50 

mg/m2 /dose) was administered orally on d1-5. TMZ (100 mg/m2 /dose) was 

administered orally on d1-5. When the maximum planned dose of TEM was 

reached (35 mg/m2 /dose), IRN was escalated stepwise from 50 to 90 

mg/m2 /dose. Pts were enrolled on 6 dose levels using the rolling-six design. 

Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were 

enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma 

(4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other 

(8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered. 

Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose 

level 3 (TEM 25 mg/m2 , IRN 50 mg/m2 , TMZ 100 mg/m2 ); both pts were on 

chronic corticosteroids. The protocol was amended to preclude chronic 

systemic steroid use and modify hyperlipidemia management. Doselimiting 

hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT 

(elevated GGT) was observed in 1 pt treated with TEM 35 mg/m2 , IRN 65 

mg/m2 , TMZ 100 mg/m2 . DLT has not been observed in 4 of the first 6 pts 

treated at the highest planned dose level (TEM 35 mg/m2 , IRN 90 mg/m2 , 

TMZ 100 mg/m2 ). Additional �Grade 3 regimen-related toxicities occurring 

in �1 evaluable pt include neutropenia (12), lymphopenia (10), 

leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5), 

hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases 

(2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1 

pt had a confirmed partial response and 4 have remained on protocol 

therapy for �1 year. Conclusions: The combination of TEM (35 mg/m2 / 

dose) d 1 and 8, IRN (90 mg/m2 /dose) d 1-5, and TMZ (100 mg/m2 /dose) d 

1-5 of a 21-d cycle appears to be well tolerated in children with refractory 

solid tumors. 


11:30 AM-12:30 PM 

A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 

72 hours every 21 days via intravenous infusion in children and adolescents 

with relapsed and refractory solid tumours. Presenting Author: Darren 

R Hargrave, Great Ormond Street Hospital, London, United Kingdom 

Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, 

JAK & ABL kinases. Aurora kinases are potential therapeutic targets in 

paediatric solid cancers. Methods: A phase I dose escalation study was 

performed using a 72 hour intravenous infusion repeated 3 weekly using a 

rolling 6 design for patients aged �2to�19 years with relapsed/ refractory 

solid tumours. Results: Eighteen patients treated with a median age of 10 

(range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2 /day. 

The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 

neuroblastomas, 3 sarcomas & 3 others. There has been only one dose 

limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2 /day. The 

majority of adverse events (AEs) have been grade 1/2 & considered 

unrelated/ unlikely related to study drug. Two patients have experienced 

Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 

haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m 2 /day & 

Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count 

and aspartate transaminase in a patient treated at 11.5 mg/m2 /day. 

Pharmacokinetics of AT9283 in this population are largely in keeping with 

those seen in adult patients at similar doses (Arkenau et al., 2011) 

although there may be greater variability. Pharmacodynamic evidence of 

aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation 

in normal skin biopsies pre & post infusion, has been documented at 

all dose levels tested. Stable disease (up to 6 cycles) has been observed in 

3 patients. Conclusions: This paediatric phase I study has demonstrated 

AT9283 administered as a 72 hour continuous infusion can be given at a 

dose level of 11.5 mg/m2 /day which is higher than the maximum tolerated 

dose observed in adult patients (9 mg/m2 /day) with advanced solid 

tumours. Myelosuppresion is the main toxicity but the regimen is well 

tolerated with preliminary anticancer activity seen in heavily pre-treated 

paediatric patients. 

Dose level mg/m2 /day 

(N) Cmax (ng/mL) AUC (ng/mL.hr) Half life (hr) Tmax (hr) 

7(3) 14.4 698 5.4 56 

9(3) 32.0 1818 4.7 56 

11.5(6) 39.4 2081 5.1 56 


11:30 AM-12:30 PM 

A phase I trial of IMC A12 and temsirolimus in children with refractory solid 

tumors: A Children’s Oncology Group study. Presenting Author: Maryam 

Fouladi, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 

Background: IMC-A12, a fully recombinant IgG1 monoclonal antibody that 

targets the human IGF-IR and inhibits downstream signaling of MAPK and 

PI3K/AKT, and temsirolimus, an mTOR inhibitor, have demonstrated 

preclinical single agent, antitumor activity against many pediatric tumors. 

A phase I and pharmacokinetic (PK) trial evaluating the combination of 

these agents was conducted in children with refractory solid and CNS 

tumors. Methods: Using a modified 3�3 design, IMC-A12 and temsirolimus 

were administered intravenously once every 7 days in 28 day cycles. 

Serial PK studies were obtained on day 1, cycle 1 and trough samples were 

obtained on days 15 and 28. Biology studies included assessment of IGFR 

and insulin receptor expression and phosphorylation in archival tumor 

samples and phosphorylation of IGFR and mTOR downstream targets in 

peripheral blood mononuclear cells (PBMC) pre and post therapy. Results: 

Thirty-nine patients [20 male, median age 11.8 years (range 1-21.5)] with 

rhabdomyosarcoma (n�10), osteosarcoma (n�6), Ewings sarcoma (n�5), 

astrocytoma (n�5), or other tumors (n�13) were enrolled; 33 were 

evaluable for toxicity. At dose level 1 [IMC-A12 (6 mg/kg); temsirolimus 

(15 mg/m2 )], 2 DLTs (grade 3 hypercholestrolemia, mucositis) occurred 

among 6 evaluable patients. Six more patients were accrued and 3 

additional DLTs were observed (grade 3 ALT, fatigue and prolonged 

thrombocytopenia � 14 days). At dose level 0 [IMC-A12 (6 mg/kg); 

temsirolimus (10 mg/m2 )], dose-limiting mucositis occured in 2/6 patients. 

At dose level -1 [IMC-A12, (4 mg/kg) and temsirolimus at (8 

mg/m2 )], 0 of 3 patients experienced a DLT. At an intermediate dose level 

[IMC-A12 (6 mg/kg) and temsirolimus (8 mg/m2 )], 1 of 6 patients 

experienced mucositis; among an expanded PK cohort for children �12 

years, none of 6 patients experienced a DLT. Target inhibition (decreased 

S6K1 and PAkt) in PBMCS were noted at all dose levels. At 8 mg/m2 , the 

median sirolimus AUC was 225 �g/ml · h (159-226), and median temsirolimus 

AUC was 3340 �g/ml · h (1894-4387), and median Cmax 1176 

�g/ml (480-2231). Conclusions: The recommended pediatric phase II 

doses for the combination of IMC-A12 and temsorolimus are 6 mg/kg and 8 

mg/m2 , respectively. 


11:30 AM-12:30 PM 

Pharmacokinetic (PK) and pharmacodynamics (PD) properties of SC-PEG 

e. coli L-asparaginase (EZN-2285) in the treatment of patients with acute 

lymphoblastic leukemia (ALL): Results from Children’s Oncology Group 

(COG) study AALL07P4. Presenting Author: Anne L. Angiolillo, Children’s 

National Medical Center, Washington, DC 

Background: Asparaginase is a critical therapeutic agent in the treatment of 

childhood ALL, and pegaspargase (Oncospar, ONC) is now the preferred 

product in COG frontline ALL trials. EZN-2285 replaces the succinimidyl 

succinate linker in ONC with a succinimidyl carbamate linker creating a 

more stable molecule. AALL07P4 was designed to determine the PK 

comparability of EZN-2285 to ONC when given intravenously in newly 

diagnosed patients with NCI high-risk (HR) B-precursor ALL. Methods: 162 

eligible patients were randomized to receive EZN-2285 at 2100 (LD, 

n�66) or 2500 (HD, n�42) IU/m 2 vs. 2500 IU/m2 of ONC (n�51) in a 2:1 

manner based on the prednisone/Capizzi methotrexate arm of COG 

AALL0232. All groups were similar demographically with the exception of 

number of patients over the age of 16 years were 6, 5, and 19 in the ONC, 

HD and LD, respectively. Results: PK, PD and targeted AEs (Gr 3-5) after 

the first doses of study drug are presented in the table below. Adverse 

events in induction were not significantly different between arms with the 

exception of a higher incidence of hyperglycemia (p�0.042). Conclusions: 

Based on Cmax , AUC0-25d , and asparaginase activity 25 days post drug, 

EZN-2285 2500 IU/m2 appears to have an improved PK/PD profile 

compared to pegaspargase 2500 IU/m2 and a comparable toxicity profile in 

children with HR ALL. 

PK/PD (mean�SD) and AEs post induction dose. 

Pegaspargase 

2500 IU/m 2 (n�43) 

EZN-2285 

2500 IU/m 2 (n�40) 

EZN-2285 

2100 IU/m 2 (n�62) 

Cmax (mIU/mL) 1,647�474 1,655�366 1,291�379 

t½ (hrs) 127�51 322�118 305�98 

AUC0-25d (mIU*hr/mL) 359,781�80,309 470,742�123,584 369,998�122,013 

AUC0-inf (mIU*hr/mL) 387,015�85,753 574,091�158,574 454,394�144,348 

Asparaginase activity (mIU/mL) 25 D 

post drug 

72.8�47.9 339.6�126.8 271.6�118.2 

Asparaginase activity >100/>400 mIU/mL 25 D 

post drug (%) 

67/0 98/28 94/14 

Plasma asparagine depletion 25/42 D 

post drug (%) 

88/8 92/72.4 93/75 

Safety population (n�54) (n�42) (n�69) 

Allergy (%) 7 2 1 

Coagulopathy (%) 0 7 3 

Hyperbilirubinemia (%) 7 12 9 

Hyperglycemia (%) 15 26 35 

Hyperlipidemia (%) 6 5 1 

Pancreatitis (%) 4 5 6 

Thrombosis (%) 0 0 6 

CNS (%) 0 0 1 



11:30 AM-12:30 PM 

The application of radiotherapy to the pediatric preclinical testing program: 

Results of a pilot study. Presenting Author: Christopher E. Pelloski, The 

Ohio State University Arthur G. James Comprehensive Cancer Center and 

Richard L. Solove Research Institute, Columbus, OH 

Background: The Pediatric Preclinical Testing Program (PPTP) has been 

successfully utilized to determine the efficacy of novel agents by testing via 

its mouse-flank in vivo model. We report on the feasibility and biologic 

outcomes of a pilot study using rhabdomyosarcoma (RMS) xenograft lines 

treated with radiotherapy (RT) alone and concurrently with the mTOR 

tyrosine kinase inhibitor, AZD8055, using the PPTP model. Methods: We 

developed a mouse flank irradiation device for daily delivery of RT in 

clinically relevant doses (2 Gy per fraction up to 40 Gy).Two RMS xenograft 

lines of the PPTP, Rh30 (alveolar) and Rh18 (embryonal), were implanted 

into SCID mice, grown to appropriate volumes and were subjected to 

fractionated RT. In a second study, daily co-administration of AZD8055 

(5-20 mg/Kg, gavage) with RT was performed. Cure rates (durable complete 

response �12 weeks post-treatment) and RT dose densities (given dose / 

initial xenograft volume, Gy/cc) were compared between groups. Results: 

With RT alone at mean dose-densities of 59-60 Gy/cc, cure was achieved in 

only 4/18 (22%) of the Rh30-bearing mice and 9/12 (75%) of the 

Rh18-bearing mice (p�0.006). Profiling data revealed higher levels of 

Fanconi anemia pathway gene expression in Rh30 compared to the more 

sensitive Rh18. Since recent data showed conditional knockout of mTOR 

resulted in the loss of FANCD2 gene expression, we postulated that 

blockade of TORC1/TORC2 with AZD8055 would reduce FANCD2 and 

increase the RT-sensitivity of Rh30. The addition of AZD8055 to RT 

resulted in a selective sensitization of the Rh30 line. With a mean RT 

dose-density of 27 Gy/cc, the cure rate in Rh30-bearing mice improved to 

11/15 (73%). For the Rh18 group, the cure rate was 7/15 (46%) at a mean 

dose density of 44 Gy/cc. Western blot analysis showed the coadministration 

of AZD8055 abrogated the brisk increase in mTOR signaling 

and FANCD2 expression after the first several 2 Gy fractions of RT; most 

strikingly in Rh30. Conclusions: This study demonstrates the feasibility of 

applying RT to the PPTP model. It recapitulated the expected clinical 

radiobiology and demonstrated its utility in preclinical testing and the 

discovery of novel mechanisms of RT resistance in pediatric tumors. 


Trends in body mass index (BMI) during and after treatment for standard 

risk (SR) acute lymphoblastic leukemia (ALL): A report from the Children’s 

Oncology Group (COG). Presenting Author: Susan Joy Lindemulder, OHSU, 

Portland, OR 

Background: Obesity is a potential complication in children treated for ALL. 

Limited data exist regarding timing of BMI changes and risk in long-term 

survivors of ALL treated without cranial radiation (CRT). This study 

describes temporal trends in BMI during and after therapy for SR-ALL and 

identifies associated factors. Methods: We conducted a retrospective cohort 

study of children with SR-ALL enrolled on two sequential clinical trials 

between 1993 and 2000 and on the COG ALTE02C2 follow-up study. 

Therapy included prednisone or dexamethasone during induction, the 

same steroid in maintenance phases, and no CRT. Standing height and 

weight was ascertained at diagnosis (dx), start of consolidation, start of 

maintenance, start of the last cycle of maintenance, and at least one year 

off therapy. Age and gender-specific BMI percentiles (BMI%) were calculated 

using 2000 CDC growth charts for patients 2-20 years. Results: The 

269 subjects were a median of 3.5 years at dx, 46.7% female, 82.3% 

white, and a median of 9.1 years since dx at the last timepoint. The BMI% 

was associated with elapsed time since dx: BMI% increased between dx 

and consolidation (50.9%-68.3%, p � 0.0001), remained stably elevated 

until the end of maintenance, and then decreased somewhat from the end 

of maintenance to the last timepoint (74.1%-70.6%, p � 0.03). After 

therapy, 18.1% of survivors were overweight (BMI% 85-95) and 20.9% 

were obese (BMI% � 95). By unadjusted linear regression, higher dx BMI% 

was positively associated with BMI% post-therapy (p � 0.0001). There was 

an interaction with steroid and dx BMI% such that the association between 

dx BMI% and post therapy BMI% was significantly greater for the 

dexamethasone group than the prednisone group (p � 0.01). There was no 

association with age at dx, gender, or race. Conclusions: In this retrospective 

study of SR-ALL survivors treated without CRT, we found that BMI% 

increased significantly in the month after dx and remained substantially 

elevated even several years after the end of therapy. Dx BMI% was highly 

associated with off-therapy BMI%, particularly in patients who had 

received dexamethasone rather than prednisone. 


617s 


11:30 AM-12:30 PM 

Ipilimumab: First results of a phase I trial in pediatric patients with 

advanced solid tumors. Presenting Author: Melinda S. Merchant, National 

Cancer Institute, Bethesda, MD 

Background: Ipilimumab is a fully-human IgG1 monoclonal anti-CTLA-4 

antibody which has been approved by the FDA for adult patients with 

metastatic melanoma . Although the approved dose is 3mg/kg every 21 

days, the dose of 10mg/kg IV every 21 days for 4 doses in combination with 

chemotherapy was well tolerated in a phase III trial enrolling adult patients 

with melanoma. Methods: This pediatric phase I, dose escalation study 

examined the safety, tolerability, pharmacokinetics, and immunogenicity 

of ipilimumab administered to patients �21yo with recurrent or progressive 

solid tumors. Ipilimumab was administered at 1, 3, 5, and 10mg/kg IV 

in a standard 3 � 3 design with 4 doses of induction therapy q3 weeks 

followed by maintenance q3 months until disease progression or unacceptable 

toxicity. Tumors were measured after 6 weeks, 12 weeks, and then 

every 3 months. Results: Twenty one patients (melanoma n�6, osteosarcoma 

n�6, soft tissue sarcomas n�7, neuroblastoma, and renal cell 

carcinoma) received a total of 57 doses of Ipilimumab to date. One of 6 

patients treated at 5mg/kg developed a dose-limiting grade 3 pancreatitis. 

.At the highest dose level of 10mg/kg, two of three patients under 12yo 

developed DLT: grade 3 colitis and concurrent norovirus in one patient, and 

self-resolving grade 3 transaminitis in a second patient. Three of three 

patients between the ages of 12 and 21yo tolerated the 10mg/kg dosing 

schedule without DLT. Across all dose levels, grade 2 or 3 adverse events 

included colitis (n�1), transaminitis (n�3), pancreatitis (n�1), autoimmune 

thyroiditis (n�2), and hypophysitis (n�1) observed between C1D8 

and C4D21. A single grade 1 rash was observed. Stable disease was the 

best response in 5 patients with a duration of 3 to 18 months. Conclusions: 

Ipilimumab can be safely administered to pediatric patients. Adolescents 

are able to tolerate the highest dose of 10mg/kg. Younger children (�12yo) 

had 2 DLTs in 3 patients at 10 mg/kg . Expansion of the 10 mg/kg cohort for 

adolescents and of the 5 mg/kg dose for the �12yo for further safety and 

pharmacokinetic information is underway. The spectrum of adverse events 

appears similar to those described in the adult trials, although there were 

no grade 2 or higher incidents of rash. 


Pharmacokinetics (PK) of bendamustine in pediatric patients with relapsed/ 

refractory acute leukemia. Presenting Author: Mona Darwish, Teva Pharmaceutical 

Industries Ltd., Frazer, PA 

Background: The PK profile of bendamustine in adult patients is well 

characterized. The objective of this analysis was to describe the pediatric 

PK profile of bendamustine relative to the adult PK profile and correlate the 

systemic exposure of bendamustine to efficacy and safety parameters. 

Methods: Samples were obtained after a single dose from patients aged 

1-19 years with relapsed/refractory acute leukemia who were enrolled in an 

open-label, nonrandomized study of bendamustine (90–120 mg/m2 , 

infused over 60 minutes). Samples were obtained prior to bendamustine 

infusion and preselected time points through 24 hours after start of 

infusion on day 1. Population PK modeling was performed using plasma 

concentration data from these patients. PK data from adults were used for 

comparison. Results: Systemic exposure of pediatric patients to bendamustine 

was similar to that obtained previously in adult patients. Mean Cmax was 6806 ng/mL and mean AUC0-24 was 8240 ng*hr/mL in pediatric 

patients, compared with a mean Cmax of 5746 ng/mL and AUC0-24 of 7121 

ng*hr/mL in adults. Similarity in exposure despite the large range of body 

surface area across the pediatric and adult populations confirms appropriateness 

of the body surface area–based dosing scheme. In pediatric 

patients, age, race, sex, or disease state had no statistically significant 

effect on systemic exposure to bendamustine. No changes in systemic 

exposure to bendamustine in the presence of a CYP1A2 inhibitor/inducer 

were observed. Differences in PK were not observed in pediatric patients 

with mild renal impairment as compared with patients with normal renal 

function. Exposure in 2 pediatric patients with moderate hepatic dysfunction 

appeared to be higher. No clear exposure-response relationship was 

observed. Infection was the only adverse event for which the probability of 

occurrence increased with increase in exposure to bendamustine. 

Conclusions: The PK profile of bendamustine in pediatric patients was 

similar to the known PK profile in adults, demonstrating that exposures 

reflective of the therapeutic range in adults were attained following 

administration of 120 mg/m2 to pediatric patients. Support: Teva Pharmaceutical 

Industries Ltd., Frazer, PA. 




Safety and biological activity of the FLT3 inhibitor lestaurtinib in infant 

MLL-rearranged (MLL-r) ALL: Children’s Oncology Group protocol 

AALL0631. Presenting Author: Di Sun, Oncology and Pediatrics, Johns 

Hopkins University School of Medicine, Baltimore, MD 

Background: MLL-r infant ALL overexpresses activated FLT3. Lestaurtinib 

potentiates chemotherapy(chemo)-induced cytotoxicity in MLL-r ALL. 

AALL0631 therapy is stratified based on age and MLL status: high risk 

(HR) �90 days, MLL-r; intermediate risk (IR) � 90 days, MLL-r; standard 

risk any age, not MLL-r. IR and HR patients (pts) get intensive chemo and 

are eligible for lestaurtinib. A safety/activity (S/A) phase to determine a safe 

and biologically active dose of lestaurtinib is followed by an efficacy phase 

randomizing MLL-r patients to chemo �/- lestaurtinib. The S/A phase 

proceeds independently for IR & HR pts, as optimal lestaurtinib dosing may 

differ between neonates and older infants. We previously reported successful 

completion of the S/A phase for IR pts; here, we report results of the S/A 

phase for HR pts. Methods: Lestaurtinib-related dose limiting toxicities 

(DLTs) were defined as grade � 3 non-heme toxicities excluding those 

expected with chemo alone (e.g., F&N/infection); a dose of lestaurtinib was 

“safe” if 0 or 1 DLTs were seen in 5 evaluable pts. FLT3 inhibition was 

assessed using a plasma inhibitory activity (PIA) assay that measures % 

inhibition of phospho-FLT3 at 5 trough time points relative to pretreatment 

baseline. A dose of lestaurtinib was “biologically active” if PIA 

was � 90% for the majority (�3 of 5) of troughs in at least 3 of 5 pts. 

Results: 11 eligible HR pts received lestaurtinib, 6 at dose level 1 (DL1, 3.5 

mg/kg/day) and 5 at DL2 (4.25 mg/kg/day). There were no DLTs in 5 

evaluable pts at DL1. The inevaluable pt discontinued lestaurtinib due to 

parental refusal, not toxicity. There was 1 DLT in 5 evaluable pts at DL2. 

The DLT was grade 4 intestinal perforation secondary to severe typhlitis 

during neutropenia following reinduction, possibly related to lestaurtinib. 

The pt was taken off protocol and chemo and died of progressive disease. 

By PIA assay, 2 of 5 pts treated at DL1, and 4 of 5 at DL2 demonstrated 

FLT3 inhibitory biologic activity. Conclusions: DL2 is safe and biologically 

active in HR pts. The efficacy phase of AALL0631 is expanding such that 

HR pts will join IR pts in being randomized (1:1) post-induction to chemo 

�/- lestaurtinib at DL2. 


Diminished asparaginase turnover due to a germ-line mutation in cathepsin 

B. Presenting Author: Dunja Maroeslea W.M. Te Loo, Radboud University 

Medical Centre, Nijmegen, Netherlands 

Background: ASNase is a key component of multi-agent chemotherapy 

protocols used in the treatment of pediatric as well as adult acute 

lymphoblastic leukemia (ALL). Patients that are treated according to fixed 

shedules show a strong inter individual variation in serum ASNase levels. 

While underexposure may compromise therapeutic benefits, strongly elevated 

serum levels may lead to serious adverse effects. In at least 10% of 

the patients the desired ASNase levels are either not reached or exceeded. 

Therefore our understanding of ASNase dynamics in vivo needs to be 

improved. Here we describe the identification of a novel mutation in the 

gene encoding Cathepsin B to diminished ASNase turnover in a pediatric 

patient with ALL. Methods: Sequencing, biochemical experiments and 

immunofluorescence. Results: A 3-year-old girl diagnosed with ALL experienced 

serious toxicity in the form of hyperammonemic encephalopathy 

during treatment with ASNase derived from Erwinia chrysantemi. Pharmacokinetic 

data showed a strongly delayed clearance of the ASNase, which 

with the standard treatment protocol resulted in extremely high serum 

ASNase levels. Plasmapheresis was performed and dosage frequencies 

were adjusted to improve the clinical status of the patient. No underlying 

metabolic disorder could be diagnosed. Based on a previous report 

describing the role of proteases in degradation of ASNase in vitro, we 

hypothesized that the cysteine protease Cathepsin B might be implicated in 

the strongly reduced clearance of ASNase in this patient. Sequencing of the 

open reading frame of the Cathepsin B gene (CTSB) revealed a single codon 

deletion in the germline of the patient, affecting a lysine residue in the 

carboxy terminus of the protein. Immunofluorescence and biochemical 

experiments show that this single amino acid deletion leads to a protein 

product that is retained in the endoplasmic reticulum and is inefficiently 

processed. Conclusions: ASNase degradation assays show that the mutant 

Cathepsin B has lost its ability to efficiently degrade ASNase which could 

explain the high levels of ASNase as observed in our patient.Together, 

these findings suggest that variations in Cathepsin B activity may influence 

serum ASNase levels in the patients. 


Serial assessment of regulatory T cells (Tregs) in pediatric AML: A 

prospective study. Presenting Author: Anuj Kumar Bansal, All India 

Institute of Medical Sciences, New Delhi, India 

Background: Data of Tregs in pediatric AML is lacking. The study objectives 

were determining Tregs in pediatric AML at diagnosis and follow up; and 

correlating with outcome. Methods: From Nov 2010-May 2011, 30 consecutive 

AML patients � 18 years were prospectively enrolled with 6 healthy 

controls. All patients received daunorubicin / cytarabine induction and 3 

courses of cytarabine. Tregs (CD4�CD25�FoxP3�) were assessed at 

diagnosis, post-induction, post-consolidation, 3 and 6 months follow up 

and relapse. Results: 30 cases with median age 9.5 years; male/female ratio 

14:16 had significantly higher baseline Tregs than healthy controls 

(12.36�4.65% vs 3.16�1.49%; p�0.0001). Patients with high Tregs 

frequency were females (p�0.044), WBC�50,000/mm3 (p�0.023), hypoalbuminemia 

(p�0.002), absence of lymphadenopathy (p�0.04) and 

linear correlation with peripheral blood blast% (r�0.55, p�0.0014). CR 

rate was 83.3% (25/30); EFS 38% and OS 73% at 14 months follow up. 

When Tregs were categorized as high and low based on median value, CR 

rate (86.6% vs 80%, p�NS), EFS [17% vs 60%, HR 1.46 (0.51-4.14) 

p�0.46] and OS (66% vs 80%, HR 0.58 (0.13-2.44) p�0.45) were not 

different. Amongst those who achieved CR, there were 7/13 relapses in 

those with high Tregs versus 3/12 in those with low Tregs (p�0.226).Tregs 

reduced post-induction (12.1�4.6 vs 6.32�2.8, p�0.000) from baseline. 

Using generalized estimating equation regression model, average 

Tregs reduction from post-induction till 3 month follow up was 0.785 

units/visit (p�0.005) in those with continuous CR(n�15) and 1.25 

units/visit (p�0.001) in those whom relapsed (n�10). Difference between 

these two groups was not significant. Tregs significantly increased at 

relapse as compared to post consolidation value (15.3�5.2 vs 4.5�1.9, 

p�0.003). Conclusions: This first study in pediatric AML demonstrates that 

Tregs is increased at diagnosis and is significantly associated with females, 

high WBC count, hypooalbuminemia, absence of lymphadenopathy and 

high peripheral blood blast%. Tregs significantly reduced post-induction on 

follow up; however, it increased at relapse. Baseline Tregs did not predict 

CR, EFS, or OS. However, there were more relapses in those with high 

baseline Tregs. 


Serial assessment of humoral immunity in pediatric AML: A prospective 

study. Presenting Author: Sameer Bakhshi, Dr. B.R. Ambedkar Institute 

Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 

India 

Background: Humoral immunity has been evaluated in pediatric ALL; data 

in pediatric AML is lacking. The objectives of this study were to assess 

humoral immunity on follow-up in pediatric AML patients. Methods: From 

April 2010-May 2011, 45 consecutive AML patients 1-18 years old were 

prospectively enrolled with 7 healthy controls. Immunoglobulin (Ig) levels 

in 45 patients and B-lymphocytes (CD19�) in 29 patients were assessed at 

diagnosis, post-induction, post-consolidation, 3 and 6 months follow-up 

and relapse. Results: At diagnosis, Ig levels were higher in patients as 

compared to healthy controls (IgG, p�0.041; IgA, p�0.07; IgM, p�0.16) 

while B-cells were lower (p�0.001). Patients with gum hypertrophy had 

low Ig levels (IgG, p�0.007; IgA, p�0.003; IgM, p�0.06). CR rate was 

84.4% (38/45); EFS 40% and OS 58% at 20 months follow-up. Postinduction, 

there was reduction in IgM (p�0.001) and IgA (p�0.048) levels 

and increase in B cells (p�0.001). Using generalized estimating equation 

regression model, average reduction from post-induction till 3 month 

follow-up was 36.9 units/visit (IgG); 10.3 units/visit (IgA); 0.32 units/visit 

(IgM) in those with continuous CR (group-1, n�24) and 91 units/visit 

(IgG); 8.9 units/visit (IgA); 1.5 units/visit (IgM) in those who relapsed 

(group-2, n�14). Difference between these two groups was significant for 

IgA (p�0.017). There was increase in IgG (p�0.52) and IgA levels (0.21) 

at relapse when compared with post-consolidation values. B-cells had an 

average increase of 3.6 units/visit (p�0.012) in group 1 and decrease of 

0.58 units/visit (p�0.82) in group 2; (group-1 vs group-2, p�0.10). There 

was no significant correlation of baseline Ig and B cells with CR rate, EFS 

and OS. Conclusions: This is the first study to evaluate humoral immunity 

serially in pediatric AML. AML patients with gum hypertrophy have low IgG 

and IgA at diagnosis. On serial monitoring, B cells show an increase in 

patients who are in continuous CR while those who relapse tend to show a 

reduction on follow-up. Further, on follow-up, although all Ig decrease, but 

the reduction in IgA is significantly lower in patients who relapse suggesting 

their possible role in disease biology. 



Contribution of diet and physical activity to metabolic parameters among 

survivors of childhood leukemia. Presenting Author: Emily S. Tonorezos, 


Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are 

at increased risk for obesity, insulin resistance and increased visceral 

adiposity. A history of cranial radiation therapy (CRT) worsens this risk. In 

non-cancer populations, adherence to a Mediterranean Diet has been 

shown to improve metabolic parameters and risk of diabetes mellitus. 

Whether diet may contribute to insulin resistance and increased adiposity 

in ALL survivors is not known. Methods: We surveyed 117 adult survivors of 

childhood ALL using the Harvard Food Frequency Questionnaire. Physical 

activity energy expenditure (PAEE) was measured with the SenseWear Pro2 

Armband. Fasting blood was obtained on all subjects and insulin resistance 

was estimated using the Homeostasis Model for Insulin Resistance (HOMA- 

IR). Visceral adiposity was measured by abdominal CT. Adherence to a 

Mediterranean Diet pattern was calculated using the index developed by 

Trichopoulou. Subjects were compared using univariate analysis. Results: 

Subjects were majority female (56%); 25% were minority or Hispanic 

white. A history of CRT was present in 15 (29%) men and 25 (38%) 

women. Among all subjects, greater adherence to a Mediterranean diet 

pattern was associated with improved HOMA-IR (p�0.14), visceral adiposity 

(p�0.03), subcutaneous adiposity (p�0.005), waist circumference 

(p�0.02), and body mass index (p�0.03) (all unadjusted analyses). The 

effect of adherence to a Mediterranean diet on insulin resistance was 

especially notable in men who did not receive CRT (p�0.06). Higher dairy 

intake was found to worsen HOMA-IR (p�0.014), but other individual 

components of the Mediterranean diet, such as low intake of meat and high 

intake of fruits and vegetables, were not significant. Inclusion of PAEE did 

not alter our findings, although higher PAEE was associated with lower body 

mass index. Conclusions: Adherence to a Mediterranean diet pattern, 

especially low consumption of dairy products, may improve insulin resistance 

in survivors of childhood ALL. Further study is warranted. 


Minimal residual disease by flow cytometry at the end of chemotherapy for 

remission induction in pediatric patients with acute lymphoblastic leukemia: 

Experience from a center in a low-income country. Presenting Author: 

Eloy Perez, Hospital Infantil de Morelia Eva Samano de Lopez Mateos, 

Morelia, Mexico 

Background: The presence of minimal residual disease (MDR) following 

therapy for acute lymphoblastic leukemia (ALL) has been shown to be an 

important prognostic marker in many studies. MRD is typically detected 

either by polymerase chain reaction amplification or by flow cytometry. 

Flow-based MRD assessment has the potential for rapidly identifying 

patients at increased risk of relapsed, allowing for prompt changes in 

therapy, including earlier intensification. There are not many information 

about the response by MRD in countries with limited resources. Methods: 

The patients included were 90 ALL patients treated at the Hospital Infantil 

de Morelia from June 1, 2009 to January 5, 2012. MRD positivity (�) was 

defined as �0.01% of the gated population. Results: MRD was obtained in 

90 patients, 38 males and 36 females. The median age was 7 years (10 

months to 15 years). The levels of MRD were: �0.01, 74 (82.2%), 

0.01-1%, 9 (10%), �1%, 7 (7.7%). There was not a statistically 

significant association between the most important ALL prognostic factors 

(Gender, Age at diagnosis, White blood cell count at diagnosis, Central 

Nervous System disease, Prednisone response, DNA Index, Immunophenotype). 

Conclusions: The good response found is similar to that reported by 

international groups, a situation which suggests that the response to 

chemotherapy is appropriate. However, cure rates are still not equal making 

it necessary to review institutional treatment protocols and social characteristics 

of the population to achieve cure rates reported by international 

groups. 


619s 


Fever at diagnosis of pediatric acute lymphoblastic leukemia (ALL): Are 

antibiotics really necessary? Presenting Author: Monica Khurana, Children’s 

Hospital Oakland Research Institute, Oakland, CA 

Background: Great variability exists in the management of suspected 

bacteremia in febrile, neutropenic pediatric ALL patients during chemotherapy. 

The National Comprehensive Cancer Network and Infectious 

Diseases Society of America encourage immediate, empiric antibiotics in 

patients with chemotherapy-induced fever and neutropenia to reduce 

infection-related mortality. No standard recommendation exists for patients 

with isolated fever at initial presentation of their ALL. This study 

evaluates bacteremic episodes in this subpopulation of pediatric patients. 

Methods: We retrospectively analyzed 245 consecutive patients with ALL at 

Children’s Hospital Oakland from 2000 through 2011. Using electronic 

medical records, we investigated each patient’s history and outcome. We 

surveyed bacteremic episodes up to 60 days after presentation per National 

Healthcare Safety Network’s guidelines. Inclusion criteria were patients 

with fever at presentation, which prompts a blood culture, and were started 

on antibiotics. We stratified bacteremic episodes into community-acquired 

(up to three days from admission) and nosocomial (four to 60 days). 

Results: Seventy-seven patients met the inclusion criteria, five of whom had 

positive cultures – four were contaminants (three coagulase-negative 

Staphylococcus and one non-anthracis Bacillus) and one was a true 

nosocomial bactermic episode (E coli). There were no infection-related 

deaths in the first 60 days of diagnosis in this cohort. Conclusions: Given 

our institution’s rarity of bacteremic episodes, we contemplate a more 

judicious use of antibiotics, including quicker narrowing of broad-spectrum 

antibiotics coverage and discontinuing all antibiotics sooner. These modifications 

may decrease bacterial resistance to antibiotics, reduce costs, and 

shorten patients’ hospitalization. We encourage other institutions to 

conduct a similar investigation. 


YM155 sensitivity in pediatric acute lymphoblastic leukemia. Presenting 

Author: Bill H. Chang, Doernbecher Children’s Hospital, Portland, OR 

Background: Despite advances in treatment and outcomes in pediatric 

acute lymphoblastic leukemia, there continue to be subsets of patients that 

are refractory to standard intensive chemotherapy. Therefore, novel agents 

are needed to further advance treatment for this disease. YM155 (Astellas) 

is a selective suppressant of survivin expression. Survivin has been shown 

to be over-expressed in malignant cells and in relapsed ALL. Early adult 

phase I/II studies show promise in both tolerability and possible efficacy in 

B-cell malignancies. Methods: Fresh diagnostic leukemic patient samples, 

ALL cell lines, and xenograft samples were obtained and subjected to 

YM155 at doses ranging from 1nM to 10�M. Samples were then tested for 

viability using standard methane-thiosulfate, apoptosis using Guava nexin 

Annexin V binding, protein expression using immunoblot, and P53 activation 

with phospho-flow cytometry. Results: The median IC50 for viability and 

apoptosis for the samples are: NCI standard risk ALL 5.3nM �3.47, NCI 

high risk ALL 91.76 nM �93.42, T-ALL 336.6nM �147.7, AML 333.6nM 

�489, Ph�ALL xenografts 3.8nM �1.04, and ALL cell lines 18.5nM 

�135. Ph�ALL samples, including primary patient, xenograft, and dasatinib 

(BMS) resistant samples remain significantly sensitive to YM155. For 

dasatinib sensitive samples, combination therapy suggests an additive 

effect by isobologram analysis. Immunoblot and RT2-PCR Arrays (Qiagen) 

identify that multiple protein expression are decreased with YM155 

treatment. Conclusions: Our data supports the model of the use of YM155 

as a treatment for ALL including an added benefit in combination with 

dasatinib in Ph�ALL. Although initial studies suggested that YM155 is a 

selective suppressant of survivin, subsequent studies are beginning to 

identify off target effects. These off target effects may enhance the drugs 

potential for activating cell death. Finally, we show that screening primary 

samples with YM155 has the potential to select a target population that is 

more sensitive to YM155 treatment. Future studies will be designed to 

develop YM155 as an additional therapeutic agent for pediatric acute 

lymphoblastic leukemia. 




Diagnostic and treatment challenges of adolescent and young adult 

oncology patients. Presenting Author: Yanqing Xu, McGill Adolescent and 

Young Adult Oncology Program, Montreal, QC, Canada 

Background: Adolescent and young adult (AYA) cancer patients are faced 

with obstacles and challenges related to their diagnosis and treatment 

compared to children and older adults. The aim of this study was to explore 

the patient and health care system-related delays in the interval from 

cancer symptom onset to diagnosis and treatment as well as to identify the 

possible contributing factors to these delays in the AYA group. Methods: 

This study was based on a questionnaire conducted in 2010-2011 

completed by patients diagnosed with a malignancy between the ages of 16 

and 39 in addition to older patients diagnosed with a pediatric type 

malignancy. Four categories of delays: patient delay (time from patient 

symptom onset until first health care contact date), health care system 

delay (time from first health care contact until diagnosis date), treatment 

delay (time from diagnosis date until first treatment) and oncologist delay 

(time from first health care contact until first medical oncologist meeting) 

were calculated. Median delay (in days) with interquartile interval (IQI) was 

the main outcome measure. Median time for each category of delay was 

further analysed to explore how they vary with different patient characteristics. 

Results: We identified a median patient delay of 30 days (IQI 1-131), a 

median health care system delay of 53 days (IQI 1-213), a median 

treatment delay of 36 days (IQI 5-92) and a median oncologist delay of 77 

days (IQI 30-281). Patient delay was affected by patient gender, age at 

diagnosis and type of first health care contact. Health care system delay 

was associated with patient marital status, financial situation and attitude 

of first health care professional. Treatment delay was related to type of 

cancer. Conclusions: The health care system delay (including oncologist 

delay) accounts for much of the delay from symptom onset to first 

treatment. Professional characteristics of frontline medical personnel as 

well as socioeconomic and biological characteristics of the patients may 

contribute to delay. Healthcare professionals and the general community as 

a whole need to be aware of the factors contributing to delay in diagnosis 

and treatment in the underserved patient population. 


Results of autologous transplants for children from a tertiary cancer center 

in India. Presenting Author: Amol Dongre, Tata Memorial Centre, Mumbai, 

India 

Background: Autologous transplantation is a curative option for children 

with various malignancies. We report the results of our center with the aim 

of evaluating toxicities and prognostic factors that may influence decision 

making to use our limited resources judiciously. Methods: Forty-six patients 

diagnosed below 18 years from 1st April 1994- 28th February 2011 were 

included in this retrospective study. Twenty-four patients had lymphoma, 

12- neuroblastoma and 10-others ( 5- acute leukemia, 4- Ewing sarcoma 

and 1 - rhabdomyosarcoma). Twenty-eight patients received peripheral 

blood stem cells, 12 – marrow and 6-both. Prognostic factors evaluated for 

overall survival (OS) and progression-free survival (PFS) were remission 

status at transplant, baseline and pre-transplant serum albumin, time 

interval between diagnosis and transplant, type of malignancy and number 

of lines of chemotherapy pre transplant. Results: Median age at diagnosis 

and transplant were 9 and 12 years respectively. Median baseline and pre 

transplant serum albumin were 3.6 and 3.9 g/dl. Median number of lines of 

chemotherapy was 2. Median time from diagnosis to transplant was 1.1 

years. Incidence of grade 3 and 4 oral mucositis and diarrhea were 46% 

and 25% respectively. At the time of transplant, 45% were in complete 

remission (CR), 41% in partial remission (PR) and 13% in refractory state. 

Total Parenteral Nutrition (TPN) was used in 63% patients with median 

duration of 11 days. No patient developed sinusoidal obstruction syndrome- 

.Median days to neutrophil and platelet engraftment were 11 and 15 days 

respectively. Neutropenic sepsis leading to death was seen in 17%. Median 

follow up was 1.5 years. At 2 years, the probability of OS and PFS were 

39% and 35% for all patients while OS and PFS for lymphoma, neuroblastoma 

and others were 45% and 32%, 17% and 0% and 50% and 40% 

respectively. CR at transplant was the most important determinant of better 

OS (59 % vs 28%; p � 0.000004) and PFS (53% vs 8%; p � 

0.0000018). Conclusions: CR at transplant is the most important prognostic 

factor. Patients with neuroblastoma have dismal outcome which 

requires reevaluation of transplant strategies for this group. 


Treatment outcomes of pediatric oncology patients in Zambia. Presenting 

Author: Jeremy Slone, Vanderbilt University School of Medicine, Nashville, 

TN 

Background: Due to challenges in the delivery of pediatric oncology care in 

low-middle income countries (LMIC), diagnosis and treatment remains 

inadequate for the majority of patients. The University of Zambia School of 

Medicine/University Teaching Hospital (UTH) and Vanderbilt University 

School of Medicine/Vanderbilt Institute for Global Health established a 

partnership to investigate treatment outcomes at UTH, the only institution 

providing pediatric oncology care in Zambia, and assess risk factors 

associated with treatment abandonment. Methods: A retrospective study 

was conducted in a cohort of patients, presenting from July 2008 – June 

2010, using an established database and medical record review. Results: 

Of the 230 children enrolled in the database, 162 met the inclusion 

criteria. The average age at diagnosis was 6.0 years; males comprised 

55.6% of the cohort; 51.6% had a histopathological diagnosis and 10.5% 

of the cohort was HIV positive. The most common diagnoses were 

lymphoma (25.9%), Wilms tumor (22.8%), and retinoblastoma (17.9%). 

Leukemia and Kaposi sarcoma accounted for 7.4% each. Death (46.3%) 

and abandonment of treatment (45.7%) were the most common outcomes 

with only 8.0% having completed treatment or currently undergoing 

treatment, including palliative regimens, at the time of data acquisition. 

Residence in Lusaka or Central provinces, closest in proximity to UTH, was 

associated with a decreased risk for abandonment of treatment (Odds Ratio 

(OR) 0.41 (95% CI 0.21-0.81, p � 0.009) while maternal education less 

than secondary school (OR 2.73 95% CI 1.2-6.6, p � 0.03) was 

associated with an increased risk for abandonment of treatment. Conclusions: 

At the only pediatric cancer center in Zambia, treatment outcomes are dire 

with the majority of the cohort abandoning treatment or dying during 

therapy. Challenges include access to cancer chemotherapy, logistical 

facilitation, fiscal support of radiotherapy, and community engagement. 

Further investigation is required to inform effective intervention strategies 

to improve outcomes. 


Evaluation of renal function in children with solid tumors: Comparison 

between estimation with Schwartz formula and EDTA clearance. Presenting 

Author: Carole Serrano, Institut Gustave Roussy-Clinical Pharmacy 

department, Villejuif, France 

Background: Using the [51Cr]-ethylenediamine tetra acetic acid ([51Cr]- 

EDTA) method provides an accurate measure of glomerular filtration rate 

(GFR) for each patient. However, this method is not always feasible in 

routine. Thus, several mathematical equations have been developed to 

predict creatinine clearance. The most widely used in pediatric patients is 

the Schwartz formula, based on patient height and serum creatinine. 

However, this method has not been validated in pediatric cancer patients. 

The aim of the present study was to compare GFR measured with the 

51Cr-EDTA method to GFR estimated with the Schwartz formula in 

patients younger than 18 years of age and treated for solid tumors. Methods: 

Data have been retrospectively collected on consecutive children treated 

between 2001 and 2011 at Institut Gustave Roussy. All of the patients had 

undergone assessment of GFR via 51Cr-EDTA clearance and estimation of 

renal function by the Schwartz formula. Exclusion criteria were serum 

creatinine under 25�mol/L or no recent dosage available. GFR analysis was 

realized using the slope intercept method after a single injection of 

51Cr-EDTA solution.. Values of the GFR were calculated by multiplying the 

volume of dilution by the slope of the single exponential fit to the three data 

points and then expressed in ml/min/1.73m². Student paired t-test (alpha 

� 0.05) was used to compare results obtained for each patient with the two 

methods. Results: 196 patients (120 males, 76 females), treated with 

various types of cancer (neuroblastoma, osteosarcoma, Ewing sarcoma, 

lymphoma. . .) Mean age was 6.7 years. Mean GFR was 127.5 ml/min/ 

1.73m² with the 51Cr-EDTA method versus 148.1 ml/min/1.73m² with the 

Schwartz formula. Mean of difference was 20.7 ml/min/1.73m² with a 

confidence interval [-25.7 ; -15.6] (p � 0.0001). Conclusions: GFR 

estimated with the Schwartz formula is statistically different from the 

isotopic method. In most cases, GFR estimated with the Schwartz formula 

is overestimated. This study highlights the lack of accuracy of this equation 

in pediatric population with cancer. The 51Cr-EDTA method must be 

preferred when a reliable and accurate evaluation of renal function is 

needed. 



Familial risk in pediatric cancer and implications for practice. Presenting 

Author: Karen Curtin, University of Utah and Huntsman Cancer Institute, 

Salt Lake City, UT 

Background: Using a unique genealogical resource, the Utah Population 

Database, we examined risk of cancer in 1st- through 3rd-degree relatives 

of 4,482 pediatric cancer cases �18 years old diagnosed between 1966 

and 2009. We quantified cancer risk in relatives of children with cancer in 

order to determine evidence of a familial aggregation of cancer, identify 

high-risk pedigrees, and inform counseling protocols for genetic testing and 

screening. Methods: We estimated cancer risk in relatives of pediatric cases 

compared to random population controls matched 5:1 on sex, birth year, 

and birthplace. Odds ratios were calculated using conditional logistic 

regression, adjusting for number of biological relatives, their degree of 

relatedness, and their person-years at risk. We included all relatives of 

cases and controls with followup who linked to a pedigree of �2 generations; 

this approach has been shown to lead to unbiased risk estimates. As 

observations within families are non-independent, a robust variance 

estimator for cluster-correlated data was incorporated. Results: Mostly 

siblings, 1st-degree relatives (N�49 affected) of pediatric cases were at 

2-fold increased risk of being diagnosed at age�19 with cancer themselves 

(p�10-4 ); siblings of cases diagnosed at age�5 had a 4-fold risk of 

pediatric cancer (p�10-7 ). Likewise, 2nd-degree relatives (N�61 affected) 

and cousins (N�105 affected) of cases had a ~2-fold risk of childhood 

cancer (p�10-4 ). Proband siblings were at increased risk for leukemia, 

brain tumor, epithelial neoplasia, and bone cancer. While 1st-degree 

relatives of pediatric cases had a slight increased risk of adult-onset cancer, 

when they do develop cancer they exhibit a 50% increased risk of a 

Li-Fraumeni Syndrome-related tumor diagnosis (N�142 affected relatives; 

p�10-4 ). Conclusions: Our findings provide evidence of familial aggregation 

of cancer and suggest a higher percent of pediatric cancers are related to 

hereditary syndromes than are adult cancers. We encourage a 3-generation 

family history be collected and routinely updated for all pediatric cancer 

patients, and those children with family histories of early-onset cancer be 

referred for genetic counseling and early surveillance when appropriate. 


Preclinical study of a Bcl-2 inhibitor in neuroblastoma. Presenting Author: 

Assila Belounis, Research Center CHU Sainte Justine, Montréal, QC, 

Canada 

Background: Neurblastoma (NB) is the most common and deadly extracranial 

solid tumor of childhood. This malignant tumor exhibits a broad 

spectrum of clinical features, including spontaneous regression or maturation 

without any treatment or progression to metastisis leading to death. 

However, in spite of many therapeutic improvements, only 60% survive 

long term. In fact, 40% of patients with high-risk NB still relapse and 

eventually die of the disease despite aggressive combinations of multiagent 

chemotherapy. In those cases, new therapeutic strategies must be 

developed. Studies have shown that BCl-2, a central anti-apoptotic protein, 

is over-expressed in NB. Although Bcl-2 is not a significant prognostic 

factor in NB, its increased expression would contribute to chemotherapy 

resistance. BCl-2 is also shown to be involved in the modulation of 

autophagy by inhibiting Beclin-1. Therefore, BCl-2 protein represents an 

attractive target for new therapeutic strategies in NB.The objective of this 

study is to determine the efficacy in vitro of Obatoclax (OB), a BCl-2 

inhibitor, used in monotherapy or in combination to cisplatine (CP), a 

classical chemotherapeutic agent used in NB treatment, on NB cell 

survival. Methods: Six NB cell lines (SK-N-DZ, SK-N-FI, SK-N-SH, N91, 

NB8 and NB10) were treated with OB alone or in association to CP. Cell 

survival was measured by MTT test. Autophagy was measured by MDC test. 

Western Blots (WB) were done to evaluate the modulation of apoptotic and 

autophagic pathways in treated cells. Results: OB used in monotherapy 

shows promising results on NB cell lines with an average IC50 of 0.12�M. 

Also, OB demonstrates synergistic effects when associated to CP. The IC50 

of CP treated cells varied from 3.183�M to 6.837�M but dropped from 

0.003�M to 0.008�M when combined with 0.5�M of OB. Moreover, our 

WB show an increase in cleaved Caspase-3 and PARP-1 expression, 

suggesting an upregulation of apoptosis in treated cells. Autophagy is also 

upregulated confirmed by an increase in autophagic vacuoles and cleaved 

LC3 II protein. Conclusions: OB used in monotherapy or in combination at 

potentially therapeutic doses shows promising results in NB. These results 

will allow for the improvement of NB treatments by introducing a new 

therapeutic strategy. 


621s 


Mitigating smoothened inhibitor-induced growth plate closure with parathyroid 

hormone. Presenting Author: Yoav E. Timsit, Novartis Institutes for 

BioMedical Research Inc., Cambridge, MA 

Background: The Hedgehog pathway plays an important role in regulating 

growth plate patency by activating PTH/PTHrP signaling, and loss of 

PTH/PTHrP signaling is an expected pharmacological effect of smoothened 

(Smo) inhibition. LDE225, a Smo inhibitor currently in phase I/II trials for 

the treatment of basal cell carcinoma (BCC) and medulloblastoma (MB), 

causes closure of the epiphyseal (growth) plate in rodents and dogs. As a 

therapeutic strategy to mitigate these effects, we investigated whether 

administration of human parathyroid hormone (PTH amino acids 1-34 or 

PTH1-34) could prevent premature growth plate closure caused by LDE225. 

Methods: Oral LDE225 was given once daily to rapidly growing male rats 

(starting at 4 or 6 weeks of age) in combination with hPTH1-34 administered 

subcutaneously as a continuous infusion (to mimic signaling by locallyproduced 

PTHrP) or as once-daily injections. Femur and tibial growth 

plates were scanned by microCT and growth plate volumes were calculated. 

Growth plates were also assessed histologically. Results: Continuous 

delivery of hPTH1-34 provided the greatest effect for maintaining patent 

growth plates compared to once-daily subcutaneous injections. However, 

the dose of continuous hPTH1-34 giving the greatest protection was not 

well-tolerated beyond 1 week due to PTH-induced hyperparathyroidism, 

confirmed by clinical chemistry and histological assessment. Reduction in 

the dose of continuous hPTH1-34 improved tolerability, but provided less 

protection to the growth plate. Once-daily hPTH1-34 injection for two weeks 

was well-tolerated, with anabolic effects clearly observed by histology and 

microCT. The extent of closure in animals co-treated with LDE225 and 

once-daily hPTH1-34 injections was less compared to that caused by 

LDE225 treatment alone. Conclusions: As shown in this preclinical model, 

hPTH1-34 administration mitigates LDE225-induced growth plate closure. 

Although hPTH1-34 shows promise experimentally, current use is restricted 

in pediatric patients and further study will be needed before considering 

hPTH1-34 treatment concurrent with LDE225 therapy in children or 

adolescents. 


Effect of insulin-like growth factor 2 gene expression on pleuropulmonary 

blastoma and embryonal rhabdomyosarcoma. Presenting Author: Rajkumar 

Venkatramani, Children’s Hospital Los Angeles, Los Angeles, CA 

Background: The sarcomatous element in pleuropulmonary blastoma (PPB) 

often cannot be differentiated from embryonal rhabdomyosarcoma (ERMS) 

by histology, particularly when characteristic elements like cartilage and 

respiratory mucosa are inapparent. The initial diagnosis is often ERMS. A 

diagnosis of PPB is based on a combination of clinical (age, location) and 

pathologic features. We hypothesized that the sarcomatous portions of PPB 

are a form of ERMS indistinguishable from typical ERMS. We reasoned that 

a detailed comparison of RNA expression could clarify this hypothesis. 

Methods: Samples from 7 PPB patients were obtained from the rhabdomyosarcomatous 

portion of the tumor by macro-dissection after pathologic 

review of all material. Representative ERMS tumor tissue was selected from 

21 ERMS cases. FFPE tissue scrolls from each case were analyzed using 

Affymetrix Human Exon arrays after RNA extraction with Agincourt Formapure 

extraction kit and amplification using the NuGEN Ovation FFPE WTA 

kit and labeling with the Encore Biotin Module. Data analysis utilized 

Partek and Genetrix software. Results: All PPB cases and 7 of 21 ERMS 

cases were � 4 years old. 20 transcripts (10 annotated, 10 non-coding 

RNAs) were significantly differentially expressed in ERMS when compared 

to PPB patients. Insulin-like growth factor 2 (IGF2) was uniformly overexpressed 

in ERMS (19/21 � 200) but was expressed at low levels in PPB 

(p�0.001). 2 ERMS cases which had low level IGF2 expression were � 4 

years of age. Expression in the other 5 ERMS aged �4 years was similar to 

ERMS overall (range, 500-2,000). No other differences between the two 

approached this degree of significance, despite a common rhabdomyogenic 

phenotype in the sarcomatous areas of PPB. Conclusions: We conclude that 

PPB is a distinct entity from most ERMS, and is not driven by IGF2 

signaling. Rare cases of ERMS in the very young are more similar to PPB 

than common ERMS. This observation is highly significant, as IGF2 is 

known to drive growth in ERMS, generally related to demethylation 

secondary to LOH of 11p. 




Circulating myeloid-derived suppressor cells in pediatric solid tumor 

patients. Presenting Author: John M. Goldberg, University of Miami Miller 

School of Medicine, Miami, FL 

Background: Cure rates have reached a plateau for many pediatric solid 

tumors. Identifying new therapeutic targets, biomarkers of response and 

prognostic indicators should improve clinical outcomes. Accumulation of 

myeloid derived suppressor cells (MDSCs) is an important mechanism of 

tumor mediated immune evasion. Increased levels of MDSCs in adult 

cancer patients correlate with a worse prognosis, and decrease in levels 

with treatment is associated with benefit. Little is known about MDSCs in 

childhood, or in children with cancer. This pilot measured levels of MDSCs 

in pediatric patients with cancer and healthy children. Methods: We 

enrolled subjects using an Institutional Review Board approved protocol 

after obtaining informed consent. Blood was obtained from 14 children 

with newly diagnosed or recurrent solid tumors at start of therapy. In 10 of 

these patients, levels were also drawn after therapy. Blood was obtained 

once from 6 healthy children in a primary care office. Samples were 

obtained concurrently with complete blood counts. MDSCs were measured 

on fresh whole blood and were defined as Lin-1�/HLADR-/CD 33�/ 

CD11b�/ by flow. Total MDSC numbers were then calculated. Results: The 

mean total number of MDSCs was 596 cells/ul at diagnosis for the 14 

children with cancer and 170 cells/ul for the 6 healthy children (t(18) � 

3.02, p � .0073). For the 10 children with cancer who had repeat values 

measured after treatment, MDSCs decreased in 4 and increased in 6. The 

mean initial MDSC count for these children was 494 cells/ul, and the mean 

post treatment count was 1716 cells/ul (t(9) � 1.81, p � .1036). Larger 

change scores tended to be associated with children treated with alkylator 

therapy followed by G-CSF. The results for percent MDSC in white cells 

mirrored those of total number. Conclusions: Circulating MDSCs were 

higher in pediatric cancer patients than healthy controls. Cancer treatment 

did not reliably reduce MDSC levels. After some treatments, the levels 

increased, potentially increasing immune tolerance. Further research is 

needed to determine if circulating MDSCs are a reliable predictive or 

prognostic marker in pediatric cancer, and whether they represent a 

potential target for therapeutic intervention. 


Diffuse pontine gliomas in children: Do changing strategies change results? 

Presenting Author: Rejin Kebudi, Istanbul University, Cerrahpasa Medical 

Faculty and Oncology Institute, Istanbul, Turkey 

Background: The prognosis of children with diffuse intrinsic pontine 

gliomas (DIPG) is dismal. Despite various studies undertaken to improve 

outcome, radiotherapy (RT) remains the standard treatment, which is 

mostly palliative. This study aims to evaluate characteristics and treatment 

outcome of children with DIPG in a single center. Methods: We retrospectively 

reviewed the demographic, clinical characteristics and treatment 

outcome of children with DIPG treated at Istanbul University, Oncology 

Institute from 1999 to 2011. We also evaluated the group that prospectively 

recieved RT with concurrent and adjuvant temozolamide after 2004. 

Results: 47 children (24 female, 23 male) with the median age of 7 years (6 

months-16 years) were analyzed. The median duration of symptoms was 30 

days (2-630 days). The frequent clinical findings were ataxia, strabismus 

and motor weakness. All patients received RT, 54-60 Gy to the tumor site. 

12 recieved only RT. 35 had concomitant and/or adjuvant chemotherapy 

with RT. 8 recieved cisplatinum, 7 vincristine. Since 2004, 20 patients 

recieved the institutional protocol consisting of temozolomide (TMZ) (75 

mg/m2/day) for 6 weeks concurrent with RT, followed by TMZ (200 

mg/m2/day) for 5 days every 28 days for 12 cycles or until progression. 

There was no major side effect due to TMZ, thrombocytopenia being the 

most frequent, but managable side effect. The median overall survival after 

diagnosis was 13 months (3-132 mo.) for the whole group. The median 

overall survival in 20 patients that received RT and TMZ [ 17 months 

(3-132 months)], was significantly superior than that in 12 patients that 

recieved only RT [ 12 months (3-20 months)] ( (p�0.03). Nimotuzumab 

was given to 4 patients that progressed after RT and TMZ. There was no 

major side effect due to nimotuzumab. One was stable for 1 year with 

significant clinical improvement, the others were stable for 5, 2 and 2 

months after nimotuzumab. Conclusions: In our series, the median survival 

was significantly superior in patients who received RT with concurrent and 

adjuvant temozolamide in comparison to patients that recieved RT alone. 

Nimotuzumab may be promising in some progressive patients, its role as 

upfront treatment needs further investigation. 


Intensive alternating 6-drug chemotherapy for high-risk nonmetastatic 

rhabdomyosarcoma in children and adolescents: Impact on survival. 

Presenting Author: Gerges Attia Demian, National Cancer Institute, Cairo 

University, Cairo, Egypt 

Background: Both 5-year overall survival (OS) and event free survival (EFS) 

for pediatric rhabdomyosarcoma (RMS) has increased in the last 3 decades 

through multimodality, risk-adapted management. The reported EFS for 

high risk RMS in children treated at the NCI in Egypt during the 1990s was 

50%. Using an intensive 6 drug alternating chemotherapy regimen in 

addition to local control measures was our aim to improve the outcome for 

this group of patients. Methods: Forty-six previously untreated patients, 

younger than 21 years of age, with localized high risk RMS received this 

regimen. High risk criteria included: (1) Localized tumors (T1) biopsied or 

incompletely resected, ortumors extending beyond the tissue or organ of 

origin (T2) completely or incompletely resected at any site (excluding orbit, 

uterus, vagina, and paratestis); (2)All node positive patients with primary 

tumor at any site; and (3) All RMS with alveolar histology at any site. 

Chemotherapy regimen comprised 27 weeks of alternating 6 drugs (carboplatin, 

doxorubicin hydrochloride, ifosfamide, actinomycin D, etoposide, 

vincristine). Local therapy (surgery, radiotherapy, or both) was offered at 

week 9. Results: Forty-six patients meeting high-risk criteria were recruited 

from September 2000 to November 2005. Median follow-up of survivors 

was 62 months. The 5-year OS and EFS for the whole group was 64% � 

10% and 47% � 8% respectively. The EFS was significantly affected by: 

the size of the tumor (�5 cmvs.� 5 cm, p� 0.03), SIOP UICC clinical 

stage (p � 0.004), IRS stage (p � 0.01), lymph node status (p � 0.02), 

surgery vs. incisional biopsy (p�0.01) and overall duration of time in which 

therapy was delivered (p � 0.04). There was significant toxicity, mainly 

hematologic, but only one treatment related fatality. Conclusions: The use 

of intensified alternating 6-drug CT did not improve the EFS compared with 

historical control although it was feasible to be delivered safely in a variety 

of outpatient settings. Surgical resection of the tumor is essential. 

Delivering therapy in a timely fashion appears to impact outcome and 

future investigations will focus on impediments to administering chemotherapy 

as scheduled. 


Demographics, treatment, and outcome of retinoblastoma: A large series 

with protocol-based management. Presenting Author: Vijay Anand Palkonda 

Reddy, Apollo Hospitals, Hyderabad, India 

Background: Retinoblastoma is the most common primary intraocular 

malignancy of childhood with incidence of 1 in 20,000 and the third most 

common pediatric cancer. In the previous decades, early diagnosis and 

treatment of retinoblastoma have improved survival rates in developed 

countries. Nevertheless, protocol based management help reduce the 

mortality rate associated with advanced tumors. The purpose of the study is 

to report demographics, management, and outcome of retinoblastoma in 

the Ocular oncology centre of South India. Methods: Consecutive case 

series of 1,543 eyes of 1,067 patients with 22 years of follow-up. 

Demographics, clinical features, treatment and outcome (survival, organ 

salvage and function salvage) were analyzed. Management comprised of 

focal therapy for small tumors, standard triple drug chemoreduction for 

larger (�4mm) tumors, high dose chemoreduction and periocular chemotherapy 

for vitreous seeds, and enucleation for advanced tumors. Adjuvant 

therapy was provided in patients with histopathologic high-risk factors for 

systemic metastasis. Orbital retinoblastoma was managed with a multimodal 

treatment protocol. Results: Sixty-six percent were �3 years of age. 

Forty-five percent were bilateral. Symptoms were leucocoria (33%), vision 

loss (10%), proptosis (6%), and squint (6%). The tumor was intraocular in 

94% and orbital in 6%. Management was by protocol and included 

enucleation (52%), chemoreduction (26%), focal therapy (11%), and 

external beam radiation (5%). Fifty-five percent of enucleated patients had 

histopathologic risk factors for metastasis and received adjuvant chemotherapy. 

Chemoreduction with focal therapy resulted in eye and vision 

salvage in 92%. Overall, 94% survived. Conclusions: Protocol-based 

management of retinoblastoma provides excellent prognosis for survival, 

eye salvage and vision salvage. 



Long-term outcomes of children with Xp11.2 translocation renal cell 

carcinoma. Presenting Author: Hiroshi Asanuma, Department of Urology, 

Keio University School of Medicine, Tokyo, Japan 

Background: We aimed to assess the clinico-pathological characteristics 

and the long-term prognosis of Xp11.2 translocation renal cell carcinoma 

(Xp-RCC) in children. Methods: A total of 52 Japanese children with renal 

tumors were presented to our institutions. Of these, 5 (10%) had RCC, and 

all RCCs were Xp11.2 translocation subtype with positive nuclear transcription 

factor E3 immunostaining. We retrospectively reviewed the pathological 

and hospital records of these 5 patients. Results: In the 1 boy and 4 girls 

with an average age of 9 years 7 months at diagnosis, the most common 

presenting complains were gross hematuria (60%) and palpable abdominal 

mass (40%). All patients had unilateral disease and there was no special 

family or medical history in any children. Computerized tomography 

revealed characteristic calcification within the tumor in 4 of the 5 patients 

(80%). In the remaining case, the lesion had high density areas with 

microcalcification, as confirmed by histopathological study. In 3 patients 

with regional lymph node metastasis, calcification was also observed in the 

metastatic lesions. Stage of the disease were stage I in 1 patient, II in 1, IV 

without and with distant metastasis in 2 and 1, respectively. All patients 

underwent transabdominal nephrectomy with regional lymphadenectomy. 

One patient with stage I disease had multiple metastases 15 months after 

surgery and died of disease in spite of interferon and chemotherapy 4 years 

postoperatively. Three patients received adjuvant interferon therapy and 2 

of them are without evidence of recurrence postoperative 19 and 14 years, 

respectively. One of them had lymph node and lung metastases 12 years 

postoperatively. The remaining one patient had multiple lymph node, lung, 

bone, and dura mater metastases at diagnosis. The latter 2 patients have 

received targeted therapy (sunitinib, temsirolimus) without their progression 

for 6 and 12 months, respectively. Conclusions: Calcification within 

the tumor and/or metastatic lesions is characteristic findings suggestive of 

Xp-RCC in children. Regional lymphadenectomy or targeted therapy may 

provide some benefit in selected pediatric patients. Long-term follow-up is 

essential in pediatric patients with RCC. 


Substitution of cisplatin for etoposide in 2 of 3 induction cycles of CAV/IE 

with subsequent irinotecan and vincristine for relapse in adults with Ewing 

sarcoma (ES) and primitive neuroectodermal tumor (PNET). Presenting 

Author: Daniel A. Rushing, Indiana University Melvin and Bren Simon 

Cancer Center, Indianapolis, IN 

Background: Treatment for adults with cyclophosphamide, doxorubicin and 

vincristine alternating with ifosfamide and etoposide (CAV/IE) for ES/PNET 

is based on the success reported in children however the same treatment in 

adults is less effective. 50% of relapsed disease is expected to occur in the 

lungs with median survival of 12.5 months (mo) after relapse. Since 

Cisplatin is used for relapse, we initially substituted cisplatin for etoposide 

in courses#2and#3ofIEfor2patients (pts) who were not responding to 

IE as determined by serial CT scanning and then used it for all pts. 

Relapsed pts were treated with irinotecan � vincristine (IRI-V) for at least 2 

cycles as salvage therapy. We report the effect of cisplatin on influencing 

the relapse pattern and the effect of IRI-V on survival for pts after relapse 

Methods: A retrospective chart review of 19 consecutive adult pts (July 

2004 to June 2011), with newly diagnosed ES /PNET were treated with 

CAV/IE as per H. Grier NEJM 2003 and modified as a 14 day cycle. 

Cisplatin 20 mg/m2 I.V.qdX4wassubstituted for etoposide for courses # 

2 and 3 of IE and combined with ifosfamide as above (IC) followed by 

surgery or RT. For pts with relapse Irinotecan was given I.V. 20mg/m2 days 

1-5 & 8-12 � vcr I.V. 2mg days1&8q21days for 2 or more cycles. Repeat 

treatment with CAV, IE or IC was also utilized for relapse. We evaluated the 

toxicities, the pattern of relapse and the survival after relapse with these 

treatments Results: Grade IV hematologic toxicity occurred in 11 of 19 pts 

treated with CAV vs. 7of 19 pts treated with IE vs. 7 of 19 pts treated with 

IC and 1 of 11 pts treated with IRI-V but 3 of those 11 pts had Grade IV 

diarrhea. Median survival was 44.8� mo for 10 pts with non- metastatic 

and 23 mo for 9 pts with metastatic disease respectively. More importantly 

median survival from the time of relapse was 22.5� mo, (range 12.7 to 

31� mo). 11 pts relapsed: 2 pts only in bone, 9 pts Local only, 0 pts had 

distant lung recurrence Conclusions: Cisplatin appears to markedly alter the 

relapse pattern in adults with ES/PNET and Irinotecan �vcr appears to 

prolong survival in relapsed pts previously treated with cisplatin. 


623s 


Preclinical study of a PARP inhibitor in neuroblastoma. Presenting Author: 

Anissa Addioui, Research Center CHU Sainte Justine, Montreal, QC, 

Canada 

Background: Neuroblastoma (NB) is the most common extracranial solid 

tumor of childhood. In spite of many therapeutic improvements, only 60% 

survive long term despite aggressive combinations of multi-agent chemotherapy. 

In previous studies, we have demonstrated that tumor initiating 

cells (TIC) expressing CD133 (CD133high ) in NB are more resistant to 

chemotherapy. Moreover, these cells express higher levels of PARP-1, a 

central protein involved in DNA repair. PARP-1 expression is significantly 

lower in NB usually showing spontaneous regression than in standard NB, 

suggesting an implication of PARP-1 in NB progression. The objective of 

this study is to determine the efficacy in vitro of AG-014699 (AG), a PARPinhibitor, 

used in monotherapy or in combination to cisplatine (CP) and 

doxorubicine (DR), classical chemotherapeutic agents used in NB treatment, 

on NB cell survival. Methods: Six NB cell lines (parental or CD133high purified by flow cytometry (FACS)) were treated with AG alone or in 

association to CP or DR. PARP-1 ELISA protein assay was used to 

determine the optimal drug concentration needed to inhibit the protein. 

Cell survival was measured by MTT test. Western Blots were done to 

evaluate any apoptotic or autophagic pathway modulations. Quantification 

of DNA damage in treated cell was done by immunofluorescence of H2A-X 

protein. Results: We showed that a 4�M concentration of AG is sufficient for 

PARP-1 inhibition. One third of celllines presented a sensitivity to AG when 

used in monotherapy with an IC50 lower than 5�M. However, AG 

demonstrated synergistic effects when associated to DR, decreasing the 

IC50 by half, although none is observed when combined to CP. Sentitivity 

of the TIC did not appear to be more important than the bulk cells. With 

increasing concentration of AG, our WB showed no increase in cleaved 

Caspase-3 suggesting no modulation of the apoptotic pathway. However, 

autophagy seemed to be upregulated confirmed by an increase in cleaved 

LC3 II protein. Double strand breaks increased 2.5 folds when 4�M AGis 

added to the IC50 of DR. Conclusions: AG used in combination at 

potentially therapeutic doses shows promising results in NB. These results 

will allow for the improvement of NB treatments by introducing a new 

therapeutic strategy. 


High-dose thiotepa: Neurotoxicity and risk factors in children with solid 

tumors. Presenting Author: Christophe Maritaz, Institut Gustave Roussy, 

Clinical Pharmacy Department, Villejuif, France 

Background: Thiotepa (TTP) is a cytotoxic agent used in children with solid 

tumors at high doses followed by autologous stem cell transplantation 

(ASCT). During these treatments, neurological adverse events (NAE) were 

observed. Causal relationships and risk factors were investigated. Methods: 

Patients with solid tumors treated with high-dose thiotepa with ASCT 

between May 1987 and March 2011 were retrospectively identified. 

Clinico-biological data were collected and NAE were identified from 

medical and nursing records. Toxicity was graded according to the NCI 

CTCAE v4.03 classification. Imputability of thiotepa was assessed according 

to Begaud et al. method. Analysis of risk factors was assessed with 

Fisher’s exact test (alpha 0.05) and relative risk was estimated by 

calculating odds ratios with their 95% confidence interval. Results: 251 

patients received 307 courses (56 patients received twice) of high-dose 

thiotepa (600 mg/m²: 82 courses; 720 mg/m²: 76 courses; 900 mg/m²: 

149 courses) with ASCT. The median age was 8.33 years (range, 1 - 31.2 

years). 81 NAE (26.4%) were described. NAE were considered “possibly” 

related to TTP in 9 courses, “likely” related to TTP in 35 courses and “very 

likely” related to TTP in 13 courses. Other NAE were assessed “doubtful” 

or “incompatible”. In these 57 NAE, neurological symptoms appeared at a 

median time of 2 days (range, 0-4days) after the introduction of TTP. 

Symptoms were headache, tremor, dizziness and confusion, blurred vision, 

seizure, pyramidal tract syndrome, cerebellar syndrome, opsoclonusmyoclonus 

syndrome and coma. These events disappeared without sequelea 

in a median time of 3 days (range, 1-8days). TTP was reintroduced in 

21 cases. NAE reappeared in 12 cases. For 3 patients with seizure during 

the first course, premedication with clonazepam prevented NAE during the 

second course. The use of analgesic for moderate to severe pain, such as 

tramadol or codeine, increased the probabiblity to have NAE (OR 5.6467; 

95CI [1.5523-21.2786]; p 0.037). Conclusions: In our study, the incidence 

of NAE related to TTP was 18.6%. The outcome was favorable 

without sequelea in all cases. TTP could be reintroduced after NAE. The 

association of TTP with tramadol increases the risk of neurotoxicity. 




Do children, adolescents, and young adults with soft tissue sarcoma benefit 

from early detection of recurrences? Results of a population-based study. 

Presenting Author: Tobias M. Dantonello, Olgahospital, Pediatrics 5, 

Klinikum Stuttgart, Stuttgart, Germany 

Background: Most patients with pediatric soft tissue sarcoma (PSTS) 

achieve a 1st remission with primary therapy, but recurrences are frequent 

and drive mortality. Relapse detection (RD) is the foundation of posttreatment 

surveillance. The rationale for frequent follow-up investigations 

is RD in an early stage with better salvage options. There is however little 

evidence regarding the value of early asymptomatic RD and it was not 

investigated by any larger or population-based study in PSTS. We determined 

whether early radiographic RD in asymptomatic patients improves 

post-relapse outcome. Methods: Patients aged � 18 years at first referencereviewed 

PSTS-diagnosis registered with CWS were enrolled if a 1st relapse 

occurred between 1/2003 and 7/2010. The methods of RD and their 

impact on outcome were evaluated. The data were correlated with the 

German Childhood Cancer Registry (GCCR), which receives all information 

about cancer patients � 18 years. Results: 235 patients from Germany (n � 

212) and Sweden/Switzerland (n � 23) were eligible. In 2010 all German 

PSTS-patients were registered both with the GCCR and CWS. The most 

common PSTS-histiotypes were embryonal (n � 76) and alveolar (n � 74) 

rhabdomyosarcoma. 156 patients had primary nonmetastatic PSTS. The 

median time to relapse diagnosis (TTRD) was 1.4 years. 118 recurrences 

were locoregional, 38 combined and 79 metastatic. In 229 patients, the 

methods leading to RD could be evaluated. 139 recurrences were detected 

because of clinical signs and symptoms, primarily observed by patients 

and/or parents in 72%. 90 RDs were radiographic in asymptomatic 

patients. TTRD did not differ between symptomatic and asymptomatic 

patients. As of 12/2011, 77/235 patients are currently alive with a median 

follow-up of 5.4 years. Overall survival from primary surgery at 3-, 5-, and 

10-years for all 235 patients was 49%, 34% and 22%. It was 43%, 29% 

and 23% for the symptomatic and 59%, 40% and 21% for the asymptomatic 

group (p � 0.05). Conclusions: In this series, early radiographic RD in 

asymptomatic PSTS-patients had no significant impact on TTRD or 

post-relapse survival, although asymptomatic patients tended to survive 

longer. 


Use of pharmacokinetic modeling to optimize direct inhibition of the 

�undruggable� target EWS-FLI1 of Ewing sarcoma. Presenting Author: 

Jeffrey Toretsky, Georgetown Lombardi Comprehensive Cancer Center, 

Washington, DC 

Background: Chimeric transcription factors are ideal anti-cancer targets; 

however, they lack enzymatic activity thus rendering them ‘undruggable’ 

proteins. The EWS-FLI1 fusion protein of Ewing sarcoma (ES) has been 

validated as an anticancer target both alone and as a partner of RNA 

Helicase A (RHA). Our prior work identified the small molecule YK-4-279 

as a specific inhibitor that blocks RHA from binding to EWS-FLI1. Blocking 

this interaction leads to apoptosis. We have modeled YK-4-279 treatment 

using ES cells to establish the duration of YK-4-279 exposure that leads to 

apoptosis. Methods: Apoptosis was measured by caspase-3 cleavage. A 

validated plasma detection method allows for HPLC measurement of 

YK-4-279. Pharmacokinetic (PK) models of YK-4-279 for both intraperitoneal 

(IP) and intravenous (IV) administration were developed in SD rats and 

BL6 mice. Results: ES cell lines were exposed to YK-4-279 over a 

time-course, followed by a caspase-3 activity assay that demonstrated a 

minimum of 16 hours exposure was necessary to achieve maximal 

apoptosis using either 3 or 10 microM compound. A dose-dependency 

assay demonstrated that while apoptosis could be achieved with 30 – 80 

microM YK-4-279 after 4 hours of treatment, caspase-3 activity was less 

than or equal to 3 microM for 16 hours. Rat PK modeling demonstrated a 

t1/2 of 30 minutes following IV administration. BL6 mice demonstrated 

similar kinetics to the rat. SCID/bg mice, which are necessary for tumor 

efficacy studies, demonstrated approximately 50% faster clearance than 

either rat or BL6 mice. Absolute bioavailability for IP administration was 

41%. Conclusions: Models will be created to optimize IP dosing regimen. 

The optimized IP dosage and dosing intervals will be evaluated in tumor 

bearing animals in order to advance development of YK-4-279. The results 

of these studies will be used to guide toxicology studies in animals. In 

addition, pharmacodynamics models are being developed to compare 

YK-4-279 levels with functional activity. The combined results of these 

investigations will lead to human clinical trials for this first-in-chemical 

class, first-in-mechanism drug candidate. 


A multidisciplinary treatment comprising standard chemotherapy with 

vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide 

for Ewing sarcoma family of tumor (ESFT) in Japan: Results of the first 

Japan Ewing Sarcoma Study (JESS) 04. Presenting Author: Atsushi 

Makimoto, National Cancer Center Hospital, Tokyo, Japan 

Background: Survival rate of ESFT in Japan was reportedly less than 50% in 

1990s. The JESS started in order to improve this condition by conducting 

clinical trials for ESFT in Japan. Methods: This is a phase II, nonrandomized 

trial to test safety and efficacy of multidisciplinary treatment 

for non-metastatic ESFT. Age under 30 is eligible. Chemotherapy regimens 

are alternating vincristine 1.5 mg/m2 on day 1, doxorubicin 37.5 mg/m2 on 

days 1 and 2, cyclophosphamide 1200 mg/m2 on day 1 (VDC) and 

ifosfamide 1800 mg/m2 on days 1 through 5 and etoposide 100 mg/m2 on 

days 1 through 5 (IE) repeating every 21 days for 52 weeks. Local 

treatment includes surgical resection and/or radiation therapy, of which 

dosage varies from 0 to 55.8 Gy based on margin of the resection and 

pathological response. Primary endpoint is 3 year progression free survival 

(PFS). Statistical design was made to test whether the lower limit of 90% 

confidence interval (CI) of PFS will exceed the threshold of 60%. Planned 

sample size is 53 patients including 10% ineligible patients. Results: 

Fifty-three patients were registered from December 2004 to May 2008. 

Among the 53 patients, 7 patients were judged ineligible after the 

registration (metastatic disease 1, changed diagnoses 6). Forty six patients 

were considered as per protocol set and used for efficacy analyses. Three 

year PFS is 71.7% (90% CI: 0.59 – 0.81). Estimated 5 year PFS and OS 

are both 69.6%. Radiographic response rate (RR) in evaluable 38 patients 

is 71.1% and pathological RR in 25 is 52.0%. In safety data, hematological 

toxicities are significant such as grade 4 neutropenia observed in 98%. 

Although there is no previously unknown adverse event reported, there are 

three patients who experienced secondary malignancies (ALL 1, MDS 1, 

osteosarcoma 1). Conclusions: A multi-disciplinary treatment comprising 

standard multi-agent chemotherapy with vincristine, doxorubicin, cyclophosphamide, 

ifosfamide and etoposide improved outcome of Ewing sarcoma 

family of tumor in Japan although statistical confirmation of absolute 

efficacy was not successful. 


Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in 

children with high-risk neuroblastoma. Presenting Author: Ami V. Desai, 

The Children’s Hospital of Philadelphia, Philadelphia, PA 

Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb) 

that significantly improves survival in high-risk neuroblastoma, was previously 

reported to be highly variable in children, and its clearance (CL, 130 

mL/h · m2 ) and volume of distribution (Vdss, 32 L/m2 ) were �10-fold 

higher than the CL and Vdss of other cMoAbs. Characterizing the PK of 

ch14.18 and the factors responsible for its variability could lead to 

alternative dosing strategies that reduce toxicity. Methods: Detailed PK 

sampling was performed prior to, during and for 25 d after 4 daily 10 h 

infusions of 25 mg/m2 of ch14.18 administered with sargramostim 

(ANBL0032) in children enrolled on an IRB-approved institutional correlative 

protocol supported by United Therapeutics Corp. Ch14.18 concentrations 

were measured with a validated ELISA with a lower limit of detection 

of 0.44 mcg/mL. PK parameters were derived using non-compartmental 

methods and reported as median (range). Results: 5 males and 4 females, 

median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on 

cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were 

re-studied on C3. Data from 3 patients are not included because pretreatment 

plasma samples contained a substance that interfered with the 

ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and 

ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220 

(120-390) h, and the CL was 11 (3.8-16) mL/h · m2 , which is similar to 

the average CL of 4 other cMoAbs (11 mL/h · m2 ). The Vdss of 2.8 (1.2-3.9) 

L/m2 approximated blood volume and was similar to the Vdss of other 

cMoAbs (1.7 L/m2 ) and humanized MoAbs (2.8 L/m2 ). AUC0-� in 2 patients 

studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690 

mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children 

are similar to those in adults receiving ch14.18 at the same dose and 

similar to other cMoAbs. Ch14.18 PK in children was less variable than 

previously reported. The identity of the interfering substance in the plasma 

of some patients requires further investigation. A limited sampling strategy 

will be developed from these data for use in larger multi-institutional PK 

studies of ch14.18. 



Ifomide/pirarubicin/etoposide/carboplatin (ITEC) as second-line chemotherapy 

for hepatoblastoma. Presenting Author: Eiso Hiyama, Hiroshima 

Univerisity, Natural Science Center for Basic Research and Development, 

Hiroshima, Japan 

Background: The Japanese Study Group for Pediatric Liver Tumor is running 

cooperative treatment studies on hepatoblastoma (HBL) since 1991. The 

main aim in JPLT-1 study was to evaluate the efficacy of cisplatin/ 

pirarubicin (CITA). A total of 145 cases were registered and their 5-year 

overall survival (OS) and event-free survival (EFS) were 73.4% and 66%, 

respectively (J Pediatr Surg 37: 851-6, 2002). Then, JPLT-2 protocol, in 

which CITA is kept as the first-line treatment, and ifomide, etoposide, 

pirarubicin, and carboplatin (ITEC) is the second-line regimen for CITAresistant 

cases, was launched to evaluate the cure rate of risk-stratified 

HBL: standard risk HBL (a tumor involving three or fewer sectors of the 

liver) and high risk HBL (a tumor involving all sectors of the liver or with 

metastasis). Methods: In JPLT-2, 281 HBL cases were registered in JPLT-2 

between 1999 and 2010, and 69 cases underwent ITEC protocol due to 

poor response to the CITA regimen. To evaluate the efficacy of the ITEC 

regimen, surgical resectability and outcome of these 69 patients who 

underwent this treatment. Results: These 69 cases were divided into 53 

high-risk (metastatic, involvement of all sectors of the liver, vascular 

invasion and/or extra-hepatic intra-abdominal disease) and 16 standardrisk 

HBL (all others). All cases were initially treated with the CITA regimen 

and then underwent the ITEC regimen due to poor response to CITA. 

Complete resection of the liver tumor could be achieved in 48 patients 

(69.6%) consisting of 13 (81%) standard, 35 (66%) high- risk cases. The 

5-year OS and EFS of the cases with standard risk HB were 96% and 76%, 

while that of the cases with high risk HB was 54% and 34%. The late phase 

complications in 281 cases were 3 cases with maldevelopment, 13 with 

cardiac complications, 20 with ototoxicity and 5 with second malignancies. 

Conclusions: As compared with the CITA-sensitive cases, ITEC regimen 

achieved similar rates of survival for CITA-resistant cases both in standard 

and high-risk HBL cases, indicating ITEC is effective as a second-line 

chemotherapeutic regimen for HBL. 


A phase II trial of docetaxel and irinotecan (DI) in children and young adults 

with recurrent or refractory Ewing sarcoma family of tumor (ESFT). 

Presenting Author: Jong Hyung Yoon, Center for Pediatric Oncology, 

National Cancer Center, Goyang, South Korea 

Background: Patients with ESFT resistant to second-line therapy, such as 

topotecan plus cyclophosphamide, have a dismal prognosis and few 

therapeutic options. Docetaxel (D), a microtubule inhibitor, demonstrated 

activity in patients with ESFT (Zwerdling T et al. Cancer 2006:106:1821- 

1828). Irinotecan (I), a toposiomerase I inhibitor, is being evaluated in 

clinical trials for ESFT. Despite the different mechanisms of action of D and 

I, and their activities as a single-agent against ESFT, DI combination has 

not been previously evaluated in ESFT. Thus, we prospectively performed a 

single-arm, phase II trial of DI in a single center in Korea. Methods: Patients 

�30 years with ESFT, who failed second-line therapy, were eligible for the 

study. D was administered IV over 60 minutes at a dose of 100 mg/m2 on 

Day 1, and I at a dose of 80 mg/m2 over 90 minutes on Days 1 and 8 of a 

21-day cycle until disease progression. The primary end-point was objective 

response assessed by RECIST; the secondary end-point was safety. All 

toxicities were graded according to the National Cancer Institute’s Common 

Toxicity Criteria (version 4.0). Results: Of seven eligible patients (4 males; 

median age, 17 years (range 5-21)), 4 were recurrent/refractory cases, and 

3 refractory cases. Median number of previous regimens was 6 (range 3-6). 

One CR, 1 PR, and 5 PD were obtained by DI combination (median number 

of cycles, 2 (range 1-15)), with objective response (CR�PR) rate of 2/7 

(28.6%). One patient with PR achieved CR with subsequent surgery. CR of 

these two patients lasted 8.9 months and 10.6 months. Of all seven 

patients fully evaluable for toxicity, grade 4 neutropenia occurred in 7 

(100%); grade 3 and 4 thrombocytopenia in 1 (14%) and 6 (86%), 

respectively; grade 3 pericardial effusion, paresthesia, motor weakness, 

oral mucositis, each in one (14%). Two patients required �1 dose delay; 2 

required �1 dose reduction due to adverse events, but no one experienced 

treatment-related mortality. Conclusions: DI combination demonstrated 

activity in children and young adults with ESFT who were heavily pretreated, 

and was feasible. 


625s 


Cell cycle and apoptosis regulatory protein (CARP)-1 expression in neuroblastoma. 

Presenting Author: Santosh S. Hanmod, Children’s Hospital of 

Michigan, Detroit, MI 

Background: Neuroblastoma (NB) is the most common extra-cranial solid 

tumor in children. The prognosis for patients with high risk NB is still poor. 

Study of additional prognostic factors will enhance current understanding 

of the tumor biology and risk stratification. CARP-1 is a recently identified 

molecule mediating apoptosis signaling by agents like doxorubicin and 

etoposide. Since these agents are used in the front line treatment of NB, we 

tested whether CARP-1 expression could be another prognostic factor in 

NB. Methods: CARP-1 expression was examined by Western blot in a pair of 

NB cell lines, SK-N-SH and SK-N-SH Dox. We reviewed medical records of 

patients with NB at Children’s Hospital of Michigan from 2000-2009 and 

examined CARP-1 expression by immune-histochemistry in the archived, 

formalin fixed paraffin embedded NB tissues. CARP-1 expression was 

recorded as positive or negative. Correlation of CARP-1 expression and 

progression free survival (PFS) was calculated. Results: CARP-1 expression 

was detected in SK-N-SH but not SK-N-SH Dox, a doxorubicin-resistant 

derivative of SK-N-SH, suggesting that resistance to doxorubicin is associated 

with decreased level of CARP-1 expression in NB cells. Of the 30 

cases studied, 53 % (16/30) expressed CARP-1. There was no significant 

difference in N-myc amplification status (13% vs.14%, p�0.3), or 

proportion of unfavorable Shimada histology (60% vs. 64%, p�0.5) 

between CARP-1 positive vs. negative groups. Twenty three percent (7/22) 

patients progressed or relapsed, including 2/16 (13%) in CARP-1 positive 

group vs. 5/14 (36%) in CARP-1 negative group (p�0.1). There was no 

significant difference in the PFS at 1 year (94% vs.79%, p�0.2) and 3 

year (86% vs.71%, p�0.2) between CARP-1 positive vs. negative groups. 

Conclusions: CARP-1 expression was decreased in doxorubicin resistant NB 

cell line. CARP-1 expression was detected in approximately half (53%) of 

NB tumors. Patients with NB who expressed CARP-1 showed trend towards 

better 1- & 3-year PFS as compared to those who did not express CARP-1, 

however, the results are not statistically significant which could be due to 

the small sample size. Further study with a larger number of patients is 

warranted to clarify these findings. 


Assessment of peripheral blood T regulatory cells (Tregs) in PNET/Ewing 

sarcoma: A prospective study. Presenting Author: Tilak Tvsvgk, Dr. B.R.A., 

IRCH, New Delhi, India 

Background: Tregs in bone marrow have been previously evaluated in PNET 

patients; however, data on peripheral blood ccirculating Tregs is lacking. 

The objective of our study was to determine baseline Treg frequency in 

PNET patients and correlate the same with patient characteristics and 

outcome. Methods: Samples of 5ml venous blood were obtained from 38 

newly diagnosed PNET patients at diagnosis along with six healthy controls. 

Flow cytometric analysis was done for detecting Treg cells 

[CD4�CD25�FoxP3�]. Results: Thirty-eight patients with median age 17 

years; male/female ratio of 5.5:1 had significantly higher baseline Tregs 

than healthy controls [9.17%�.3.08 vs 3.16�1.49%; p��0.0001]. 

Eight patients (21.1%) had fever at baseline presentation. The disease was 

extra-skeletal in one and metastatic at baseline in 11 (28.9%) patients. 

Ten patients relapsed on standard protocol of therapy and seven died. The 

median Treg frequency was 8.84% (Range: 2.49-16.31). When the Tregs 

were categorized as high and low based on the median value, patients with 

fever had a significantly higher Tregs than those without fever 

[11.3%�.3.5% vs 8.6% �. 2.7%; p�0.02]. No significant association of 

peripheral blood Treg cells frequency was noted with other factors like age, 

sex, metastatic disease, relapse or death. The EFS was 55% and OS 70% 

of the entire cohort at a median follow up of 14 months. There was no 

significant difference in the EFS or OS between the high and low Treg cell 

groups [EFS- 52% vs 64%; p�0.99 and OS-75% vs 70%; p�0.26]. 

Conclusions: This is the first study on circulating Tregs in PNET, and it 

shows that the peripheral blood Treg frequencies are higher in these 

patients as compared to healthy controls. Further, PNET patients with fever 

had significantly higher Treg frequency. However, Tregs did not differ with 

respect to metastatic disease at presentation, EFS or OS. 




A phase I trial of MK 2206 in children with refractory solid tumors: A 

Children’s Oncology Group study. Presenting Author: Christine L. Phillips, 

Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 

Background: AKT, a serine threonine protein kinase, is activated downstream 

of phosphatidylinositol 3-kinase (PI3K) which transmits signals 

from cytokines, growth factors and oncoproteins to multiple targets. 

Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT 

pathway is downstream of most of the common growth factor tyrosine 

kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of 

tumor progression in many cancers. AKT protein kinase is activated in many 

pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, 

neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. 

MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated 

antitumor activity in in vitro and in vivo cancer models.A phase I trial 

evaluating MK2206 was conducted in children with refractory solid 

tumors. Methods: Using a rolling-6 design, MK2206 was administered 

either once every 7 days (schedule 1), or once every other day (schedule 2) 

in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and 

trough samples were obtained on days 7, 14, 21 and 28. Biological studies 

included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and 

post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: 

Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] 

with malignant glioma (14), ependymoma (4), hepatocellular carcinoma 

(3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were 

fully evaluable for toxicity (schedule 1 n�17; schedule 2 n�17). Schedule 

1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2 ; grade 4 

hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2 . There were no 

DLTs at 35 mg/m2 and dose level 4 (58 mg/m2 ) is currently open for patient 

accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline 

phosphatase in 1/6 patients at 90 mg/m2 ; grade 3 rash in 1/6 patients at 

120 mg/m2 ), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: 

The recommended pediatric phase II dose of weekly MK2206 is 120 

mg/m2 and the last cohort of patients to the every other day dosing schedule 

of MMK206 is enrolling. PK and PD data are currently being analyzed and 



Integration of genomic and proteomic data to identify MYCN-regulated 

genes, proteins, and interaction networks in neuroblastoma cells. Presenting 

Author: Kolbrun Kristjansdottir, University of Chicago, Chicago, IL 

Background: Neuroblastoma is the most common extracranial solid tumor 

found in children. The most common marker prognostic of poor outcome is 

amplification of the MYCN oncogene, yet the biological programs by which 

MYCN affects its aggressive phenotype are largely unknown. In order to 

identify biological pathways affected by MYCN amplification, we performed 

global analysis of genes and proteins in the Tet 21/N neuroblastoma cell 

line. Methods: MYCN expression in Tet21/N cells is regulated by tetracycline. 

Gene arrays were performed on MYCN-high and MYCN-low Tet21/N 

cells and SH-EP parental cells using Affymetrix GeneChip Human Exon 1.0 

ST. For proteomic analysis, the cells were labeled with stable isotopes for 

relative quantitation, enriched for phosphoproteins to enhance detection of 

signaling proteins, and analyzed by GeLC-MS/MS analysis. Integrative 

pathway analysis was performed on the genomic and proteomic datasets 

using DAVE and GeneGo. Results: Integrating genomic and proteomic data 

in MYCN-high and MYCN-low expressing cells identified 88 proteins and 

300 genes that change in abundance. We compare these results with 

previous studies and find both novel and previously identified genes and 

proteins. Integrating proteomic and genomic data identified over 50 gene 

products that are present in both analyses and are altered in abundance in 

response to modulating MYCN expression. The majority of these have 

discordant abundance changes, with protein levels more frequently altered 

with no change in gene expression. We have validated changes in protein 

levels using Western blots including NPM1 and MATR3. We present 

interaction networks and pathways that correlate with MYCN expression. 

Conclusions: We showed a significant discordance between gene and 

protein expression, underscoring the need for integrative genomic and 

proteomic analysis to describe complex systems. Our analysis identified 

previously reported and novel genes and proteins and networks regulated by 

MYCN expression that may provide new insights into the biology of 

MYCN-amplified tumors. 


Development of an open-source, flexible framework for interinstitutional 

data sharing and collaboration. Presenting Author: Chaim Kirby, University 

of Chicago, Chicago, IL 

Background: Clinical information, “-omic” datasets, and tissue samples are 

becoming more difficult to harmonize and manage for advanced data 

mining. We believe that clinical research data can be centralized and 

provide direct access to sample availability and associated data from a 

variety of information stores. Methods: We obtained a standardized set of 

anonymized patient data from the International Neuroblastoma Risk 

Group. The cohort consists of more than 11,000 children diagnosed 

worldwide between 1974 and 2002. The data consist of 34 metrics, such 

as age at diagnosis, stage of tumor, and other clinical and biological 

markers. We instantiated the dataset into a Postgres database, and using 

the Django web framework, created a data model for rapid development of 

tools and views and built a front-end interface for generating complex 

queries. To test the feasibility of accessing information on disparate and 

geographically distinct data samples, we have a formal agreement with the 

Children’s Oncology Group Tumor Bank at The Research Institute at 

Nationwide Children’s Hospital. Based on query results, we consume the 

Tumor Bank tissue inventory data through a web-facing application 

programming interface. The end-user is presented only with the number of 

patients who match their query search terms and for whom tissue samples 

are available. Results: We have completed our initial implementation and 

have agreements for collaboration with other international consortium 

groups. We have created a paradigm for statisticians to securely update and 

add data, and a verification system checks for internal validity and provides 

a report of the transaction. Our system can initiate queries and accept 

results in a variety of standards-compliant formats, and will be available in 

demonstration form by May 2012. Conclusions: Querying patient data while 

interrogating external sources allows researchers to observe which ancillary 

data and samples are available and to quickly download data or request any 

samples. While designed around a neuroblastoma dataset, our system can 

be applied to a variety of clinical scenarios and will be made available 

through an open-source license. 


Proton radiotherapy for rhabomyosarcoma: Preliminary results from a 

multicenter prospective study. Presenting Author: Torunn I. Yock, Massachusetts 


Background: Pediatric rhabdomyosarcoma (RMS) is commonly cured with 

chemotherapy and radiation. However, late effects of radiotherapy (RT) can 

be disabling. Proton RT irradiates less normal tissue, which should result in 

fewer late side effects of treatment. The purpose of this study was to 

describe the disease control and side effect profile of proton RT in RMS 

patients (pts). Methods: Eligible pts included those with localized disease 

and metastatic embryonal RMS if age 2-10. All pts were treated with VAC 

(vincristine, actinomycin, cyclophosphamide) based chemotherapy and 

proton RT, median dose 50.4 Gy (36-50.4 GyRBE). Concurrent enrollment 

in COG protocols was allowed. All pathology/imaging was reviewed at the 

treating institution. Results: 47 pts with RMS were prospectively enrolled 

from January 2005 to June 2011 and evaluable for analysis. Median age 

was 3.1 yrs, (range 0.6-15.6 years; M/F ratio 23:24). There were 1, 7, 37, 

and 2 Group I, II, III and IV and 14, 12, 19 and 2, Stage I-IV pts 

respectively, and 33 with embryonal 14 with alveolar/other. Most common 

sites included PM (48.9%), orbital (23.4%) bladder/prostate (6.4%), H&N 

non-PM (6.4%), extremities (4.3%), trunk/abdomen 2.1%), perineal/anal 

region (2.1%) and other (6.4%). Median follow-up is 15.2 months. 

One/two-year overall survival (OS) and progression-free survival (PFS) for 

the entire group is 94/81% (OS) and 79/73% (PFS). 2-year OS for stage 

I,II/III,IV pts is 91/66% (OS, p�0.114) and two-year PFS for these pts is 

86/57%, respectively, (p�0.083. 16 (34%) had grade 3/4 acute toxicities 

attributable to the radiation during treatment, the most common of which 

was mucositis/oral pain (12.8%), anorexia (4.3%), and erythema (4.3%). 

Among the 24 pts analyzable for late toxicities with at least 2 yrs of follow 

up, there were no grade 3 or 4 late toxicities attributable to radiation. 

Conclusions: Early results of this prospective trial demonstrate comparable 

disease outcomes and thus far limited late effects in a young pediatric RMS 

population. However, additional follow up is needed to determine if protons 

truly reduce rates and severity of late effects compared with photon cohorts 

published in the literature. 



A national survey of general internists’ preferences and knowledge gaps 

regarding the care of childhood cancer survivors. Presenting Author: Tara 

O. Henderson, University of Chicago Pritzker School of Medicine, Chicago, 

IL 

Background: Although most childhood cancer survivors (CCS) report obtaining 

health care in the community, primary care physicians’ views and 

knowledge regarding the long-term follow-up (LTFU) care of CCS are largely 

unknown. Methods: Surveys were mailed to a random sample of 1,907 

general internists under age 65 years from the American Medical Association 

Physician Masterfile in November 2011. A second mailing to nonresponders 

is ongoing. Results: 892 (47%) physicians have responded. 

Respondents have practiced a median of 10 years (range: 3-20), and see a 

median of 70 patients/week (range: 40-100). 46% are in solo/group 

practice, 17% in multi-specialty practice, and 14% in academic practice. 

In the last five years, 53% have seen at least one CCS, 71% of whom have 

never received a treatment summary. 85% prefer to care for CCS in 

consultation with a cancer center based physician. A vignette of a 

29-year-old female treated for Hodgkin lymphoma with mantle radiation at 

age 16 was provided and participants were asked a series of questions 

regarding monitoring for late effects. The percentage of responses that were 

concordant with available LTFU Surveillance Guidelines were: breast 

cancer, 29%; cardiac, 15%; thyroid, 77%; and all three recommendations, 

only 5%. By logistic regression, greater likelihood of concordance with at 

least one surveillance recommendation was associated with being female 

(OR�2.0 95% CI 1.3-3.1), seeing more patients/week (OR�1.4 per SD 

increase, 95% CI 1.1-1.7) and more years in practice (OR�1.3 per SD 

increase, 95% CI 1.0-1.6). The two modalities felt to be most useful for 

independent care of CCS by internists were access to LTFU guidelines and 

receiving a patient-specific care plan from the cancer center. Conclusions: 

Although the majority of internists are willing to follow CCS, they appear 

unfamiliar with the available LTFU guidelines and prefer to care for 

patients in collaboration with a cancer center based physician. 


Insurance retention in adolescent and young adult survivors of malignancies 

in a vertically integrated health care system. Presenting Author: Robert 

Michael Cooper, Kaiser Permenante, Los Angeles, CA 

Background: Adolescents and Young Adults (AYA) with cancer are a unique 

population of patients. This group is afflicted with a wide range of cancer 

types. AYA patients often have delays in diagnosis due to issues related to 

insurance and continuity of care and have less participation clinical trials 

related to other age groups. Survivors are at risk of late effects of treatment. 

A vertically integrated health care system with a comprehensive electronic 

medical record provides an ideal opportunity to care for adolescent and 

young adult (AYA) cancer survivors and conduct survivorship research. In 

this system, patients who complete oncology care return to primary medical 

care but can be tracked in a systematic fashion. Methods: We evaluated the 

insurance retention of survivors of AYA malignancies by querying the 

Cancer Registry and identified 13,240 known survivors of malignancies 

diagnosed within the system between 1990 and 2005. We looked at the 

percentage of survivors who were still cared for in our system at certain time 

points after diagnosis. We then reanalyzed the group by ethnicity, disease, 

and age at diagnosis. Results: The retention rate for all patients was 88% at 

1 year, 64 % at 5 years, and 52% at 10 years. The retention rates were 

similar regardless of ethnicity. When we looked at the influence of age at 

time of diagnosis we noted that the younger the patients were at diagnosis 

the lower the percentage of those retaining insurance at the 10 year time 

point. We analyzed the group by the more common cancers and noted that 

patients diagnosed with breast cancer had greatest retention at 10 years of 

68%. Conclusions: The lengthy insurance retention of adolescent and 

young adult cancer survivors makes a vertically integrated medical care 

system an ideal population laboratory for cancer survivorship research in 

this understudied population of cancer survivors. 


627s 


Patient-perceived facilitators in the transition of survivorship care from the 

pediatric to adult care setting. Presenting Author: Karim Thomas Sadak, 

Children’s National Medical Center, Washington, DC 

Background: Survival rates in childhood cancer continue to rise. A new 

challenge has emerged in optimizing the transition of pediatric survivorship 

care to similarly focused programs that are age-appropriate. The purpose of 

this study is to identify components of a clinical survivorship program that 

facilitate the transition of care for adult survivors of childhood cancer from 

the pediatric to adult care-setting. Methods: A descriptive study of childhood 

cancer survivors was conducted using a cross-sectional study design. 

A questionnaire was used to identify which clinical components of a 

survivorship program most influenced the decision to transition care to an 

adult medical center. Primary data collection occurred through the mail. 

Secondary mechanisms included an online version of the questionnaire 

and in-person enrollment during survivorship clinic visits. 140 survivors 

were eligible but only 129 had valid addresses and received the questionnaire. 

The study endpoint was achieved when the response rate reached 

80% (n�103). A descriptive review of clinical program components was 

performed using a frequency analysis. Results: Of 129 invited survivors, 

103 participated (80%). Mean and median age-range was 20-24 years. 

There were 49 males (48%) and 54 females (52%). The most common 

diagnoses were leukemia (40/103), lymphoma (20/103), and CNS tumors 

(9/103). When asked if the participant was willing to transition their 

survivorship care to an adult facility, 97 (95%) responded affirmatively. 

The clinical components most frequently rated “Very Important” in the 

decision to transition survivorship care were the acceptance of insurance 

(80/103, 78%) followed by the presence of providers knowledgeable in 

childhood cancer (68/103, 66%). The clinical components most frequently 

rated “Very Important” or “Important” were flexible scheduling 

(102/103, 99%) followed by comprehensive care being offered (101/103, 

98%). Conclusions: The decision to transition survivorship care to ageappropriate 

care-settings is complex and not well understood. Issues 

related to insurance, clinical team composition, and scheduling appear to 

be most important for young adult survivors making this decision. 


Psychological study of adolescent and young adult (AYA) cancer patients 

and their parents throughout and beyond their cancer treatment: A pilot 

study. Presenting Author: Helen Hatcher, University of Cambridge, Department 

of Oncology, Cambridge, United Kingdom 

Background: The cancer journey for an AYA is often complicated by 

diagnostic delays, poor prognosis and negative physical and psycho-social 

consequences. Distress of young patients and survivors is often overlooked 

and the real incidence of psychopathology remaining hidden. We aimed to 

understand the psychological impact and identify which factors most affect 

the patient experience. Methods: 172 patients on the Cambridge AYA 

register were invited to take part. Patients were asked to complete 2 

questionnaires, SCL90 and RSQ, measuring psychological symptoms and 

response styles respectively, and to take part in a semi-structured interview. 

Parents were asked to complete the York Survey and be interviewed. 

Results: 33 patients and 45 parents/others were recruited. Questionnaires 

completed: 33 SCL90 and RSQ; 42 York Survey. Interview data from: 23 

patients, 26 parents, 3 others. Patient sample: 16 male, 17 female; mean 

age (recruitment) � 20.76 (16-26); age (diagnosis) � 17.26 (12-24). 

Diagnoses evenly distributed across solid and haematological malignancies. 

All patients had experienced significant levels of psychological 

distress at some point in their cancer journey. 51% reached caseness on 

the SCL90 (showed a symptom profile consistent with a high risk of a 

disorder). Caseness increased with age and was correlated with higher 

rumination scores. Positive influences included family, friend and peer 

support, good communication and support from the AYA service and 

specialist nurses. Negative influences included delayed diagnosis, poor 

communication styles, anxiety about long term effects and lack of appropriate 

psychological support. Conclusions: We have shown evidence of 

elevated psychological symptoms in this population. Patients and their 

families have prioritized clear needs; early diagnosis, high quality of 

information and communication, access to psychological help at each 

stage and post treatment help in gaining independence and planning for a 

positive future. We should work towards meeting these needs for this 

vulnerable group. 




Trends in survival of childhood solid tumors diagnosed 1985-2008 in the 

Nordic countries. Presenting Author: Milada Cvancarova, Cancer Registry 

of Norway and University of Oslo, Oslo, Norway 

Background: Classification of childhood solid tumors differs greatly from 

tumors diagnosed in adults. Thus establishment of childhood cancer 

registries is essential to monitor changes and progress in cancer care. 

Methods: All individuals born in the Nordic countries are allocated a unique 

ID number and have access to comprehensive health care services. Further, 

it is required by law that all new cases of cancer are reported to cancer 

registries. This makes it possible to achieve almost complete registration of 

all cancer cases and their status together with information regarding the 

cancer tumour and its treatment. Status registrations were made partly 

from national population registries and partly from death registries only, as 

conditions differ between countries. Crude survival was modelled using the 

Kaplan-Meier method stratified by selected diagnostic groups, age groups 

and diagnostic period. The crude estimates were compared with log-rank 

tests. Results: In total, 12,343 children �15 yrs of age were diagnosed with 

cancer during 1986-2010 in the Nordic regions (Denmark, Finland, 

Iceland, Norway, Sweden) and classified according to Birch & Marsden 

classification. Data were collected at the NOPHO solid tumour registry 

located at the Cancer Registry of Norway. The overall incidence for the 

whole period was 11.2 per 100,000 children per year. The overall 5-year 

survival for all solid tumours reached 80.0 %, 95% CI [79.3 to 80.7] %. 

There was a significant increase in survival for those diagnosed after 1991, 

p � 0.001. Children diagnosed when older than 10 years reached higher 

5-yrs survival than those diagnosed �5 yrs, 82.4% and 78.3%, respectively. 

The highest 5-yrs survival was seen for retinoblastoma (97.0%), 

germ.cell neoplasm (90.8%), renal tumours (88.3%) and lymphomas 

(88.2%). The lowest 5-yrs survival was observed for sympathetic nervous 

system (65.4%). The highest increase in survival was seen for non-Hodgkin 

lymphoma pts, 77.2% diagnosed 1986-1990 vs. 85.9% diagnosed 

2001-05. Conclusions: There has been some improvement in survival in 

recent time periods, especially for some diagnoses. However, there were no 

changes in overall survival wrt sex and only very limited changes in overall 

survival by age groups. 


Effectiveness of using cardiac biomarkers to detect late anthracycline 

cardiotoxicity in childhood leukemia survivors. Presenting Author: Beata 

Mladosievicova, Comenius University, School of Medicine, Bratislava, 

Slovakia 

Background: Cardiotoxicity is usually detected only when clinical symptoms 

or progressive cardiac dysfunction has already occurred. Cardiac biomarkers 

(troponin T and N-terminal fragment brain natriuretic peptide precursor) 

have been hypothesized to reflect subclinical anthracycline 

cardiotoxicity earlier than echocardiography. This study aims to assess the 

effectiveness of using cTNT and NTproBNP in asymptomatic long-term 

survivors of childhood leukemia treated with and without antracyclines 

(ANT). Methods: Sixty-nine childhood leukemia survivors 5-25years after 

completion of therapy were evaluated with immunochemical analysis of 

cTnT and NT-proBNP and echocardiography. Patients from group I (n � 

36) received combined therapy with anthracyclines (ANT) with total 

cumulative dose 95-600 (median 221) mg/m2 , patients from group II (n � 

33) received therapy without anthracyclines (nonANT). Control group 

consisted from 44 age- and gender-matched apparently healthy subjects. 

Results: Levels of NTproBNP were significantly higher in ANT group than in 

controls (median 51,52 vs 17,37 pg/ml; p�0.0026). Patients treated with 

ANT had significantly increased median values of NTproBNP compared 

with patients in non ANT group (51,52 vs 12,24 pg/ml; p�0.0002). CTnT 

levels remained below the diagnostic cut-off levels in all groups. No patient 

had echocardiographic abnormalities, but significant differences were 

found in mean values of left ventricular ejection fraction and deceleration 

time between patients treated with and without ANT. Conclusions: Assessment 

of plasma NTproBNP concentrations may be an effective tool for 

detection of late subclinical cardiac damage in survivors of childhood 

leukemia previously treated with low ANT doses. Higher NTproBNP levels 

in patients after ANT therapy might reflect an initial stage of cardiotoxicity 

before the development of echocardiographic abnormalities. This study 

was supported by a grant from Ministry of Health 2007/42-UK-18, 

Slovakia. 


Bleomycin-associated lung toxicity in childhood cancer survivors. Presenting 

Author: Alexandra Patricia Zorzi, The Hospital for Sick Children, 


Background: Bleomycin has been established as a pulmonary toxin, but the 

risk for toxicity in survivors of childhood cancer is poorly characterized. 

Methods: We conducted a cross-sectional study of lung function in survivors 

of childhood Hodgkin lymphoma and germ cell tumor treated with bleomycin 

at our institution between 1997 and 2010. We assessed their most 

recent post-therapy pulmonary function test (PFT). Spirometry and lung 

volumes were categorized as normal, restrictive, obstructive or mixed. 

Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or 

abnormal. Results: 195 patients were treated with bleomycin. Ten died of 

non-pulmonary causes. Of 185 survivors, 143 (77%) had complete data 

available for analysis. Median cumulative bleomycin dose was 60U/m2 (IQR 30-60). Three patients (2%) had a history of acute bleomycin toxicity. 

PFTs were performed a median of 2.3 years (IQR 1.4-4.9) from completion 

of therapy. Spirometry was abnormal in 58 patients (41%); of whom 5 (9%) 

had respiratory symptoms. 42 (70%) had obstructive, 11 (18%) restrictive 

and 5 (9%) mixed ventilatory defects. Abnormalities were mild in 53 

(91%), moderate in 3 (5%) and severe in 2 (4%). DLCO was abnormal in 

27 patients, 26 (96%) of whom had mildly reduced DLCO and were 

asymptomatic. Univariate analysis did not demonstrate a significant 

association between gender, smoking, lung metastases, lung radiation, 

chemotherapy regimen, or autologous transplant and abnormal lung 

function. Disease relapse was associated with abnormal lung function 

(p�0.01). Smoking (p�0.04) and relapse (p�0.03) were associated with 

abnormal DLCO. The odds ratio of developing abnormal spirometry for each 

1unit/m2 increase in bleomycin was 1.01 (95% CI 1.00-1.02, p�0.07). 

Conclusions: Childhood cancer survivors treated with bleomycin frequently 

have evidence of asymptomatic abnormalities on PFT. The current recommendation 

for pulmonary function testing in childhood cancer survivors 

appears justified. 


A phase II study of dasatinib therapy in children and adolescents with 

newly diagnosed chronic phase chronic myelogenous leukemia (CML-CP) 

or Philadelphia chromosome-positive (Ph�) leukemias resistant or intolerant 

to imatinib. Presenting Author: Michel Zwaan, Erasmus University 

Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands 

Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in 

adult patients (pts) with newly diagnosed Ph� CML-CP; CML resistant/ 

intolerant to prior therapy, including imatinib; and Ph� acute lymphoblastic 

leukemia (ALL). There are no established dasatinib treatment regimens 

for children/adolescents with relapsed/refractory leukemia, but pediatric 

trials are underway. A phase I dose-escalation study of dasatinib in 

pediatric pts with refractory solid tumors (n�28) and imatinib-refractory, 

Ph� leukemia (n�11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response 

(CyR) in all evaluable CML pts (n�9) (Aplenc, J Clin Oncol 2011). 

Preliminary results from a phase I dose-escalation study in pediatric pts 

with subtypes of relapsed/refractory leukemia (NCT00306202) indicate 

that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 

[abstr 2265]). Further study of dasatinib in pediatric pts is warranted. 

Methods: To evaluate the safety and efficacy of dasatinib monotherapy in 

children/adolescents with newly diagnosed CML-CP or Ph� leukemias 

resistant/intolerant to imatinib, a phase II nonrandomized, global study of 

dasatinib in pts birth to �18 y is ongoing (NCT00777036): Cohort 1 (C1), 

Ph� CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph� ALL, 

accelerated or blast phase CML pts resistant/intolerant to or relapsed after 

imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph� 

CML-CP pts. Treatments are once daily with dasatinib 60 mg/m2 (C1/C3) or 

80 mg/m2 (C2) for �24 months. Primary endpoints are major CyR (C1), 

complete hematologic response (C2), and complete CyR (C3). Secondary 

endpoints include safety, tolerability, best response, time to/duration of 

response, survival, and molecular response rates. BCR-ABL mutations are 

evaluated. First patient first visit was March 2009; estimated trial completion 

is September 2016. As of January 2012, 63 pts (n�27 aged �12 y; 

n�36 aged �12 y) have been treated in C1/C2 (n�41) and C3 (n�22). 

Enrollment is ongoing at 79 sites. 



Intraperitoneal radioimmunotherapy (RIT) for desmoplastic small round 

cell tumor (DSRCT). Presenting Author: Shakeel Modak, Memorial Sloan- 


Background: DSRCT, a rare sarcoma of adolescents and young adults arises 

from serosal surfaces typically the peritoneum. It is characterized by 

t(11;22)(p13;q12) chromosomal translocation; and is lethal in �80% of 

patients despite aggressive surgery and chemoradiotherapy. Disease recurrence 

often presents as multifocal peritoneal implants, making it uniquely 

suited for intraperitoneal (IP) targeting. Since DSRCT is radiosensitive, we 

hypothesize that improving local control with targeted radiotherapy may 

reduce relapse and enhance survival. IP RIT, by virtue of prolonged 

residence time, and slow/incomplete transfer to the circulation, may 

selectively target IP disease while minimizing organ toxicity. The anti-4Ig- 

B7H3 murine monoclonal antibody 8H9 binds to 96% of primary DSRCT 

with restricted reactivity to normal tissue (Med Pediatr Oncol 39:547). 

131I-8H9 targets DSRCT xenografts and has proven safe at 80mCi when 

injected intrathecally (J Neurooncol 97:409). 124I-8H9, a novel positronemitting 

radioimmunoconjugate is ideally suited for quantitative imaging 

and pharmacokinetic (PK) studies. Methods: We have initiated a phase I 

study to test the safety of IP RIT using 131I-8H9 in patients with DSRCT 

(clinicaltrials.gov NCT01099644). Cohorts of 3-6 patients are treated with 

131 2 2 I-8H9 at escalated doses from 30mCi/m -60mCi/m as a single IP 

injection. An IP tracer dose of 2mCi124I-8H9 is given prior to 131I-8H9 to 

acquire high-resolution PET images and data on 8H9 tumor targeting and 

biodistribution. PK is also studied using serial blood draws. Patients are 

monitored for toxicity clinically and biochemically. Response to treatment 

is assessed using RECIST criteria and via a follow up 124I-8H9 PET scan if 

tumor targeting is noted on initial imaging. Hematopoietic stem cells are 

harvested a priori to reverse myelosuppression if any. Three cohorts of 

patients (n�9) up to 50mCi/m2 have completed therapy thus far without 

dose-limiting toxicity or myelosuppression. This is the first study of IP RIT 

in pediatrics, and the first to use PET for IP RIT. Data obtained will be 

critical in establishing safety of IP 131I-8H9 in children and young adults, 

and in designing phase II trials to study efficacy of IP RIT for DSRCT. 

TPS9597^ General Poster Session (Board #46B), Sun, 8:00 AM-12:00 PM 

The BERNIE study: A phase II study evaluating addition of bevacizumab 

(Bv) to chemotherapy in children and adolescents with metastatic rhabdomyosarcoma 

(mRMS) and non-rhabdomyosarcoma soft tissue sarcoma 

(mNRSTS). Presenting Author: Julia C. Chisholm, The Royal Marsden NHS 

Foundation Trust, Sutton, United Kingdom 

Background: Despite therapeutic advances, patient outcomes in mRMS and 

mNRSTS remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 

2008) indicated that Bv is well tolerated in children with refractory solid 

tumors and yielded pharmacokinetic (PK) data that support further studies 

of Bv in childhood cancer. Reports of Bv used in children with solid tumors 

showed safety profiles consistent with data from adults. Methods: In this 

phase II trial, 150 patients aged 6 months to 18 years who present with 

mRMS or mNRSTS are randomized to receive 18 months of standard 

combined modality therapy as per EpSSG guidelines, either alone or with 

Bv. Treatment consists of 2 phases: induction therapy [9 three-weekly 

cycles including 4 cycles of IVADo (ifosfamide, vincristine, actinomycin D, 

and doxorubicin), followed by 5 cycles of IVA (i.e., without doxorubicin)] 

and maintenance therapy (12 four-weekly cycles of vinorelbine and 

cyclophosphamide). Local therapy is considered after the 6th induction 

cycle. Primary endpoint is event-free survival (EFS). PK sampling is 

performed on all patients randomized to the experimental arm during the 

first 4 cycles of induction. After the primary efficacy and safety analysis, all 

patients who have not met the primary endpoint are followed for at least 47 

months for survival and long-term effects of treatment. The study enrolled 

75 patients between July 2008 and January 2012; 37 patients discontinued 

study treatment (including 17 patients who died, all due to disease 

progression) and 9 patients have completed study treatment. 


629s 


The HERBY study: A phase II open label, randomized, multicenter, 

comparative study of bevacizumab (Bv)-based therapy in pediatric patients 

with newly diagnosed supratentorial high-grade glioma (HGG). Presenting 

Author: Jacques Grill, Institut Gustave Roussy, Villejuif, France 

Background: Despite therapeutic advances, outcomes in pediatric HGG 

remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 2008) 

indicated that Bv is well tolerated in children with refractory solid tumors 

and yielded pharmacokinetic (PK) data that support further studies of Bv in 

childhood cancer. Reports of Bv used in children with solid tumors showed 

safety profiles consistent with data from adults. Methods: 120 evaluable 

patients aged 3-18 years with newly diagnosed histologically confirmed 

WHO grade 3or 4 HGG are randomized to receive standard combined 

modality therapy as currently adopted worldwide by the pediatric neurooncology 

community with or without Bv. Treatment consists of 6 weeks of 

concomitant TMZ and local radiotherapy, followed by a 4-week TMZ 

treatment break and 48 weeks of adjuvant TMZ with or without Bv every 

other week. Primary endpoint is event-free survival (EFS). Progression is 

based on RANO criteria. Secondary endpoints are overall survival (OS), 

safety, feasibility, and tolerability. PK sampling is performed during cycles 

1-4 of the adjuvant TMZ phase on all patients randomized to receive Bv. 

Health-related quality of life, neurocognitive functions, MGMT methylation 

status, functional changes in tumor based on magnetic resonance diffusion 

& perfusion imaging and spectroscopy are explored as well as the 

correlation of biomarkers with clinical activity and adverse events. All 

randomized patients will be followed for at least 3 years. Analysis of EFS 

and secondary endpoints will be performed after the 120 patients evaluable 

for EFS have been followed for 1 year. Multimodal imaging will provide 

a platform to develop new imaging criteria for pediatric neuro-oncological 

treatment response. An updated OS and safety analysis will be performed 3 

years after the last patient has been randomized. The first patient was 

randomized in October 2011; completion of the study is expected in 2016. 


630s Sarcoma 


Predicting survival in primary resected retroperitoneal soft tissue sarcoma: 

A specific nomogram built on three major sarcoma center data sets. 

Presenting Author: Alessandro Gronchi, Fondazione IRCCS Istituto Nazionale 

Tumori, Milano, Italy 

Background: To build a specific nomogram for predicting postoperative 

overall survival (OS) in primary retroperitoneal soft tissue sarcoma (RPS). A 

few single institutions attempts are already available, but due to the rarity 

of the disease they are based on limited number of cases with inherent 

limitations. In an attempt to improve the predictive capability of such a 

prognostic model we utilized series from 3 major sarcoma centers. Methods: 

We included patients with primary localized RPS resected with curative 

intent between 1999 and 2009 at 3 institutions (1 European and 2 North 

Americans). Univariable (Kaplan Meier plots) and multivariable (Cox 

model) analyses were carried out. Prognostic covariates were: Age (modeled 

as continuous covariate using 3 knot restricted cubic spline transformation); 

Tumor size (modeled as continuous covariate using 3 knot 

restricted cubic spline transformation); Grade (I,II,III); Histological subtype 

(Leiomyosarcoma, DD Liposarcoma, WD Liposarcoma, MPNST, Pleomorphic 

Sa, SFT, Other); Multifocality (no,yes); Quality of surgery 

(macroscopically complete, incomplete); radiation therapy (RT, done/not 

done). A backward selection procedure, based on the Akaike Information 

Criterion (AIC), was applied to select the Cox model covariates. The model 

discriminative ability was estimated by means of bootstrap-corrected 

Harrel C statistic. Results: 526 patients were identified. At a median 

follow-up of 45 months (interquartile range: 22-72 months) 174 deaths 

were recorded. 5-yr and 7yr OS (95% confidence interval) were 56.4% 

(51.1,62.2%) and 50.1% (44.1,57.0%). The backward selection procedure 

by AIC criterion lead to exclude RT from the covariates set. All other 

covariates proved to be statistically significant in the final multivariable Cox 

model. The Bootstrap-corrected Harrell C statistic was 0.74. Of interest, 

size of the tumor and age of the patient had a bimodal contribution to the 

risk of death and the combination of histological subtype and grade proved 

significant. Conclusions: A new multi-institution RPS specific nomogram is 

now available for prognostication in the clinic and patient selection in 



Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified 

liposarcoma. Presenting Author: Mark Andrew Dickson, Memorial Sloan- 


Background: CDK4 is amplified in approximately 90% of well-differentiated/ 

de-differentiated liposarcomas (WD/DDLS). The selective CDK4/CDK6 

inhibitor PD0332991 (PD) inhibits growth and induces senescence in 

liposarcoma cell lines and xenografts. In a phase I trial of PD, several 

patients with progressive WD/DDLS had prolonged stable disease for 

several years. To determine the safety and efficacy of PD, a phase II study 

was performed. Methods: Participants were patients with advanced WD/ 

DDLS. Eligibility criteria were age�18 years, measurable WD/DDLS 

(RECIST 1.1), documented progression on at least one systemic therapy 

directly before enrollment, CDK4 amplification by fluorescence in situ 

hybridization and retinoblastoma protein (RB) expression by immunohistochemistry 

(�1�). Pts received oral PD 200mg daily for 14 consecutive 

days in 21-day cycles. The primary endpoint was progression-free survival 

(PFS) at 12 weeks. Based on historical data, a promising result was defined 

as a 12-week PFS of �40% and not promising as �20%. The sample size 

was up to 28 evaluable patients. If 9 patients were progression free at 12 

weeks, then PD would be considered to have activity in WD/DDLS. Results: 

Of 44 patients screened (42/44 CDK4 amplified; 41/44 RB�), 29 were 

enrolled and 27 were evaluable for the primary endpoint. Median age was 

65 (range 37-83); 52% were male; ECOG scores were 0 (69%) or 1 (31%), 

and the median number of prior regimens was 1 (range 1-5). PFS at 12 

weeks was 70% (19/27 patients; 90% CI 56-100%), and thus the study 

significantly exceeded its primary endpoint. At the data cutoff, the median 

PFS was 18 weeks. Seven patients remain on study with stable disease at 

18-48 weeks of followup. Grade 3 and 4 events included anemia (grade 3, 

14%), thrombocytopenia (grade 3, 17%; grade 4, 14%), neutropenia 

(grade 3, 41%; grade 4, 7%) and febrile neutropenia (3%). Dose reductions 

were required in 24% of patients. Conclusions: Among patients with 

WD/DDLS with CDK4 amplification and RB expression who had actively 

progressing disease despite prior systemic therapy, treatment with the 

CDK4 inhibitor PD0332991 was associated with improved PFS. A randomized 

phase 3 trial is planned. 


How well do we communicate risk? An evaluation of AJCC version 6 and 7 

staging systems for soft tissue sarcomas. Presenting Author: Robert G. 

Maki, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 

Present address: Departments of Medicine, Pediatrics, and Orthopaedics, 

Mount Sinai School of Medicine, New York, NY 

Background: Cancer staging systems allow physicians to communicate risks 

of a particular clinical situation with one another and with patients. Few 

data have been presented to support the update of a commonly employed 

staging system for soft tissue sarcoma (STS). We examined American Joint 

Committee on Cancer (AJCC) versions 6 (2002) and 7 (2010) staging 

systems for patients with primary STS using a single institution clinically 

annotated prospective database. Methods: Subsets of the prospectively 

collected Memorial Sloan-Kettering Cancer Center STS database of 8647 

patients from 1982 to 2010 were examined with respect to criteria of the 

AJCC versions 6 and 7 staging systems. Results: Tumor size does not appear 

to be adequately addressed in version 6 or 7. Relapse-free survival was 

statistically worse for increasing size of primary STS �5, 5-10, 10-15, and 

�15 cm; in comparison, overall survival decreased over three size categories 

(�5, 5-10, �10 cm). Tumor depth, a statistically significant factor in 

patient outcomes that is included in version 6, is functionally omitted in 

version 7. Patients with node involvement without other metastases fare 

statistically worse than patients with large, high grade tumors without nodal 

metastasis, as shown previously. Version 6 and 7 criteria do not address 

effects of primary anatomic site and histology, even for tumors with same 

FNCLCC grade. Sarcoma subtypes defined after publication of FNCLCC 

criteria are difficult to incorporate into existing guidelines. Conclusions: 

Improved prognostication of STS outcomes is better achieved by staging 

according to anatomic primary site, depth, and a larger number of size 

categories. Histology-specific nomograms improve prognostic accuracy, 

such as those for liposarcoma, GIST, or rhabdomyosarcoma. Staging 

accuracy increases at the cost of portability and simplicity. The increasing 

difficulties with use of a single STS staging system highlight the potential 

benefit of newer techniques, such as patient-specific nomograms or 

Bayesian networks. Staging systems will require significant modifications 

to incorporate increasingly sophisticated molecular diagnostics. 


A phase II multicenter study of the IGF-1 receptor antibody cixutumumab 

(A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with 

refractory IGF-1R positive (�) and negative (-) bone and soft tissue 

sarcomas (STS). Presenting Author: Gary K. Schwartz, Memorial Sloan- 


Background: Preclinical studies demonstrate synergistic anti-tumor activity 

by inhibiting mTOR and IGF-1R. This study evaluated the safety and 

efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (�) STS 

(Arm A), IGF-1R (�) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). 

Methods: An optimal Simon 2 stage design was used for each arm. The 

primary end-point was progression free survival (PFS) at 12 weeks. Based 

on historical data, a 40% PFS rate was considered promising and a 20% 

PFS non-promising (type I/ II error, 0.05/0.10). �5 PFSs at 12 weeks were 

required in the first 19 and �16 PFSs were required in a total of 54 pts to 

consider each arm positive. Key eligibility: measurable disease (RECIST 

1.1), age �18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 

mg) were administered IV weekly. Pre and post treatment tumor biopsies 

and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers 

participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R 

by immunohistochemistry (IHC; 54% �) and 171 were treated: mean age 

47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities 

�10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) 

analysis, each arm of the study achieved its primary 12 week PFS end-point 

(�16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm 

C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), 

(0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in 

weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 

17.9), respectively, and for chondro (n�18), Ewing’s (n�24), and osteo 

(n�23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), 

respectively. Westerns on 32 matched pair tumor biopsies indicate 

inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts 

(Arm C), 5 were IGF-1R (�) by western. Plasma biomarkers did not 

correlate with PFS. Conclusions: A12 and TEM met its primary end-point of 

improved PFS in pts with metastatic sarcoma. This effect was independent 

of IGF-1R status by IHC. These results support further clinical development 

of this combination in bone and STS. 



A first-in-human, phase Ib combination study to assess safety, pharmacokinetics 

(PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a 

Notch inhibitor, RO4929097, in patients with advanced sarcoma. Presenting 

Author: Mrinal M. Gounder, Memorial Sloan-Kettering Cancer Center, New York, 

NY 

Background: Aberrant Hedgehog and Notch signaling is seen in sarcoma and 

anti-tumor activity is enhanced by inhibiting both pathways. This first in man 

Phase Ib study evaluated safety and efficacy of the combination of GDC-0449 

(G), a smoothened inhibitor with RO4929097 (R), a gamma-secretase/notch 

inhibitor. Methods: The study evaluated fixed dose G (150 mg qd) for 21 days 

followed by G � R at either 10 mg (level 1) or 15 mg (level 2) QD. At MTD pts 

were evaluated with G � R (without “lead in” G) or single agent R. Pre and post 

treatment tumor biopsies were obtained to assess notch and hedgehog inhibition. 

PK was assessed for each drug. Key eligibility: advanced sarcoma, ECOG 

� 2, age � 18 and prior therapies � 4. RECIST response was assessed Q6 wks. 

Results: 34 pts had a median age of 53 yrs (23-78), median priors 3 and various 

histologies [liposarcoma (7), chondrosarcoma (7), leiomyosarcoma (4), osteosarcoma 

(2), GIST (2) and other (12)]. No DLT was seen. Common (�10 %) grade 

�3 toxicity was hypophosphatemia (18%). Systemic exposure (AUC0-24 and 

Cmax) of G was similar to established studies (not shown). AUC0-24 and Cmax of R 

was significantly lower (~70%) when administered with G (Table). However, 

measurement of unbound, free drug (Cfree) of R showed comparable levels 

between single agent R and G � R, but not when G was a “lead in” (Table). 

Target inhibition of the notch pathway (cleaved notch) and pAkt was observed in 

matched tumor biopsies with both arms. Durable SD was seen in both arms: 

myxoid chondrosarcoma (56 wks), liposarcoma (24� wks), clear cell (21� wks), 

desmoid (17� wks), spindle cell (15� wks) and chondrosarcoma (13� wks). 

Conclusions: The combination of G�R is well tolerated and the RP2D is G 150 

mg qd and R 15 mg qd without a “lead in” G. Despite reduction in total levels of 

R in the combination, free drug was similar and inhibits target. Disease stability 

was seen with R and R � G. Further clinical development of notch and hedgehog 

inhibitors in sarcomas is warranted. 

PK of R �Lead in G� then G � R G�R R 

AUC0-24 714 3150 4477 

Half life hr 21 17.5 28 

Tmax hr 2.75 2 2 

Cmax ng/mL 87.6 382 535 

Trough total ng/mL 28 38 103 

Trough free 0.5 0.9 1 


An open-label international multicentric phase II study of nilotinib in 

progressive pigmented villo-nodular synovitis (PVNS) not amenable to a 

conservative surgical treatment. Presenting Author: Isabelle Ray-Coquard, 

GINECO and Centre Leon Berard, Lyon, France 

Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a 

rare pathological entity affecting the synovium in young adults. This 

neoplastic disease is driven by a t(1;2) translocation which results in the 

fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on 

M-CSF receptor pathway which could be of therapeutic interest in pts with 

non resectable PVNS. Methods: In this open-label International, multicenter, 

non-randomized, phase II study the primary objective is to evaluate 

the efficacy of nilotinib treatment in patients (pts) with progressive or 

relapsing PVNS not amenable to surgery or in whom surgery would be 

mutilating, as measured by the 12-week progression-free rate (12-w PFR) 

validated by an independent committee. Using a Bayesian design with a 

stopping rule for futility, interim analyses were planned after the inclusion 

of 10 pts and then every 5 pts. Results: From December 2010 to November 

2011, 33 pts with progressive disease from 17 institutions from Europe 

and Australia were enrolled. 14 pts (median age 37 y (range: 19-68), 7 

males) were analyzed in the 2nd interim analysis. Median time since 

diagnosis was 4.4 years (range: 0.2-26). Primary tumour was located on a 

knee for 10 pts (71%) and on hip (1 pt, 7%), finger (7%), foot (7%), hand 

(7%), respectively. 69% of pts had a inoperable PVNS and 31% had a 

resectable tumour but requiring mutilating surgery. All pts started nilotinib 

at the planned dose of 800 mg/day. At a median follow-up of 8.9 months 

(range: 0.6-11), 2 pts had a dose reduction and 1 pt had discontinued 

nilotinib after 14 days due to toxicity. Nilotinib was well tolerated, with only 

2 pts experiencing grade 3 adverse events (anorexia: 1 pt; hepatic failure: 1 

pt).The 12-w PFR was 85.7% (95%CI, 57.2%-98.2%), in favour of the 

study continuation. No OR was observed at w-12; 1 pt (7%) was in PR at 

w-30. Updated results will be presented after the 3rd interim analysis. 

Conclusions: Nilotinib treatment induces disease stabilisation in a large 

proportion of PVNS patients with non resectable disease or in whom 

resection would be mutilating. 

Sarcoma 

631s 


GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma 

Group (FSG)/French and U.S. National Cancer Institutes phase II collaborative 

study. Presenting Author: Antoine Italiano, Institut Bergonié, Bordeaux, 

France 

Background: Chondrosarcomas (CS) exhibit a strong activation of hedgehog 

(Hh) signaling which plays a crucial role in cartilage tumorigenesis. 

Preclinical data show that hedgehog blockade reduces strongly chondrosarcoma 

cell proliferation and tumour size. GDC-0449 is a small-molecule 

antagonist of the Hh pathway. Methods: This is a multicentric single-arm 

phase 2 clinical trial based on two-stage Simon’s design which assesses 

safety and efficacy of GDC-0449 in patients (pts) with advanced CS. All pts 

had to have documented progressive disease (PD) as per RECIST 1.1 before 

study entry. Pts receive GDC-0449 150mg (oral route), daily until PD or 

unacceptable toxicity. The primary endpoint is the 6-month non-PD rate 

according to RECIST. Based on the following hypotheses: 20% 6-month 

non-PD rate (H0), 40% acceptable 6-month non-PD rate (H1), 10% type I 

error rate, 90% power, a total of 37 assessable pts are necessary (17 for the 

first stage � 20 for the second stage). Following the inclusion of the first 17 

pts, if � four pts are progression-free at 6 months, the accrual will 

continue. In order to account for not assessable pts (�/- 10%), 41 pts will 

be recruited. Accrual started in February 2011 in six centers of the FSG. 

Results: As of January 24 2012, 40 pts (28 males, 12 females) have been 

included in the study. Median age is 59 years (30-86). The most frequent 

histological subtype is conventional CS (n�32). Twenty eight pts (70%) 

had grade 1 or 2 adverse events (AE) possibly related to the drug whereas 3 

pts (7.5%) had grade 3 or 4 AE. The planned interim statistical analysis 

performed after central histological and radiological review showed that 

four patients out of the first 17 evaluable patients had stable disease 

indicating that GDC-0449 had reached the primary endpoint to justify 

continuing accrual after the 1st step of the study. 15 pts are still on 

treatment. Molecular analyses are available for 21 pts. No mutation of SMO 

was detected. qRT-PCR experiments and PTCH sequencing are ongoing. 

Conclusions: GDC-0449 is well tolerated and shows some activity in a 

subset of pts with advanced CS. Final clinical and molecular data will be 

presented at the meeting. 


Masitinib mesylate in imatinib-resistant advanced GIST: A randomized 

phase II trial. Presenting Author: Antoine Adenis, Centre Oscar Lambret, 

Lille, France 

Background: Masitinib is an oral tyrosine kinase inhibitor with greater in 

vitro activity and selectivity than imatinib against wild-type and juxtamembrane 

mutations of KIT (Dubreuil, 2009, PLoSONE). This trial studied 

efficacy and safety of masitinib at 12 mg/kg/day and sunitinib at 50 mg/day 

for the treatment of imatinib-resistant GIST. Methods: Patients with 

inoperable, locally advanced or metastatic GIST and showing disease 

progression while treated with imatinib 400 mg/day received either 

masitinib or sunitinib until progression. Primary endpoint was PFS evaluated 

with RECIST with OS as a secondary endpoint. Based upon an 80% 

power to detect with a Fleming design a median PFS �3 months (alpha 

10%, unilateral), a population of 44 patients (22 per arm) was required. 

Stratification was applied based on mutation status. Results: 44 patients 

(exon 11 [66%], exon 9 [11%], wild-type or other [5%], not done at 

baseline [18%]) were randomized into masitinib (n�23) or sunitinib 

(n�21) treatment-arms from 9 centers between 02/2009 and 09/2011. 

After a median follow-up of 14 months, median PFS was 3.9 months 

(95%CI [2.6;8.1]) for masitinib vs 3.8 months [1.9;11] for sunitinib. Of 

those patients progressing under masitinib, 88% received sunitinib in third 

line. Median OS was not reached (NR) (95%CI [21;NR]) for masitinib vs 15 

months [9.4;22] for sunitinib. The 18-month and 24-month OS rates for 

masitinib vs sunitinib were 79% (95%CI [53;92]) vs 20% [1.5;55], and 

53% (95%CI [9.5;84]) vs 0%, respectively. Similar results were seen in 

the exon 11 subpopulation with median OS for masitinib NR (95%CI 

[NR;NR]) vs 15 months [9.6;22] for sunitinib. The safety profile of 

masitinib was better than sunitinib with a lower occurrence of severe 

related adverse events (AEs) (17% vs 52%) and related AEs leading to 

discontinuation (0% vs 9.5%). In masitinib treated patients, nausea, 

diarrhea and asthenia were the most common related AEs. Conclusions: 

Although PFS curves looked similar, this study apparently showed a longer 

survival in the masitinib treatment-arm with a better safety profile than 

sunitinib. Masitinib may potentially offer patients a new active compound 

for advanced GIST in the second-line setting. 


632s Sarcoma 


Randomized phase III trial of regorafenib in patients (pts) with metastatic 

and/or unresectable gastrointestinal stromal tumor (GIST) progressing 

despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID 

trial. Presenting Author: George D. Demetri, Dana-Farber Cancer Institute, 

Boston, MA 








4:45 PM-5:45 PM 

Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as 

maintenance therapy in advanced sarcoma patients following clinical 

benefit from prior standard cytotoxic chemotherapy: Long-term (> 24 

months) overall survival results. Presenting Author: Jean-Yves Blay, University 

Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France 

Background: The mammalian target of rapamycin (mTOR) regulates cell 

growth and proliferation and is abnormally activated in many sarcomas. 

Ridaforolimus, an oral mTOR inhibitor, demonstrated clinical activity in 

previous nonrandomized trials in advanced sarcomas following failure of 

prior chemotherapy. Methods: An international, multicenter, placebocontrolled, 

phase 3 trial was conducted to evaluate maintenance therapy 

with ridaforolimus in patients with metastatic soft-tissue or bone sarcomas 

who achieved disease control from prior chemotherapy. Patients were 

randomized (1:1) to receive oral ridaforolimus (40 mg) or placebo once 

daily for 5 days each week. The primary endpoint was progression-free 

survival (PFS); secondary endpoints included overall survival (OS) and 

safety and tolerability. For OS, patients were to be followed at 3-month 

intervals for at least 24 months and up to 60 months after randomization. 

Results: 702 of 711 randomized patients received treatment. At the time of 

the data cutoff for OS (386 deaths), patients in the study population had 

been followed for at least 15 months. Median OS was 93.3 weeks with 

ridaforolimus vs 83.4 weeks with placebo (hazard ratio [HR]�0.88; 95% 

confidence interval [CI]: 0.72, 1.08; P�0.23). Ridaforolimus significantly 

improved PFS vs placebo (HR�0.72; 95% CI: 0.61, 0.85; P�0.0001; 

median PFS: 17.7 weeks vs 14.6 weeks); PFS improved across all 

prespecified baseline characteristics. As expected from the class of mTOR 

inhibitors, the most common adverse events with ridaforolimus were 

stomatitis, thrombocytopenia, noninfectious pneumonitis, hypertriglyceridemia, 

hyperglycemia, infections, and rash. Conclusions: Oral ridaforolimus 

was generally well-tolerated and significantly improved PFS in 

metastatic sarcoma patients with benefit from prior chemotherapy, offering 

an effective treatment alternative to surveillance alone. Results of a 

long-term OS analysis (prespecified to occur at 67% mortality, 24 months 

minimum follow-up) in the intent-to-treat population will be available in 

early 2012. 


4:45 PM-5:45 PM 

PALETTE: Final overall survival (OS) data and predictive factors for OS of 

EORTC 62072/GSK VEG110727, a randomized double-blind phase III 

trial of pazopanib versus placebo in advanced soft tissue sarcoma (STS) 

patients. Presenting Author: Winette T.A. Van Der Graaf, Department of 

Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, 

Netherlands 

Background: At ASCO 2011 we presented an increase in median progressionfree 

survival (PFS) of pazopanib of 13 weeks (median 7 to 20 weeks; HR 

0.31) in a randomized double-blind, placebo-controlled phase III trial in 

advanced non-adipocytic STS patients pretreated with chemotherapy. Now 

we present final OS data and predictive factors for OS, such as ethnicity, 

ancestry and well-known prognostic and predictive factors in STS patients 

treated with chemotherapy. Methods: At clinical cut-off median follow-up 

was 25 months. Comparison of both treatments for OS was performed using 

a two-sided log rank test stratified for number of prior lines of systemic 

therapy for advanced disease and WHO performance status (PS). HR was 

calculated with a 2-sided CI. A Kaplan-Meier OS curve was used. Baseline 

characteristics as potential predictive factors for OS were: PS (0 vs 1), 

number of lines of prior therapy for advanced disease (0-1 vs 2�), age 

(�55 yrs vs � 55 yrs), gender, ethnicity (Hispano or Latino vs other), 

geographic ancestry (White Caucasian, Asian, other), tumour grade (1-2 vs 

3), histology (leiomyosarcoma vs synovial sarcoma vs other). A Cox model 

was fitted with the investigated factor, treatment arm and associated 

interaction factor. Data of all 369 randomized patients (123 placebo, 246 

pazopanib) were used for the analyses. Results: Median OS (95% CI) was 

10.7 (8.7-12.8) in the placebo versus 12.5 (10.6-14.8) months in the 

pazopanib group, HR: 0.86 (0.67-1.1). Post study protocol systemic 

treatment was administered in 63% of placebo, and in 49% of pazopanib 

treated patients. None of the investigated factors showed any statistical 

significant predictive value for OS. Conclusions: Although pazopanib 

demonstrated a statically significant increase in PFS compared to placebo, 

final OS analysis, which showed a trend in favor of pazopanib in patients 

with metastatic non-adipocytic STS, did not reach statistical significance. 

The factors studied were not predictive for OS. 


4:45 PM-5:45 PM 

Phase I study of neoadjuvant chemoradiation (CRT) plus sorafenib (S) for 

high-risk extremity soft tissue sarcomas (STS). Presenting Author: Janelle Marie 

Meyer, Oregon Health & Science University Knight Cancer Institute, Portland, 

OR 

Background: We previously reported a regimen of epirubicin/ifosfamide (E/I) and 

hypofractionated radiation (RT) followed by surgery and postoperative E/I. We 

hypothesize that S � CRT is safe and augments activity through anti-angiogenic 

mechanisms. We performed dynamic contrast-enhanced MRI using shutter 

speed pharmacokinetic analysis (SSM DCE-MRI) to assess preoperative therapy 

effect. Methods: Subjects with �5 cm, grade 2-3 extremity STS were treated in 

cohorts of escalating S dose using a 3�3 design based on dose-limiting toxicity 

(DLT) during the first 8 weeks. Daily S was initiated 14 days prior to E/I (E 30 

mg/m2 /day days 1-3 and I 2.5 g/m2 /day days 1-3 every 21 days for 3 pre- and 3 

postoperative cycles). 28 Gy preoperative RT was administered in 8 fractions 

during cycle 2 (E omitted). Primary objective was to determine maximum 

tolerated dose (MTD). DCE-MRI was performed at baseline, after 2 weeks S, and 

prior to surgery. Results: 16 subjects were enrolled. Histologies included 

pleomorphic (5), synovial (5), liposarcoma (3), other (3). All were extremity (12 

lower, 4 upper) tumors. Median tumor size was 11.7 cm. The MTD of S was 400 

mg daily (see table). Most common grade 3/4 adverse events among all dose 

levels were neutropenia (94%), anemia (75%), hypophosphatemia (69%), 

thrombocytopenia (56%), neutropenic fever/infection (50%), and hypokalemia 

(31%). 38% developed wound complications requiring surgical intervention 

including amputation in 1 subject. 44% had �95% histologic necrosis at 

surgery. No subjects have recurred with median follow-up of 15 (6-27) months. 

8 subjects underwent DCE-MRI. Changes in SSM DCE-MRI biomarkers after 2 

weeks S correlated with histologic response (R2�0.71). Conclusions: The 

addition of S to CRT is feasible with promising activity that warrants further 

investigation. Rate of wound complications is similar to other reports of 

preoperative radiation. SSM DCE-MRI detected changes in tumor perfusion after 

only 2 weeks of S and may prove useful to assess early drug effect in STS. 

S (mg) #DLTs/subjects DLT Grade 

200 1/6 Mucositis 3 

400 1/7 Syncope 3 

800 3/3 -Neutropenic sepsis, thrombosis, HFS 

-Rash, HFS 

-Rash 


4,3,3 

3,3 

3


4:45 PM-5:45 PM 

18f-FDG-PET imaging as an early survival predictor in patients with 

high-grade soft tissue sarcomas undergoing neoadjuvant therapy. Presenting 

Author: Ken Herrmann, UCLA, Los Angeles, CA 

Background: Neoadjuvant therapy is associated with considerable toxicity 

and limited survival benefits in patients with soft tissue sarcoma (STS). We 

prospectively evaluated whether 18F-FDG PET/CT (PET) imaging after the 

initial cycle and after end of neoadjuvant therapy could predict overall 

survival in these patients. Methods: 76 patients (primary STS: n�57; 

metastatic disease: n�19) with high grade STS were included in this study. 

PET was performed prior to (n�76), after one cycle (n�52) and after the 

end of neoadjuvant therapy (n�74). Overall survival was correlated with 

changes of SUVpeak, RECIST, histopathological response and other 

parameters predictive of STS survival. Results: One-, two- and five- year 

survival rates were 95�3.0%, 86�4.6% and 68�6.6% for primary STS. 

Corresponding one- and two- year survival rates for recurrent/metastatic 

STS were 77�10.0% and 47�12.1%. Optimal cut-off for early decreases 

in SUV peak were significant predictors of survival in log-rank test 

(p�0.027 and p�0.043). However, late decreases in SUV peak were only 

predictive in primary STS (SUV peak decrease 57%; p�0.035) but not in 

recurrent/metastatic STS (SUV peak decrease 52%; p�0.057). In primary 

STS, 7/15 early PET non-responders but only 4/24 early PET responders 

died during follow up (p�0.068). Conclusions: 18F-FDG-PET seems feasible 

to predict survival after the initial cycle of neoadjuvant chemotherapy 

in both patients with primary STS and recurrent/metastatic STS and can 

potentially serve as an intermediate endpoint biomarker in clinical research 

and patient care. 


4:45 PM-5:45 PM 

Growth modulation index and RECIST-based STBSG-EORTC criteria for the 

assessment of drug activity in advanced soft tissue sarcoma (ASTS) 

patients (pts). Presenting Author: Sophie Cousin, Centre Oscar Lambret, 

Lille, France 

Background: Despite promising phase II trial results, most of new drugs 

failed to improve the overall survival (OS) in ASTS pts. The choice of the 

endpoint in early trials remains crucial. We have evaluated the Growth 

Modulation Index (GMI) as potential endpoint. The GMI is defined as the 

Time To Progression with the second (or n�1) line of chemotherapy (TTP2) 

divided by the TTP with the first (or n) line (TTP1). Methods: We have 

carried out a retrospective multicenter study in pts receiving second-line 

chemotherapy after failure/intolerance to doxorubicin-based regimens. 

Data collected included best response(s), TTP1 & TTP2 and OS. Treatments 

have been classified as �active� treatment according to the EORTC- 

STBSG criteria (3-month Progression-free rate �40% or 6-month 

PFR�14%: including trabectedin, ifosfamide, gemcitabine�docetaxel for 

all subtypes and weekly paclitaxel for angiosarcoma) versus non-active 

drugs. Comparisons used chi-2 tests and Log-rank tests. We performed a 

logistic regression analysis for identifying factors associated with longer 

GMI. Results: The study population consisted in 106 men and 121 women, 

the median age was 57 years. 110 pts (48.4%) have received �active 

drugs�. The median TTP1, TTP2 and GMI were 197 days, 134 days and 

0.75, respectively. The median OS was 446 days. 70 pts experienced 

GMI�1.33 (30.6%). There was a strong relation between best objective 

response and GMI (p�0.0001). The treatment with �active drug� was not 

associated with an improvement of the OS: 490 days 407 versus days 

(p�0.524). The median OS of pts with GMI�1, GMI�[1.00-1.33] and 

GMI�1.33 were 324, 302 and 710 days, respectively (p�0.0001). None 

of the following factors were associated with GMI�1.33 in logistic 

regression analysis: age, gender, histological subtypes, grade, metastasis 

locations, interval between diagnosis & metastasis, association with ifosfamide 

or dacarbazine in 1st-line regimen or treatment with �active drug� in 

second-line. Conclusions: GMI seems to be an interesting endpoint providing 

additional information compared to classical criteria. GMI�1.33 is 

associated with significant improvement of the OS. 

Sarcoma 

633s 


4:45 PM-5:45 PM 

Growth modulation index (GMI) as a metric of clinical benefit assessment 

among advanced soft tissue sarcoma (ASTS) patients receiving trabectedin 

as salvage therapy. Presenting Author: Nicolas Penel, Centre Oscar 

Lambret, Lille, France 

Background: Von Hoff has proposed GMI �1.33 in cancer clinical trials as a 

sign of drug activity. GMI is the ratio between time to progression (TTP) 

with the nth line (TTPn) of therapy divided by the TTPn-1 with the n-1th line 

of therapy. With this endpoint, each patient is his/her own control. Methods: 

We have carried out a retrospective analysis of 279 pretreated ASTS 

patients treated in four consecutive phase II trials with trabectedin 1.5 

mg/m², given as a 24-hour infusion every 3 weeks. Results: The study 

population consisted of 170 women and 109 men with a median age of 52. 

The two most common histologies were leiomyosarcoma (145 patients, 

52%) and liposarcoma (59, 21%). 142 (51%) patients received one prior 

line and 137 (49%) �2 lines. The median TTPn was 2.8 months (range: 

0.2-26.8), whereas the median TTPn-1 was 4.0 months (range: 0.3-79.5). 

The Spearman correlation coefficient between TTPn-1 and TTPn was 0.07 

(p�0.23). The median GMI was 0.6 (range: 0.0-14.4). 177 patients 

(63%) had a GMI �1, 21 (8%) a GMI � 1-1.33 and 81 (29%) a GMI 

�1.33. The median overall survival (OS) strongly correlated with GMI 

groups: OS was 9.1, 13.9 and 23.8 months, respectively (p�0.0005, 

log-rank test). There were also a strong correlations between response rate 

and GMI (p�0.0001, Fisher exact test), and between GMI and progressionfree 

survival (�0.0001, log-rank test). The logistic regression analysis 

retained only performance status (PS) [OR�1.76 if PS�0; p�0.04] 

associated with GMI�1.33. Sarcoma grade (p�0.21), histological subtype 

(p�0.16), and number of prior chemotherapy lines (p�0.95) were not 

associated with GMI�1.33. Conclusions: Overall,�30% of patients experienced 

GMI�1.33 regardless of histological subtype or grade, and number 

of prior lines of chemotherapy. Patients with PS�0 benefit more from 

trabectedin. GMI�1.33 is associated with longer OS (median �24 

months). GMI is better defined than previously described parameter such 

as �Tumor Growth Rate� (Lopez-Martin, Abstract 3293, ASCO 2003). GMI 

as an indicator of drug activity merits further exploration in this setting. 


4:45 PM-5:45 PM 

A prognostic nomogram for prediction of recurrence following surgical resection 

of desmoid tumors. Presenting Author: Aimee Marie Crago, Department of 

Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 

Background: Desmoid tumors can respond to novel chemotherapeutics (e.g., 

sorafenib). We sought to construct a postoperative nomogram identifying 

desmoid patients who are at high-risk for local recurrence and potential 

candidates for systemic therapy. Methods: Desmoid patients undergoing resection 

from 1982-2011 were identified from a single-institution prospective 

database. Cox regression analysis was used to create a desmoid-specific 

recurrence nomogram integrating clinical risk factors. Results: Desmoids were 

treated surgically in 495 patients (median follow-up 60 months). Of 439 

patients undergoing complete gross resection, 100 recurred (92 within 5 years 

of operation). Five-year recurrence-free survival (RFS) was 71%. Only 8 patients 

died of disease, all after R2 resection (6 with intraabdominal desmoids). 

Radiation was associated with worse RFS (p�0.001). Multivariate analysis 

suggested associations between recurrence and extremity location, young age, 

and large tumors, but not margin (Table). Abdominal wall tumors had the best 

outcome (5-year RFS 92% vs. 34% in patients �25y.o. with large, extremity 

tumors). Age, site and size were used to construct an internally-validated 

nomogram (concordance index 0.703). Integration of margin, gender, depth, 

and presentation status (primary vs. recurrent disease) did not improve concordance 

significantly (0.707). Conclusions: A postoperative nomogram including 

only size, site and age predicts local recurrence and aids in counseling patients. 

Systemic therapies may be tested in young patients with large, extremity 

desmoids, but surgery alone is curative for most abdominal wall lesions. 

Multivariate analysis 

factor Hazard ratio (95% C.I.) P value 

Margin status (R1 vs. R0) 0.99 (0.65, 1.52) 0.97 

Presentation (recurrent vs. primary) 1.16 (0.70, 1.90) 0.57 

Depth (deep vs. superficial) 1.37 (0.54, 3.45) 0.51 

Gender (female vs. male) 1.32 (0.82, 2.10) 0.25 

Site (vs. abdominal wall) 

Extremity 5.02 (2.14, 8.42) �0.001 

Chest wall 3.12 (1.20, 8.42) 0.020 

Intraabdominal 2.73 (0.98, 7.59) 0.054 

Other 1.54 (0.31, 7.63) 0.60 

Size (>10 cm vs. 65y.o.) 

634s Sarcoma 


4:45 PM-5:45 PM 

Is CTNNB1 mutational analysis predictive for progression in patients with 

sporadic desmoid tumors primarily observed? Presenting Author: Chiara 

Colombo, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy 

Background: Recently, a wait and see (W&S) approach has been proposed 

for patients affected by desmoid tumor (DT). Specific CTNNB1 mutation 

has been correlated with higher risk of recurrence after surgical resection. 

Aim of this study was to evaluate the correlation between CTNNB1 

mutation type and time to progression in patients primarily observed (TTP). 

Methods: We included all consecutive patients:(1) primarily observed at the 

Fondazione IRCSS Istituto Nazionale Tumori (Milano, Italy) or Institut 

Gustave Roussy (Paris, France) for primary sporadic DTs (2) with available 

FFPE preserved tissue for CTNNB1 mutational analysis, (3) with measurable 

disease and adequate follow-up. TTP from date of diagnosis to date of 

radiological (PRO-R) or symptomatic (PRO-S) progression were conducted 

by Kaplan-Meier method and log-rank test to compare strata. Results: A 

total of 79 patients (August 2002- July 2011) were included (81% female, 

19% male); median age was 34 (IQ, 10-77); sites distribution: abdominal/ 

chest wall (75%), extremity (21%), intra-abdominal (4%). CTNNB1 

mutations were observed in 76% of DT samples: 41A (48%), 45F (25%), 

45P (2%); 24% were WT. Median follow-up was 19 mo (IQ, 11-28). 

Thirty-six patients experienced progression (86% PRO-R, 14% PRO-S): 

41A (47%), 45F (55%), 45P (100%), WT (26%). An inferior TTP at 36 

months was observed in mutated patients vs WT, while no difference was 

detected for specific subtype mutated patients (WT 68%, 45F 24%, 

41/45P 35%, p� 0.045). A variety of different treatments including 

surgery, hormonal therapy, chemotherapy, antiCOX2 or persistent W&S 

approach were proposed at progression. Forty-two patients did not receive 

any treatment. Conclusions: A clear trend towards a lower risk of progression 

was observed in WT patients, but no difference between specific mutated 

patients (45F vs 41/45P) was observed. Prospective studies to eventually 

clarify the potential role of CTNNB1 as prognostic tool in tailoring desmoids 

treatment are presently underway. 


4:45 PM-5:45 PM 

Localized angiosarcomas (AS): Identification of prognostic factors (PF) and 

analysis of treatment impact—Series from the French Sarcoma Group 

(GSF/GETO). Presenting Author: Clothilde Lindet, Centre Oscar Lambret, 

Lille, France 

Background: AS represents less than 2% of all adult soft tissue sarcoma. PF 

and role of respective (neo)-adjuvant treatments in management of localized 

AS remain badly established. Methods: We have conducted a retrospective 

multicentre study (June 1980-October 2009) of 107 patients with 

localized AS. All cases have been centrally reviewed by pathologist expert. 

Univariate and multivariate analysis were conducted to identify independent 

PF. Overall survival (OS) and Local Recurrence Free Survival (LRFS) 

were estimated using the Kaplan-Meier method. Impact of treatments had 

been explored with Cox Model after adjustment to the PF. Results: The sex 

ratio was 18/89 (0.2). Median age was 71 years. 22% (24/107) and 62% 

(67/107) of patients developed AS in preexisting lymphoedema and in 

irradiated field, respectively. 71 cases (66%) were superficial. The most 

frequent primary locations were: limbs (35, 33%), chest wall (32, 29%) 

and breast (22, 20%). Grade was 1 in 21/103 (20%), 2 in 35/103 (34%) 

and 3 in 47/103 cases (46%). Treatments consisted in surgery, adjuvant 

radiotherapy and (neo)-adjuvant chemotherapy in, respectively, 95, 27 and 

27 cases. R0 margin was obtained in 49 cases. The median OS and LRFS 

were, respectively, 38.8 months and 27 months. In multivariate analysis, 

the following PF influenced the OS: lymphedema (HR�2.02 [1.15-3.55]) 

and size�5cm(HR�1.48 [1.01-2.45]). After adjustment to these PF, R0 

margins was the sole treatment parameter improving the OS (HR�0.19 

[0.05-0.73]). In multivariate analysis, the following PF influence the 

LRFS: Age�70 (HR�1.68 [1.02-2.76]) and pre-existing lymphedema 

(HR�2.07 [1.15-3.75]). After adjustment to these prognostic factors, R0 

margins (HR�0.48 [0.38-0.69]) and adjuvant radiotherapy (HR�0.29 

[0.10-0.83]) improved the LRFS. Conclusions: Pre-existing lymphedema, 

tumour size and age�70 are the major PF in patients with localized AS. 

The achievement of R0 margins is of major importance for improving the 

outcome whatever the endpoint (OS, LRFS) Adjuvant radiotherapy decreased 

the local recurrence. (Neo)-adjuvant chemotherapy does not 

influence survivals. 


4:45 PM-5:45 PM 

Desmoid fibromatosis and pregnancy: A multi-institutional analysis of recurrence 

and obstetric risk. Presenting Author: Marco Fiore, Fondazione IRCCS 

Istituto Nazionale dei Tumori, Milan, Italy 

Background: Desmoid fibromatosis (DF) may be diagnosed during or after 

pregnancy (P). However, the risk of progression during P, or in women of 

child-bearing age with DF prior to P, is unknown. Furthermore, obstetric risks 

have not been well described. Methods: Institutional databases were reviewed at 

3 sarcoma referral centers in Europe and US for women with sporadic DF from 

1985 to 2011. Pregnancy and treatment data, outcomes, and obstetric 

complications were recorded. Results: Overall 75 women were identified. DF was 

diagnosed during P in 17 women (Group A) or within 6 mo after P in 10 (Group 

B), was in situ at the time of P in 29 women (Group C), or had been resected prior 

to P in 19 (Group D). Anatomic site, outcomes, and treatment for each group are 

in the Table. Among patients operated at diagnosis, 2/11 (18%) recurred (Group 

A�B). Among the entire cohort, 15 women (20%) recurred after definitive 

treatment and only 6 (8%) needed multiple treatments after P. Ten spontaneous 

regressions occurred after P (13%). Twelve women had further P following the 

DF-related one, and 3 (25%) needed treatment after the subsequent P. At a 

median follow up of 35 mo from P, 17 women did not receive any treatment 

(23%), and 39 remain disease-free (52%). Caesarean section was needed in 14 

cases (19%), but only in 1 expressly due to DF. DF-related P was associated with 

abortion in 6 cases (4 spontaneous, 2 voluntary); in no case was it caused by the 

presence of DF. Conclusions: DF developing prior to or during P may progress 

during the course of P or thereafter. Spontaneous regression after P was also 

observed. When resected, P-related DF rarely recurs. Wait & see is an option as 

well. DF history is not an indication for therapeutic abortion nor a contraindication 

against subsequent P. 

A B C D 

Total number 17 10 29 19 

Abdominal wall 11 (64%) 6 (60%) 14 (48%) 14 (73%) 

Limbs 1 (6%) 2 (20%) 11 (38%) 2 (11%) 

Visceral 4 (24%) 2 (20%) 1 (4%) 2 (11%) 

Other 1 (6%) 0 3 (10%) 1 (5%) 

Primary / recurrent 17/0 10/0 19/10 17/2 

DF progression during or after P 12 (70%) - 16 (55%) 4 (21%) 

Treatment after progression 9 (53%) - 8 (28%) 3 (16%) 

Surgery (*1 ILP) 5 - 6* 2 

Medical therapy 4 - 2 1 

DF progression after definitive treatment 3 (18%) 1 (10%) 8 (28%) 3 (16%) 

Spontaneous regression 1 (5%) 1 (10%) 7 (24%) 1 (5%) 


4:45 PM-5:45 PM 

Activity of sorafenib in radiation-associated breast angiosarcomas harboring 

MYC and FLT4 amplifications. Presenting Author: Sandra P. D’Angelo, 


Background: Angiosarcomas (ASs) are rare, aggressive vascular malignancies 

of endothelial cell differentiation which arise de novo or secondary to 

radiation therapy (RAS.) A subset of patients(pts) with AS harbor mutations 

in KDR (VEGFR-2) or overexpression of MYC and/or FLT4(VEGFR-3). MYC 

& FLT4 gene amplifications occur almost exclusively in RAS. These 

alterations provide a rationale for investigating agents that target angiogenesis 

in RAS. In a phase II trial of sorafenib, AS pts had a partial response 

(PR) of 14%; targeting the appropriate pt population may be essential. We 

hypothesize that co-amplification of MYC & FLT4 may be predictive of 

response to sorafenib. Methods: Using our institutional sarcoma database & 

data query system, we identified AS patients treated with sorafenib at 

Memorial Sloan-Kettering Cancer Center between 1992-2011. Molecular 

analysis performed on available tissue. With IRB approval, clinical information 

was collected. Results: We identified 10 women with RAS that received 

sorafenib. Average age 68 (range 51-84.) 7 pts had distant metastatic 

disease. Median lines of systemic therapy prior to sorafenib: 2 (range 1-4.) 

Sorafenib was first line in 60% of pts, administered at 400mg daily and 

adjusted for toxicity. Best responses included: complete response (CR) 

2/9(22%), PR 1/9(11%), stable disease (SD) 5/9(56%) range 5-23m, 

progressive disease 1/9(11%) for a clinical benefit rate of (CR�PR�SD) 

89%. Responses were seen in patients with lung metastases (n�2) and 

locally advanced disease (n�1) and were durable for 17, 42 and 26 

months. Median duration on therapy was 15 months (range 0-42 months.) 

7 pts underwent molecular analysis: co-amplification of MYC & FLT4 3 pts 

(30%); MYC amplification 4 pts (40%); KDR mutation 0 patients. Of the 3 

responders, MYC & FLT4 co-amplification were observed in 2 patients and 

not evaluated in one. Conclusions: Sorafenib is active against RAS of the 

breast. In this small series, complete and partial responses were seen in 

patients with co-amplification of MYC & FLT4. This observation requires 

further study. Performing molecular studies on all AS pts will help define 

the pathophysiology of this deadly disease to guide rationale clinical trials. 



4:45 PM-5:45 PM 

Phase II study of sorafenib mesylate (So) in patients (pts) with evolutive 

and advanced epithelioid hemangioendothelioma (EHE) or hemangiopericytoma/solitary 

fibrous tumor (SFT). Presenting Author: Christine Chevreau, 

Institut Claudius Regaud, Toulouse, France 

Background: There is no standard of care for both rare sarcomas. Regarding, 

the important vascularization of EHE and SFT, we explored the activity/ 

toxicity of So in pts with these sarcomas. Methods: We conducted a 

multicenter one-step phase II trial of So (800 mg/d). The primary endpoint 

was the 9-months progression-free rate (9-PFR). According to EORTC 

criteria, So is considered as promising drug if 6-PFR�14%. All pts have 

had documented progressive disease at entry. Results: 20 pts (15 EHE & 5 

SFT) were enrolled from June 2009 to February 2011 in the 8 participating 

institutions. 12 men and 8 women. Median age was 57. The most common 

primaries were superficial trunk (8 cases) and liver (4 cases). PS were 0 in 

10 cases, 1 in 7 cases and 2 in 3 cases. 16 pts had metastasic disease , 

especially in lung (15), liver (6) and bone (4). Eight pts received prior 

chemotherapy (Doxorubicin : n� 8 cases and taxane : n �3). The median 

So treatment duration was 124 days. 9 pts experienced grade-3 toxicities; 

the most frequent grade-3 toxic events were hand foot syndrome (5 pts), 

myalgia (1), stomatitis (1), anorexia (1), diarrhea (1) and arterial hypertension 

(1).Because of this toxicity, treatment discontinuation was necessary 

in 6 cases and dose reduction was necessary in 5 pts. The 9-PFR was 6/18 

(33.3% [11.5-55.1]). The 2, 4 and 6 PFR were 15/18 (83.3%), 8/18 

(44.4%) and 7/18 (38.8) respectively We observed 2 partial responses 

lasting 2 and 9 months in 2 pts with EHE. Analysis of the predictive value of 

circulating pre-angiogenetic biomarkers is ongoing. Conclusions: According 

to the STBSG-EORTC criteria (3-PFR�40% & 6-PFR�14%), So is a 

promising drug for EHE and SFT pts. Further trials is needed, especially a 

discontinuation randomized trial. 


4:45 PM-5:45 PM 

Tenosynovial giant cell tumor (TGCT)/pigmented villonodular synovitis 

(PVNS): Outcome of 313 patients before the era of kinase inhibitors. 

Presenting Author: Emanuela Palmerini, Istituto Ortopedico Rizzoli, Bologna, 

Italy 

Background: Tenosynovial giant cell tumor (TGCT) is a rare, usually benign 

neoplasm of synovium and tendon sheath. TGCT is classified as localized or 

diffuse according to the extent of synovial involvement. Surgery is the 

primary treatment, but the recurrence rate is high, with possible multiple 

recurrences, joint function deterioration and decline in quality of life. 

Recent data suggest a role for TKIs in advanced disease. In order to identify 

prognostic factors for recurrence, a retrospective pooled analysis was 

carried out in three institutions (Istituto Ortopedico Rizzoli, Bologna, Italy; 

Istituto Nazionale Tumori, Milano, Italy; Memorial Sloan Kettering Cancer 

Center, New York, USA). Methods: Clinical charts and pathology reports of 

patients (pts) treated in the period 1998-2008 were examined. Results: 

The study included 313 pts, 177 F and 136 M; median age: 36 years 

(range: 11-89 years). Most (64%) pts had tumors in the knee (15% ankle, 

11% hip, 10% other). Tumor size was: �2 cm in 24% of pts, 2-5 cm in 

44%, �5 cm in 32%. A diffuse pattern was reported in 69% of pts. The 

resection status was available in 289 pts: 51% had R0 surgery, 28% R1 

and 21% R2. No metastases were documented. Local recurrence was 

reported in 76 pts (median time to recurrence: 15.7 months). With a 

median follow-up of 4.2 years, 5-year local recurrence-free survival (LRFS) 

was 66% (95% CI: 59 - 73). Size (� 2 cm 80% vs. 2-5 cm 67% vs. �5cm 

62%, p�0.04), gender (F 73% vs. M 56%, p�0.02), type (localized 78% 

vs. diffuse 61%, p�0.02), and resection status (R0 76% vs. R1 55%, vs. 

R2 57%, p�0.002) influenced 5-year LRFS, whereas age, tumor location 

and bone involvement did not. The 5-year 2nd LRFS was 43% (95% CI: 28 - 

59). Multiple (2 to 5) local recurrences were observed in 39% of relapsed 

patients. Conclusions: The study confirms TGCT propensity to multiple local 

recurrences. Diffuse type, suboptimal surgery, male gender and larger 

tumors increase the recurrence risk. In order to improve the probability of 

local control, studies addressing the role of TKIs could be considered in 

subsets of patients. 

Sarcoma 

635s 


4:45 PM-5:45 PM 

Optimizing the therapy of desmoplastic small round cell tumor: Combined 

experience from the two major cancer centers. Presenting Author: Vivek 

Subbiah, Division of Cancer Medicine, University of Texas M. D. Anderson 


Background: Desmoplastic small round cell tumor (DSRCT) is a rare 

translocation-positive (EWS-WT1)sarcoma subtype that often presents as 

diffuse peritoneal sarcomatosis in male adolescents and young adults. The 

objective of this study was to assess the survival of patients with DSRCT 

from the two major cancer centers. Methods: A multi-center retrospective 

review was performed of patients diagnosed with DSRCT treated at The 

University of Texas MD Anderson Cancer Center (MDACC) and Memorial 

Sloan-Kettering Cancer Center (MSKCC). Results: Of the 197 pts evaluated 

at both cancer centers (109 from MSKCC and 88 from MDACC) 87 % were 

male. The mean age was 25 � 11 years; 139 (70.6%) underwent surgery; 

38 ( 19.6%) had debulking surgery, 30 received radiation therapy, and 27 

underwent hyperthermic chemotherapy after debulking (CHPP), 11 had a 

stem cell transplant. 112 patients were seen after 2003 in both the centers 

vs 85 before 2003. Neoadjuvant chemotherapy included Ewing’s-like 

chemotherapy with MSKCC’s P6 regimen (�18 yrs of age) and VAI in 

adults. We further analyzed the MDACC cohort. In univariate analysis 

radiotherapy, surgery, CHPP, removal of primary mass � metastases, age � 

30 and patients treated after 2003 were associated with significantly 

improved overall survival. Multi-variate analysis showed that patients 

treated after 2003 had 59% lesser hazard (HR�0.41) than those treated 

earlier (p�0.04). Comparing 1990-2003 vs. 2004-2010 survival �3 yr 

with DSRCT was �25 % and is now �50 %, a significant improvement. 

Conclusions: We present long-term outcomes for the largest series of 

patients diagnosed with DSRCT. A multidisciplinary approach to DSRCT 

treatment is required to prolong 3- and 5-yr overall survival. Our recent 

improved outcomes required not only aggressive chemotherapy but also 

regional local control measures. Best adjuvant therapy remains to be 

determined. A treatment algorithm will be proposed. 


4:45 PM-5:45 PM 

Advanced chondrosarcomas: Role of chemotherapy and survival. Presenting 

Author: Binh Bui Nguyen, Institut Bergonie, Bordeaux, France 

Background: There are no data about the role of chemotherapy in patients 

with advanced chondrosarcomas. Methods: From 2000 to 2011, 98 

patients with a confirmed diagnosis of advanced chondrosarcomas were 

referred to one of the 8 participating institutions, and their medical records 

reviewed. Results: Median age was 46 years (range 16-82). The most 

frequent histological subtype was conventional chondrosarcoma (n�60, 

61%). 83 patients (85%) had metastatic disease ( lung n�71, bone n�23, 

liver n�6) and 15 patients (15%) had locoregional unresectable disease. 

30 patients (31%) had � 2 metastatic sites. 63 patients (64%) received 

1st-line combination agent chemotherapy. 70 patients (71%) received a 

1st-line anthracycline-containing regimen (doxorubicin � cisplatin �/ifosfamide: 

n�30, doxorubicin or pegylated liposomal doxorubicin: n�18, 

doxorubicin � ifosfamide �/- dacarbazine: n�16, others� 6). RECIST 

objective response was observed in 14 patients (14%), all but two treated 

with anthracyclines. 30 patients (31%) had stable disease � 6 months. 

Median progression-free survival (PFS) and overall survival (OS) were 5.3 

months (95% CI: 2.8-7.7) and 19 months (95% CI: 14-24) respectively. 

Performance status (PS) � 2 was the sole factor significantly associated 

with OS. Conclusions: Chemotherapy is associated with a 6-month nonprogression 

rate of about 45% in patients with advanced chondrosarcoma. 

Best supportive care should be considered in patients with poor PS. These 

data should be used as a reference for response and outcome in the 

assessment of investigational drugs in advanced chondrosarcoma. 


636s Sarcoma 


4:45 PM-5:45 PM 

Cetuximab and EGFR inhibitors in patients with neurological symptoms 

due to chordoma. Presenting Author: Ola Linden, Department of Oncology, 

Lund University Hospital, Lund, Sweden 

Background: Chordomas are rare tumours located along the neuraxis, 

showing limited sensitivity to radiotherapy and lack of response to chemotherapy. 

However, tyrosine kinase inhibitors (TKIs) have been reported to 

have an effect. Following the failure of single-agent treatment in a young 

patient using cetuximab, we decided to treat patients (pts) with neurological 

symptoms with dual targeting of the epidermal growth factor receptor 

(EGFR), based on a case report by Hof et al., who successfully used dual 

targeting of EGFR, and supporting in vitro data. Methods: Eight consecutive 

pts with neurological symptoms at referral were treated with cetuximab 

(250 mg/m2 weekly) and an EGFR signalling inhibitor (250 mg gefitinib or 

150 mg erlotinib daily). The duration of treatment was not decided in 

advance. Results: EGFR expression on tumour cells was variable but 

present in all pts. Six pts were evaluable. One tetraplaegic pt died of an 

unknown cause and one pt on lithium carbonate discontinued treatment 

before the first follow-up due to renal toxicity. Four pts showed neurological 

improvement. Two of these regained and one improved the ability to walk, 

and a fourth, with a sacral tumour, improved his voiding ability. The fifth pt 

had clinically stable disease and, although the PET scan showed improvement, 

the treatment had to be discontinued due to skin toxicity. One pt 

showed progressive disease. In the four pts responding neurologically, 

improvement was noted already by the end of the third week. Three pts were 

retreated without failure while on treatment. The first pt who regained the 

ability to walk is still walking at 52� months. This pt, while still responsive 

to cetuximab and erlotinib, has failed to respond to single-agent treatment 

with imatinib, sorafenib or everolimus. The second pt who regained walking 

ability had severe alcoholism and died while being treated. The third is still 

walking at 16� months. All pts exhibited significant cutaneous side 

effects, in some cases necessitating intermittent interruption of therapy. 

Conclusions: Treatment with cetuximab and TKIs can thus achieve meaningful 

and long-lasting clinical improvement in pts with paresis due to 

chordoma, and is feasible in pts with limited comorbidities. 


4:45 PM-5:45 PM 

Lapatinib in advanced chordoma: A phase II study. Presenting Author: 

Silvia Stacchiotti, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 

Italy 

Background: To report on a prospective Phase II, investigator-driven, 

collaborative study to explore the activity of lapatinib, a dual EGFR and 

ErbB2 inhibitor, in EGFR-positive advanced chordomas. Methods: From 

December 2009 to December 2011, 19 advanced progressing chordoma 

patients entered this study (mean age: 59 yrs – range � 35-75; PS: 0-3 - 

�2 � 52%; site: sacrum � 68%, spine � 21%, skull base � 11%; disease 

extent: metastatic � 68%, locally advanced � 32%). EGFR expression was 

evaluated by immunohistochemistry in all patients. EGFR activation was 

detected in 15 of 17 evaluable cases by phospho-arrays and/or real-time 

PCR and/or fluorescence immunostaining. EGFR FISH analysis showed 

high level of gene gain in 4. HerB2 status is under evaluation. Patients 

received lapatinib 1500 mg/day (dose intensity in excess of 1250 mg/day), 

until progression or toxicity. The primary study end-point was response rate 

(RR) as for Choi criteria extended to MRI. Secondary end-points were RR by 

RECIST, PFS by Choi, OS, clinical benefit rate (CBR) (CR�PR�SD�6mos), 

correlation between EGFR status and response. Results: 16 pts are 

evaluable for response (3 too early); 4 patients are still on treatment. 3 

patients (19%) had a partial response (PR) and 8 (50%) a stable disease 

(SD) as their best Choi response, corresponding to RECIST SD in all cases. 

The 3 cases with a PR by Choi had a minor decrease in size; another patient 

had a mixed response. The CBR was 19%. Median PFS as for Choi was 5.5 

(range � 2-12�) months, with 1 patient being progression-free at 18 

months. Toxicity was as expected. In one case treatment was interrupted 

due to side effects. No correlation was observed between EGFR expression/ 

activation and response. Conclusions: This Phase II study showed a modest 

activity of lapatinib in chordoma. EGFR expression was not predictive of 

response. The clinical relevance of EGFR targeting in chordoma needs to be 

further investigated. 


4:45 PM-5:45 PM 

Establishment of a chordoma xenograft and in vivo testing of compounds 

identified by high-throughput screening. Presenting Author: Matteo Maria 

Trucco, The Johns Hopkins University, Baltimore, MD 

Background: Chordoma is a rare primary bone malignancy that arises in the 

skull base, spine and sacrum and originates from remnants of the 

notochord. Therapy primarily consists of surgical resection and radiation. 

These tumors are typically resistant to conventional chemotherapy, and to 

date there are no FDA-approved agents for chordoma. The lack of in vivo 

models of chordoma has impeded the development of new therapies for this 

tumor. Methods: Primary tumor from a classic sacral chordoma was 

obtained, immediately processed into a single cell suspension and injected 

in to the parasacral area of a NOD/SCID/IL-2R gamma-null mouse, and 

tumor grew after 3 months. The NIH Chemical Genomics Center performed 

high-throughput screening of 2,816 compounds. Two established chordoma 

cell lines, U-CH1 and UCH2B, were treated and cell viability 

measured by CellTiter-Glo assay. Cells were incubated for 48 hours with 

drug concentrations ranging from 0.5nM to 46uM. The screen yielded 

several compounds that showed activity and two were tested in the 

xenograft. Results: We have established a xenograft model of dedifferentiated 

chordoma. High-throughput screening of compounds identified compounds 

that show activity against chordoma cell lines. In vivo testing of two 

identified compounds showed a dramatic reduction of tumor growth. 

Conclusions: We have established a xenograft model of dedifferentiated 

chordoma. High-throughput screening of compounds identified compounds 

that show activity against chordoma cell lines. In vivo testing of two 

identified compounds showed a dramatic reduction of tumor growth. 


4:45 PM-5:45 PM 

Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase 

inhibitor (HDACi), in patients (pts) with advanced, previously treated soft 

tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French 

Sarcoma Group. Presenting Author: Philippe Alexandre Cassier, Centre 

Léon Bérard, Lyon, France 

Background: Treatment options are limited for pts with advanced pretreated 

STS. HDACi have shown activity in preclinical models of STS and SCT 

Methods: Pts with advanced pretreated STS and SCT were enrolled in this 

open label, single arm, multicenter phase II study. Panobinostat was given 

orally, 40 mg thrice per week. The primary end-point was 3-month 

progression-free rate according to RECIST 1.1 using central review. 

Fleming-A’Hern single-stage design for phase II trials was used, and 

assuming a type I error alpha of 5% with 90% power, 15/47 pts were 

needed to be progression free at 3 months to reject a rate of 20%. Results: 

Fifty three pts were enrolled between January 2010 and January 2011. 

Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 

had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had 

metastatic disease. The most common sites were the lung and the liver. All 

but one pt had documented disease progression prior to study entry. The 

median number of prior lines of therapy was 2 (range 1-7). Panobinostat 

dose was lowered to 20 mg thrice a week after 11 pts were enrolled based 

on the recommendation of an independent safety committee. Fifty-two pts 

were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) 

reported at least one adverse event (AE) and 22 (42%) reported at least one 

treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were 

thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the 

primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free 

at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS 

and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two 

patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best 

response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 

with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 

with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 

mg thrice a week. Efficacy in unselected advanced STS was limited 

although some patients had prolonged SD. Activity in pts with SCT warrants 

further investigation. 



4:45 PM-5:45 PM 

Phase I study of doxorubicin (D) plus anti-insulin-like growth factor 1 receptor 

(IGF-1R) antibody cixutumumab (IMC-A12) in advanced soft tissue sarcoma 

(STS). Presenting Author: Rashmi Chugh, University of Michigan, Ann Arbor, MI 

Background: IGF1R is overexpressed in many STS, but its exact role in the biology 

of the disease is unclear. Anti-IGF1R antibody cixutumumab (C) has shown 

acceptable toxicity in a single-agent phase 2 study of STS. Here we performed a 

dose escalation study of C with D in STS. Methods: Eligible pts had advanced 

STS, ECOG �2, age�16, �1 prior chemotherapy, fasting glucose�120 mg/dL 

and acceptable organ function. C was administered IV over 60 min on D1,8,15 at 

one of three dose levels and D as a 48 hr infusion on D1 of a 21-day cycle. After 6 

cycles of combination rx, pts with SD or better continued on single agent C. The 

Time-to-Event Continual Reassessment Method (TITE-CRM) was used to estimate 

the probability of DLT at each dose level and to assign patients to the dose 

with the estimated probability of DLT closest to but not exceeding 30%. Results: 

30 pts with STS were enrolled between 9/08-1/12. Median age was 64 (range 

29-80); 17M/13 F, 7 pts received prior chemo. One pt withdrew prior to rx; 5 pts 

are on active rx. Reasons for discontinuation were: progression (18), toxicity (3), 

death (1), pt decision (2). DLTs observed were hyperglycemia and mucositis. 

Grade 3 decrease in cardiac left ventricular ejection fraction was observed in 2 

pts at dose level 2 after 4 or more cycles. Common G1/2 nonhematologic AEs: 

nausea (73%), fatigue (68%), pain (59%), diarrhea (41%), constipation (36%), 

hyperglycemia (32%), mucositis (32%), nail changes (27%), weight loss (27%). 

Gr3/4 toxicities in �10%: hyperglycemia (18%), lymphopenia (18%), anemia 

(14%), neutropenia (14%), thrombocytopenia (14%). Median PFS was 5.3 

months, 95% CI 2.7 -7.9 months. Four of 22 pts (18%) evaluable for response 

achieved a PR. Conclusions: C and D is tolerable and the recommended phase II 

dosing is dose level 3. The potential of cardiotoxicity should be monitored and 

assessed further in ongoing studies of this regimen. 

Dose 

level 

1: C: 1 mg/kg 

D: 75 mg/m2 2: C: 3 mg/kg 

D: 75 mg/m2 3: C: 6 mg/kg 

D: 75 mg/m2 Pts enrolled 

(evaluable) 

DLTs 

observed 

TITE-CRM estimates 

Probability of DLT 95% Credible interval 

Objective 

responses 

4 (4) 0 4.7 1.1 – 14.7 1 

13 (13) 2 6.5 1.6 – 18.4 2 

13 (10) 0 9.7 4.8 – 24.3 1 


4:45 PM-5:45 PM 

Efficacy of a phosphoinositol 3 kinase (PI3K) inhibitor in gastrointestinal 

stromal tumor (GIST) models. Presenting Author: Thomas Van Looy, 

Laboratory of Experimental Oncology and Department of General Medical 

Oncology, KU Leuven and University Hospitals, Leuven, Belgium 

Background: PI3K signaling is crucial for GIST proliferation and survival. 

We assessed the efficacy of the PI3K inhibitor NVP-BEZ235 (BEZ), alone 

or in combination with imatinib (IM), in GIST xenografts. Methods: Nude 

mice were grafted bilaterally with human GIST, carrying either KIT exon 9 

(GIST-BOE, dose-dependent IM resistant) or exon 11 (GIST-DFR, IM 

sensitive) mutations. Animals, randomized into four groups (n�8/group) 

were dosed orally for 2 weeks with either vehicle, IM (50mg/kg/bid), BEZ 

(10mg/kg/qd), or IM�BEZ. Treatment efficacy was assessed by tumor 

volume, histopathology and Western immunoblotting. Moreover tumor 

regrowth was evaluated for 3 weeks after treatment cessation. Results: As a 

single agent IM and BEZ stabilized tumor growth of both GIST-BOE and 

DFR. Moderate to significant tumor regression was observed in GIST-BOE 

under BEZ (by 27%), and IM�BEZ (66%), and also in GIST-DFR under IM 

(75%) and IM�BEZ (75%). In GIST-BOE significant reduction in mitotic 

index was observed under BEZ (8.5 fold) and IM�BEZ (8.5 fold) as 

compared to control. In GIST-DFR mitotic activity was virtually absent 

under all regimens. Apoptotic activity increased significantly after treatment 

with IM (5.5 fold) and IM�BEZ (14.0 fold) in GIST-DFR, whereas it 

was almost unaffected by BEZ as single agent, as well as in all treatment 

groups in GIST-BOE. By Western, PI3K signaling was incompletely inhibited 

in all groups in GIST-DFR, and after BEZ in GIST-BOE. Complete 

inhibition of PI3K signaling was observed only after combination treatment. 

After treatment cessation long-lasting growth-inhibition was observed 

in IM�BEZ treated GIST-DFR. Moreover, mitotic index after BEZ 

and BEZ�IM in GIST-DFR was lower than in control even after treatment 

withdrawal. Conclusions: BEZ shows significant efficacy in GIST xenografts. 

Furthermore, combination with IM shows synergistic and long-lasting 

effects even after treatment withdrawal, which is not the case with drugs 

routinely used for GIST treatment. 

Sarcoma 

637s 


4:45 PM-5:45 PM 

Immunohistochemical identification of SDHA-mutant gastrointestinal stromal 

tumors (GISTs). Presenting Author: Andrew J. Wagner, Dana-Farber 


Background: GISTs are most commonly driven by activating mutations in 

KIT or PDGFRA. However, 15% of GISTs in adults and �90% in children 

lack such mutations. A subset of KIT/PDGFRA wild-type GISTs shows 

distinctive morphologic and clinical features and loss of expression of 

succinate dehydrogenase (SDH) B. Only a fraction of SDHB-deficient 

GISTs carry loss-of-function mutations in SDHB or SDHC. Due to the 

complexity of its locus and the presence of several pseudogenes, SDHA is 

rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of 

expression of SDHA and SDHB in paraganglionomas. We sought to 

determine whether SDHA IHC could identify GISTs with SDHA mutations. 

Methods: Tumors (n�11) with features of SDH-deficient GIST (gastric 

origin, epithelioid morphology, multinodular/plexiform architecture) were 

selected from pathology archives under an IRB-approved protocol. Expression 

of SDHA and SDHB was determined on tumor sections by IHC. 

Genomic DNA was isolated from SDHA-negative tumors and amplified 

using primers specific to introns flanking each of the 15 SDHA exons. 

Amplicons were bidirectionally sequenced and compared to genomic 

repository data. Exons with somatic mutations were also examined in DNA 

from corresponding normal tissue to determine germline status. Results: All 

tumors (100%) were deficient for SDHB expression by IHC. Four of 11 

(36%) SDHB-deficient GISTs also lacked expression of SDHA. SDHA 

expression was intact in the 7 remaining tumors, including 3 with known 

SDHB (n�2) or SDHC (n�1) mutations. Nonsense mutations in SDHA 

were identified in all 4 SDHA-deficient tumors, caused by a single base pair 

(bp) substitution (n�3) or a single bp deletion (n�1), and heterozygous 

mutations were also found in DNA from normal tissue of all 4 patients. 

Somatic loss of the 2nd allele has thus far been found in 3 of 4 tumors; 2 by 

loss of heterozygosity and 1 by a 13-bp deletion. Further analysis of the 4th specimen is ongoing. Conclusions: SDHA mutations are a common cause of 

SDH-deficient GISTs and result in combined loss of expression of both 

SDHA and SDHB. Loss of SDHA expression by IHC reliably predicts SDHA 

mutations and can be used to select cases for SDHA genetic testing. 


4:45 PM-5:45 PM 

Neoadjuvant treatment of locally advanced GIST: Results of APOLLON, a 

prospective, open label phase II study in KIT- or PDGFRA-positive tumors. 

Presenting Author: Peter Hohenberger, Department of Surgery, Mannheim 

University Medical Center, Mannheim, Germany 

Background: Imatinib may significantly downstage the metastatic GIST. 

This prospective, phase II, open-label trial of neoadjuvant imatinib evaluated 

the overall tumor response and progression rate of disease in locally 

advanced, non-metastic patients. Methods: Inclusion criteria were: KIT 

(n�39) or PDFRA (n�6) positive GIST, proven by biopsy and IHC. Tumors 

had to be locally advanced, potentially resectable, M0. Patients received 

400 mg of imatinib daily (KIT exon 9 mutations: twice daily) for 6 months, 

in the absence of disease progression or unacceptable toxicity. At two 

months 18F-FDG-PET examination was performed to assess response in 

paralle to CT imaging. Adjuvant treatment postoperatively was not part of 

the study protocol (CST1571-BDE43, NCT00112632). Median follow-up 

is 36 months in 39 patients. Results: From 7/2005 to 10/ 2009, 41 

patients (16f, 25 m, mean age 54 yrs) were recruited to the trial with an 

average tumor size of 10.8 cm. One patient died from myocardial infarction 

3 weeks after start of treatment, all other patients completed the protocol. 

In two patients dose reduction/interruption due to toxicity was required. 

34/41 patients underwent resection of the tumor after a median of 200 d 

(range 57-394), while two patients had to be operated early due to disease 

progression. R0 resections were performed in 30/34 patients, two patients 

showed M1 disease at resection. Five patients showed developed progression 

postop., resulting in a PFS rate at 3 years of 85.2%. No patient has 

died so far from the disease. Conclusions: Neoadjuvant treatment with 

imatinib for six months is a safe treatment in patients with locally advanced 

disease. The extent of the operation can be significantly downsized after 

pretreatment. Despite the fact that no adjuvant treatment was foreseen, the 

progression-free rate at 3 years postoperatively is promising. 


638s Sarcoma 


4:45 PM-5:45 PM 

Phase I trial of panobinostat (P) and imatinib (IM) in patients with 

treatment-refractory gastrointestinal stromal tumors (GIST). Presenting 

Author: Sebastian Bauer, Sarcoma Center, West German Cancer Center, 

Essen, Germany 

Background: Panobinostat (LBH589; P) is a pan-deacetylase-inhibitor that 

has preclinical activity in combination with IM in GIST models in vitro and 

in vivo. Aim of this study was to determine the maximum tolerated dose 

(MTD) and dose-limiting toxicities (DLT) of escalating doses of P in 

combination with IM in patients with GIST who have failed IM and sunitinib 

treatment. Methods: This was a two-center phase I study using a 3�3 

design with a prespecified expansion of the MTD cohort. IM was administered 

at a dose of 400mg qd. Following a 7 day run-in phase, escalating 

doses of P were added. The starting dose for P was 20 mg given as a 

three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Doses 

were increased by 10 mg if no dose limiting toxicities emerged. Blood 

samples were drawn for PK and biomarker assessments of IM, its main 

metabolite N-desmethyl-IM, and P using a validated RP-HPLC method. 

Acetylation of histone A3 was evaluated in peripheral blood mononuclear 

cells (PBMNC) as pharmacodynamic marker for P activity. Metabolic 

response using PET (EORTC-PET study criteria) was assessed on day 7 of 

IM run-in and after 3 weeks of combined treatment with IM and P. Results: 

In total 12 extensively pretreated (median 5 pretreatments) pts (4 f, 8 m; 

median age 56 y, 34-75 y) received study treatment at 2 dose levels (DL). 2 

dose-limiting toxicities (grade 4 thrombocytopenia) occurred at DL 2 (30 

mg). Most common AEs were thrombocytopenia, anemia, fatigue, nausea, 

emesis, diarrhea, creatinine elevation, abdominal cramping, and weight 

loss. DL 1 (20mg) was declared MTD, and 5 additional pts were enrolled at 

DL1. Analysis of P and IM PK revealed mean peak concentration of 14.8 

�/- 9.5 ng/ml for P (20 mg). IM plasma concentrations with 400 mg 

once-daily administration were 2.8 � 1.1 �g/mL at peak and 1.2 � 0.4 

�g/mL at trough. Histone A3 acetylation was demonstrated in PBMNC from 

pts treated at DL 1. 11 pts were evaluable for PET response: 1 had mPR, 7 

had mSD and 3 had mPD. Longest treatment duration was 17 weeks 

(median: 6wks). Conclusions: P in combination with IM is moderately 

tolerated. Evidence of target inhibition at the MTD was associated with 

limited clinical activity in heavily pretreated pts with GIST. 


Characteristics of sarcoma patients with long-term response to gemcitabine 

and paclitaxel. Presenting Author: Daniela Katz, Sharette Institute of 

Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 

Background: The combination of fixed-dose-rate gemcitabine and docetaxel 

has demonstrated efficacy in advanced uterine leiomyosarcoma and nonleiomyosarcoma 

sarcomas. We evaluated the tolerability and efficacy of 

modified taxol-gemcitabine (GemTax) protocol for patient with advanced 

sarcoma. The protocol was designed on a weekly basis to reduce toxicity. 

The purpose of this retrospective study was to evaluate the characteristics 

of long term-responders (�12 treatments) to weekly GemTax, among 

pre-treated advanced high-grade sarcoma patients. Methods: From May 

2004 to October 2011, 48 advanced sarcoma patients were treated with 

combination paclitaxel (60-90 mg/m2) and gemcitabine (600-900 mg/m2 

over 100 min), on days 1,8 of every 3-week cycle or on days 1, 8 and 15 of 

every 4-week cycle at a wide-range treatment lines. Two patients are still on 

the protocol. Results: Fifteen patients (6 males and 9 females) completed 

12 weekly treatments or more (mean 22.3 range 12-37) of which 4 

completed �30 treatments. These include 5 leiomyosarcomas (one retroperitoneal), 

2 uterine leiomyosarcomas, 3 MFH, 2 spindle sarcoma, 1 

osteosarcoma, 1 adamantimoma and 1 pleomorphic rhabdomyosarcoma. 

GemTax was administered as 1st or 2nd line treatment in 2 and 8 patients, 

respectively, and as 3rd -6th line in 5. Of these patients, none achieved 

complete response (CR), 7/15 (47%) achieved a partial response (PR) and 

8/15 (53%) had stable disease (SD). Median treatment duration was 10.3 

months (range 4-22) Median progression-free survival was 28.85 months 

(range 5-84 months), and median overall survival was 51.2 months (range 

16-95 months). A lower starting dose of paclitaxel (60-70 mg/m2) and 

gemcitabine (600-700 mg/m2) characterized the 4 patients with responses 

�30 cycles. Only five patients required dose reduction ranging 

between 10-40% due to grade 3 hematological toxicity. None of these 

patients, however, had febrile neutropenia, or bleeding events, and all 

non-hematologic toxicities including neurotoxicity were manageable. 

Conclusions: GemTax is a reasonable treatment option for patients with 

advanced pre-treated high-grade sarcomas. The regimen is well tolerated 

and dose adjustments do not seem to impact response. 


4:45 PM-5:45 PM 

Dasatinib first-line treatment in gastrointestinal stromal tumors: A multicenter 

phase II trial of the SAKK (SAKK 56/07). Presenting Author: 

Michael Montemurro, Centre Pluridisciplinaire d’Oncologie, University 

Hospital Lausanne, Lausanne, Switzerland 

Background: First line imatinib has improved the outcome of patients (pts) 

with gastrointestinal stromal tumor (GIST), but primary and secondary 

resistance remain a problem. Dasatinib is a second generation tyrosine 

kinase inhibitor (TKI) and inhibits the activity of bcr-abl, src-family kinases 

along with a number of other oncogenic kinases including kit. In vitro, 

dasatinib has shown activity against imatinib-resistant cell lines. Routinely, 

pts diagnosed with GIST and treated with TKIs are monitored by 

computed tomography (CT). 18F-fluorodeoxyglucose positron-emissiontomography 

(FDG-PET) measures tumor metabolic activity for early response 

assessment, which might be of particular use in the clinical trial 

setting. Methods: This two-stage phase II trial investigated dasatinib in pts 

with TKI-naïve GIST. Dasatinib starting dose was 2x70mg/day in pts with 

histologically proven, FDG-PET positive GIST. Response evaluation was 

done by serial CT and FDG-PET using EORTC PET response criteria (Young 

et al. 1999). Elective surgery was allowed after 6 months of trial treatment. 

Primary endpoint was response (CR�PR) by FDG-PET after one month of 

dasatinib. Results: 47 of planned 52 pts have been enrolled from December 

2007 to November 2011, when the trial was terminated due to slow 

accrual. 43 pts were eligible. Median age was 61 years, 24 pts were male, 

19 female and 41 had a performance status of 0 or 1. At a median 

follow-up of 11.9 months, 20 pts were still on treatment. Pts went off trial 

for elective surgery (n�6), progression (n�11), toxicity (n�3), and three 

patients died (one on-drug). 5% of pts experienced G4, and 38% of pts G3 

toxicity, which were most often gastrointestinal or pulmonary. 28% had 

their dose reduced or interrupted. The primary endpoint, FDG-PET response 

rate (CR�PR) at 4 weeks was 67% (13 CR, 16 PR, 7 SD, 3 PD, 4 

not evaluable). Median progression-free survival is 11.1 months and 

median overall survival not yet reached. Conclusions: Dasatinib shows 

promising efficacy in TKI-naïve pts with FDG-PET positive GIST. Mutational 

data will be presented at the meeting. 


Effect of metastasis surgery on overall survival in patients (pts) with 

advanced soft tissue sarcoma (ASTS): A subanalysis of the PALSAR trials. 

Presenting Author: Nuria Kotecki, Centre Oscar Lambret, Lille, France 

Background: The role of surgery in pts with ASTS remains controversial. We 

have conducted an exploratory retrospective analysis of the role of metastasis 

surgery in ASTS pts receiving 1st-line chemotherapy (CT). Methods: The 

database includes all pts enrolled in PALSAR-1 and PALSAR-2 trials 

[Fayette 2009; Bui-Nguyen 2011], treated with dose-intensified MAID or 

high-dose CT with peripheral blood stem cells support as 1st-line treatment 

of ASTS. In our analysis, the primary endpoint is overall survival (OS). 

Log-ranks are used for univariate analysis and Cox model for multivariate 

analysis. Impact of treatments had been evaluated after adjustment to 

confounders (Cox Model). Confounders were defined as parameters with 

significantly different distribution in pts who underwent metastasis surgery 

and those who did not (p�0.05) and significantly associated with OS 

(p�0.05). Results: The database consists of 410 pts (160 in PALSAR-1 

and 248 in PALSAR-2) with a median age of 43. Among them, 77 patients 

(18%) underwent metastasis surgery. At the end of the treatment, 61 pts 

experienced complete response (CR), 45 with CT alone and 16 with 

metastasis surgery and CT. The median follow-up was 29 months. The 

median OS was 35.7 months (29.9-41.5). The following parameters are 

associated with longer OS in univariate analysis: primary location 

(p�0.0001), performance status (p�0.010) and absence of liver metastasis 

(p�0.001). We identified 4 factors associated with metastasis surgery 

(n�76): limb/trunk primaries, young age, absence of liver metastasis and 

absence of progression of the target lesions after 4 cycles. The sole 

identified confounder was primary location. In multivariate analysis the 2 

categories of patients experiencing significant longer OS are those with CR 

without surgery (HR�2.2, [1.7-5.8], p�0.0001) and those with CR 

following metastasis surgery (HR�3.8, [2.3-6.2], p�0.0001). Conclusions: 

Among the pts with ASTS receiving poly-CT as 1st-line treatment, the OS of 

pts experiencing CR with or without metastasis surgery appears similar. 

Metastatis surgery without CR does not offer significant OS advantage. 



Phase Ib/II study of INNO-206 (EMCH-doxorubicin) in patients with soft 

tissue sarcoma. Presenting Author: Sant P. Chawla, Sarcoma Oncology 

Center, Santa Monica, CA 

Background: The safety and preliminary tumor response of a doxorubicin 

conjugate, INNO-206, was evaluated primarily in patients with metastatic 

STS who progressed on prior chemotherpy. INNO-206 consists of doxorubicin 

attached to an acid-sensitive linker that binds covalently to cysteine-34 

in circulating albumin. Methods: INNO-206 was administered IV at doses of 

either 230, 350 and 450 mg/m2 (165, 260 and 325 mg/m2 dox. eq.) every 

21 days for up to 8 consecutive cycles. Subsequent dose levels were 

administered if � 2/5 or 4/8 patients experienced a non-hematological 

dose-limiting toxicity during Cycle 1. Tumor response was monitored every 

other month and treatment continued until tumor progression or unacceptable 

toxicity. Standard safety monitoring was performed and cardiac 

function was followed periodically using MUGA or cardiac ultrasound. 

Results: As of January 11, 2012, 25 patients were entered in the study. 

21/25 patients had STS of various types. Of the 5 patients treated at 230 

mg/m2 INNO-206, 1 subject had grade 3 fatigue and acid reflux. Of the 

initial 5 patients entered at the 350 mg/m2 dose, no individuals experienced 

a grade 3 or 4 non-hematological toxicity during cycle 1. 2 patients 

treated at the 450 mg/m2 dose developed grade 3 oral mucositis during 

cycle 1. No patient exhibited cardiotoxicity as determined by MUGA or 

cardiac ultrasound. The MTD was determined to be 350 mg/m2 INNO-206 

(260 mg/m2 dox.eq.). 15 more patients were entered at this dose (total of 

20 patients). Of the 16 patients with STS, 3 objective partial responses 

(one of whom received prior doxorubicin) are ongoing as well as 10 patients 

with stable disease (range 2-7 months). 1 patient had progressive disease 

at the first evaluation. 2 patients died within the first cycle, one due to 

progressive disease and the other due to sepsis. Conclusions: INNO-206 is 

an active drug for the treatment of patients with advanced STS who have 

failed prior chemotherapy. Cumulative doses of 2000 mg/m2 of doxorubicin 

equivalents have been achieved, which is over 3 1/2 x the peak 

cumulative dose of standard doxorubicin. Adverse events are primarily 

hematological and no cardiotoxicity has been observed. 


A retrospective study from the Royal Marsden Hospital (RMH) of patients 

with malignant perivascular epithelioid cell tumors (PEComa) receiving 

treatment with sirolimus (SI) or temsirolimus (TSI). Presenting Author: 

Joanna Vitfell Pedersen, Sarcoma Unit, The Royal Marsden Hospital, 


Background: Perivascular epithelioid cell tumors (PEComas) are rare tumors 

driven by tuberous sclerosis complex gene mutations causing upregulation 

of mTOR. Two studies reporting a total of five patients (pts) have described 

the treatment of PEComa by mTOR inhibition. We report the outcome of 7 

pts with PEComa treated with SI or TSI at RMH. Methods: A retrospective 

analysis was performed on all pts with PEComa referred to the Sarcoma unit 

at RMH between 2000 and 2011. Data collected included gender, 

performance status, site of primary tumour, tumour size, surgery, SI/TSI 

and SI/TSI dose, toxicity according to common toxicity criteria (CTC) 

version 2.0 and response by RECIST. Results: Five (71%) pts were female, 

median age was 46 years. Two (29%) had metastatic disease at baseline. 

Most common primary site was the gastrointestinal tract (29%). Six pts 

received SI, one TSI. Median treatment duration was 131 days (7-1135). 

TSI was given at 25 mg IV weekly. Median starting dose of SI was 3 mg daily 

(1-4), median highest dose was 4 mg daily (1-5). Best responses by 

computed tomography (CT) scan by RECIST criteria were partial response: 

3 (43%), stable disease: 2 (29%) and progressive disease (PD): 1 (14%). 

One pt only received 7 days of SI and was therefore not evaluable. Two pts 

continue on treatment, 3 stopped due to PD, one stopped due to grade (gr) 

3 thrombocytopenia and one due to gr 3 cough, but two weeks later had 

confirmed PD on CT. Other toxicities reported were generally mild (gr 1/2) 

and included mucositis (n:3), rash (n:2), fatigue (n:1), anaemia (n:1), 

tooth pain (n:1) and oedema (n:1). One pt experienced a grade 3 trigeminal 

nerve pain leading to dose reduction in SI. Therapeutic drug monitoring was 

not performed. Conclusions: Our study confirms that SI and TSI are well 

tolerated with good clinical response and supports the continuous administration 

of SI or TSI for PEComas. A median treatment time of only 131 days 

indicates that most pts have a good response to treatment, but responses 

are sometimes short-lived and further treatment options are needed, 

justifying further research into inhibitors of this signalling pathway. 

Sarcoma 

639s 


Analysis of a neoadjuvant regimen with a fixed dose of doxorubicin followed 

by a 10-day course of 27 Gy radiation in the treatment of soft tissue 

sarcoma (STS) of the extremity/trunk. Presenting Author: John Mathews, 

Scott and White Memorial Hospital, Temple, TX 

Background: Local tumor control and preservation of limb function are 

major goals of treatment of STS. With current standard of combining 

limb-sparing surgery and 5-6 weeks of neoadjuvant or adjuvant 50-65 Gy 

radiation, reducing local recurrence has been a challenge with rates of 

15-30%. Eilber et al. (Cancer Treatment Symposia 1985; 3:49-57) used a 

fixed daily dose of doxorubicin for three days with radiation of 35Gy. This 

yielded a 5% local recurrence, while wound complication rate was 35 %. 

We reduced the radiation dose to lower the wound complications rate. We 

report a cohort of patients treated in this manner at our institution. 

Methods: After a baseline echocardiogram, patients received a radiosensitizing 

dose of intravenous doxorubicin (30mg/day) for 3 consecutive days, 

then radiation with 2.7 Gy in 10 fractions, followed by limb sparing surgery. 

After IRB approval, we retrospectively analyzed records of 191 patients 

during the treatment period from 1991 to 2010. Data extracted included 

local tumor recurrences and wound complications defined as non-healed 

wound at 1 month, number of limb salvage surgeries and involvement of 

surgical margins. Results: Of the 191 patients, median age was 53 (range, 

13-89). Stages at presentation included I, II, III and IV, with 2%, 33%, 

61%, 4% respectively. The median follow up was 5 years. Of the 24 types 

of sarcomas treated, pleomorphic sarcoma was the most common at 21%. 

The local recurrence rate was 5% (95% CI, 2.7-8.6%) and local wound 

complications were 21% (95% CI, 15-28%). Most (172 or 90%) of 

patients were able to undergo limb salvage surgery while 19 (10%) required 

amputation. Of the 172 patients that had limb salvage, 97% (95% CI, 

93-98%) had wide surgical margins, three had � 2 cm margins and two 

had involved margins. Conclusions: To our knowledge, this is the largest 

study showing that this short two week course of chemoradiation is 

effective in achieving high rate of local control, acceptable wound complication 

rate, wide surgical margins and limb salvage in the treatment of STS. 

Randomized trials are warranted to confirm results. 


Palliative ambulatory 14-day infusional ifosfamide in the outpatient setting 

for treatment of advanced soft tissue sarcomas (STS): “Old wine in a new 

bottle.” Presenting Author: Salma Moona Alam, Sarcoma Unit,The Royal 

Marsden Hospital NHS Foundation Trust, London, United Kingdom 

Background: Ifosfamide (IFO) has recognised activity in soft tissue sarcomas. 

There is evidence for improved cytotoxicity and tolerability utilising a 

prolonged 14 day infusional outpatient regimen compared with the 

standard 3-day regimen (Loeffler et al 1990). We undertook a retrospective 

review of all patients treated with this regimen from September 2008 - 

December 2011 to determine toxicity and treatment response. Methods: 

Pts. were identified from our database and demographics, histological 

subtype, toxicity and survival outcomes were collected. IFO was given via 

central venous access using 2x7daypumps at 1g/m2/day with mesna for 

14 days q 4 weekly. Oral sodium bicarbonate was used to maintain alkaline 

urine with oral mesna for haematuria, and thiamine for symptoms of 

encephalopathy as required. Results: 29 patients (pts), with advanced 

sarcoma, median age 56 years (27-76 yrs), 14F 15 M, median number of 

cycles � 1 ( 1-9). At baseline: PS 0�1, 1�24, 2�4. 18 pts had 

de-differentiated liposarcoma (D-LPS), 6 synovial sarcoma, 5 had other 

subtypes. 12 pts received only 1 cycle, with 5 stopping due to encephalopathy. 

Ten patients developed encephalopathy, 9 occurring in cycle 1, other 

toxicity was tolerable, with Gr 2-3 nausea (15 pts) and vomiting (9pts) and 

only 2 Gr 3 episodes of myelotoxicity for all cycles. 4 patients achieved PR, 

(2 with D-LPS and 2 with Synovial sarcoma) 11 pts. had SD. Median PFS 

was 19 months and OS was 12.5 months. 2 pts. with D-LPS had a 

sustained prolonged response of 15 and 16 months. Conclusions: Infusional 

IFO is generally well tolerated; however a significant incidence of 

neurotoxicity was seen. Pts. with D-LPS demonstrated best response to 

treatment, a sarcoma subtype that has previously failed to respond to 

systemic therapy. This regime warrants further investigation. 


640s Sarcoma 


Gemcitabine/docetaxel for metastatic or locally advanced soft tissue 

sarcoma: A retrospective single-center experience. Presenting Author: 

Gerlinde Egerer, Department of Hematology, Oncology, and Rheumatology, 

Heidelberg University Hospital, Heidelberg, Germany 

Background: Soft tissue sarcoma (STS) represent a group of rare malignant 

tumors. Survival for patients with disseminated disease is dismal. Gemcitabine/docetaxel 

(GD) is a commonly used systemic 2°-line regime in this 

setting. Methods: Here we report on our single center experience of GD (G 

900 mg/m² or 675 mg/m² d1�8 and D 100 mg/m² d8) in STS. Patients 

were retrospectively analysed. Restaging according to RECIST criteria of 

primary tumor site and metastases was performed every 3 cycles or on 

clinical progression. Progression-free (PFS) and overall survival (OS) were 

estimated using the method of Kaplan and Meier. Results: Between 2005 

and 2011, 34 STS patients (male�20, female�14, median age 59 years 

[range 32-75]) were treated with GD at our institution. Histological 

subtypes comprised leiomyo- (n�13), lipo- (n�7), pleomorphic- (n�6), 

rhabdomyo- (n�3), synovial sarcoma (n�2), and other subtypes (n�3) 

with tumor grades being G1 (n�1), G2 (n�9) and G3 (n�24). Primary 

tumor sites included extremities (n�19), abdomen/retroperitoneum (n�10), 

trunk (n�3), and others (n�2). Metastases were found in lung (n�26), soft 

tissue/solid organs (n�12), bone (n�8) and lymph nodes (n�5). Patients 

had received no (n�2),1(n�22), 2 (n�9) or 3 (n�1) previous lines of 

CTX. A total number of 158 cycles was administered with a median number 

of 6 cycles (range 1-6) per patient. Best response by RECIST criteria after 3 

cycles of treatment was PR (n�2, 6%). Disease stabilisation (SD) was 

achieved in further 22 subjects, resulting in a clinical benefit rate (CBR) of 

70%. Median PFS and OS for the whole population were 7.7 and 15.3 

months, respectively. PFS at 6 months was 62%. Patients responding to 

therapy had a significantly longer median PFS with 8.6 months (p 

�0.0001; HR 33.1) and OS with 22.5 months (p�0.0001; HR 20.2). 

Major toxicities included hand-foot syndrome (n�10), febrile neutropenia 

(n�7), mucositis (n�7), oedema (n�5), hematological toxicity (n�4) and 

polyneuropathy (n�3), leading to dose reductions in 10 patients. 

Conclusions: GD is an active regimen in STS with tolerable side effects. 

CBR was 70% after 3 cycles. Patients achieving at least SD had a 

significantly prolonged PFS and OS. 


Sarcoligo: Impact of local ablative treatment of oligometastatic sarcomas 

on overall survival. Presenting Author: Juliette Thariat, Centre Antoine- 

Lacassagne, Nice, France 

Background: 40-50% of sarcomas become metastatic. Median survival of 

metastatic patients has improved over time. The probably multifactorial 

reasons for such improvement are not fully clear. Noteworthy, for patients 

with a controlled primary and a limited number of lung metastases, 

complete resection of their metastases yields survival rates of up to 40% at 

three years. Advances in surgery, radiotherapy and radiofrequency have 

fostered the use of local treatments for various metastatic sites (lung, liver, 

spine...). Methods: A multicentric retrospective study of the Groupe 

Sarcome Francais (GSF-GETO); approved by the nationally-review board 

and ethical committee, was conducted to assess the impact of local 

ablative treatment on overall survival. Patients who had had oligometastases 

(any site, 1-5 synchronous metastases) at diagnostic or during the 

course of disease between 2000 and 2010 were included. Results: Median 

age of the 243 oligometastatic sarcoma patients was 53 years-old (11-86). 

Patients had grade I, II and III in 7.5%, 29.6% and 63.3% of cases, 

respectively with various histologies. 69% of patients underwent local 

ablative treatment of metastases. Median follow-up was 59 months 

(4-212) for living patients. Median overall survival was 51 months (1-348). 

On univariate analysis, grade, histology, absence of chemotherapy, local 

ablative treatment (surgery, irradiation, radiofrequency or chemoembolisation) 

correlated with survival but not age or site of oligometastasis. On 

multivariate analyses, grade (hazard ratio HR 0.12 [CI95 0.3-0.6]) and 

local ablative treatment (HR 3.8 [CI95 2.1-7.1]) remained significant. 

Conclusions: Local ablative treatment of metastases is associated with 

better survival in sarcoma patients with oligometastatic disease. The role of 

the locoregional treatment of metastases and its impact on quality of life 

should be assessed prospectively. 

10041^ General Poster Session (Board #47B), Sun, 8:00 AM-12:00 PM 

Pharmacokinetic analyses of vorinostat in patients with metastatic soft 

tissue sarcoma. Presenting Author: Thomas Schmitt, Department of 

Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, 

Heidelberg, Germany 

Background: New treatment options for patients with metastatic soft tissue 

sarcoma (STS) are urgently needed. Preclinical studies suggest activity of 

vorinostat (V), a histone desacetylase (HDAC) inhibitor, in STS. Methods: 

We initiated a multicenter, open-label, non-randomized phase II trial 

(SAHA-I, NCT00918489) to investigate efficacy and safety of V in patients 

with metastatic STS failing 1°-line anthracycline-based CTX. Patients were 

treated with V 400 mg po QD for 28 days followed by a therapy-free period 

of 7 days. Blood samples for pharmacokinetic (PK) analyses were collected 

on day 7 of treatment cycle 1. Samples were acquired before and 30, 60, 

90, 120, 240, 360, and 480 minutes after oral administration of V. 

Plasma- and intracellular concentration of V in peripheral blood mononuclear 

cells (PBMCs) was determined by mass spectrometry. Statistical 

differences were assessed by Wilcoxon matched-pairs signed rank test. 

This trial is ongoing. Results: Data on PK was available for n�8 subjects 

(male�4, female�4, median age�62 years). In plasma samples, mean 

Cmax (maximum concentration), tmax (time to reach max. concentration), 

AUC (area under the plasma-concentration time curve), t1/2 (elimination 

half-life) and Cl/F (apparent total clearance) were 350 ng/mL, 101 min, 

71.1 min*�g/mL, 103 min and 5903 mL/min. The corresponding parameters 

in PBMCs were 558 ng/mL, 97.5 min, 208.4 min*�g/mL, 286 min 

and 2475 mL/min, respectively.The AUC plasma/PBMC ratio was 2.93, 

indicating accumulation of V in PBMCs. Differences in AUC (p�.008) and 

t1/2 (p�.01) reached statistical significance. Conclusions: Interestingly, 

significantly higher concentrations of V were achieved in PBMCs andelimination 

half-life was prolonged compared to plasma. These results suggest 

potent intracellular activity of V. 


Clinical activity of mTOR inhibition in combination with cyclophosphamide 

in the treatment of recurrent nonresectable chondrosarcomas. Presenting 

Author: Ofer Merimsky, Sourasky Medical Center, Tel Aviv, Israel 

Background: Chondrosarcomas (CS) represent a heterogeneous group of 

rare sarcomas, poorly responsive to chemotherapy or radiotherapy. When 

local therapies in recurrent or metastatic disease are exhausted, chemotherapy 

plays a marginal role. Different molecular pathways have been 

shown to be activated in CS. In this retrospective study we summarize our 

experience in treating a cohort of patients with recurrent nonresectable CS 

with a combination of sirolimus and cyclophosphamide. Methods: Nine 

consecutive patients with nonresectable CS were offered off-label treatment 

with sirolimus and cyclophosphamide between 2007-2011. Tumor 

response, progression-free survival (PFS), adverse events and other relevant 

clinical data were analyzed. Results: The median patients’ age was 52 

(range, 35-68). Median disease-free interval (DFI) since the primary 

diagnosis was 24 months. Median time from the disease recurrence to 

initiation of sirolimus and cyclophosphamide treatment was 20.9 months 

due to additional local surgical treatments/excision of metastases/slow and 

asymptomatic progression. One (11%) objective response was observed 

and five (56%) patients had stabilization of disease for at least 6 months. 

One patient has been treated for only 3.5 months and reported symptomatic 

improvement at this stage, two patients had progressive disease. 

Median time to treatment failure (TTF) was 15 months (range, 2.8-30.3). 

No significant adverse events were observed. Conclusions: Although advanced 

CS remains an incurable disease, our experience suggests that a 

combination of sirolimus and cyclophosphamide is well-tolerated and has 

meaningful clinical activity with clinical benefit rate of 67%. Further 

prospective studies are warranted. 



High-dose ifosfamide (HDI) in metastatic synovial sarcoma: The Institut 

Gustave Roussy experience. Presenting Author: Arslane Skander Rahal, 


Background: Synovial sarcoma (SS) is one of the most chemo-sensitive 

histological subtypes of sarcoma but with a dismal prognosis. In metastatic 

setting, Anthracyclin/ifosfamide-containing chemotherapy (CT) regimen is 

the gold standard of treatment in front-line therapy. Patients (pts) with 

resistant diseases are candidates to investigational drugs or higher dose 

ifosfamide regimen in selected pts. Methods: Pts treated in our institution, 

with histological confirmation of advanced SS, adequate organ function 

and in good condition (PS�2) were included in this retrospective analysis. 

Pts who progressed after 1–2 chemotherapy lines received High-dose 

ifosfamide (HDI) in the form of 4 g/m2 daily (over 24 hours CI) for 3 days for 

a total dose of 12 g/m2 ; cycles were given with growth factor support and 

were repeated every 3 weeks. The primary endpoints were PFS and overall 

response rate (ORR); the secondary endpoints OS and toxicity profile. AE 

were assessed by NCI-CTC v. 3.0. Results: 34 pts (21 males) with a median 

age of 39 years (range 19-66) received this HDI regimen. PS was 0-1 in 

90%. 95% of pts received prior doxorubicin, ifosfamide or both, 7 patients 

had 2 prior lines. Grade III monophasic pattern was seen in 21 patients, 

grade II in 13. 171 cycles were delivered, median number of cycles was 4 

(2-10). The objective responses were CR 0; PR 15; SD 14; PD 2; and NE 3, 

resulting in an ORR of 44%. The clinical benefit rate was 85%. Median 

PFS: 11.6 months (95% CI: 9-14). Eleven pts were amenable to a 

subsequent resection of residual disease. Common adverse events included 

grade III/IV neutropenia: 47%, febrile neutropenia: 12%, thrombocytopenia: 

12%, cystitis: 3%, neurologic: 3%. There was no treatment 

related death. Conclusions: HDI demonstrated clinically meaningful efficacy 

with manageable toxicity in pts who failed previous standard Ifosfamide 

dose. Ifosfamide remains the most active agents in SS and high 

dose regimen have to be considered in pts previously treated with 

ifosfamide. 


Rechallenge with ifosfamide-containing regimen as salvage option for 

patients with metastatic soft tissue sarcomas progressing after multiple 

pretreatments. Presenting Author: Mathias Hoiczyk, Sarcoma Center, West 

German Cancer Center, Essen, Germany 

Background: Ifosfamide (I) is commonly used in first or second-line 

treatment of locally advanced or metastatic soft tissue sarcomas (STS). The 

clinical efficacy of a rechallenge with ifosfamide (IR) or I-containing 

regimen (ICR) is unclear. We conducted a retrospective analysis of our 

institutional database (n�1354) of pts who received IR or ICR. Methods: 

66 STS pts were identified, who had received more than one I-based 

regimen. Ifosfamide retreatment was given in neoadjuvant (n�26), adjuvant 

(n�18) or metastatic settings (n�22) and most patient were pretreated 

with doxorubicin (D; 94%). PFS was determined from first 

administration of IR until disease progression, OS from R until last 

follow-up or death. ORR (RECIST) was assessed to determine the clinical 

benefit rate (CBR) defined as CR, PR plus SD. Covariates were age, gender, 

histology, pretreatment, dose intensity, response and toxicity. Results: 

Median age at time of first I was 45y (range: 17-74, 44% f 56% m). Median 

time from diagnosis until first ICR treatment was 4mo. Median time from 

first I until IR, which was given as median 3rd-line treatment (2-9 lines), 

was 17 mo. Histologies were 12 leiomyo-, 11 lipo- 13 pleomorphic,14 

synovial, 4 rhabdomyosarcomas and 12 other subtypes. Pts received a 

median of I 9.6 g/m²/cycle and a median of 4 cycles. I was given as 

monotherapy (38%) or in combination (D: 45%, other 17%). Overall 

median PFS was 5mo with PFS-rates of 63% at 12 and 25% at 24 wks. 

Median PFS was 6 mo for ICR and 2 mo for IR. The median OS was 36 mo 

from time of first diagnosis of metastases or locally advanced disease. ORR 

was 29% for I/D combination (CBR 70%) and 12 % for I monotherapy 

(CBR: 52%). 22 pts received a second IR with a median of 2 cycles (27% 

PR; CBR:77%; 69% combinations). Most common toxicities for IR/ICR 

were neutropenia (42%), encephalopathy (21%) and neutropenic fever 

(18%). Dose reductions were necessary in 18% of pts and treatment was 

stopped in 8% due to toxicity. No significant cardiotoxicity was observed. 

Conclusions: Patients with soft tissue sarcomas who had at least disease 

stabilization after initial ifosfamide-based therapy may derive substantial 

clinical benefit from a rechallenge. 

Sarcoma 

641s 


Clinical effectiveness of recombinant adenovirus human p53 gene combined 

with hyperthermia in treatment of advanced soft tissue sarcoma. 

Presenting Author: Shaowen Xiao, Peking University Cancer Hospital and 

Institute, Beijing, China 

Background: Soft tissue sarcoma in advanced stage usually resist to both 

chemo- and radiotherapy. Several studies indicated that rAdp53 can 

reverse this resistance and enhance the effectiveness of radiotherapy, 

chemotherapy and hyperthermia. This study is to evaluate the efficacy and 

safety of recombinant adenovirus human p53 gene (rAdp53) combined 

with hyperthermia and radiation in treatment of advanced soft tissue 

sarcoma. Methods: From Nov. 2001 to July 2011, 30 patients with 

advanced soft sarcoma were enrolled in this study. All cases received 

hyperthermia treatment, once a week for total of 9 times, and intratumoral 

injection of rAdp53 at dose of 1x1012 virus particles (vp) for 8 times. 

Radiation were given 48 hours after the first rAdp53 injection at a dose of 

2Gy/f, five fractions a week for a total dose 16~70Gy /8~35f/2~8w, at an 

average of 56.3�5.3 Gy. Patients were monitored for response and adverse 

events. Results: The median follow-up time was 96 months. Among these 

patients, one case (3.3%) achieved complete response (CR), 9 (30%) 

cases had a partial response (PR), and 18 (60.0%) cases had a stable 

disease (SD). The overall clinical effectiveness rate (CR�PR�SD 

� 6months) was 83.3.0% (25/30). One-year survival rate is 56.6% 

(17/30), 2-year survival rate is 23.3% (7/30), 3-year survival rate is 10.0% 

(3/30), and 5-year survival rate is 6.7% (2/30). Overall median survival 

time was 18.1 months and median TTP was 13 months. No significant 

adverse events were noted, except for transient fever associated with 

rAdp53 administration. Conclusions: rAdp53 combined with hyperthermia 

and radiation is effective and safe modalities in treatment of advanced soft 

tissue sarcoma. 


Association between body weight and efficacy outcomes during trabectedin 

therapy for recurrent advanced soft tissue sarcoma (STS). Presenting 

Author: Maurizio D’Incalci, Istituto di Ricerche Farmacologiche, Milan, 

Italy 

Background: Trabectedin is the first marine-derived antineoplastic drug 

approved in Europe for the treatment of patients with recurrent advanced 

STS. Different studies have implicated tumor-derived cytokines as mediators 

of cachexia in cancer patients. Preclinical studies have demonstrated 

that trabectedin acts on tumor microenvironment particularly reducing 

IL-6, which is involved in cancer-induced cachexia (Germano et al. 2011, 

Ligouri et al. 2011). Methods: This exploratory retrospective analysis 

evaluated the association between body weight increase during treatment 

with respect to baseline and efficacy outcomes in 319 adult patients with 

recurrent STS. Patients were treated in four phase II trials with trabectedin 

at the approved dose of 1.5 mg/m2 , given as a 24-hour infusion every 3 

weeks. An analysis of the concordance between weight increase and 

objective response (OR) rate, tumor control (TC) rate (OR�stable disease 

lasting �3 months), progression-free survival (PFS) and overall survival 

(OS) was performed. Results: Correlation between weight increase and 

responses was observed: 68% of patients who achieved OR and 70% of 

patients with TC increased their weight for a median of 1.2 kg. Remarkably, 

PFS (5.1 vs. 1.9 months; p�0.0001, log rank) and OS (21.0 vs. 8.2 

months; p�0.0001, log rank) were significantly prolonged in patients who 

gained weight during treatment. Six and 12-months Kaplan-Meier PFS 

estimates and survival rates at 12, 24 and 36 months were also better in 

those patients. Additionally, in Cycle 1-2, a significant relationship 

between weight increase and improved median PFS (4.2 vs. 2.2 months; 

p�0.0001) and OS (19.4 vs. 9.3 months; p�0.0002) was observed. This 

is in concordance with the tendency to gain weight starting from the first 

cycle of treatment. Conclusions: This analysis suggests that weight gain is 

associated with favorable efficacy outcomes when patients are treated with 

trabectedin. Further research is needed to assess the prognostic value of 

weight changes as a complementary source of evaluation on the long-term 

clinical outcomes and impact of trabectedin on tumor microenvironment. 


642s Sarcoma 


Differential gene expression in liposarcoma: Insight into pathways for 

dedifferentiation? Presenting Author: Dale Han, H. Lee Moffitt Cancer 

Canter & Research Institute, Tampa, FL 

Background: Liposarcoma (LPS) dedifferentiation signifies conversion to a 

clinically aggressive phenotype, but the biologic processes required for this 

change have not been determined. We describe differential gene expression 

patterns between well-differentiated (WD) and dedifferentiated (DD) 

tumors to determine pathways involved in LPS dedifferentiation. Methods: 

From 1999 to 2006, 121 fatty tumors were resected at a single institution. 

Twenty tumors, consisting of atypical lipomatous tumors (ALT), WD LPS or 

DD LPS, were randomly selected and clinicopathologic characteristics were 

retrospectively reviewed. Gene expression profiling was performed on 

extracted RNA using the Affymetrix GeneChip platform. Differentially 

expressed genes were obtained and gene network analysis was done using 

GeneGO by MetaCore. Results: Median age was 59 years and 70% of cases 

were male. WD tumors, consisting of 3 ALT and 6 WD LPS, were compared 

with 11 DD LPS. After a median follow-up of 64 months, 7 patients had 

died of whom 6 had DD LPS. DD histology was associated with lower overall 

survival (p�0.05). Significance Analysis of Microarrays for WD tumors vs. 

DD LPS using a 0% false discovery rate showed differential expression of 

188 genes. Network analysis of genes from WD tumors vs. DD LPS showed 

significant (p�0.001) differential regulation of glucose-activated transcription 

factor ChREBP (carbohydrate response element binding protein), a key 

element involved in lipogenesis, gluconeogenesis and glycolysis. There was 

also significant differential regulation of insulin signaling, PI3K-dependent 

and PKA signal transduction pathways and of amino acid, fatty acid and 

glucose metabolism pathways (p�0.05). These pathways, based on Gene 

Ontology cellular processes, mapped to gene networks primarily involved in 

lipid metabolism (p�0.05). Conclusions: Differential expression of genes 

involved in lipid metabolism networks is seen in DD LPS and changes in 

lipid metabolism may be associated with dedifferentiation. These differential 

gene expression patterns may help identify fatty tumors potentially at 

risk for progressing to a malignant or DD state and provide prognostic 

factors and therapeutic targets for patients with LPS. 


Does combined dose intensification radiotherapy improve disease control 

in resectable retroperitoneal sarcoma? Long-term results of a phase I/II 

trial. Presenting Author: Myles J. F. Smith, Department of Surgical 

Oncology , Toronto, ON, Canada 

Background: Late failure is a challenging problem in retroperitoneal 

sarcoma (RPS) and reported 10 yr overall survival (OS) rates range from 

20-30%. Use of preoperative external beam radiotherapy (XRT) in the 

management of RPS remains controversial. No RCT and very few prospective 

trials of any type have been completed. We investigated the effects of 

preop XRT plus dose escalation with early postop brachytherapy (BT) on 

long term survival and recurrence in RPS. Methods: From 06/96 to 10/00, 

40 patients (25 female) with resectable RPS were entered onto a phase I/II 

trial of preop XRT (50 Gy) plus postop BT (20-25 Gy). As previously 

reported, BT to the upper abdomen was associated with significant grade 

III-V postop toxicity, and from 12/98 on, BT was applied only to cases 

where the “field at risk” excluded the upper abdomen. Kaplan Meier 

survival curves were constructed; OS and recurrence free survival (RFS) 

were compared by log rank (SPSS 19.0). Results: Median age at study entry 

was 58 (38-70) yrs. Twenty nine patients presented to our center with 

primary disease (73%), and 22 (55%) had high grade tumors. All patients 

had preop XRT and total gross resection, while half (n�19) received BT. As 

of 12/2011, median follow-up time is 108 mos. For the entire study cohort, 

OS at 5 and 10 yrs were 70% and 65%, respectively; RFS at 5 and 10 yrs 

were 65% and 58%, respectively. RFS at 5 yrs was reduced in high vs. low 

grade RPS (50% vs. 83%, p�0.028), but by 10 yrs. was similar in high and 

low grade tumors (50% vs. 67%, p�ns). RFS was reduced in patients who 

presented with recurrent vs. primary disease (27% vs. 69% at 10 yrs., 

p�0.018), as was OS (36% vs. 76% at 10 yrs., p�0.034). Neither OS nor 

RFS was improved in the cohort of patients who received BT compared to 

the cohort who did not: at 10 yrs. RFS was 53% �BT and 62% -BT, while 

OS was 53% and 76%, respectively, p�ns. Conclusions: In this prospective 

study with mature follow-up, long term OS and RFS in patients who 

underwent combined preop XRT plus resection of RPS compare favorably 

with those reported in retrospective institutional and population-based 

series. Postoperative BT did not contribute to disease control. 


Interest of tumor to liver ratio 18F-FDG uptake in positron emission 

tomography for detection of neurofibrosarcoma in neurofibromatosis 1 

patients. Presenting Author: Patrick Combemale, Centre Leon Berard, 

Lyon, France 

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are 

difficult to detect in neurofibromatosis 1 (NF1) individuals. The 18F FDG 

positron emission tomoscintigraphy (FDG PET) is a useful tool. The 

Standard Uptake Value (SUV) is the gold standard but it is subject to 

individual variation among patients and medical centers. So we assessed 

the interest of FDG PET based on a specific tumor to liver uptake ratio (T/L) 

instead of SUV to find a reproducible and constant cut-off for detecting 

malignant tumors. Methods: From 2000 to 2010, we conduct a multi 

centric study: all patients with NF1 and presenting clinical signs of MPNST 

suspicion (increased tumor size, induration or pain) underwent a FDG PET. 

Preliminary study estimated a T/L ratio of 1.5 as cut-off for malignity. 

Based on semi-quantitative analysis of FDG PET images, patients were 

compared with this cut-off value. Results: 98 patients with 125 tumors 

were included. FDG PET evaluation identified 42/125 suspected lesions 

with T/L � 1.5; among these 30 MPNST and 12 benign lesions were found. 

83/125 tumors were classified as non-suspicious and 82 were actually 

benign according to histology or long term follow up. The 1.5 T/L cut off 

corresponds to 99 % Negative Predictive Value (NPV) and 71% Positive 

(PPV). The positive likelihood ratio (LR) was thus equal to 7, 69 and the 

Negative LR to 0, with 97% sensitivity and 87% specificity. When T/L ratio 

is � 1.5, MPNST is eliminated with 99% NPV, thus avoiding useless 

surgery. When T/L ratio is above 1.5, there is a strong suspicion of 

malignancy. But there is a risk of false positivity, which requires discussion 

before any therapeutic decision. On the over hand we found no significant 

correlation between SUVmax and malignancy. Conclusions: This study 

confirms the FDG PET in the detection of NF1-associated MPNST. The 

tumor/liver ratio with a cut off 1.5 has a very sensitive and specific value to 

sort out malignant from benign tumors and thus provides adequate surgery. 

More this semi-quantitative analysis method is just as easy as SUV, more 

sensitive and more reproducible. 


Geriatric high-grade soft tissue sarcoma (G-HG STS): An analysis of 116 

patients (pts) evaluating prognostic factors and clinical outcomes stratified 

by histology. Presenting Author: Richard Hong Hui Quek, National Cancer 

Centre, Singapore 

Background: STS in geriatric pts is not well studied. We evaluated 

prognostic factors and clinical outcomes in elderly pts with HG STS. 

Methods: Single centre retrospective study. G-HG STS pts defined as age 

� 65 yrs seen in our centre from 2002 - 2011 with complete medical 

records were identified. Charlson age-comorbidity score was assessed for 

each pt. Results: 116 pts from 4 most common HG STS histo-types 

representing 69% of pts in the geriatric STS cohort were analysed; 

leiomyosarcoma (LMS, 14%), non well-differentiated liposarcoma (nWD- 

LPS, 9%), angiosarcoma (AS, 30%), and undifferentiated pleomorphic 

sarcoma (UPS, 47%). Median age was 72 yrs, 81% presented with 

localised disease; of 78% of these localised pts who had curative surgery, 

49% received adjuvant therapy, of whom 92% had radiotherapy (RT) only. 

AS arises more commonly from the head/neck region (p�0.001) and fewer 

receive curative surgery (p�0.006). In 43 pts who had metastases either at 

diagnosis or relapse, 33% received first-line palliative chemotherapy with a 

response rate of 27% in evaluable pts. At a median follow-up of 15.8 mths, 

overall survival (OS) for the entire cohort was 25.1 mths, 30.5 vs 3.9 mths 

in pts presenting with localised vs metastatic disease respectively 

(p�0.0001). In pts who had curative surgery for localised disease, overall 

relapse-free survival (RFS) was 17.7mths; 26.8 mths vs 16.0 mths vs 7.3 

mths vs 12.5 mths in LMS, nWD-LPS, AS and UPS respectively. In 

univariate analysis, adjuvant RT, non-head/neck primary and sarcoma 

subtype were associated with improved RFS. In multivariate analysis, 

adjuvant RT (p�0.001), sarcoma subtypes AS (p�0.011) and UPS 

(0.012) vs LMS remained significant. In pts with metastatic HG STS either 

at diagnosis or relapse, overall median OS was 5.9 mths; 5.9 mths (LMS), 

30.5 mths (nWD-LPS), 6.4 mths (AS) and 4.3 mths (UPS). In univariate 

analysis, presence of bone metastases was significantly associated with 

inferior OS (p�0.0029). Charlson score did not correlate with RFS or OS. 

Conclusions: Prognosis of G-HG STS appears poor particularly in AS and 

UPS. Adjuvant RT improves outcomes in this group of pts and should not be 

omitted based on age alone. 



Phase II study of neoadjuvant high-dose ifosfamide with concurrent 

radiotherapy followed by surgical resection in high-risk soft tissue sarcoma: 

A Spanish Group for Research on Sarcomas (GEIS) study. Presenting 

Author: Xavier Garcia del Muro, Instituto Catalan Oncologia, Barcelona, 

Spain 

Background: High-dose ifosfamide (HDI) has shown promising activity as 

single agent in first-line chemotherapy for advanced soft tissue sarcoma 

(STS). The purpose of this study was to assess the activity and toxicity of a 

preoperative doxorubicin-free regimen of HDI given concurrently with 

radiotherapy (RT) and followed by surgery in patients (pts) with localized 

high-risk STS. Methods: Pts with localized � 5 cm grade 2-3 and deep STS 

of the extremities and trunk wall, �65 years, no prior chemotherapy and 

ECOG PS 0-1 were enrolled in this multicenter phase II study. Pts received 

3 cycles of preoperative HDI at a dose of 12 gr/m2 by continuous infusion 

over 5 days every 3 weeks, with mesna and prophylactic GCSF support, and 

concomitant external beam RT to a total dose of 50 Gy, followed by surgical 

resection. Postoperatively, pts with pathological response received 2 cycles 

of HDI and those with positive surgical margins 16 Gy of RT. The primary 

study endpoint was pathologic response (� 95% pathologic necrosis). A 

Simon 2-stage design (response rate P0�15%, P1�35%, ��0.10, 

��0.10) required at least 2 responses in the first 17 pts to expand to a 

second cohort, and 7/32 responses to be considered of positive. Results: 

From March 08 to December 10, 34 pts were included. Two pts were 

ineligible. Median age was 54 (18-65). Tumor location was extremity (28 

pts) and trunk wall (4). Preoperative planned treatment was completed in 

87.5% pts. HDI was completed in 87.5% pts while RT in 94% pts. Grade 

3-4 toxicities included neutropenic fever (3 pts), anemia (4), asthenia (2), 

infection (2) and radiation dermatitis (2). 31 pts underwent surgery: 27 

were R0 resections, of which 2 were amputations, and 4 were R1 

resections. Pathologic response was � 95% necrosis in 9 pts (28%) and 

50%-94% necrosis in 12 pts. After a median follow-up of 21 months, 

estimated 2-year rates for disease-free survival and overall survival were 

58% (95%CI, 40%-77%) and 77% (95%CI, 61%-93%), respectively. 

Conclusions: Preoperative treatment with HDI given concurrently with RT in 

pts with high-risk STS is feasible and safe, yielding promising pathologic 

response rates. 


Early response to neoadjuvant chemotherapy (NAC) in combination with 

regional hyperthermia (RHT) to predict long-term survival for adult-type 

high-risk soft tissue sarcoma (HR-STS): Results of the EORTC-ESHO 

intergroup phase III study. Presenting Author: Rolf D. Issels, Universitaet 

München, Grosshadern, Munich, Germany 

Background: A randomized phase III completed trial showed that RHT 

added to NAC was beneficial in terms of local progression-free (LPFS), and 

disease-free (DFS) survival. Overall survival (OS) was improved in patients 

(pts) who completed the preoperative induction therapy with RHT (Lancet 

Oncol 2010). Here we analyzed both the radiographic (RR) and histopathologic 

(HR) response as early predictors for survival. Methods: 341 pts were 

randomized to receive 4 cycles of NAC � RHT (169 pts) or NAC alone (172 

pts) as induction therapy. RR (CR/PR vs NC/PD) and HR (�75% vs �75% 

necrosis) were used to define responder vs non-responder. Predictive 

impact of response on LPFS, DFS, DDFS (distant disease-free survival) and 

OS was evaluated by intention-to-treat using Kaplan-Meier estimates and 

the log-rank test. Stratified (surgery before study entry yes/no; extremity vs 

non-extremity tumors) multivariate analyses were carried out by Cox 

regression. Results: Early response in pts with measurable disease was 

performed in 238 pts (103 pts not evaluable because of surgery before 

study entry). In the NAC�RHT group (114 pts) response rate was 49.1% 

(56 responders: RR: 18; HR: 22; RR � HR: 16) and substantially higher 

(p�0.001) compared to the NAC alone group (124 pts) which was 26,6% 

(33 responders: RR: 7; HR: 17; RR � HR: 9). In the NAC � RHT group, 

tumor response was associated with improved DFS (HR 0.58 CI 0.36-0.95; 

p�0.031) and OS (HR 0.50 CI 0.27-0.90; p�0.020) but not LPFS (HR 

0.91 CI 0.49-1.71; p�0.78). For responders, OS median time was � 120 

months vs 33 months for non-responders. For the entire NAC � RHT group 

(169 pts, including pts with surgery before study entry) response remained 

predictive for better OS (HR 0.54 CI 0.32-0.94; p�0.028) and was also 

associated with better DDFS (HR 0.47 CI 0.27-0.83; p�0.009). 

Conclusions: Adding RHT to NAC as induction therapy compared to NAC 

alone leads to significantly higher early response in almost half of the pts 

classified as responders which translates in better OS and prevention of 

distant metastases. 

Sarcoma 

643s 


The Italian Rare Cancer Network. Presenting Author: Roberta Sanfilippo, 

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 

Background: Rare cancers (RC) are a challenge in terms of quality of care, 

access to health resources and clinical research. The Italian Rare Cancer 

Network (RTR: “Rete Tumori Rari”) is a clinical collaborative effort to 

improve quality of care in adult rare solid cancers in Italy. RTR enables 

institutions to share clinical cases and to rationalize access to distant 

reference centers minimizing patient migration. It indirectly promotes 

collaborative clinical research by encouraging accrual into clinical trials 

and supporting observational studies. Methods: RTR includes 150 oncology 

institutions across Italy. Clinical cases are shared asynchronously over a 

secure Web resource. Data, images and transactions are stored in an online 

clinical record. Patients are shared: 1. �logically”, when they are dealt with 

following common clinical practice guidelines; 2. �virtually”, when they are 

discussed over the network between two or more centers; 3: �physically�, 

when they are referred to an excellence center for a specific treatment 

modality. Pathology review is arranged through transferal of paraffinembedded 

specimens and upload of consultations. While it was chosen not 

to implement telepathology facilities, a teleradiology resource is now 

available. Results: From 2003 to 2011, more than 5,000 rare cancers 

cases (mostly sarcomas) have been uploaded. More than 1,300 teleconsultations 

have been delivered, while more than 1,000 patients moved across 

the network during their experience of disease. 700 cases were reviewed 

pathologically: amongst 365 cases originally diagnosed as soft tissues 

sarcomas up to 2010, treatment-relevant discordances were recorded in 

more than one third. An observational prospective study on gastrointestinal 

stromal tumors was done, enrolling 800 patients. An original paper 

documenting the activity of a drug in a highly specific sarcoma subgroup 

was published. Conclusions: Clinical asynchronous online collaboration on 

RC is feasible through a Web-based secure environment and proved the 

most practical way of clinical distant sharing. Pathologic review was a 

crucial network service, with a special added value in RC. Retrospective 

and prospective observational studies, and unplanned observations in very 

rare cases, were an interesting by-product. 


Delay in diagnosis and treatment of soft tissue sarcomas (STS): Causes of 

late intervention and their role in prognosis—A prospective, multidisciplinary 

group study. Presenting Author: Alessandro Comandone, Piedmontese 

Group for Sarcomas/Italian Sarcoma Group, Torino, Italy 

Background: STS are 1% of malignant tumors in adults. Rarity, heterogeneity 

in presentation, low expertise in primary care physicians (PCP) or in 

general hospitals, organisation problems in specialized centers may cause 

a delay in both diagnosis and treatment. Aim of this study is to acknowledge 

the barriers to optimal care and the consequences of the delay on 

prognosis. Methods: Patients with STS of the extremities, trunk, retroperitoneum 

treated and followed from 1999 to 2011 by the same multidisciplinary 

group were included. Time and pattern of symptoms onset, 

anatomic site, tumor volume, patients’ age, gender and home, interval 

between diagnosis and surgical treatment or neoadjuvant chemotherapy; 

time to start adjuvant RT or CT were considered in a univariate - 

multivariate analysis. Results: 449 adult patient (53% F, 47% M, median 

age 55 years) were followed for a median time of 116.38 months. 65.7% of 

STS were at the extremities, 17.6% retroperitoneal, 16.7% at the trunk 

wall. Median volume at diagnosis was 8 cm for trunk and extremities; 15 

cm for retroperitoneum. Commonest histologies: liposarcoma. 18.2%; 

leiomyo 16.8%; mixofibro 13.6%. Increasing mass, pain, and abdominal 

disconfort were the main revealing signs of diseases. Median time of delay 

were: from onset of symptom to first medical visit 68 days for trunk and 

extremities, 82 for retroperitoneum; 104 days from symptoms to histological 

diagnosis; 129 days from symptoms to start of therapy. Time to surgery 

after definitive diagnosis was 12 days in extremities and 21 in abdomen. 

Adjuvant CT started 22 days after surgery for extremities, 25 in trunk, 35 in 

retroperitoneum. RT initiated after 78 days. Longer delay in treatment lead 

to worse prognosis: MS 89.95 months if delay was � 3 months; 190.40 

months if wait was � 3 months (p 0.007). Conclusions: Low self 

consciousness of the patient; misdiagnosis or inadequate approach in 

general hospitals; late referral to specialized centres are 75% of the cause 

of wasted time. Organization problems at the referral Centre concur for 

25% of delay. Guidelines implementation and educational programme 

among general population and PCP are necessary. 


644s Sarcoma 


Prospective web-based collection of sarcoma cases diagnosed and treated 

in France: Experience of the NetSarc network of the French Sarcoma Tumor 

Boards. Presenting Author: Francoise Ducimetiere, Centre Léon Berard, 

Lyon, France 

Background: The management of sarcomas, as for all rare tumors, is 

hampered by the limited dissemination of medical knowledge. Management 

within a specialized multidisciplinary sarcoma tumor board (STB) 

improves compliance to clinical practice guidelines. Since 2010, a 

national network with a dedicated system for referral, gathering the 26 

regional STBs, is supported by the French NCI. Its objectives are to monitor 

the management of sarcomas and give equal access to expertise and 

innovative treatments to all patients with sarcoma. We report here the first 

experience of a web-based data collection from these STBs. Methods: The 

expected incidence of sarcoma in France is 6.1/105 /year, ie 4000 new 

cases per year. A website collecting all files discussed in the 26 STBs was 

generated from Jan 2010 (www.netsarc.org). The prospective collection of 

clinical data, STB decision and patient follow-up was implemented in the 

national database (40 items). Results: 7472 patients were accrued during 

2 years, 6202 (83%) had sarcoma, 2860 (46%) were new cases, 

representing 36% of expected incident cases. The number of new cases 

discussed in STB increased between 2010 and 2011 (�38%). Patients 

were referred to the STB (2010-2011; % of cases) prior 1) to biopsy 

(9%-15%), 2) to first surgery (34%-39%), 3) to adjuvant treatment 

(35%-34%), after treatment (14%-8%) and at time of relapse (8%-4%). 

15% had a metastases at initial diagnosis. The R0�R1 resection rates for 

primary surgery were 55% vs 42% within vs outside the STB centers of 

NetSarc. 8% of declared patients were proposed to inclusion into a clinical 

trial. Conclusions: This web-based tool enabled the description of the 

activity of the STB at the national level. Clinical practices improved 

between 2010 and 2011, but 64% of new cases of sarcoma were not 

discussed in the referent STB prior to surgery. The yearly follow-up of the 

database will help to monitor evolution of clinical practices. 


Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal 

sarcomas: A 10-year follow-up study. Presenting Author: Nicole J. Look Hong, 


Background: Patients with high-risk extremity and truncal soft tissue sarcomas 

(STS) are at considerable risk for recurrence. A regimen of preoperative mesna, 

doxorubucin hydrochloride (Adriamycin), ifosfamide, and dacarbazine (MAID), 

interdigitated with radiotherapy (RT), followed by resection and postoperative 

chemotherapy with or without RT, has demonstrated high rates of local and 

distant control. The goal of this series is to study outcomes of our most recent 

cohort of patients treated on this regimen. Methods: We retrospectively reviewed 

records of 55 consecutive patients with STS of the extremity or superficial trunk 

who completed all phases of treatment at our institution from January 2000– 

July 2011. Clinicopathologic characteristics and patient outcomes were analyzed. 

Results: Fifty-five patients were analyzed and had a median age of 53 years 

(range 18-73). The median tumor size was 10.1cm (range 2.5-35.5 cm). 

Twenty-seven (49%) and 28 (51%) patients had grade 2 and 3 tumors, 

respectively. Margins were negative in 49 (89%) patients, and positive in 6 

(11%) patients. At a median follow-up of 43 months, there were 7 (13%) 

locoregional, and 17 (31%) distant recurrences. The local and distant 5-year 

recurrence-free survival (RFS) rates were 92% and 64%, respectively. The 

5-year overall (OS) and disease-specific survival rates were 86% and 89%, 

respectively. There were no treatment-related deaths or secondary myelodysplasias. 

There were no significant predictors of OS or RFS. Conclusions: Outcomes of 

a contemporary cohort of patients with extremity and truncal STS treated with an 

intense regimen of neoadjuvant chemoradiotherapy and surgery are consistent 

with previous reports from our institution and better than reports of chemotherapy 

alone. 

Comparison of interdigitated chemoradiotherapy with adjuvant/neoadjuvant 

chemotherapy. 

N 5-year OS 5-year distant RFS 

Current (2012) 1 

55 86 % 64% 

Gotzak et al. (2001) 2 

134 65% - 

DeLaney et al. (2003) 1 

48 87% 75% 

Sarcoma Meta-Analysis 

Collaboration (2007) 3 

1568 ~65% ~ 60% 

Radiation Therapy Oncology Group trial 9514, 

Kraybill et al. (2010) 1 

64 71% 64% 

Mullen et al. (2011) 1 

48 84% 80% 

1 2 3 

MAID chemoradiotherapy. Neoadjuvant chemotherapy. Adjuvant chemotherapy. 


Advanced soft-tissue sarcoma in patients over age 75: Patterns of care and 

survival. Presenting Author: Delphine Garbay Decoopman, Institut Bergonié, 

Bordeaux, France 

Background: There are no data regarding the management and the outcome 

of elderly patients (pts) diagnosed with advanced soft-tissue sarcoma 

(STS). Methods: The charts of pts aged � 75 years and diagnosed with 

metastatic and/or unresectable STS between 1990 and 2011 at Memorial 

Sloan Kettering (New York) and Institut Bergonié (Bordeaux, France) were 

reviewed. Results: 189pts were included.Median age was 79 years (range 

75-93).160 pts (84.5%) had metastatic disease. The most frequent 

histological subtype was leiomyosarcoma (n�57, 30%). The median 

age-adjusted Charlson comorbidity score was 10 (range 5-17). 120 pts 

(63.5%) received systemic therapy whereas 69 pts (36.5%) were managed 

with best supportive care (BSC) only. Pts who received BSC only were more 

likely � 80 years old (58% versus 38%, p�0.01) and with performance 

status (PS) � 2 (35% versus 14%, p�0.01). Single agent and combination 

therapy were delivered in 87 (72.5%) and 33 (27.5%) cases respectively. 

67 pts (56%) received a 1st-line anthracycline-containing regimen. The 

median progression-free survival of pts treated with systemic therapy was 4 

months (95% CI: 2.5-5.5). 21 pts (17.5%) had to stop 1st line treatment 

because of toxicity. On multivariate analysis, age � 80 years, PS � 2, and 

single-agent therapy were significantly associated with poor PFS. 51 pts 

received one or more further lines of therapies. At the time of analysis, 170 

pts (90%) had died. 96% of deaths were related to the disease. The median 

OS for the entire cohort of pts was 9.6 months (95% CI: 7.3-12). The 

1-year and 2-year OS rates were 43% (95% CI: 36–50), and 22% (95% CI: 

16–28), respectively. The median OS of pts managed with systemic 

therapy and BSC were 12.5 months (95% CI: 8.4-16.6) and 5.1 months 

(95% CI: 3.7-6.5), respectively (p�0.02). However, on multivariate 

analysis, PS � 2 and age-adjusted Charlson score � 10 were the sole 

independent factors significantly associated with OS. Conclusions: A high 

proportion of elderly pts with advanced STS were considered unfit for 

chemotherapy. The OS of STS pts � 75 years who were managed with 

systemic therapy seems similar to that of younger pts. Further efforts are 

needed to better define the optimal care for fit and unfit elderly pts with 

advanced STS. 


Risk factors leading to grading changes within 300 low-grade soft tissue 

sarcomas. Presenting Author: Tanja Koshrawipour, BG University Hospital 

Plastic Surgery, Bochum, Germany 

Background: Soft tissue sarcomas (STS) are rare, mesenchymal derived 

tumors. Based on malignancy, three grades are distinguished with G1 

equaling low grade, G2 intermediate grade and G3 high grade, respectively. 

Studies have shown that some G1 tumors which underwent complete 

surgical resection reoccurred as lesions with a grading shift from G1 to 

higher malignancy. This grading change is referred to as up grading. 

Patients with grading changes were thoroughly examined in our study. Our 

aim was to find possible risk factors for up gradings, such as age, 

localization of tumor and tumor type. Methods: This retrospective case 

control study evaluated 333 Patients, who, between 1996 to 2011 were 

treated for G1 STS at Bergmannsheil Bochum, university clinic. These 

patients received complete initial surgical resection. Among our 333 

patients, 9.9% (n�33) developed up gradings of their STS. These were 

then reviewed more closely in the aim of finding possible risk factors. We 

did not exclude any patients from our data or deliberately pick any grading 

changers and regard our collective as randomly sampled. The processed 

data includes age, gender, tumor type, tumor localization, occurrence of 

recidive and grading change. Results: Patients with up gradings were found 

to have a higher mean age of 4, 5 years than reference collective. The tumor 

type has a strong, statistically significant effect on grading change as 

patients with fibrosarcomas have a threefold risk of developing up gradings 

when compared to patients with other G1 STS. Conclusions: Our results 

indicate that age and tumor type play the key role in the development of up 

gradings in low malignant STS .Patients aged 60 and above diagnosed with 

fibrosarcomas are at a 3 times higher risk of developing a grading change as 

opposed to patients younger than 60 with other low grade STS than 

fibrosarcoma. We discussed the significance of these risk factors and 

argued whether, in addition to wide tumor resection, a short term 

postoperative radiotherapy should be applied for these patients to improve 

therapeutical outcome. 



Treatment outcomes of primary mediastinal and intrathoracic great vessels 

sarcoma: Royal Marsden Hospital experience. Presenting Author: Shir 

Kiong Lu, Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, 


Background: Sarcoma of the mediastinum and great vessels remain a rare 

subgroup of soft tissue sarcoma and prognosis remains poor with patients 

(pts) often presenting with advanced disease. There is no standard 

treatment due to paucity of data hence its management relies on case 

series. To date this is the largest series of pts reported. Methods: 

Retrospective analysis of pts identified anonymously from a prospectively 

maintained database of the sarcoma unit. Results: 46 pts were included in 

the analysis. The median age at diagnosis was 45.9 with a male: female 

ratio of 1.2: 1. 60% of pts presented with localised disease. The most 

common histological subtype was spindle cell sarcoma followed by angiosarcoma. 

The heart (n�21), majority in the atria, was the commonest 

primary site. 28 pts presented with localised disease of which 21 had 

surgery and 16 received chemotherapy (CT). 4 pts received multi-modality 

treatment. 83% of pts with metastases had CT. 6 of them attained stable 

disease, 1 had partial response and 4 (Ewing’s, rhabdomyosarcoma and 

angiosarcoma) had complete response. 31 pts developed disease recurrence 

of which 58% had initial localised disease. 6 pts had metastectomy, 

19 received palliative CT and 11 had palliative radiotherapy (RT). RT of 

50-60Gy to the heart or mediastinum was delivered to 61% of pts with 

initial localized disease and 33% of pts with metastases. 2 pts had 

documented post-treatment cardiac complication. After a median follow up 

of 2.16 years, the median event-free survival was 0.97 years (95%CI 

0.65-1.30), median overall survival (OS) was 1.7 years (95% CI 0.70- 

2.71) and 5 year OS was 17.9%. Conclusions: The optimal management in 

this disease is unclear. In this study, surgery was frequently implemented 

in both localised and metastatic settings but challenges remain in 

achieving clear margins. Chemotherapy has a role and it is key to identify 

chemosensitive subtypes. RT is offered as an adjunct following suboptimal 

resection. Despite aggressive treatments, this group of young pts had high 

recurrence rate and poor prognosis. Multi-modality treatment may have a 

role in selected pts but its efficacy and long-term cardiac sequelae need to 

be evaluated prospectively. 


Rechallenge with trabectedin in patients with locally advanced or metastatic 

soft tissue sarcoma following drug holiday: The experience of the 

French Sarcoma Group (FSG). Presenting Author: Esma Saada, Centre 

Antoine Lacassagne, Nice, France 

Background: Trabectedin (T) is a marine-derived alkaloid used to treat 

advanced soft tissue sarcomas (STS) after ifosfamide and/or anthracyclins 

failure. Since then, the FSG evaluated the clinical benefit in readministrating 

T after an initial hold, either medically indicated or upon 

patient’s request. Methods: Following an online request, clinical and 

histopathological data were collected from six centers of the FSG who 

declared to have rechallenged patients. Baseline data were collected and 

analyze will be used. Results: From 1999 to 2011, 49 pts with T drug 

holiday have been identified (26 male/ 23 female), with a median age of 50 

y [23-75]. Most frequent histotypes were: myxoid liposarcoma (18, 

36.7%), leiomyosarcomas (13, 26.5 %) and well-differentiated/dedifferentiated 

liposarcoma (9, 18%). WHO grade were 1 in 14 (29%), 2 in 19 

(39%) and 3 in 5 (10%) pts respectively. Patients who had a maximum of 

2, 3 or 4 therapeutic sequences (TS) with T (drug-holiday and rechallenge) 

were 41/49 ,7/49 and 1/49 respectively. Median number of cycles for 1, 2, 

3 and 4 TS were 7 [3-21], 6 [2-30], 6 [2-9] and 6. Median total number of 

cycles was 15 [6-43]. Median duration of drug-holiday for 1, 2 and 3 TS 

were 11 [3-91], 7 [2-29] and 4 months [1-5]. Grade 3-4 toxicities 

incidence decreased with the number of TS (occurred in 36%, 29%, 14% 

and 0% of pts with 1, 2, 3 and 4 TS) as well as mean T dose per cycle (1.3 

mg/m², 1.2 mg/m², 1.1 mg/m² and 1.1 mg/m² for TS 1, 2, 3, 4). Efficacy 

decreased with number of TS (Number of CR/PR/SD/PD were 1 (2%)/15 

(31%)/33 (67%)/0 for TS1; 0/4 (8%)/29 (59%)/16 (3%) for TS2; 0/1 

(14%)/2 (29%)/4 (57%) for TS3 and 0/0/0/1(100%) for TS4). Median 

overall survival was 5.0 y [2.7-7.3] since T introduction, and 1.5 y 

[0.1-4.8], 0.8 y [0.5-1.3] and 0.6 y following 2nd , 3rd and 4th T 

reintroduction respectively. Objective response after TS2 were seen in 4 

cases of grade 1 sarcomas. Conclusions: Due to the lack of cumulative 

toxicities over time with T, its rechallenging in responding patients to T (no 

progression under T) have to be considered in advanced STS. 

Sarcoma 

645s 


Drug treatment (tx) patterns and survival among patients (pts) with metastatic or 

recurrent soft tissue sarcoma (m/rSTS) refractory to at least one prior therapy. 

Presenting Author: Michael Wagner, Dana-Farber Cancer Institute/Harvard 


Background: Limited clinical data on real-world practice patterns are available for 

care of pts with m/rSTS. This study evaluated drug tx patterns and outcomes in 

m/rSTS pts following failure of prior chemotherapy based on data from a U.S. 

referral academic cancer center. Methods: Data from medical records consented 

for research use were retrospectively reviewed at Dana-Farber Cancer Institute 

for pts with m/rSTS who were �18 years, commenced 2nd-line systemic therapy 

between 1/1/2000 and 2/4/2011, had confirmed disease progression on or after 

1st-line therapy and had �3 months of observation. Pts were excluded if they 

had been diagnosed with gastrointestinal stromal tumor, bone sarcoma or 

dermatofibrosarcoma protuberans, or had ever been treated with pazopanib. 

Histologic subtype, tx type and duration, tx modifications (e.g., discontinuation) 

and reasons for modifications were examined. Overall survival, time to progression 

and clinician-assessed tumor response were collected. Results: Study pts 

had leiomyosarcoma (n�50), synovial cell sarcoma (n�7), liposarcoma (n�5) 

and other histologic subtypes (n�39). These 101 pts received an average 4 lines 

of tx (maximum�10 lines). Wide variations were noted in each line of tx (Table) 

with no consistent nor dominant regimens. Median 2nd-line tx duration was 4.1 

months (95%CI 2.9-5.0). Among 98 pts who discontinued 2nd-line tx, 72 

(73%) did so due to progressive disease, 10 due to “completion” of planned tx, 

and 6 to adverse events. Median progression-free survival from initiation of 

2nd-line tx varied across regimens from 2.0 to 6.5 months (overall median 5.5 

months). Conclusions: The wide variation in �2nd-line tx confirms there is no 

single “standard” of care for m/rSTS. The majority of pts discontinued 2nd-line 

tx due to progressive disease and often received additional lines of tx, indicating 

frequent physician and pt switching of tx. 

Number pts receiving 

Line of AnthracyclineGemcitabine- Alkylating Angio-genesis 

therapy basedbased agent inhibitor Trabectedin Total 

Taxanebased 

Other 

txt 

1st 44 29 9 5 4 0 10 101 

2nd 26 28 12 7 13 3 12 101 

3rd 12 12 15 12 16 1 9 77 

4th 7 5 13 10 9 1 3 48 

5th 0 5 12 5 8 0 2 32 

6th 2 2 8 3 2 0 1 18 


Bone metastases in soft tissue sarcoma patients: A survey of natural, 

prognostic value, and treatment. Presenting Author: Bruno Vincenzi, 

Università Campus Bio-Medico, Rome, Italy 

Background: Given the limited data currently available, we surveyed the 

natural history of bone metastases in patients affected by soft tissue 

sarcoma (STS). Methods: This retrospective, multicenter, observational 

study evaluated data from 135 patients with STS metastatic to the bone 

who presented between 2001 and 2011. For all patients, we recorded the 

primary tumor histological subtype, bone metastases characteristics (onset, 

site), type of treatment received (surgery, radiotherapy, zoledronic 

acid), type and frequency of skeletal related events (SRE) and disease 

outcome. Results: The most represented histological subtypes among the 

enrolled patients were leiomyosarcoma (27%), angiosarcoma (13%) and 

spindle cell sarcoma (8%). The spine was the most common site for bone 

involvement (51%), followed by hip/pelvis (20%), long bones (15%) and 

other sites (14%). In 27% of cases, bone metastases were present at the 

time of diagnosis. Fiftyfour patients (40%) developed SREs and the 

median time to first SRE (if developed) was 4 months. The most common 

SRE was the need for radiotherapy occurring in 28% of patients followed by 

pathologic fracture (22%). Patients survived for a median of 6 months after 

bone metastases diagnosis. The occurrence of a SRE was associated with a 

decreased overall survival (P�0.04). A subgroup analysis revealed that 

zoledronic acid significantly prolonged median time to first SRE (5 versus 2 

months; P � 0.002). Conversely, It did not determine an improvement in 

terms of overall survival, even if favorable trend was identified (median, 7 

versus 5 months, respectively; P � 0.105). Conclusions: This study 

illustrates the burden of bone disease from STS and supports the use of 

zoledronic acid in this setting. 


646s Sarcoma 


Head and neck sarcomas: A comprehensive cancer center experience. Presenting 

Author: Mohamedtaki Abdulaziz Tejani, University of Rochester Medical 

Center, Rochester, NY 

Background: Head/neck sarcomas are rare, accounting for 1% of head/neck 

malignancies and 5% of sarcomas. There are about 1000 cases/year in the U.S. 

comprising of many histologic subtypes making rigorous study of these tumors 

difficult. Outcomes have historically been worse in this anatomic group due to 

unique obstacles encountered during their treatment. Methods: We retrospectively 

analyzed cases of head/neck soft tissue sarcomas treated at Fox Chase 

Cancer Center (1999–2009). Study objectives were to describe clinicopathologic 

characteristics, treatment and outcomes of adult head/neck sarcoma 

patients and identify prognostic factors for disease control and survival. Cox 

proportional hazards regression analysis was performed to identify predictors of 

DFS and OS. The HR and 95% CI for Cox model and median DFS/OS from 

Kaplan-Meier curves were calculated. Results: 31 patients were identified. 

Median age was 50 (range 15–91). 23 patients were male. Most tumors were 

high grade (25) and almost all were localized at presentation (29). Common 

histologies were synovial cell (6), rhabdomyosarcoma (5), angiosarcoma (4), 

lipsarcoma (4) and leiomyosarcoma (3). 25 patients with localized stage 

underwent excision: 9 had surgical resection only, 10 had surgical resection with 

neo/adjuvant radiation and 6 had surgical resection as well as neo/adjuvant 

chemotherapy and radiation. 7 patients required re-excision to achieve negative 

margins. Median DFS was 1.1 years (95% CI: 0.7–12.1) and median OS was 3.3 

years (95% CI: 2.1-5.4). Of 16 patients with recurrent disease, 12 were local. 

Patients with positive margins had worse DFS (p�0.04) and OS (p�0.03). 

Tumors greater than 5cm were associated with worse DFS (p�0.07). Age and 

grade did not correlate with outcome. Conclusions: Head/neck sarcomas are 

difficult to completely excise due to anatomic constraints and local recurrence 

rates are high. Achieving a negative margin is critical in improving outcome. 

Median DFS and OS are worse than those achieved with other subsites. 

Head/neck sarcomas are best managed in a multi-disciplinary setting. 

Univariate association 

DFS OS 

HR 95% CI p HR 95% CI p 

Neg vs. pos margins 4.03 1.05-15.39 0.04 4.47 1.14-17.58 0.03 

Size 5cm 3.00 0.91-9.91 0.07 1.66 0.55-4.99 0.37 


Preclinical study of trabectedin (TR) and poly(ADP-ribose)polymerase 1 

(PARP-1) inhibitor combination in soft tissue sarcoma (STS). Presenting 

Author: Ymera Pignochino, Institute for Cancer Research and Treatment, 

Candiolo, Italy 

Background: TR is an alkylating agent approved in Europe for the treatment 

of advanced STS as second/third line therapy. TR binds to the minor groove 

of DNA and interferes with gene transcription and nucleotide excision 

repair mechanism, inducing DNA double strand breaks (DSBs), and S/G2 

cell cycle arrest. There is a strong clinical interest to increase TR activity 

combining it with other anti-cancer drugs. PARP-1 inhibitors disable DNA 

base-excision repair mechanism causing the accumulation of DSBs and 

look like a reasonable TR partner to be explored. We focused our in vitro 

studies on the effects of the combination of TR with the PARP-1 inhibitor 

Olaparib (OL). Methods: We explored the activity of TR-OL combination 

against a panel of different histotypes of STS cell lines, evaluating cell 

viability after 72h treatment with escalating doses of TR (0-2 nM), OL 

(0-20 �M), and their constant combination. Following colony formation, 

cell cycle, apoptosis (annexin V�/PI�) and DNA damage (phospho-histone 

H2AX - Ser139) were checked. Results: The TR-OL combination strongly 

affects STS cell viability, showing synergism (Combination Index � 1, 

based on Chou–Talalay method) on 8 out of 13 cell lines tested. We 

observed a strong synergism, as a massive reduction of colony growth 

(402.91, MES-SA, and DMR-SN-8.4.98 lines) induced by the combination 

if compared with each single agent (78% vs. ~27% : p�0.05). OL 

potentiates the S/G2 cell-cycle arrest caused by TR at 48h (Control� 29%, 

TR� 33.4%, OL� 31.5%, TR-OL� 80.9%), and induces a strong increase 

of the apoptotic cells at 72h (Control� 17.4%, TR� 28.3%, OL� 33.5%, 

TR-OL� 56.8%). Furthermore, the TR-OL synergism on DNA damage is 

confirmed by a significant increase of the DSBs marker (Control� 8.7%, 

TR� 59.5%, OL� 23.8%, TR-OL� 76.5%). Conclusions: These results 

validate the biological rationale to combine TR and PARP-1 inhibitors in 

STS and suggest assessing this drug combination in the clinical setting. 


Response to radiation therapy in solitary fibrous tumor/hemangiopericytoma. 

Presenting Author: Giacomo Baldi, Fondazione IRCCS Istituto 

Nazione dei Tumori, Milan, Italy 

Background: To reporton the activity of radiotherapy (RT) in a retrospective 

series of solitary fibrous tumors (SFT)/hemagiopericytoma (HCP), a rare soft 

tissue sarcoma subtype whose sensitivity to RT is poorly known. Methods: 

We retrospectively reviewed all patients with a diagnosis of SFT/HCP whom 

we saw from 2005 to 2011, focusing on cases treated with RT in 

neoadjuvant, adjuvant, exclusive, palliative settings. Patients who received 

concomitant chemotherapy were excluded. We confirmed diagnosis by 

review in all cases. We evaluated the overall response rate (RR) by RECIST. 

Results: Nineteen patients were identified (males � 9, females � 10; 

median age � 61 years, range 39-85; site of primary� 6 meninges, 4 

pleura, 3 pelvis, 3 retroperitoneum, 2 limbs, 1 abdominal wall; site of RT� 

5 bone and soft tissue, 5 pelvis, 3 soft tissue, 2 meninges, 2 retroperitoneum, 

1 abdominal wall, 1 pleura; reason for RT� 3 neoadjuvant, 2 

adjuvant, 2 exclusive and 12 palliative setting). Median RT dose was 42 Gy 

(range 12-60). Seventeen of 19 pts are evaluable for response (2 adjuvant). 

The RR was: 29% (4 pts) partial response, 65% (12 pts) stable disease 

(SD), 6% (1 pt) progressive disease (PD). All patients treated with 

neoadjuvant RT had a RECIST SD as best response to pre-operative 

treatment with evidence of pathologic response in 2 of 3 cases. Conclusions: 

Contrary to what is widely thought,this retrospective analysis suggests that 

SFT/HCP is sensitive to radiation therapy. Prospective studies are needed. 


Global differences in chemotherapeutic regimens of soft tissue sarcoma 

(STS): Results of PALETTE, an EORTC 62072/GSK VEG110727 global 

network phase III trial of pazopanib versus placebo. Presenting Author: 

Sandrine Marreaud, EORTC Headquarters, Brussels, Belgium 

Background: The global PALETTE EORTC/GSK network study on advanced 

STS patients (pts) randomized 223 European (EU), 43 American (US), 81 

Asian, and 22 Australasian (AUS) pts between pazopanib and placebo. 

Prior to study entry pts should have received at least one anthracycline 

containing regimen, and preferably, if pts’condition allowed, all available 

standard chemotherapy treatments for STS in their countries. We investigated 

the differences in chemotherapy pts received prior- and post-protocol 

at a global level. Methods: Pts were grouped by continent. Pre- and 

post-protocol chemotherapeutic treatments (txs) were analyzed. The number 

of prior lines of systemic tx for advanced STS was divided between 0-1 

vs 2 or more. Chemotherapy was studied in detail between Asian and other 

countries. Fisher’s exact test was used for statistical analysis. Results: Data 

from all 369 pts were analyzed. (Neo-) adjuvant systemic tx was given in 

21% of EU, 23% of US, 36 % of Asian and 41% of AUS pts. In advanced 

STS: 2 or more lines of prior systemic txs were administered in 60% of EU, 

84% of US, 42% of Asian, 22% of AUS pts before study entry. Prior to 

study entry 68% of EU, 65% of US, 84% of Asian and 68% of AUS pts 

received ifosfamide(or analogs); after protocol 21 % of EU, 14% of US, 

13% of Asian and 5% of AU pts. There were significant differences in 

chemotherapy between Asian (n�81) and other (n�288) pts: prior to 

protocol trabectedin was administered in 1 vs 21%; gemcitabine 19 vs 39 

%; cisplatin: 36 vs 5%; etoposide 32 vs 4% (all p�0.001), and docetaxel: 

17 vs 31 % (p�0.004) of pts. Post-protocol trabectedin was given to 4 vs 

34% (p�0.001), gemcitabine both in 19%; cisplatin 10 vs 4% (p�0.01); 

etoposide 12 vs 6%, and docetaxel 20 vs 12 % (both, p�0.02) of pts. 

Conclusions: The PALETTE study showed considerable intercontinental 

differences in chemotherapeutic txs for advanced STS pre- and post study 

drug. These differences might be due to availability and reimbursement of 

drugs, clinical studies and the practice patterns of sarcoma specialists 

world-wide. This is of particular interest for the design of future randomised 

global clinical trials in advanced STS. 



Whole-body PET/MR in soft tissue sarcoma (STS) patients. Presenting 

Author: Stephan Richter, Medizinische Klinik und Poliklinik I, University 

Hospital Carl Gustav Carus Dresden, Dresden, Germany 

Background: PET/MR (positron emission tomography/magnetic resonance 

imaging) is a new whole-body hybrid imaging technique that combines 

metabolic and cross-sectional diagnostic imaging. To date the only available 

clinical data are drawn from feasibility studies in small series of head 

and neck cancers and intracranial tumors. Imaging by combined PET and 

computed tomography (PET/CT) has been investigated in STS for biopsy 

guidance, response assessment and grading. Methods: This exploratory 

analysis evaluated the outcomes of PET/MRI in 21 patients with STS in 

different treatment settings: (a) neoadjuvant setting, (b) metabolic-driven 

local therapy in metastatic sarcoma, and (c) palliative treatment. For 

examination we used an Ingenuity PET/MR system (Philips Healthcare). It 

combines a 3-Tesla MRI and a PET scanner with time-of-flight technology. 

Results: PET/MR shows a high contrast imaging without significant artifacts 

or distortions. (a) Four patients with high-risk sarcoma (3 rhabdo, 1 

pleomorphic) completed the planned neoadjuvant therapy. Change in 

tumor size did not correlat with pathologic response, whereas surgical 

outcome was well predicted by metabolic changes. Due to this finding the 

preplanned course of chemotherapy for one patient was changed. (b) To 

prolong disease stabilization of 3 patients with a remnant metabolic activity 

in a single spot they underwent a surgical resection of a single metastatic 

lesion or had a local radiotherapeutic approach. (c) In 3 patients with stable 

disease after first-line treatment with combination of anthracyline and 

ifosfamide persisting metabolic activity indicated a switch to another 

alternative 2nd line regime. Trabectedin as 2nd line therapy decreased 

metabolic activity that finally resulted in a tumor regression. Conclusions: 

To our knowledge this is the first report on patients with STS examined with 

whole-body-PET/MR. PET/MR is feasible in STS and may provide valuable 

information in treatment, monitoring and prognosis of patients with STS. 

This technique may help to choose accurate and on-time treatment option 

without unnecessary time delay. Further prospective studies to evaluate 

PET/MR in STS are warranted. 


Multimodality therapy for pulmonary metastasis in sarcoma patients: 

Results of a single institution. Presenting Author: Nasreen A Vohra, H. Lee 

Moffitt Cancer Canter & Research Institute, Tampa, FL 

Background: Pulmonary metastasectomy (PM) for sarcoma can result in 

significant long term survival in carefully selected patients (pts). We report 

our experience with pulmonary metastasectomy. Methods: After IRB approval, 

120 pts who underwent PM for sarcoma at Moffitt Cancer Center 

from 1999 to 2011 were reviewed. Survival was calculated according to the 

Kaplan-Meier method with Cox proportional hazard univariate (UV) and 

multivariate (MV) models used to analyze relationships between clinicopathologic 

variables and overall survival (OS). P-value � 0.05 was 

considered significant. Results: Median age was 51 yrs, 95(79%) pts had 

soft tissue sarcomas with pleomorphic being most common. Of the 

25(21%) osseous sarcomas, osteosarcoma was most common. 20(15%) 

had synchronous metastasis (mets); of the pts with local disease only, 

median time to recurrence from primary resection was 13 months (mo). OS 

from initial resection was 55 mo for pts with local disease only vs. 27 mo for 

pts with synchronous mets. On UV analysis, use of radiation, number of 

index lesions, presence of synchronous mets and time to recurrence 

achieved significance. On MV analysis, only shorter time to recurrence 

(p�.03) and presence of synchronous mets (p�.04) were independent 

predictors of poor survival. 63(52%) pts [26(22%) neoadjuvant, 19(16%) 

adjuvant, 18(15%) both] received chemotherapy for the primary tumor, 

while 57(48%) did not. There was a trend towards poor survival in pts 

receiving chemotherapy compared to pts receiving no chemotherapy 

(p�0.06, HR 1.59). In addition 40(34%) pts received chemotherapy prior 

to PM with no difference in OS compared to pts who did not get 

chemotherapy (p�0.1, HR 1.55). 71(59%) had 1 PM, 32(27%) had 2 and 

17(14%) had 3 or more PM with OS being 17 mo, 37 mo and 34 mo in 

each group, respectively. A higher number of PM was associated with 

improved survival (p�.01). Conclusions: Pts with a shorter disease free 

interval have a decreased OS as do pts with synchronous mets. Pts 

undergoing multiple PM have a survival benefit likely resulting from 

favorable disease biology. Failure of chemotherapy to show a survival 

benefit may be a result of selection bias for patients with aggressive disease 

being treated with chemotherapy. 

Sarcoma 

647s 


Neoadjuvant chemotherapy for adult soft tissue sarcomas: A phase II trial. 

Presenting Author: Samuel Aguiar, A.C. Camargo Cancer Hospital, Sao 

Paulo, Brazil 

Background: Treatment of soft tissue sarcomas (STS) is characterized by 

high rates of local control, but poor overall survival because of distant 

relapses and high rates of wound complications, when preoperative 

radiation is used. The objective of this study was to test the effectiveness of 

a protocol with neoadjuvant chemotherapy for STS. Methods: A phase II 

single-arm prospective trial was carried out. Only adult patients with high 

grade extremity lesions and tumors deep and larger than 5 cm were 

included. A total of four cycles of chemotherapy was administered 

pre-operatively. The chemotherapeutic regimen was: ifosfamide – total of 

9.0 g/m2 per cycle, infused in 2 hours from Day 1 to Day 5 (1.8 

mg/m2/day). Half of the equivalent dose of mesna was infused 15 min 

pre-ifosfamide and 4 hours post-ifosfamide. Doxorubicin – total of 60mg/m2 

per cycle, was infused in bolus on Day 1. Filgrastima 300 mcg, SC, was 

administered after the last dose of chemotherapy for 5 days. Radiation was 

given after surgery. Toxicity was classified by the NIH Toxicity Criteria and 

response was determined by the RECIST criteria. The others endpoints 

were the amputation and the wound-related complication rates. Results: 

Between January, 2005 and May, 2011, 42 patients were included. 

21(50%) patients have completed the 4 cycles. Nineteen patients (45.2%) 

have grade 3 or 4 toxicity, and one (2.3%) death related to treatment had 

occurred. Between severe complications, febrile neutropenia was the most 

frequent. By using the RECIST criteria, we observed 10(24.5%) cases of 

progression, 24(58.5%) cases of stable disease, and 7(17%) partial 

responses. No complete clinical or radiological response was observed. In 

the pathological analysis of the surgical specimens, 4(9.7%) cases showed 

no residual disease (complete pathological response), and a total of 6 

(14.6%) showed � 5% of viable residual cells. The amputation rate was 

4.8% (2 cases) and complications related to the wound were observed in 9 

patients (21.9%). Conclusions: The protocol showed a good rate of 

objective and pathological response, low rate of complications related to 

the operative wound, and maintained an acceptable amputation rate. On 

the other hand, we observed high rate of progression, by RECIST criteria. 


Atypical vascular neoplasms and risk of development of angiosarcoma. 

Presenting Author: Vinod Ravi, University of Texas M. D. Anderson Cancer 


Background: Atypical vascular neoplasms are rare cutaneous lesions that 

develop following radiation therapy to the breast that have evidence of 

atypia but do not meet all criteria for a diagnosis of angiosarcoma. They 

typically have a benign course and are managed by surgical resection. 

Histopathological changes consistent with atypical vascular neoplasm are 

commonly found adjacent to angiosarcoma and have lead some investigators 

to believe that these may be precursor lesions to development of 

angiosarcoma. Methods: We performed a retrospective review of all patients 

with a diagnosis of atypical vascular neoplasm from 2002 to 2012. Patient 

with a prior/concurrent history of angiosarcoma were excluded from the 

analysis. Primary objective of the study was to determine the percentage of 

patients with atypical vascular neoplasms that progressed to angiosarcoma 

on long-term follow-up. Results: 37 patients were identified in the tumor 

registry at MD Anderson cancer center with a diagnosis of atypical vascular 

neoplasm between 2002 and 2012 with a median follow-up of 24 months. 

The median age of the study population was 53. Females represented 89% 

of the study population. Atypical vascular neoplasms occurred most 

frequently in the breast/chest (70%) and 68% of patients had a prior 

history of breast cancer. 54% of patients had prior radiation therapy. The 

median time to development of atypical vascular neoplasms from radiation 

therapy was 52 months. Among patients who underwent surgical resection 

with negative margins, there were no recurrences. We failed to observe any 

progression to angiosarcoma in the study population. Conclusions: Patients 

with atypical vascular neoplasms may not progress to angiosarcoma and are 

best managed with surgical resection. 


648s Sarcoma 


Effect of anti-�1 integrin antibody on lung seeding of osteosarcoma cells in 

live mice visualized by single-cell in vivo imaging. Presenting Author: 

Hiroaki Kimura, Department of Orthopaedic Surgery, Graduate School of 

Medical Science, Kanazawa University, Kanazawa, Japan 

Background: Integrins play a role in tumor growth and metastasis (Int. J. 

Cancer 129, 2905-2915, 2011). However, the effect of integrin inhibition 

has not been visualized on single cancer cells in vivo. In this study, we used 

a powerful subcellular in vivo imaging model to demonstrate how an 

anti-integrin antibody affects seeding and growth of osteosarcoma cells on 

the lung. Methods: The 143B human osteosarcoma cell line expressing red 

fluorescent protein (RFP) in the cytoplasm and green fluorescent protein 

(GFP) in the nucleus was established. Using the double-labeled osteosarcoma 

cells, single cancer-cell seeding in the lung after i.v. injection of 

osteosarcoma cells was imaged in live mice. Results: The anti-b1 integrin 

monoclonal antibody, AIIB2, greatly inhibited the seeding of cancer cells 

on the lung while a control antibody had no effect. To image the efficacy of 

the anti-integrin antibody on spontaneous metastasis, mice with orthotopically-growing 

143B-RFP cells in the tibia were also treated with AIIB2 or 

control anti-rat IgG1 antibody. After 3 weeks treatment, mice were 

sacrificed and primary tumors and lung metastases were evaluated with 

fluorescence imaging. AIIB2 significantly inhibited spontaneous lung 

metastasis but not primary tumor growth. In a separate experiment, the 

anti-�1 integrin antibody increased survival in the orthothopic osteosarcoma 

model. Conclusions: The efficacy of the anti-�1 integrin antibody 

against metastasis may be due to inhibition of lung seeding of the cancer 

cells. The increased survival of mice with orthotopically-growing 143B-RFP 

treated with AIIB2 may be due to inhibition of metastasis, which in turn 

may be inhibited by effect of the anti-�1 integrin on cancer-cell seeding in 

the lung. 


Age as a prognostic factor in osteosarcoma: Survival analysis. Presenting 

Author: Maria Pallotta Guadalupe, Hospital Italiano de Buenos Aires, 

Ciudad Autonoma de Buenos Aires, Argentina 

Background: Studies comparing survival between adult and paediatric 

population with osteosarcoma are scarce and contradictory. Generally 

adults were excluded from analysis in historical series. End Point: evaluate 

age as prognostic factor in ostosarcomas IIb treated exclusively by a 

multidisciplinary group in a single institution. Methods: 132/278 patients 

with histological diagnosis of osteosarcoma IIb were selected. All were 

treated exclusively in our hospital from July 1988 until December 2010. 

Patients 17 years old or younger were considered paediatric. They all 

received presurgical chemotherapy with the same scheme: ifosfamide � 

doxorrubicin � high dose methotrexate. Univariate analysis was made 

(Fischer exact test). Survival was calculated wih Kaplan-Meier actuarial 

method. Curves were compared with log rank test. Multivariate Cox analysis 

was made. Results: Median age was 19.6 years (std: 9,1; range 5-58). 

Adults: 77, children: 55. No differences were detected between the two 

age groups regarding: elevated alkaline phosphatase, kind of surgery 

(amputation vs. limb sparing), relapse site (lung, local, other), necrosis 

greater than 90% or number of lung resections. There was a tendency 

towards axial localization in adults (p�0.05). No paediatric patient had 

inadequate medical intervention, but it was present in 14.3% of adults 

(p�0.002). 5 year Overall survival (5y OS) in children was 85,2% 

compared with 61,8% in adults (p�0.005); Disease free survival (DFS) 

had a non significant tendency to be better in children (69.6% vs. 51,3%). 

Variables associated with worse OS were: axial location (p�0.01), elevated 

alkaline phosphatase (0.003), amputation (p�0.008), local relapse or 

systemic non-lung metastasis (p� 0.001), necrosis less than 90% (0.001). 

Multivariate Cox analysis showed association between OS and paediatric 

population (p�0.01) and necrosis greater than 90% (p�0.001), while 

DFS was associated with necrosis greater than 90% (p�0.01) and elevated 

alkaline phosphatase (p�0.05). Conclusions: Paediatric population presents 

better survival compared to adults in our institution. Differences in 

tumour biology and in the mode of presentation related to age may be the 

explanation. 


Navigation-assisted surgery for bone and soft tissue tumors with bony 

extension. Presenting Author: Makoto Ieguchi, Department of Orthopedic 

Surgery, Yodogawa Christian Hospital, Osaka, Japan 

Background: In recent times,minimally invasive surgery, such as endoscopic 

surgery, has gained a lot of popularity.The navigation system was 

introduced to orthopedic surgery in the 1990s. These days, computed 

tomography (CT)-based navigation systems are commonly used in spine 

and joint replacement surgery because of their precision. The aim of our 

study was to evaluate the accuracy and efficacy of navigation-assisted 

excision of bone and soft tissue tumors. Methods: From January 2006 to 

December 2009, we performed navigation-assisted surgery in 16 patients 

(11 men and 5 women; mean age, 39 years; range, 13-70 years). We 

diagnosed 9 benign bone tumors and 7 malignant bone and soft tissue 

tumors. In 2 patients, the malignant soft tissue tumors infiltrated the 

adjacent bones. We performed excisional biopsies for the benign tumors 

and en bloc excisions for the malignant tumors. In all the cases, the point 

registration method was used with 10 skin markers that were placed around 

the tumor. Each excisional difference between the preoperative and 

postoperative plans was evaluated histologically or by postoperative CT. 

Results: The mean preoperative registration matching time was 12.8 min 

(range, 8-25 min). The total mean preparation time was 24 min (range, 

16-35 min). The mean accuracy of this system, which was determined 

using the skin markers, was 0.93 mm (range, 0.6-1.5 mm). All biopsied 

and excised specimens were evaluated by pathologic examination and 

postoperative CT imaging. The mean difference between the planned 

margin and postoperative CT or the excised histological specimen was 0 to 

4 mm. The mean follow-up period was 53.2 months (range, 10-70 

months). There were no local recurrences, except for a case of chordoma 

that required excision of skip metastases and a case of extraskeletal 

osteosarcoma, in which the patient died from the disease. Conclusions: We 

report our experience with navigation-assisted surgery for bone and soft 

tissue tumors performed using skin markers. Navigation-assisted surgery 

was indicated in the case of sufficiently reliable, accurate, and minimally 

invasive resections. 


Efficacy of newly developed platinum complexes against osteosarcoma, 

bone-targeting platinum, and proteasome inhibitory platinum. Presenting 

Author: Kentaro Igarashi, Department of Orthopaedic Surgery, Kanazawa 

University, Kanazawa, Japan 

Background: Cisplatin is one of the most effective anti-cancer drugs 

available for the treatment of human solid tumors including osteosarcoma. 

As we had already reported, we have utilized caffeine in our chemotherapy 

protocol. And we achieved excellent clinical results. But effectiveness of 

cisplatin has been limited by side effects, and resistance. Here we 

developed two novel platinum compounds. 3Pt is trinuclear platinum 

complex bearing geminal bisphosphonate moieties, 1Pt is mononuclear 

platinum complex which has proteasome inhibitory activity. We performed 

comparative studies of our novel platinum compounds with osteosarcoma. 

Methods: Two novel platinum complexes were synthesized by Prof. Odani at 

school of pharmaceutical sciences of our university and cisplatin and 

caffeine were obtained from constructor. Three cell lines (MG63, 143B, 

and LM8) were used. Cell survival after a 72 hrs exposure to these 

compounds was assessed by WST-8 assay, and IC50 value was calculated 

for each compound. Apoptosis was assessed by DNA fragmentation and 

Annexin V-FITC/propidium iodine assay. Results: Each compound strongly 

caused concentration-dependent cytocidal effect. IC50 value of trinuclear 

compound is superior to cisplatin, and both complexes showed caffeine 

potentiation. Apoptosis induction and acetylation of histon H2AX were 

observed. In vivo, 1Pt showed almost same, 3Pt showed strong antitumor 

effect compared to cisplatin. Conclusions: Two novel platinum compounds 

that we developed showed strong ant-tumor effect in osteosarcoma in vitro 

and in vivo. As bisphosphonate has high affinity to calcium ions, 3Pt targets 

bone tissue and expected to reduce side effects at extraskeletal sites and to 

overcome the drug resistance. Proteasome inhibitory platinum compound 

has never been reported before, we will investigate its anti-tumor mechanism 

precisely. 



Study of the expression of integrin pathway’s proteins as predictive markers 

of response to neoadjuvant chemotherapy in pretreatment biopsies of 

patients with high-grade osteosarcoma. Presenting Author: Elizabeth Laurence 

Cohen-Jonathan Moyal, Institut Claudiusr Regaud-INSERM 1037, 

Toulouse, France 

Background: Up to now, chemosensitivity to neoadjuvant chemotherapy 

performed for patients with osteosarcoma is evaluated on the surgical 

resection by the evaluation of the percentage of necrotic cells. No 

predictive profile of chemotherapy has been described yet. Because we 

have previously shown that integrin pathway controls genotoxic-induced 

cell death and hypoxia via ILK, FAK and RhoB, we hypothesized that the 

expression of the proteins involved in this pathway in pre-treatment 

biopsies could be associated with sensitivity to chemotherapy in osteosarcoma. 

Methods: We studied by immunohistochemistry �1, �3, �5, integrins, 

ILK, FAK, GSK-3�, RhoB and Ang-2 expression in 36 osteosarcomas 

biopsies of patients obtained before treatment. All the patients were 

treated by the SFOP OS94 chemotherapy protocol and underwent wide 

conservative surgery. Response to preoperative chemotherapy was assessed 

on the surgical resection by the Rosen’s protocol. An immunoreactive 

score (IRS) was assessed, combining the percentage of positive tumour 

cells and staining intensity. We evaluated the correlation of the selected 

markers expression with response to preoperative chemotherapy and 

clinical outcome. Results: FAK expression was statistically linked with ILK 

expression (rho�0.43; p�0.020), �1integrin expression with FAK expression 

(rho�0.51); p�0.003), RhoB with ILK expression (rho�0.55; 

p�0.002), and �1 with �3integrin expression (rho�0.70; p�.001), 

suggesting that a regulation of the integrin pathway that we studied might 

exist in high grade osteosarcoma. Moreover, the combination of �5 

integrin, FAK and GSK-3� discriminated good and poor responder to 

chemotherapy (89.9%; 95% CI� [77.4;1.00], yielding a sensitivity of 

94.1%, a specificity of 85.7% and a diagnostic accuracy of 90.3%. 

Conclusions: We report for the first time a protein expression profile on 

pre-treatment biopsies associating �5 integrin FAK and GSK-3� related 

with a poor response to neoadjuvant chemotherapy. This profile could help 

to select patients for clinical trials using inhibitors of this pathway in 

association with chemotherapy. 


Primary localized gastrointestinal stromal tumors (GIST) of the duodenum: 

Final results of a French Sarcoma Group (FSG) retrospective review of 110 

patients (pts). Presenting Author: Thanh Khoa Huynh, University Hospital 

La Timone, Marseille, France 

Background: Duodenal GISTs represent 3-5% of all GISTs with limited 

understanding of patient outcomes from small series. We conducted a 

retrospective analysis of primary localized duodenal GISTs over the past 18 

years. Methods: Pts were identified in two ways: a group of 101 pts reported 

via survey from 20 FSG centers, and a group of 9 pts enrolled in the BFR14 

trial. Results: Pts were:55 females, 55 males, with a median age of 57 years 

(30-84), and median ECOG 0 (0-3). Abdominal pain, anemia, and GI 

bleeding were the most common symptoms. Tumors (T) originated mainly 

in D2 (41%), or D3 (27%), with a median size of 5 cm (1.5-30). All pts 

except four had resection of the primary T. Surgical procedures were: local 

resection (LR) [segmental duodenectomy (n�31), wedge local resection 

(n�31), local excision (n�6)], and duodenopancreatectomy (DP, n�20). 

Resections were R0 in 84 pts (79%), R1 in 6 pts (6%). T characteristics 

included: KIT� (n�100), CD34 � (n� 54), mitoses/50 HPF � 5(n�70), or � 5(n�24), Miettinen low-risk (n�37), and high-risk (n�19), necrosis 

(n�29), spindle cell (n�84). Genotype was evaluated in 36 cases: KIT 

exon 11 mutant (n�30), no mutation (n�4), and KIT exon 9 mutant 

(n�2). 12 pts received neoadjuvant imatinib (IM) therapy resulting in 6 

PR, 3 SD, 1 PD. 17 pts received adjuvant IM therapy. With a median FU of 

32 months (1-250), 95 pts (86%) are alive. Twenty-eight (26%) pts 

relapsed: 6 LR, and 26 metastases. The 4-year OS and EFS rates were 

89.5% and 68.2 %. The 6-year OS and EFS rates were 89.5% and 36.5%. 

Univariate analysis showed that: age and ECOG PS have an impact on OS 

(p� 0.008, p �0.001), necrosis, spindle-cell type, T size, mitoses/50 

HPF, and Miettinen risk were predictive of relapse (p� 0.001). In 

multivariate analysis tumor size and mitoses/ 50 HPF only were predictive 

of relapse (p� 0.001). Conclusions: Pts with resected duodenal GIST have 

a reasonably favourable prognosis. LR rather than DP should be pursued if 

possible to preserve optimal pancreas function. Neoadjuvant IM may 

potentially allow a proportion of patients requiring DP to undergo LR. 

Adjuvant IM should be systematically discussed with a patient based on the 

individual-risk of recurrence. 

Sarcoma 

649s 


Association of the genetic variants in the nucleotide excision repair genes 

XPA and XPC with cisplatin-induced hearing loss in patients with osteosarcoma. 

Presenting Author: Melanie M. Hagleitner, Radboud University 

Medical Centre, Nijmegen, Netherlands 

Background: Cisplatin is a widely used and effective chemotherapeutic 

agent in the treatment of osteosarcoma. However, cisplatin-induced 

ototoxicity is a serious problem, affecting more than 60% of patients and 

compromising language and cognitive development. Unfortunately, individuals 

at risk to develop ototoxicity cannot be identified upfront. Genetic 

variants in genes involved in the metabolism of cisplatin may predispose to 

cisplatin-induced hearing loss and help to identify patients at risk. 

Methods: In a candidate gene pathway approach, we selected 224 SNPs in 

30 candidate genes related to Platinum-DNA repair pathways and genotyped 

for a discovery group of 105 patients with osteosarcoma for these 

variants. Cisplatin-induced ototoxicity (n � 47), defined as the development 

of grade 2–4 hearing impairment using Common Terminology Criteria 

for Adverse Events (CTCAE version 3), showing a hearing loss of �25 dB at 

frequencies of 4–8 kHz, was associated with genetic variation. A replication 

study was performed in a independent cohort of 51 patients with 

osteosarcoma. Genotyping was performed using the Illumina GoldenGate 

assay. Association analysis and meta-analysis were performed using the 

whole genome association analysis toolset PLINK. Results: In the discovery 

cohort a total of 13 SNPs were significantly (p value � 0.05) associated 

with ototoxicity. Upon meta-analysis, addition of the replication set 

resulted in lower p-values for 2 SNPs. The two SNPs showing a strong 

association with hearing loss in patients with osteosarcoma were rs2805835 

in the gene XPA (p-value 0.01, OR�2.7 (95%CI: 1.20-6.15) and 

rs2227999 in XPC (p-value 0.02; OR�3.2 (95% CI:1.19-8.80). 

Conclusions: The Nucleotide Excision Repair (NER) genes XPA and XPC 

form an important molecular mechanism by which cisplatin DNA adducts 

can be repaired and it has recently been shown that these genes have a high 

expression in the cochlea. Our data suggest that genetic variants in these 

genes, may contribute to cisplatin ototoxicity. This study should be viewed 

as the first step in the development of genetic markers to predict 

cisplatin-induced ototoxicity in individual patients. 


Relationship of CUL4A gene underexpression and prognosis in localized 

high-risk soft tissue sarcoma (STS) patients of limbs or trunk wall. 

Presenting Author: Javier Martin Broto, Hospital Universitario Son Espases, 

Palma de Mallorca, Spain 

Background: Genes involved in cell cycle checkpoints and chromosome 

stability seem to be relevant in distant metastases appearance in STS. 

CUL4A is an E3 ubiquitin ligase that has been related to both p16 

activation and maintenance of genomic stability. Expression of CUL4A has 

been scarcely described in some tumors with divergent outcome and there 

are no publications regarding its expression in STS patients. We previously 

showed that protein underexpression of CUL4A in metastatic STS was 

related to poor survival. Methods: The expression level of CUL4A was 

determined by quantitative qPCR and was retrospectively performed in a 

subset of 39 high-risk (grade 3, deep tumours and � than 5 cm) localized 

STS of limbs or trunk wall patients for which histological material and 

clinical data were available. Patients of this series were enrolled prospectively 

into a randomized clinical trial conducted by the Italian and Spanish 

sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of epirrubicin 

and ifosfamide. Differences in PFS, RFS, and OS were calculated using 

log-rank test Results: The median age was 51 years with a median follow-up 

of 52 months. The pathologic subtypes were undifferentiated pleomorphic 

sarcoma (35.3%), synovial sarcoma (23.5%) and mixed subtypes (41.2%). 

Location was distributed as inferior limbs (66.6%), upper limbs (25.5%) 

and trunk wall (7.9%). No relationship was seen between CUL4A expression 

and clinical variables (histologic types, location, size or response to 

neoadjuvant treatment). The expression level of CUL4A was significantly 

associated with events of progression, 65% vs 32%, p �0.037, for 

expression values under and over the median respectively. Regarding 4 y 

actuarial survival, there was a significant worse PFS and RFS for patients 

underexpressing CUL4A (p�0.041 and 0.009 respectively) and a trend 

towards worse OS (p�0.056). Conclusions: Expression of CUL4A gene 

shows a prognostic role in sarcomas within this high risk localized subset of 

STS patients. The outcome of this exploratory analysis is aligned with our 

hypothesis that genes implicated in cell cycle regulation and chromosome 

stability could play a relevant prognostic role in STS. 


650s Sarcoma 


Results of pulmonary metastasectomy for osteosarcoma in the pediatric 

age group. Presenting Author: Bassam Redwan, Division of Thoracic 

Surgery, University Hospital of Muenster, Muenster, Germany 

Background: Despite multimodal treatment concepts and complete surgical 

resection, prognosis in pediatric patients with pulmonary metastases from 

osteosarcoma has remained limited due to frequent relapse of disease. We 

investigated the results of an aggressive surgical approach. Methods: In a 

retrospective study, procedures and outcomes of pulmonary metastasectomy 

in the pediatric age group (up to 18 years) at our institution were 

analyzed over a period of 10 years (1999-2009). Resection of the primary 

osteogenic tumor and chemotherapy (CROSS-96-protocol and EURAMOS- 

1-protocol) were performed prior to thoracic surgery. Results: Forty-five 

pediatric patients (20 females) underwent pulmonary metastasectomies 

via sternotomy or sequential anterolateral thoracotomy at a mean age of 14 

(6 -18) years. At primary surgery, a mean number of 7.9 (1 – 53) palpable 

suspicious lesions were resected per patient. Histo-pathological evaluation 

revealed 3.7 (0 – 40) metastases per patient. Mean total duration of surgery 

was 152 (46–323) minutes. Mean hospital stay was 10 days (3 – 33). 

In-hospital and 30-day mortality was 0%. The overall survival at 1 and 5 

years was 97.8% and 77.3%, respectively. Mean disease-free-survival was 

12.2 (3.2-38.0) months. In 19 (42.2 %) patients recurrent pulmonary 

metastases were detected and re-thoracotomies were required. Up to 7 

procedures per patient were performed. Overall survival for patients 

undergoing more than one surgical procedure for recurrent lung metastases 

was not statistically different from survival in patients without relapse (p � 

0.05). Survival was significantly better in patients initially presenting with 

less than 10 metastases (85.3 % vs. 54.1 % at 5 years, p � 0.028). 

Conclusions: Complete pulmonary metastasectomies are essential in pediatric 

osteosarcoma patients with lung metastasis. Repeated resections for 

recurrent relapses improve survival and may allow for long-term event-freesurvival. 


Multimodality treatment of pediatric and adult patients with Ewing sarcoma: 

A single-institution experience. Presenting Author: David Lorente, 

Medical Oncology Department, Valencia, Spain 

Background: Treatment of Ewing sarcoma pts. usually follows pediatric 

protocols, both in children and in adults. However, older patients fare 

poorly in most series. We analyze our experience with the 2001 protocol of 

the Spanish Society of Pediatric Oncology. Methods: Retrospective analysis. 

Schema: 6 cycles (cy) of VIDE chemotherapy (CT: vincristine, ifosfamide, 

etoposide, doxorrubicin). If no progression, local treatment (surgery 

or RT) and consolidation adjusted to risk: VACx8 (vincristine, dactinomycin, 

ciclophosphamyde) in standard-risk pts; if increased risk (axial, 

complete response in lung metastases or non-pulmonary metastases) 

VACx1, high-dose CT (busulphan-melphalan) and autologous transplant 

(ATSP). Analysis: induction CT toxicity, pathological response rates, 

consolidation treatment, disease-free (DFS) and overall survival (OS) 

(Kaplan- Meier). Log-rank and Cox regression analysis of prognostic factors 

in OS. Results: 35 patients (01.2003-05.2011). 60% male. Median age 

16 y (r 7-57). Axial (43%), extremities (34%), extra-osseous (18%) and 

ribs (9%). Metastases: 54% (lung 58%, bone 26%, others 12%). � 1 

location: 29%. Induction CT: 83% received 6 cy. 6% early progressions 

and 3% toxic deaths. 196 cycles of CT. Dose reduction (etoposide) in 60%. 

Grade 3-4 toxicity: neutropenia 13%, anemia 14%, neutropenic fever 

13%, diarrhoea-stomatitis 7%.Local treatment: surgery (49%), radiotherapy 

(29%), none (22%). In 17 resections, � 90% necrosis in 53%. 

Consolidation: VACx8 29%; VACx1-ATSP in 34%; 37% other treatments 

(progression). No ATSP-related mortality. Median follow-up: 36 m ( 5-101 

m). Median DFS 25 m (16-34 m). Median OS 28 m (15-41 m), 3-year OS 

40%. Median time to progression 7 m (0.4-15 m). Median OS from 

progression 7 m (0.4-15 m). Age � 15 years, a non-axial primary and no 

extra-pulmonary metastases were favourable prognostic factors in the 

univariate analysis. Conclusions: Induction CT with the VIDE regimen is 

feasible in most patients, with a low risk of early progression. Hematological 

toxicity is substantial but manageable. Adults patients have a worse 

prognosis compared to pediatric patients. Unfortunately, survival after 

progression is dismal. 


EURAMOS-1 study: Recruitment, characteristics, and initial treatment of 

more than 2,000 patients (pts) with high-grade osteosarcoma. Presenting 

Author: Jeremy Whelan, University College Hospital, London, United 

Kingdom 

Background: EURAMOS is a transAtlantic collaboration formed to improve 

survival in osteosarcoma by conducting RCTs in a clinically relevant 

timeframe. EURAMOS-1, the largest study conducted in this rare cancer, 

has completed accrual. It includes two randomized comparisons investigating 

treatment optimization on the basis of histological response to 

neoadjuvant chemotherapy. Methods: Pts �40yrs with resectable, high 

grade extremity or axial osteosarcoma were eligible for registration. All were 

planned for 2 cycles of neoadjuvant methotrexate, doxorubicin, cisplatin 

(MAP) then surgical resection of the primary tumour. Pts with complete 

macroscopic resection and no disease progression were eligible for randomization: 

[i] “good responders”, �10% viable tumor, MAP �/- 18m 

maintenance pegylated interferon; [ii] “poor responders”, �10% viable 

tumor, MAP vs MAPIE (MAP � ifosfamide, etoposide). Target sample size 

was ~1,260 pts randomized requiring ~2000 pts registered estimating a 

non-randomization rate of 30-35%. Results: From Apr 2005 to Dec 2011, 

2,260 pts were registered and 1,332 randomized from 17 countries, 320 

sites: median age 14yrs (IQR 11-17); 59% male; 50% femoral site; 23% 

definite/possible metastases; 92% conventional osteosarcoma (diagnostic 

biopsy). At Sep 2011 planned IDMC review, neoadjuvant treatment data 

were known for 2024 pts; 1926 (95%) completed 2 cycles pre-operative 

MAP with 3 treatment related deaths. 59% pts were randomized; nonconsent 

was the most frequent reason for non-randomization. Relative to 

expected age-specific incidence (UK NCIN 1979-2007) there was apparent 

under recruiting of older pts: females �15yrs and all pts �19yrs, with 

greater under recruitment of females than males �35yrs. Pts 20-29yrs 

were less likely to be randomized than those aged 5-19 and �30 yrs, 52% 

vs 57-62%. Conclusions: EURAMOS-1 demonstrates that large RCTs are 

feasible in rare cancers with inter-continental collaboration and is a model 

for future trials. Neoadjuvant MAP was safe in a geographically diverse 

cohort. Improving clinical trial access and randomization rates for young 

people is still required. Multiple funders detailed at bit.ly/ymUR9w. 


A retrospective safety analysis of adult patients treated with high-dose 

methotrexate for osteosarcoma in Stockholm, Sweden. Presenting Author: 

Daniel Alm, Oncology, Stockholm, Sweden 

Background: Patients with osteosarcoma are routinely treated with pre- and 

post-operative chemotherapy that includes high-dose methotrexate. The 

treatment is associated with a risk of severe renal and hepatic toxicity. 

Methods: All patients with osteosarcoma that had received at least one cycle 

of high-dose methotrexate at the adult oncology department, Karolinska 

University Hospital were retrospectively identified. Treatment toxicity, 

including hematologic, renal, hepatic toxicity, infections and oral mucositis 

were registered and graded according to CTCAE v 4.0. A possible 

relationship between methotrexate blood concentration and toxicity was 

investigated. Results: Sixteen eligible patients that had received a total of 

103 cycles of high-dose methotrexate were identified. Ten patients 

experienced a severe hepatic toxicity, (Grade 3, n�5 and Grade 4, n�5). 

Grade 3 renal toxicity was seen in one patient and although reversible, it led 

to treatment interruption. Reversible, grade 2 elavation of serum creatinine 

occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 

patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia 

was a common event (Grade 3, n�5 and Grade 4, n�2) but no 

severe bleeding complications were observed. One patient died as a result 

of multi-organ failure two days after methotrexate administration. Methotrexate 

blood concentration at 24 hours from administration could predict 

for renal toxicity (p�0.005, by chi-square test), but not for other toxicity. 

Conclusions: High-dose methotrexate in adult patients with osteosarcoma 

was frequently associated with severe, however reversible toxicity. 



Activity of MK1775, a selective Wee1 inhibitor, alone or in combination 

with gemcitabine, in sarcomas. Presenting Author: Jenny Kreahling, H. Lee 


Background: Sarcomas consist of more than 50 subtypes of mesenchymal 

tumors. Doxorubicin alone or in combination has been the primary therapy 

for treatment of sarcomas; however, the response rates are suboptimal in 

many of the more common adult subtypes of soft tissue sarcoma. 

Accordingly, new agents are needed for the treatment of this heterogeneous 

group of diseases. Wee1 is a critical component of the G2/M cell cycle 

checkpoint control and mediates cell cycle arrest by regulating the 

phosphorylation of CDC2. Methods: MK1775 treatment of multiple sarcoma 

preclinical models at clinically relevant concentrations leads to 

unscheduled entry into mitosis and initiation of apoptotic cell death. In our 

current study we have investigated the therapeutic efficacy of MK1775 in 

sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo in a 

xenograft model of osteosarcoma both alone and in combination with 

gemcitabine. Results: In patient-derived bone and soft tissue sarcoma 

samples ex vivo treatments show MK1775 in combination with gemcitabine 

causes significant apoptotic cell death suggesting that this treatment 

may represent a novel approach in the treatment of sarcomas. The cytotoxic 

effect of Wee1 inhibition on sarcoma cells appears to be independent of 

p53 mutational status. Furthermore, in a patient-derived osteosarcoma 

xenograft mouse model we show the therapeutic efficacy of MK1775 in vivo 

by utilizing magnetic resonance imaging (MRI) and diffusion MRI methods. 

Our data shows MK1775 in combination with gemcitabine dramatically 

slows tumor growth, increases apoptotic cell death and increases CDC2 

activity. Cell viability, a clinically established prognostic indicator of 

survival, was lowest with the combination and very low in animals treated 

with MK1775 alone. This was mainly due to increased mineralization of the 

tumors. Caspase-3 was increased in MK1775 treated animals by immunohistochemistry 

as well. Conclusions: These results together with the 

promising safety profile of MK1775 strongly suggest that this drug can be 

used as a potential therapeutic agent alone or in combination with 

gemcitabine in the treatment of both adult as well as pediatric sarcoma 

patients. 


Early assessment of MCV to predict clinical outcome in patients with 

advanced gastrointestinal stromal tumors (GIST) receiving imatinib. Presenting 

Author: Anastasia Constantinidou, The Royal Marsden Hospital NHS 

Foundation Trust and the Institute of Cancer Research, London, United 

Kingdom 

Background: In patients with advanced GIST, imatinib trough levels have 

been associated with a lower rate of clinical benefit. Anecdotal observations 

have suggested that commencing treatment with imatinib may be associated 

with an increase in red blood cell size as measured by MCV and MCH, 

indicating the effect of imatinib on KIT signalling in the bone marrow. 

Methods: In this retrospective review we examined a possible connection 

between changes in MCV and MCH after the first 3 months (mo) of 

treatment with imatinib and progression-free survival (PFS). Data for 

patients with inoperable advanced or metastatic GIST treated between 

2000 and 2011 were available for analysis. Patients were categorised in 

quartiles according to the distribution of the percentage of change of MCV 

and MCH between start of imatinib (baseline) and 3 (�/- 0.5) mo (ratio 

%�MCV change at 3 mo/MCV at baseline). PFS curves were plotted using 

the Kaplan-Meier method and compared using the log rank test. Results: 

One hundred and thirty patients were eligible for analysis and the 

demographics were: male:female 84:46, median age at presentation: 60.5 

(23.5-86.5) years, commonest primary tumour sites: stomach (72/130) 

and small bowel (44/130), commonest metastatic site: liver (76/130). In 

the patients with a 10% or over increase in MCV (p75-p100) at the 3 mo 

(�/-0.5) time point a significantly longer PFS was observed compared to 

those with a smaller magnitude of change (PFS of 37.1 mo vs 24.3 mo, 

p�0.032). A similar trend although not statistically significant was 

observed in patients with MCH of 15% or over (p75-p100) with PFS of 

34.0 mo vs 25.8 (p�0.125). The two parameters (MCV and MCH) showed 

a high correlation of percentage change (r2�0.85). The patients with a 

10% MCV increase and /or 15% MCH increase (total�40) showed a 

significantly longer PFS (34.0 mo) compared to those with lower percentage 

change (PFS� 24.3) p�0.035. Conclusions: Simple laboratory parameters 

may be indicators of imatinib pharmacokinetics and may therefore be 

used as surrogate markers of clinical outcome. Larger prospective studies 

are required to confirm the results of this study. 

Sarcoma 

651s 


Pharmacokinetics of escalated dose of imatinib in patients with advanced 

gastrointestinal stromal tumors. Presenting Author: Changhoon Yoo, Department 

of Oncology, Asan Medical Center, University of Ulsan College of 

Medicine, Seoul, South Korea 

Background: Although escalated dose (ED, 800 mg daily) of imatinib (IM) is 

one of important options in resistant gastrointestinal stromal tumors (GIST) 

on standard dose (SD, 400mg daily), there has been lack of pharmacokinetic 

data at ED. We therefore explore the potential relationship between 

IM plasma trough level (Cmin), and clinical outcomes or toxicities in 

patients treated with ED. Methods: Between 2008 and 2011, steady-state 

IM Cmin was measured in 66 patients with GIST who received ED of IM 

using liquid chromatography-tandem mass spectrometry. Percent change 

from IM Cmin at SD was calculated in 43 patients that both SD and ED IM 

Cmin were measured. The association with efficacy and toxicity was 

analyzed with grouping patients into quartiles according to IM Cmin at ED 

and percent change. Results: Median age was 59 years (range, 36–77) and 

40 patients were male. KIT exon 11 and 9 mutation was detected in 32 and 

18 patients, respectively. At ED, partial response was achieved in 4 

patients (6%) and stable disease was in 32 patients (48%). The median 

progression-free survival was 4.2 months (95% CI, 1.8-6.6) and overall 

survival was 38.5 months (95% CI, 7.6-69.3). The mean (� standard 

deviation) IM Cmin at ED was 3552 (� 1540) ng/mL. IM Cmin was 

significantly increased after dose escalation (p �0.001), and mean percent 

change from IM Cmin at SD was 162% (� 100). Body surface area 

(p�0.01), hemoglobin (p�0.001), and neutrophil count (p�0.006) were 

significant covariates for IM Cmin at ED in multivariate analysis. The group 

of quartiles of IM Cmin at ED and percent change was not associated with 

response and survival outcomes. However, grade 3-4 hematologic or grade 

2-4 non-hematologic toxicity was observed in 9% (1/11) of patients in the 

lowest percent change quartile (Q1, �90%) compared with 56% (18/32) 

in Q2 to Q4 (p�0.012), although absolute values were not associated with 

toxicity. Conclusions: In GIST patients treated with ED of IM, IM Cmin was 

not associated with response and survival. Clinically significant toxicity 

following dose escalation was correlated with percent change of IM Cmin, rather than absolute values. Monitoring of IM Cmin might help to predict or 

manage ED of IM induced toxicity. 


SDHA and SDHB mutations in KIT/PDGFRA WT gastrointestinal stromal 

tumors. Presenting Author: Margherita Nannini, Seragnoli Department and 

GIST Study Group, University of Bologna, Bologna, Italy 

Background: KIT/PDGFRA wild-type (WT) GISTs harbour mutations on 

SDHB and SDHC and, more recently, we described mutations on SDHA 

using massively parallel sequencing approach. We sequenced SDHA and 

SDHB genes in a larger series in order to validate the data. Methods: SDHA 

gene (1-15 exons) and SDHB gene (1-8 exons) (even not all exons in all 

samples) were sequenced on tumor (T) and/or peripheral blood (PB) of WT 

GIST patients by Sanger Sequencing method. DNA was extracted from 

tumor specimens by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) and 

amplified with specific primer pairs designed to amplify exons but not 

SDHA pseudo-genes located on chromosomes 3 and 5. Then, PCR products 

were purified with the Qiaquick PCR purification kit (Qiagen, Milan, Italy) 

and sequenced on both strands using the Big Dye Terminator v1.1 Cycle 

Sequencing kit (Applied Biosystems). Sanger sequencing was performed 

on ABI 3730 Genetic Analyzer (Applied Biosystems). Results: SDHA gene 

exons were sequenced on a total of 27 WT GIST patients, in particular on T, 

PB and both from 12, 6 and 9 patients respectively. SDHB gene exons were 

sequenced on a total of 18 out of 27 patients, in particular on T, PB and 

both from 7, 8 and 3 patients respectively. 8 SDHA mutations were found 

in 5 samples (18.5%). Besides those previously identified, 5 new SDHA 

mutations were found in other 3 samples: one sample harboured R171C 

and R589Q heterozygous missense mutation in exons 5 and 13 respectively. 

The other one harboured G419R and E564K heterozygous missense 

mutations in exons 9 and 13 respectively. The third sample harboured a 

delCAG immediately upstream of exon 5, in heterozygosis on PB and in 

homozygosis on T. A SDHB heterozygous mutation (301delT) in exon 4 was 

found on 1 PB sample. Conclusions: the presence of SDHA mutations has 

been confirmed in a subgroup of WT GIST patients. All subunits of SDH 

complex should be sequenced on WT GIST patients in order to explore the 

frequency and any linkage between each other and the pathogenetic and 

clinical significance. 


652s Sarcoma 


Diagnosis and initial evaluation of patients with gastrointestinal stromal 

tumor (GIST): An observational study of 1,226 patients. Presenting Author: 

Jonathan C. Trent, University of Miami Sylvester Comprehensive Cancer 

Center, Miami, FL 

Background: The GIST registry (reGISTry) is an observational database 

designed to determine diagnostic method and evaluation of GIST patients 

outside of clinical trials. We previously described differences in treatment 

of patients in community versus academic centers (Pisters, Ann Oncol 

2011;22:2523-9). Herein we present distinct differences in the diagnosis 

and initial evaluation of patients with GIST. Methods: The analysis cutoff 

date was May 2010. Patient demographics, presenting symptoms, diagnostic 

methodology, and KIT and PDFGRA mutations were described. For 

localized tumors, size and mitotic index (MI) were collected. Results: 1226 

patients were included in this analysis. Initial diagnosis was most commonly 

made by surgeons (54.6%) and gastroenterologists (15.7%). Primary 

management decisions were made at time of diagnosis by medical 

oncologists (53%) and surgeons (53%) (sum �100% due to �1 responses/ 

site). 84% were symptomatic at diagnosis, while 16% were diagnosed 

incidentally. Diagnostic procedure was performed during surgery (75%) 

and/or by endoscopy (22%) or interventional radiology (11%) using 

percutaneous core biopsy or fine needle aspirate. Initial diagnostic imaging 

was by CT scan (76%), endoscopy (25%), ultrasound (12%), or a 

combination. Most primary GISTs were located in the stomach (55%) or 

small intestine (28%). At diagnosis, localized and metastatic disease was 

seen in 83% and 17% of patients, respectively, with metastases mainly in 

the liver (62%) and/or peritoneum (36%). KIT immunostaining was 

performed in 93% of patients, with 98% positive. Mutation analysis was 

carried out in 8% of cases (57% KIT exon 11 and 12% exon 9 mutations). 

Of localized primary tumors, 52% were �5 cm in size and 23% had �5 

mitoses per 50 high-power fields. Conclusions: We found that initial 

diagnosis is made by several different modalities. The majority of GIST 

patients are managed by medical and surgical oncologists. Most patients 

with localized tumor were at intermediate risk of recurrence and would be 

considered for adjuvant imatinib therapy. 


Outcomes of multivisceral resection of gastric gastrointestinal stromal 

tumors. Presenting Author: Sabha Ganai, University of Chicago Medical 

Center, Chicago, IL 

Background: Despite the recent introduction of imatinib and laparoendoscopic 

techniques to the management of gastric gastrointestinal stromal 

tumors (GISTs), outcomes remain uncertain in the setting of multivisceral 

involvement. Methods: We conducted a retrospective review of 73 consecutive 

patients who underwent resection of gastric GISTs from October 2002 

through December 2011. Median follow-up was 22 months (interquartile 

range [IQR] 6-37). Results: Patients were 51% female, with a mean age of 

65 � 12 years and BMI of 30 � 8 kg/m2 . Patients undergoing multivisceral 

resection (n�14) had a longer interval from diagnosis to surgery (7.3 [IQR 

1.9 – 15.0] vs. 1.3 [IQR 0.7-4.2] months, p�0.01), greater use of 

neoadjuvant imatinib (64% vs. 3%, p�0.0001), and greater preoperative 

tumor size (12 � 8 vs. 4 � 3 cm, p�0.0001) in comparison to gastric-only 

resections (n�59). Patients were less likely to be managed laparoscopically 

(7% vs. 71%, p�0.0001), had a longer operative time (310 � 117 

vs. 145 � 62 min, p�0.0001), and were less likely to be R0 (71% vs. 

98%, p�0.001). While patients undergoing multivisceral resection were 

more likely to have a pathological complete response to therapy (29% vs. 0, 

p�0.001), they were also more likely to have metastatic disease present 

(29% vs. 0, p�0.001). Hospital length of stay was greater (median 8 [IQR 

6-9] vs. 3 [IQR 2-6] days, p�0.0001). There were no significant differences 

in grade or mitotic index between groups. There was greater use of 

adjuvant imatinib (64% vs. 25%, p�0.05). Overall survival was less in 

patients undergoing multivisceral resection (64% vs. 87% at 3 years, 

p�0.05), as was disease-free survival (52% vs. 71% at 3 years, p�0.05). 

Median overall and disease-free survival were 43 and 22 months after 

multivisceral resection for gastric GISTs. Controlling for tumor size, grade, 

resection status, and the use of neoadjuvant imatinib, multivisceral 

resection and use of adjuvant imatinib were both independent predictors of 

disease-free survival (p�0.05). Conclusions: Multivisceral involvement is 

associated with tumors of greater size and, despite an increased use of 

neoadjuvant imatinib, it is associated with poor outcome for patients with 

gastric GISTs. 


Masitinib in imatinib-naive advanced gastrointestinal stromal tumor (GIST): 

Five-year follow-up of the French Sarcoma Group phase II trial. Presenting 

Author: Axel Le Cesne, Institut Gustave Roussy, Villejuif, France 

Background: Masitinib is a tyrosine kinase inhibitor that in vitro has greater 

activity and selectivity than imatinib against KIT. This multicenter, open 

label, phase 2 study evaluated efficacy and safety of masitinib as a first-line 

treatment of advanced GIST. Initial results with a median follow-up of 34 

months, were previously reported in EJC 2010. We present here 5-year 

follow-up data from the same series with updated safety and survival data. 

Methods: Imatinib-naïve patients (pts) with inoperable, advanced GIST 

received oral masitinib (7.5 mg/kg/day) until progression, refusal or 

toxicity. Results: Thirty pts with a median age of 58 years (60% of males) 

were included from 06/2005 to 04/2007 in 5 institutions. At the cut-off 

date of 13/09/2011, 7/30 pts (23%) were still under treatment with 

median follow-up of 65 months and the median overall survival (OS) had 

not yet been reached (NR). The 5-year OS rate was 61.5% (95% CI 

[41.1;76.6]) (see Table). Among patients with confirmed KIT exon 11 

mutation, 8/9 pts (89%) were still alive with one pt having died from 

non-treatment related causes (surgical complication) following a complete 

response while receiving masitinib. No additional progressions have been 

reported giving a total of 14 events (13 progressions and 1 death). Updated 

median PFS was 41.3 months (95% CI [17.5;53.8]).No additional grade 

3/4 adverse events have been reported. Conclusions: Long term results of 

masitinib confirm an interesting activity with prolonged PFS and OS. The 

median PFS rate in masitinib compares very favorably to that of imatinib, 

which is reported as 18 months (JCO 26:626, 2008). The 5-year OS rates 

for masitinib in the overall and exon 11 populations also compare favorably 

to imatinib, both of which are reported at �50% for imatinib (JCO 26:626, 

2008; JCO 28:1247, 2010). These results support the head to head 

comparison with imatinib in the currently ongoing phase 3 randomized 

clinical trial in first line advanced GIST pts. 

All (N�30) Exon 11 (n�9) 

Median OS (months) [95%CI] NR [53;NR] NR [65;NR] 

Month-36 86.5% [68.0;94.7] 88.9% [43.3;98.4] 

48 76.2% [56.4;87.9] 88.9% 

60 61.5% [41.1;76.6] 88.9% 

72 55.9% [34.7;72.6] 71.1% [23.3;92.3] 


Single-dimension CT measurements with RECIST 1.1 to evaluate liver 

metastases in GIST patients on imatinib. Presenting Author: Gaia Schiavon, 

Department of Medical Oncology, Erasmus University Medical Center - 

Daniel den Hoed Cancer Center, Rotterdam, Netherlands 

Background: Tumor response assessment to therapy is crucial in oncology, 

both in daily practice and research.We analyzed the morphology of liver 

metastases (LM) in gastrointestinal stromal tumors (GIST). Aims were to 1) 

determine whether uni-dimensional measurements of tumor lesions (according 

to RECIST 1.1) are accurate reflections of their volumes and 2) 

estimate eventual bias in volume change calculations, as introduced by 

using only the longest diameter. Methods: 78 GIST patients with LM were 

evaluated at baseline (n�139 lesions), 3 (n�129), 6 (n�128), and 12 

months (n�108) after imatinib therapy. LM were segmented semiautomatically 

on standard CT scans. All measurements at baseline were 

obtained by 2 independent investigators and agreement between observers 

was assessed with Bland-Altman plots. Values for segmented volume (Vs; 

mL), maximum transaxial diameter (MTD; mm), and elongation value (EV, 

defined as 1 - [width/length], where EV of 1 � fully ellipsoidal and 0 � fully 

spherical) were reported for each lesion at several time-points. A calculated 

volume (Vc) of each LM was also generated using the MTD, with the 

hypothesis that metastases were fully spherical. Results: At baseline, 44% 

(61/139) of the LM was spherical and 56% (78/139) was ellipsoidal. Their 

EV ranged from 0.08 to 0.94 (mean, 0.53�0.17). During treatment, 

overall 42% of the lesions kept their morphology (spherical or ellipsoidal) 

and the other half changed from spherical to ellipsoidal or vice versa. At 

baseline, there was strong inter-observer agreement in the determination of 

Vs, with mean inter-observer variability of 1.5% (95% CI, -14.5% to 

17.5%). The difference between Vs and Vc was highly significant 

(P�0.0001). Vc overestimates the actual volume of 35% (95% CI, -26% 

to 95%). Conclusions: LM are not always spherical and can change their 

morphology during imatinib therapy. Therefore, a lesion’s single largest 

trans-axial dimension, as used in RECIST 1.1, is not an accurate surrogate 

of its actual volume. Further studies are warranted to fully understand the 

clinical impact of these findings and to assess whether we should apply 

different criteria for response assessment to therapies in solid tumors. 



Explored prognostic factors for survival in patients with advanced GIST 

treated with standard dose imatinib (IM): Results from the BFR14 phase III 

trial of the French Sarcoma Group. Presenting Author: David Pérol, Centre 

Léon Berard, Lyon, France 

Background: Factors predicting progression free survival (PFS) and overall 

survival (OS) of patients (pts) with advanced GIST treated with 400 mg 

daily dose IM included in the BFR14 study with a median follow up of 54 

months (CI95%:47-61) was investigated evaluating added prognostic 

factors. Methods: 434 pts were included in this prospective multicenter 

trial from June 2002 to July 2009. After 1, 3 and 5 yrs of IM 400mg/day, 

pts free from progression were randomly offered to continue or interrupt (I 

arm) IM. Prognostic factors for overall survival were investigated in the 

entire cohort (randomized and not randomized pts) included in the BFR14. 

Survival was defined from the date of inclusion to the date of death for OS or 

to the first occurrence of disease progression under imatinib or death for 

PFS. A multivariate cox model including statistical significant baseline 

characteristics tested in univariate were included in a backward procedure 

d to identify independent prognostic factors for PFS then OS. Results: As of 

January 2012, there were 285 progressions (65%) and 161 deaths (37%). 

The median PFS of the entire cohort was 29 months (CI95%: 24-33) and 

the 4 and 5-yrs PFS were 31% and 24% respectively. A low tumour volume 

at inclusion, PS (0), sex (female), CD34 positivity on tumor cells were the 

four independent prognostic factors of a higher PFS. The 5-yrs OS was 54% 

(CI95%: 48-60). A higher OS was independently predicted by gender 

(female), PS (0), platelets count (�400 giga/L) and CD34 expression on 

GIST cells. Median PFS and OS were slightly superior in this more recent 

series as compared to B2222 consistently with the improved outcome of 

patients with low tumor volume. Conclusions: OS and PFS are predicted by 

gender, PS and CD34 expression in this large series of pts treated with 

standard dose IM. The biological significance of CD34 expression on tumor 

cells has to be explored in GIST. 


Characteristics of gastrointestinal stromal tumor (GIST) patients receiving 

short-term versus long-term imatinib (IM) adjuvant therapy: A chart review 

analysis. Presenting Author: Annie Guerin, Analysis Group, Inc., Boston, MA 

Background: In clinical practice, significant variability is seen in duration of 

adjuvant IM use. The objective of this study is to compare characteristics of GIST 

pts receiving adjuvant IM for a short (6-12 months) vs extended period (�24 

months) to better understand factors that may influence treatment (trt) duration 

decisions. Methods: Physician prescribing patterns and clinical information on 

adult pts with primary resectable Kit positive GIST initiating IM �84 days 

post-surgery was collected from 248 U.S. oncologists using online data 

collection forms. In addition to physicians’ perception of short- vs long-term use, 

pts’ risk assessment, trt, demographics, and comorbidities were collected for 

246 short-term and 395 long-term IM pts. Characteristics were compared using 

Wilcoxon and Chi-square tests. Results: While pts were similar in age [59.0 vs. 

58.1, P �.23], ethnicity, and region of residence, the short-term group included 

fewer males (57.7% vs 69.6%, P �.01) and had a higher prevalence of 

cardiovascular (11.4% vs 5.8%, P � .01) and ischemic heart diseases (5.3% vs 

1.5%, P�.01). Differences were also observed in indicators of pre-treatment risk 

profile (tumor size, location, and rupture during surgery, mitotic count, and 

Miettinen score) (Table). Findings were consistent with main reasons reported by 

physicians for prescribing adjuvant IM over longer duration; in addition to pt risk 

profile (76.6%), tolerability (70.6%), younger pts (59.7%), safety (39.1%), trt 

response (29.8%), and economic reasons (26.2%) were other reasons impacting 

trt decisions. Conclusions: Pt risk is an important factor in physicians’ decisions 

to prescribe adjuvant IM for extended duration. However, age, tolerability, and 

comorbidities, also play an important role. 

Long-term Short-term 

Tumor characteristics 

Size (mean � SD) 

Rupture during surgery, % 

8.2 � 7.0 7.2 � 7.6 * 

Yes 2.5 5.7 * 

No 91.9 92.3 

Unknown 

Location, % 

5.6 2.0 * 

Stomach 53.9 44.3 * 

Small intestine 29.6 27.6 

Rectum 1.3 2.0 

Other 15.2 26.0 * 

Miettinen risk (mean � SD) 

Mitotic rate (/HPF; %) 

0.4 � 0.3 0.3 � 0.3 * 

< 5 9.6 16.7 * 

5 30.9 33.3 

6–10 33.7 31.3 

>10 17.7 11.8 * 

N/A 

* Significant at 5% level. 

8.1 6.9 

Sarcoma 

653s 


The role of surgical cytoreduction before imatinib therapy in patients with 

advanced GIST. Presenting Author: Hojung An, Division of Medical 

Oncology, Asan Medical Center, Seoul, South Korea 

Background: Despite dramatic improvement of survival with introduction of 

imatinib mesylate, resistance to imatinib eventually develops in most of 

patients with advanced gastrointestinal stromal tumor (GIST). It is well 

known that baseline tumor size is an important factor related to imatinib 

resistance. We hypothesize that decreasing tumor size by surgery before 

starting imatinib may delay the emergence of resistance and improve 

prognosis in patients with advanced GIST. Methods: From 2001 to 2010, 

102 patients with initially metastatic GIST and 147 patients with recurrent 

GIST were enrolled in this analysis. Patients with local relapse only were 

excluded because they were potentially curable by surgery alone. Patients 

were categorized into two groups according to the extent of cytoreduction; 

i.e., patients whose initial tumor bulk reduced �75% surgically before 

starting imatinib (group A) and the others (group B). Results: Among total 

249 patients, 62 patients received initial surgery. 35 (14%) patients 

whose tumor bulk reduced � 75% were categorized into group A, and the 

remaining 214 (86%) were in group B. In group A, the median age was 

younger; more patients were initially metastatic; peritoneal metastases 

were more frequent; but liver metastases were less. The total tumor size was 

significantly reduced from median 122 mm before cytoreduction to 0 mm 

after on CT scans in group A. With a median follow-up of 42.7 months, 

progression-free survival (PFS) tended to be better in group A than in group 

B in univariate analysis (HR�0.60; 95% CI, 0.36-1.02; p�0.061), but 

PFS was not statistically different between the two groups in multivariate 

analysis (p�0.488). Meanwhile, absence of KIT exon 11 mutation 

(p�0.007), baseline total tumor size � 150mm (p�0.043), and granulocyte 

count � 5000/mm3 (p�0.009) remained independent poor prognostic 

factors. Conclusions: Despite marked decrease of total tumor size, the 

outcomes were not significantly improved in patients receiving initial 

cytoreduction more than 75% of baseline tumor bulk before starting 

imatinib. These results suggest that initial cytoreduction does not have 

beneficial role in advanced GIST, so imatinib should be still the first 

treatment of choice in this population. 


Effect of five years of imatinib on cure for patients with advanced GIST: 

Updated survival results from the prospective randomized phase III BFR14 

trial. Presenting Author: François Bertucci, Institut Paoli-Calmettes, Marseille, 

France 

Background: We previously demonstrated that interruption of imatinib (IM) 

after 1, 3, and 5 yrs in responding patients (pts) with advanced GIST is 

associated with rapid relapse but reintroduction of IM allowed tumor 

control in almost all pts. Here, we examined the outcome of patients 

randomized in the interruption arm (I arm), and notably the characteristics 

of those not yet progressing. Methods: This prospective multicenter BFR14 

study was initiated in June 2002 and closed for inclusion in July 2009. 

Seventy-one non-progressing patients were randomized in the I arm after 1 

(N�32), 3 (N�25) and 5 years (N�14) of IM 400 mg/day. IM (same dose) 

was reintroduced in case of progressive disease (PD). Results: The median 

follow-up (FU) from randomization was 74, 48 and 22 months for pts 

randomized at 1, 3 and 5 yrs of IM treatment respectively. Updated survival 

data (January 2012) are summarized in the table. Out of the 3 pts not 

progressing in the I arm at 1 yr, 1 pt had refused to stop IM and 1 pt had a 

localized GIST with small residual disease at inclusion. Out of the 3 pts not 

progressing in the I arm at 3 yrs, 1 pt had refused to stop IM and 2 pts were 

included after complete resection of both primary tumor and metastases 

with a small residual disease. The FU of pts randomized at 5 yrs was short 

but out of the 5 non progressive pts, 2 are considered in PD on functional 

imaging (January 2012), 2 had a locally advanced GIST subsequently 

operated during IM and before randomization, and 1 had no target lesion at 

inclusion (resection of synchronous metastases). Conclusions: All but one 

pts with residual masses under IM and randomized in the I arm have 

relapsed. Six out of 7 patients not yet progressing in the I arm had reached 

complete remission following surgery at inclusion or before randomization 

(initial resection/debulking of metastases). 

Parameter 1 yr 3 yrs 5 yrs 

Randomized pts (I/continuous [C] arms) 58 (32/28) 50 (25/25) 27 (14/13) 

Median PFS (months) I/C arms 

7/29 

9/49 

13/not reached 

(p) 

p�0.0001 

p�0.0001 

p�0.017 

2-y PFS (%) : I/C arms 13 [4-26] p / 11[2-27]p/80[58-91] 28[6-57]p/ 

62 [40-77] 

92 [54-99] 

No. pts non-progressive (I arm) (%) 3/32(9) 3/25(12) 5/14(35) 

Post-randomization FU (months) 64, 73, 90 23, 46, 54 2, 3, 17, 18, 25 


654s Sarcoma 


Analysis of the quality of reporting surgical procedures in patients undergoing 

resection for primary gastrointestinal stromal tumors: A reporting tool 

derived from the EORTC–STBSG 62024 trial. Presenting Author: Peter 

Hohenberger, Universitätsklinikum Mannheim, Mannheim, Germany 

Background: Features of surgery for the primary tumor (rupture, extent and 

completeness of resection) contribute significantly on the indication for 

adjuvant treatment in patients with GIST. No reporting tool for surgery for a 

primary GIST has been established. EORTC 62024 is a phase III trial 

evaluating the use of adjuvant imatinib in GIST and was used for an 

analysis of the data of surgical procedures. Methods: 908 pts. from 11 

countries were recruited. At study entry, a copy of the surgical record and 

pathology report had to be submitted in addition to the case record forms 

(CRFs) which included a surgical questionnaire on 19 items on the 

circumstances of the resection (elective/emergency, GIST diagnosis established 

preop., tumor rupture, R-status, concordance of preop. and intraop. 

staging, surgical technique, complications). We then reviewed the original 

documents and compared them with the documentation on the CRFs. The 

full set of data was available from 793/906 patients (87.3%). Results: The 

diagnosis of GIST was known preop. in 58% of the cases, and 12% of the 

pts. had been treated as an emergency. The R0 resection rate was 87%. 

The incidence of tumor rupture was 9% and 24% of the pts. had undergone 

lymphadenectomy. The consistency between pre- and intraoperative findings 

was 82%. The concordance between CRFs and original documents 

was 77%. Concordance of the original documents with the surgical 

questionnaire (CRFs) was critical in 4/19 items. Discrepancies and 

misinterpretation rates were highest when data managers from medical 

oncologists had completed the CRFs based on letters of patient discharge. 

Based on the evaluation, the surgical reporting tool can be refined and 

shortened to 13 items for future applications. Conclusions: Findings at 

surgery for the primary tumor not properly reported might significantly 

influence the decision of whether or not to treat patients with adjuvant 

imatinib. The refined surgical reporting tool could be helpful to gather all 

relevant information about the intraoperative elements of surgery for the 

primary GIST. Surgeons are to be asked to report those data themselves. 


Doxorubicin, cisplatin, and ifosfamide (API) as first-line therapy for 

relapsed or metastatic uterine leiomyosarcoma. Presenting Author: Julien 

Hadoux, Institut Gustave Roussy, Villejuif, France 

Background: Uterine leiomyosarcomas (ULMS) are rare gynecologic malignancies 

characterized by a poor prognosis due to a high rate of local and 

metastatic recurrences. Chemotherapy (CT) with doxorubicin or ifosfamide 

or both is associated with a 10 to 30% objective response rate (ORR) and a 

cisplatin-based multiCT approach achieved a good response rate (DECAV 

therapy: API � dacarbazine � vindesine, 54% ORR in uterine sarcomas), 

though toxic. We aimed to determine efficacy and toxicity of doxorubicin, 

cisplatin and ifosfamide (API) combination as first line treatment of 

metastatic or relapsed ULMS (MRULMS). Methods: This monocentric study 

included MRULMS pts with a physiological age � 65 y. CT consisted in 

doxorubicin 50 mg/m² d1, ifosfamide 3 g/m²/d d1d2 � mesna, cisplatin 75 

mg/m² d3, � G-CSF; q 3 weeks. Results: Results in 38 pts with MRULMS 

were analyzed; median age was 51 (40-64), median cycles of CT was 5; 8 

(21%) pts were treated for local relapse, 21 (55.3%) for metastatic disease 

and 9 (23.7%) for both. Metastatic sites were: lungs in 16 pts (42.1%), 

pelvis in 7 pts (18.4%), liver in 7 pts (18.4%), peritoneum in 6 pts 

(15.8%) and bone in 5 pts (13.2%); 14 pts (36.8%) had a multisite 

metastatic disease. Main grade 3-4 toxicities in 38 pts were neutropenia 

(74%), thrombopenia (60%), anemia (55%), fatigue (18%) and vomiting 

(13%). Febrile neutropenia was observed in 35% of pts and 1 patient died 

of septic shock after cycle 1. Thirty four pts were evaluable for response (4 

pts had complete surgery at relapse) and 16 pts responded (4 CR � 12 PR) 

(ORR: 47%); 23.5% and 29.4% of the pts had respectively stable and 

progressive disease. For all pts (38) and evaluable pts (34), median PFS 

were 9.8 and 9.5 months and OS 27 and 25.3 months respectively. 

Conclusions: Despite toxicity observed, API is an effective treatment which 

compares favorably with other first line therapies for MRULMS pts. 


Genome-wide analysis and characterization of an online sarcoma cohort. 

Presenting Author: Kimberly E. Barnholt, 23andMe, Inc., Mountain View, 

CA 

Background: Recruitment of an adequately sized cohort for genome-wide 

studies presents a serious challenge for rare diseases such as sarcoma. 

Traditional barriers to participation include proximity of clinical centers 

and motivation or ability to travel. 23andMe’s web-based platform provides 

increased accessibility to research participation, facilitating rapid recruitment 

of patients (pts) and enabling a large-scale genome-wide association 

study (GWAS) of sarcoma. Methods: Sarcoma pts were recruited through 

web and email campaigns, patient advocacy groups, physician offices, and 

events. Pts provide IRB-approved consent, complete surveys, and receive 

updates about research progress through an online account. In collaboration 

with an uncompensated panel of academic experts, an online survey 

was developed to collect patient-reported data on diagnosis, family history, 

symptoms and treatment. Results: This web-based approach has accrued 

the largest genotyped, recontactable sarcoma cohort to date. In 20 months, 

772 sarcoma pts have enrolled, 683 have been genotyped and 611 have 

provided data online. The cohort is primarily of European ancestry (92%), 

disproportionately female (72%), with an average age of 51 (� 15 years). 

More than 88% of pts indicated a soft tissue sarcoma diagnosis, with 

leiomyosarcoma, liposarcoma and “malignant fibrous histiocytoma” being 

the most commonly reported subtypes. Over 36% of pts report undergoing 

active treatment of some type. Association scans were conducted across a 

set of 8,058,452 imputed SNPs, using 568 unrelated sarcoma cases of 

European ancestry and �70,000 unrelated population controls from the 

23andMe database. Initial results have identified no significant genomewide 

associations for general sarcoma risk, despite having �90% power to 

detect risk variants with �5% minor allele frequency and odds ratio �2.5, 

suggesting the absence of common variants with strong shared effects 

across sarcoma subtypes. Conclusions: This pilot study demonstrates 

feasibility of rapid recruitment and longitudinal engagement of pts through 

online technology. Such techniques may significantly accelerate, and in 

some cases fully enable, large-scale genomic studies of sarcoma and other 

rare diseases. 


A phase Ib/II study evaluating the efficacy of doxorubicin (D) with or 

without a human anti-PDGFR� monoclonal antibody olaratumab (IMC- 

3G3) in the treatment of advanced soft tissue sarcoma (STS). Presenting 

Author: William D. Tap, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: PDGFR� is a receptor commonly overexpressed in STS. 

Olaratumab is a fully human IgG1 MAb which specifically binds to human 

PDGFR� and blocks PDGFR-mediated signaling pathways. Olaratumab 

demonstrated significant tumor inhibition as a monotherapy and in combination 

with standard chemotherapy in preclinical human sarcoma xenograft 

models. A Phase 1b/2 clinical trial for patients with advanced or 

metastatic STS is currently enrolling patients in 9 sites across the United 

States; approximately 45 patients have been randomized. Methods: In 

Phase 1b, patients received olaratumab (15 mg/kg) via intravenous 

infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour 

after olaratumab on Day 1. Phase 1b was completed without encountering 

dose-limiting toxicities; enrollment into Phase 2 has begun. The primary 

endpoint of the Phase 2 portion is to compare progression-free survival in 

patients with advanced STS when treated with D plus olaratumab versus D 

alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are 

required to be � 18 years old with ECOG 0-2, have appropriate organ 

function and histologically confirmed, measurable, and advanced STS. 

There is no restriction on the number of prior therapies. Patients are 

randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule 

as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. 

Upon completion of 8 cycles, patients in Arm A continue with olaratumab 

monotherapy. Patients in Arm B who develop disease progression during or 

after treatment can subsequently receive olaratumab monotherapy. Patients 

are stratified to treatment arms according to PDGFR� expression 

(positive vs. negative), number of previous lines of treatment, sarcoma 

subtype, and ECOG performance status. Response assessment occurs 

every 6 weeks. Exploratory analyses include biomarkers of olaratumab 

pharmacodynamic activity including PDGF ligands, PDGFR downstream 

molecules, VEGF, and changes in vascularity of tumor specimens. 



Randomized phase III, multicenter, open-label study comparing TH-302 in 

combination with doxorubicin versus doxorubicin alone in subjects with 

locally advanced unresectable or metastatic soft tissue sarcoma. Presenting 

Author: Sant P. Chawla, Sarcoma Oncology Center, Santa Monica, CA 

Background: A hypoxic microenvironment characterizes solid tumors including 

soft tissue sarcoma (STS) and is associated with chemotherapy 

resistance. TH-302, a prodrug of the alkylating agent bromo-isophosphoramide 

mustard (BR-IPM) is reduced in hypoxic environments, releasing 

Br-IPM. Combining D with TH-302 should effectively target both the 

normoxic and hypoxic regions of STS. TH-302 was investigated with 

full-dose D (75 mg/m2 ). The regimen was well tolerated, �60% completed 

6 cycles. DLTs at higher doses were infection with neutropenia and grade 4 

thrombocytopenia. The efficacy was higher than generally reported with 

single agent D (Sleijfer, The Oncologist, 2005). At MTD (75 mg/m2 D and 

300 mg/m2 TH-302) best response were 2 (2%) CR, 30 (34%) PR, 43 

(48%) SD. Median PFS and OS were 6.7 and 17.5 months, respectively. 

Based upon these data, a study (NCT01440088) is ongoing to assess the 

benefit of adding TH-302 to the standard D as first-line therapy of STS. 

Methods: The randomized (1:1) phase III study of TH-302 (300 mg/m2 ) 

with D versus D alone was initiated September 2011. Target goal is 450 

patients. TH-302 is administered IV over 30-60 minutes on Days 1 and 8 

(21-day cycle). D (75 mg/m2 , bolus or continuous) is administered Day 1 

starting 2-4 hrs after TH-302 when used in combination. Patients receiving 

TH-302 plus D without progression after 6 cycles may continue on TH-302 

alone. Key eligibility criteria: locally advanced unresectable or metastatic 

STS untreated with chemotherapy (adjuvant allowed), ECOG 0/1, measurable 

disease (RECIST 1.1) and adequate hematologic, hepatic, renal 

function. A FDA Special Protocol Agreement was reached on study design 

and analyses. Primary efficacy endpoint is overall survival (OS) comparison 

of the combination vs D. The study is designed to detect a 40% 

improvement in OS with 85% power and one-sided alpha of 2.5%. An 

interim futility PFS analysis is scheduled after 113 PFS events. Significant 

improvement in PFS (one-sided p � 0.10) is required to continue. A further 

analysis for early efficacy stoppage is scheduled after 175 OS events. IDMC 

will monitor safety and efficacy. 

TPS10102^ General Poster Session (Board #54G), Sun, 8:00 AM-12:00 PM 

Masitinib in comparison to imatinib as first-line therapy of patients with 

advanced gastrointestinal stromal tumor (GIST): A randomized phase III 

trial. Presenting Author: Antoine Adenis, Centre Oscar Lambret, Lille, 

France 

Background: Masitinib is an oral tyrosine kinase inhibitor (TKI) that has 

greater in vitro kinase activity and/or selectivity than imatinib against KIT 

and PDGFRA/B. A phase 2 study has previously reported that masitinib 

treatment produced clinically relevant activity in imatinib-naïve patients 

with advanced GIST. Considering the promising long term response 

observed in overall survival (OS) (see Table) there is compelling evidence to 

compare masitinib against imatinib (the current standard of care) in the 

first-line setting. Methods: A multicenter, randomized, open label, phase 3, 

1:1 study to compare efficacy and safety of masitinib (7.5 mg/kg/day) to the 

active control of imatinib (400 or 600 mg/day) in first-line treatment of 

patients with advanced GIST. Primary endpoint is progression-free survival 

(PFS), with secondary endpoints including OS, time to progression (TTP), 

and clinical response rates (RECIST). Based on a planned sample size of 

222 patients (111/arm) this 15% non-inferiority study was designed to 

have an 85% power using a 95% two-sided CI of the hazard ratio. Patient 

eligibility criteria include: histologically proven, metastatic or locally 

advanced nonresectable, or recurrent post-surgery GIST; TKI naïve patient 

or patient previously receiving imatinib only as a neoadjuvant or adjuvant 

therapy; and confirmed KIT-positive or PDGFRA-positive tumors. Recruitment 

is ongoing. On 09/2011, the DMC recommended continuation of this 

study. Clinicaltrial.gov: NCT00812240. 

Masitinib phase 2 a 

Imatinib phase 3 b 

{Meta-analysis data} c 

Dose 7.5 mg/kg/d 400 mg/d 800 mg/d 

Population, N 30 345 {818} 349 {822} 

Median follow-up (months) 65 54 

Median OS (months) [95%CI] Not reached [53; -] 55 {49} 51 {49} 

Month-12 97% 86% {90%} 86% {90%} 

24 90% 76% {80%} 72% {80%} 

36 87% 64% {60%} 62% {61%} 

48 76% 56% {56%} 56% {56%} 

60 62% 48% {45%} 49% {45%} 

Confirmed exon 11, n 9/30 (30%) 283/397 (71%) d 

Median OS(months) [95%CI] Not reached [65; -] 60 

Month-12 100% 93% 

24 89% 80% 

36 89% 70% 

48 89% 63% 

60 89% 51% 

a Blay, JCO 29: 2011 (suppl 4; abst 85); b Blanke, JCO 2008, 26:626; c GSTMA Group. JCO 2010, 28:1247; d 

Heinrich, JCO 2008, 26:5360. 

Sarcoma 

655s 


Randomized multicenter phase III trial of trabectedin (T) versus doxorubicinbased 

chemotherapy as first-line therapy in patients with translocationrelated 

sarcoma (TRS). Presenting Author: Jean-Yves Blay, Centre Léon 

Bérard, Lyon, France 

Background: One third of sarcoma histotypes have specific chromosomal 

translocations which result in abnormal transcription factors, integral to the 

change to a malignant phenotype. T is the first of a new class of anti-tumor 

agents with a transcription-targeted mechanism of action. In vitro evidence 

exists of the ability of T to interfere with the aberrant transcription factor’s 

binding to DNA promoters in TRS. Patients with TRS, such as myxoid/round 

cell liposarcomas (MRCL) have benefited from long-lasting tumor control in 

response to T. Methods: A randomized, phase III study of T (1.5 mg/m2 in 

24-h intravenous infusion every 3 weeks [q3wk]) vs doxorubicin 75 mg/m2 q3wk, or doxorubicin 60 mg/m2 with ifosfamide 6-9 g/m2 q3wk) as first line 

treatment in patients with advanced TRS. Primary aim: to determine the 

efficacy of T vs doxorubicin-based therapy by comparing progression-free 

survival (PFS) in each arm. Secondary aims: comparison of PFS rates at six 

months, response rate (RR), PFS and RR by histological type (MRCL vs 

other subtypes), overall survival, safety, exploratory response evaluation by 

Choi criteria and pharmacogenomic analyses. Patients with confirmed TRS 

of the following subtypes: MRCL, alveolar soft part sarcoma,angiomatoid 

fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell 

tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid 

sarcoma,myxoid chondrosarcoma and synovial sarcoma, are stratified by 

performance status (PS 0 vs 1-2) and sarcoma subtype (MRCL vs other 

subtypes) and randomized (1:1 ratio) to T or doxorubicin � ifosfamide. 

Confirmation of the translocation by fluorescence in situ hybridization is 

compulsory for inclusion in the primary efficacy analysis. An adaptive 

design was chosen to test the reduction in relative risk of progression or 

death with T, an interim analysis will be conducted with 45 PFS events 

from 80 evaluable patients. To date 117 patients have been enrolled from 

six countries and 29 centers. An independent data monitoring committee 

met on 15 November 2011 and concluded that the trial should continue as 

planned. 


Randomized multicenter double-blind phase II trial: The immunological 

adjuvant OPT-821 with or without a trivalent ganglioside vaccine in 

metastatic sarcoma patients following metastasectomy. Presenting Author: 

Richard D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York, 

NY 

Background: The gangliosides GM2, GD2, and GD3 are strongly expressed 

in sarcoma and represent novel antitumor targets. We have demonstrated 

the safety and immunogenicity of individual monovalent ganglioside 

conjugate vaccines when administered with OPT821, a synthetic saponin 

adjuvant that augments the T-cell response. Antitumor effects are observed 

with anti-ganglioside antibodies in preclinical models, with greatest benefit 

seen in the micrometastatic setting. Patients (pts) with metastatic sarcoma 

rendered disease-free by surgery are at high risk for disease recurrence, 

with no therapy demonstrated to improve outcomes. Therefore, this 

population is ideally suited to test the efficacy of vaccine induced 

anti-ganglioside antibodies. We thus initiated this randomized doubleblind 

phase II study of OPT821 with or without a trivalent ganglioside 

vaccine composed of GM2, GD2 lactone and GD3 lactone conjugated to 

KLH, an immunogenic carrier protein. Methods: A total of 134 pts will be 

randomized on a 1:1 basis stratified by disease state (relapsed disease vs 

metastasis at time of diagnosis), disease-free interval and number of 

relapses. Key inclusion criteria include stage IV sarcoma (locoregional 

recurrence is not sufficient) rendered disease-free following surgery or 

multi-modality therapy, no more than 8 weeks since surgery, and no 

continuous use of anti-inflammatory medications. Pts with Ewings sarcoma, 

GIST and rhabdomyosarcoma (except pleomorphic/anaplastic) are 

ineligible. Eligible pts will receive 10 subcutaneous injections in the 

outpatient setting over 84 weeks. The primary endpoint is progression-free 

survival (PFS). Secondary objectives include overall survival (OS) and 1and 

3-year PFS rate. Exploratory objectives include correlation of serologic 

response to outcome, comparison of tumor ganglioside expression at 

baseline and at recurrence, and analysis of circulating tumor cells. 

Enrollment began in July 2010. As of January 1, 2012, 83 patients had 

been recruited from 12 participating sites. Clinicaltrials.gov#: 

NCT01141491. Funded by Mabvax Therapeutics and NIH (R21CA13386). 


656s Tumor Biology 


Gene expression-based predictors of chemotherapy response in basal-like 

breast cancer. Presenting Author: Aleix Prat, Lineberger Comprehensive 

Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 

Background: The Basal-like subtype is generally associated with high 

chemo-sensitivity, but not all tumors respond and/or benefit to the same 

extend. In this study, we sought to identify gene expression predictors of 

neoadjuvant chemotherapy sensitivity in Basal-like breast cancer. Methods: 

Expression of 542 genes was measured using the Nanostring nCounter 

platform from 69 FFPE pre-treated samples of the GEICAM/2006-03 

phase II trial, which were treated with epirrubicin/cyclophosphamide 

followed by docetaxel�/-carboplatin. Research-based PAM50 and Claudinlow 

predictors were also evaluated. The association between response 

(Miller-Payne criteria) and gene/signature expression was assessed by 

multivariable ordinal logistic regression. Significant findings were evaluated 

in 109 independent triple-negative and Basal-like tumors treated with 

anthracycline/taxane-based chemotherapy (Hatzis et al.). Finally, interaction 

tests were performed to identify genes/signatures associated with 

carboplatin response. Results: In GEICAM/2006-03, 61/69 (88%) tumors 

were identified as Basal-like by PAM50. High correlation to the Basal-like 

centroid, or high expression of proliferation-related genes (i.e. FANCA), 

were found to be significantly associated with high chemo-sensitivity, 

whereas high expression of genes associated with mesenchymal/stem cell 

biological processes (i.e. SNAI1 and IL6) and/or luminal differentiation 

(i.e. MUC1 and FOXA1) were significantly associated with chemoresistance; 

similar findings were observed in Hatzis et al. Finally, high 

expression of genes associated with proliferation/DNA-repair (i.e. ATR) and 

tight junctions (i.e. CLDN3/4/7) were found associated with carboplatin 

response, whereas expression of the Claudin-low signature was found 

associated with carboplatin resistance. Conclusions: High expression of 

Basal-like and/or proliferation-related genes and low expression of luminal/ 

mesenchymal/stem cell-like biological processes were consistently identified 

as predictive of chemotherapy response. Our data suggests that gene 

expression profiling might help shed light into the biological and clinical 

heterogeneity of Basal-like breast cancer. 


A heuristic platform for clinical interpretation of cancer genome sequencing 

data. Presenting Author: Eliezer Mendel Van Allen, Dana-Farber Cancer 


Background: The ability to identify and effectively sort the full spectrum of 

biologically and therapeutically relevant genetic alterations identified by 

massively parallel sequencing may improve cancer care. A major challenge 

involves rapid and rational categorization of data-intensive output, including 

somatic mutations, insertions/deletions, copy number alterations, and 

rearrangements into ranked categories for clinician review. Methods: A 

database of clinically actionable alterations was created, consisting of over 

100 annotated genes known to undergo somatic genomic alterations in 

cancer that may impact clinical decision-making. A heuristic algorithm was 

developed, which selectively identifies somatic alterations based on the 

clinically actionable alterations database. Remaining variants are sorted 

based on additional heuristics, including high priority alterations based on 

presence in the Cancer Gene Census, biologically significant cancer genes 

based on presence in COSMIC or MSigDB, and low priority alterations in the 

same gene family as biologically significant cancer genes. The heuristic 

algorithm was applied to whole exome sequencing data of clinical samples 

and whole genome sequencing data from a cohort of prostate cancer 

samples processed using established Broad Institute pipelines. Results: 

Application of the heuristic algorithm to the prostate cancer whole genome 

rearrangement data identified 172 (out of 5978) rearrangements involving 

actionable genes (averaging 2-3 events per tumor). Furthermore, two 

clinical samples processed prospectively were analyzed, yielding three 

potentially actionable alterations for clinical review. Conclusions: The 

heuristic model for clinical interpretation of next generation sequencing 

data may facilitate rapid analysis of tumor genomic information for 

clinician review by identifying and prioritizing alterations that can directly 

impact care. Our platform can also be applied to research data to 

prospectively explore clinically relevant findings from existing cohorts. 

Future analytical approaches using heuristic or probabilistic algorithms 

should underpin a robust prospective assessment of clinical cancer 

genome data. 


Estrogen receptor alpha (ESR1) gene amplification status and clinical 

outcome in tamoxifen-treated postmenopausal patients with endocrineresponsive 

early breast cancer: An analysis of the prospective ABCSG-6 

trial. Presenting Author: Christian F. Singer, Medical University of Vienna, 

Department of OB/GYN, Vienna, Austria 

Background: Estrogen receptor alpha (ER�) expression is a prognostic 

parameter in breast cancer and predicts response to endocrine therapy. 

One of the factors important for protein expression is amplification of its 

encoding gene ESR1. We have investigated the value of ESR1 amplification 

in predicting the long-term clinical outcome in tamoxifen-treated 

postmenopausal women with endocrine-responsive breast cancer. Methods: 

394 patients who had been randomized into the tamoxifen-only arm of the 

prospectively designed endocrine ABCSG-06 trial and in whom FFPE tumor 

tissue was available were included in this analysis. Immunohistochemical 

ER� expression was evaluated both locally and centrally using the Allred 

score, while ESR1 gene amplification status was evaluated by FISH 

analysis using the ESR1/CEN6 ratio. Results: ESR1 copy number gains 

were detected in 187 of 394 (47%) tumor specimen and was associated 

with favorable clinical outcome. At a median follow-up of 10 years, women 

with intratumoral ESR1 copy number gains had a significantly longer 

distant recurrence-free survival (adjusted HR for relapse 0.48; 95% CI 

0.28-0.83; p�0.009) and breast cancer-specific survival (adjusted HR for 

death 0.46; CI 0.46-0.71; p�0.006) when compared to women with 

normal ESR1 copy numbers. Immunohistochemical ER� protein expression, 

evaluated by Allred score, was significantly correlated with ESR1 copy 

number alterations (p�0.0001; Chi-Square test), but did itself not allow to 

discriminate between patients with poor and good prognosis. Conclusions: 

ESR1 amplification status is an independent and powerful predictor for 

long-term distant recurrence-free and breast cancer-specific survival in 

postmenopausal women with endocrine-responsive early-stage breast cancer 

who received 5 years of tamoxifen. 


Circulating tumor cell counts (CTC) as prognostic of overall survival (OS) in 

SWOG S0421-docetaxel with or without atrasentan for metastatic castration 

resistant prostate cancer (mCRPC). Presenting Author: Nicholas J. 

Vogelzang, Comprehensive Cancer Centers of Nevada and US Oncology 

Research, Las Vegas, NV 

Background: CTC are promising biomarkers in mCRPC but have not been 

prospectively validated for docetaxel treatment (Rx). Using CellSearch 

technology (J&J), we enumerated CTC in this Phase 3 trial & assessed 

prognostic value for OS. The aim of this correlative study nested within 

0421 was to compare CTC via CellSearch technology to newer microfilter 

technologies (Cote & Goldkorn PIs RO1 CA141077). Comparative data 

analysis is ongoing. Methods: CTC were drawn at baseline (d1) & pre-cycle 2 

(d21) of Rx & shipped overnight to a central site for enumeration (CTC/7.5 

ml). Cox regression evaluated the association between OS and (i) baseline 

CTC counts & (ii) CTC dynamics (d1 to d21) in pts with good (�5) vs. poor 

(��5) baseline CTC counts. Receiver operator characteristic (ROC) analysis 

and Characteristics & Regression Trees (CART) were used to explore 

further prognostic CTC cutpoints for 2-yr survival. Results: Of 263 patients 

(pts) consented, 238 were evaluable at d1 & 232 at d21. At d1 median 

CTC was 5 (range 0-5916) & d1 CTC � vs. �� 5 was associated with 

baseline PSA (mean 99 vs. 320 ng/ml, p�0.004) and worse bone pain 

(36% vs. 51%, p�0.03). There was a significant difference in OS for d1 

CTC � vs. ��5, with a hazard ratio (HR) of 2.92 (95% CI 1.92-4.43, 

p�0.001) after adjustment for PSA & other factors. In pts with low d1 CTC 

(� 5), an increase in CTC was associated with shorter OS, HR 4.04 (95%CI 

1.56-10.44, p�0.004); in pts with high d1 CTC (��5), a ��2-fold 

decrease in CTC was associated with longer OS, HR 0.45 (95%CI 

0.24-0.84, p�0.012); adjusting for risk factors. D1 CTC and 2-year 

survival had ROC AUC of 0.781. CART analysis identified prognostic 

subgroups based on CTC of 0, 1-5, 6-53, and �53: (HR 0.36, 0.77,1.3 

and 2.8). Conclusions: In this phase 3 trial, d1 CTC was prognostic of OS 

after risk factor adjustment. CTC dynamics from d1 to d21 were also 

prognostic of OS. These data are an exploratory subset analysis of the 

overall study. Yet, they comprise the largest docetaxel-based prospective 

cohort to date, which validates a 5 CTC prognostic threshold for OS & 

identifies new potential prognostic subgroups that may extend the clinical 

utility of CTC enumeration in mCRPC. 



Gene expression profiles of circulating tumor cells in metastatic breast 

cancer patients. Presenting Author: Bianca Mostert, Department of Medical 

Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer 

Center, Rotterdam, Netherlands 

Background: A circulating tumor cell (CTC) count is an established 

prognostic factor in metastatic breast cancer. Besides enumeration, CTC 

characterization promises to further improve outcome prediction and 

treatment guidance. We have previously shown the feasibility of measuring 

the expression of a panel of 96 clinically relevant genes in CTCs in a 

leukocyte background, and in the current study, we determined the 

prognostic value of CTC gene expression profiling in metastatic breast 

cancer. Methods: CTCs were isolated and enumerated from blood of 130 

metastatic breast cancer patients prior to start of first-line systemic, 

endocrine or chemotherapeutic, therapy. Of these, 103 were evaluable for 

mRNA gene expression levels measured by quantitative RT-PCR in relation 

to time to treatment switch (TTS). Separate prognostic CTC gene profiles 

were generated by leave-one-out cross validation for all patients and for 

patients with �5 CTCs per 7.5 mL blood, and cut-offs were chosen to 

ensure optimal prediction of patients who might benefit from an early 

therapy switch. Results: In the total cohort, of whom 56% received 

chemotherapeutic and 44% endocrine therapy, baseline CTC count (�5 

versus �5 CTCs/7.5 mL blood) predicted for TTS (Hazard Ratio (HR) 2.92 

[95% Confidence Interval (CI) 1.71 – 4.95] P �0.0001). A 16-gene CTC 

profile for all patients and a separate 9-gene CTC profile applicable for 

patients with �5 CTCs were identified, which distinguished those patients 

with TTS or death within 9 months from those with a more favorable 

outcome. Test performance for both profiles was favorable; the 16-gene 

profile had 90% sensitivity, 38% specificity, 50% positive predictive value 

(PPV) and 85% negative predictive value (NPV), and the 9-gene profile 

performed slightly better at 92% sensitivity, 52% specificity, 66% PPV and 

87% NPV. In multivariate Cox regression analysis, the 16-gene profile was 

the only factor independently associated with TTS (HR 3.15 [95%CI 1.35 

– 7.33] P 0.008). Conclusions: Two CTC gene expression profiles were 

discovered, which provide prognostic value in metastatic breast cancer 

patients. This study further underscores the potential of molecular characterization 

of CTCs. 


DEAR1, a novel tumor suppressor, negative regulator of epithelialmesenchymal 

transition, and prognostic factor in non-small cell lung 

cancer. Presenting Author: Alfonso Quintas-Cardama, University of Texas 


Background: DEAR1, also known as TRIM62, maps to 1p.35, a genomic 

interval within which loss of heterozygosity occurs at high frequency in 

carcinomas. DEAR1 has been proposed as a regulator of cell polarity in 

vitro. Methods: We genetically engineered mice lacking DEAR1 alleles at 

murine chromosome 4. To study the impact of DEAR1 loss in lung cancer, 

DEAR1 deficient mice were crossed to mice carrying the latent mutant 

K-ras G12D allele (K-ras LA1 ). Results: No survival difference was observed 

between DEAR1 �/� and DEAR1 �/� mice (729 vs 699 days, p�0.98) but 

they were markedly shorter than that of DEAR1 wild-type littermates (803 

days, p�0.01). Over 90% of mice developed tumors, mainly adenocarcinomas, 

including invasive and/or metastatic lung cancer in 23% of cases. 

DEAR1-deficient K-ras LA1 mice had reduced life span compared with 

DEAR1 �/� :K-ras �/LA1 littermates (184 vs 291 days, p�0.0001). The 

survival of DEAR1 �/� :K-ras �/LA1 and DEAR1 �/� :K-ras �/LA1 mice were 

similar (180 vs 153 days, p�0.38) and qPCR and IHC analyses suggested 

loss of the wild-type DEAR1 allele. The survival of DEAR1-deficient 

K-ras LA1 

mice was also shorter than that of control p53�/� :K-ras�/LA1 mice 

(240 days; p�0.01). The metastasis incompetent K-ras LA1 –positive LKR13 

cell line after shRNA DEAR1 knock-down and cell lines derived from 

DEAR1-deficient K-ras LA1 tumors recapitulated an invasive phenotype in 

transwell migration and 3D culture assays and a metastatic phenotype on 

SC or IV injection into immunocompetent wild-type littermates. The latter 

was associated with epithelial-mesenchymal transition involving loss of 

E-cadherin and DEAR1 expression and upregulation of vimentin, Twist, 

and CD44. DEAR1 downregulation was very prevalent in a non-small cell 

lung cancer (NSCLC) tissue array with 214 samples. Patients with early 

stage NSCLC and loss of DEAR1 expression had a markedly shorter time to 

relapse compared to those retaining DEAR1 expression (5.1 vs 2.87 years, 

p�0.049) and worse 5-year relapse-free and overall survival rates. 

Conclusions: DEAR1 is a novel tumor suppressor that negatively regulates 

EMT and promotes lung cancer metastasis. DEAR1 loss is a poor prognostic 

factor in NSCLC. 

Tumor Biology 

657s 


Circulating DNA analysis and concordance with tumor section analysis in 

the detection of KRAS and BRAF point mutations from metastatic 

colorectal cancer. Presenting Author: Alain R. Thierry, Sysdiag UMR3145 - 

CNRS, Montpellier, France 

Background: We developed a specific method for circulating cell-free DNA 

(ctDNA) enabling the detection of point mutations. CtDNA exists at high 

level in patients with different types of cancer, and presents great potential 

in regards, in particular, to its low invasiveness, rapid data turnaround and 

cost effectiveness. We described here the first blinded prospective study on 

the comparison of KRAS and BRAF mutational status data obtained from 

the analysis of ctDNA and tumor section. Methods: Intplex is a refined 

Q-PCR-based method specifically designed to analyze ctDNA. IntPlex 

allows not only the detection of point mutations, but also the determination 

of tumor-ctDNA concentration and fragmentation index simultaneously. 

Intplex sensitivity is 0.01% (mutant to WT ratio) and is unprecedented 

among Q-PCR-based methods. The study was conducted from a multicenter 

cohort of 79 metastatic CRC patients not having received chemo- or 

radio-therapy within the month prior to blood sample collection. Results: 

Mutational status could not be determined in 9 samples with one of the two 

methods. CtDNA analysis showed 100% specificity and 87% sensitivity for 

KRAS detection (only three samples are misclassified) as compared to 

tumor section analysis with 23/70 (33%) positive samples, the concordance 

value being 96%. For BRAF mutation, the method exhibited a 

specificity and a sensibility of 100% with 5/70 (7%) positive samples 

(concordance of 100%). When combining KRAS and BRAF mutations, 

100% specificity, 89% sensibility and 98% concordance were determined. 

The three discordant samples may be explained by the malignant genotype 

of primary tumor versus metastasis, or by the sensitivity of our detection 

method. The mutation load (median, 12.4%) expressed as the proportion 

of mutant allele in ctDNA is highly variable (0.037% to 69%) among 

mutated samples showing a very high inter-individual heterogeneity. 

Conclusions: Our blinded prospective multicenter study clearly showed for 

the first time that tumor section analysis might be advantageously replaced 

by ctDNA analysis, enlarging personalized medicine power for cancer 

patients. 


Rare epidermal growth factor receptor (EGFR) mutations in 10,117 

patients with non-small cell lung cancer (NSCLC) evaluated by the French 

ERMETIC IFCT network: Clinical, molecular, and survival data. Presenting 

Author: Michele Beau-Faller, CHU Strasbourg, Strasbourg, France 

Background: The EGFR exon 19 deletion and exon 21 L858R mutation are 

associated with response to EGFR-TKI. However, the correlation with 

response to EGFR-TKI remains unclear for rare exon 18 and 20 EGFR 

mutations. We investigated the clinical features of NSCLC patients with 

exon 18 and exon 20 EGFR mutations, analyzed response to EGFR-TKI and 

patient’s survival. Methods: Between 2005 and 2011, all rare exon 18 and 

20 EGFR mutations were collected from 10117 cases of NSCLC in 15 of 

28 French NCI molecular genetic laboratories. Results: During the study 

period, EGFR mutations were identified in 1048 (10.35%) out of the 

10117 performed tests and 108 rare mutations (10.3%) were identified in 

103 patients, including 25 never identified mutations. Among them, 48 

mutations were localized at exon 18 and 60 at exon 20, with 3 out of the 4 

identified T790M exon 20 mutations associated with L858R mutation. 

Only 5 other rare mutations were associated with EGFR 19 or 21 mutations. 

38 patients received EGFR-TKI (erlotinib, n�32; gefitinib, n�6). Among 

the 36 evaluable patients, best response on TKI was progression in 18 

patients (50%), stabilization in 11 (30.5%) and partial response in 7 

(19.4%). Tumor control rate observed in exon 18 mutations was 61% 

(8/13) and 50% (13/26) in exon 20 mutations. For the EGFR-TKI treated 

patients, the median PFS was 6 months (2-53). Median OS was 15 months 

(1-92), with no difference between the EGFR-TKI treated patients or not. 

Conclusions: Prevalence of rare EGFR mutations was 1.06% of all tested 

NSCLC and 10.35% of all EGFR mutations. Tumor control on TKI was 

observed in half of the patients. Reports of NSCLC harboring rare mutations 

are important to help the decision-making process in this subset of 

patients. 




11:30 AM-12:30 PM 

Next-generation RNA sequencing reveals transcriptomic changes after 

brief exposure to preoperative nab-paclitaxel, bevacizumab, and trastuzumab. 

Presenting Author: Vinay Varadan, Philips Research North America, 

Briarcliff Manor, NY 

Background: Identification of differentially expressed transcripts after brief 

exposure to preoperative therapy can help determine likely response 

markers. We quantify and compare differential gene and isoform expression 

using RNA-seq on patient samples with 10 day exposure to one dose of 

trastuzumab, bevacizumab or nab-paclitaxel. Methods: We sequenced 

transcriptomes of 23 pairs of core biopsy RNA from breast cancers pre/post 

10 day exposure to therapy. Paired-end sequencing was done on the 

Illumina GAII platform using amplified total RNA with 74bp read length, 

yielding data on transcript abundance for a total of 22,160 genes and 

34,449 transcripts. Differential expression of transcripts between pre/post 

samples was estimated assuming Poisson-distributed read-counts, followed 

by multiple testing correction and enrichment analysis of 185 KEGG 

pathways. Results: PAM50-based clustering showed individual samples 

cluster together, demonstrating that tumor subtypes do not change over the 

10-day treatment (SABCS 2011). We identified genes that were significantly 

differentially expressed (p�0.05; FDR�0.1) in at least 60% of 

samples within each therapy arm: 780 genes in trastuzumab, 302 in 

bevacizumab, and 176 in nab-paclitaxel. Surprisingly, only THAP11 and 

TINF2 were common amongst them. THAP11 is involved in stem cell 

maintenance and TINF2 is important for regulation of telomere length. 

Immune system and metabolism-related pathways were commonly affected 

(p�0.05) across all arms. The bevacizumab arm showed significant 

down-regulation of angiogenesis-associated genes: ESM1 and VEGFR2 in 

� 80% of samples. The nab-paclitaxel arm exhibited changes in TGF-beta 

signaling, Nod-like receptor and Wnt signaling. The trastuzumab arm 

exhibited consistent alteration of ErbB2 and mTOR pathways, with SOX11 

and TOP2B downregulated in every sample. Conclusions: This is the first 

study to compare gene expression with brief exposure across therapies 

using RNA-seq technology. The unique aspects of transcriptional response 

to each treatment underscore the need for specific markers of therapeutic 

response to nab-paclitaxel, bevacizumab and trastuzumab. 


11:30 AM-12:30 PM 

PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous 

assessment of MAPK pathway aberrations. Presenting Author: Filip Janku, 

Department of Investigational Cancer Therapeutics (Phase I Program), 


Background: Loss of PTEN function increases PI3K/mTOR signaling. 

Preclinical data suggest that PTEN aberrations can predict sensitivity to 

drugs targeting the PI3K/mTOR pathway. Methods: Tumors from 461 

patients with diverse cancers referred to the Clinical Center for Targeted 

Therapy were tested for cytoplasmic immunohistochemical expression of 

PTEN using the following scoring system: negative (no staining); positive 

(intact staining); reduced staining, with stroma serving as an internal 

positive control. Whenever possible, tumors were also tested for mutations 

in the MAPK pathway (KRAS, NRAS, and BRAF). We analyzed outcomes of 

patients treated with PI3K /mTOR with respect to their PTEN status. 

Results: Of 461 patients, 47 (10%) had negative PTEN expression, 168 

(36.5%) had positive PTEN expression, and 246 (53.5%) had reduced 

PTEN. In tumor types with �10 patients tested, negative PTEN was most 

frequent in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 

20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary 

(3/24, 13%), and prostate cancers (2/19, 11%). Of 206 patients tested for 

MAPK (KRAS, NRAS, and BRAF) pathway mutations, patients with either 

negative or reduced PTEN had more MAPK mutations than patients with 

positive PTEN expression (72/144, 50% vs. 20/62, 32%, p�0.02). A total 

of 153 (33%) patients received therapies with PI3K /mTOR inhibitors and 

17 (11%, 95% CI 0.07-0.17) achieved a partial response (PR). Proportions 

of PRs were 2/13 (15%) for PTEN negative, 3/50 (6%) for PTEN 

positive, and 12/90 (13%) for reduced PTEN. There was no significant 

difference in PR rate amongst patients with positive PTEN expression 

compared to patients with negative or reduced PTEN (3/50, 6% vs. 

14/103, 14%; p�0.27). Conclusions: Complete loss of PTEN expression 

was found in 10% of patients. Positive PTEN expression was found in 

36.5% of patients. PTEN status did not predict response to PI3K/mTOR 

inhibitors, perhaps because patients with negative and reduced PTEN 

expression had a higher incidence of simultaneous MAPK (KRAS, NRAS, 

BRAF) mutations. 


11:30 AM-12:30 PM 

Early change in 18-fluorodeoxyglucose (FDG) uptake on positron emission 

tomography (PET) to predict response to preoperative systemic therapy 

(PST) in HER2-negative primary operable breast cancer: Translational 

breast cancer research consortium (TBCRC008). Presenting Author: Roisin 

M. Connolly, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins 


Background: PST allows for improved surgical outcomes and response 

assessment without compromising long term outcomes. PST is an attractive 

model for assessing surrogate markers of response to therapy. We 

hypothesized that changes in tumor standardized uptake values corrected 

for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of 

therapy would predict pathological complete response (pCR) to PST in 

women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods: 

TBCRC008 is a multicenter placebo-controlled trial that investigates pCR 

following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel 

with or without vorinostat. FDG-PET followed by tumor biopsies were 

performed at baseline and C1D15. We correlated % reduction in SULmax 

on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no 

invasive cancer in breast/axilla). We compared % reduction in SULmax 

between responders (pCR) and non responders (no pCR) using nonparametric 

Wilcoxon rank sum test. We explored association of % reduction in 

SULmax at pre-specified cutoff with response using Fisher’s exact test and 

logistic regression. We correlated baseline, C1D15, and % change in Ki67 

at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled 

(10/2009-11/2011), 40 have completed study PST and surgery (median 

age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an 

intent to treat analysis (n�39), we observed a significant difference in 

median % reduction in SULmax between responders vs not (66.6% vs 

32.4%, p �0.001). We observed a higher proportion of reduction in 

SULmax � 60% in responders vs not (80% vs 3.5%, p �0.001). The 

differences in baseline, C1D15 and % change in Ki67 were not significant 

between responders and non-responders. Conclusions: Change in SULmax 

on FDG-PET 15 days after initiating PST was significantly greater in 

patients with pCR versus no pCR. Future studies will determine whether 

altering therapy based on early changes in SULmax will improve pCR. 

Unblinded data from all participants will be presented at the meeting. 


11:30 AM-12:30 PM 

Analysis of the intratumoral heterogeneity of PIK3CA mutant alleles in 

breast cancer (BC): Implications for the luminal (LUM) phenotype. Presenting 

Author: Leticia De Mattos-Arruda, Medical Oncology Department, Vall 

d’Hebron University Hospital, Barcelona, Spain 

Background: The hyperactivation of the phosphatidylinositol 3-kinase 

(PI3K) pathway may confer endocrine therapy resistance and is an 

attractive target for LUM patients (pts). However, PI3KCA mutations could 

be heterogeneously distributed within the tumor as different genetic clones 

and this could have therapeutic implications. Our aim was to assess the 

frequency of PIK3CA mutant alleles in different BC phenotypes. Methods: 

DNA was obtained from 75 consecutive BC FFPE samples and was profiled 

with the OncoCarta Panel v1.0 (Sequenom). Frequencies of mutant alleles 

(% mutant allele, mA) of PIK3CA mutations were extracted from the 

MassARRAY spectrum data. The viable tumor area (TA) was scored by H&E. 

Pts were stratified by BC phenotypes: ER�/HER2- (LUM); HER2� (HER2); 

triple negative (TN). Results: 25.3% of pts had PIK3CA mutations. The 

mean PIK3CA mA (p�0.04) and mean TA (p�0.07) differed among 

phenotypes. LUM tumors demonstrated greater frequencies of PIK3CA 

mutation (38% vs.15%, p�0.05) and mean PIK3CA mA (31% vs.17%, 

p�0.01) than non-LUM.There was a significant linear correlation between 

mA and TAfor LUM tumors (r�0.91); when HER2 and TN tumors were also 

considered this relation was less pronounced (r�0.66). Overall, LUM pts, 

median age 55 (42-84), had significantly better clinical outcomes 

(p�0.00024), whilst analyses of prognosis did not differ among LUM pts 

(PIK3CA mutant vs. wild-type, p�0.68) nor mutant pts (LUM vs. non- 

LUM, p�0.36). Outcomes will be presented. To assess the intratumoral 

heterogeneity of PIK3CA mutations, we determined the mA/TA ratio. The 

mA/TA ratio should be 0.5 for a homogeneous distribution of the heterozygous 

PIK3CA mutation. The ratio of LUM patients was close to 0.5, while 

for non-LUM it was lower, suggesting a non-homogeneous distribution of 

PIK3CA mutant alleles in non-LUM tumors. Conclusions: Our analysis 

indicates that LUM tumors tend to be homogeneous regarding PIK3CA 

mutation as compared to HER2 and TN. This suggests that PIK3CA 

oncogenic activation could be an early hit for tumor initiation in LUM 

tumors, which could be more specifically targetable; thus, pts would derive 

greater benefit from PI3K-inhibitors plus hormonal therapy. 



11:30 AM-12:30 PM 

Dynamic contrast-enhanced MRI versus 18F-misonidazol-PET/CT to predict 

pathologic response in bevacizumab-based neoadjuvant therapy in 

breast cancer. Presenting Author: Jesus Garcia-Foncillas, Oncology Department, 

Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma 

de Madrid, Madrid, Spain 

Background: To investigate the role of DCE-MRI versus 18F-Misonidazole 

(FMISO) positron emission tomography (PET/CT) in the prediction of 

pathological response to bevacizumab-based neodajuvant therapy. Methods: 

73 chemotherapy naïve, stage II and III breast cancer (BC) patients (pts) 

were enrolled in a phase II, single-arm, multicenter, open-label and 

prospective clinical trial. Pts received single infusion of bevacizumab (15 

mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy 

(NAC) consisting of 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 

mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5), followed by 

surgery. Tumor proliferation, hypoxia and perfusion were evaluated respectively 

using 18F-Fluorothymidine (FLT) and 18F-Misonidazole (FMISO) 

positron emission tomography (PET/CT) and dynamic contrast enhancement 

magnetic resonance (DCE-MR). Serial imaging studies were performed 

in parallel at several time points including baseline (BL) and 14-21 

days after bevacizumab alone (C1). Results: After only one administration of 

bev, tumor proliferation and perfusion assessed using FLT-PET and 

DCE-MRI significantly decrease (-26% and -46%, p�0.001) but these 

changes were not found to be associated with final response. Most 

important, changes in tumor hypoxia induced by bevacizumab was significantly 

associated with pathological response (p� 0.004) and was an 

independent predictor of response in multivariate analysis (RR�0.95, IC 

95% 0.92-0.99, p�0.02). Decrease in FMISO uptake �10% yielded a 

ROC curve area of 0.7 (95% CI: 0.56 - 0.85) with high specificity (94%). 

Conclusions: Our findings suggest a significant value of early changes in 

tumor hypoxia assessed by FMISO-PET as a biomarker of pathological 

response in bevacizumab-based neoadjuvant therapy in breast cancer. 


11:30 AM-12:30 PM 

A translational study to investigate the association between smoking-induced 

lung inflammation and lung metastases (LM) from breast cancer (BC). Presenting 

Author: Patrick Glyn Morris, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: Retrospective and preclinical studies suggest that smokers are at 

increased risk for LM from BC, possibly mediated by lung inflammation and the 

bioactive lipid, PGE2. To investigate this link in pts, we examined urinary 

PGE-M, a stable end metabolite of PGE2. Methods: A translational study was 

conducted, consisting of pts with LM (n�100), pts with mets but no known lung 

mets (NKL, n�100) and controls (CTRLS) with a history of BC (n�200). Pts 

receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), 

blood (biomarkers), had BMI measured, and completed a validated questionnaire 

(smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, 

normalized to urinary creatinine and compared between grps in both 

univariate and multivariate models, correcting for covariates. Results: From 

09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There 

were no significant differences between grps in smoking and NSAID exposure 

(table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) 

compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, 

P�0.001). In univariate analysis, smoking pack year was associated with PGE-M 

(��0.13, P�0.01), and ever smokers with LM had the highest PGE-M (med 7.4; 

range 0.8-28.9). In a multivariable model ever smokers with LM had higher 

PGE-M than never smoking CTRLS (P�0.03). Pts with �24 pack year smoking 

history and LM had the highest co-variate-adjusted log PGE-M (P�0.03). In this 

model, age (P�0.001), pack year smoking hx (P�0.02), receipt of chemoRx �1 

mth (P�0.003) and BMI (P�0.002) were all associated with higher PGE-M. 

Conversely, receipt of NSAIDs �7 days was associated with lower PGE-M 

(P�0.001). Conclusions: Increased lung inflammation, as characterized by 

PGE-M, occurs in ever smokers with LM from BC, supporting the hypothesis that 

changes in the lung microenvironment (“soil”) predispose to metastasis. 

Baseline characteristics 

LM 

N�100 

NKL 

N�100 

CTRLS 

N�200 P 

N(%) N(%) N(%) 

Ever smokers 44 (44) 48 (48) 104 (52) 0.3 

Pack year smoking Hx, med (range) 24 (1-126) 20 (1-150) 20 (1-150) 0.5 

NSAIDs < 7 days 48 (48) 45(45) 92 (46) 0.9 

ChemoRx



11:30 AM-12:30 PM 

Mutational analysis of circulating tumor cells in breast cancer patients by 

targeted clonal sequencing. Presenting Author: Xunhai Xu, New York 

Presbyterian-Columbia, New York, NY 

Background: The molecular signature of circulating tumor cells (CTCs) may 

serve as a surrogate marker for accurate description of the metastatic tumor 

of interest, especially in the setting of treatment response and selection. 

We present a method for mutational analysis of CTCs in metastatic breast 

cancer (MBC) patients by using an emulsion-formulated, semiconductorbased, 

targeted clonal sequencing platform. Methods: CTCs in MBC 

patients were enriched by a microfluidic OncoCEE device using antibodies 

against both epithelial and mesenchymal markers. Genomic DNA was 

extracted from enriched CTC samples. Emulsion-based multiplex-PCR 

targeted for various cancer genes was performed, after which semiconductorbased 

deep sequencing was completed. The read error rates were analyzed 

based on quality score and context of sequence including homopolymers. 

Statistical significance for each mutational analysis was assessed using a 

method based on beta-binomial distribution. Results: Of the 17 patients 

samples obtained, we were able to enrich CTC samples in 9 of them (CTC 

range 1-1063, median�12). Multiplex targeted sequencing was performed 

on DNA from the enriched CTC patient samples (purity range 

0.3-6%). Greater than 3000-fold coverage was accomplished. Missense 

mutations at E545D on PIK3CA (p� 2.0e-07), F354L on STK11 (p�2.0e- 

04), and Q61R on NRAS (p�2.0e-07) were detected. Novel mutations of 

L540F and Q1033K within the hot spot regions of PIK3CA were observed 

(p�1.3e-04). Genomic DNA from WBCs from a healthy female was 

analyzed concurrently as a negative control, in which none of the mutations 

were observed. Conclusions: Mutational analysis of CTCs in MBC patients 

can be accomplished by deep sequencing. We developed a de novo protocol 

for clonal mutation analysis on CTCs in MBC and detected various 

significant and novel mutations. We anticipate reporting sequencing 

results on CTCs and matched WBCs, as negative controls, from 40 MBC 

patients. This will provide the foundation for the future studies in which we 

will compare the mutational profile between CTCs and primary/metastatic 

tumors. We intend to validate clonal mutational analysis of CTCs as a 

predictive blood-based biomarker in subsequent trials. 


11:30 AM-12:30 PM 

Genetic variation in CYP19A1 and response to exemestane: Survival in early 

breast cancer in the Dutch TEAM trial. Presenting Author: Daniel Houtsma, 

Department of Clinical Oncology, Leiden University Medical Center, Leiden, 

Netherlands 

Background: In patients with endocrine-sensitive breast cancer treated with 

adjuvant aromatase inhibitors (AI) it is unclear which patients will develop a 

recurrence and who will benefit from AI’s. Variations in the aromatase gene 

(CYP19A1) are associated with altered estrogen levels and altered aromatase 

activity. The aim of this study was to examine the effect of SNPs in the CYP19A1 

gene on survival in a prospective cohort of breast cancer patients treated with 

adjuvant exemestane. Methods: Patients of whom tissue was available and who 

were treated with five years of exemestane were selected from the Tamoxifen 

Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor 

samples and 30 SNPs were identified using a tagging SNP approach, aiming for 

80% coverage of CYP19A1. Genotypes were determined with taqman assays. 

Primary endpoint of the study was relapse-free survival (RFS) and secondary 

endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and 

Cox proportional hazards models assessed survival differences. Analyses were 

adjusted for age at diagnosis, tumor size, nodal status, histological grade, 

surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were 

included in the analyses and genotypes were obtained in 722 cases. A significant 

association with worse RFS was found with two SNPs: rs7176005 and 

rs16964211, showing hazard ratios (HR) of 3.48 and 5.42 for the homozygeous 

variant types respectively. These SNPs, as well as a third SNP, rs6493497, were 

also significantly associated with OS (HR 5.87, 5.3 and 3.36 respectively). 

Conclusions: Germline variations in the CYP19A1 gene are related to a worse 

outcome in early breast cancer patients treated with exemestane. These findings 

may contribute to the individualization of hormonal therapy in breast cancer. The 

relation between RFS and SNP’s in CYP19A1. 


genotype 

Univariate HR 

(95% CI) P value 

Multivariable HR 

(95% CI) P value 

rs7176005 0.015 0.033 

CC 578 1 (ref) 1 (ref) 

CT 130 1.83 (1.15-2.91) 1.75 (1.05-2.92) 

TT 8 2.78 (0.68-11.4) 3.48 (0.83-14.6) 

rs16964211 0.021 0.019 

GG 629 1 (ref) 1 (ref) 

AG 67 1.04 (0.52-2.06) 0.52 (0.23-1.17) 

AA 4 5.82 (1.43-23.7) 5.42 (1.25-23.4) 


11:30 AM-12:30 PM 

Intraoperative detection of lymph node metastasis using one-step nucleic 

acid amplification (OSNA) in breast cancer patients: Effect on second 

surgery rate and delay for adjuvant therapy. Presenting Author: Sophie 

Klingler, Centre Alexis Vautrin, Vandoeuvre-lès-Nancy, France 

Background: Sentinel lymph node (SLN) analysis is conventionally analysed 

using HES and CK19 immunohistochemistry. In case of SLN involvement, 

a second surgery is required for axillary lymph node (ALN) resection thus 

delaying the initiation of adjuvant therapies. Methods: 381 pts with invasive 

breast cancer were considered in this retrospective study. SLN were 

detected using combined radio-isotope and color detection. SLN involvement 

was analysed using OSNA for CK19 mRNA, in 100 pts (group 1) and 

compared to conventional histopathology in 281 pts (reference population, 

group 2). In all cases, control cytology was performed. Results: No 

significant difference was found between group 1 and 2 regarding patients 

characteristics, tumor localization, size, grade, steroid receptors and HER2 

expression and the mean number of SLN analysed per pt, 2.4 (range 1-7) 

and 2.5 (range 1-8), respectively. Considering positive SLN as “��” 

(CK19 mRNA copy number�5000), “�” (250 � CK19 mRNA copy 

number � 5000) and positive by inhibition in group 1 and macro-, 

micrometastases and isolated tumor cells in group 2, no difference in 

lymph node involvement rate was found between the two groups with 29.0 

and 29.9% of positive SLN, respectively. Only one discordance case was 

observed with negative OSNA analysis and positive cytology with isolated 

tumor cells. Using OSNA intraoperatively, the mean time to process SLN 

was 42 min (range 10-104) allowing immediate ALN resection. Significant 

(P�.01) reduction of re-intervention rate was observed when OSNA was 

used (9 vs 39%), including margins insufficiency (5 vs 13%), ALN 

resection (3 vs 15%) or both (1 vs 11%). Delay before adjuvant therapy was 

also significantly (P �.01) reduced when OSNA was used with 43 (range 

20-82) vs 59 (range 14-212) days. Conclusions: Results achieved with 

OSNA are fully consistent with those achieved using conventional immunohistochemistry 

analysis. SLN analysis using OSNA avoids a second operation 

in most patients for ALN resection and shortens the delay for adjuvant 

therapy. 


11:30 AM-12:30 PM 

64Cu-DOTA-trastuzumab-PET imaging in patients with HER2-positive breast 

cancer. Presenting Author: Kenji Tamura, Department of Breast and 

Medical Oncology, National Cancer Center Hospital, Tokyo, Japan 

Background: Targeting of HER2 with trastuzumab (T) is a well-established 

strategy in the metastatic and adjuvant setting in HER2 positive breast 

cancer (HER2-BC). Although HER2 status is routinely determined using 

immunohistochemistry or fluorescence in situ hybridization, technical 

problem can arise when lesions are poorly accessible. HER2 expression can 

vary during the course of the disease, and there can be discordance in 

HER2 expression across tumor lesion even in the same patients. Noninvasive 

HER2 imaging is crucial needed to solve these problems. Previous 

imaging using 111In or 89Zn- trastuzumab produced high radiation exposure 

to patients by their long half life (�67.9and 78.4h) and low resolution 

image. Half life of 64Cu is 12.7h. We performed a feasibility study of the 

64Cu-1, 4, 7, 10- tetraazacylododecane-N,N’,N�,N�’-tetraacetic acid 

(DOTA)-T to perform PET imaging in patients with HER2-BC. Methods: 

Patients with HER2-BC received 150 MBq of 64Cu-DOTA-T and underwent 

PET scan 1, 24 and 48h after the injection. Six patients were evaluated 

internal dosimetry by collecting radioactivity data of blood and normal 

tissue in each time point from PET study, and radiation exposure by 

collecting clothes, linen and urine to test feasibility for outpatients. Results: 

Fifteen patients who received T therapy were enrolled in the “first-inhuman” 

trial. All patients had no severe toxicity. Radiation excretion 

evaluating clothes, linen were under background level. Radiation exposure 

of 64Cu-DOTA-T was equivalent to that of conventional 18F-FDG-PET. Distribution of liver, kidney, spleen, and blood vessel was 2-8 SUV, and 

uptake in other normal tissue was low. At visual examination, in two 

patients brain metastases were clearly visualized by 64Cu-DOTA-T-PET, suggesting that there are disruptions of the blood-brain barrier at the site of 

the brain metastases. The sternum bone metastasis was well visualized and 

quantitatively monitored according to the response by T. Primary breast 

cancers, lymph node metastases and lung metastases could also be 

visualized at the lesion indentified by CT. Conclusions: 64Cu-DOTA-T-PET was feasible test even for outpatient, and provides specific and high 

resolution image in HER2 positive lesion. 



11:30 AM-12:30 PM 

Reproducibility, performance, and clinical utility of a genetic risk prediction 

model for prostate cancer in Japanese patients. Presenting Author: 

Shusuke Akamatsu, Department of Urology, Kyoto University Graduate 

School of Medicine, Kyoto, Japan 

Background: Prostate specific antigen (PSA) is widely used as a diagnostic 

biomarker for prostate cancer (PC). However, due to its low predictive 

performance, many patients without PC suffer from the harms of unnecessary 

prostate needle biopsies. The present study aims to evaluate the 

reproducibility and performance of a genetic risk prediction model and 

estimate its utility as a diagnostic biomarker in a clinical scenario. Methods: 

We created a logistic regression model incorporating 16 SNPs that were 

significantly associated with PC in a genome-wide association study of the 

Japanese. The model was validated by two independent sets of samples 

comprising 3,294 cases and 6,281 controls. Various cut offs were 

evaluated to be used in a clinical scenario. Results: The area under a curve 

(AUC) of the model was 0.679, 0.655, and 0.661 for the samples used to 

create the model and those used for validation respectively. The AUC of the 

model was not significantly altered in samples with PSA 1-10 ng/ml. 

24.2% and 9.7% of the patients had odds ratio �0.5 (low risk) or �2 (high 

risk) in the model, and assuming the overall positive rate of prostate needle 

biopsies to be 20% in PSA gray zone (PSA 2-10 ng/ml), the positive biopsy 

rates were 10.7% and 42.4% respectively for the two genetic risk groups. 

Conclusions: The genetic risk prediction model was highly reproducible, 

and its predictive performance was not influenced by PSA. The model could 

have a potential to affect clinical decision when it is applied to patients 

with gray-zone PSA, which should be confirmed in future clinical studies. 


11:30 AM-12:30 PM 

The effect of two BRM promoter variants on the risk of stage I/II upper 

aerodigestive tract cancers. Presenting Author: Kit Man Wong, University of 


Background: BRM is a key subunit of the chromatin remodeling complex 

SWI/SNF and a putative tumor suppressor gene that is silenced in 15-20% 

of many solid tumors (PMID 15722796). Evidence suggests that it is 

epigenetically regulated, as two BRM promoter insertion variants (BRM- 

741 and BRM-1321) may lead to gene silencing by recruiting histone 

deacetylases. The presence of both homozygous BRM-741 and BRM-1321 

highly correlate with loss of BRM expression and function in lung tumors, 

while increasing smoking-related lung cancer by two-fold (PMID 

21478907). Also, the pharmacologic reversal of epigenetic changes of 

BRM offers a potential novel therapeutic approach (PMID 21478905). We 

assessed whether these BRM variants are associated with the risk of upper 

aerodigestive tract cancers, focusing on Stage I/II tumors that would most 

benefit from new screening and prevention strategies. Methods: BRM was 

genotyped by qPCR using TaqMan probes. 1,008 controls were matched to 

595 cases by frequency distribution based on age, gender and smoking 

status. Multivariate logistic regression generated adjusted odds ratios 

(aOR). Results: The 595 cases were: 115 esophageal, 278 lung, and 202 

head and neck cancers. 51% were adenocarcinomas; 60% were Stage I. 

The frequency of homozygozity was: BRM-741, 26%; BRM-1321, 23%; 

both variants, 15%. In the combined analysis, there was significant 

correlation between malignancy and homozygous BRM-741 (aOR 1.91 

(95%CI 1.3-2.4); p�0.001) or BRM-1321 (aOR 1.94 (95%CI 1.4-2.7; 

p�3x10E-4). Being homozygous for both BRM variants carried an even 

greater risk (aOR 2.45 (95%CI 1.6-3.9); p�1x10E-5). This correlation was 

similar for adenocarcinomas (aOR 2.53 (95%CI 1.4-4.2); p�6x10E-4) 

and squamous cell carcinomas (aOR 2.33 (95%CI 1.3-4.4); p�8x10E-4). 

The increased cancer risk was also similar between these subgroups: head 

and neck, esophageal and lung cancers; Stage I and II patients; smokers 

and non-smokers. Conclusions: The two homozygous BRM variants increase 

the risk of early stage upper aerodigestive tumors by more than two-fold 

independent of smoking status. BRM promoter variants and their potential 

epigenetic effect may be early events in the evolution of these cancers. 

Tumor Biology 

661s 


11:30 AM-12:30 PM 

BAP1: The first mutated gene causing familial uveal melanoma. Presenting 

Author: Johan Hansson, Department of Oncology-Pathology, Stockholm, 

Sweden 

Background: Uveal melanoma (UM) is a rare malignancy with a poor 

prognosis. Familial predisposition to UM is rare and accounts for only a few 

percent of all cases. The genetic background of hereditary UM is unknown 

and the aim of our project was to identify susceptibility gene(s) for UM. 

Methods: We identified a family with hereditary predisposition for UM – the 

proband of which is a young female diagnosed with UM at age 16 who 

within 6 months developed liver metastases. We also identified two older 

paternal relatives who were diagnosed with UM at 39 and 44 years of age, 

respectively. We performed massively parallel sequencing using the Illumina 

Hiseq2000 technology on germline DNA from the proband, her 

parents and a healthy sibling. After QC and mapping against the human 

reference genome the average coverage across the exome was between 35 

and 86 for the four sequenced samples. Results: Out of more than 260,000 

single nucleotide variants (SNVs) and small insertion / deletion variants 

(indels), 51 gene variants were filtered out by being novel, shared by the 

affected proband and her father (considered an obligate mutation carrier), 

but not by the healthy mother, of predicted functional importance and /or 

located within strongly conserved regions. The strongest candidate among 

these was a loss of function-variant in the BAP1 gene, since BAP1 has been 

suggested as a tumor suppressor in several cancer-related syndromes, 

including cases of UM. The sequence data indicated an insertion of one 

base-pair in exon 3 of the BAP1 genecausing a frame-shift and subsequently 

a truncated protein lacking all its functional domains. The 

mutation was also present in UM tumor tissue from the two deceased 

paternal relatives and was found to segregate with the UM phenotype in the 

family. We also detected loss of heterozygosity in the tumor of the proband, 

supporting BAP1 as the causative gene in this family. Conclusions: The 

identification of BAP1 as the gene responsible for this syndrome is the first 

demonstration of a germline mutation causing UM. This enables us to 

identify and monitor risk individuals belonging to mutation positive 

families with predisposition to UM, and possibly other cancer syndromes. 

We are continuously screening other cases of familial UM for mutations in 

BAP1. 


11:30 AM-12:30 PM 

Prognostic significance of LINE-1 methylation level in the upper gastrointestinal 

cancer. Presenting Author: Yoshifumi Baba, Kumamoto University, 

Kumamoto, Japan 

Background: Genome-wide DNA hypomethylation plays a role in genomic 

instability and carcinogenesis. DNA methylation in long interspersed 

nucleotide element-1 (LINE-1) is a good indicator of global DNA methylation 

level. Although LINE-1 methylation level is attracting interest as a 

useful marker for predicting cancer prognosis, the prognostic significance 

of LINE-1 hypomethylaiton in the upper gastrointestinal cancer [i.e., 

esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC)] 

remains unclear. Methods: Using 217 ESCC and 207 GC specimens, we 

quantified the LINE-1 methylation using bisulfite-pyrosequencing technology. 

During the follow-up, there were a total of 63 ESCC recurrences, 51 

ESCC deaths and 56 GC deaths. The median follow-up time for censored 

patients was 2.8 years. A Cox proportional hazards model was used to 

calculate the hazard ratio (HR), adjusted for the clinical, epidemiological, 

and pathological variables. The term “prognostic marker” is used throughout 

this study according to the REMARK Guidelines. Results: ESCCs and 

GCs showed significantly lower LINE-1 methylation levels compared to 

matched normal mucosa (p�0.0001). In ESCC, LINE-1 hypomethylation 

was significantly associated with disease-free survival [log-rank p�0.0008; 

univariate HR� 2.32, 95% confidence interval (CI) 1.38-3.84, p�0.0017; 

multivariate HR�1.81, 95% CI 1.06-3.05, p�0.031] and cancer-specific 

survival (log-rank p�0.0020; univariate HR�2.21, 95% CI 1.33-3.60, 

p�0.0026; multivariate HR�1.87, 95% CI 1.12-3.08, p�0.018]. We 

found a significant modifying effect of the tumor stage on the relationship 

between LINE-1 methylation and the recurrence rate (P for interaction � 

0.031). In GC, LINE-1 hypomethylation was significantly associated with 

cancer-specific survival (log-rank p�0.029; univariate HR�2.01, 95% CI 

1.09-3.99). Conclusions: LINE-1 hypomethylation is associated with shorter 

survival in both ESCC and GC, suggesting that it has potential for use as a 

prognostic biomarker. 




11:30 AM-12:30 PM 

Next-generation sequencing of FFPE solid tumor specimens for clinical 

use. Presenting Author: Roman Yelensky, Foundation Medicine, Cambridge, 

MA 

Background: As more therapies targeting genomic alterations become 

available, genotyping (e.g., by Sequenom) is increasingly performed in 

tumor types where mutational status may drive treatment choice. Nextgeneration 

sequencing (NGS) technology can expand on genotyping of 

individual base pairs because it can detect mutations across entire exons, 

copy changes and fusion genes. However, for NGS to be clinically viable, it 

must be made compatible with FFPE tissues and shown concordant with 

best current diagnostic methods. Methods: To explore a potential clinical 

role for NGS, we selected 120 FFPE specimens (68 NSCLC, 32 CRC, 20 

melanoma) previously tested for 97 oncogenic mutations in 8 oncogenes by 

Sequenom, and sequenced all exons of 182 cancer genes. Genotyping and 

sequencing were both performed in CLIA compliant labs. DNA was 

extracted from 4x 10� unstained sections from the diagnostic FFPE block, 

followed by library construction and hybridization capture of 3230 exons 

and 37 commonly rearranged introns. Average coverage of �900X uniquelymapping 

reads was obtained. Sequence data were analyzed for all genomic 

alterations and examined for potentially actionable mutations. Results: 

High concordance was noted between Sequenom and NGS: 103 and 105 

mutations were called by the two technologies, respectively, at mutually 

tested sites, with 97 mutation calls in common. Notably, mutant allele 

frequencies in concordant calls ranged as low as 2% by NGS, highlighting 

the sensitivity of detection enabled by both approaches. Furthermore, in 

45/120 (38%) specimens, NGS revealed additional alterations that may 

confer sensitivity or resistance to approved or experimental targeted 

therapies and thus plausibly influence treatment decisions. These included 

39 copy changes or loss-of-function variants best assayed by an NGS 

approach. Conclusions: Our results demonstrate technical feasibility and 

highlight potential benefits of comprehensive cancer gene characterization 

through next-generation sequencing of clinical FFPE specimens. As NGS is 

the most practical means to detect all classes of somatic alteration in a 

small, clinically relevant sample, we suggest that this type of testing will 

become an essential component of patient care. 


11:30 AM-12:30 PM 

Frequency and clinical characterization of NSCLC patients harboring 

PIK3CA mutations identified within a regional screening network. Presenting 

Author: Masyar Gardizi, Lung Cancer Group Cologne, Center for 

Integrated Oncology, University Hospital Cologne, Cologne, Germany 

Background: PIK3CA mutations are a rare oncogenic event of potential 

therapeutic relevance in NSCLC. Here we report frequency and characteristics 

of patients with PIK3CA mutated lung tumors. Methods: Patients with 

NSCLC and PIK3CA mutations were identified within our regional Network 

for Molecular Screening in Lung Cancer. We further analyzed the presence 

of BRAF, KRAS, EGFR mutations as well as ALK translocation, ERBB2 and 

FGFR1 amplifications in PIK3CA mutated samples. Clinical data on age, 

sex, TNM classification and tumor stage, histological type, grading, overall 

survival, smoking status, comorbidity, BMI and secondary malignancies 

were retrieved from clinical charts in accordance with the local ethics 

committee. Results: PIK3CA mutations were detected with a frequency of 

3.7% (24% exon 20,76% exon 9) in 1000 patients. Histologically 32% 

were defined as squamous cell carcinoma, 48% as adenocarcinoma and 

18% other histological subtypes or NSCLC-NOS. Exon 9 mutations were 

present in the acinar and lepidic subtype, whereas exon 20 mutations were 

seen in the papillary and solid subtype. Cooccuring genetic lesions were 

observed in 16% (mutations in KRAS�2, EGFR�1, BRAF�1; FGFR1 

amplification�2). 14 were female, 23 male with a mean age of 69 years. 

21 of these patients were further clinically annotated. 11 patients 

presented with stage IIIb/IV eligible for palliative treatment and 10 stage I – 

IIIa eligible for surgical therapy �/- adjuvant therapy. All but 1 patient were 

smokers with an average BMI of 26,2kg/m2 with a typical high load of 

comorbidity mainly of cardiovascular diseases, 8 of 21 patients showed 

prior malignancies in their medical history. The median overall survival 

within this population has not been reached yet. Conclusions: Screening for 

PIK3CA mutations is feasible. A high proportion (38%) of patients with 

PIK3CA mutated lung cancer have prior malignancies and show a high load 

of comorbidity. Furthermore PIK3CA mutations are not exclusive to KRAS, 

EGFR or BRAF mutations or FGFR1 amplifications. Successful identification 

of patients with oncogenic lesions in lung cancer in a screening 

network might allow future personalized treatment of these patients. 


11:30 AM-12:30 PM 

Prospective study of oncogenic mutations in circulating cell-free DNA 

(cfDNA) using a multiplex sequencing platform for patient (pt) allocation to 

phase I clinical trials. Presenting Author: Michael Ong, Royal Marsden 

Hospital and Institute of Cancer Research, Sutton, United Kingdom 

Background: Studies suggest that tumoral cfDNA can be isolated from 

plasma and used as a biomarker. Methods: We conducted a prospective 

study in adult pts with advanced cancer referred for phase I clinical trials 

Sep09-Dec10 (A: Pilot Phase n�104) and Jan11-Sep11 (B: Expansion 

Phase n�176). cfDNA and tumor DNA from formalin-fixed paraffinembedded 

(FFPE) tissue were isolated, quantified, and analyzed for 238 

mutations in 19 oncogenes by the Sequenom OncoCarta Panel 1.0. 

Mutation data were used for trial allocation when available. Pt data and 

outcomes were collected. Statistical inferences used Wilcoxon rank-sum 

and Pearson’s Chi-squared. Results: 280 pts enrolled including breast (60), 

colorectal (42), ovarian (37), lung (31), and prostate (20); median age 

60yrs [23-81]; 93% ECOG PS 0-1. cfDNA in 95% and FFPE in 60% were 

analyzed. Median time to cfDNA result, trial allocation and consent were 7 

[5-14], 6 and 23 d. Median cancer pt cfDNA concentration (ng/ml) (A: 18 

[1-1600]; B: 34 [16-1657]) was higher than 20 healthy volunteers (6 

[5-13] A: p�0.0001) and higher in metastatic vs locally advanced cancer 

(A: 21 vs 4 p�0.0006; B: 42 vs 24 p�0.066). Pts with higher than 

median [cfDNA] had shorter median survival (MST) than below (A: 217 vs 

274 d, HR 1.72 95% CI 1.07-2.65, p�0.025; B: MST not reached yet). 

Mutations were found in 89 pts (32%), including KRAS (11%), PIK3CA 

(5%), MET (5%), BRAF (4%), and AKT (2%). cfDNA mutations (57 pts, 

21.5%) were mainly found above the median [cfDNA] (A: 41 vs 17% 

�2�6.9, p�0.009; B: 24 vs 11% �2�5.0, p�0.025). Of 155 pts with 

both cfDNA and FFPE available, 68 had mutations detected: 30 identical 

in cfDNA and FFPE; 28 in FFPE alone and 10 in cfDNA alone. Overall, 153 

pts were treated on a phase I trial; 23 pts had relevant mutation data and 

received a trial targeting the PI3-Akt-mTOR axis. Conclusions: Higher 

cfDNA is associated with greater disease burden, worse prognosis, and 

higher mutation detection rate, suggesting cfDNA is tumorally derived. 

Moreover, cfDNA can be analyzed for oncogenic mutations in a time-frame 

suitable for clinical decision making, making it a potentially useful 

non-invasive adjunct to tumour DNA analysis. 


11:30 AM-12:30 PM 

Association of EGFR mutation or ALK rearrangement with expression of 

DNA repair and synthesis genes in never-smoker females with pulmonary 

adenocarcinoma. Presenting Author: Xiaoxia Chen, Department of Oncology, 

Shanghai Pulmonary Hospital, Tongji University; Tongji University 

Medical School Cancer Institute, Shanghai, China 

Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic 

lymphoma kinase (ALK) rearrangement was found not only predict the 

efficacy of targeted drugs, but also associate with the efficacy of chemotherapy 

drugs in non-small cell lung cancer (NSCLC) patients. We investigated 

the relationship of EGFR mutation status or ALK rearrangement and 

DNA repair or synthesis genes, such as excision repair cross-complementing 

1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate 

synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a 

potential explanation for these observations. Methods: In this surgical 

series, 104 resected lung adenocarcinomas from nonsmoker females were 

analyzed concurrently for the EGFR mutation, ALK rearrangement status 

and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR 

mutation detection was performed by the method of ADx-ARMS, ALK 

rearrangement was detected by PCR and the mRNA expression of different 

genes were tested using the method of real-time PCR. Results: 73 (70.2%) 

patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. 

The ERCC1 mRNA level in patients with EGFR mutation was 

3.44�1.94�10 -3 

, which is significantly lower than in the patients with 

ALK positive and both negative(4.60�1.95�10 -3 and 4.95�2.33�10 -3 

respectively, P�0.010). While the TS mRNA levels were significantly lower 

in the patients with EGFR mutation(1.15�1.38�10 -3 VS 

2.69�3.97�10 -3 , P�0.006) or ALK positive (1.21�0.78�10 -3 VS 

2.69�3.97�10 -3 , P�0.020) than in patients with both negative. 

Conclusions: NSCLC specimens harboring activating EGFR mutations are 

more likely to express low ERCC1 and TS mRNA levels, while NSCLC 

patients with ALK rearrangement are more likely to express low TS mRNA 

levels, which could be helpful to select a proper chemotherapy regimen for 

NSCLC patients with known EGFR mutation or ALK fusion status. 



11:30 AM-12:30 PM 

New microRNA-based diagnostic test for lung cancer classification. Presenting 

Author: Ranit Aharonov, Rosetta Genomics, Rehovot, Israel 

Background: Lung cancer is the leading cause of cancer deaths in the US. 

Treatment options are determined by tumor subtyping, for which there is 

lack of standardized, objective, and highly accurate techniques. In 20%- 

30% of cases significant limitations of tumor quantity and quality prevent 

full classification of the tumor using traditional diagnostic methods. Using 

microRNA microarray data generated from over a hundred formalin-fixed, 

paraffin-embedded (FFPE) primary lung cancer samples, we have identified 

microRNA expression profiles that differ significantly for the main lung 

cancer types. Based on these findings, we have developed and validated a 

microRNA-based qRT-PCR assay that differentiates primary lung cancers 

into four types: squamous cell carcinoma, non-squamous non-small cell 

lung cancer, carcinoid and small cell carcinoma. Methods: Over 700 

primary tumor samples from different histological types of lung cancer were 

collected. Samples included FFPE blocks from resection or biopsies and 

cell blocks from cytology specimens including fine needle aspiration, 

bronchial brushing and bronchial washing. High-quality RNA was extracted 

from the samples using proprietary protocols. Expression levels of potential 

microRNA biomarkers were profiled using microarrays followed by a 

sensitive and specific qRT-PCR platform. An assay for lung tumors 

classification using 8 microRNAs on qRT-PCR was developed based on 

data from 261 samples. This assay was validated on an independent 

blinded set of 451 cytological and pathological samples. Results: Using the 

expression levels of 8 microRNAs measured in qRT-PCR, accurate classification 

of the primary lung tumors into the four main cancer types is 

obtained. The microRNA-based assay reached an accuracy of 94%. 

Moreover, cytological samples composed over 50% of the validation set 

and reached an accuracy of 95%. Conclusions: We present here a new 

microRNA-based assay for the classification of the four main types of lung 

cancer based only on the expression of 8 microRNAs. This assay displays 

very high levels of accuracy for both pathological and cytological samples. 

The assay comprises a standardized, well-tested and objective tool which 

can assist physicians in the diagnosis of lung cancer. 


11:30 AM-12:30 PM 

Molecular gene expression profiling to predict the tissue of origin and direct 

site-specific therapy in patients (pts) with carcinoma of unknown primary 

site (CUP): Results of a prospective Sarah Cannon Research Institute 

(SCRI) trial. Presenting Author: Frank A. Greco, SCRI/Tennessee Oncology, 

PLLC, Nashville, TN 

Background: Tumor profiling is an emergent technique to determine tissue 

of origin in CUP patients. However, the value of these predictions in 

improving treatment efficacy is unknown. In this prospective trial, we used 

tumor profiling results to direct site-specific therapy for CUP pts. Methods: 

A 92-gene RT-PCR assay (CancerTYPE ID; bioTheranostics, Inc.) was 

performed on tumor biopsies from previously untreated CUP pts who 

consented. When a tissue of origin was predicted, pts who were treatment 

candidates were assigned standard site-specific first-line therapy. Results: 

Between 10/08 and 12/11, 289 pts were enrolled, 252 had successful 

assays performed, and 247 (98%) had a tissue of origin predicted. 224 pts 

were eligible for treatment; 197 pts received assay-directed treatment. 

120 of 224 treated pts (54%) had assay diagnoses of tumor types known to 

derive substantial benefit from standard site-specific treatment (bladder 

27, colorectal 26, NSCLC 24, breast 10, ovary 10, kidney 9, prostate 4, 

germ cell 4, others 6 (3 sites), while 104 pts (46%) had assay diagnoses of 

relatively resistant tumors (biliary tract 45, pancreas 12, gastroesophageal 

10, liver 7, sarcoma 5, cervix 5, others 20 (8 sites). Median OS for all 

treated pts was 10.8 months (mos); OS for 197 pts with assay-directed 

treatment was 12.2 mos (versus 6.0 mos for 27 pts receiving empiric 

therapy). Median OS was better in the 120 pts with assay diagnoses of more 

responsive tumor types (12.8 vs 7.4 mos; p � .027). Median OS (mos) in 

specific subgroups: pancreas 9, kidney 12, colon 12, NSCLC 16, ovary 30. 

Conclusions: This is the first prospective trial in which molecular profiling 

has directed site-specific therapy in CUP pts. Assay-directed therapy in 

197 pts produced a median OS (12.2 mos) that compares favorably with 

previous empiric CUP therapy. CUP pts predicted to have more responsive 

tumor types had longer survival compared to less responsive types, 

suggesting accurate identification by the assay. These results strengthen 

the rationale for molecular profiling in CUP management. 

Tumor Biology 

663s 

CRA10529 Poster Discussion Session (Board #22), Tue, 8:00 AM-12:00 PM 

and 11:30 AM-12:30 PM 

Regional screening network for characterization of the molecular epidemiology 

of non-small cell lung cancer (NSCLC) and implementation of 

personalized treatment. Presenting Author: Thomas Zander, Lung Cancer 

Group Cologne, Center for Integrated Oncology, University Hospital Cologne, 

Cologne, Germany 








Homeobox B9: A potential surrogate marker for bevacizumab in combination 

with chemotherapy in colorectal cancer. Presenting Author: Yoshinori 

Hoshino, Department of Surgery, Keio University School of Medicine, 

Tokyo, Japan 

Background: Homeobox B9 (HOXB9) is known to be overexpressed in 

human breast cancer and profoundly related to tumorigenicity, lung 

metastasis and radio-resistance. (Hayashida, PNAS 2010, and Chiba, 

PNAS 2011). However, little is known about the relation between the 

expression of HOXB9 and angiogenesis in colorectal cancer (CRC). We 

aimed to clarify the impact of HOXB9 in CRC and evaluate the importance 

for bevacizumab treatment. Methods: The expression of HOXB9 in human 

CRC specimens was analyzed. Then, we introduced HOXB9 construct into 

human CRC cell lines and examined TGF� signaling and angiogenic 

factors. Xenograft model was established by these cell lines either with or 

without the administration of bevacizumab (5mg/kg, weekly) intraperitoneally. 

Finally, we examined the mRNA levels of consecutive patients who 

were treated by chemotherapy with bevacizumab in our institute and 

calculated the Kaplan- Meier curve with log-rank test. Results: 47 of 69 

surgical specimens (67%) showed positive expression of HOXB9 mRNA. 

The high HOXB9 mRNA levels significantly correlated with poor differentiation 

and liver metastasis. The HOXB9-overexpressed cell lines showed 

significantly higher expression of TGF� signaling target genes and angiogenic 

factors. HOXB9 overexpression significantly increased tumor volume 

and burden with higher microvessel density in vivo, even though the cell 

proliferation decreased in vitro. Notably, HOXB9-overexpressed tumor was 

dramatically shrunk by administration of bevacizumab (tumor shrinkage 

rate; 93% vs. 42% in HT29, 83% vs. 27% in HCT116). Patients with high 

expression of HOXB9 in tumor showed significantly longer progression free 

and overall survival periods (n�39). Conclusions: Our results demonstrated 

that patients with high expression of HOXB9 in tumor had better prognosis 

with bevacizumab treatment but worse without. In vivo and in vitro 

experiments revealed that HOXB9 might orchestrate angiogenesis and 

establish positive feedback between cancer cells and microenvironment. 

Bevacizumab might inhibit the feedback to reduce tumor growth dramatically. 

Therefore, HOXB9 may work as a potential surrogate marker of 

bevacizumab treatment in CRC. 




VEGF polymorphism may be associated with overall survival in lapatinibtreated 

breast cancer patients with brain metastases. Presenting Author: 

Colin F. Spraggs, GlaxoSmithKline, Stevenage, United Kingdom 

Background: Lapatinib is a dual HER2/EGFR tyrosine kinase inhibitor (TKI) 

approved in combination with capecitabine or letrozole for patients with 

HER2� metastatic breast cancer (MBC). Consistent with TKI therapies, 

patient response is variable and suggestive of additional determinants of 

sensitivity and resistance. This exploratory pharmacogenetic study sought 

to identify germline genetic variants that associate with lapatinib treatment 

outcomes in HER2� MBC patients. Methods: Fifty five functional single 

nucleotide polymorphisms (SNPs) in 24 candidate genes were evaluated in 

a subset of MBC patients participating in two clinical trials: EGF105084: 

lapatinib monotherapy in HER2� MBC patients with recurrent brain 

metastases following trastuzumab and cranial radiotherapy (n�120) and 

EGF104900: lapatinib plus trastuzumab (n�92) and lapatinib monotherapy 

(n�103) in HER2� MBC patients with disease progression 

following trastuzumab. Testing for associations of SNPs with progression 

free survival (PFS) and overall survival (OS) during lapatinib treatment was 

performed using Cox proportional hazards methods, with covariate adjustment. 

Markers were considered to be significantly associated if they 

achieved a predefined multiple testing threshold of p�0.0003. Results: No 

SNPs were significantly associated with PFS in either study. A SNP in 

VEGFA (rs3025039, 936C�T) was significantly associated with improved 

OS (p�0.0002) for the T allele carriers, with an allelic hazard ratio of 0.21 

(0.08-0.52) in EGF105084. The association was not seen in EGF104900. 

This SNP is located in the 3’ UTR gene region, the T allele is associated 

with lower serum VEGFA levels and reduced breast cancer risk [Krippl et al, 

2003, Int J Cancer 106: 468; Kataoka et al, 2006, Cancer Epidemiol 

Biomarkers Prev, 15:1148]. Conclusions: A germline variant in VEGFA may 

be associated with survival outcome in MBC patients with brain metastases 

who are treated with lapatinib. This may represent activation of VEGF 

angiogenic pathways to overcome HER2 inhibition in patients carrying the 

higher expression genotype. These associations are considered exploratory 

and require confirmation in an independent dataset. 


Molecular characterization of circulating tumor cells in human metastatic 

colorectal cancer. Presenting Author: Jorge Barbazan, Translational Oncology 

Laboratory, Medical Oncology Department, Santiago de Compostela, 

Spain 

Background: Metastatic colorectal cancer (mCRC) relies on the detachment 

of aggressive malignant cells from the primary tumor into the bloodstream, 

being this Circulating Tumor Cells (CTC) the principal source of the further 

metastasis. Clinically, the presence of CTC is associated with poor 

prognosis and there exists a clear necessity for more specific and efficient 

chemotherapies in the treatment of mCRC. Our aim was to overcome this 

adverse scenario through the massive molecular profiling of the CTC 

population isolated from mCRC patients. Methods: CTC’s were magnetically 

isolated by using anti-EpCAM coupled magnetic beads from 6 mCRC 

patients and 3 healthy controls. The presence of CTCs was evaluated by 

citokeratins 8, 18 and 19 staining. RNA from CTCs was amplified by a 

whole transcriptome amplification system (WTA) and resulting material was 

hybridized onto gene expression arrays. Bioinformatics were used to array 

analysis. Selected genes were validated by RT-qPCR. Results: 410 transcripts 

were found to specifically characterise the CTC population after 

array signals comparison between mCRC patients and controls. Gene-gene 

interaction analysis generated networks related with cell migration, adhesion 

or apoptosis resistance. Gene ontology revealed similar functions. 

Signalling pathways such as RhoA, PKA, ILK, integrins or actin cytoskeleton 

signalling were found as relevant in CTCs. Eleven genes (TGFB1, APP, 

TIMP1, CD9, CLU, ITGB5, LIMS1, RSU1, VCL, BMP6 and TLN1) were 

validated by real-time PCR in 20 mCRC patient and 10 control samples. All 

genes showed a significantly higher expression in patients (p�0.0001). 

Except from TLN1 and CD9, all genes had a prognostic value in terms of 

progression free survival (p�0.05). Conclusions: We described the molecular 

profiling of CTCs in stage IV CRC patients, characterized by a migratory 

and invasive phenotype. Specific and sensitive diagnostic/prognostic markers 

were obtained. Our strategy represents an innovative and promising 

approach in the clinical management of mCRC patients. 


Isolation of circulating tumor cells using a novel EMT-based capture 

method. Presenting Author: Rhonda Lynn Bitting, Duke Cancer Institute, 

Durham, NC 

Background: Circulating tumor cells (CTCs) have potential prognostic, 

predictive and surrogate implications in oncology. In patients with metastatic 

castration-resistant prostate cancer (CRPC) and breast cancer (BC), 

we have shown that CTCs isolated using epithelial cell adhesion molecule 

(EpCAM) ferromagnetic capture express mesenchymal markers, including 

N- and O-cadherin, suggesting phenotypic plasticity and the presence of 

epithelial-mesenchymal transitions (EMT). Therefore, we postulate that 

during metastasis, tumor cells exist as a spectrum of epithelial to 

mesenchymal phenotypes and may not be captured with existing EpCAMbased 

CTC technology. The goal of this study is to identify CTCs in CRPC 

and BC patients using a novel mesenchymal-based capture method. 

Methods: In patients with advanced CRPC and BC, two EDTA and one 

CellSave tube of blood are collected. Using the CellSearch system (Veridex, 

USA), CTCs are captured with either anti-N-cadherin (N-cad) or anti-Ocadherin 

(O-cad) ferrofluid and detected cells (events) are defined as 

beta-catenin and DAPI positive, CD45 negative intact cells. We evaluated 

the performance of these EMT-based ferrofluids in healthy volunteers, 

control cells, and in a pilot study of patients with CRPC, and compared 

enumeration of cells using novel vs. standard EpCAM-based capture 

methods. Results: In healthy volunteers, rare events were detected using 

the novel capture methods. In CRPC patients, O-cad capture detected more 

events in 3 of 5 subjects than EpCAM-based capture, and the majority of 

captured cells were cytokeratin negative. See table below. Conclusions: 

These preliminary results suggest that a novel CTC phenotype exists in 

CRPC based on EMT properties, particularly overexpression of O-cadherin. 

Further characterization of these cells from patients with advanced PC, BC, 

and other solid tumors will provide insight into EMT and metastasis biology. 

O-cad capture, beta-catenin� N-cad capture, beta-catenin� EpCAM capture, cytokeratin� 

Healthy volunteers 0-51 events (mean 5.95) n�21 0-4 events (mean 0.28) n�25 NA 

CRPC patients 0-465 events (mean 138.4) n�5 0-2 events (mean 1.2) n�5 1-123 CTCs (mean 50.8) n�5 


Profiling of circulating tumor cells isolated from 105 metastatic gastric 

cancer patients revealed HER2 overexpression/activation for potential use 

in clinical setting. Presenting Author: Saswati Hazra, Prometheus Laboratories 

Inc., San Diego, CA 

Background: Gastric cancer (GCA) is the second leading cause of cancer 

mortality in the world. Survival of patients with advanced GCA treated with 

chemotherapy remains low. New targeted therapies are urgently needed. 

There is mounting evidence of the role of HER2 overexpression in patients 

with GCA, and it has been highly correlated to poor outcomes with more 

aggressive disease. The ability to accurately determine HER2 status by 

testing circulating tumor cells (CTCs) may improve patient treatment by 

allowing ongoing assessment of HER2 status during treatment and/or 

identifying additional patients who could potentially benefit from HER2targeted 

therapy. Methods: The Collaborative Enzyme Enhanced Reactiveimmunoassay 

(CEER) was utilized to determine the expression and activation 

(phosphorylation) levels of HER2 in CTCs isolated from blood specimens 

obtained from 105 metastatic GCA patients. Results: Utilizing the CEER 

platform, the levels of HER2 expression and phosphorylation were determined 

for CTCs isolated from metastatic GCA patients. Evaluable CTCs 

were found in 33% (35/105) of enrolled patients. Out of 35 patients, 7 

patients (20%) have high HER2 over expression, 6 patients (17%) have 

moderate HER2 expression and 11 patients (31%) have HER2 activation 

(phospho positive) with no HER2 over-expression. Conclusions: When CTCs 

were present, the CEER assay identified varying levels of HER2 involvements 

in 68% of metastatic GCA patients. HER2 positive CTCs could serve 

as a prognostic and/or predictive marker in patients with advanced GCA and 

CTC-HER2 profile shifts can be utilized to monitor the treatment efficacy. 



In vivo isolation of circulating tumor cells in non-small cell lung cancer 

(NSCLC) patients by a medical device. Presenting Author: Lukasz Gasiorowski, 

Medical University Poznan, Poznan, Poland 

Background: Currently, circulating tumor cells (CTCs) are isolated in vitro 

from small limited volumes of blood samples. Furthermore, CTC results for 

NSCLC as a prognostic and stratification biomarker are scarce. The aim of 

the study was to assess a functionalized and structured medical wire 

(FSMW) for in vivo isolation of CTCs directly from the blood of NSCLC 

patients, and to compare it to the Cell Search method. Methods: The device 

was inserted in a cubital vein through a standard cannula for thirty minutes. 

The interaction of target CTCs with the FSMW was mediated by an antibody 

directed against the epithelial cell adhesion molecule (EpCAM). To confirm 

the CTCs binding to the wire, the immunohistochemical staining against 

EpCAM as well as CD45 for negative cell selection was performed. There 

were 72 applications of the wire in 48 stage I-IIIB NSCLC patients (12 

double applications) and 12 non cancer patients. Enumeration data was 

available for 34 NSCLC patients and 8 non cancer patients. For 34 

patients, samples were also tested in the Cell Search system. Results: The 

device was well tolerated in all 72 applications without side effects. We 

obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with 

a median (range) of 13 (0-300) CTCs. The sensitivity was similar for early 

and late stage NSCLC patients. In the non-cancer patients, no CTCs were 

detected (100 % specificity). In 2 of 34 samples (5.8%), CTCs were 

detected by the Cell Search method. In all matched pairs, the FSMW 

detected the same number or more CTCs compared to the Cell Search 

method. Conclusions: Whilst well tolerated without side effects, the CTC 

detection rate of the FSMW in NSCLC patients was �90%. In contrast, 

�10% detection was obtained using the Cell Search analysis. No CTCs 

were detected in non-cancer patients. This proof of concept study may have 

important clinical implications, as the implementation of the device into 

clinical practice may improve early detection, prognosis and therapy 

monitoring of NSCLC patients. The method may also allow the molecular 

analysis of the CTCs, with the possibility of establishing more personalized 

treatment regiments. 


Prognostic and diagnostic value of Ewing family of tumors (EFTs)associated 

fusion transcripts detected in peripheral blood specimens. 

Presenting Author: Joanna Przybyl, Department of Molecular Biology, 

Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 

Warsaw, Poland 

Background: EFTs are characterized by chromosomal translocations leading 

to formation of oncogenic EWSR1-FLI1 fusion gene in 85-90% of cases. 

The aim of the study was to detect circulating tumor cells (CTCs) carrying 

EWSR1-FLI1 fusion transcript in peripheral blood and assess their added 

value to standard diagnostic procedures and utility as a prognostic marker 

in EFTs. Methods: 10mL of whole blood was collected from 35 untreated 

adult EFTs patients at the diagnosis (period: 2008-2011, median age 27 

years) and 13 healthy controls. 13 patients presented metastatic disease 

(M1) at the diagnosis. Nested RT-PCR was applied in triplicate for the 

detection of EWSR1-FLI1 transcript. Blood specimen was regarded CTCpositive 

when at least 2 out of 3 nested RT-PCR assays were positive and 

results were confirmed by sequencing. FISH assay for EWSR1 rearrangement 

was performed on FFPE tumor tissue in 28 available cases. Median 

follow-up was 16 months. Results: EWSR1-FLI1 transcript was detected in 

peripheral blood of 71.4% (n�25) of patients. FISH assay was positive for 

EWRS1 rearrangement in 58% of cases. In 10 patients, where FISH assay 

could not be performed due to insufficient quality or lack of material, 

nested RT-PCR provided confirmation of immunopathological diagnosis. 

Specificity of RT-PCR blood test in healthy control was 91.4% (12/13 

negative; p�0.0001). Median overall survival (OS) was 18 months. 

CTC-positive patients showed the trend for longer OS than CTC-negative 

patients (1-year OS: 89% vs. 58%; p�0.07), but longer follow-up is 

needed. Conclusions: Our results show that the fusion transcript detection 

in peripheral blood specimens may be a useful additional test to the 

standard clinicopathological diagnosis of EFTs. High detection rate of 

EWSR1-FLI1 transcript in peripheral blood of EFTs patients at the 

diagnosis may imply EFTs as a systemic disease with clinically evident 

metastases or micrometastases at presentation. Prognostic significance of 

CTCs in EFTs warrants further studies. 

Tumor Biology 

665s 


A new medical device for in vivo capturing of circulating tumor cells in 

breast cancer (BC) patients. Presenting Author: Dawid Murawa, Wielkopolska 

Cancer Centre, Poznan, Poland 

Background: In BC, the number of circulating tumor cells (CTCs) is 

discussed as a prognostic and stratification biomarker, and could also 

reflect treatment efficacy. Currently, CTCs are isolated ex vivo from a small 

volume of blood. Results from a larger volume of blood are scarce. The aim 

of the study was to assess a functionalized and structured medical wire 

(FSMW) for in vivo capturing of CTCs directly from the blood stream of BC 

patients. Methods: The device was inserted in a cubital vein through a 

standard cannula for thirty minutes. The interaction of target CTCs with the 

FSMW was mediated by antibodies directed against the epithelial cell 

adhesion molecule (EpCAM). To confirm binding of CTCs to the wire, the 

immunohistochemical positive staining against EpCAM as well as negative 

staining for CD45 was performed. There were 54 applications of the wire in 

42 stage I-IV BC patients (12 double applications). Enumeration data from 

37 BC patients with 49 applications (5 failed subsequent analyses) were 

assessed. CTC counts on 23 devices were directly compared to counts by 

CellSearch. Results: The device was well tolerated in all 54 applications 

without side effects. We obtained in vivo isolation of CTCs in 44 of 49 

applications to BC patients (89.7 %). The sensitivity was similar for early 

and late stage BC patients. The median (range) of isolated EpCAM-positive 

CTCs was 5 (0-515). The CellSearch method reached a sensitivity of 

18.5%. In all paired samples the number of CTCs detected with the FSMW 

was higher or equal to CellSearch, regardless of the disease stage. Linear 

regression of the data of the double application of the FSMW showed a very 

good concordance (r2 � 0.97, p�0.0001). Conclusions: Whilst well 

tolerated without side effects, the CTC detection rate of the FSMW in BC 

patients was nearly 90 %. CTC detection was obtained in 18.5% by the 

CellSearch. Double application of FSMWs in the same patient indicates 

ample precision. This proof of concept study may have important clinical 

implications, as the device may improve early detection, prognosis and 

therapy monitoring of BC patients. The molecular analysis of the captured 

CTCs could become a breakthrough in personalized medicine. 


Circulating melanoma cells isolated from clinical blood samples and 

characterized by full-length mRNA sequencing at single-cell level. Presenting 

Author: Yu-Chieh Wang, Department of Chemical Physiology, The 

Scripps Research Institute, La Jolla, CA 

Background: Melanoma is the most aggressive type of skin cancer. Latestage 

melanoma is highly metastatic and currently lacks effective treatment. 

This discouraging clinical observation highlights the need for a better 

understanding of the molecular mechanisms underlying melanoma initiation 

and progression and for developing new therapeutic approaches based 

on novel targets. Although genome-wide transcriptome analyses have been 

frequently used to study molecular alterations in clinical samples, it has 

been technically challenging to obtain the transcriptomic profiles at 

single-cell level. Methods: Using antibody-mediated magnetic activated 

cell separation (MACS), we isolated and individualized putative circulating 

melanoma cells (CMCs) from the blood samples of the melanoma patients 

at advance stages. The transcriptomic analysis based on a novel and robust 

mRNA-Seq protocol (Smart-Seq) was established and applied to the 

putative CMCs for single-cell profiling. Results: We have discovered distinct 

gene expression patterns, including new putative markers for CMCs. 

Meanwhile, the gene expression profiles derived of the CMC candidates 

isolated from the patient’s blood samples are closely-related to the 

expression profiles of other cells originated from human melanocytes, 

including normal melanocytes in primary culture and melanoma cell lines. 

Compared with existing methods, Smart-Seq has improved read coverage 

across transcripts, which provides advantage for better analyzing transcript 

isoforms and SNPs. Conclusions: Our results suggest that the techniques 

developed in this research for cell isolation and transcriptomic analyses can 

potentially be used for addressing many biological and clinical questions 

requiring genomewide transcriptome profiling in rare cells. 




HER2 expression on circulating tumor cells (CTC) in patients with early 

HER2-positive breast cancer: Results of the German SUCCESS B trial. 

Presenting Author: Bernadette Anna Sophia Jaeger, Department of Gynecology 

and Obstetrics, Ludwig-Maximilians-University, Munich, Germany 

Background: Recent reports showed a discrepancy in the Her2-status of 

metastases or minimal residual disease in blood and bone marrow compared 

to the primary tumor in patients with breast cancer. The Her2-status 

of CTC was prospectively evaluated in the German multicenter SUCCESS B 

study. Methods: The SUCCESS B trial is a randomized Phase III study 

comparing FEC-Docetaxel (Doc) vs. FEC-Docetaxel-Gemcitabine (Doc-G) 

as well as Her2 targeted therapy with Trastuzumab as adjuvant treatment in 

patients with early, Her2 positive, node positive or high risk node negative 

primary breast cancer. As part of the translational research program, 23ml 

of peripheral blood were drawn before adjuvant chemotherapy. In 638 

samples CTC and Her2-status were assessed using the CellSearch System 

(Veridex, USA). After immunomagnetic enrichment with an anti-Epcamantibody, 

cells were labeled with anti-CK8/18/19, anti-CD45 antibodies as 

well as a fluorescein conjugate antibody for Her2 phenotyping. Cutoff for 

CTC-positivity was �1 CTC and for Her2 �1 CTC with strong Her2-staining 

(��). Results: 40.2% of pts (n�257) were positive for CTC (mean 4.52; 

range 0-1689). The number of detected CTC was distributed as follows: 1 

CTC (n�112; 43.6%), 2 CTC (n�65; 25.3%), 3 CTC (n�36; 14.0%), 4 

CTC (n�12; 4.7%) and �5 CTC (n�31; 12.1%). Her2 status on CTC was 

negative or weak in 12.5% (n�32) and 8.9% (n�23) of CTC positive 

patients respectively and therefore categorized as Her2 negative. In 21.4% 

(n�55) we detected moderate and in 57.2% (n�147) strong Her2staining 

of �1 CTC per sample. Therefore 57.2% of CTC-positive samples 

were diagnosed as Her2 positive and 21.4% as questionable. No association 

was found between the detection of CTC or the Her2-status on CTC 

with tumor size, histopathological grading, hormone receptor status or 

axillary lymph node involvement. Conclusions: The data of this trial 

confirms the frequent discordance of Her2 expression on CTC compared to 

the primary tumor. Survival data within the Success B trial will give further 

insight into the tumor biology of Her2 positive disease and the role of the 

Her2-status on CTC to predict treatment efficacy. 


Serum hepatocyte growth factor and interleukin-6 as prognostic markers 

for stage III non-small cell lung cancer. Presenting Author: Hideki Ujiie, 

Department of Thoracic Surgery, Saitama Cancer Center, Saitama, Japan 

Background: We surveyed prognostic biomarkers for resectable non-small 

cell lung cancer (NSCLC). Methods: We obtained preoperative serum from 

109 patients admitted to our facility, and measured the levels of hepatocyte 

growth factor (HGF), interleukin-6 (IL-6), and nicotinamide 

N–methytransferase (NNMT) in the sera by the ELISA method. We also 

examined the clinical backgrounds of the patients. Results: The median 

HGF and IL-6 contents in sera from 109 patients were 860 pg/ml and 2.7 

pg/ml, respectively. Analysis of survival curves indicated that HGF or IL-6 

levels higher than the median were associated with poor overall survival 

(HGF, P � 0.019; IL-6, P � 0.002). On the other hand, carcinoembryonic 

antigen (CEA), a known tumor marker, and NNMT, which we found to be a 

candidate tumor marker, exhibited no correlation with the prognosis. The 

tumor status (pT factor) and stage were strong prognostic indicators (P � 

0.001). In addition, we analyzed stage III lung cancer alone. Higher HGF or 

IL-6 levels were associated with poor overall survival (HGF, P � 0.016; 

IL-6, P � 0.013). Disease-free survival was also affected by these cytokine 

contents, but not statistically significantly. The prognosis of patients with 

adenocarcinomas (ADC) was better than that of patients with other 

histological types. However, the pT factor and nodal status (pN factor) were 

not associated with the survival of stage III patients. Conclusions: The levels 

of HGF and IL-6 in serum could be useful prognostic indicator of the 

survival of stage III NSCLC patients undergoing surgery and chemotherapy. 


Detection and HER2 expression of circulating tumor cells in advanced 

gastric cancer patients. Presenting Author: Satoshi Matsusaka, Department 

of Gastroenterology, Gastroenterology Center, Cancer Institute Hospital; 

Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese 

Foundation for Cancer Research, Tokyo, Japan 

Background: This study was aimed at detecting and HER2-expressiong 

circulating tumor cells (CTC) in peripheral blood of chemo-naïve or 

chemo-resistant patients with advanced gastric cancer. Methods: All 

patients were enrolled using institutional review board-approved protocols 

at the Cancer Institute Hospital in the Japanese Foundation for Cancer 

Research and provided informed consent. The study population consisted 

of patients of age 18 years or older with histologically proven advanced 

gastric cancer. A total of 140 patients with advanced gastric cancer were 

enrolled into a prospective study. We used CellSearch system for detection 

and HER2 expression for CTC. Results: We detected �1 CTC/7.5ml in 80 of 

140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 

CTC-positive patients (23.8%), including 6 patients with HSR2-negative 

primary tumors. 21 patients with HER2-positive primary tumors administered 

trastuzumab in combination with chemotherapy (Xeloda�cisplatin; 

15, weekly Paclitaxel; 5). We detected �1 CTC/7.5ml at the baseline in 11 

of 20 patients with trastuzumab treatment. HER2-positive CTCs were 

observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2positive 

CTC at the baseline were shorter PFS than those with HER2negative 

CTC at the baseline. Conclusions: HER2 expression on CTC was 

associated with chemo-resistance. Information on the HER2 status of CTC 

might be helpful for stratification of HER2-directed therapies. 


Promoter methylation of MGMT in paired primary and recurrent glioblastomas. 

Presenting Author: Li Bie, The First Hospital of Jilin Universtiy, 

Changchun, China 

Background: Epigenetic sliencing of MGMT gene promoter in primary 

glioblastomas (GBM) of pts subsequently treated with temozolomide (TMZ) 

is associated with prolonged survival. Further, several studies have observed 

a change in MGMT silencing in paired primary and recurrent GBM. 

However, the relationship between this “MGMT switch” and patients 

outcome is largely unknown. Methods: The study involved primary and 

recurrent tumor tissue samples from 53 GBM pts diagnosed and treated 

within the First Hospital of Jilin University from Jan 2003 to Nov 2010. 

After surgical treatment, all pts were subjected to radiotherapy with 

concomitant administration of TMZ (75 mg/m2 /d), followed by 5 cycles of 

adjuvant TMZ given at 4-weeks intervals. Pts that experienced recurrent 

tumors received TMZ at a dose of 200 mg/m2 /5 days for 4 weeks. 53 pts 

underwent 58 further operations after recurrence (5 pts received a third 

surgery). MGMT promoter methylation levels were determined using qMSP. 

The relationship between “MGMT switch” and clinical outcome was 

investigated. Results: Fifty three (M/F�33/20; median age: 49.2�3.6, 

range: 19.5-72.3 ys) underwent a first operation for GBM. qMSP analysis 

revealed MGMT promoter methylation in 19 pts (35.8%, group A, OS 31.5 

ms); no methylation in 34 pts (64.2%, group B, OS 7.9 ms). In the 

recurrent tumors, MGMT promoter methylation was detected in 25 pts 

(47.2%); and no methylation in 28 pts (52.8%). Comparison of individual 

pairs of primary and recurrent GBMs revealed a changed methylation status 

in 10 (18.9%), including eight changed from unmethylated to methylated 

tumors (15.1%, group C, OS 29.4 ms), two changed from methylated to 

unmethylated tumors (3.8%, group D, OS 10.5 ms). Median overall 

survival was 12.1 ms. MGMT promoter methylation was significantly 

associated with a favorable clinical outcome (group A vs group B, 

p�0.0027). The outcome of pts were not significant different between A 

and C (p�0.01). Conclusions: The methylation status of the MGMT 

promoter was altered in 10 (18.9%) of 53 recurrent GBM after chemoradiotherapy. 

Eight pts changed from unmethylated to methylated who have a 

median overall survival similar to methylated pts. The pts changed from 

methylated to unmethylated who have poor outcome. 



DJ-1 as a predictor of pathologic complete remission of neoadjuvant 

chemotherapy with breast cancer patients. Presenting Author: Takahiko 

Kawate, Basic Pathology, National Defence Medical Colleage, Saitamaken, 

Japan 

Background: DJ-1 is a multifunctional protein which is encoded by the 

causative gene of familial Parkinson disease (i.e., PARK7), and is associated 

with carcinogenesis. DJ-1 is also a candidate marker for the presence 

of breast cancer cells, in which it is secreted in nipple fluid and serum. We 

previously reported that a DJ-1 expression pattern that is low at the protein 

level and high at the mRNA level is associated with DJ-1 secretion. This 

secretory expression pattern correlated with a negative hormone receptor 

status and with unfavorable clinical outcome in breast cancer patients. 

However, the association of the DJ-1 secretion pattern with therapeutic 

effect has yet to be determined. Methods: A total of 299 patients received 

neoadjuvant chemotherapy and surgery from 2002 to 2010 at our 

institution. We performed immunohistochemistry and in-situ hybridization 

of DJ-1 in both the needle biopsy and operative specimens of 147 cases 

with a follow-up time of 3.1 years. The average degree of staining intensity 

was evaluated semi-quantitatively using an image analyzer. Univariate and 

multivariate analyses were used to evaluate the predictive value of the 

therapeutic effect of neoadjuvant chemotherapy. Results: A low expression 

of DJ-1 protein was detected in the needle biopsy and operative specimens 

of 89 of the 147 cases, regardless of a high or maintained mRNA level. The 

tumor response was evaluated as pathological complete remission (pCR) in 

39 cases and as non-pCR in the remaining 108 cases. A low expression of 

DJ-1 protein, which was detected in 34 (87.2%) pCR cases, was a 

significant predictor on univariate analysis (P �0.001). On multivariate 

analysis, a low expression of DJ-1 was shown to be a significant independent 

predictor similar to established predictors such as estrogen receptor 

status and human epidermal growth factor receptor 2 score. Conclusions: A 

low expression of DJ-1 protein can serve as a novel and important predictor 

of a neoadjuvant chemotherapeutic effect, as well as a promising indicator 

for serologic diagnosis in breast cancer patients. 


Evaluation of CYP3A5, VEGF-a, and VEGFR2 polymorphisms as markers of 

sunitinib toxicity. Presenting Author: Cristina Rodriguez de Antona, Spanish 

National Cancer Research Center, Madrid, Spain 

Background: Sunitinib (Sun) is a multitargeted tyrosine-kinase inhibitor 

approved for the treatment of renal cell carcinoma (RCC), GIST and 

pancreatic neuroendocrine tumors (pNETs). It is known that a polymorphism 

in Sun metabolizing gene CYP3A5, was associated with an increased 

risk of dose reductions due to toxicity (tox). Additionally, polymorphisms in 

VEGF-A and VEGFR2 were suggested to increase the risk of hypertension 

(HT) during treatment (García-Donas, et al. Lancet Oncol 2011). These 

data have not been validated so far. We aim to assess the value of these 

polymorphisms as markers of tox using a wide range of solid tumors treated 

with Sun. Methods: In this non-interventional and retrospective study, DNA 

was collected from 28 patients with different pathologies (16 pNETs, 5 

medullary thyroid carcinomas, 2 NETs of the lung, 2 undifferentiated 

follicular carcinomas, 1 undifferentiated papillar carcinoma, 1 GIST, and 1 

carcinoid of the rectum) treated with Sun in a daily practice setting. 

Genotyping for CYP3A5*1 allele (rs776746), VEGF-A -2578C�A 

(rs699947) and VEGFR2 Q472H (rs1870377) was performed. Associations 

between the genotypes and Sun dose reductions and HT were 

performed using univariable analyses. Results: In agreement with previous 

reports, we found that VEGF-A rs699947 conferred a statistically significant 

increased risk of developing HT during treatment (HR�9.8, 

95%CI�1.2-82.0, P�0.034). CYP3A5*1 high metabolizing allele showed 

a trend towards the increase in the risk of Sun dose reductions due to tox 

(HR�2.4, 95%CI�0.8-6.8, P�0.11) with a median time to dose reduction 

of 7.0 months for wild type homozgygous patients and 4.6 months for 

heterozygous patients. A trend was also found on the relation between 

VEGF-A rs699947 A/A patients (HR�3.8, 95%CI�0.8-16.8, P�0.080) 

and dose reduction risk. No significant associations were found for VEGFR2 

rs1870377. Conclusions: The present study suggests that VEGF-A rs699947 

is a risk factor for Sun HT and has a role in other tox leading to dose 

reductions. Similarly, CYP3A5*1 shows a trend towards an increased risk 

of Sun dose reductions. If confirmed, these markers could be used to 

identify a subset of patients with an increased risk of Sun toxicity. 

Tumor Biology 

667s 


Correlation between miRNA (miR) and gene expression profiles (GEP) and 

response to neoadjuvant chemotherapy (NT) in patients with locally 

advanced and inflammatory breast cancer (BC). Presenting Author: Sierra 

Mi Li, City of Hope, Duarte, CA 

Background: GEP may predict for pathologic complete response (pCR). 

Correlation between miRs, GEP, and pCR may reveal novel targets. 

Methods: Patients (pts) with HER2- BC were randomized to receive 

docetaxel, doxorubicin, cyclophosphamide (TAC, arm A) or A and C given 

every 2 weeks x 4, followed by carboplatin and nab-paclitaxel (arm B). Pts 

with HER2� BC received NT per arm B, with trastuzumab added (arm C). 

Core biopsies were snap-frozen prior to NT, and RNA extracted for gene 

array analysis (Agilent 44K microarray) and deep sequence miRNA analysis 

(Solexa/Illumina platform). HER2 testing by IHC [3�] or FISH and/or gene 

array was carried out (Blueprint). MiRs were measured in 72 of 119 

enrolled pts. Of 882 miRNAs reported by Solexa sequencing, 487 were 

assessed (observed at raw counts � 10 in at least 3 pts). TargetScan was 

used to obtain miRNA targets and negative correlation between miR and 

mRNA expression was applied. Results: In 44 HER2- cases, we found 17 

miRs differentially expressed between pts who achieved pCR vs. pts who 

did not (� pCR), 13 with predicted targets by TargetScan (TS). We found 

28 canonical pathways (including Embryonic Cell, EGF signaling, Estrogendependent 

signaling) affected by the identified miRs, and inclusive of 74 

target mRNAs identified (Agilent) and correlating with pCR. The top 

overexpressed miRs are 31 [gene targets: FZD4]; 18a [IGF1, ALDH5A1]; 

19a [PIK3R, IGF1]) and 3 lowest expressors are miR-190b [MMP1]; 29c 

[FOS, WNT5B]; 342-3p [BMP7]. Among the 28 HER2� cases there were 

14 miRNAs differentially expressed between BCs with pCR vs �pCR, and 8 

had predicted targets from TS. We found 10 canonical pathways (including 

p53, HER-2, PTEN) affected by miRs, which included 44 target mRNAs 

(Agilent) correlating with pCR. The most overexpressed miRs are miR-708 

[gene target: RRM2B; 193a-p5 [BMPR1B, RPRM] ; 92b [CCNE2, DKK2]. 

The lowest expressors are: miR-30a [FZD1, SMAD1, TP63]; miR-450-5p 

[FOXO1, WINT5A, ERBB2]; miR-497 [PIK3R1, FGFR1, FOXO1]. 

Conclusions: Combined assessment of miRNA and gene expression patterns 

is feasible, and may yield information leading to individualized and 

improved NT. 


Pharmacogenetic predictors of adverse events in stage II-III colon cancer 

(CC) patients treated with oxaliplatin and fluoropyrimidines-based adjuvant 

chemotherapy (CT): A GEMCAD study. Presenting Author: Ana Custodio, 

Department of Medical Oncology, La Paz University Hospital, Madrid, 

Spain 

Background: Although the benefit of oxaliplatin-based adjuvant CT has been 

demonstrated in patients with resected stage II-III CC, the recommendation 

to administer postoperative treatment must consider its potential 

adverse events. Predicting individual patients´risk of severe toxicity could 

potentially improve the quality of care by allowing individualization of 

treatment. We investigate the utility of determining single nucleotide 

polymorphisms (SNPs) in genes involved in oxaliplatin and fluoropyrimidines 

metabolisms to predict the toxicity of adjuvant CT in stage II-III CC 

patients. Methods: DNA was extracted from formalin-fixed paraffinembedded 

samples from 379 surgically treated high-risk stage II (27.71%) 

and stage III (72.29%) CC patients receiving adjuvant CT (54.35% 

FOLFOX, 45.65% XELOX) from January 2004 to December 2008. Genotyping 

was performed for 35 SNP in 18 genes using the MassARRAY 

(SEQUENOM) technology. Results: A total of 89 (23.4%) patients experienced 

at least one grade 3-4 adverse event. The most common grade 3-4 

toxicities were neutropenia (15.3%), diarrhea (8.17%) and neurotoxicity 

(7.65%). The MTHFR rs1801133 C�T C/C (30.1% C/C, 17.5% C/T, 

21.7% T/T; p�0.043) and XRCC2 rs3218408 T�G T/T (28.3% T/T, 

16.2% G/T and 10% G/G; p�0.007) genotypes were associated with 

higher risk of any grade 3-4 toxicities, whereas the incidence of severe 

toxicity was lower in patients with the UMPS rs3772807 G�C C/C (14% 

C/C, 21% C/G, 28.9% G/G; p�0.021) and DPYD rs970337 G�A A/A 

(16.7% A/A, 21.1% A/G, 30.1% G/G; p�0.028) genotypes. In addition, 

the DPYD rs970337 G�A A/A genotype was associated with a lower rate of 

grade 3-4 diarrhea (5% A/A, 9.4% A/G, 8.1% G/G; p�0.030), the ABCG2 

rs3114018 A�C C/C genotype with an increased rate of grade 3-4 

neutropenia (15.2% C/C, 6.3% A/C, 4.5% A/A; p�0.034) and the ERCC1 

rs11615 T�C T/T genotype with a lower rate of grade 3-4 neurotoxicity 

(5.4% T/T, 9.1% C/T, 10.2% C/C; p�0.032). Conclusions: Our data 

suggest that SNPs in genes involved in oxaliplatin and fluoropyrimidines 

metabolisms can potentially predict severe toxicity in stage II-III CC 

patients treated with adjuvant CT. 




Different EGFR/KRAS mutation spectrums in lung cancer between never 

smokers and heavy smokers. Presenting Author: Kazuya Takamochi, 

Juntendo University School of Medicine, Tokyo, Japan 

Background: EGFR mutations are more commonly found in lung adenocarcinomas 

in never smokers, while KRAS mutations are more frequently 

present in those in heavy smokers. Although the incidence is low, EGFR 

mutations are also found in tumors in heavy smokers and KRAS mutations 

also occur in tumors in never smokers. Therefore, there may be different 

biological characteristics in EGFR/ KRAS mutated lung cancers according 

to the smoking status. Methods: This was a retrospective review of 382 

patients with surgically resected lung cancers between February 2009 and 

March 2011. The clinicopathological factors (age, gender, histology, serum 

CEA level, pathological nodal status, lymphatic permeation, and blood 

vessel invasion) and EGFR/KRAS mutation spectrums were compared 

between never smokers (pack-year � 0, n � 161) and heavy smokers 

(pack-year � 20, n � 167). Results: EGFR mutations were detected in 88 

(55%) never smokers and in 33 (20%) heavy smokers. In contrast, K-ras 

mutations were detected in 7 (4%) never smokers and in 31 (19%) heavy 

smokers. Both EGFR and KRAS mutations were more frequently observed 

in female never smokers and in male heavy smokers. The spectrum of both 

EGFR and KRAS mutation differed according to the smoking status. Minor 

EGFR mutations other than exon 21 L858R and exon 19 deletions that are 

activating mutations indicating the efficacy of EGFR tyrosine kinase 

inhibitors (TKIs) were more frequently found in heavy smokers than in never 

smokers. G¡A transitions were more common KRAS mutations in never 

smokers and G¡T transversions that are thought to be related to exposure 

to the polycyclic aromatic hydrocarbons found in cigarette smoke were 

more common KRAS mutations in heavy smokers. Conclusions: The 

EGFR/KRAS mutation spectrums in lung cancer were quite different in 

never smokers and heavy smokers. Further study is needed to evaluate the 

relationship between the efficacy of such molecular targeting agents as 

EGFR TKIs and the EGFR/KRAS mutation spectrums. 


Prediction of late metastasis in node-negative breast cancer. Presenting 

Author: Marcus Schmidt, Department of Obstetrics and Gynecology, 

Johannes Gutenberg University, Mainz, Germany 

Background: Prediction of late metastasis is of clinical relevance in breast 

cancer. However, systematic genome-wide studies to identify genes associated 

with increased risk of metastasis 5 or more years after surgery are 

scarce. Methods: We examined the natural course of disease in three 

previously published cohorts (Mainz, Rotterdam, Transbig) including 766 

node-negative breast cancer patients with gene array data who did not 

receive systemic chemotherapy in the adjuvant setting. We established a 

Cox regression based method adjusted for multiple testing that identified 

genes predicting late metastasis (5 or more years after surgery). Only those 

genes were accepted that showed similar results in all three cohorts. 

Metastasis-free survival (MFS) was analyzed with univariate and multivariate 

Cox regression. Results: We identified 9 genes [ABCC5 (Hazard Ratio 

(HR) 2.19, p�0.003), EDDM3B (HR 3.58, p�0.044), RAD23B (HR 

0.37, p�0.001), XYLT2 (HR 2.19, p�0.027), DDX18 (HR 0.35, 

p�0.006), GPBP1L1 (HR 0.20, p�0.018), UBB (HR 9.73, p�0.025), 

RPS24 (HR 0.20, p�0.050), GPC1 (HR 2.36, p�0.013)] predicting late 

metastasis. These genes retained their independent prognostic significance 

after adjustment for established clinical factors (age, tumor size, 

grade, hormone receptor status, HER2) and biological motives like estrogen 

receptor, proliferation, B or T cells. These late-type genes are largely 

associated with resistance to hypoxia, apoptosis and DNA damage, suggesting 

that they might contribute to persistence of disseminated tumor cells. 

Conclusions: Genes associated with late metastasis offer a perspective to 

identify breast cancer patients suitable for additional and prolonged 

therapies. 


Combined targeting of LSD1 (KDM1A) and histone deacetylases exerts 

superior efficacy against human AML. Presenting Author: Warren Fiskus, 

University of Kansas Medical Center, Kansas City, KS 

Background: LSD1 (KDM1A) is FAD-dependent histone H3K4Me2 demethylase. 

Inhibition of LSD1 increases H3K4Me3-a permissive mark for gene 

expression, and inhibits growth of pluripotent cancer cells. We have 

previously noted that treatment with the histone deacetylase (HDAC) 

inhibitor panobinostat (PS) depletes EZH2 (the catalytic subunit of the 

polycomb repressive complex 2, PRC2) and disrupts its interaction with the 

other PRC2 proteins, attenuates LSD1, and de-represses growth inhibitory 

and pro-apoptosis genes. Methods: In the present studies, we determined 

the chromatin effects and the pre-clinical in vitro and in vivo anti-AML 

activity of the novel, non-monoamine oxidase, reversible inhibitor of LSD1, 

HCI2509 (100 to 500 nM), alone and in combination with PS, utilizing 

cultured (OCI-AML3 and HL-60) and primary human AML blast progenitor 

cells. Results: Treatment with HCI2509 dose-dependently increased the 

levels of H3K4Me3, p16, p27, and CEBP� in cultured AML cells. This 

correlated with inhibition of cell growth and induction of morphologic 

differentiation in AML cells. Exposure to HCI2509 disrupted the binding of 

LSD1 with the co-repressor CoREST and HDAC1. Treatment with PS (10 to 

50 nM) dose-dependently depleted not only LSD1 but also EZH2, SUZ12 

and BMI1 in AML cells. Co-treatment with PS enhanced the chromatin 

modifying effects of HCI2509. The combination also synergistically induced 

loss of viability of cultured and primary AML cells (combination 

indices, CI �1.0). Following tail vein infusion and establishment of AML by 

OCI-AML3 cells in NOD-SCID mice, treatment with HCI2509 (25 mg/kg, 

b.i.w, IP, for 3 weeks) improved survival, as compared to the control mice 

(p �0.001). HCI2509 treatment (15 mg/kg IP) also dramatically improved 

survival of NSG mice with established human AML following tail-vein 

injection of primary AML blasts expressing FLT3-ITD. Survival was further 

improved upon co-treatment with HCI2509 and PS (5 mg/kg IP, MWF). 

Mice did not experience any toxicity or weight loss. Conclusions: Combined 

epigenetic therapy with HCI2509 and PS exerts superior pre-clinical 

activity, warranting further in vivo development and testing of HCI2509 

against human AML. 


Prognostic role of microRNA polymorphisms in advanced gastric cancer 

patients. Presenting Author: Linnea Stenholm, University Hospital Aachen, 

Aachen, Germany 

Background: As little is known about the impact of microRNA (mir) 

polymorphisms on prognosis of advanced gastric cancer (AGC) we sought to 

determine their impact on overall survival (OS) in these patients (pts). 

Methods: Pts were treated with either 5-fluorouracil, leucovorin and 

oxaliplatin (FLO) or with additional docetaxel (FLOT) in frame of a phase III 

or 3 phase II trials of the Arbeitsgemeinschaft Internistische Onkologie. All 

pts consented genetic analyses. DNA was extracted from whole blood 

samples (n�515) and polymorphisms of mir26a1 (rs7372209), mir27a 

(rs895819), mir100 (rs1834306), mir125a (rs12975333), mir146a 

(rs2910164), mir196a2 (rs11614913), mir219-1 (rs107822) and mir423 

(rs6505162) were genotyped using PCR-based methods. Hetero- and 

homozygous variant genotypes were grouped versus homozygous wild type 

genotypes. Selection of clinical and genetic parameters for the final 

multivariate model was based on univariate and multivariate Cox-regression 

analyses with a cut-off value of p � 0.25 and included 498 pts. Results: 

Median age was 67 (range 23 to 86) years. 42% were treated with FLO and 

58% with FLOT with a median OS of 14 months. Multivariate analyses 

revealed following associations: Genetic factors significantly associated 

with OS were mir26a1 variant genotypes (HR 1.3 [95%CI (1.01;1.6), 

p�.025]), mir27a variant genotypes (HR 1.3 [95%CI (1.01;1.6), p�.036]) 

and mir196a2 variant genotypes (HR 0.8 [95%CI (0.6;0.99), p�.046]). 

Clinical factors with significant impact on OS were ECOG 2 performance 

status (HR 1.9 [95%CI (1.3;2.8), p�.002]), curative surgery of advanced 

disease (HR 0.3 [95%CI (0.1;0.5), p�.001]) and locally advanced disease 

(HR 0.5 [95%CI (0.3;0.7), p�.001]). Combined analyses of the identified 

adverse genotypes of mir26a1, mir27a and mir196a2 resulted in a median 

OS of 9, 13, 14 and 17 months for pts with 0 (n�72), 1 (n�193), 2 

(n�171) and 3 (n�54) adverse genotypes (p�.029), respectively. 

Conclusions: In addition to established clinical factors, mir26a1, mir27a 

and mir196a2 polymorphisms were significantly associated with OS. Our 

data suggest a strong impact of these mir polymorphisms on prognosis in 

AGC and might be of help for a better guidance of treatment decisions. 



Activation of and dependence on ataxia telangiectasia mutated kinase in 

PTEN-deficient tumor cells. Presenting Author: Nuala McCabe, Almac 

Diagnostics, Craigavon, United Kingdom 

Background: Loss of PTEN function has been widely reported to cause 

up-regulation of the PI3K/AKT signalling pathway resulting in increased 

cell growth, proliferation and survival. More recently it has been reported 

that PTEN null cells demonstrate genomic instability and have increased 

production of reactive oxygen species (ROS) and oxidative stress induced 

DNA damage. Ataxia Telangiectasia Mutated (ATM) is the primary response 

kinase, which responds to stalled DNA replication and DNA double strand 

breaks due to oxidative DNA damage. Methods: A metagene representing 

ATM activation was generated from cell line data and used to perform 

hierarchical clustering analysis of public DNA microarray profiling datasets 

of breast cancer, ovarian cancer and glioblastoma with known PTEN 

IHC/mutation status. Furthermore, we ask if ATM activation may be 

therapeutically exploited in PTEN null tumours using ATM specific siRNA 

and compounds in 2 PTEN isogenic cell line model systems. Results: We 

show that PTEN null cells have elevated levels of ROS, DNA damage and 

have endogenous activation of ATM, an enzyme important in responding to 

DNA damage resulting from oxidative stress. We hypothesised that PTEN 

deficient tumours may rely on ATM enzyme for survival. To investigate this 

we generated a 189-gene list representing ATM activation and used this to 

perform hierarchical clustering analysis of a breast cancer DNA microarray 

dataset. This list was able to significantly cluster tumours with known loss 

of PTEN expression (p�0.004). Furthermore, this gene list was able to 

segregate PTEN null/mutant tumours from PTEN wild-type tumours in 2 

independent datasets of glioblastoma and ovarian cancer (p�0.015 and 

p�0.012). In addition, we found that inhibition of ATM using the selective 

inhibitor KU-55933 caused DNA damage, cell cycle arrest and apoptosis 

specifically in PTEN deficient cells when compared to PTEN wild-type 

cells. Conclusions: These observations suggest that ATM may represent a 

therapeutic target in PTEN deficient tumours and furthermore ATM 

activation may be the basis of a biomarker of PTEN status in human 

cancers. 


Topoisomerase II alpha gene status, HER2, and microtubule-associated 

protein tau as predictors of pathologic complete response after neoadjuvant 

chemotherapy. Presenting Author: Agust Barnadas, Hospital de la Santa 

Creu i Sant Pau, Medical Oncology Department, Barcelona, Spain 

Background: There is growing evidence that topoisomerase II-alpha 

(TOPOII�) is a marker for anthracycline-, and microtubule-associated 

protein tau (MAPT) for taxane sensitivity. HER2 has been described as a 

marker of both anthracycline and taxane sensitivity.The goal of our study 

was to examine the predictive and prognostic value of TOPOII�, MAPT and 

HER2 expression in breast cancer patients (pts) who received neoadjuvant 

chemotherapy (NAC) based on anthracycline-taxane regimens. We analyzed 

the relationship between these biomarkers and pathological complete 

response (pCR), disease-free survival (DFS) and overall survival (OS). 

Methods: Between November 1993-2009, 140 pts (mean age 52 years) 

with locally advanced breast cancer (T1-4, N0-3, M0) were retrospectively 

studied. The study contained 2 groups: group A included 85 pts who 

received NAC with an anthracycline-taxane regimen and group B included 

the last 55 pts who received NAC with only an anthracycline-based 

regimen. HER2 was tested by immunohistochemistry (IH) or FISH, TOPOII� 

by CISH and MAPT by IH. Expression of these proteins was evaluated in 

core needle breast biopsy. Results: Overall, 12 pts (8.5%) had a pCR. 

TOPOII� was amplified in 6 (4%) of the tumors. Among pts without 

amplification, 6 (4%) had deletion of the TOPOII�, and 10 (7%) polysomia 

of chromosome 17. TOPOII� gene aberrations (amplification, deletion, 

polysomia), which was present in 22 (25%) of the tumors, was a strong 

predictive factor for pCR (p�0.018) but showed no direct association with 

prognostic outcome in multivariate analysis. HER2 amplification, which 

was present in 16% (21) of the tumors, show no direct association with 

pCR, DFS or OS. Finally, differences by treatment arm or pCR in low versus 

high MAPT expression groups were not observed, indicating that MAPT is 

not a useful predictive marker for taxane-based chemotherapy. In multivariate 

analysis high MAPT expression was associated with longer DFS 

(p�0.002). Conclusions: TOPOII� gene aberrations but not HER2 are 

highly predictive of pCR for anthracycline-based regimen. MAPT is not 

associated with response to taxanes but has a prognostic value. 

Tumor Biology 

669s 


Central review of discordant samples for microarray based on ER, PR, and 

HER2 and local IHC/FISH assessment worldwide from 827 patients. 

Presenting Author: Jelle Wesseling, Netherlands Cancer Institute - Antoni 

van Leeuwenhoek Hospital, Amsterdam, Netherlands 

Background: Differences in fixation and IHC and subjective interpretation 

can substantially affect the accuracy and reproducibility of estrogen 

receptor (ER), progesterone receptor (PR) and HER2 expression. The 

commercially available TargetPrint test measures the mRNA expression 

level of ER, PR and HER2 and is 98% concordant with centrally assessed 

ER as presented by Viale et al, SABCS 2011. This study compares results 

from the microarray-based TargetPrint with IHC and FISH (for HER2 

IHC2�) generated by local standard procedures. Methods: Fresh tumor 

samples (core needle biopsies or surgical) were collected for 831 patients 

diagnosed with breast cancer stage I to IV (Feb 2008 - Jan 2011) from 22 

hospitals from Europe, New Zealand, Japan and US. The results of the 

IHC/FISH assessments performed according to the local standards at the 

hospitals were compared to the quantitative gene expression readouts with 

TargetPrint. Discordant cases were centrally reviewed for IHC/FISH assessment. 

Results: Of the 831 samples, IHC assessment was unknown for 4 ER/ 

PR samples; HER2 was unknown for 12 samples. Comparison of IHC and 

gene expression read out by TargetPrint showed a concordance of 95% for 

ER; 83% for PR and 94% for HER2. In this study, 3% of all IHC ER positive 

samples were classified negative by microarray, and 11% of IHC PR 

positive samples were classified negative by microarray. For HER2, 4% of 

IHC/FISH HER2 positive samples were classified negative by microarray 

and 2% of IHC/FISH HER2 negative samples were classified positive by 

microarray. Most notably, all available 5 ER IHC negative/TargetPrint 

positive samples turned out to be positive with central re-assessment. 

HER2 IHC2� samples with discordant classifications for TargetPrint and 

local assessment are currently being reviewed for FISH/SISH assessment. 

Conclusions: Microarray based readout of ER, PR and HER2 status using 

TargetPrint is fairly comparable to local IHC and FISH analysis in 827 

analyzed samples in various hospitals worldwide. However, re-assessment 

of discordant cases –especially IHC ER-/TargetPrint ER� cases- confirms 

TargetPrint to be a useful high quality second opinion for local IHC/FISH 

assessment. 


ALK amplification and crizotinib sensitivity in non-small cell lung cancer 

cell lines and patients report. Presenting Author: Kalai Khadija, Institut 


Background: ALK high copy number (HCN) seems to be a frequent event, 

described in 13-17% of Non-small cell lung cancer (NSCLC). The goal of 

this study was to describe ALK genomic aberrations on NSCLC patients and 

cell lines, to explore the ALK HCN response to crizotinib through in vitro 

assays and to report three patients case. Methods: 191 Paraffin embedded 

specimens from advanced NSCLC patients and 27 NSCLC cancer cell lines 

were screened for ALK copy number by fluorescent in situ hybridization 

(FISH). Crizotinib sensitivity was evaluated in 9 cell lines through WST1 

assays and clonogenic tests. Three patients exhibiting ALK HCN were 

assessed for response to crizotinib. Results: EML4-ALK translocation was 

present in 22 pts (11.5%). 21 pts (11%) exhibited over 6 copies of ALK.6 

(22%) cell lines displayed more than 5 copies of ALK, 19 (70%) presented 

a gain of 3 or 4 ALK copy number, only one cell line exhibited normal ALK 

copies and one harbored EML4-ALK translocation. FISH with CEP2 

revealed a polysomy of chromosome 2 in cases with ALK HCN.Out of the 9 

cell lines tested, 4 ALK HCN cell lines (H661, A427, BEN, H1299) 

exhibited increased sensitivity for crizotinib vs. 3 low ALK copy number 

(LCN) cell lines (H1975, H1651, H1650) with a low sensitivity. Median 

IC50 with crizotinib values was1750 nM [300-2800nM] in ALK HCN cell 

lines vs 4500 nM [800-8000nM] in ALK LCN cell lines, p�0.35. 3 

patients with ALK HCN tumor received crizotinib ( in 4th , 5th and 6th -line 

therapy) for 2, 3 and 5 months with stable disease as best response and 

clinical benefit in 2 pts. Conclusions: ALK HCN may predict sensitivity to 

crizotinib. A clinical study is planned in ALK HCN pts. 




Exosomal-miRNA profiles as diagnostic biomarkers in cervical cancer. 

Presenting Author: Hirotaka Nishi, Department of Obstetrics and Gynecology, 

Tokyo Medical University, Tokyo, Japan 

Background: MicroRNA (miRNA) expression is altered in cancer cells and 

associated with the development and progression of various types of 

cancer. miRNA could serve as diagnostic or prognostic biomarker for 

cancer patients. Our study was designed to analyze circulating exosomalmiRNA 

in patients with cervical cancer. Methods: Total RNA was extracted 

from serum in healthy women and patients with cervical intraepithelial 

neoplasia (CIN) and cervical cancer. We first explored miRNA expression 

profiles using miRCURY LNA microRNA Array (Exiqon) in each six 

malignant and healthy serum samples. miRNAs with significant differences 

in expression were validated in larger sample sets by a quantitative 

real-time RT-PCR using TaqMan gene expression assays (Applied Biosystems). 

Results: Six of 1223 miRNAs compared in serum samples from 

cervical cancer and normal control were found to have a �3.0-fold change 

with a P value �0.01 using miRCURY LNA microRNA Array. In a validation 

set (n�101), expression of 3 of the 6 miRNAs, miR-483-5p, miR-1246 

and miR-1275, was significantly different between the cervical cancer 

(n�40) and control (n�20) samples. We also found that the median levels 

of these miRNAs were significantly higher in patients with cervical cancer 

(n�40) than those in CIN (n�41). Circulating miRNAs were not correlated 

with clinical-pathological parameters except for miR-1246. Compared to 

patients with squamous cell carcinoma, the miR-1246 level was significantly 

higher in those with adenocarcinoma. Whereas, receiver-operator 

characteristic (ROC) curve analyses suggest that these serum miRNAs may 

be useful markers for discriminating patients with cervical cancer from 

healthy controls. Conclusions: Expression of circulating miR-483-5p, 

miR-1246 and miR-1275 is significantly higher in the blood of cervical 

cancer patients compared to controls and may potentially serve as a useful 

biomarker for cervical cancer diagnosis. Especially, miR-1246 may be a 

candidate for early detection of cervical adenocarcinoma. Larger-scaled 

studies are warranted to fully explore the role of circulating exosomalmiRNAs 

in cervical cancer. 


Use of next-generation sequencing (NGS) to detect high frequency of 

targetable alterations in primary and metastatic breast cancer (MBC). 

Presenting Author: Lajos Pusztai, University of Texas M. D. Anderson 


Background: The aim of this study was to assess the frequency of genomic 

alterations in breast cancer potentially treatable with approved targeted 

agents or investigational drugs in clinical trials. NGS was performed in a 

CLIA setting (Foundation Medicine). Methods: DNA was extracted from 

needle biopsies of 33 pre-therapy primary and 17 MBCs (mean age 52 yrs; 

58% ER�, 20% HER2�, 30% triple negative) obtained prospectively for 

biomarker discovery and preserved in RNAlater. Patients with MBC 

received an average of 7 drugs (range 5-17) including adjuvant therapy 

before biopsy for this research; 13 biopsies were from soft tissues, 3 from 

liver and 1 from bone. Sequencing was targeted to 3230 exons in 182 

cancer-related genes and 37 introns in 14 genes often rearranged in 

cancer. Average median depth was �1200x. Results: All biopsies yielded 

sufficient DNA. NGS revealed a total of 117 known driver mutations across 

36 genes (per-tumor average�2.5, range 1-6), including 37 base substitutions 

(32%), 28 indels (24%), 42 amplifications (36%) and 10 homozygous 

deletions (9%). NGS identified HER2 gene amplification in 6/7 cases 

scored HER2� by FISH. The average number of functionally important 

alterations was surprisingly similar, 2.3 in primaries vs 2.8 in heavily 

treated MBCs (p�0.32). Remarkably, 25/33 (76%) of primary and 14/17 

(82%) of MBCs had at least 1 genomic alteration targetable with an FDA 

approved drug or novel agent in clinical trials. These included: ERBB2 

alterations (n�9), PIK3CA mutations (n�8), NF1 mutations (n�4, candidate 

for PI3K/MEK inhibitors), AKT1-3 mutations (n�5, PI3K inhibitors), 

BRCA1/2, (n�6, PARP inhibitors), and CCND2 (n�3)/CDKN2A (n�3) 

mutations (CDK inhibitors). Numerous other alterations with less apparent 

therapeutic implications were also observed. Conclusions: Comprehensive 

NGS profiling in breast cancer needle biopsies showed high frequency of 

genomic alterations linked to a clinical treatment option or clinical trials of 

targeted therapies. These results demonstrate it is feasible to use NGS to 

guide targeted therapy. Prospective testing of the diagnostic/predictive 

value of this patient selection approach is currently under way. 


Evaluation of gene expression by RNA-seq after single dose of trastuzumab 

(T) reveals predictors of pathologic complete response (pCR) in HER2positive 

early breast cancer. Presenting Author: Natalie Galanina, Yale 

University School of Medicine, Yale Comprehensive Cancer Center, New 

Haven, CT 

Background: The use of a ‘brief exposure’ to single agent T allows the 

measurement of dynamic changes in the transcriptome that may predict 

response to T-based combinations. We have shown that most gene 

expression changes in HER2� tumors treated with T occur in tumors that 

ultimately achieve a pCR. Our further analysis suggests several patterns of 

transcriptional change in pCR tumors suggesting different mechanisms of 

action of T. RNA-seq analysis provides more in-depth annotation of these 

mechanisms. Methods: Fresh tumor core biopsies were taken at a 2 week 

time point after a single dose of T (8mg/m2) from 80 HER2� early breast 

cancer patients enrolled on a clinical trial of T�T�C. Nucleic acids were 

extracted using Qiagen AllPrep and were analyzed with Illumina HT12v3 

Beadchip and Illumina 610 QUAD V1 SNP arrays. RNA was also processed 

for sequencing using the Ovation RNA-Seq System and paired-end sequenced 

using an Illumina Genome Analyzer IIxRNA-seq data was analyzed 

with Tophat/Cufflinks. Network analysis was performed with Metacore. 

Results: Among pCR tumors, distinct patterns of differential expression 

pre/post T were observed, in both microarray and RNA-seq data. ERBB2 

down-regulation was characteristic of pCR in one subgroup by microarray. 

In this group, differentially expressed genes belonged to interaction 

networks involved in apoptosis and cell cycle regulation. In contrast, 

tumors with no change in ErbB2 showed differentially expressed genes that 

belonged to networks related to chromatin assembly and regulation of 

immune pathways. NOLC1, RPL41, ZCHHC17, and B2M had altered 

alternative splicing product distributions in both groups. In the ERBB2 

down-regulated group, genes with changed expression were enriched for 

targets of STAT3 and YY1. Conclusions: RNA-seq and microarray reveal 

distinct responses in tumors that achieve pCR to T-containing regimens. 

These methods provide predictive markers for validation in subsequent 



EGFR exon 20 insertion mutations: Incidence and clinicopathologic 

characteristics in U.S. patients with lung adenocarcinoma. Presenting 

Author: Maria E. Arcila, Memorial Sloan-Kettering Cancer Center, New 

York, NY 

Background: Activating insertion mutations in exon 20 of EGFR are reported 

in a small subset of lung adenocarcinomas (ADC). In contrast to the classic 

EGFR mutations, they appear to confer primary resistance to currently 

approved EGFR tyrosine kinase inhibitors. Their incidence and clinicopathologic 

features are not well established. Methods: Lung ADCs (n�1500) 

were screened for major activating mutations in EGFR (exons 19 and 21) 

and KRAS (exon 2). Negative cases were tested for EGFR exon 20 

insertions by a PCR-based sizing assay. Extended testing for additional 

recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 

and AKT was performed in all cases by Sequenom mass spectrometry. A 

subset of cases was also tested for ALK rearrangements by FISH. Results: 

We identified 32cases withEGFRexon 20 insertions, accounting for 11% of 

all EGFR mutations. EGFRexon 20 insertions were mutually exclusive with 

the other genetic alterations tested except for PIK3CA mutations. The 

incidence was higher among never-smokers (p�0.0001) but there was no 

association with sex, ethnic origin or stage at diagnosis. Insertions were 3, 

6, 9 or 12bp; 9bp insertions were most common (50%, 16/32). Morphologically, 

90% of tumors were moderate to poorly differentiated with a 

predominant mixed ADC phenotype. Conclusions: EGFR exon 20 testing 

may identify a unique subset of EGFR mutant lung ADCs which is 

significantly larger than previously reported, making this the third most 

common type of EGFR mutation after exon 19 deletions and L858R. This 

population could potentially benefit from alternate targeted therapies, 

many of which are currently in clinical development. 



Independent validation of prognostic value of 22 micrornas (miRs) in stage 

I-II squamous cell lung cancer (SqCLC). Presenting Author: Marcin Tomasz 

Skrzypski, Medical University of Gdansk, Gdansk, Poland 

Background: About 50% of NSCLC patients (pts) will develop distant 

metastases following pulmonary resection. Currently, apart from clinical 

stage at diagnosis, there are no reliable factors to select high risk pts for 

adjuvant chemotherapy. We previously demonstrated prognostic value of 

22 miRs in frozen tissue samples of early stage SqCLC, and the feasibility 

of their expression assessment in formalin fixed paraffin embedded (FFPE) 

samples (Skrzypski et. al. J Clin Oncol 2010;28;15s). In this study, we 

validated the prognostic value of these miRs in an independent cohort of 

early SqCLC pts. Methods: FFPE tumor samples were obtained from 132 

stage I-II SqCLC pts who underwent radical pulmonary resection, 42% of 

whom developed distant metastases. Median follow-up of pts who did not 

develop metastases was 5.6 years (range, 4.1-10.0 years). miRs were 

isolated from tumor tissue with RecoverAll kit (Ambion). Expression of 22 

miRs previously found to be related to the risk of metastases was analyzed 

by RT-PCR assay (Appliedbiosystems). Raw data were normalized vs. the 

expression of U6. Individual miRs and the risk score comprising 5 most 

predictive miRs were correlated with distant metastases-free survival 

(MFS). Results: Eight miRs were significantly relatedtoMFS. MiR-192 was 

significantly correlated with MFS (p�0,0007; p�0,02 after correction for 

multiple comparisons). The 5-miR risk score was an independent prognostic 

factor (p�1.70E-06) in a multivariate analysis comprising stage 

(p�1,10E-03) and histological grade (p�0,46). Using the median of the 

risk score as a cut-off value, the median MFS was 1.73 years in the high risk 

group, and not reached in the low risk group (HR�2.11). The sensitivity 

and specificity of the risk score to predict the occurrence of distant 

metastases were 66% and 64%, respectively. Conclusions: Risk score 

based on expression of 5 miRs is a strong and independent predictor of 

distant relapse in operable early SqCLC. 


Effect of the loss of the type III TGF� receptor during tumor progression on 

tumor microenvironment: Preclinical development of TGF� inhibition and 

TGF�-related biomarkers to enhance immunotherapy efficacy. Presenting 

Author: Brent Allen Hanks, Duke University Medical Center, Durham, NC 

Background: Overall, the clinical efficacy of tumor immunotherapy has been 

limited. Our incomplete understanding of the complex interplay between 

tumors and the immune microenvironment has contributed to these 

modest outcomes. Our work has revealed that several tumors downregulate 

the expression of the type III TGF� receptor (T�RIII) with progression. 

T�RIII is shed from the cell surface to generate soluble T�RIII (sT�RIII) 

which is capable of sequestering TGF�. Methods and Results: Using both 

breast cancer and melanoma tumor models we have demonstrated that the 

loss of T�RIII expression is associated with diminished tumor infiltrating 

CD8� T cells and increased regulatory T cells (Tregs) within the tumor 

microenvironment. Our data implies that these alterations correlate with 

suppressed tumor antigen-specific T cell responses and more rapid disease 

progression. We show that these changes are due to enhanced TGF� 

signaling within the immune compartment of the tumor microenvironment 

resulting in enhanced expression of the indoleamine 2,3-dioxygenase 

immunoregulatory enzyme by local plasmacytoid dendritic cells (DCs) as 

well as increased expression of the Treg-recruiting CCL22 chemokine by 

local myeloid DCs. Microarray analysis indicates that these same gene 

expression associations also exist in human breast cancers. Consistent with 

these studies, we have demonstrated that TGF-� inhibition synergistically 

enhances the efficacy of a Her2/neu vaccine in a breast cancer model and 

that plasma levels of sT�RIII correlate with clinical response and overall 

survival in stage III melanoma patients. Conclusions: We have elucidated a 

novel mechanism that tumors utilize to suppress the generation of 

anti-tumor immunity by establishing a link between the loss of an 

endogenous suppressor of tumor metastasis, T�RIII, and the generation of 

an immunotolerant tumor microenvironment. We are pursuing a phase I 

clinical trial to investigate the efficacy of combining a TGF-� inhibitor with 

a tumor vaccine while also determining if sT�RIII may function as a 

predictive biomarker for this approach. 

Tumor Biology 

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Lymphopenia combined with low TCR diversity to predict overall survival in 

metastatic breast cancer patients. Presenting Author: Manuarii Manuel, 

Centre de Recherche en Cancérologie de Lyon, Inserm U1052 CNRS 

5286, Centre Léon Bérard, Lyon, France 

Background: Lymphopenia (�1 Giga/L) before initiation of chemotherapy is 

a predictive factor for toxicity and death in metastatic phase for cancer 

patients. Combinatorial diversity of T Cell Receptor beta chain (TCR-ß), as 

a measure of T cell repertoire diversity, was investigated and tested either 

alone or in combination with lymphopenia as a prognostic factor for overall 

survival (OS) in first line treatment of metastatic breast cancer (MBC) 

patients. Methods: Using semi quantitative multiplex PCR, the V-D-J 

combinatorial diversity of the TCR was measured on cryo-preserved blood 

samples from 2 cohorts of MBC patients before the initiation of the first line 

chemotherapy: in an experimental cohort (cohort A, n�66) and in a 

validation series (cohort B, n�67). A prognostic score, defined NDL 

(Number & Diversity of Lymphocytes) combining lymphocyte count and 

TCR diversity was delineated. Univariate and multivariate analysis of 

prognostic factors for OS were performed in both cohorts. Results: Lymphopenia 

(�1 Giga/L) was associated with shorter OS for cohort B while TCR 

diversity �33% (called divpenia) was associated with a reduced OS in 

cohort A. The combination of lymphopenia with low TCR diversity (called 

lympho-divpenia) was associated with poor OS compared to patients with 

either lymphocyte count �1 Giga/L or diversity �33% or both, in cohort A 

(median OS: 7.6 vs 24.5 months, p.value �0.0006) and cohort B (median 

OS 10.6 vs 22.9 months, p.value �0.0035). In a multivariate analysis, 

including all significant clinical factors from the univariate analysis (PS, 

liver metastasis, hemoglobin) lympho-divpenia was found to be an independent 

prognostic factor in the pooled cohort (A�B) (p�0.005) along with 

triple negative tumors (p�0.011) and hemoglobin level (11.5 g/dL) 

(p�0.009). Conclusions: NDL score combining lymphopenia and reduced 

TCR diversity seems to be a strong prognostic factor for OS and could be 

use to improve care quality of MBC patients. 


Involvement of NK cell molecular signatures in favorable prognosis of 

breast cancer patients. Presenting Author: Maria Libera Ascierto, National 


Background: Tumor cell recognition by NK cells is mediated by the 

interaction of activating and inhibitory NK cell receptors with their ligands 

expressed on tumor cells. In addition, NK cells express adhesion molecules 

that facilitate formation of the immunological synapse with the tumor 

targets. Here, we investigated whether the coordinate expression of NK 

activating receptors and adhesion molecules could provide a signature to 

segregate breast cancer patients into relapse and relapse-free outcomes. 

Methods: Gene expression profiling, RT-PCR screening and survival analysis 

were performed on RNA extracted from primary breast cancers. Tumors 

were obtained from patients experiencing either 5-8 years relapse-free 

survival or tumor relapse within 1-3 years following initial treatment. 

Results: Tumors from patients with a favorable prognosis were characterized 

by increased expression of genes involved in NK cell interaction with 

tumor cells and its activation signaling. In particular, up-regulation of 

Natural Cytotoxicity Receptors (NCRs), leukocyte function-associated antigen 

1 (LFA-1), CD226 (DNAM-1) and CD96 was observed in relapse-free 

patients. Thus, the expression of the NK activating receptors and relevant 

adhesion molecules involved in NK cell:target interactions can predict 

relapse free survival in breast cancer patients. Conclusions: Results from 

the present study, highlighted the effector cooperation between the innate 

and adaptive immune components within the tumor microenvironment. 

The NK cells parameters identified in this study, together with the 

prognostic B and T cell signatures previously reported by us, represent a 

powerful tool for predicting breast cancer outcome which might be easily 

introduced in clinical practice. 




Comparative analysis of myeloid-derived suppressor cell (MDSC) subsets in 

patients with gastrointestinal (GI) malignancies. Presenting Author: Austin G. 

Duffy, National Cancer Institute/National Institutes of Health, Bethesda, MD 

Background: Immunotherapy represents a potential new treatment option for 

patients with cancer. Myeloid derived suppressor cells (MDSCs) constitute a 

heterogenous cell population, which inhibit the host anti-tumor immune 

response, limiting the effectiveness of both immune and non-immune treatments. 

MDSC are known to be increased in patients with GI cancer. Characterization 

of MDSC in humans has been difficult with heterogeneous phenotype 

classification. Differences in processing are also potentially important. The aim 

of this study was to perform a comparative analysis of MDSC subsets in patients 

with GI cancer. Methods: Fluorescence activated cell sorting (FACS) analysis was 

performed on PBMC and whole blood (WB) from healthy adults (N�44) and 

patients with GI cancer (N�41). MDSC subsets were enumerated using the 

following antibodies: anti-CD14; anti-CD15; anti-HLA-DR; anti-CD33; anti- 

CD11b; 7-AAD. Suppressor function of MDSC subsets was tested using FACS 

sorted MDSC subpopulations co-cultured with CD3/CD28-stimulated autologous 

effector cells. Proliferation and IFN-g were measured. Results: The frequencies 

of Monocytic (Def: CD14 � , HLA-DR -/low ) and Granulocytic (Def: CD15 � ,CD14 - 

CD33 � CD11b � ) MDSC are shown in the table below. Monocytic MDSC were 

increased in the blood of patients (vs control; P�.0001) and frozen (vs fresh 

PBMC; P�.05). While CD15� cells were increased in cancer patients we did not 

find an increase in granulocytic MDSC. Functional studies will also be presented. 

Conclusions: Monocytic MDSC are more frequent in patients with advanced GI 

cancer compared to healthy volunteers. An increase in this population was also 

found in WB and frozen PBMC compared to fresh PBMC reflecting the need for 

homogenous preparation in studies evaluating this population in humans. While 

CD15�CD14- cells were also increased in cancer patients we did not find an 

increase in CD14-CD15�CD33�CD11b� cells. 

CD14�ve, HLA-DR -/low* CD15�ve,CD14-veCD33�CD11b�* 

Patient PBMC 5.5 3.1 

Healthy PBMC 1.2 4.55 

Frozen PBMC (healthy) 4.16 3.3 

Frozen PBMC (patient) 10 1.36 

Patient WB 2.5 15 

Healthy WB 

* Rel frequency. 

0.8 17.65 


Extracellular matrix and breast cancer cells’ response to trastuzumab: The 

role of glycosaminoglycans, heparanases, and syndecan-1. Presenting 

Author: Maria Aparecida Silva Pinhal, Universidade Federal de São Paulo, 

Sao Paulo, Brazil 

Background: Trastuzumab is an antibody anti-epidermal growth factor 2 

receptor (HER2), which improves disease-free and overall survival in HER2 

positive breast cancer. Nevertheless, many patients become resistant to 

this treatment. Heparanase (HPSE) is an enzyme that is responsible for 

removal of heparan sulfate (HS) chains from proteoglycans, generating free 

oligosaccharides that modulate many physiopathological functions, including 

tumor developing. We have analyzed whether some extracellular matrix 

components influence trastuzumab efficacy. Methods: Heparanase-1 

(HPSE-1) overexpression effect was analyzed using MCF7 cells stable 

transfected with HPSE-1 cDNA (MCF7-HPSE-1). HPSE-1, HPSE-2, Syndecan-1 

(Syn-1) and HER2 expression, HPSE-1 activity and cell viability were 

evaluated in different breast cancer cells treated or not with trastuzumab. 

The glycosaminoglycans synthesis and shedding were also evaluated. 

Trastuzumab and HS binding were analyzed by confocal microscopy and 

Fluorescence Resonance Energy Transfer (FRET). Results: MCF7 transfected 

with HPSE-1 cDNA becomes completely resistant to trastuzumab. 

HS affinity by Trastuzumab was then tested, showing that they bind in high 

levels and this binding is necessary to antibody activity. In MCF7 cells, 

trastuzumab decreases HPSE-1, HPSE-2, HER2 and Syn-1 mRNA expression, 

while in MCF7-HPSE-1 the antibody increases the expression of these 

molecules. Conclusions: Our results have demonstrated that an ideal 

concentration of HS in cell surface, regulated by trastuzumab, is necessary 

to its action, beyond HER2 high levels. High HS concentration at cell 

surface enhances the antibody amount disposable to interact with HER2 in 

cell surface, determining breast cancer cells susceptibility to trastuzumab. 

These new insights could be useful when devising strategies for overcoming 

trastuzumab resistance in HER2 positive cancers. Supported by FAPESP, 

CNPq, CAPES. 


Correlation of the maximum standardized uptake value for f-18 fluorodeoxyglucose 

with molecular subtype and survival in advanced breast cancer. 

Presenting Author: Zhen Jia, Fudan University Cancer Center, Shanghai, 

China 

Background: Tumor glucose metabolism correlates with tumor biology and 

clinical outcome of breast cancer patients. This prospective cohort study 

was to explore correlations of 18F-FDG uptake, a surrogate for glucose 

metabolism, with molecular subtypes in women with advanced breast 

cancer. Methods: Patients diagnosed as advanced breast cancer were 

enrolled in the study. PET/CT was performed and the Maximum Standardized 

Uptake Value (SUVmax) of each lesion was documented as baseline, 

so was clinical and treatment information. Diagnosis of malignant nature of 

a lesion was confirmed by pathology or further follow-up. Patients who had 

got a progressive disease in the efficacy assessment were assigned new 

treatments as per-institutional guidelines. Results: 244 patients met the 

criteria and were all put into this analysis. Independent factors for 

influencing SUVmax value included luminal subtype (p� 0.002), triplenegative 

subtype (p�0.001), ER status (p� 0.028), Her-2 status 

(p�0.001), and CEA level (p�0.001). A higher SUVmax was significantly 

associated with poorer median PFS (6.9 vs. 8.1 months, p�0.040) and OS 

(13.8 vs. 16.9 months, p�0.003). Cox Regression analysis showed that 

SUVmax value, previous treatments, subsequent treatments and treatment 

efficacy were four independent prognostic factors for PFS, while age, 

menopausal status, disease free interval, 4 subtypes, previous treatments, 

number of metastatic sites, SUVmax value and subsequent treatment 

efficacy were independent prognostic factors for OS. Conclusions: 18F-FDG uptake correlates with molecular subtypes in women with advanced breast 

cancer. Baseline SUVmax is an independent prognostic factor for survival 

of patients with advanced breast cancer, especially those with luminal 

subtypes. 


Detection of EML4-ALK in serum RNA from lung cancer patients using 

MassARRAY platform. Presenting Author: Keita Kudo, Thoracic Oncology 

Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 

Tokyo, Japan 

Background: The presence of the transforming fusion gene EML4-ALK in 

non–small cell lung cancer (NSCLC) is a predictive marker for the efficacy 

of ALK kinase inhibitors. The break apart fluorescence in situ hybridization 

(FISH) assay has served as the standard test for identification of NSCLC 

patients with ALK gene rearrangement. Circulating RNA in plasma/serum is 

an emerging field for noninvasive molecular diagnosis. We previously 

developed a MassARRAY assay to detect nine types of EML4-ALK fusion 

gene (variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, and 7). The assay is based upon 

region-specific PCR followed by specific single-base primer extension 

reactions; the extended products are resolved using MALDI-TOF mass 

spectrometry. In this study, we evaluated whether EML4-ALK fusion RNA 

could be detected in serum obtained from NSCLC patients. Methods: The 

RNA was extracted from serum obtained from 12 lung cancer patients with 

ALK rearrangements by FISH analysis. The extracted RNA was reverse 

transcribed into cDNA, and the resultant cDNA was amplified by nested 

PCR. The PCR product was subjected to MassARRAY assay to identify 

EML4-ALK variants. Results: The EML4-ALK RNA (variant 1 and 3) was 

detected in serum from 2 of 12 patients. These are confirmed by 

subcloning and sequencing. Conclusions: The detection of EML4-ALK in 

serum RNA samples by MassARRAY assay is feasible. This noninvasive 

assay will be useful in patients with insufficient or unavailable tumor 

specimens. Additional experiments will reveal the sensitivity and specificity 

of this detection system. 



Hybrid PET-MRI of the breast: A promising tool for the characterization of 

breast tumors. Presenting Author: Katja Pinker-Domenig, Medical University 

Vienna, Department of Radiology, Division of Molecular and Gender 

Imaging, Vienna, Austria 

Background: To evaluate if PET-MRI of breast tumors improves staging of 

breast cancer and obviates unnecessary breast biopsies. Methods: 106 

patients with breast tumors detected by mammography or ultrasound and 

classified as BIRADS 3-5 were included in this IRB approved prospective 

study. All patients were examined with dedicated 18FDG-PET-CT and 3T 

multiparametric MRI of the breast. Examinations were scheduled no longer 

than 7 days apart. MRI protocol included: a diffusion-weighted sequence 

(DWI), a T2-w sequence and a contrast-enhanced combined high temporal 

and spatial resolution 3D-T1-w sequence before and after application of a 

standard dose Gd-DOTA. For PET-CT patients fasted at least 6 h before 

injection of approx. 300 MBq 18F-FDG based on the patients weight. 

Scanning was started 45 min after injection. Blood glucose levels were 

�150 mg/dl. A prone PET dataset over the breasts was acquired using a 

positioning device allowing the same patient geometry as the breast MRI 

coil. CT data was used for attenuation correction. Co-registration of imaging 

data and image fusion were performed. PET-MRI was assessed for lesion 

morphology and EH-kinetics according to BI-RADS and restricted diffusivity 

with an ADC threshold 1.25 x10-3mm2/s set as the cut-off for 

malignancy. Lesions were assed for 18F-FDG–avidity and classified as 

positive when 18F-FDG-uptake was greater than blood-pool activity. Additionally, 

nodal status was recorded for each technique and patient. 

Histopathology was used as the standard of reference. Results: PET-MRI 

achieved an excellent sensitivity of 100%. Specificity was increased from 

68% to 80% as compared to routinely used MRI. Diagnostic accuracy of 

PET-MRI for diagnosis of breast cancer was 95%. PET-MRI would have 

obviated unnecessary breast biopsies in 80% of benign breast lesions 

without missing any cancers. Additionally, PET-MRI increased sensitivity 

in the detection of lymphnode metastases from 70% to 87% compared to 

MRI alone. Conclusions: With PET-MRI unnecessary breast biopsies can be 

obviated without missing any cancers. PET-MRI increases overall diagnostic 

accuracy in the diagnosis of breast cancer and lymphnode metastases 

for an accurate staging. 


The effect on detection rate of second cancers after the addition of MRI to 

conventional screening mammography in patients with a history of breast 

cancer. Presenting Author: Chana Weinstock, University of Maryland 

Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 

Background: Mammography is currently used in the surveillance of breast 

cancer survivors, who are at increased risk of developing ipsilateral and 

contralateral breast cancers regardless of age at diagnosis or time since 

diagnosis. Several prospective studies have shown the utility of breast MRI 

in other high risk populations; however, little data exists on the use of MRI 

for surveillance of breast cancer survivors. We aimed to compare the 

outcome of surveillance breast MRI vs. mammography in this population. 

Methods: We identified women �65 with non-metastatic breast cancer or 

DCIS with at least one MRI performed at our center �11 months after 

initial diagnosis, along with a mammogram done within 6 months of the 

MRI. We compared the outcome of MRI and mammography in terms of 

biopsies performed as well as in detection of new cancers. Results: Of 512 

consecutive charts reviewed, 204 patients met inclusion criteria, 105 

(51.4%) of whom were African-American. The average number of MRIs per 

patient was 2.3 (range 2-7), with a total of 474 MRIs performed between 

2005 and 2011. MRI resulted in BIRADS scores of 1 or 2 in 73.5% of 

studies vs. 84.4% for mammography. There were 19 biopsies performed 

due to MRI findings alone, 7 done due to mammographic findings alone, 

and 6 biopsies done based on abnormalities seen on both MRI and 

mammography. There were 7 malignancies identified based on an abnormal 

MRI, 3 seen on both MRI and mammography, and none identified via 

mammography alone. The malignancies identified via MRI alone included 

1 patient with DCIS, 5 with stage I disease, and 1 with isolated lung 

metastases. Of the 10 recurrences detected, 5 (50%) were in African 

Americans. Two patients developed interval cancers within 6 months of 

normal screening MRI and mammography. Sensitivity and specificity for 

MRI were 83.3% (95% CI 0.51-0.97) and 92.2% (95% CI 0.87-0.95), vs. 

25% (95% CI 0.05-0.57) and 94.8% (95% CI 0.90-0.97) for mammography. 

Positive and negative predictive values were 40% and 98.9% for MRI 

vs. 25% and 95.2% for mammography. Conclusions: Gadoliniumenhanced 

breast MRI is a useful surveillance modality in breast cancer 

survivors � age 65. Prospective studies are needed in this population. 

Tumor Biology 

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Online biomarker validation of survival-associated biomarkers in breast and 

ovarian cancer using microarray data of 3,862 patients. Presenting Author: 

Balazs Gyorffy, Joint Research Laboratory of the Hungarian Academy of 

Sciences and the Semmelweis University, Budapest, Hungary 

Background: The pre-clinical validation of prognostic gene candidates in 

large independent patient cohorts is a pre-requisite for the development of 

robust biomarkers. Today, curated microarray cohorts combined with 

appropriate clinical data offer a cost effective tool to prescreen potential 

new biomarkers. In present study we expanded our online Kaplan-Meier 

plotter tool to assess the effect of genes on ovarian cancer prognosis. 

Methods: Gene expression data and survival information of breast and 

ovarian cancer patients were downloaded from GEO and TCGA. To analyze 

the prognostic value of the selected gene in the various cohorts the patients 

are divided into two groups according to the quantile expression of the 

gene. Filtering is implemented for stage, grade, and histology subtypes. 

Follow-up threshold is implemented to exclude long-term effects. A 

Kaplan-Meier survival plot is generated and significance is computed in the 

R statistical environment using Bioconductor packages. The combination 

of several probe sets can be employed to assess the mean of their 

expression as a multigene predictor of survival. Results: All together 1,390 

ovarian cancer patients and 2,472 breast cancer patients were entered into 

the database. These groups can be compared using relapse free survival 

(n�2,324 in breast cancer and 1,090 in ovarian cancer) or overall survival 

(n�464 and n�1,287). We used this integrative data analysis tool to 

validate the prognostic power of 37 ovarian cancer associated biomarkers 

identified in the literature. Of these, CA125 (p�3.7e-5, HR�1.4), CDKN1B 

(p�5.4e-5, HR�1.4), KLK6 (p�0.002, HR�0.79), IFNG (p�0.004, 

HR�0.81), P16 (p�0.02, HR�0.66) and BIRC5 (p�0.00017, HR�0.75) 

were associated with survival. Conclusions: We set up a global online 

biomarker validation platform to mine all available microarray data to 

assess the prognostic power of 22,277 genes in 2,472 breast and 1,390 

ovarian cancer patients. Registration-free online access at: http:// 

www.kmplot.com/. 


FDG-PET and CT as early predictors of outcome in NSCLC patients treated 

with erlotinib. Presenting Author: Robert Iannone, Merck, North Wales, PA 

Background: Tumor metabolism as assessed by FDG-PET is an early 

biomarker for clinical benefit in oncology. This multi-national study 

evaluated associations of changes in mean standardized uptake values 

(SUVmean) of FDG and tumor burden with disease control rates (DCR: 

CR�PR�SD), PFS and OS in 48 NSCLC patients (EGFR mutants or 

favorable clinical/demographic characteristics) treated with erlotinib. The 

primary hypothesis was that changes in SUVmean at day 8 predicted DCR. 

Methods: Patients were scanned by FDG-PET (twice pre-therapy, 1 and 3 

weeks post-therapy) and CT (same as FDG-PET and every 6 weeks 

post-therapy until progression or death). Early response biomarkers included 

the decrease in SUVmean (DiSUV), sum of diameters (DiSOD) and 

sum of volumes (DiSOV). For the primary hypothesis, metabolic response 

(MR) was defined as a decrease of �2SD the variability between baseline 

PET scans (30%). Exploratory analyses of the biomarkers at various 

thresholds were performed. Results: The primary hypothesis was met: DCR 

was 34.6% (80% CI: 17.5%, 48.2%) higher in patients with a MR at day 8 

(p � 0.033); the association was stronger for day 22. The table compares 

hazard ratios derived from the �optimal� % decrease (smallest upper 80% 

confidence limit) over the 10% to 50% (by 10%) range for all biomarkers 

and time points, by PFS and OS. Conclusions: FDG-PET was predictive for 

clinical responses after 8 days of treatment. Comparing all biomarkers, 

DiSOV had stronger associations than both DiSUV and DiSOD with PFS or 

OS. For NSCLC treated with erlotinib in this clinical context, the decrease 

in CT-based tumor volume may be a better early predictor of clinical 

outcome than FDG-based SUVmean. Hazard ratio and the 80% confidence interval by change in biomarker and 

time. 

Time Outcome DiSOD DiSOV DiSUV 

Day 8 OS 0.41 (0.21,0.80) 0.18 (0.07,0.47) 0.47 (0.23,0.93) 

PFS 0.40 (0.25,0.65) 0.24 (0.14,0.39) 0.57 (0.34,0.93) 

Day 22 OS 0.39 (0.21,0.75) 0.23 (0.09,0.60) 0.45 (0.23,0.88) 

PFS 0.17 (0.10,0.30) 0.19 (0.12,0.32) 0.21 (0.09,0.46) 

Day 43 OS 0.13 (0.05,0.36) 0.10 (0.04,0.28) 

PFS 0.22 (0.12,0.41) 0.12 (0.06,0.24) 

Based on the �optimal� % decrease, over the 10% to 50% (by 10%) range, in 

biomarker which yielded the smallest, upper 80% confidence interval. 




Correlation of ERCC1 expression on circulating tumor cells with progressionfree 

survival in metastatic non-small cell lung cancer patients treated with 

platinum-based chemotherapy. Presenting Author: Jonathan Riess, Stanford 

University School of Medicine, Stanford, CA 

Background: Biomarkers predicting efficacy of chemotherapy are highly 

desirable. Fiber array scanning technology (FAST) is a novel method of 

detecting circulating tumor cells (CTCs) that does not employ an EpCam 

enrichment step. The purpose of this study was to use FAST to evaluate 

ERCC1 expression on CTCs to determine whether ERCC1 expression 

correlates with progression-free survival (PFS) in patients who received 

platinum-based chemotherapy for metastatic non-small-cell lung cancer 

(NSCLC). Methods: Peripheral blood from one hundred enrolled patients 

with metastatic NSCLC was collected by two institutions (Stanford Cancer 

Institute and Billings Clinic Cancer Center). FAST was used to identify 

individual CTCs on immunofluorescence by pancytokeratin antibodies. 

Nuclear localization of ERCC1 expression by immunofluorescence was 

quantified on individual CTCs. Total patient ERCC1 levels were determined 

from the average expression of all the CTCs in each patient sample. 

Fifty-seven of the one hundred patients enrolled received platinum chemotherapy. 

Seventeen of those fifty-seven patients (30%) had � 2 evaluable 

intact CTCs and were analyzed retrospectively. Linear regression (F-test) 

was used to evaluate the correlation between ERCC1 expression and PFS. 

Kaplan-Meier survival analysis (log-rank test) was used to compare PFS in 

patients with CTCs with no detectable ERCC1 expression versus patients 

with CTCs that expressed any level of ERCC1. Results: PFS decreased with 

increasing ERCC1 expression (P�0.04 F-test, linear regression). Lack of 

ERCC1 expression was associated with longer PFS (266 days vs. 172 days, 

log-rank test P�0.02). The difference in survival was statistically significant 

with a hazard ratio of 4.20 (95% CI 1.25-14.1, p�0.02, log-rank 

test). Conclusions: In this small study, using FAST to isolate CTCs, low 

expression of ERCC1 on evaluable CTCs correlated with increased PFS in 

patients with metastatic NSCLC who received platinum chemotherapy. A 

larger, prospective study to validate these retrospective results is warranted. 


A gene expression profile test that distinguishes ovarian from endometrial 

cancers. Presenting Author: Anita Lal, Pathwork Diagnostics, Redwood 

City, CA 

Background: The differential diagnosis between primary epithelial ovarian 

and endometrial cancers is often unresolved because the histologic 

subtypes of these two tumor types can have very similar histology and 

immunohistochemical appearance. Here we report the development and 

validation of a gene expression profile (GEP) diagnostic test (Pathwork 

Tissue of Origin Endometrial Test) that distinguishes ovarian and endometrial 

cancers in formalin-fixed, paraffin-embedded (FFPE) specimens using 

a 316–gene classification model. Methods: The test was clinically validated 

in a blinded study using a pre-specified algorithm and microarray 

data files for 75 metastatic, poorly differentiated or undifferentiated 

primary FFPE tumor specimens that had either a known clinical diagnosis 

of ovarian or endometrial cancer and belonged to one of the 14 ovarian and 

endometrial WHO histologic subtypes on the test panel. Results: Classification 

biomarkers, empirically selected by machine learning, included 

several genes such as homeobox transcription factors and kallikrein 

peptidases with known function in the biology of ovarian and endometrial 

cancers. The Tissue of Origin Endometrial Test accurately identified the 

primary site for 94.7% (95% CI, 87% to 99%) of ovarian and endometrial 

cancers. Other measures of test performance include an area under the 

ROC curve of 0.997 and a diagnostic odds ratio of 406. Test performance 

did not change significantly when stratified by specimens from metastases 

(90.5%) or by poorly differentiated and undifferentiated primary tumors 

(96.3%). All stages of ovarian and endometrial cancers were included in 

the validation study and had agreements of 85% to 100% with the clinical 

diagnosis. In a precision study, concordance in test results was 100%. 

Reproducibility in test results between three laboratories had a concordance 

of 94.3%. Conclusions: The GEP test identified specific ovarian and 

endometrial cancer morphologies even when a clear distinction could not 

be made by histologic criteria. The GEP test can aid in resolving an 

important differential diagnostic question in gynecologic oncology and may 

impact clinical management of these patients as well as entry opportunities 

into clinical trials. 


Accuracy of microRNA-based classification of metastases of unknown 

primary. Presenting Author: Nicholas Pavlidis, Ioannina University Hospital, 

Ioannina, Greece 

Background: Identification of the tissue of origin of metastatic tumors is 

important for estimation of prognosis and patient management. Carcinoma 

of unknown primary (CUP) is not uncommon in oncology, representing 

3-5% of all newly found malignancies. We used a microarray-based test 

that uses the expression of 64 microRNAs to retrospectively evaluate 

tumors from CUP patients. Methods: A cohort of resected metastatic lesions 

from patients diagnosed with CUP was studied blindly on the microRNAbased 

test. The cohort included 93 samples (from 92 patients) with tissue 

adequate for the test. Eight samples failed due to inadequate RNA quality; 

85 samples (84 patients) were processed successfully. Test results were 

compared with clinical presentation including imaging, pathological data 

(histology and IHC) at initial CUP diagnosis and with clinical management 

and outcome data at the completion of each patient�s follow up. Results: 

The test results were fully concordant with the diagnosis based on all the 

clinical and pathological information available including follow-up and 

outcome in 92% of patients compared to ~70% agreement with the 

patients’ diagnosis at initial presentation, before additional data gathered 

throughout patient management. Two different metastases from the same 

patient yielded the same result. The microRNA test assigned a single tissue 

of origin for 51 patients and two tissues of origin in 33 patients, with the 

first being the more likely diagnosis. When comparing only the first (or 

single) diagnosis, a concordant level of 88% was achieved. Conclusions: In 

a retrospective, well studied cohort of metastases from CUP patients, a 

previously developed test based on the expression profile of 64 microRNAs 

allowed accurate identification of tissue of origin in 92% of the cases. This 

study validates the high accuracy of the test on real CUP patients. The high 

concordance of the test results to the final tissue of origin diagnosis of the 

patient, even in cases where the initial diagnosis at CUP presentation was 

discordant, demonstrates the importance of the test in yielding additional 

data valuable for patient management at an early stage of the patient’s 

treatment plan. 


Use of early 18f-fluorodeoxyglucose-positron emission tomography to 

predict clinical outcome of patients with advanced non-small cell lung 

cancer on gefitinib treatment versus carboplatin plus paclitaxel. Presenting 

Author: Masaki Kanazu, National Hospital Organization Kinki-Chuo Chest 

Medical Center, Sakai, Japan 

Background: Early prediction of clinical efficacy is of great value in cancer 

patients in avoiding unnecessary toxicities and giving them another chance 

for different treatments. This study aimed to assess the 18F-fluorodeoxyglu cose-positron emission tomography (FDG-PET) at 3 days on treatment as an 

early predictor of clinical outcome in patients with advanced non-small cell 

lung cancer (NSCLC) treated with gefitinib and in those treated with 

cytotoxic chemotherapy. Methods: This study comprised two groups: 

patients with stage IIIB or IV NSCLC were treated with gefitinib (250mg) 

once daily (gefitinib group) or with carboplatin (AUC 6, day 1) plus 

paclitaxel (200mg/m2 , day 1) q21 days (CP group) according to the 

physicians’ choice. FDG-PET was performed before, 3 days on and 28 days 

on each treatment. Reduction of tumor FDG uptake was assessed by using 

standardized uptake value (SUV). Metabolic response was defined as 

reduction of FDG uptake in the tumor � 25% according to the criteria of 

the European Organization for Research and Treatment of Cancer. Metabolic 

response was correlated with clinical outcomes. Results: This study 

included 38 patients: 19 in gefitinib group and 19 in CP group. Reduction 

of SUV at 3days on treatment preceded tumor shrinkage more closely in 

gefitinib group. Metabolic response was significantly correlated with longer 

progression-free survival (PFS) in gefitinib cohort (median PFS 15.8 

months [95% CI 13.2-18.4] vs. 3.7 months [95% CI 0.1-8.0], p � 

0.001), but not in CP group (median PFS 5.7 months vs. 2.9 months, p � 

0.054). Furthermore, metabolic response was significantly correlated with 

longer overall survival (OS) in gefitinib group (median OS 28.7 months 

[95%CI 23.5-33.9] vs. 9.8 months [95% CI 2.1-17.5], p � 0.009), but 

not in CP group (median OS 13.9 months vs. 10.5 months, p � 0.56). In 

multivariate analysis using Cox hazards models, metabolic response was a 

significant predictive factor of PFS and OS. Conclusions: Reduction of SUV 

levels on FDG-PET at 3 days on treatment may predict response and 

survival in gefitinib-treated patients with advanced NSCLC. 



Preoperative detection of circulating tumor cells in patients with colorectal 

carcinoma: Correlation with clinicopathologic variables and recurrence. 

Presenting Author: Hideyasu Sakihama, Gastroenterological Surgery 1, 

Hokkaido University Graduate School of Medicine, Sapporo, Japan 

Background: The role of circulating tumor cells (CTC) in the management of 

colorectal cancer patients has not fully established. The aims of this study 

are to investigate the relationship between the presence of CTC with 

clinicopathological variables and recurrence by magnetic activated cell 

sorting (MACS) system. Methods: Peripheral blood samples were collected 

from 80 patients. Enrichment of CTC was performed by direct immunomagnetic 

labeling of EpCAM positive cells in peripheral blood. Subsequently, 

double immunofluorescence for cytokeratin and CD45 was performed to 

detect CTC. Peripheral blood samples from twenty healthy volunteers were 

used as controls. Results: Preoperative positive rate of CTC was 35% while 

specificity was 100%. No CTC was found in peripheral blood from healthy 

volunteers. No correlation was found between the presence of CTC and 

location of tumors, grade of differentiation, vessel invasion, lymph node 

metastasis or TNM stages. On the other hand, the depth of invasion (0% in 

Tis, 11.1% in T1, 18.2% in T2 and 34.7% in T3�T4, P�0.05) and tumor 

recurrence (28.2% for initial operation and 88.9% for reoperative surgery 

for tumor recurrence, P�0.001) closely correlated with the presence of 

CTC. Preoperative positive rate of CTC among patients who have recurred 

postoperatively was 75%. Conclusions: Our results indicate that detections 

of CTCs correlate with the depth of invasion and tumor recurrence. 

Preoperative presence of CTCs might be a strong predictor for tumor 

recurrence. 


Defining a FISH chromosomal aneusomy panel for predicting lung cancer in 

the setting of CT-detected lung nodules. Presenting Author: Wilbur A. 

Franklin, University of Colorado Denver, Denver, CO 

Background: Early detection of lung cancer by CT is supported by the 

National Lung Screening Trial; but while sensitivity of CT is high, specificity 

is low. Biomarkers to predict the malignant nature of CT detected lung 

nodules would have great clinical utility. We previously found in a nested 

case-control study that a 4-target chromosomal aneusomy (CA) FISH panel 

exhibited sensitivity/specificity of 76%/88% in sputum samples of heavy 

smokers obtained within 18 months of lung cancer diagnosis. We hypothesized 

that CA-FISH may be an effective biomarker to assist with clinical 

decisions in the setting of CT detected lung nodules of indeterminate 

etiology and attempted to identify a more effective reagent. Methods: 

Homebrew probes encompassing genomic sequences of EGFR, NXK2-1, 

PIK3CA, MYC, BRF2, SOX2, PPMID, FGFR1 and the commercial reagent 

LSI D5S721/D5S23 (Abbott Molecular) were combined in 2-4-target FISH 

assays to investigate tissue copy number in early stage lung squamous cell 

carcinoma (SCC, N�19) and adenocarcinoma (AC, N�20). Logistic 

regression models were used to estimate predictive discrimination [sensitivity, 

specificity, area under the ROC curve (AUC)]. Results: Copy number 

gain was largely detected for all markers (mean range 3.39 - PPMID to 4.67 

- MYC). Mean copy number of PI3CA, BRF2, SOX2 and FGFR1 were 

significantly higher in SCC than AC, while NKX2 and MYC were marginally 

higher in AC than SCC. Gene amplification was detected for all 9 markers, 

most frequently for SOX2 and FGFR1 (6 and 5 cases) with significant 

overlap between FGFR1/BRF2 and SOX2/PIK3CA. Based on the AUC 

results and the existence of targeted inhibitors, the probe set EGFR/FGFR1/ 

MYC/PIK3CA was selected as a candidate for further development as an 

adjunct to CT screening for early detection. For this selected set,the 

optimal cutoff based in the linear predictor from logistic regression yields a 

sensitivity and specificity of 0.85. Conclusions: A highly sensitive/specific 

CA-FISH probe set was identified which may well complement CT screening 

in the early diagnosis of lung cancer. This probe set will be tested in the 

setting of CT detected lung nodules. (Supported by LUNGevity and 

NCI-Lung Cancer SPORE grants). 

Tumor Biology 

675s 


Retrospective analysis of gene expression profiling and TTF-1 staining in 

cancer of unknown primary (CUP). Presenting Author: Wendy M. Chiang, 

Tufts Medical Center, Boston, MA 

Background: CUP involves extensive use of immunohistochemical (IHC) 

stains because no individual marker is highly both site specific or sensitive. 

IHC algorithms lack standardization and may even eliminate actual primary 

sites. Extensive validation studies with gene expression profiling (GEP) has 

shown it be a new diagnostic technique that further contributes tumor site 

location in CUP. Thyroid transcription factor-1 (TTF-1) IHC stain is 

commonly used to identify the pulmonary origin of CUP (particularly 

adenocarcinoma) and is often used to exclude lung primary in CUP 

patients. This study evaluates the utility of TTF-1 staining in lung primaries 

(specifically non-small cell lung carcinoma - NSCLC) of CUP to GEP 

testing. Methods: This retrospective study contains data obtained from a 

registry of physicians who received the GEP-based Tissue of Origin (TOO) 

test (Pathwork Diagnostic, Sunnyvale, CA) between 07/2009 and 12/2009 

on CUP cases. Sixty-six physicians contributed 111 TOO test cases. Only 

cases that had TTF-1 done were included for analysis and these were 

compared to TOO NSCLC results. Results: Out of 111 cases, there were 73 

analyzable TTF-1 results with 12 cases of NSCLC and 61 cases of 

non-NSCLC by TOO (see TABLE). Assuming that the results of TOO testing 

accurately indicated the true primary site, the sensitivity and specificity of 

TTF-1 was 50% and 90%, respectively. The false negative rate was 50%, 

indicating that half of the identified NSCLC cases in this series had 

negative TTF-1. On the other hand, 10% of the 61 cases with primaries 

other than NSCLC (none of whom had thyroid cancer), had positive TTF-1. 

The “false positive” TTF-1 cases comprised 4 ovarian, 1 breast and 1 

colorectal as the site of origin. Conclusions: TTF-1 has limited utility in 

identifying NSCLC in the setting of CUP. Half of NSCLCs identified by TOO 

testing had negative TTF-1, and 10% of non-lung primaries were TTF-1 

positive. Negative TTF-1 should not be used to exclude NSCLC in the 

workup of CUP. 

NSCLC by TOO Non- NSCLC by TOO Total 

TTF-1 stain positive 6 (TP) 6 (FP) 12 

TTF-1 stain negative 6 (FN) 55 (TN) 61 

Total 12 61 73 

Sensitivity 0.50 

Specificity 0.90 

False negative rate (1-sensitivity) 0.50 

False positive rate (1-specificity) 0.10 


89 Zr-bevacizumab PET imaging in metastatic renal cell carcinoma patients 

before and during antiangiogenic treatment. Presenting Author: Sjoukje 

Oosting, Department of Medical Oncology, University Medical Center 

Groningen, Groningen, Netherlands 

Background: Renal cell cancer (RCC) is characterized by high VEGF 

production leading to excessive angiogenesis. To visualize VEGF, we 

performed serial 89Zr-bevacizumab-PET scans before and during antiangiogenic 

treatment in RCC patients. Methods: Metastatic (m) RCC patients 

who received sunitinib (50 mg once daily, 4 out of 6 weeks) or bevacizumab 

(10 mg/kg every 2 weeks) plus interferon (IFN 3-9 MU 3x/week), underwent 

89Zr-bevacizumab-PET scans at baseline and after 2 and 6 weeks, and CT 

scans at baseline and every 3 months. Tracer uptake in tumor lesions was 

quantified with maximum Standardized Uptake Value (SUVmax). Relationship 

between baseline and � SUVmax and time to progression (TTP) was 

analyzed. Wilcoxon test was used to compare scans, Kaplan-Meier method 

for survival analysis. Results: 22 out of 26 patients were evaluable, 11 per 

treatment. On 89Zr-bevacizumab-PET, 131 out of 231 lesions � 10 mm 

(detection limit) were visible and 125 quantifiable. Mean SUVmax at 

baseline was 10.1 (SD 8.4; range 2.3 - 46.9). During bevacizumab/IFN 

treatment, SUVmax consistently decreased (mean decrease 47.0% 95% CI 

39.1-54.9, P�0.0001) at 2 weeks with a further decrease of 9.7% (95% 

CI 0.86-18.5, P�0.016) at 6 weeks. After 2 weeks sunitinib, there was 

only a modest decrease in mean SUVmax (14.6%, 95% CI 1.57-27.63, 

P�0.0064) with a wide range (-80.4% to �269.9%) and an overshoot of 

84.4% (95% CI 47.8-120.9, P�0.0001) after 2 drug free weeks. TTP was 

longer in (n�15) patients with baseline SUVmax � 11.1 (highest normal 

tissue uptake) in the 3 most intense lesions than in those with a lower value 

(median 89.7 vs 22.8 weeks, HR 0.16, 95% CI 0.04 - 0.70). TTP was 

longer in patients (n�11) with an absolute � SUVmax �6.00 in the most 

intense lesion at 2 weeks (HR 0.25, 95% CI 0.06-0.98). Conclusions: 

89Zr-bevacizumab-PET visualizes tumor lesions in mRCC patients. Different 

changes in tumor tracer uptake after start of bevacizumab/IFN versus 

sunitinib indicate that these drugs induce different angiogenic responses. 

High baseline SUVmax and large change in SUVmax corresponded with 

longer TTP, suggesting that 89Zr-bevacizumab-PET may help to identify 

patients who benefit the most from antiangiogenic treatment. 




Antigens diagnoses in paraneoplastic neurological syndromes. Presenting 

Author: Halina Rudnicka, Maria Sklodowska-Curie Memorial Cancer Center 

and Institute of Oncology, Warsaw, Poland 

Background: At present, paraneoplasmatic neurological syndroms (PNS) 

are thought to be autoimmunological disorders. Neurological symptoms in 

PNS result from the disturbance of the nervous system, with a participation 

of the immune response triggered by the aberrant expression of the 

so-called onconeuronal antigens of a tumour. Very important for PNS 

diagnostics is the investigation of antineuronal antibodies (ANA) in the 

serum. Different types of ANA are frequently associated with specific 

tumors and with specific neurological syndromes.Investigations of serum 

ANA in patients with breast cancer with the symptoms of PNS. Methods: 

Investigations of ANA in serum were performed with the indirect immunofluorescence 

test but the type of ANA was analyzed by the Western Blot 

(WB) method . The presence of these antibodies which are included to the 

group of “the so called well characterized” is believed to be a definite (95 – 

100%) determinant of the PNS diagnosis. Results: We examined 147 

patients with breast cancer suspected to have PNS, hospitalized at Breast 

Cancer Clinic of the Institute of Oncology in Warsaw. The immunofluorescence 

test was positive in 92 patients, however in 24 patients the WB 

occurrence of “the well characterized” antibodies was found. In this group 

we observed: in 4 patients the cerebellar degeneration (anti-Yo, anti-Ma2); 

in 6 patients brainstem encephalitis and encephalomyelitis combined with 

sensory neuropathy (anti-Ma2, anti-CV2, anti-Yo, anti-Hu, anti-Ri); 4 

myastenic syndrome (anti-Hu,anti-Ri,anti-Ma2/Ta); 5 sensory neuropathy 

(anti-Hu, anti-Yo, anti-Ma2, anti-Ri); and in single cases we also observed 

polyneuropathy: Guillain-Barre (Ma2): Miller-Fisher syndrom (anti-Ma2/ 

Ta); cancer-associated retinopathy (anti-Yo); dermatomyositis (anti-Ri) and 

scleroderma (anti-Yo). Conclusions: Our analysis indicates that the investigation 

of the presence of ANA in the serum is the important in the diagnosis 

of PNS in patients with breast cancer. The types of ANA correspond to the 

individual paraneoplastic neurological syndromes which opens the proper 

methods of treatment in PNS. 


Estimation of expected survival time using gene expression profiling for 

tumor site origin. Presenting Author: William David Henner, Pathwork 

Diagnostics, Redwood City, CA 

Background: Expected survival is an important factor in treatment selection 

and patient decision making. Gene expression profiling for tissue of origin 

(GEP TOO) can be used to classify metastatic and poorly-differentiated 

tumors according to the most likely primary site for difficult-to-diagnose 

tumors. The Pathwork Tissue of Origin Test, (Redwood City, CA) generates 

Similarity Scores (SS), one for each of the 15 tissues on the Tissue of Origin 

Test Panel and sum to 100. The highest SS has been validated as the most 

likely tissue of origin in a large validation study (Pillai et al. 2010). This 

abstract reports the relationship between the highest SS for a sample and 

patient survival. Methods: Two cohorts were analyzed in IRB-approved 

studies. Cohort 1 consisted of 45 patients with carcinoma of unknown 

primary treated empirically with therapy for carcinoma of unknown primary 

with known outcome data including survival. Cohort 2 consisted of 107 

patients receiving the TOO test in routine clinical practice and included in a 

decision impact registry study. The relationship between the highest SS 

generated by the TOO test was examined using parametric (Gamma) and 

non-parametric (Cox Proportional Hazards) regression models with covariates 

of age, gender and median survival of the cancer type indicated. 

Logrank tests were performed to compare survival in patients with SS above 

or below 50 in each cohort. Results: The highest SS generated by the TOO 

Test was strongly and positively correlated with patient survival in both 

Cohort 1 (p � 0.0093, Cox PH) and in Cohort 2 (p�0.0045, Gamma). In 

Cohort 1, survival for patients with a SS � 50 was 5.9 mos and for patients 

with a SS � 50 was 9.7 mos (p�0.03, logrank). In Cohort 2, survival for 

patients with a SS � 50 was 10.6 mos and 22.6 mos for patients with a SS 

� 50 (p�0.0073, logrank). Conclusions: The Similarity Scores generated 

by GEP TOO Test have been validated as an aid to diagnosis for 

difficult-to-diagnose malignancies. Two independent studies of this GEP 

TOO Test demonstrated a strong positive relationship between the highest 

SS and survival. This has the potential to expand the clinical utility of this 

test beyond diagnosis to include prognosis. Further studies to examine this 

question are underway. 


Antagonistic activity of acolbifene, fulvestrant, tamoxifen, and raloxifene 

on cancer-associated genes in the mouse mammary gland. Presenting 

Author: Ezequiel Calvo, Molecular Endocrinology, Oncology and Human 

Genomics Research Center, Laval University and Laval University Hospital 

Research Center, Quebec City, QC, Canada 

Background: The efficacy and exceptionally good tolerance of estrogen 

blockade in the treatment of breast cancer is well recognized. Acolbifene 

(ACOL) is a novel and unique SERM completely free of estrogen-like 

activity in both the mammary gland and uterus. To better understand the 

specificity of ACOL, we have investigated its effect on the expression of a 

set of genes modulated by estradiol (E2) in the mouse mammary gland. 

Methods: ACOL, tamoxifen (TAM), raloxifene (RALOX) and fulvestrant 

(FULV) were administered (0.01 mg/mouse; sc) to ovariectomized (OVX) 

mice or to OVX mice simultaneously treated with E2 (0.05 �g/mouse; single 

sc injection). Microarray screening followed by Q_RTPCR was used to 

identify a reproducible set of E2 responsive genes. Results: From 128 genes 

significantly modulated by E2, 108 genes were up-regulated and 20 were 

down-regulated. Forty-nine of these genes were associated with tumorigenesis 

while 22 are known to be associated with breast cancer. This set of 49 

genes were used to determine the specificity of ACOL compared to another 

pure antiestrogen in the mammary gland and uterus, namely FULV, as well 

as to the mixed estrogen antagonists/agonists TAM and RALOX, in their 

ability to block the effect of E2. Efficacy of reversal of the effect of E2 was 

94%, 63%, 45% and 90% for ACOL, FULV, TAM and RALOX, respectively. 

The overlap between all treatments was 30.6% (15/49). ACOL reversed the 

effect of E2 on 42 of the 49 (85.7%) cancer-related genes. Between the 

genes up-regulated by E2 and reversed by ACOL, seven are considered as 

prognostic markers in breast cancer, namely Fgfr3, Fos12, Junb, Jdp2, 

Gdf15, Greb1 and Tgm2. On the other hand, two genes down-regulated by 

E2, namely Foxa1 and Fgfr2, were restored by ACOL. Conclusions: Taken 

together, these data offer new information for a better understanding of the 

previously demonstrated potent tumoricidal action of ACOL in human 

breast cancer xenografts. The data also suggest, under the tested conditions, 

superiority of ACOL over TAM and the other compounds to reverse the 

effect of E2 on specific gene expression, thus supporting the interest of this 

new 3rd generation SERM for the hormonal therapy and prevention of breast 

cancer. 


Novel malignant-mesothelioma-associated antigens (Gene-X and THBS-2) 

in the diagnosis of malignant pleural mesothelioma (MPM). Presenting 

Author: Fumihiro Tanaka, University of Occupational and Environmental 

Health, Kitakyusyu, Japan 

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive 

malignant tumor of the pleura associated with asbestos exposure, and its 

diagnosis is usually difficult at early stage. We identified novel mesothelioma-related 

antigens, Gene-X and thrombospondin-2 (THBS-2), recognized 

by tumor-infiltrating B cells (Cancer Sci 2009), but the clinical 

significance in the diagnosis of MPM remains unclear. Methods: A total of 

120 patients, who presented with a suspicion of MPM and received pleural 

biopsy, were reviewed; 97 patients were finally diagnosed with MPM and 

27 were with non-malignant diseases (NM). The antibody-titers against 

Gene-X and THBS-2 in the sera were measured by ELISA method. Results: 

The serum antibody-titer against THBS-2 was significantly higher in MPM 

patients than in NM (P�0.01), but there was no difference in the serum 

antibody-titer against Gene-X (Table). The receiver operating characteristic 

(ROC) curve analysis showed a significant diagnostic value of serum 

antibody-titer against THBS-2 with the area-under curve of 0.886 (95% CI, 

0.797 - 0.975; P�0.001) in discrimination of MPM from NM diseases; the 

sensitivity and specificity, when the cut-off value was 0.08, were 72.2% 

and 95.5%, respectively. Conclusions: The serum antibody-titer against 

THBS-2 can be a useful non-invasive marker in the diagnosis of MPM. 

Antigens 

MPM 

(n�97) 

Non-malignant 

(n�23) 

p value 

(Mann-Whitney) 

Gene-X 

(mean) 0.49 0.48 p�0.997 

(median) 0.39 0.36 

THBS-2 

(mean) 0.11 0.02 p�0.001 

(median) 0.10 0.00 



Multiplex TaqMan assays for a 7-gene prognostic immune response score to 

differentiate risk among women with ER-negative breast cancer. Presenting 

Author: John J. Sninsky, Celera Corporation, Alameda, CA 

Background: Teschendorff et al. (Breast Cancer Res 2008) reported a 

7-gene, immune response-enriched gene expression classifier using microarrays 

that was prognostic in women with ER-negative breast cancer. To 

facilitate further evaluation of the prognostic value of a classifier in archival 

fixed tumor tissue, we developed two multiplex TaqMan assays to quantify 

the expression levels of these genes, then trained and validated a 7-gene 

immune response score (IRS). Methods: RNA was extracted from FFPE 

sections of 185 ER-negative breast cancer patient samples from Mayo 

Clinic (n�81), Guy’s Hospital (n�50) and California Pacific Medical 

Center (CPMC) (n�27). Patients (N� and N-) did not receive adjuvant 

therapy and were followed for a minimum of 5 years. Amplification of i) 

LY9, TNFRSF17, HLA-F, and IGLC2 and ii) XCL2, SPP1, C1QA and two 

reference genes NUP214 and PPIG were carried out in two multiplex 

RT-PCR TaqMan reactions and relative expression levels were determined 

using the DDCT method. The training set, comprised of the Mayo Clinic 

samples, was used to develop an IRS by using a summation of expression 

levels of the 7 genes. Association of the IRS with distant metastasis was 

assessed using a Cox proportional hazards model. The score was subsequently 

tested in a validation set (Guy’s � CPMC). Results: The amplification 

efficiency of each gene within the multiplex reactions was comparable 

to singleplex reactions. Duplicate amplifications showed excellent assay 

reproducibility and sensitivity (R2�0.98). The hazard ratio for a single 

standard deviation decrease in the IRS was 1.45 (95% CI 0.99-2.12, 

p�0.056) in the training set and 2.18 (1.32-3.61, p�0.002) in the 

validation set. ROC curves of continuous IRS to predict distant metastasis 

within 5 years had AUC of 0.74, 95% CI � 0.60-0.88. Conclusions: Robust 

multiplex TaqMan assays for FFPE tissue extracted RNA were developed for 

a 7-gene IRS. Increases in risk are associated with decreases in the IRS. 

Immune related gene expression clearly plays an important role in the 

spectrum of risk of ER-negative tumors. Additional signatures are in 

development that further support this conclusion. 


Multisite validation of a 92-gene molecular classifier: Diagnostic accuracy 

and clinical utility in metastatic cancer. Presenting Author: Catherine A. 

Schnabel, bioTheranostics, Inc., San Diego, CA 

Background: Accurate tumor classification is increasingly critical to individualized 

care as patient outcomes improve with use of targeted cancer 

therapies and predictive biomarkers. In metastatic cancers of uncertain or 

unknown origin, identification of a primary site remains equivocal in a 

significant number of cases. Gene expression signatures may improve 

accuracy and specificity of tumor classification, however, large-scale, 

blinded validation studies that demonstrate stable performance in metastatic 

and poorly differentiated cases are currently lacking. Methods: Seven 

hundred and ninety cases (51% female, 44% metastatic, 63% grade 2 and 

3, 14% limited tissue specimens) representing 28 tumor types and 50 

subtypes were processed and adjudicated between Mayo Clinic, UCLA and 

Massachusetts General Hospital. Blinded FFPE tumor sections were 

submitted and tested using a 92-gene RT-PCR assay (CancerTYPE ID, 

bioTheranostics Inc.). Molecular predictions were evaluated for concordance 

with the reference diagnosis; diagnostic accuracy between clinical 

subsets was compared. Results: The 92-gene assay demonstrated overall 

sensitivities of 87% for tumor classification and 82% for subtyping. 

Forty-seven (5.9%) cases were considered unclassifiable. Comparative 

analysis of performance between metastatic (n�329) and primary (n�414) 

tumors showed no statistically significant difference in accuracy (85% vs 

88%, p�0.16). Similarly, no significant decreases in performance were 

observed across histological grades (p�0.58) and when comparing limited 

tissue to excisional biopsy specimens (p�0.16). Strong precision was 

demonstrated for accurate identification of a primary tumor in tissues 

biopsied from common metastatic sites, reported as positive predictive 

values of 100% for lung, brain and peritoneum, 92% for ovary and 80% for 

liver. Conclusions: Results from this multisite, blinded study validate the 

diagnostic accuracy of the 92-gene assay for classifying a diverse set of 

tumors, and support its clinical utility in the diagnosis of metastatic tumors 

to determine tissue of origin, and in the differential diagnosis of metastatic 

vs new primary disease. 

Tumor Biology 

677s 


Specific and sensitive detection of BRAF and KRAS mutations in clinical 

samples. Presenting Author: Vanessa Kelchner, Swift Biosciences, Inc, 

Ann Arbor, MI 

Background: The development of highly sensitive and specific genotyping 

assays that are suitable for clinical research and molecular diagnostics 

opens new opportunities for the detection, assessment, and research of 

cancer. Swift Biosciences has developed myT Primer qPCR technology 

which has unique structural and thermodynamic properties that enables 

highly sensitive mismatch discrimination. The myT Primer reagents can 

detect 1% mutant BRAF or KRAS present in a background of 103 wild-type 

genomic DNA copies with no background signal from wild-type. A separate 

ultrasensitive BRAF format has been developed which enables the detection 

of a single mutant BRAF copy in � 104 wild-type genomic DNA copies, 

representing 0.01% detection. Methods: To evaluate the performance on 

clinical samples, DNA was prepared from 26 melanoma, 40 colorectal, and 

49 lung tumor fresh frozen and FFPE samples, and their corresponding 

normal adjacent samples. qPCR was performed using standard cycling 

conditions in single tube format with allele-specific myT primers to assess 

two BRAF alleles or seven KRAS alleles. Performance of the assay was 

evaluated on the ABI 7500, CFX96, and Roche LightCycler. A subset of 

samples were selected for validation by Sanger sequencing. Results: 

Mutations of BRAF in melanoma, colorectal, and lung tumors were 

observed to be 46%, 5%, and 2%, in concordance with published data for 

the frequency of BRAF mutations. Mutations of KRAS in colorectal cancer 

were observed to be in 17/40, or 42% of samples, consistent with 

published reports of KRAS in colorectal cancer. 34% of lung cancer 

samples had a KRAS mutation, also consistent with available statistics. 

Mutation status was confirmed with Sanger sequencing in the subset of 

selected samples. Conclusions: The extreme selectivity of the myT BRAF 

Primers makes them well suited for genotyping of conventional FFPE and 

frozen tissue samples, whereas the ultrasensitive format is ideal for use 

with difficult samples such as needle biopsies, CTCs, and serum. The 

extreme selectivity of these primers results in a definitive Yes/No answer 

and eliminates the need to use a delta Ct method. 


A pilot study on the clinical value of 18F-sodium fluoride PET/CT in 

advanced prostate cancer. Presenting Author: Joseph W. Kim, Medical 

Oncology Branch, National Cancer Institute, National Institutes of Health, 

Bethesda, MD 

Background: We evaluated the clinical utility of 18F-sodium fluoride PET/CT 

bone scan ( 18F-NaF) in the detection of bone metastases in patients (pts) 

with prostate cancer in comparison with Technetium-99m MDP bone scan 

(TcBS). Methods: In a prospective study, from October 2010-December 

2011, 30 prostate cancer pts (ages 51-79), 21 with known bone metastases 

and 9 without known bone metastases, had18F-NaF and a TcBS 

performed. Abnormal foci of uptake on both TcBS and 18F-NaFwere classified as benign, malignant or indeterminate. Benign lesions included 

uptake in the joints and linear uptake at the endplates of the vertebral 

bodies consistent with degenerative changes. Malignant uptake on 18F-NaF scans was confirmed by characteristic osteoblastic features on CT. All TcBS 

and 18F-NaF were reviewed by an experienced nuclear medicine physician. 

For the patient-based analysis, scan results were categorized as positive 

(POS) � any malignant lesion; indeterminate (IND) � not distinctly 

malignant or benign; negative (NEG) � benign lesions only. Results: In the 

lesion-based analysis, 21 of 30 (70%) pts had more malignant lesions 

identified on 18F-NaF than on TcBS. The mean number of additional 

malignant lesions per patient on 18F-NaF vs TcBS was 4. Eight of the 30 pts 

had same number of malignant lesions identified in both studies. One of 30 

pts had one less malignant lesion identified on 18F-NaF than on TcBS. CT 

correlation by 18F-NaF PET/CT of this particular lesion did not confirm 

osteoblastic feature. Malignant lesion distribution on 18F-NaF included: 

spine (28%), thorax (26%), pelvis (24%), long bones (13%) and skull 

(10%). In the patient-based analysis, 24 pts (80%) were POS by 18F-NaF, of whom 14 pts were POS, 8 were IND, and 2 were NEG by corresponding 

TcBS; in the 4 pts with NEG 18F-NaF, zero were POS, 2 were IND and 2 

were NEG by corresponding TcBS. Conclusions: 18F-NaF identified more 

malignant lesions than TcBS. 18F-NaF may also add useful information in 

the management of advanced prostate cancer pts with and without known 

bone metastases. 




Next-generation sequencing (NGS) to identify actionable genomic changes 

in common and rare solid tumors: The FMI experience with the initial 50 

consecutive patients. Presenting Author: Gary A. Palmer, Foundation 

Medicine, Cambridge, MA 

Background: Solid tumor (ST) oncology has been transformed by the linkage 

of genomic changes with targeted therapeutics. Unfortunately, most STs 

still have no alteration detected with currently available assays. Thus, more 

informative testing platforms are needed to analyze genomic changes in 

FFPE biopsy samples often limited by tumor size, heterogeneity and ploidy. 

Methods: We reviewed the genomic profiles of the first 50 clinical 

specimens received by our CLIA lab (Foundation Medicine) and analyzed by 

our NGS assay (Ross J. ASCO 2011). 182 genes known altered in STs and 

14 genes known rearranged in STs were included. Genomic alterations 

were categorized as “actionable” if linked to an approved therapy in the ST 

under study or another ST (e.g. ALK rearrangement in lung or breast cancer, 

respectively), a known or suspected contraindication to a given therapy 

(e.g. KRAS G12D in colorectal cancer) or a clinical trial linked to the 

alteration (e.g. mTOR inhibition in a tumor with STK11 loss). Results: Fifty 

tumor specimens were received from 50 patients (median age 54, 

F/M�30/20) representing 35 sites. Two samples failed analysis and 6 had 

no detectable genomic alteration. Among 16 primary tumor types, lung 

(n�15), colorectal (n�7), sarcoma (n�5), breast and esophageal/gastric 

(n�4 each) were most common. We reported 135 genomic alterations 

(mean 2.8, range 0-6) unequivocally involved in oncogenesis and 69 

actionable alterations. At most, 29 of these (42%) would have been 

detected by current assays (138% increase with NGS). Thirty seven 

patients had one or more actionable alterations (range 1-4) detected by 

NGS (74%, 95% CI 60-85%) versus only 21 (42%, 95% CI 28-57%) in 

whom changes would have been detected by current assays. Conclusions: 

Use of a broad, comprehensive NGS assay identifies an unprecedented 

number of actionable genomic alterations across a variety of STs from 

routine FFPE samples. This assay can serve as a paradigm for improving 

access to approved therapies in STs, minimizing use of ineffective 

therapies and enhancing enrollment in rationally chosen trials. Ongoing 

and planned trials will study the impact on several efficacy endpoints. 


Genomic profiling of non-small cell lung cancer (NSCLC) for personalized 

targeted therapy using CT-guided transthoracic needle biopsy (TTNB). 

Presenting Author: Ritu R. Gill, Brigham and Women’s Hospital, Harvard 


Background: Genomic profiling for personalized targeted therapy is emerging 

for NSCLC. DFCI introduced systematic testing for mutations in BRAF, 

HER2, PIK3CA and ALK translocations in addition to EGFR and KRAS in 

July 2009 as part of a prospective study. We report the utility, efficacy and 

safety of CT guided TTNB in this cohort. Methods: Patients with stage IV or 

relapsed NSCLC seen at the DFCI were referred to BWH for CT guided TTNB 

of their tumors to identify driver mutations prior to starting therapy. 

Pathology specimens were dissected and analyzed by PCR-Sanger sequencing 

for mutations in selected exons of EGFR, KRAS, BRAF, PIK3CA and 

HER2. ALK rearrangements were detected with fluorescence in-situ hybridization 

(FISH). Testing was performed after the pathologist deemed that 

the tissue was adequate. Complications such as pneumothorax and 

hemorrhage were recorded. Admission rates were also recorded. Results: 

Between 7/1/2009 and 1/09/2011, 81 patients underwent TTNB. The 

median age was 63 years. 54 (67%) were female, 66 (88%) were 

former/current smokers and 58(72%) had stage IIIB/IV disease. 64(79%) 

patients had sufficient tissue on core biopsies for genomic profiling, 4 (6%) 

of the 64 patients failed analysis for ALK rearrangements due to less than 

50 tumor cells on the hybridized slide. The number of samples obtained 

ranged from 1-5 (2 cm 18-20 (G)). Lesions biopsied ranged in size from 

1.2–8.9 cm. Mutations were identified in 38/81 (46.9%) patients (EGFR: 

18; KRAS: 17; ALK: 2;PIK3CA: 1). 23(28.3%) had pneumothoraces 

15(�10%), 5 (10-30%) and 3(�30%). 6 (7%) patients needed chest 

tubes. 9 (11%) were admitted post procedure for observation (8 for (24hrs) 

and 1 (72hrs). 19(23%) (18 grade1; 1 grade 2) had intra-parenchymal 

hemorrhage. A higher rate of pneumothorax was observed with the 18 

gauge needles (p �.05). 15 of 20 (75%) patients with EGFR, HER2, BRAF 

or ALK alterations were treated with molecularly targeted therapy based on 

their genetic alteration. Conclusions: CT guided TTNB is a feasible, safe and 

efficacious technique for genomic profiling for targeted therapy and 

enables the acquisition of sufficient tissue for gene mutation analyses. 


Combining semiconductor-based sequencing with amplicon-based cancer 

gene panels: A rapid next-gen approach to clinical cancer genotyping. 

Presenting Author: Christopher L. Corless, Knight Diagnostic Laboratories, 


Background: Bringing next-gen sequencing into clinical (CLIA-licensed) 

laboratories is an important step in the advancement of personalized 

cancer care. We have validated a new sequencing approach on the Ion 

Torrent (IT) PGM using the AmpliSeq Cancer Panel, which covers hotspot 

regions across 46 commonly mutated cancer genes. Methods: The AmpliSeq 

panel is comprised of 190 primer pairs that are co-amplified in a 

single tube to generate amplicons for sequencing. In our testing only 10ng 

of input DNA was used. Initial PCR was for 20 cycles, after which the 

amplicons were ligated with sequencing/barcode adapters, amplified for an 

additional 7 cycles, and then subjected to emulsion PCR. The resulting 

nanospheres were sequenced on an IT 316 chip. Results: We sequenced 44 

samples of FFPE-derived tumor DNA that were previously genotyped on a 

mass spectroscopy (MS)-based panel. Samples were barcoded and sequenced 

in batches of 4, yielding an average of 2034 reads per amplicon 

(range: 95-5162) and an average read length of 76bp. Overall, 95.4% of 

reads were on target, and 79% of reads were AQ20 or better; 95% of the 

190 amplicons had over 500 reads. All 42 known point mutations were 

accurately identified by the variant caller software. Seventeen in/dels from 

4 to 63 bp in length were at least partially visible upon manual inspection 

of the read alignments, but some were not accurately called by the 

software. In addition, 22 new mutations were identified in gene regions not 

covered on our MS-based panel. We demonstrated sensitivity to the level of 

5% mutant allele, and the correlation between allelic ratios measured by 

MS and IT sequencing was excellent (r2�0.81). Two DNA samples from 

laser-captured tumor worked well with the AmpliSeq Panel. Conclusions: 

Combining solid-state sequencing with a highly multiplexed PCR method 

for library construction is a rapid (48 hr) approach for next-gen sequencing 

of clinical cancer samples. The process is highly scalable and larger, 

cancer-specific amplicon panels are in development. Automated identification 

of in/dels remains a challenge in next-gen sequencing output. 


Prevalence of TP53 p.R337H mutation in children with cancer from a 

public hospital in southern Brazil. Presenting Author: Juliana Giacomazzi, 

Programa de Pós Graduação em Medicina: Ciências Médicas, Universidade 

Federal do Rio Grande do Sul (UFRGS) e Laboratório de Medicina 

Genômica, Centro de Pesquisa Experimental, Hospital de Clinicas de Porto 

Alegre (HCPA), Porto Alegre, Brazil 

Background: Childhood cancers are a common feature in Li-Fraumeni/Li 

Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a 

germline TP53 mutation. Recently, a specific germline mutation in exon 10 

of the TP53 gene, p.R337H, has been reported at a high prevalence in 

Southeastern Brazil. Initial studies on this mutation claimed that the main, 

if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma 

(ADR). However, others recent reports identified p.R377H carriers 

among LFL families and among a larger spectrum of tumors, such as 

choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study 

was to assess the frequency of the p.R337H mutation in children 

diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central 

nervous system tumors, leukemia, germline cell tumors and Wilm´s tumor) 

at the Children´s Cancer Institute of Rio Grande do Sul (Brazil) between 

1998 and 2011. Methods: Family history (FH) was recorded in pedigrees, 

and DNA was extracted from peripheral blood and FFPE samples by 

standard methods. Screening for the p.R337H mutation was performed by 

allelic discrimination (TaqMan assay) and by TP53 exon 10 sequencing. 

Results: Analysis of 295 children diagnosed with tumors of the LFS/LFL 

spectrum identified the p.R337H mutation in 9/11 (81,8%) children with 

ADR (including a homozygous p.R337H individual) and in 2/2 (100%) 

children with CPC. All individuals had loss of heterozygosity in the tumor 

and in all cases the mutant allele occurred on the same founder haplotype. 

One hundred fourth-six (49,5%) patients had a cancer FH in first or second 

degree relatives, 47 (16,0%) had a FH of breast cancer and 49 (16,6%) 

had FH of LFL consistent with Chompret and/or Birch criteria. Conclusions: 

These results confirm the strong association of p.R337H with ADR and 

CPC. A FH consistent with LFL syndrome is present in a high proportion of 

children diagnosed with tumors of the LFS/LFL spectrum in Southern 

Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith 

Kline. 



Prognostic value of “angiogenic” risk score in early-stage NSCLC. Presenting 

Author: Elena Sanmartin, Fundación para la Investigación del Hospital 

General Universitario de Valencia, Valencia, Spain 

Background: Angiogenesis is a key mechanism in tumor growth and 

dissemination mainly regulated by VEGF family members. We analyze the 

expression of 11 angiogenic genes in a cohort of resectable NSCLC patients 

and correlate them with clinico-pathological variables and prognosis. 

Methods: RNA was obtained from tumor and normal lung specimens from 

175 NSCLC patients. RT-PCR was performed to assess the expression of 

HIF1-A, PIGF, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2, 

VEGFR3, NRP1 and NRP2. Relative expression was normalized by an 

endogenous gene (GUS) using the Pfaffl formulae. Differences were 

considered statistically significant at p�0.05. Results: We found that 

tumor samples had a significant higher expression of PIGF and lower 

expression of VEGFD, VEGFR2, and VEGFR3 compared with normal tissue 

(2.76X, 0.035X, 0.417X and 0.426X, respectively). The group of patients 

with higher expression levels of VEGFA or PlGF had a significantly reduced 

TTP (p�0.024 and p�0.027, respectively) and OS (p�0.055 and 

p�0.048, respectively) whereas those patients with values of VEGFB or 

VEGFD below the median had reduced TTP (p�0.020 and p�0.135, 

respectively) and OS (p�0.003 and p�0.089, respectively). The multivariate 

Cox regression analysis revealed that VEGFA, VEGFB and PlGF were 

independent prognostic markers for TTP and OS and based on these results 

we generated an “angiogenic” risk score model. TTP and OS were 

significantly different among the low, medium and high risk score patients 

(Table). Conclusions: VEGF family members are master control genes of the 

angiogenic process and have a crucial role in the prognostic of the disease. 

We found differences in the expression of four genes between tumor and 

normal lung samples. An “angiogenic” risk score (based on the expression 

of PlGF, VEGF-A and VEGF-B) significantly predicts OS and TTP in our 

cohort of early-stage NSCLC patients. Validation in an independent cohort 

is needed. Supported by grants PS09-01149 and RD06/0020/1024 from 

ISCIII. 

TTP OS 

Risk score N Median 95% CI p N Median 95% CI p 

Low 45 NR - 0.001 47 NR - �0.0001 

Intermediate 47 NR - 50 NR - 

High 41 12.7 5.1-20.3 42 18.8 13.9-23.6 


Retrospective EGFR mutation testing of clinical specimens from the 

EURTAC trial of erlotinib in non-small cell lung cancer (NSCLC) using a 

novel allele-specific PCR (AS-PCR) assay. Presenting Author: Susana 

Benlloch, Pangaea Biotech, USP Dexeus University Institute, Barcelona, 

Spain 

Background: Anti-EGFR inhibitors are superior to chemotherapy in first-line 

therapy of advanced EGFR-mutant NSCLC. The EURTAC trial was a 

randomized Phase III trial of erlotinib vs. chemotherapy in patients with 

EGFR-mutant NSCLC. Interim results showed significant improvement in 

progression-free survival (R. Rosell, ASCO 2011). An accurate rapid in vitro 

diagnostic for EGFR mutations is needed to select patients for this therapy. 

Methods: Prospective EGFR mutation testing for the trial was performed on 

laser-capture microdissected tumor cells using a combination of 3 labdeveloped 

tests (LDTs), including a Length Analysis of Fluorescentlylabeled 

PCR (Genescan) method for exon 19 deletions, a Taqman-based 

PCR assay for exon 21 mutation with laser-capture macrodissected tumor 

cells, and secondary Sanger sequencing. A subset of samples from the trial 

was retrospectively tested with an AS-PCR assay (cobas EGFR mutation 

test) which detects L858R and � 29 exon 19 deletions. The test provides 

automated results within 8 h; the DNA required can be isolated from one 

5-micron tissue section. Four methods were compared: AS-PCR assay, 

LDT, direct Sanger sequencing and massively parallel sequencing (MPS; 

454, Branford, CT). Results: LDT results were obtained for 1044 screened 

patients. Residual tumor blocks were available for 487 patients (47%), 

including 303 wild-type, 172 mutant (135 enrolled on the trial) and 12 

inconclusive cases by the LDT. Comparison of AS-PCR and LDT results 

showed a positive percent agreement (PPA) – 93.7% (CI 88.8%, 96.5%), 

and negative percent agreement (NPA) – 97.5% (94.9%, 98.8%). Comparison 

of AS-PCR and Sanger results showed a PPA of 96.6% (91.7%, 

98.7%) but an NPA of 88.3% (84.1%, 91.5%). Among 34 AS-PCR � 

/ 

Sanger- case, MPS confirmed the presence of exon 19 deletions in 25 cases 

and L858R mutations in 7. Direct comparison of AS-PCR and MPS results 

showed a PPA of 93.1% (88.1%, 96.1%) and NPA of 97.7% (95.0%, 

98.9%). Clinical outcomes for cases with mutations detected by the 

AS-PCR test will be presented. Conclusions: The AS-PCR assay was highly 

concordant with the LDT and MPS, and more sensitive than Sanger 

sequencing. 

Tumor Biology 

679s 


Activation of angiogenic pathway in the prediction of pathologic response to 

bevacizumab-based neoadjuvant therapy in breast cancer. Presenting 

Author: Jose Manuel Lopez-Vega, Hospital Universitario Marques de 

Valdecilla, Cantabria, Spain 

Background: To evaluate potential biomarkers of pathological response to 

bevacizumab-based neoadjuvant therapy in untreated breast cancers (BC) 

patients recruited in a phase II, multicenter clinical trial. Methods: Patients 

received a single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to 

the beginning of neoadjuvant chemotherapy (NAC) consisting in 4 cycles of 

docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ 

kg) every 21 days (C2-C5) following by surgery. Biomarker expression was 

assessed by immunohistochemistry (Ki67, CD31, CD31/Ki67, VEGFR2, 

pVEGFR2 [Y951]) before and after bevacizumab infusion (C1). Gene 

expression was analyzed using Affimetrix Human Gene ST 1.0. Results: This 

analysis was performed on 73 patients (49 yr, range 29-70). Twenty (27%) 

patients obtained best response (G4-G5) whether 50 (68%) were considered 

as no responder (G1-G2-G3). Response was associated with negative 

estrogen receptors expression (p�0.02) and high Ki67 basal and after C1 

expression (p�0.009 and p�0.01). Six (54%) of the triple negative 

tumors were responders (p�0.05). Interestingly, change in pVEGFR2 

[Y951] staining induced by bevacizumab administration was found significantly 

associated with response (p�0.0). Decrease in the phosphorilation 

status of VEGFR2 (Y951) �70% yielded a receiver operating characteristic 

(ROC) curve area of 0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity 

and 95% specificity. The positive and negative predictive values for this 

marker were 60% and 64%, respectively. The change in phosphorilation 

status of VEGFR2p remains a significant predictor biomarker of response in 

multivariate analysis (OR�0.9, IC%95 0.96-0.99, p�0.04) after adjusting 

for clinical-pathological characteristics. Conclusions: These findings 

suggest the role of the phosphorilation status of VEGFR2 as predictive 

biomarkers of pathological response to bevacizumab in neoadjuvant setting 

in breast cancer. 


Response and long-term outcomes after neoadjuvant chemotherapy: Pooled 

dataset of patients stratified by molecular subtyping by MammaPrint and 

BluePrint. Presenting Author: Stefan Gluck, University of Miami/Sylvester 

Comprehensive Cancer Center, Miami, FL 

Background: Classification of breast cancers into molecular subtypes may 

be important for the proper selection of therapy for patients with early 

breast cancer. Previous analyses had shown that breast cancer subtypes 

have distinct clinical outcome (Sorlie, PNAS, 2001; Esserman, BCRT, 

2011). Herein, we analyze using MammaPrint together with an 80-gene 

molecular subtyping profile (BluePrint) the response to neo-adjuvant 

chemotherapy and long term outcomes. Methods: This study was carried out 

on data from 144 patients from the I-SPY I trial; 232 patients from 

biomarker discovery program at MD Anderson (133 and 99 respectively; 

Hess, 2006, JCO; Iwamoto, 2011, BCRT); and 68 patients from City of 

Hope (Somlo, ASCO, 2010). All patients were treated in the neo-adjuvant 

setting with standard chemotherapy. MammaPrint and BluePrint were 

determined on 44K Agilent arrays run at Agendia or available through the 

I-SPY 1 data portal, or from Affymetrix U133A arrays. MammaPrint and 

BluePrint resulted in 4 distinct molecular groups: Luminal A (MammaPrint 

Low-risk/Luminal-type), Luminal B (MammaPrint High-risk/Luminal-type), 

Basal-type and HER2-type. Results: The overall pCR of this patient cohort 

was 22% but differed substantially among the subgroups. pCR was 

observed in 5% of the Luminal-A samples and 10% of Luminal-B, in 39% 

of the HER2-type samples and in 33% of the Basal-type samples. Patients 

with Basal-type tumors had a 5-year DFS of 71%; HER2-type had a 5-year 

DFS of 67%(n�71); 69% in HER2-type subgroup not treated with 

HER2-targeted therapy (n�45); Luminal-B type had a 5-year DFS of 77% 

and Luminal-A type showed 5-year DFS of 95%. Conclusions: We observed 

marked differences in response and DFS to neo-adjuvant treatment in 

groups stratified by MammaPrint and BluePrint. These findings confirm 

differences in chemotherapy response among molecular subgroups and 

indicate that the BluePrint and MP profile used for this analysis helps to 

further establish a clinical correlation between molecular subtyping and 

treatment outcomes. 




The efficacy of targeted next-generation sequencing for detection of 

clinically actionable mutations in cancer. Presenting Author: Yu-Ye Wen, 

Baylor College of Medicine, Houston, TX 

Background: The emergence of next-generation sequencing (NGS) technologies 

has significantly accelerated the identification of cancer-causing 

mutations and the development of personalized cancer care. However, the 

clinical application of these technologies to detect cancer gene mutations 

has been extremely limited due to the long turn around time, the high cost, 

and large amount of input DNA required by existing NGS-based tests. 

Methods: We have assessed the performance of a novel NGS technology that 

merges multiplex PCR with ion semiconductor sequencing (AmpliSeq, Life 

Technologies, Inc.) in our clinical diagnostic laboratory. The test interrogates 

739 common mutations in 46 cancer genes including many clinically 

actionable mutations concurrently. First, we studied 12 tumor samples 

including 4 archived FFPE, 4 blood/bone marrow, and 4 cell line samples 

with known mutations to evaluate the sensitivity and specificity of the test. 

We then studied 34 de-identified, archived FFPE tumor samples of 

unknown genotype to further evaluate the efficacy of the test. Results: We 

successfully identified all known mutations previously detected by Pyposequencing 

or Sanger sequencing technologies. Multiple serial dilution 

studies showed that the test could detect mutations at frequencies as low 

as 5% with 99% confidence. For the samples of unknown genotype, we 

detected 23 COSMIC mutations in 16 samples including HRAS, BRAF, 

MET, TP53 mutations in lung cancer, KRAS, PIK3CA, TP53, APC, BRAF, 

ERBB2 mutations in colon cancer, TP53 and KRAS mutations in breast 

cancer, and KIT and PDGFRA mutations in GIST. Analysis of the variant 

call data showed that a minimum of 100X coverage is required in order to 

detect mutations at 10% frequency or above; a minimum 300K final library 

reads are necessary in order to minimize/eliminate amplicon dropout. 

Conclusions: The targeted NGS test can effectively detect cancer gene 

mutation with input DNA as low as a few nanograms, turn around time can 

be as short as two days, and can significantly lower cost compared to 

traditional Sanger sequencing. Our experience demonstrates that this 

technology holds great potential for clinical use, including diagnostic and 

therapeutic applications. 


A circulating epithelial cell type merging stem cell, EMT, and hypoxic 

stress markers in early and advanced breast cancer. Presenting Author: Leo 

Habets, Metares e.V, Aachen, Germany 

Background: MAINTRAC as developed by our coworkers from Jena finds 

more CETC. They found CETC in 90% of high risk patients. Circulating cells 

in epithelial mesenchymal transition (EMT�) should be detectable in early 

disease. Methods: 2 colours (7AAD, EP-FITC) detected living and dead 

cells. Cells in EMT (EP-FITC, Vim-PE) were analysed in paralell. Complex 

marker expression urged us to introduce a three colour technique. 1. 

EPCAM-FITC, Vimentin-PE and DAPI , marking living or dead cells in EMT. 

2. EP-FITC, Vim-PE and CD44 PB for stemness. ACA9 (hypoxia) and 

PARP-1 expression (genotox) were used too. Results: In the 2 colour phase 

we examined CEC in 110 patients with early disease and 44 patients with 

metastasis. Cells were detectable in both disease situations in 50 and 60% 

of patients, in a control population only in few patients low numbers were 

found. In non cancer situations e.g liver disease high numbers of EMT�cells 

were found.The results of 3 colour analysis are shown in the table. No clear 

differences between the classical risk groups are found, other subgroups 

are too small yet to be considered. Conclusions: Our findings show that in 

both disease situations cells merging EMT, stemcells ( EP�,Vim�.CD44�) 

and other markers are detectable. This cell type however is found also in 

non cancer conditions.We hypothesize that hypoxia is the common driver. 

Metastasis gives different patterns. Highly aggressive cancers show often 

none or few cells. In less agressive disease high cell numbers are found. We 

need to characterize the �benign� EMT phenomenon, as it could mingle 

with �real� CTC. Definitely liver is the source of these benign cells. Multi 

colour analysis will reveal the differences. Nevertheless monitoring of this 

special cell type could give new insights in the metastatic process in early 

and late disease. 

Cell type EMT living EMT total EMT�CD44 

CEC per ml �250 �250 �250 �250 �250 �250 

ALL 56 44 21 79 25 75 n�60 

N0 80 20 41 59 57 43 n�36 

N� 64 26 51 49 34 66 n�24 

Lum A 48 52 20 80 34 66 n�30 

Lum B 48 52 31 69 23 77 n�29 

Advanced 39 61 27 73 37 63 n�40 

Controls 98 2 91 9 81 19 n�112 

�Liver � 10 90 22 78 n�84 


Serum HER2 in the context of circulating tumor cells in patients with 

metastatic breast cancer. Presenting Author: Volkmar Mueller, University 

Medical Center Hamburg, Gynecology, Hamburg, Germany 

Background: Circulating tumor cells (CTC) reflect an aggressive tumor 

behavior by hematogenous tumor cell dissemination. Overexpression of 

HER2 in breast cancer (BC) is associated with increased angiogenesis and 

therefore potentially linked to increased hematogenous tumor cell spread. 

The aim of the analysis was to investigate whether concentrations of serum 

HER2 (sHER2) deliver prognostic information in the context of CTC 

detection in metastatic BC patients. Methods: Blood was obtained in a 

prospective multicenter setting from 254 patients with metastatic BC at 

the time of disease progression. sHER2 was determined using a commercial 

ELISA-kit (Wilex). CTC were detected with the CellSearch system 

(Veridex). Patients received systemic treatment according to national and 

international guidelines including HER2-targeted treatment. Results: Five 

or more CTC were detected in 122 of 245 evaluable patients (49.8%).119 

of 251 (47%) metastatic patients had serum sHER2 levels above 15ng/ 

mL. Median PFS was 9.2 months (95%-CI: 9.9 – 13.0 mths) with elevated 

sHER2 versus 11.4 mths (9.9 – 13.0 mths) with non-elevated levels 

(p�0.07). OS was 17.4 mths (14.6 – 20.3 mths) vs. 26.5 mths 

(23.1-29.8 mths; p�0.01). In patients with 5 or more CTC, serum levels 

were above the cut-off for sHER2 in 61% vs. 33% in those with less than 5 

CTC (p� 0.01). Patients with elevated sHER and 5 or more CTC hat a PFS 

of 9.1 mths (7.2 – 11.1 mths) and a OS of 14.5 mths (11.8 – 17.2 mths), 

those with non-elevated sHER2 and less than 5 CTC a PFS of 12.1 (10.1 – 

14.1 mths) and a OS of 29.5 month (25.4 – 33.6 mths) (p�0.15 for PFS 

and p� 0.01 for OS). Including sHER2, CTC and established prognostic 

factors in the multivariate analysis, the presence of CTC, line of therapy, ER 

and HER2 status of the primary tumor remained independent predictors of 

OS. Conclusions: Elevated serum levels of sHER2 are associated with the 

presence of CTC and indicate poor clinical outcome. However, sHER2 has 

no independent prognostic value when presence of CTC were taken into 

account. 


Exploratory study of histopathological and biomolecular characteristics of 

breast cancer in two different populations: African (Tanzania) and Caucasian 

(Italy). Presenting Author: Patrizia Serra, Unit of Biostatistics and 

Clinical Trials, IRST, Meldola, Italy 

Background: There is little information available on the clinical and 

molecular epidemiology of breast cancer in Sub-Saharan African women. In 

Tanzania, breast cancer mortality is the second cause of death after cancer 

of the uterine cervix, with the majority of tumors diagnosed at a very 

advanced stage. We aimed to compare the distribution of histopathological 

and biomolecular characteristics (ER, PgR, Ki67, HER2, grading) of breast 

cancer in African (Tanzania) and Caucasian (Italy) patients. Methods: 142 

women with invasive breast cancer, 71 from Tanzania and 71 from Italy, 

were considered. Histopathological classification and biomolecular determinations 

were performed at the Biosciences Laboratory of the Cancer 

Institute of Romagna (I.R.S.T., Meldola, Italy) as part of a joint Cancer 

Control Project between I.R.S.T and the Bugando Medical Center in 

Mwanza, Tanzania. All cases were evaluable for histopatological characterization, 

while biomolecular determination was possible in only 61 of the 

African patients. Hormone receptor status and Ki67 were determined by 

IHC; HER2 was evaluated by IHC for the African population and by FISH for 

the Italian one. Results: Whilst histopathological patterns were similar in 

the two populations, some biomolecular characteristics differed substantially. 

Of note, 64% of African breast cancer patients had ER negative 

tumors compared to only 17% of the Caucasian population. Important 

differences were observed in high Ki67 (�15%) values: 76% in Tanzanian 

women vs 58% in Italian breast cancer cases. HER2 positivity rates also 

differed in the two populations (25% in Tanzanian and 17% in Italian 

patients), as did the incidence of triple negative disease (13% and 7% in 

African and Caucasian populations, respectively). Conclusions: This preliminary 

study shows that breast cancer in African (Tanzanian) women is 

characterized by a high frequency of HER2 positive, ER negative, highly 

proliferating tumors. These biological patterns, together with very advanced 

stage at diagnosis, could be considered the main prognostic factors related 

to the high mortality rates for breast cancer in this African population. 



The components of progression as explanatory variables for overall survival 

in the RECIST database. Presenting Author: Saskia Litière, European 

Organisation for Research and Treatment of Cancer, Brussels, Belgium 

Background: Progressive disease (PD) according to RECIST 1.1 (Eisenhauer 

et al, 2009) is defined as one or more of (1) PD of measurable target 

lesions, (2) the presence of a new lesion (NL) or (3) the unequivocal PD of 

non-target disease (NT-PD). We explored the impact of these components, 

varying over time, on predicting overall survival (OS) in the RECIST 

database residing at EORTC (Bogaerts et al, 2009). Methods: Data was 

selected from 12 randomized clinical trials (3530 patients with breast, 

lung or colorectal cancer). A maximum of 5 target lesions was used to 

determine the sum of diameters. The following were calculated or assigned 

at each measurement time t: best response (BR) was best % improvement 

from baseline up to t (0% if no improvement - 100% if complete response 

(CR)); tumor growth (TG) was the weekly rate of increase from nadir to t (0 if 

no increase; irrespective of prior shrinkage), presence of NL (yes/no), and 

occurrence of NT-PD (yes/no); categories were not mutually exclusive. OS 

was analyzed by tumor type using a Cox regression model, adjusting for 

baseline sum, and including BR, TG, presence of NL and NT-PD as time 

dependent covariates. Results: Thirty-six percent of patients had NL, 26% 

had NT-PD, 11% achieved CR and 14% did not have shrinkage of target 

lesions, while 46% experienced TG (median strongest growth per patient of 

0.5 mm/week). Regardless of tumor type, the presence of NL (Hazard Ratio 

(HR) ranging 1.4-2.5), NT-PD (HR 1.2-2.5) and TG (per 1mm/week 

increase; HR 1.1-1.4) were associated with worse OS, while achieving CR 

was associated with a longer OS (HR 0.2-0.8). Further analyses exploring 

the functional shape of the association between BR and TG, and OS are 

ongoing. This includes putting TG in contrast with the more usual % cutoff 

defining target PD. Conclusions: All three components of PD according to 

RECIST are independently strongly associated with OS. Quantification 

such as this will enable a better understanding of the role of each 

component (e.g. clinical aspect of NT-PD assessment) in PD evaluation. 

Work is ongoing to incorporate this information into an updated RECIST 

with enhanced prediction of subsequent survival. 


Monitoring of plasma pro-GRP level during EGFR-TKI treatment. Presenting 

Author: Yuko Kawano, Cancer Institute Hospital of the Japanese 

Foundation for Cancer Research, Tokyo, Japan 

Background: Lung cancers harboring mutations in the epidermal growth 

factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors 

(EGFR-TKI), but drug resistance invariably emerges. The major acquired 

mechanisms of resistance are the EGFR T790M mutation or MET gene 

amplification. Transformation from NSCLC into small-cell lung cancer 

(SCLC) has been recently identified in acquired resistance to EGFR-TKI. 

However, it is difficult to predict the transformation during EGFR-TKI 

treatment because obtaining serial and sufficient specimens for biopsy is 

difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive 

tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in 

EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels 

could predict SCLC transformation in resistance to EGFR-TKI. Methods: 

From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC 

who received EGFR-TKI treatment were enrolled. Plasma was obtained 

from these patients before EGFR-TKI treatment and when EGFR-TKI 

treatment failed. Pro-GRP and CEA levels were measured and compared 

before and after treatment. Results: Patient characteristics for 49 patients 

(15 men, 34 women) were as follows: median age, 62 years (41–81 years); 

histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR 

mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 

patients had received EGFR-TKI treatment (45 with gefitinib and 4 with 

erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD 

in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at 

pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI 

treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the 

Pro-GRP levels had increased after treatment, but the CEA level did not 

increase. Objective responses to cytotoxic chemotherapy were noted in all 3 

patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma 

Pro-GRP during EGFR-TKI treatment may be useful for early detection of 

SCLC transformation in resistance to EGFR-TKI. 

Tumor Biology 

681s 


pAKT expression in paraffin-embedded xenograft tumors after fixation 

delays and human breast cancer by optimized immunohistochemistry. 

Presenting Author: Sherry X. Yang, Division of Cancer Treatment and 

Diagnosis, National Cancer Institute, Bethesda, MD 

Background: With progress in targeting PI3K/AKT pathway in the treatment 

of a wide range of cancers, it is getting more important than ever for 

optimization of detection method of AKT kinase, a central effector of the 

pathway, in archived tissues. Recently, we found that pAKT-S473 (pAKT) 

significantly predicts paclitaxel benefit in breast cancer (JCO 28: 2974, 

2010), in which a good analytical and clinical performance of quantitative 

pAKT immunohistochemistry (IHC) was demonstrated. The current study 

evaluates pAKT stability in human breast cancer xenograft tumors after 

delays in fixation, and assesses a detection window following fixation delays 

with an established cutoff [staining index (SI) � 2]. Methods: Xenograft 

tumors with high (MDA-MB-468) and intermediate levels (MDA-MB-231) 

of pAKT were fixed or snapped frozen in 10% neutral-buffered formalin or 

liquid nitrogen after delays post-excision. pAKT staining was performed in 

xenograft tumors and 96 cases of human surgical breast tumors by our 

optimized and traditional IHCs, and Western blot. Results: The mean SIs 

were 133, 121, 112, 94, 84, and 66 using optimized, and in contrast were 

51, 44, 29, 14, 12, and 6.4 on traditional method at 0, 15, 30, 60, 120 

and 180 min (2.6-fold by comparing the optimized with the traditional at 

baseline) in MDA-MB-468 xenograft tumors. pAKT level was ½ by the 

optimized, similar to the level detected by Western blot, relative to 1/8 of 

the baseline by the traditional (10.6-fold) at 180 min. The logarithmic 

decline rate by the optimal was 3.1 times (95% CI, 2.4 - 3.7) less than that 

of the traditional (normal approximation; 2-sided P � 0.0001). pAKT 

expression was observed in 38.5% (37/96 ) of surgical breast tumors, 

comparable to 38% (606/1581) in a large cohort derived from the NSABP 

B-28 trial. There was little loss of pAKT in MDA-MB-231 xenograft tumors 

up to 180 min by IHC and Western blot. Conclusions: The optimized pAKT 

IHC significantly increases the sensitivity of detection with a large window 

for positivity. It is suitable for use in archived human specimens although it 

warrants further standardization and validation among research laboratories 

and perhaps diagnostic laboratories in the future. 


Anti-AML activity of a novel beta-catenin antagonist BC2059. Presenting 

Author: Kapil N. Bhalla, University of Kansas Medical Center, Kansas City, 

KS 

Background: The canonical WNT-�-catenin pathway is essential for selfrenewal, 

growth and survivalof AML stem and progenitor cells. Deregulated 

WNT signaling inhibits degradation of �-catenin, causing increased nuclear 

translocation and interaction of �-catenin with the TCF/LEF transcription 

factor, which up regulates cyclin D1, Myc and survivin expression in AML 

progenitor cells. BC2059 (�-Cat Pharmaceuticals) is a potent, small 

molecule, anthraquinone oxime-analog, which inhibits WNT-� catenin 

pathway by promoting the degradation and attenuation of �-catenin levels. 

Methods: We determined the in vitro anti-AML activity of BC2059 (BC) 

(250 to 1000 nM) against cultured and primary human AML blast 

progenitors, as well as evaluated the in vivo anti-AML efficacy of BC in 

NOD-SCID and NOD-SCID-IL2� receptor deficient (NSG) mice. Results: BC 

induced cell cycle G1 phase accumulation and apoptosis (40%) of the 

cultured OCI-AML3, HL-60 and HEL92.1.7 (HEL) AML cells. BC dosedependently 

also induced apoptosis of primary AML versus normal progenitors. 

Treatment with BC resulted in proteasomal degradation and decline in 

the nuclear levels of �-catenin, which led to decreased activity of the 

LEF1/TCF4 transcription factor highlighted by reduced TOP-FLASH luciferase 

activity in the AML cells. This was associated with reduced protein 

levels of cyclin D1, MYC and survivin. Co-treatment with BC and the 

histone deacetylase inhibitor panobinostat (PS) (10 to 20 nM) synergistically 

induced apoptosis of cultured and primary AML blasts. Following tail 

vein infusion and establishment of AML by OCI-AML3 or HEL cells in 

NOD-SCID mice, treatment with BC (5, 10 or 15 mg/kg b.i.w, IV) for three 

weeks demonstrated improved survival, as compared to the control mice (p 

�0. 001). Survival was further improved upon co-treatment with BC and 

PS (5 mg/kg IP, MWF). BC treatment (5 or 10 mg/kg IV) also dramatically 

improved survival of NSG mice with established human AML following 

tail-vein injection of primary AML blasts expressing FLT3 ITD. Mice did not 

experience any toxicity or weight loss. Conclusions: These findings highlight 

the notable pre-clinical in vitro and in vivo activity and warrant further 

development and in vivo testing of BC against human AML. 




Evaluation of the clinical utility of kallikrein-related peptidase 6 gene 

(KLK6) downregulation in breast cancer. Presenting Author: Kleita Michaelidou, 

Department of Biochemistry and Molecular Biology, University of 

Athens, Panepistimiopolis, Athens, Greece 

Background: Breast cancer (BC), the most common malignancy among the 

female population, remains a crucial public health problem. The identification 

and exploitation of novel molecular biomarkers can contribute in the 

multidimensional approach which is required for optimal management of 

BC patients. The abnormal expression of several KLK members has been 

documented for breast cancer. Interestingly, many of these genes are found 

to be potential prognostic markers for this malignancy. KLK6 expression is 

positively associated with tumor progression in various human malignancies; 

however in breast cancer, it can restrain tumor progression. We 

therefore sought to investigate the possible clinical value of KLK6 as a 

breast cancer biomarker. Methods: Total RNA was isolated from 107 breast 

tumors and their matched normal compartments. After testing the quality 

of the extracted RNA, cDNA was prepared by reverse transcription. 

Quantitative Real-time PCR was performed, for KLK6 mRNA quantification, 

using the SYBR Green chemistry. Relative quantification analysis was 

made using the comparative Ct (2-��C T) method. HPRT1 was used as an 

endogenous control gene and BT-474 breast cancer cell line served as a 

calibrator. Results: KLK6 mRNA levels were significantly downregulated in 

the cancerous breast tissue specimens compared to their normal counterparts 

(p�0.001). Additionally, a negative association was observed between 

KLK6 expression status and tumor stage, given the fact that 54.2% 

of less advanced breast tumors (TNM stage� T2a) were KLK6-positive 

compared to the 34.6% of more advanced-stage tumors (TNM �T2a) 

(p�0.034). Moreover, a statistically significant negative correlation was 

documented between KLK6 mRNA levels and estrogen (p�0.001) and 

progesterone receptor (p�0.003) statuses. Conclusions: The downregulation 

of KLK6 in cancerous compared to normal sections of breast tissue 

samples reflects the reported tumor suppressor properties of KLK6 gene in 

breast malignancies. Furthermore, the negative association of KLK6 mRNA 

expression with tumor stage, ER and PR statuses reveals the putative role of 

KLK6 as a promising prognostic breast cancer biomarker. 


Study of the usefulness of angiotensin type 1 receptor (AGTR1) as a 

possible response predictor in patients with metastatic breast cancer 

(mBC) subjected to chemotherapy and treatment with bevacizumab 

(AVALUZ Study). Presenting Author: Juan De la Haba- Rodriguez, Hospital 

Universitario Reina Sofía, Cordoba, Spain 

Background: Angiotensin type 1 receptor (AGTR1) is a membrane receptor 

implicated in the regulation of arterial pressure. It has also been related to 

carcinogenesis and tumor spread, and participates in neoangiogenesis. 

AGTR1 is expressed in a number of neoplasms as BC. In a previous 

neoadjuvant study, a significant relationship was observed between AGTR1 

expression and CR to a regimen of chemo and bevacizumab (B). To study 

and confirm the relationship between tumor expression of AGTR1 and 

response to a regimen of chemo and B in pts with mBC. Methods: AGTR1 

expression was subjected to immunofluorescence (monoclonal AGTR1 

sc1173 antibody, Santa Cruz Biotechnology, CA, USA Dilution 1:50) in 50 

samples of mBC pts from the AVALUZ study treated with first line 

bevacizumab 10 mg/kg, paclitaxel 150 mg/m2 and gemcitabine 2000 

mg/m2 d 1 and 15 c/28 d until PD, unacceptable toxicity or medical 

decision. Immunoreactivity was reported as negative (0), low positive (1�) 

and high positive (2�). RNA was extracted from paraffin blocks, using the 

QIAamp DNA FFPE Tissue Kit and Deparaffinization Solution (QIAGEN) 

and expression of AGTR1 candidate gene was quantified using reverse 

transcription-PCR (RT-PCR). Results: 60% of the samples expressed 

AGTR1 (26% weak and 34% intense) – expression being more frequent in 

HR � tumors (65% vs 45%). Among the 50 samples analyzed, measurable 

disease was present in 39 pts. Treatment activity was significantly greater 

in the tumors AGTR1 expression 2� (p�0.009) (Table). With a median 

follow-up of 19.30 months, the progression-free interval was longer in the 

tumors with intense AGTR1 expression (17.7 vs 10.8 months, p�0.132). 

More consolidated PFS and OS will be presented. Conclusions: AGTR1 

expression may be useful as a predictor of response to chemo and 

bevacizumab. Prospective studies are needed to confirm these findings. 

AGTR1 expression/objective response CR PR SD PD 

Intense AGTR1 expression (N:14 ) 35.7% (5) 64.3% (9) 0% 0% 

Negative or weak AGTR1 expression (N:25) 4% (1) 56.0% (14) 28% (7) 12 (3%) 

CR: complete response, PR: partial response, SD: stable disease, PD: progression disease 


p53 mutations in advanced cancers: Clinical characteristics and outcomes 

in a phase I setting. Presenting Author: Rabih Said, Department of 

Investigational Cancer Therapeutics (Phase I Program), University of Texas 


Background: p53 mutation is one of the most common mutations in human 

tumors and plays an important role in apoptosis, genomic stability and 

inhibition of angiogenesis. Methods: We retrospectively reviewed 121 

consecutive patients (pts) with solid tumors referred to the Clinical Center 

for Targeted Therapy (Phase I program) who were tested for p53 mutation, 

and compared clinical characteristics and outcomes in p53 positive vs. 

wild-type (wt) pts. Results: Of the 121 tested pts, 65 (53.7%) were p53 

mutation-positive. The presence of p53 mutation was not associated with 

sex and race. Tumors with p53 mutation metastasized more often to the 

liver (44 pts (67.7%) with mutated p53 vs. 26 pts (46.4%) with wt p53, 

p�0.0264); there was no difference in metastasis to the bones, lungs, 

brain, soft tissues and adrenals. p53 mutation also showed a trend toward 

an association with PTEN-loss (13 out of 43 (30%) with p53 mutated vs. 4 

out of 37 (11%) with wt p53, p�0.053). Among pts with the p53 

mutation, the best median progression-free survival (PFS) prior to phase I 

trial entry was 10.97 months (range 0.85–29.04 months) when the 

treatment regimen included bevacizumab and 4.37 months (range 0.92– 

14.98 months) when the treatment did not include bevacizumab 

(P�0.0046). Among patients with wt p53, there was no significant 

difference in PFS between bavacizumab-containing regimens and regimens 

without bevacizumab. The median OS from diagnosis was 7.7 years 

(95% CI 6.32–9.84 years) vs. 11.8 years (95% CI 10.37 years, not 

attained) for p53 mutant vs. wild-type disease (p � 0.03). Univariate 

analysis for OS from diagnosis showed that mutated p53, Hispanic race (vs. 

Caucasians) and the shorter time from diagnosis to metastasis were 

associated with a worse prognosis. Conclusions: Tumors with p53 mutation 

have a more aggressive clinical behavior, metastasize more to the liver and 

may have a higher rate of PTEN loss compared to tumors with wt p53; In 

addition, anti-angiogenic agents may be of therapeutic value in p53mutated 

pts. 


The lipid metabolome of clear cell renal cell carcinoma (CCRCC). Presenting 

Author: Saby George, Roswell Park Cancer Institute, Buffalo, NY 

Background: The commonest type of kidney cancer is CCRCC. Treatment 

approaches mostly target aberrant vasculature. However, kidney cancer is 

also known to accumulate lipids and a detailed knowledge of the lipid 

species present in these tumors could lead to a better understanding of the 

underlying aberrant metabolic pathways and suggest possible treatment 

strategies. Lipidomics is an emerging field driven by rapid advances in 

mass spectrometry (MS), and is widely used to discover biomarkers. We 

attempt to identify the lipidomic profile of CCRCC using a liquid chromatography 

MS-based approach (LC-MS). Methods: We utilized 6 fresh frozen 

representative samples of CCRCC and matching non-tumor areas of kidney 

from nephrectomy samples. Lipids and other non-polar cellular constituents 

were extracted from both CCRCC and control tissues by methyl-t-butyl 

ether /methanol. LC-MS based lipid profiling was performed on a Waters 

Q-ToF Premier MS coupled with Ultra Performance LC. The peak detection 

and alignment across all chromatograms were performed using the XCMS 

software (v 1.14.1, Scripps Center for Metabolomics). Statistical comparisons 

of the intensities of aligned peaks were performed using the XCMSbuilt-in 

Welch’s t-test. Results: The outcome of XCMS was converted to a 

table that contains fold change, p-value and mass to charge ratio (m/z) for 

each peak, its corresponding retention time, and the integrated peak 

intensities from all samples. 224 peaks out of 1419 differed between 

CCRCC and the control group, with p �0.05, calculated by XCMS. About an 

equal number of analytes increased or decreased in CCRCC compared with 

control samples. Preliminary attempts to identify the analytes included use 

of METLIN (Scripps Center for Metabolomics) and HMDB (Human metabolome 

database, Genome Alberta & Genome Canada) databases. Many of the 

hits identified phosphatidylcholines, phosphatidylethanolamines, triacylglycerols 

and diacylglycerols, as well as other lipid species. Conclusions: 

The lipid metabolomic profile varied significantly between CCRCC and 

control. Further studies are required to confirm the identities of the lipid 

species contributing to this variation by obtaining structural information 

using tandem MS (LC-MS/MS). 



Cytokeratin 19 fragment (CYFRA21-1) to predict the efficacy of epidermal 

growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small 

cell lung cancer (NSCLC) harboring EGFR mutation. Presenting Author: 

Kosuke Tanaka, Division of Integrated Oncology, Institute of Biomedical 

Research and Innovation, Kobe, Japan 

Background: EGFR mutation is independently associated with a favorable 

response in NSCLC patients receiving EGFR-TKIs, regardless of gender or 

smoking history. However, recent reports have indicated that squamous 

cell carcinoma patients harboring EGFR mutations show a worse response 

to EGFR-TKIs than adenocarcinoma patients. We hypothesized that serum 

CYFRA21-1 is a predictive marker in EGFR mutated patients treated with 

EGFR-TKIs. Methods: We retrospectively screened 160 NSCLC patients 

harboring EGFR mutations (exon 19 deletions, L858R in exon 21, or other 

minor mutations) who received either gefitinib or erlotinib between 1992 

and 2011. Patients were screened for histology, sex, age, smoking status, 

efficacy of EGFR-TKI and tumor markers (CEA/CYFRA21-1) at initial 

diagnosis. Results: Out of 160 eligible patients treated with EGFR-TKIs, 77 

patients with high CYFRA21-1 level (�2 ng/ml) showed statistically shorter 

progression-free survival (PFS) than 83 patients with normal CYFRA21-1 

level (median PFS 7.5 vs 14.0 months, p�0.006). No significant difference 

in PFS was observed between high CEA group (�5 ng/ml) and normal 

CEA group (median PFS 8.6 vs 11.2 months, p�0.2423). Multivariate 

analysis revealed that high CYFRA21-1 level is independently associated 

with PFS (HR 1.35; p�0.002) as well as squamous cell carcinoma (HR 

1.40; p�0.020) and performance status 2-4 (HR 2.63; p�0.003). No 

statistically significant difference in overall survival (OS) was observed 

between high CYFRA21-1 group and normal group (median OS 24.8 vs 

39.1 months, p�0.104). Conclusions: High CYFRA level patients have 

significantly shorter PFS, which may indicate that this subgroup has a 

larger squamous component and thus less response to EGFR-TKIs. Serum 

CYFRA21-1 level is a predictive marker of EGFR-TKIs efficacy and EGFR 

mutated patients can be divided into two subgroups according to CY- 

FRA21-1 level at initial diagnosis. 


Use of proteomic analysis of LKB1/AMPK/mTOR pathways to identify 

IGF-1R pathway upregulation with LKB1 loss or mTOR inhibition in 

NSCLC: Implications for targeted combinations. Presenting Author: Emrullah 

Yilmaz, Baylor College of Medicine, Houston, TX 

Background: LKB1 is a serine/threonine kinase which is mutated in 

20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor 

suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion 

suppresses AMPK, leading to increased mTOR signaling. We investigated 

the signaling pathways modulated by LKB1 mutations and by mTOR 

inhibition in NSCLC. Methods: Protein expression in cell lines was measured 

by reverse phase protein array. Differences in protein expression at 

baseline in LKB1 wild-type versus mutant cell lines and the effects of 

protein modulation by treatment were assessed by ANOVA. Results: LKB1 

mutant cell lines had lower expression of phosphorylated AMPK and TSC 

(p�0.01 for both) consistent with prior observations. In addition, mutant 

cell lines expressed higher levels of proteins in the IGF1R pathway 

including IGFR1b (p�0.0001); AIB1, which is known to upregulate IGF1 

(p�0.0001); and IGFBP2 (p�0.016). LKB1 mutant cell lines (n�11/25) 

were 1.5-fold more sensitive to the AMPK activator metformin, although 

this did not reach statistical significance (p�0.10). Expression levels of 

IGF1R pathway proteins increased significantly after 48h treatment with 

metformin, the mTOR inhibitor temsirolimus, and the dual PI3K/mTOR 

inhibitor PI103. For example, IGFBP2 and AIB1 were elevated after 

metformin treatment (p�0.02 and 0.005, respectively); IRS1 and IGFR1 

were elevated after temsirolimus or PI103 (p�0.05 for both). Following 

treatment with metformin and temsirolimus, there was also increased pAkt, 

a downstream target of IGF1R and activator of mTOR (p�0.01 for both). 

Modulation of the IGF1R pathway by these drugs was independent of LKB1 

mutation status. Conclusions: LKB1 mutant cell lines have increased IGFR 

activity with higher baseline IGFR1, IGFB2 and AIB1, suggesting that IGFR 

may be a potential therapeutic target in LKB1 mutant tumors. In addition, 

inhibition of the mTOR pathway upregulates the IGFR pathway possibly as 

a feedback mechanism. These results support the investigation of IGFR 

inhibitors in combination with drugs targeting the mTOR pathway, particularly 

for tumors bearing LKB1 mutations. 

Tumor Biology 

683s 


Evaluation of EZH2 SNPs in cholangiocarcinoma patients. Presenting 

Author: Elisa Paolicchi, Department of Internal Medicine, University of 

Pisa, Pisa, Italy 

Background: Cholangiocarcinoma (CCA) is an aggressive tumor arising from 

biliary tract epithelium.CCA is the second most common primary hepatic 

malignancy, with a progressive increasing incidence in western countries. 

Polycomb group protein Enhancer of Zeste homolog 2 (EZH2) is overexpressed 

in several human carcinomas, including CCA, where EZH2 overexpression 

is associated with tumor progression. The aim of this study is to 

evaluate the correlation between candidate EZH2 Single Nucleotide 

Polymorphisms (SNPs) with clinical outcome in CCA patients. Methods: 

Genomic DNA was extracted from blood samples of 75 patients [44 male 

and 31 female, with average age of 62.3 (range, 26-80 years)] affected by 

hystologically confirmed advanced CCA, treated with the epirubicincisplatin-xeloda 

(ECX) regimen. We performed an in silico characterization 

to select EZH2 SNPs (rs2302427 C/G, rs6464926 C/T, rs17171119 T/G 

and rs887569 C/T) from 26 EZH2 SNPs described previously. Genotyping 

was performed through Taqman PCR. Prognostic value of selected EZH2 

SNPs was assesses by correlation with time to progression (TTP) and overall 

survival (OS). OS and TTP curves were obtained through Kaplan-Meier 

method, and comparison with survival distribution was evaluated with 

logrank test. Results: Through specific software (PROMO 3.0, MicroSNiper 

and Gene Card) we performed an in silico analysis based on functional 

characterization criteria (transcription factor binding-TFB, miRNA binding 

and missense mutations). We selected 4 EZH2 SNP alleles showing 

specific relevance in CCA because of their differential TFB affinity 

(PPAR�/RXR�, E2F-1, Pax-5 and p53). The rs887569 C/T SNP was 

significantly associated with clinical outcome. The TT genotype predicted a 

significantly longer OS in CCA patients (TT vs CT-CC p�0.026). Moreover, 

the TT genotype showed a trend-like association with reduced risk of death 

(HR�0.59, 95%CI�0.33-1.05, p�0.075), at multivariate analysis. 

Conclusions: These results suggest the role of rs887569 EZH2 SNP as a 

possible predictive marker of OS in advanced CCA patients treated with 

ECX regimen, and offer a potential new tool for treatment optimization. 


Evaluation of circulating biomarkers of bone metastasis in early-stage 

breast cancer. Presenting Author: Windy Marie Dean-Colomb, University of 


Background: Bone is the preferred site for metastasis of breast cancer, 

affecting approximately 70% of women with advanced disease. N-terminal 

of procollagen type 1 (P1NP), c-terminal peptide crosslinks (CTX), Osteocalcin 

(OC) and interleukin-6 (IL-6) are markers of bone turnover that may 

have clinical utility as predictors of breast cancer recurrence in the bone. 

Methods: Serum was collected from 168 patients with stage I/II/III breast 

cancer prior to treatment from 09/2001 to 12/2008 and stored at -80 C. 

Serum levels of P1NP, CTX, OC and IL-6 were determined using the 

Roche’s Elecsys 2010 automated immunoassay system. Correlations of 

biomarker levels with time to bone metastasis (BM) development were 

assessed with Cox proportional hazards regression analysis and the Kaplan- 

Meier method. Results: Among the 168 patients analyzed, 60 patients 

subsequently developed BM. The biomarkers all had skewed distributions 

with long right tails and thus were all analyzed on the log scale. Residual 

analysis suggested non-linear relationships between each biomarker and 

risk of developing BM during follow-up. Thus, we fit Cox proportional 

hazards regression models for each biomarker with quadratic polynomials 

(on the log scale). On univariate analysis, these analyses generated p � 

0.33 for IL-6, 0.26 for osteocalcin, 0.40 for CTX, and 0.032 for P1NP. 

Adjusting for clinical factors (stage, age, race, post menopausal, ER/PR 

status, HER2 status, nuclear grade) yielded p � 0.0035 for the quadratic 

polynomial for log P1NP. A cut-point of 75 ng/mL identified patients with a 

short time to development of BM. The 1, 3, and 5-year freedom-from-BM 

probabilities were 96%, 77% and 66% for the 150 patients with P1NP 

values � 75 ng/mL and 88%, 45%, and 36% for the 16 patients with 

P1NP values � 75 ng/mL. The hazard ratio comparing patients with P1NP 

values � 75 ng/mL to patients with P1NP values � 75 ng/mL was 3.0 

(95% CI, 1.5 - 6.2) and p � 0.0075 ng/mL. After adjustment for clinical 

factors, the hazard ratio was 3.4 (1.5, 7.6) with p � 0.0026. Conclusions: 

Serum P1NP levels �75 ng/mL correlate with a shorter time to development 

of BM in patients with stage I-III breast cancer. 




Isolation and expansion of circulating tumor cells (CTC) from melanoma 

patients using a novel cell culture technique. Presenting Author: John R. 

McGregor, TrueCells, LLC, Las Vegas, NV 

Background: Identification of rare (�2-5) circulating tumor cells (CTC) in 

7.5 ml blood by immunofluorescence assay (IFA) correlates with a poor 

prognosis in colon, breast, prostate and lung cancer. Changes in CTC count 

during treatment also predict the eventual patient progression and survival 

in these cancers. Existing assays do not detect melanoma CTC, however. In 

addition, isolation of viable CTC remains problematic. To overcome these 

limitations we attempted to develop novel melanoma CTC assays, using IFA 

and cell culture approaches. Methods: Blood samples were obtained from 

patients and controls following informed consent. The buffy coat (white 

cells � tumor) was isolated by Ficoll/Hypaque centrifugation, and split into 

6 replicate cultures in proprietary TrueCells medium. After 21 days in 

culture, tumor colonies were counted, and stained for melanoma and 

leukocyte markers. Buffy coat cells from parallel blood samples were 

stained with a panel of CSPG4-specific mAb (a pan-melanoma marker) on 

ultraclean glass slides for analysis by immunofluorescence microscopy. 

Results: Blood samples were obtained from 16 melanoma patients, ages 

28-87. Eight patients were men and 8 were women. CSPG4 � events (�2) 

were detected in 8/16 patients by IFA (range 0-52). In contrast, tumor cell 

colonies of �50 cells grew in 12 out of 16 patients with Stage 3 or 4 

melanoma (range 0-1054), shown in Table. Cells isolated from CTC 

colonies produced melanin, stained for CSPG4 and other melanoma 

markers, but not for leukocyte markers. Control cultures grew no tumor 

colonies. Conclusions: Our pilot study shows that melanoma CTC can be 

identified by both IFA and cultured from blood in many patients with stage 

3 or 4 melanoma. These CTC exhibited cytologic characteristics diagnostic 

of melanoma. The culture assay may represent a useful means of enumerating, 

isolating, and expanding viable melanoma CTC for further molecular 

study. 

Melanoma patients 

IFA Culture 

Pos assay Median Mean St dev Pos culture Median Mean St dev 

Control 0 of 5 0.0 0.0 0.0 0 of 5 0.4* 0.4* 0.8 

Stage 1-2 0 of 1 0.0 0.0 0.0 0 of 1 0.0 0.0 0.0 

Stage 3 1 of 4 1.0 1.3 1.3 3 of 4 320.5 285.3 209.6 

Stage 4 7 of 11 3.0 8.3 15.0 9 of 11 500.0 343.4 221.8 

*Non-tumor. 


Role of proliferation in response to neoadjuvant chemotherapy in GEICAM/ 

2006-03 and GEICAM/2006-14 breast cancer patients. Presenting Author: 

E. Alba, Hospital Clínico Universitario Virgen de la Victoria, Málaga, 

Spain 

Background: Ki67 proliferation biomarker determined by immunohistochemistry 

(IHC) has been studied as a prognostic and predictive factor in 

Operable Breast Cancer (OBC). Ki67 modifications after neoadjuvant 

endocrine therapy have been correlated with long term outcome. However, 

there is no robust data about its predictive role in Neoadjuvant Chemotherapy 

(NC). In this study, we investigated Ki67 value as predictor of NC 

efficacy. Methods: 193 patients (pts) from 2 GEICAM phase II randomized 

trials (2006-03 and 2006-14) were included: 78 (40%) received epirubicine 

plus cyclophosphamide followed by docetaxel (EC-D), 41 (21%) EC-D 

plus carboplatin, and out of the 74 HER2� pts, 37 (19%) received EC-D 

plus tratuzumab and 37 (19%) EC-D plus lapatinib. Median age was 49 

years. From series, 87% were invasive ductal carcinoma, 58% premenopausal, 

50% grade III, 23% luminal , 39% basal and 38% HER2�. Ki67 

was centrally assessed by IHC (MIB1 clone) and median score was 40% 

(range 1-100%). Pathological Complete Response (pCR), defined as 

absence of invasive cells in breast and lymph nodes, was achieved in 56 pts 

(29%). Univariate and multivariate logistic regression models were used to 

study the association of each clinical-pathological variable with pCR. ROC 

curves were used to determine the most accurate ki67 cut-off for predicting 

NC response. Results: Ki67�50% was defined as the most accurate 

threshold to select patients obtaining benefit from NC. In the univariate 

analysis, histological grade (p�0.01), treatment (P�0.006), ER 

(p�0.0001), PR (p�0.0001), HER2 (p�0.01), and Ki67�50% 

(p�0.0003) were statistically associated with pCR. A multivariate logistic 

regression showed that only Ki67� 50% (p�0.0003; OR�5.4 CI95% 

2.1-13.4), ER (p�0.0001; OR�0.2 CI95% 0.1-0.4), and HER2 status 

(p�0.0001; OR�8.8 CI95% 3.3-23.6) were predictive for pCR 

(AUC�0.7812). Conclusions: These results suggest that a high proliferation 

in breast cancer measured by Ki67 marker is an independent 

predictive factor for pCR in an unclassified HER2 population of OBC 

patients treated with NC. 


Zoledronic acid effect on circulating RANK/RANK-l/OPG axis in cancer 

patients. Presenting Author: Toni Ibrahim, Osteoncology Center, Istituto 

Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy 

Background: Bone metastasis disrupts bone integrity through loss of the 

balance between osteoclastic-mediated osteolysis and osteoblastic osteogenesis. 

The RANK/RANK-L/OPG axis governs osteoclastogenesis and bone 

resorption. We evaluated the trend of markers over time. Secondary aims 

were to study the predictive role of different circulating markers in the 

response to Zoledronic Acid (ZA) with respect to objective response and to 

skeletal-related events (SREs). Methods: The study prospectively evaluated 

levels of RANK, RANKL and OPG transcripts by Real-Time PCR and VEGF 

and NTX expression by ELISA in the peripheral blood of 49 consecutive 

patients with advanced breast, prostate or lung cancer (36, 7 and 6, 

respectively). Enrolled patients were at first diagnosis of bone metastases 

and had not previously undergone treatment with bisphosphonates. Patients 

received the standard schedule of ZA (4 mg infusion every 28 days) 

for about 12 months, undergoing blood tests and instrumental evaluation 

before the first infusion of ZA and every 4 months thereafter. Results: 

Median RANKL values after 12 infusions of ZA had decreased by 22% with 

respect to baseline whereas OPG, had increased by about 96%, with a 56% 

decrease in the RANKL/OPG ratio. NTX decreased over time (p�0.0001). 

On the basis of ROC curve analysis, RANKL was the most accurate marker 

for bone response with an AUC of 0.74 (95% CI 0.54-0.93). No 

correlations were found between circulating markers and SREs. Conclusions: 

The present work is one of the few prospective studies carried out on the 

circulating markers that are potentially associated with bone metastases. 

Our findings would seem to indicate that ZA decreases osteoclast activity 

through RANK/RANKL/OPG pathway modulation and that RANKL may play 

a role in the prediction of objective response to ZA. Confirmation of results 

is needed in a larger case series. 


Predictive impact of RRM1 protein expression on vinorelbine efficacy in 

NSCLC patients randomized in a chemotherapy phase III trial. Presenting 

Author: Adam Vilmar, Department of Oncology, Finsen Centre, National 

University Hospital, Copenhagen, Denmark 

Background: Platinum based doublets remain the cornerstone of treatment 

in non-small cell lung cancer (NSCLC) and often includes gemcitabine. A 

biomarker predicting sensitivity to this antimetabolite would represent a 

major step forward in the management of advanced disease. Ribonucleotide 

reductase subunit M1 (RRM1) has been of some value in NSCLC but 

evidence is not uniform. Accordingly, we explored the predictive role of 

RRM1 in patients with advanced NSCLC. Methods: 443 patients with 

advanced NSCLC were randomized in a phase III trial to regimen A 

(paclitaxel and cisplatin with gemcitabine) or regimen B (cisplatin and 

vinorelbine). Immunohistochemical evaluation of RRM1 was performed on 

mainly bioptic material and correlated to response rates, progression free 

survival (PFS) and overall survival (OS). Results: 261 (58.9%) patients had 

representative tissue samples for RRM1 evaluation. Disease control rate, 

PFS and OS were significantly improved in patients with RRM-negative 

tumors receiving regimen B as compared to patients with RRM-positive 

tumors (68.8% vs. 31.2%, P � 0.046 , 6.90 months (mths) (95% CI 

5.83-7.96) vs. 3.93 mths (95% CI 3.11-4.76), P � 0.000 and 11.57 

mths (95% CI 9.65-13.48) vs. 7.4 mths (95% CI 5.37-9.43), P � 0.002, 

respectively). However, this was not the case for patients receiving regimen 

A (67.6% vs. 32.4%, P � 0.366, 6.73 mths vs. 7.6 mths, P � 0.207, 

11.07 mths vs. 12.37 mths, P � 0.103, respectively ). Together with 

histological subtype, RRM1-positivity emerged as the only other significant 

prognostic variable with a hazard ratio of 1.56 (95% CI 1.38-2.35, P � 

0.033) in multivariate analysis for patients treated with regimen B. 

Conclusions: RRM1 protein expression was without predictive impact in 

patients treated with cisplatin, paclitaxel and gemcitabine. Surprisingly, 

the predictive power proved robust in the cisplatin and vinorelbine arm 

across classic endpoints confirmed by multivariate analysis. These findings 

may suggest that RRM1 is involved in vinorelbine sensitivity and warrant 

further research which will be presented shortly. 



Biomarkers that predict sensitivity to heat shock protein 90 inhibitors 

(HSP90i). Presenting Author: Komal L. Jhaveri, Memorial Sloan-Kettering 


Background: HSP90 is an attractive target in tumors as it mediates the 

maturation and stabilization of client oncoproteins. HSP90i are potentially 

active in a variety of tumors, but therapeutic benefit is confirmed in only a 

small subset to date. Predictive biomarkers could identify patients (pts) 

and/or tumors with sensitivity to HSP90i improving the therapeutic index. 

We explored potential biomarkers across multiple studies of HSP90i. 

Methods: Archived pre-treatment tumor specimens from pts treated with 

any of several HSP90i (17-AAG, 17-DMAG, CNF2024, retaspimycin & 

ganetespib) on 8 phase I/II trials at MSKCC from 1999 to 2011 were 

identified. The following antibodies were validated at MSKCC and tumor 

tissue was tested by immunohistochemistry (IHC) with results defined for 

each as: ER, PR & AR: �1% pos & �1% neg; HSP90 & HSP70: 0, 1� neg 

&2�, 3� pos; PTEN: 0, 1� neg&2�pos; HER2: 0, 1� neg, 2� 

equivocal, 3� pos; EGFR: 0 neg & 1�,2�,3�pos. Clinical response was 

correlated with IHC using Fisher’s exact test. Results: Of the 164 pts 

identified, adequate tissue was available for 51, including 11 different 

solid tumors & 1 CML. Breast (N�31), melanoma & prostate (N�4 each) 

were most frequent. The mean age at primary diagnosis was 50 yrs (24-81). 

The median no. of lines of prior chemotherapy for metastatic disease was 2 

(0-8). The mean duration of HSP90i therapy was 79 days (0-411). There 

were 19 responses (5 PR; 14 SD); 14/19 responses strongly correlated with 

HER2� status (p � 0.001); 1 pt with ER�/HER2-/EGFR- & 4 with EGFR 

�/HER2-/ER- disease also responded. A correlation for ER & EGFR with 

response was not excluded (p�0.07 & p�0.086 respectively). Conclusions: 

Our findings confirm HER2 as a sensitive client and an effective biomarker 

for sensitivity to HSP90 inhibitors. ER & EGFR did not meet statistical 

significance but may warrant further exploration in prospective settings. 


Serum activinA and TGF-� as biomarkers of breast cancer bone metastasis 

behavior. Presenting Author: Christina L. Addison, Ottawa Hospital Research 

Institute, University of Ottawa, Ottawa, ON, Canada 

Background: Bisphosphonates (BP) are prescribed to pts with metastatic 

bone disease every 3-4 weeks regardless of individual risk for skeletal 

related events (SREs). In an era of personalized medicine this “one size fits 

all” approach is not appropriate and novel markers of SRE risk are required. 

TRIUMPH is an ongoing clinical trial evaluating 12 weekly IV BP therapy 

for 1 year in women with low risk bone metastases from breast cancer (BC) 

as defined by the bone resorption marker C-telopeptide (CTx,) levels �600 

ng/L. This sub-study evaluated the utility of novel biomarkers in better 

predicting the risk of developing SREs. Methods: Serum obtained from pts 

at baseline and 6 weeks post-entry were analyzed for tumor growth factor-� 

(TGF-�) and activinA levels by ELISA (sensitivity ~15-30 pg/ml). Levels 

were correlated with pt parameters including time to development of bone 

metastasis, and number of previous SREs using linear regression analysis. 

Changes in levels of biomarkers from baseline to 6 weeks were used to 

calculate odds ratios using logistic regression analysis. Results: Baseline 

activinA correlated with baseline CTx and bone specific alkaline phosphatase 

(p�0.004 and p�0.0001 respectively). Baseline activinA also correlated 

with weight (p�0.02), BMI (p�0.007) and trended towards total 

number of prior SREs (p�0.07). Baseline TGF-� correlated with pt age 

(p�0.02), weight (0.006), BMI (p�0.0005) and duration of metastatic 

bone disease (p�0.004), but did not correlate with any other biomarker. 

Change in activinA (baseline to week 6) was the only biomarker that 

trended to predict coming off study early (p�0.053) as per protocol (i.e. 

CTx�600 ng/ml, SREs or pt/physician choice). Conclusions: Baseline levels 

of activinA trended to predict incidence of SREs in patients with bone 

metastases, and changes in levels from baseline to 6 weeks trended to 

predict coming off study early. These findings warrant future studies in BC 

pts assessing activinA as a predictor of risk associated with breast cancer 

bone metastases. This study was conducted with the support of the Ontario 

Institute for Cancer Research through funding provided by the Government 

of Ontario, and with funding from the Ontario Chapter of the Canadian 

Breast Cancer Foundation. 

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685s 


Effect of everolimus on angiogenic biomarkers in patients with tuberous 

sclerosis complex (TSC): Results from EXIST-1 and EXIST-2. Presenting 

Author: David Neal Franz, Cincinnati Children’s Hospital Medical Center, 

Cincinnati, OH 

Background: The efficacy and safety of everolimus, an oral mTOR inhibitor, 

was assessed in two randomized, double-blind, placebo-controlled, phase 

3 trials: EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400). EX- 

IST-1 examined everolimus for the treatment of subependymal giant cell 

astrocytoma (SEGA) associated with TSC and EXIST-2 for the treatment of 

renal angiomyolipoma (AML) associated with either TSC or sporadic 

lymphangioleiomyomatosis. In each instance, everolimus was superior to 

placebo for the primary endpoints, SEGA and renal AML response rates. 

Inhibitors of mTOR have antiangiogenic effects on tumor growth in vitro 

and in vivo. Methods: Patients were randomized to receive everolimus 

(n�78) starting at 4.5 mg/m2 /day (target trough, 5-15 ng/mL) or placebo 

(n�39) in EXIST-1 and 10 mg/day everolimus (n�79) or placebo (n�39) 

in EXIST-2. Plasma samples were taken at baseline and pre-dosing on day 

1 of weeks 4, 12, 24, 36, and 48 of treatment. Angiogenic markers of 

interest were vascular endothelial growth factor (VEGF)-A and -D, placental 

growth factor (PlGF), soluble VEGF receptor-1 (sVEGFR1), soluble VEGF 

receptor 2 (sVEGFR2), c-Kit, and collagen type IV. Results: Compared with 

placebo, a sustained ~30% and ~60% increase in VEGF-A was observed in 

the everolimus arm of EXIST-1 and EXIST-2, respectively. A concomitant 

decrease in collagen type IV (~25% EXIST-1; ~45% EXIST-2) and 

sVEGFR2 (~25% both trials) was also observed in the everolimus arm. A 

sustained decrease (~60%) in VEGF-D was observed in the everolimus arm 

of EXIST-2, but not EXIST-1. In both studies, no change was observed in 

PlGF, sVEGFR1, or c-Kit plasma concentrations in the everolimus arm or 

any biomarkers evaluated in the placebo arm. Baseline sVEGFR2 and 

VEGF-D were ~40% and ~4-fold higher, respectively, while VEGF-A was 

~50% lower in EXIST-2 compared with EXIST-1. A similar baseline plasma 

concentration for the other biomarkers was noted in both studies. 

Conclusions: Patients presenting with SEGA or renal AML associated with 

TSC had a reduction in plasma concentrations of sVEGFR2, collagen type 

IV, and VEGF-D (AML only) and an increase in VEGF-A. Everolimus may 

have antiangiogenic properties in TSC patients. 


Identification and validation of plasma protein biomarker panels for breast 

cancer diagnosis by using multiple reaction monitoring-based mass spectrometry. 

Presenting Author: Hyeong-Gon Moon, Department of Surgery, 

Seoul National University Hospital, Seoul, South Korea 

Background: Multiple reaction monitoring-based mass spectrometry (MRM- 

MS) has the ability to perform a wide range of proteome analysis in a single 

experiment using a small volume of specimen. We aimed to develop a 

plasma protein signature for breast cancer diagnosis using the MRM-MS 

technology. Methods: Previously, we have identified lists of breast cancerrelated 

proteins from various models of proteomic discovery including 

cancer plasma vs healthy plasma, cancer cell line secretome vs nontumorigenic 

cell line secretome, cancer tissue vs normal tissue, and 

literature search. Based on these protein panels, total of 29 proteins were 

selected for further experiments. We verified and validated the protein 

signature in two independent cohorts of breast cancer patients and healthy 

women. Results: In the verification cohort of 80 breast cancer patients and 

80 healthy women, MRM-MS showed significant differences in plasma 

concentration for 11 proteins. Among them, the difference was not 

significant for 4 proteins when the cases were limited to stage I and II 

patients. Based on p values and consistent expression level along the AJCC 

stages, we have created a plasma protein signature comprised of 3 plasma 

proteins. The 3 plasma protein signature effectively discriminated cancer 

and healthy cases with the AUC of 0.831 (sensitivity 78.7%, specificity 

78.7%). The performance of the 3 plasma protein signature was validated 

in the cohort of 100 cancer patients and 100 healthy women. The accuracy 

of the 3 protein signature was still meaningful with the AUC of 0.746 and 

0.797 for all stages and stage I or II patients, respectively. Conclusions: The 

3 plasma protein signature for breast cancer diagnosis, developed by the 

MRM-MS technology, showed promising results in the present study. 




Diurnal proteomics and biomarker discovery in indolent versus aggressive 

chronic lymphocytic leukemia patients. Presenting Author: Georg A. 

Bjarnason, Sunnybrook Odette Cancer Centre, University of Toronto, 


Background: In rodents, 10-20% of the genome has a 24-hour (h) rhythm in 

RNA expression. A molecular clock consisting of transcription / translation 

feedback loops of clock-genes controls this rhythmicity. In a microarray 

study (Affymetrix HG_U133_Plus2 chip) on RNA extracted from CLL cells 

sampled every 4 hours over 24 hours (6 samples) from 3 male (M) and 6 

female (F) patients (pts) with chronic lymphocytic leukemia (CLL) we found 

15,094 and 13,415 rhythmic transcripts (Cosinor analysis) in M and F 

respectively, only 6,629 of which were common to both M and F. We 

hypothesized that these gender differences in rhythmic RNA expression 

might have clinical implication for biomarker discovery with some important 

biomarkers only found at a certain times of day and with gender 

differences. Methods: Sampling was performed again at 6 time points in M 

and F CLL patients with indolent CLL (10pts, 5 M, 5F) and aggressive CLL 

(10 pts, 5M, 5F). An 8-plex iTRAQ kit was employed for mass spectrometry 

(MS) based relative quantification. Each iTRAQ block comprised all 

time-points for a single patient including a universal control. Results: At 

least 300 proteins were identified at a 95% confidence level in each iTRAQ 

experiment. Of these, 74 proteins displayed significant change between 

aggressive and indolent pts in 24-hour average or single time point 

normalized expression based on a non-parametric U-test (p�0.05). The 

JTK_CYCLE algorithm was used to detect 24-hour rhythmic patterns in the 

proteomic datasets. Significant rhythmic expression was found for 44 

proteins (p�0.10) identified by iTRAQ. Data for each time point were 

independently analyzed using an in-house Butterfly clustering algorithm 

based on discrete dynamical systems. The 4 PM time point was found to be 

optimal for stratifying aggressive and indolent disease. Cellular pathways 

with significant association to differentially expressed proteins included 

PPAR signaling, fatty acid metabolism, and granzyme-A signaling. Confirmation 

by selected reaction monitoring (SRM) MS is ongoing. Conclusions: 

Rhythmic protein expression may have clinical implications for biomarker 

discovery. 


Synthetic lethality of EGFR blockade in the context of tumor hypoxia. 

Presenting Author: Haruhiko Makino, University of Texas SouthWestern 

Medical Center Department of Radiation Oncology, Dallas, TX 

Background: Hypoxia induces a wide spectrum of biological responses in 

tumors that alter tumor radio-sensitivity. In several tumors, including 

non-small cell lung carcinoma (NSCLC), the epidermal growth factor 

receptor (EGFR) is frequently over-expressed and activated in response to 

hypoxia, although the precise role of EGFR in hypoxia-associated radioresitance 

is unclear. Activating mutations in EGFR have been clinically linked 

to dramatic responses to EGFR tyrosine kinase inhibitors. We previously 

demonstrated that NSCLCs harboring activating EGFR mutations are 

radiosensitive with severe deficits in the non homologous end-joining 

(NHEJ) repair of DNA damage. Methods: We investigated hypoxia associated 

radiation responses in a panel of NSCLC cell lines and immortalized 

human bronchial epithelial cells expressing wild type EGFR (WT) or 

expressed EGFR forms with somatic activating L858R or DE746-E750 

mutations (MT). Results: (1) Relative to WT EGFR, MT EGFR expression is 

associated with significantly higher radiosensitivity under chronic hypoxia 

(2) Under hypoxic conditions, MT EGFR expression is associated with a 

unique spectrum of DNA damage responses (DDR) that significantly 

deviated from canonical response of WT EGFR expressing NSCLCs (3) 

Genome wide gene expression analysis identified a dramatic hypoxiaassociated 

DDR shift to selective down-regulation of homologous recombination 

(HR). Moreover, MT EGFR deficits in NHEJ caused a synthetic 

lethality effect in the context of hypoxia through a simultaneous blockade 

of HR and NHEJ. (4) Blockade of WT EGFR by the anti-EGFR monoclonal 

antibody, cetuximab perfectly recapitulated the contextual synthetic lethality 

of MT EGFR expression. (5) Cetuximab had a dramatic synergistic effect 

on survival of rat lung orthotopic tumors where hypo-fractionated radiotherapy 

or cetuximab alone had marginally controlled tumors. Conclusions: 

The data support a critical role for EGFR-mediated DNA repair in hypoxia 

associated tumor radio-resistance. Furthermore, this role could be a target 

for refractory hypoxic EGFR-WT tumor especially in the context of hypofractionated 

radiotherapy which, in its current form, is potentially counterproductive 

for hypoxic tumors. 


New mechanistic insights into possible radiobiologic and pathophysiologic 

explanations for unexpectedly impressive outcomes data observed for 

hormone-refractary metastatic prostate cancer patients treated with radium 

223. Presenting Author: Roger M. Macklis, Cleveland Clinic Foundation 

and Taussig Cancer Center, Cleveland, OH 

Background: The ALSYMPCA Trial of 223Ra (“Alpharadin”) for men with 

metastatic castrate-resistant prostate cancer was a Phase III randomized 

trial comparing 223Ra plus SOC vs best SOC. This trial was stopped early 

after 922 patients enrolled at over 100 centers achieved primary (overall 

survival) and all secondary endpoints including median survived (14 vs 

11.2 m) time to first SRE (13.6 m vs 8.4 m) and time to PSA 

progression.These unexpectedly positive results prompted us to review 

some of the unique aspects of alpha-particle radiobiology and ultra-short 

range molecular targeting capabilities. Methods: Literature analysis. Results: 

The highly energetic alpha particles such as those released during decay of 

223Ra (T1/2 � 11.4 mins) display unique radiobiologic and dosimetric 

aspects. The nuclear dose required in vitro for approximately 90% target 

cell kill is less than 1 Gy and electron micrographs shortly after exposure 

confirm bizarre blebbing and condensation of chromosomal material 

characteristic of apoptosis. Bovine aortic endothelial cells exposed to alpha 

particle radiation indicate that the radiobiologic effects depend heavily on 

cell culture condition with nonuniform DNA strand break damage observed 

in isolated detached cells. The subcellular alpha particle path length 

appears to allow specific target cell populations to be killed within bony 

stroma without excessive damage to nearby sensitive hematopoietic cells. 

223Ra treatment in rodent models showed that this family of Ca �� analogs 

delivers extremely high doses to stromal elements such as bone-resorbing 

osteoclasts and this selectivity may aid in decreasing SREs. Conclusions: 

We highlight the fact that some basic radiobiologic and cell compartmentspecific 

stromal localization principles known to be effective in alpha 

particle radiopharmaceutical therapy may contribute to the very positive 

clinical outcomes observed while allowing subcellular damage accumulation 

to target cell groups. 


Using CHFR expression to predict response and survival after first line 

treatment with carboplatin-paclitaxel in NSCLC. Presenting Author: Rathi 

Narayana Pillai, Winship Cancer Institute, Emory University, Atlanta, GA 

Background: The identification of resistance mechanisms for conventional 

chemotherapy in lung cancer is of fundamental importance not only for 

personalization of chemotherapy but also for the subsequent development 

of novel targeted approaches to overcome this resistance. Currently, there 

is no clinically validated test for the prediction of response to tubulintargeted 

agents in NSCLC. Our previous preclinical work identified Checkpoint 

with Forkhead and Ringfinger domain” (CHFR) as a predictor of 

taxane cytotoxicity in in vitro models. The current work assessed the 

translational significance of this finding in a cohort of US veterans treated 

at a single-institution. Methods: We studied a cohort of patients with 

advanced NSCLC treated with taxane-containing frontline regimens at the 

Atlanta VA Medical Center between 2000 and 2009. Archived paraffinembedded 

tissue was retrieved and stained for CHFR expression using 

standard immunohistochemical techniques. Level of protein expression 

was assessed by light microscopy and scored for intensity of CHFR staining. 

Intensity of staining was correlated with clinical outcome including 

objective response and median overall survival using Chi-Square test and 

Cox proportional models. Results: We analyzed tumor samples from 45 

eligible patients with median age 62.6 years, M/F (44/1). In this cohort, 

high expression of CHFR is strongly associated with adverse outcomes: the 

risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel 

was 54% in patients with CHFR-high vs. only 18% in those 

with CHFR-low tumors (HR 3.1; 95% CI 1.09-9.04; p�0.02). Median 

overall survival was strongly correlated with response to first-line therapy 

(clinical benefit: 9.24 months; PD: 4.7 months; p�0.001) and with CHFR 

expression status (CHFR low: 10 months; CHFR high: 5.6 months; p 

�0.01). Conclusions: CHFR expression is a novel predictive marker of 

response and overall survival in NSCLC patients treated with taxanecontaining 

chemotherapy. 



DNA damage responses in relation to late effects following radiotherapy for 

early breast cancer. Presenting Author: Melvin Chua, University College 

London Cancer Institute, London, United Kingdom 

Background: In this study, we assessed if induction of apoptosis in G0 blood 

lymphocytes following ex vivo irradiation correlated with clinical radiosensitivity 

and DNA double-strand (DSB) repair in breast radiotherapy (RT) 

patients. Using small molecule inhibitors, we examined the relationship 

between DSB repair and radiation-induced apoptosis. Methods: Breast 

cancer patients with minimal (controls) or marked late RT changes (cases) 

were selected. DSB were quantified by �H2AX/53BP1 immunostaining 0.5 

and 24 h after exposure of lymphocytes to 0.5 and 4 Gy, respectively. 

Induction of apoptosis was assessed 48 h after 8 Gy using a fluorochrome 

inhibitor of caspases (FLICA) assay. Apoptotic cells were defined by small 

cell size and positive FLICA signal, measured using flow cytometry. Small 

molecule DNA-PK (Nu7441) and ATM (Ku55933) inhibitors were used at 

concentrations of 1 �M and 10 �M, respectively. Results: Despite similar 

foci induction at 0.5 h, residual foci levels 24 h after 4 Gy differed 

significantly between cases and controls (Foci per cell � 12.7 in cases, n � 

8 vs 10.3 in controls, n � 8, p � 0.002). In contrast to residual foci levels, 

comparable levels of apoptosis were observed between cases and controls 

48 h after 8 Gy. Mean proportion of apoptotic cells was 37.2% in cases and 

34.7% in controls (p � 0.413). Residual foci levels were not correlated 

with levels of apoptosis in lymphocytes of the same patients (R � -0.059, p 

� 0.785). To determine if apoptosis is modulated by DSB repair, apoptosis 

measurements were repeated in lymphocytes treated with Nu7441 to 

inhibit non-homologous end-joining. We observed that Nu7441-treated 

cells had higher levels of residual foci and apoptosis compared to 

mock-treated cells, 48 h after 1 Gy. This effect was wholly dependent on an 

active ATM function as cells treated simultaneously with Nu7441 and 

Ku55933 had extremely low levels of apoptosis, comparable to levels 

observed in cells treated with Ku55933 alone. Conclusions: Higher levels of 

residual DSB observed among radiosensitive patients suggest a role for 

DSB repair in the pathogenesis of late radiation-induced effects. Induction 

of apoptosis appears to be dependent on DSB end-joining following 

exposure to ionising radiation. 


In silico identification of an epithelial core signature in human tumors. 

Presenting Author: Chirayu Pankaj Goswami, Center for Computational 

Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, 

IN 

Background: Gene expression analysis is performed on grossly selected 

specimens often without any microscopic analysis of tumor content. In 

studies where histological analyses have been performed, cases having 

80% or more tumor content are used for microarray analysis. The variability 

in amount of epithelial and stromal cells may generate to misleading 

differential expression analysis and selection for wrong targets for therapeutics. 

It is also often unclear, whether the genes identified are stromal or 

epithelial in origin. The goal of this study was to identify genes that define 

core epithelial phenotype; these genes could provide means of normalization 

of expression data. Methods: The CABIG GSK microarray (HG- 

U133_plus_2) data consisting of 950 cell lines from carcinoma (n�562), 

non-carcinoma (n�385) and normal tissue (n�3) was analyzed to identify 

epithelial specific genes. 10 carcinomas each from 11 sites (n�110) and 

an equal number of non-carcinomas were randomly selected. In silico 

analyses were performed by 1) identifying genes differentially expressed 

between carcinoma and non-carcinoma samples using a one way ANOVA; 

2) identifying gene signature associated with carcinoma using Predictive 

Analysis of Microarrays (PAM) and 3) a weighted gene coexpression 

network analysis (WGCNA) was performed to identify co-expression modules. 

A similar analysis was also performed on tissue samples (E-GEOD- 

12360) from carcinomas and non-carcinomas. Venn-diagram was generated 

to identify intersecting set. Results: Comparison of the carcinoma and 

non-carcinoma samples using ANOVA identified 1455 differential expressed 

gene probes in cell lines and 540 gene probes in tissues 

(FDR�1E-10). The cell lines analysis identified 5 modules and a 65-gene 

signature (43 core and 22 accessory set) that was specific for epithelial 

cells. In the tissue analysis a 188-gene signature was similarly identified. 

Cross-comparison identified a smaller 31 gene intersecting set; this was 

not associated with loss of discriminatory power. Conclusions: A 31 geneset 

which can be used to determine the epithelial content of heterogeneous 

tumors, was identified. This study has the potential to significantly impact 

the use of microarray based gene expression data. 

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687s 


Correlation between in vitro chemotherapy sensitivity and PARP-1 expression 

in patients with breast cancer. Presenting Author: Cornelia Liedtke, 

University of Muenster, Muenster, Germany 

Background: Based on its potential use as a therapeutic target through 

PARP inhibitors expression of Poly-A-Ribose-Polymerase-1 (PARP-1) has 

come into scientific focus. Furthermore, it could be demonstrated that 

cytoplasmic PARP-1 expression varies depending on molecular breast 

cancer subtypes and that it correlates with an increased response to 

neoadjuvant taxane-anthrazykline containing chemotherapy (von Minckwitz 

et al., J Clin Oncol 2011). In-vitro-chemotherapy sensitivity and 

resistance assays (CSRAs) are a means to directly measure chemotherapy 

sensitivity in a given tumor uninfluenced by host factors. Methods: We 

conducted a systematic immunohistochemical tissue-microarray (TMA)based 

analysis of 550 samples of invasive breast cancers to evaluate the 

expression of a set of molecular markers including estrogen receptor (ER), 

progesterone receptor (PR) and HER2 as well as PARP-1. Triple negative 

breast cancers (TNBC) were identified through lack of (over-)expression of 

ER, PR and HER2. All carcinomas were analyzed in an in vitro CSRA 

protocol for epirubicin/docetaxel (ED) and epirubicin/cyclophosphamide 

(EC). In-vitro-chemotherapy sensitivity was analyzed using an adenosine 

triphosphate (ATP) bioluminescence assay. Results: Moderate/high expression 

of PARP-1 was found in 48 and 33% of cases with TNBC and 

non-TNBC, respectively (p�0.015). No correlation between TNBC phenotype 

and cytoplasmic expression was observed. However, increased expression 

of both cytoplasmic and nuclear PARP-1 was correlated with an 

increased in-vitro sensitivity against ED (p�0.012 and 0.025, respectively) 

but not EC (p�0.27 and 0.62, respectively). Conclusions: Our 

results support previous observations demonstrating a significant correlation 

between expression of PARP-1 and an increased sensitivity against 

taxane-anthracycline chemotherapy independent of tumor phenotype. 


Intestinal HIF-2 to protect against radiation-induced gastrointestinal syndrome. 

Presenting Author: Cullen M. Taniguchi, Stanford University 

Medical Center, Stanford, CA 

Background: Gastrointestinal (GI) toxicity accounts for significant morbidity 

during systemic chemotherapy or abdominopelvic radiation therapy. Unfortunately, 

there are no effective preventative treatments. Hypoxic signaling 

through hypoxia-inducible factor-1 (HIF-1) and -2 (HIF-2) is critical for 

intestinal homeostasis during inflammatory challenges and was posited to 

play a role in radioprotection. Methods: We stabilized both HIF-1 and HIF-2 

pharmacologically with the prolyl hydroxylase inhibitor DMOG and with 

transgenic mice. Male C57/Bl6 mice eight weeks of age were pretreated 

with saline or 8mg DMOG 16hrs and 4hrs prior to being irradiated with a 

single fraction of 20Gy to the abdomen using a modified TLI jig that shields 

the upper body of the mouse to reduce hematopoietic toxicity. After XRT, 

the mice got daily doses of saline or DMOG for 5 days. Results: Mice treated 

with DMOG had a 1.5-fold enrichment of crypt regeneration in the colon as 

determined by microcolony assay (13.3�3.4 vs 21.2�1.7 crypts/section, 

saline vs DMOG, n�10/group, p�0.005). Death from GI radiotoxicity can 

result from compromised epithelial integrity. We tested epithelial and 

barrier function by gavaging irradiated mice with FITC-dextran, which 

undetectable in the blood unless the GI epithelia is compromised. 

Treatment with DMOG decreased FITC-dextran uptake by 4-fold over 

controls (52.6�14.7 vs 12.4�3.4 mcg/ml, n�6/group, p�0.02). These 

physiologic improvements translated to improved overall survival with 

DMOG treatment after being exposed to 20Gy of abdominal radiation 

(p�0.03). To determine if the radioprotective effect of DMOG was specific 

to HIF-1 or HIF-2, we overexpressed stabilized HIF1 or HIF2 in the 

intestinal epithelia using a lox-stop-lox (LSL) system and Villin-Cre. The 

overexpression of HIF1 had no effect on survival (p�0.22), while mice with 

intestinal-specific HIF2-overexpression had significantly improved survival 

after receiving 20Gy of abdominal radiation (p�0.001). Conclusions: 

Activation of HIF-2 is sufficient to protect mice from lethal doses of 

abdominal radiation may provide a novel class of treatments to protect the 

GI epithelium from the deleterious side effects of chemotherapy and 

radiation. 




Molecular profiling of uveal melanoma patients. Presenting Author: Zoran 

Gatalica, Caris Life Sciences, Phoenix, AZ 

Background: Although uveal melanoma represents only 5% of all melanomas, 

it is the most common primary intraocular malignancy of the adult 

eye. Approximately 50% of patients will develop metastases which are 

resistant to medical interventions. There is a great need for improved 

therapy as the prognosis is poor for advanced stages. Our study was 

undertaken to investigate the presence of novel therapeutic targets. 

Methods: We analyzed 49 uveal melanoma patients with immunohistochemistry 

for 16 markers including cKIT, PDGFR, cMET, PTEN and IGF1R. 

Further, microarray analysis was performed on 29 samples using the 

Illumina platform. We also investigated amplification of EGFR and mutational 

analysis of cKIT, BRAF, KRAS and NRAS on a smaller patient subset. 

Results: Overexpression of KIT at the protein and RNA level was 74% (28 

out of 38) and 45% (13 out of 29), respectively. Expression of cKIT did not 

correlate with gain-of-function cKIT mutations in any of the 34 samples 

tested. In our study, MET was overexpressed in 15 out of 17 cases at the 

RNA level and IGF1R was high in 4 out of 6 patients indicating poor 

prognosis. PTEN expression by IHC was present in 90% (36 out of 40) 

patients indicating the PI3K pathway is not activated in the majority of 

uveal melanoma patients. BRAF was wildtype in all 42 patients tested. 

Similarly, no KRAS or NRAS mutations were detected. Protein and RNA 

expression of PDGFR were low in our patients. MGMT was lost in 16 out of 

40 patients at the protein level and 10 out of 29 patients at the RNA level. 

EGFR expression, copy number and protein levels were low in the patients 

tested. Conclusions: Our data on cKIT suggests that it is a promising target 

in uveal melanoma. Low expression of MGMT in about a third of our 

patients may indicate the likelihood of favorable response to dacarbazine 

and temozolomide. There are currently several clinical trials investigating 

various cKIT inhibitors, as well as temozolomide in advanced uveal 

melanoma patients. Our findings highlight the importance of molecular 

profiling uveal melanoma patients. 


The PARSC trial, a prospective study for the assessment of recurrence risk 

in stage II colon cancer patients using ColoPrint. Presenting Author: Ramon 

Salazar, Institut Catala d’Oncologia, Barcelona, Spain 

Background: An 18-gene expression profile, ColoPrint, has been developed 

for identifying colon cancer patients more likely to develop recurrent 

disease and who would be candidates for adjuvant chemotherapy. The gene 

signature was validated in public datasets and independent patient cohorts 

(stage II and III patients). Uni-and multivariate analysis was performed on 

the pooled stage II patient set (n�320) (median follow-up 70 months). 

ColoPrint classifies 65% of stage II patients as Low Risk. The 3-year RFS 

was 91% for Low Risk and 74% for High Risk patients with a HR of 2.9 

(p�0.001). ColoPrint was the only significant prognostic marker in the 

subgroup of patients with T3-MSS phenotype (Tabernero, ASCO GI 2012). 

Methods: A blinded prospective trial, PARSC (Prospective study for the 

Assessment of Recurrence risk in Stage II colon cancer patients) using 

ColoPrint has been initiated. Objectives are: (1)To validate the performance 

of ColoPrint in estimating the 3-year relapse rate in patients with 

stage II colon cancer. (2) To compare the risk assessment in stage II 

patients using the ColoPrint profile vs a clinical risk assessment based on 

Investigator’s assessment of risk and ASCO high-risk recommendations. (3) 

To investigate therapy as a potential confounding factor for ColoPrint 

results. (4) To assess the performance of ColoPrint in estimating the 3-year 

relapse rate in patients with stage III colon cancer. Inclusion criteria: age � 

18 years, adenocarcinoma of the colon, stage II and III, no prior neoadjuvant 

therapy, no synchronous tumors, fresh tumor sample, and written 

informed consent. The treatment of the patient is at the discretion of the 

physician adhering to National Comprehensive Cancer Network (NCCN)approved 

regimens or a recognized alternative (blinded for ColoPrint 

result). The trial started in Sept. 2008 with currently 32 participating sites 

in 11 countries. Thus far, 340 eligible stage II and 280 stage III patients 

have been enrolled. The aim is to enroll 575 stage II patients. Clinical trial 

registry number: NCT00903565. 

TPS10631 General Poster Session (Board #53H), Mon, 1:15 PM-5:15 PM 

Detection of discordant HER2 status by FISH in circulating tumor cells and 

disseminated tumor cells in early-stage breast cancer using a microfluidicbased 

cell enrichment and extraction platform (OncoCEE). Presenting 

Author: Savitri Krishnamurthy, University of Texas M. D. Anderson Cancer 


Background: Evaluation of HER2 in circulating (CTCs) and disseminated 

(DTC) tumor cells may aid therapy in breast cancer. We report here the 

discordance in HER2 status in CTCs and DTCs in early stage breast cancer 

by fluorescence in situ hybridization (FISH) using a microfluidic cell 

platform (OncoCEE). Methods: Blood (10ml) and BM (1-2ml) from patients 

with Stage T1 and T2 breast cancer was collected in OncoCEE-Sure 

collection tubes. Mononuclear cells were recovered using a Percoll density 

gradient method, incubated with a mixture of 10 primary capture antibodies 

(Abs), and introduced into streptavidin coated OncoCEE microchannels 

for tumor cell capture. For blood samples, captured cells were stained with 

anti cytokeratin (CK) and CD45 Abs for CTC enumeration followed by FISH 

using probes specific to centromere 17 and HER2. For BM samples, 

captured cells were subjected to HER2 FISH analysis. The ratio of 

HER2:CEP17�2.0 in any CK�/ CD45- and CK-/CD45- cell was regarded 

as positive for HER2. Results: Blood and BM from 68 patients (68 Blood, 

54 BM; 54 matched blood and BM) with stage T1N0 (41), T1N1 (6), T2N0 

(11), T2N1(2), T2N2 (1), T2N3 (2) with HER2� (n�7) and HER2- 

(n�61) breast cancers were studied. The 7 patients with HER2 � primary 

tumor had HER2� DTCs in 3/7 (43 %) and HER2 � CTCs in 1/6 (17 %) 

patients. HER2 � DTCs and HER2 � CTCs occurred in 10/47 (21%) and in 

4/57 (7%) patients with HER2- primary breast tumors. The discordance of 

HER2 status was observed in 14% in CTCs and in 22% in DTCs. 

Conclusion: 1. The cell enrichment and extraction microfluidic platform 

(OncoCEE) provides a sensitive approach for evaluation of HER2 in CTCs 

and DTCs. 2. CTCs and DTCs acquired HER2 gene amplification in 21% 

and 7% of patients with HER2 negative early stage primary breast cancer. 

3. CTCs and DTCs lost HER2 gene amplified status in 57% and 83% of 

patients with HER2 positive early stage primary breast cancer. 4. The 

clinical significance of alterations in HER2 status among CTCs and DTCs in 

early stage breast cancer needs further investigation. 

TPS10633^ General Poster Session (Board #54B), Mon, 1:15 PM-5:15 PM 

Emerging findings in the Cancer Research UK stratified medicine program. 

Presenting Author: Emily Shaw, Cancer Research UK, London, United 

Kingdom 

Background: Molecular analysis of tumours may be used to identify those 

predicted to benefit from novel targeted therapies. The Cancer Research 

UK programme is piloting plans to apply such testing broadly across the UK 

healthcare system, linking molecular phenotype to clinical outcomes. 

Methods: The Stratified Medicine Programme (SMP) aims to develop a 

model for high quality, large-scale molecular characterization of cancer 

specimens through an initiative developed in partnership with AstraZeneca, 

Pfizer, the UK Department of Health and academic researchers. Phase 

One of the SMP is a two year feasibility study. It aims to demonstrate the 

submission of consented blood samples and sections of surplus diagnostic 

formalin-fixed paraffin-embedded tumour tissue from 9,000 patients at 

centres across the UK to one of three ‘technology hubs’ for mutation testing 

of genes of potential clinical interest (KRAS, BRAF, NRAS, PIK3CA, TP53, 

PTEN, TMPRSS2-ERG, EGFR, EML4-ALK and KIT) in six selected tumour 

types. The tests are technically validated and will be completed in clinically 

relevant timescales. Data including pathological and treatment information 

and clinical outcome is also collected for the recruited patients, linked to 

the genetic data and stored in a central data repository hosted within the 

National Cancer Registration Service. The study opened in September 

2011 at 7 sites across the UK and by the end of 2011, 760 patientswith 

breast, lung, prostate, colorectal, ovarian cancer or metastatic malignant 

melanoma had consented to participate. 142 sets of molecular results had 

been returned to clinical teams. Updated figures will be presented at the 

meeting, by which time the programme is projected to have accrued 4000 

subjects. By 2013, we hope to have developed a scalable model for routine, 

high quality, prospective molecular characterisation of tumours for NHS 

cancer patients, with consent for the collection, storage and research use of 

population-scale genetic and clinical outcome data. We will report the 

emerging results from the Stratified Medicines Programme and early 

insights into implications for wider implementation across the UK healthcare 

system. 



Highly sensitive determination of PIK3CA exon 9 and 20 hotspot mutations 

in breast tumors. Presenting Author: Alexandre Harle, Centre Alexis 

Vautrin, Pathology and Tumor Biology Dept, EA4421 SiGReTO Nancy 

University, Vandoeuvre-lès-Nancy, France 

Background: Hotspot mutations in exons 9 (E542K and E545K) and 20 

(H1047L and H1047R) of PIK3CA gene encoding for the p110� catalytic 

subunit of Phosphatidylinositol 3-kinases (PI3K) are found in approximately 

25% of breast carcinomas. PIK3CA mutations cause the overactivation 

of PI3K/AKT/mTOR pathway and lead to resistance to anti-HER2 

targeted therapies in breast cancers, are involved in response to anti-mTOR 

agents and are proposed as molecular diagnosis marker for PI3K inhibitors. 

A highly sensitive method is required to detect PIK3CA mutations in 

paraffin-embedded tumor tissues. Methods: We developed a real-time PCR 

assay using allele-specific scorpion primers and amplification refractory 

mutation system (PCR-ARMS) to detect hotspot mutations in exons 9 

(E542K and E545K) and 20 (H1047L and H1047R) of PIK3CA of PI3K. 

Results: PIK3CA mutations were analyzed in 102 paraffin embedded breast 

tumors (88 invasive ductal carcinomas and 14 lobular ductal carcinomas). 

All specimens were validated by pathologist examination and processed for 

DNA extraction and PCR. PIK3CA exon 9 and 20 mutations were found in 

22.5% of the specimens, 39.1% in exon 9 (26.1% for E542K, 13.0% for 

E545K) and 60.9% in exon 20 (17.4% for H1047L and 43.5% for 

H1047R). These results were comparable to the literature data (�²�0.327 

;p�0.05). PCR ARMS was found to be highly sensitive, able to detect 0.5 

% mutated DNA. Conclusion: PCR ARMS assay is highly sensitive for 

PIK3CA exon 9 and exon 20 hotspot mutations analysis in breast 

carcinomas as molecular marker for anti-HER2 and PI3K inhibitors 

response prediction. 

Tumor Biology 

689s 

TPS10635 General Poster Session (Board #54D), Mon, 1:15 PM-5:15 PM 

ACRIN 6684 assessment of tumor hypoxia in glioblastoma using 18Ffluoromisonidazole 

with PET and MRI. Presenting Author: Elizabeth Robins 

Gerstner, Massachusetts General Hospital, Boston, MA 

Background: Glioblastoma (GBM) is an aggressive type of primary malignant 

brain tumor and despite treatment with surgery, radiation, and temozolomide 

(TMZ) chemotherapy, median overall survival (OS) remains poor. A 

pathologic hallmark of GBM is tumor necrosis, a suspected result from 

endogenous tumor hypoxia. Angiogenesis is stimulated by hypoxia-driven 

signaling cascades and is required for tumor proliferation. The inefficient 

blood supply of these hypoxic tumors also limits the efficacy of chemotherapy 

and radiotherapy. Surviving hypoxic tumor cells may be selected 

out and proliferate as a more aggressive tumor subtype, therefore hindering 

OS. 18F-Fluoromisonidazole (FMISO) is a PET radiotracer whose uptake in 

hypoxic tissues can be measured radiographically. The degree of tumor 

hypoxia has been negatively associated with time to tumor progression and 

survival (Spence et al, 2008). Knowledge of the degree/distribution of 

tumor hypoxia by PET uptake and perfusion MRI parameters may provide 

prognostic information and help guide therapy for patients with GBM. 

Methods: In this phase II prospective single arm multi-institution study, 

patients will undergo baseline FMISO PET and MR imaging two weeks prior 

to chemoradiotherapy (CRT). A subset of patients will receive a second 

FMISO PET one week prior to CRT to assess reproducibility. Clinical 

outcomes of OS and 6-month progression-free survival (PFS-6) will be 

correlated to PET and MRI parameters. Eligibility: Pathologically confirmed 

GBM with residual tumor after surgery (including T2/FLAIR hyperintensity 

consistent with tumor) scheduled to receive standard fractionated radiation 

therapy and temozolomide alone or with an anti-VEGF agent or PARP 

inhibitor. Current enrollment: 22 patients of 50 sample size Contact 

information: Please contact the PI, Elizabeth R. Gerstner, MD 

(egerstner@partners.org) for additional information. Significance: With a 

better understanding of the extent of tumor hypoxia and changes in hypoxia 

levels from treatment, more effective therapies could be developed to 

inhibit GBM growth, target hypoxic areas and individualize patient care. 


Publication-Only Abstracts 

Publication-only abstracts, which are selected to be published in conjunction with the 2012 Annual Meeting, 

but not to be presented at the Meeting, can be found online in full-text, fully searchable versions at 

abstract.asco.org and JCO.org. 

The publication-only abstracts are not included in the print volume, but are citable to this Journal of Clinical 

Oncology supplement. Please refer to the following example when citing publication-only abstracts: 

J Clin Oncol 30, 2012 (suppl; abstr e12000)

Author Index 

Note: Numerals refer to abstract number. Accepted abstracts not presented at the meeting (designated by �e�) are available in full-text versions on ASCO.org. 

A 

A’Hern, Roger 2540 

Aabakken, Lars e14637 

Aaitel, Andrea e15083 

Aapro, Matti S. 9133 

Aaseboe, Ulf 7001 

Aasebø, Ulf 7027 

Aaseem, Aarifah e11053 

Abacioglu, Ufuk e16015 

Abad, Albert 9129 

Abad, Leslie W TPS4675^ 

Abaid, Lisa e15500 

Abakar-mahamat, Abakar 

5075 

Abal, Miguel 10534 

Abali, Huseyin 9050 

Abalo, Alicia 10534 

Abbadessa, Giovanni 4006 

Abbas, Ghulam 7074 

Abbas, Haider LBA4001, 

e13007 

Abbas, Kanza S e17018 

Abbas, Laura 9589 

Abbasi, Fatima 6581 

Abbott, David H e15167 

Abbotts, Rachel 1014 

Abboud, Christelle e15524 

Abboud, Miguel e20004 

Abboud, Steven F. 6081 

Abbruzzese, Bonnie e21066 

Abbruzzese, James L. 4051, 

4054, 4060, 4116, 4130, 

4131 

Abda, Naima e18124 

Abdalla, Iman A. e16031 

Abdel Halim, Inas Ibraheim 

e15129 

Abdel Karim, Nagla TPS3116 

Abdel-Fatah, Tarek M. A. 

1013, 1014, 1098 

Abdel-Rasoul, Mahmoud 609 

Abdel-Wahab, Omar Ibrahim 

6606 

Abdelhafez, Mohamed F 

e19021 

Abdelrahman, Fadwa e15024 

AbdelRehem, Rania Naguib 

4116 

Abdelsalam, Mahmoud 

e18001 

Abdelsalam, Mohamed 

e14664 

Abdi, Ehtesham A. 9087, 

e15152 

Abdolmohammadi, Alireza 

e16545 

Abdool, Adam 5510 

Abdous, Belkacem 9138 

Abdul Rahman, Rozana 

e14705 

Abdul Razak, Albiruni Ryan 

5587 

Abdulkader, Ihab 10534 

Abdullaev, Zied TPS7609 

Abdullah, Nik Azim Nik 4106 

Abe, Hajime e11564 

Abe, Hiroaki e11007 

Abe, Seiji e13029 

ABE, Tatsuya e19508 

Abe, Tetsuya 6112 

Abedin, Sameem 1085 

Abel, Gregory Alan 6012, 

6103, e18530 

Abenhardt, Wolfgang 3588 

Abeni, Chiara e14018 

Aberki, Clemence 6594 

Abern, Michael 4670 

Abernethy, Amy Pickar 2021, 

6041, 6047, 6051, 6102, 

9128, TPS9153, e15061, 

e16556 

Abgrall-Barbry, Gaelle 9080 

Abhyankar, Dhiraj J. e13548 

Abhyankar, Sunil H. 10605 

Abid, Arifa 6620 

Abidi, Muneer Hyder 6549 

Abidoye, Oyewale O. 1526 

Aboagye, Eric e21093 

Abonour, Rafat 8037, 

e18556 

Abou-Alfa, Ghassan K. 4057, 

9105 

Aboukameel, Amro e21057 

Aboulafia, David Michael 

4030 

Abraham, Anasooya A 6016 

Abraham, Christine e15131 

Abraham, Deepak T e19562 

Abraham, Jame 611 

Abraham, Joseph 6067 

Abraham, Kathryn 7022 

Abraira, Victor e21104 

Abramovici, Olivia 5565 

Abrams, Judith 6549 

Abrams, Thomas Adam 3537, 

4027, 4112, 4125, 

e19586 

Abramson, David H. 8549, 

8598 

Abramson, Jeremy S. 8060, 

e18520 

Abramson, Vandana Gupta 

510 

Abrantes, Fernanda L. 9523 

Abravaya, Klara e21111 

Abreu, Andre Luis de Castro 

e15060, e15171, e15212 

Abrey, Lauren E. 2006, 2008 

Abrial, Catherine 1051 

Abruzzese, Elisabetta 6503 

Abu Awwad, Raed e12019 

Abu Hazeem, Mahmoud 

e14641 

Abu Hejleh, Taher 6034 

Abu sabaa, Amal e15530 

Abu Salah, Jehad e14025 

Abu-Khalaf, Maysa M. 508, 

1045, 10508 

Abujamra, Ana Lucia e13546 

Abukhdeir, Abde e18147 

Abuodeh, Yazan Asad e15024 

Acerbi, Irene e11096 

Acevedo, Agustin 1111 

Acevedo, Andres e12039 

Acevedo-Gadea, Carlos 

Rodrigo 5529, 5532 

Acharya, Sandip TPS6638 

Acharya, Shivani Anil 3011 

Achatz, Maria Isabel 1522 

Achour, Nacredine e14148 

Acikalin, Arbil e11088 

Acikgoz, Ozgur e14618 

Acin, Yolene TPS10102^ 

Ackerl, Michael 2071 

Ackerman, Allison 8569 

Ackermann, Elizabeth J. 

e13562 

Ackland, Stephen P. e14166 

Ackloo, Suzanne 10622 

Acoba, Jared David 1599 

Acosta, Daniel e20513 

Acosta, Soraida 2527 

Acquaviva, Jaime 3090 

Acton, Gary TPS6637 

Adab, Kalid e18534 

Adachi, Mitsuru e13029 

Adai, Alex 3630 

Adair, Beth 4526 

Adair, Courtney A 7072^ 

Adam, Barbara e15081 

Adam, Clovis 2023 

Adam, Kiraely 10051, 

e20509 

Adam, Paul J. 3092 

Adam, Rene 3547 

ADAM, Virginie 9080 

Adamia, Sophia 6606 

Adamo, Barbara TPS656, 

e11056 

Adamo, Vincenzo 4627, 

e11056 

Adamoli, Laura 546, 1049, 

1115 

Adamowicz, Krzysztof e21099 

Adams, Bonne J. 3034, 

3042^ 

Adams, Daniel e21079 

Adams, Jacqueline e19513 

Adams, John 1581 

Adams, Judith A. 4021 

Adams, Laurel M. e13596 

Adams, Ramon 5102 

Adams, Richard A. 2522, 

3516, 3530 

Adams, Rosemary Frances 

1066 

Adams, Shari TPS3112 

Adams, Sylvia 2589, e11064, 

e11529 

Adams-Campbell, Lucile L. 

e14005 

Adamson, Douglas 1094 

Adamson, Laura M 611 

Adamson, Peter C. 9500 

Adavikolanu, Kesava 

Ramgopal e12501 

Addeo, Raffaele e14135 

Addioui, Anissa 9563, 9570 

Addison, Christina L. 10620 

Adel, Nelly G. 4057, 6613 

Adelberg, David E. 4569 

Adelberg, David 3043 

Adelson, Kerin B. e21032 

Adelstein, David J. e14611, 

e14665 

Adelusola, Kayode e11554 

Ademuyiwa, Foluso Olabisi 

e11563, e19568 

Adenis, Antoine 3010, 3502, 

3507, LBA4003, 4091, 

10007, 10089, 10092, 

10095, TPS10102^, 

e14560, e14650 

Aderka, Dan e14143 

Adesunkanmi, Abdulrusheed 

Kayode e11554, e12022 

Adesunloye, Bamidele 4569, 

e13122 

Adetchessi, Tarek e19539 

Adetiloye, Adebayo e11554 

Adhami, Faisal e21064 

Aditi, Bhatt e14721 

Adjei, Alex A. 3029, 4117, 

4545, 7073, 7541, 7555, 

7605, 8519, e13006, 

e17535 

Adjei, Araba 7555, e18118 

Adjei, Brenda A. 6086 

Adjiri-Awere, Alfred 3086 

Adkins, Douglas 5501, 10003 

Adolf, Guenther R. 3092 

Adra, Thais Rodrigues 

e15562 

Adsay, Volkan e14170, 

e14692 

Adua, Daniela e14096 

Advani, Anjali S. 6501, 6521 

Advani, Ranjana 8060, 8070, 

e13079 

Adzovic, Sonja 4633 

Aebi, Stefan Paul e19648 

Aegerter, Philippe 8540 

Aerts, Cindy 2507 

Aerts, Isabelle 9517, 9519, 

9538 

Aerts, Joachim 7019 

Affronti, Mary Lou 2074^ 

Afonso Afonso, Francisco J. 

e15076, e15077, e18040 

Afonso Gomez, Ruth e11081 

Afonso, Francisco Javier 

e15067 

Afonso, Noemia e15532 

Afshari, Ashkan 1132 

Aft, Rebecca 2525 

Aftimos, Philippe TPS652 

Agafitei, Raluca Dana 4096 

Agajanian, Richy 4550 

Agami, Reuven e13515 

Agaoglu, Fulya Yaman 9567 

Agar, Meera 2604, TPS9153 

Agarwal, Amit e16023 

Agarwal, Gaurav e16023 

Agarwal, Jaiprakash e16021 

Agarwal, Neeraj 4506, 4511, 

4525, 4536, 4538, 4663, 

10503, e13596 

Agarwal, Roshan 3022 

Agarwal, Vijay e13554 

Agarwala, Sandeep 9580 

Agarwala, Sanjiv S. e15115 

Agarwala, Sanjiv S 8511, 

e13088 

Agbakwuru, Augustine 

e11554, e12022 

Agbarya, Abed 9052 

Agbo, Felix 3045 

Agelaki, Sofia 7564 

Agelidou, Athina 7564 

Agelidou, Maria 7564 

Agerholm-Larsen, Birgit 2069 

Aggarwal, Ashutosh N e18009 

Aggarwal, Charu 7092, 7595 

Aggarwal, Rahul Raj 4664 

Aggarwal, Shyam e18041 

Agha, Mounzer E. 6563 

Aghajanian, Carol 5030, 

5043, 5054 

Aghi, Manish K. 2101 

Aglietta, Massimo 530, 4110, 

9005, 10009, 10066, 

10067, e15073, e15133, 

e15192, e20512 

Agloria, Maliha e11541 

Agnelli, Giancarlo e19612 

Agnese, Doreen Marie 1125 

692s Numerals refer to abstract number

Agrawal, Kamal e14186 

Agrawal, Kireet e14186 

Agrawal, Neeraj R. 4574 

Agrawal, Nishant e16061 

Agrawal, Priya e18523 

Agrawal, Rajiv 511 

Agrawal, Ritesh e16023 

Agrawal, Shruti 2510, 

TPS2622 

Agre, Pat 9105 

Agresta, Samuel V. TPS3111 

Aguado Loi, Claudia X 1608 

Aguayo, Cristina 1570 

Aguayo-Hiraldo, Paibel I. 

6568, 6608 

Aguggini, Sergio e11546 

Aguiar Bujanda, David 7011 

Aguiar, Samuel 10069, 

e14119 

Aguila, Christian e12027 

Aguilar Marin, Ivan Carlos 

e15036 

Aguilar, Alfredo e19636 

Aguilar, José Luis 1607 

Aguilar-Mahecha, Adriana 

TPS1139 

Aguin Losada, Santiago 

e14733, e19505 

Aguirre, Lina 1558 

Aguirre, Mercedes 8572 

Agulnik, Jason Scott 6058, 

e18061, e18098, e19626 

Agulnik, Mark 5500, 10003, 

TPS10099, TPS10103 

Agus, David B. 4656, 

TPS4693 

Agustoni, Francesco 9133 

Aharonov, Ranit T. e14067 

Aharonov, Ranit 10528, 

e21008 

Ahern, Charlotte H 9500, 

9540, 9581 

Ahluwalia, Manmeet Singh 

2014, 2076, 2092, 2093, 

2096, 2100 

Ahmad, Aamir e21057 

Ahmad, Ahmad e15042 

Ahmad, Ateeq 3089^ 

Ahmad, Hilal e16057 

Ahmad, I. 3089^ 

Ahmad, Javed e20508 

Ahmad, Saif e14100 

Ahmad, Shakil e13039 

Ahmad, Syed A e14714 

Ahmadi, Hamed 4589, 

e15060 

Ahmadi, Tahamtan e18529, 

e18540 

Ahmadzadehfar, Hojjat 

e14565 

Ahmed, Alaa Abdelhalim 

e19568 

Ahmed, Asra Z. 8011 

Ahmed, Eliyaz e11053 

Ahmed, Gul e14111 

Ahmed, Mashrafi e11539 

Ahmed, Mohamed e15530 

Ahmed, Rakib Uddin e11533 

Ahmed, Sairah 8040 

Ahmed, Samreen 530 

Ahmed, Shabina Roohi 3020, 

TPS3117 

Ahn, Hanjong 4628, e15080 

Ahn, Hee Kyung 644, 7104, 

e16003, e18148 

Ahn, Ji Yeong e14504, 

e14652 

Numerals refer to abstract number 

Ahn, Jin Seok 644, 1003, 

2542, 7004, 7104, 

e14580, e18148 

Ahn, Jin-Hee TPS649, 1003, 

2542, 4544^, e11504, 

e11508, e12029, e13104, 

e13560, e15064, e15080 

Ahn, Joong Bae 3606, 

e14081, e14084 

Ahn, Myung-ju 7004, 7104, 

7533, TPS7614, e16003, 

e18148 

Ahn, Peter H. e19507 

Ahn, Sei-Hyun 578, e11504, 

e11508 

Ahn, Seung Do e18501 

Ahn, Soo Kyung 1133, 

e21160 

Ahn, Yong Chan 7004 

Ahn, Yongchel e15080 

Ahnen, Dennis J. 3567 

Ahrendt, Gretchen M. 1107 

Ahrendt, Steven Arthur 

e14184 

Ahrens, Marit 10032^, 

10046 

Ährlund-Richter, Lars 4561, 

e13518 

Ahsan, Habibul e15086 

Aiello, Rosa Anna 623 

Aigner, Julia 1096 

Aihara, Kazuyuki e15201 

Aihara, Taichi e21031 

Aihara, Tomohiko 1106 

Aiken, Christine TPS3643 

Aiken, Robert TPS2107 

Aikou, Takashi 1106 

Ailawadhi, Sikander 6605 

Ain, Kenneth B. e16035 

Airoldi, Mario 5546, 5548, 

e11524 

Aisner, Dara L 7504, 7534 

Aisner, Joseph TPS3112 

Aissat-Daudigny, Louiza 3052 

Ait-Oudhia, Sihem e14690 

Aitini, Enrico LBA5003 

Aizpurua, Miren e21021 

Ajaikumar, Basavalinga S. 

1093, e11511, e12030, 

e14675, e14721, e19619 

Ajaikumar, Basavalinga S 

e11027, e11043 

Ajani, Jaffer A. 4069, 4077, 

4078, 4081, 4086, 

e14547, e14548 

Ajavon, Yves 3547 

Ajiki, Tetsuo e14518 

Akagi, Yoshito 3558, e14077 

Akaike, Makoto 3524 

Akakura, Koichiro e15201 

Akakura, Nobuaki 3593 

Akamatsu, Hiroaki 7088, 

e21007 

Akamatsu, Hiroki 3607 

Akamatsu, Shusuke 10520 

Akard, Luke Paul 6513, 

6596, 6604, 6605 

Akay, Catherine 1102 

Akaza, Hideyuki e15004, 

e15098, e15106 

Akazawa, Kohei 1119, 

TPS1141 

Akbulut, Hakan 1572, 9050, 

e19024 

Akcakanat, Argun 1054 

Akcali, Zafer e14698 

Akdas, Atif 4 

Akdeniz, Aydan e11515 

Akewanlop, Charuwan e14051 

Akgun, Zuleyha e16015 

Akhtar, Tanveer 6612 

Akhurst, Timothy J. 3563 

Akimoto, Tetsuo 5542, 

e17554 

Akimov, Mikhail 530, 7543 

Akin, Sema 10552 

Akin, Yildiz 5578 

Akinkuolie, Akinbolaju Andrew 

e11554 

Akintayo, Adebowale O 2576 

Akita, Hirotoshi 7571, 

e17520, e18135 

Akiyama, Hirohiko 10542 

Akiyama, Hirotoshi e14047, 

e14050, e14624 

Akiyama, Nobu 9053 

Akiyama, Shoko e19611 

Akiyoshi, Kohei e14126 

Aklilu, Mebea 2561 

Akmaev, Slava 3015 

Akmaev, Viacheslav R e14593 

Akpek, Gorgun e19565 

Akpeng, Belinda 5506 

Akram, Madeeha e14658 

Akram, Muzaffar 10618 

Aksamit, Inga e14118 

Aksnes, Anne-Kirsti TPS4694 

Aksnessæther, Bjørg Yksnøy 

7027 

Aksoy, Sercan e11009, 

e11011, e11033, e11093, 

e13031, e14526 

Aktas, Bahriye 552, 556, 

624, 1077, TPS1146, 

10599 

Akula, Komala 1097 

Al Ali, Najla 6586, 6588 

Al Banna, Amr e18061 

AL Basmy, Amany e16002 

Al Husaini, Hamed Homoud 

e15530 

Al mubarak, Mustafa e15530 

Al Nasrallah, Nawar 4534 

Al Saleh, Khalid e16002 

Al Sayyad, Said e18564 

al Zoubi, Mazhar 629 

Al-Ahmadie, Hikmat 4527 

Al-Ali, Haifa Kathrin 6514^ 

Al-Ali, Haifa-Kathrin 

TPS6642^ 

Al-Ameri, Ali e17004 

Al-badawi, Ismail e15530 

Al-Batran, Salah-Eddin 4065, 

4072, 4080, 4083, 4090, 

TPS4138, 10552, e14557, 

e21063 

Al-Dalee, Abdelmuniem 

e19524, e19525, e19526 

Al-Dayel, Fouad e20508 

Al-Kali, Aref 6614 

Al-Matwari, Majid e11046 

Al-Mousa, Abdelatif e15024 

Al-muderis, Omar 10039 

Al-Muhaderis, Omar 10060 

Al-Nahhas, Adil e21093 

Al-Refaie, Waddah B. 6016 

Al-Rifai, Taha e18510 

Al-Shamsi, Humaid Obaid 

e14001, e17532 

Al-Tourah, Abdulwahab J. 

8049 

Al-Zoubi, Ammar 8011 

Alabek, Michelle 1512 

Alabiso, Oscar LBA7501 

Alalawi, Raed e21105 

Alam, Farida e18068 

Alam, Salma Moona 10039 

Alam, Salma 9589 

Alanee, Shaheen e15022 

Alarcon Rozas, Ashley 606 

Alarcon-Rozas, Ashley E. 

2531 

Alashwah, Ahmed 5557 

Alatise, Olusegun Isaac 

e12022 

Alattar, Mona Lisa 6558 

Alba, E. 4630, 10500, 

10616, e14115 

Alba, Emilio 530 

Albain, Kathy S. CRA6009, 

9018 

Albanell, Joan 10500, 10616 

Albanese, Christopher 3095 

Albani, Fiorenzo 2057 

Albany, Costantine 4534, 

e15213 

Albarel, Frédérique 8568 

Albelda, Steven 7077, 7092 

Alberghini, Marco 10022 

Alberola, Vicente 1531 

Albers, Peter 4522, 4525, 

4530, 4590, 4601, 

e15112, e15195 

Albert, Daniel 9515 

Albertelli, Manuela 1604, 

e19038 

Alberti, Antonio Maria 

e11039, e12510 

Alberti, Paola 9090 

Albertini, Mark R. e19047 

Alberts, David Samuel 5015 

Alberts, Steven R. 3514, 

3526, 3564, 3617, 

e13052 

Albertson, Tina Marie 3069 

Albiges, Laurence 601, 4540, 

4554, 4621, e15049 

Albino, Miguel E. 1060 

Albino, Vittorio e14130 

Albright, Frederick S. 6583 

Albus, Kerstin 10526 

Alcaide, Julia e14116 

Alcantara, Jose 3093 

Alcindor, Thierry 10010, 

e14020 

Alcorn, Sara 9132 

Aldabbagh, Kais 10042 

Aldape, Kenneth D. 2001, 

2002, 2003, 2019 

Alderson, Derek TPS4143 

Aldrich, Melinda C 7008 

Aldridge, Julie 8516, 9022 

Aldridge, Lynley 6111 

Aldrighetti, Luca 4110 

Aleem, Aamer 6612 

Aleixo, Sabina B. 606 

Alekseev, Boris TPS4692^ 

Alektiar, Kaled M. 9104 

Aleman, Berthe M 8039 

Alemar, Barbara 10593, 

e13546 

Alert, Jose 2515 

Alessandria, Sebastian 

e15507 

Alessandroni, Paolo 4084 

Alessi, Alessandra e21118 

Alessi, Barbara 9005 

Alexander, Brian Michael 

2005 

Alexander, Gwen e14160 

Alexander, H. Richard 8570 

Alexander, Joseph e16545 

Alexander, Maurice 6042 

Alexander, Sarah 9076 

Alexandre, Jerome 9011 

Alexandrow, Mark e21155 

693s

Alexanian, Raymond 8093 

Alexeev, Boris Y. 4501 

Alfaro, Iván E. 3072 

Alfaro, Maricarmen e19636 

Alfonsi, Marc e16044, 

e16055 

Alfonsi, Simona e14086, 

e21070 

Algazi, Alain Patrick 3102, 

8510, 8580, TPS8602, 

e19046 

Algazy, Kenneth M. e16062 

Alger, Beverly 8524 

Algret, Nathalie 9538 

Alguire, Kathryn B. 4127 

Alhan, Nurcan e11023 

Ali, Asma 1542, e19545 

Ali, Haider e14073 

Ali, Haris e15066 

Ali, Haythem Y. 5508 

Ali, Khaled B. 2081, 

TPS4684 

Ali, Maria e19527 

Ali, Mohammed Faisal 

e13053 

Ali, Mohammed Javed 9515, 

9568 

Ali, Mohammed e14132 

Ali, Sana e13053 

Ali, Sayed Sahanawaz 550 

Ali, Shadan e21057 

Ali, Shihab e18520 

Ali, Suhail M. 501, 607, 614, 

7054, 7055, e14520, 

e15062, e15121, e15170, 

e17560 

Aliaga, Luis Alberto e19576 

Aliberti, Sandra e15073, 

e20512 

Alibhai, Shabbir M.H. 6005 

Alici, Suleyman 638 

Alidzanovic, Lejla e14099 

Alikhan, Mir Asif e16513 

Alila, Hector 3060 

Alimoghaddam, Kamran 6556 

Alipour, Sina 3560 

Alistar, Angela Tatiana 

e21109 

Alizadeh, Arash A. e21071 

Aljadir, David Naji e13126 

Aljitawi, Omar Salah 10605, 

e13568 

Aljubran, Ali Husain e19524, 

e19525, e19526 

Aljumaily, Raid e17547, 

e17550 

Alkaied, Homam e14704, 

e18574 

Alkhasawneh, Ahmad e14612 

Alkhateeb, Ahmed e14520 

Alkhazna, Ammar Ali e21085 

Alkis, Necati e14526 

All-Eriksson, Charlotta 10521 

Allam, Emad S. 6079, 6081, 

e19593 

Allan, Suzanne 3022 

Allanore, Laurence 10049 

Allard, Aurore TPS5112 

Allegra, Carmen Joseph 3505, 

3579, 3602, TPS4136 

Allegrini, Giacomo 629, 

3546, e18074 

Allen, Ace e13551 

Allen, Andrew R. 4041, 

e13028 

Allen, Christian e19598 

Allen, Deborah 3031, 3087, 

3529, 5020 

Allen, Ian M. 4658, 6032, 

6037 

Allen, Jeffrey Warren 

TPS1137, 3032, 7005 

Allen, Jill N. 4021, 4027, 

e14615 

Allen, Joanna e14015 

Allen, Joshua e11544 

Allen, Pamela e14669 

Allen, Peter J 3577, 3620 

Allen, Richard Read e16541, 

e16550 

Allendorf, John e14708 

Allevi, Giovanni e11546 

Allgeier, Anouk 2 

Allison, Roger 5518, 5591 

Allmer, Cristine 9057 

Allo, Ghassan 1036, 5105 

Allo, Julio 9023, 9025, 9096 

Alloisio, Marco 7061 

Allred, Alicia J 3528 

Allred, Donald Craig 503 

Allred, Jacob B e13501 

Allum, William H. TPS4143 

Alm, Daniel 10083 

Almagro, Elena e11527, 

e12015, e17502, e17515 

Almanaseer, Imad e12002 

Alnajjar, Abdulsalam e14154 

Alnajjar, Hussain M 4640, 

e15100 

Aloia, Thomas A. 4116 

Aloisi, Alessia 5093, 5094, 

e15547, e15550, e15551, 

e15553 

Aloj, Luigi e19034 

Alonso Bermejo, Miguel 

e18040 

Alonso Martinez, Milagros 

5595 

Alonso Soler(1), Sonia 

e11543, e19596 

Alonso, Lorenzo e14115 

Alonso, M Carmen 1120, 

10555 

Alonso, Maria Carmen 

e19576 

Alonso, Paloma e11517 

Alonso, Teresa e20513 

Alonso, Vicente 3553, 3571, 

3586, e14041, e14097, 

e14671 

Alonso-Alconada, Lorena 

10534 

Alonso-Basanta, Michelle 

e12508 

Alonso-Espinaco, Virginia 

3553 

Alonso-Guadalajara, Juan 

Domingo e14671 

Alonso-Jaudenes Curbera, 

Guillermo e21002 

Alonso-Nocelo, Marta 10534 

Aloshin, Vladimir A. e19012 

Alpaugh, R. Katherine 605 

Alran, Severine e15524, 

e15535 

Alrwas, Anas e19009 

Alsamarai, Susan 6033 

Alsfeld, Leonard C e19008 

Alsibai, Khaled e16019 

Alsina, Maria 3014, 3062 

Alsina, Melissa 8012, 8035 

Altavilla, Giuseppe e18039 

Altena, Renske 4528, 

e15035 

Alter, Blanche P 5563 

Althaus, Betsy 528 

Altieri, Dario C. e13504 

Altintas, Sevilay 1129 

Altiok, Soner 10084 

Altman, Jessica K. 6520 

Altmannsberger, Hans-Michael 

e14557 

Altshuler, David 2081 

Altundag, Kadri 1572, 

e11009, e11020, e11033, 

e11080, e11092, e11093, 

e11509 

Altundag, Mustafa Kadri 

e11011, e11026 

Altundag, Ozden e11011, 

e11023, e11026, e11045, 

e11515, e14174, e15572, 

e15573 

Altwairgi, Abdullah Khalaf 

500, e11005, e19541 

Alumkal, Joshi J. 4549, 

TPS4697 

Aluri, Jagadeesh 3016 

Alva, Ajjai Shivaram 4586 

Alvarado Miranda, Alberto 

1607, e11016, e12027 

Alvarado-luna, Gabriela 

e11098 

Alvarez Bernardi, Julio 

e11028 

Alvarez Gomez, Elena e18040 

Alvarez, Carlos e18044 

Alvarez, Delia 3034, 3042^ 

Álvarez, Elena e18070 

Alvarez, Inaki e11074 

Alvarez, Isabel 10512, 

10595, e11081 

Alvarez, Lucia e15521 

Alvarez, Martina e14115 

Alvarez, Rene J 3019 

Alvarez, Ricardo H. 594, 

1102, 3010, 9072 

Alvarez, Ronald David 5036, 

5060, 5062^, e13087 

Alvarez, Ruth e11545 

Alvarez, Sonsoles e14058 

Alvarez-Gallego, Mario 1570 

Alvarez-Gallego, Rafael 4040 

Alvarez-Reeves, Marty 9007 

Alve, Abigail e19048^ 

Alvear, Maria 5078 

Alvelo-Rivera, Miguel e17528 

Alverdy, John C. 10090 

Alves, Beatriz da Costa Aguiar 

e11059 

Alves, Marclesson S. e18078 

Alves, Marcos Pantarotto 

5567 

Alvfors, Carina 7539 

Alyasiry, Amer 2525 

Alyasova, Anna 4501 

Amaadour, Lamiae e18124 

Amadio, Giulia 5059 

Amadio, Placido e15544 

Amador, Rosa Mari-a 2527 

Amadori, Dino 9005, 10601, 

10615, e11054, e17546, 

e18045 

Amakye, Dereck Dokyi 9519, 

9562 

Amalfitano, Andrea 2585 

Amalraj, Jerrin e19619 

Amant, Frederic 5071 

Amarantidis, Kiriakos e14567 

Amaravadi, Ravi K. 3029, 

3102, e13604 

Amarti, Affaf e11502 

Amato, Robert J. e15124 

Amatruda, Thomas 2569 

Amatu, Alessio 3570 

Amaya De Carrillo, Carla 5096 

Amaya, Alex 2555, TPS3110 

Ambady, Prakash e11085, 

e12509 

Ambinder, Richard F. 8003 

Ambros, Peter F 9583 

Ambros, Tadeu Frantz 595, 

e11038 

Ambrose, Robert e15138 

Ambrosini, Grazia 8598 

Ambrosone, Christine B. 

e11563 

Amdur, Richard 8103 

Amela, Eric 10027, e14560 

Ameri, Pietro e19038 

Ames, Matthew M. 9581, 

e13086 

Ames, Patricia 4052 

Ameye, Lieveke e18006 

Amiel, Gilad TPS4678 

Amillano, Kepa 1011 

Amin, Asim e13088 

Amin, Hesham M. 3107^ 

Amin, Mahul 10584 

Amin, Shahla e17009 

Amin, Shubarna 6087 

Amini, Arya 7043, e14669 

Amir, Eitan 558, 1597, 4535, 

6043, e13001 

Amir, M I 7009 

Amiri-Kordestani, Laleh 2548, 

e13122 

Amler, Lukas C. 2568, 5575, 

e13048 

Amling, Christopher L 2564 

Ammendola, Michele e21113, 

e21134 

Amodu, Leo 10061 

Amonkar, Mayur 604 

Amoroso, Domenico e18074 

Amoruso, Alessia e14156 

Amos, Christopher I. 1520 

Ampil, Fred e11541, e16009 

Ampollini, Luca e17546 

Amrane, Selma e16546 

Amrein, Philip C. 6526, 

6606, 6617, 6618, 6621, 

6629 

Amstutz, Platte T 6581, 

e21079 

Amthauer, Holger TPS4148 

Amtmann, Dagmar 9008 

An, Hojung 10093, e11504 

An, Shejuan 7039, e18090 

An, Sungwhan 3606 

An, Tongtong 7537, 7545, 

e18022, e18035 

Anagnostopoulos, Ioannis 

8030 

Anaissie, Elias J. e18555, 

e18576 

Anak, Ozlem 3099 

Anaka, Matthew 8542 

Anan, Keisei 588 

Anand, Aseem 4516, 4562 

Anand, Banmeet 4568 

Anastasopoulou, Eleftheria 

625, 2508, e15125 

Anastassopoulos, Kathryn P. 

e18559 

Anaya, Daniel A. 10000 

Anchineyan, Pichandi e19619 

Anchisi, Sandro 9059, 

e11048 

Ancukiewicz, Marek 1026, 

2009, 2010, 4112 

Anderes, Kenna Lynn 

e13562, e13575, e13577, 

e21058 


Andergassen, Ulrich 1072, 

1600^, 10540 

Anders, Carey K. TPS656, 

1524 

Anders, Robert e14538 

Andersen, Mads Hald 2565, 

2574 

Andersen, Peter e16045 

Andersen, Rikke Fredslund 

3573 

Anderson, Abraham 4005 

Anderson, Clay M. 8534 

Anderson, Garnet L 1501, 

5015 

Anderson, James Robert 9535 

Anderson, John 4509 

Anderson, Kenneth Carl 8016, 

8043, 8106, TPS8112, 

TPS8113 

Anderson, Lee 8592 

Anderson, Lynn 9530 

Anderson, Mark Daniel 2030 

Anderson, Matthew L. 2558 

Anderson, Michelle A e14578 

Anderson, Peter Meade 

10021 

Anderson, Richard 1094 

Anderson, Roger T. 6052 

Anderson, S. Keith 2015 

Anderson, Sonya 9134 

Anderson, Stewart J. TPS657 

Anderson, Tara B. 8011 

Anderson, William F. 1603 

Andersson, Michael TPS653 

Andersson, Roland 4041 

Ando, Kiyoshi 6527, 8023, 

8029 

Ando, Koji e14033, e14601 

Ando, Masahiko 6112, 7003, 

7000, 10577, e18128 

Ando, Masahiro 7565 

Ando, Masashi 10519, 

e19535 

Andrade, Felipe e11513 

Andrade, Gabriela Maria 7008 

Andre, Charles 2070 

Andre, Elisabeth 10031 

Andre, Fabrice 515, 543, 

TPS648, TPS667, 1091, 

TPS1148, 1601 

Andre, Maria do Rosário 

e13119 

Andre, Thierry 2537^, 

LBA3500^, CRA3503, 

3506, 3535, e14650 

Andreas, Karen 7556 

Andreas, Stefan 7001 

Andreason, Molly 555, 563, 

6063 

Andreeff, Michael 6576, 

6585, TPS6635 

Andreetta, Claudia 1044, 

e13058, e13070 

Andreis, Daniele e11546 

Andreis, Federica e14018 

Andreoli, Claudio 1500 

Andreopoulou, Eleni 515, 

e11010 

Andreou, Cal 4550 

Andres, Bianca 10041^ 

Andres, Christian 8563 

Andres, Raquel 1001, 10052 

Andresen, Corina TPS4682, 

5591, 8594 

Andreu, Monica e11028 

Andrews, Barry 8056 

Andrews, Bethany Michelle 

e16038, e19534 

Andrews, James 1608 


Andrezalova, Iveta e19020 

Andria, Michael L e14028 

Andriole, Gerald L. 4646 

Andritsos, Leslie A. 6508 

Andrulis, Irene L. 1502 

Andrulis, Mindaugas 6519 

Andrykowski, Michael A. 

e16564 

Ang, Celina 3577 

Ang, Joo Ern 5022 

Ang, K. Kian 5530, 5561, 

5583, 5589 

Ang, Mei-Kim 3098, 5551, 

5580, e16024 

Ang, Siok Hoon 5551, 5580 

Angelico, Mario TPS4151 

Angelini, Francesco e18065 

Angelov, Lilyana 2018 

Angelsen, Anders 4508 

Angelucci, Michela 5093, 

5094, e15547, e15550, 

e15553 

Angevin, Eric 2583 

Anghileri, Elena 2083 

Angioli, Roberto 5093, 5094, 

e15547, e15549, e15550, 

e15551, e15553 

Angiolillo, Anne L. 9543 

Angiuoli, Samuel V. 3068 

Anglaret, Bruno 8014 

Angleitner-Boubenizek, Lukas 

5080 

Angrilli, Francesco 8006 

Anguera, Georgia e15159 

Anguille, Sébastien 2506, 

e13051 

Angulo, Patricia e19618 

Anido, Urbano e14733, 

e15067, e15076, e15077, 

e15079, e19505 

Ann, Mi Sun e18519 

Anne, Pramila R. 3621, 

e11505, e19507 

Annecke, Katja 1072, 1081 

Annels, Nicola E. 4653, 

e15517 

Annesi, Diego 8513 

Annetta, Alessandro e19002 

Annunziata, Christina M. 

2545 

Annunziata, Mario 6603, 

9120 

Anract, Philippe 10056 

Ansa, Benjamin 5570 

Ansari, Aziz e19588 

Ansari, Daniel 4041 

Ansari, Rafat H. 7555 

Anschuetz, Julia e15566 

Ansell, Peter J e13583 

Ansell, Stephen Maxted 8043, 

8053, 8060 

Anselmetti, Giovanni Carlo 

e20512 

Anshushaug, Malin 9040 

Anson-Cartwright, Lynn 4535 

Antelo, Maria L e21086 

Anthoney, David Alan 2552 

Anthony, Lowell Brian 

e14610 

Anthony, Stephen Patrick 

TPS1143, TPS3111 

Antic, Vladan TPS7615 

Antoine, Eric-Charles e11019 

Antoine, Martine e18075, 

e18089 

Antolino, Giusy e17006, 

e18563, e18566 

Antón Aparicio, Luis M. 

e15076, e15077, e15079, 

e15112 

Anton, Antonio 1001, 10512, 

10595 

Antón-Aparicio, Luis e14595, 

e21002 

Antonarakis, Emmanuel S. 

4559, 4654, TPS4697, 

e15188 

Antonelli, Giovanna e18002 

Antonescu, Cristina R. 

10001, 10019 

Antonescu, Cristina 10002, 

10003 

Antoni, Giorgia 9006, e19634 

Antonia, Scott 2501, 

CRA2509, 2559, TPS2620, 

7065, 7509, e17559 

Antonio, Anna Liza M 6105 

Antonio, Heriton MR 1075 

Antoniotti, Carlotta 3518, 

3540, 3546, 3549, 3585 

Antoniou, Antonis C. 1545 

Antoun, Sami 4621, 5569, 

9026^, e13118 

Antsaklis, Aris 5033 

Antunes, Ana e18111 

Antunes, Luis Carlos Moreira 

e14597 

Antunez de Mayolo, Jorge 

7546 

Anwar, Muhammad Suhail 

e15534 

Anyang, Bean N. 1070 

Anyang, Bean 7022 

Aoe, Keisuke 7042 

Aoki, Daisuke 5003 

Aoki, Yoichi 5086 

Aparicio Gallego, Guadalupe 

e15076, e15077, e15079 

Aparicio, Ana 4533, e15092 

Aparicio, Jorge 3586, 3618, 

10082, 10547, e14097 

Aparicio, Luis Anton e14671, 

e15067, e15149 

Aparicio, Thomas 4018, 4091 

Aparisi, Francisco e17545, 

e18049, e18053 

Aparo, Santiago e14019, 

e14682 

Apelian, David TPS3638, 

e14501 

Apisarnthanarax, Smith 7098, 

e18032 

Aplenc, Richard 1504 

Apolikhin, Oleg TPS4692^ 

Apollinari, Serena e13098 

Apollo, Arlyn J. 4057 

Apolo, Andrea Borghese 

3043, 4569, 4581^, 4592, 

10589 

Aponte, Luis 10074 

Apostolikas, Nikiforos e11519 

Appel, Burton 9524 

Appelbaum, Frederick R. 

6502 

Apperley, Jane 6503, 10550 

Appignanesi, Remo 9098 

Appleman, Leonard Joseph 

TPS1138, 2553, 3019, 

3037, 3049, 3054, 

e13576 

Aprile, Giuseppe 3518, 3546, 

3549, 3555, 3612, 

TPS3637, e14040 

Aqua, Keith A. e15546 

Aquilina, Michele e11054 

Aquino, Luciana Carla Martins 

de e14027 

Aragaki, Aaron K 1501 

Aragon-Franco, Raul e15584 

Arai, Daisuke e18058 

Arai, Roberto J. e11513 

Arai, Yasuyuki e15065, 

e15069 

Araki, Nobuhito 10009, 

10067 

Araki, Toshimitsu e21053 

Arance, Ana M 8517 

Arance, Ana Maria e19023 

Aranda, Enrique 3571 

Aranda, Sanchia 9124 

Arantes, Heloisa 606 

Arastu, Nabeel H. 6093 

Araten, David J. e21082 

Araujo, Bertha Catherine B. 

e16046 

Araujo, Dejka M. 10071, 

e19520 

Araujo, John C. e15151 

Arauz, Gabrielle 4548, 

TPS4697 

Aravantinos, Gerasimos 5033 

Araya, Tomoyuki e17540 

Arbani, Tammy TPS661 

Arbaud, Alexandre TPS9154 

Arber, Daniel 6072 

Arber, Nadir 1507, 1564 

Arcaini, Luca 8006 

Arcamone, Manuela 8066 

Arcasoy, Murat O. 6624 

Arce, Claudia e11016 

Archila, Pilar e18114 

Arcila, Giovanna e19604 

Arcila, Maria E. 7532, 7578, 

10560 

Arcos, Rebecca 3001 

Arcury, Justin T. e14724 

Arcusa Lanza, Angels 10500, 

10616 

Ardavanis, Alexandros 625, 

2508, 10606, e11073, 

e21098 

Ardenkjaer-Larsen, Jan Henrik 

4660 

Ardizzone, Antonino e11001 

Ardizzoni, Andrea e18021, 

e18096 

Arellano, Martha Lucia 6520 

Arena, Francis P. 559, 

TPS4134 

Areses Manrique, Carmen 

e18040, e18146 

Aresti, Unai e17522, e21009 

Argiles, Guillem 3005, 3014 

Argiris, Athanassios 2610, 

3049, 3073, 5541 

Arguello, David 1040, 10630 

Argyriou, Andreas 9090 

Arias, Fernando e14057 

Arias-Pulido, Hugo 5549 

Arican, Ali e15104 

Arifi, Samia e11502, 

e11516, e14725, e14726, 

e18124 

Ariga, Takuro e15533 

Arik, Zafer e11009, e11033, 

e11093, e13031 

Arima, Yoshimi 635 

Arin-Silasi, Dan 5099, 

e15581 

Aristarco, Valentina 519 

Arita, Shuji 3045 

Ariyan, Charlotte Eielson 

8583 

695s

Arkenau, Hendrik-Tobias 

2540, 3000, 3041, 3097, 

e13585 

Arkhiri, Peter e20501 

Arlen, Aimee Ginsburg 

e16536 

Arlen, Philip M. 2517, 3043, 

4569 

Armaghany, Tannaz e14667, 

e16009 

Armakolas, Athanasios 583 

Armand, Corine e15109 

Armendariz, Pedro e14057 

Armengol Alonso, Alejandra 

e15567 

Armenian, Saro 9505 

Armitage, James O. 8047 

Armstrong, Andrew J. 4515, 

4519^, 4550, 10533 

Armstrong, Anne 530 

Armstrong, Dawn Elizabeth 

e14073 

Armstrong, Deborah Kay 

5062^, 9103 

Armstrong, Elizabeth 

TPS4134 

Armstrong, Graham 4121 

Armstrong, Gregory T. 6030, 

9505, 9514, 9528, 9531 

Armstrong, Joanne 1608 

Arnal, Francisco e21002 

Arnaldez, Fernanda Irene 

9511 

Arndt, Diane 3013 

Arnedos, Monica 1091, 1601 

Arneson, Thomas J. 4659, 

e15169 

Arnold, Andrew Michael 7511 

Arnold, Angela G. 5043 

Arnold, Dirk CRA3503, 4090, 

4095^, e14162 

Arnold, Julie 3567 

Arnold, Susanne M. e16035, 

e21000 

Aroch, Ilan 1564 

Aron, Monish e15060, 

e15171 

Aronow, Mary E 8071 

Arons, Evgeny 2503^ 

Aronson, Melyssa 5026 

Arora, Amit 3545 

Arora, Madan L. 3619, 

e14045, e15554 

Arora, Neeraj K 9130 

Arora, Rajender Singh 

TPS649 

Arora, Reety 8577 

Arora, Sameer e14694 

Arowolo, Olukayode Adeolu 

e11554 

Arpaci, Erkan e14526 

Arpaci, Fikret 6550 

Arpino, Grazia TPS654^, 

1554 

Arqueros, Cristina e15159 

Arra, Claudio e11052, 

e13539 

Arrabal, Rafael 7011 

Arranz Arija, Jose Angel 

TPS4672, TPS4674 

Arranz, Jose Angel TPS4685, 

e15041 

Arranz, Juan Luis 5520, 

e15094, e18069, e18106, 

e21015 

Arriaga, Yull Edwin e15066 

Arrichiello, Cecilia e14130 

Arrieta, Oscar 1607, 7068, 

e18028, e18114, e19594, 

e19618 

Arrighi, Giada 629 

Arrigo, Carmela e18039 

Arrigoni, Pierre Paul 2082 

Arrington, Amanda Kathleen 

1117 

Arriola, Edurne 7554 

Arrossi, A. Valeria e18085 

Arrowsmith, Edward 8556 

Arroyo, Gerardo F. e14521 

Arsenault, Daniel M. e16518 

Arsenault, Youri e13027 

Arslan, Bulent e14610 

Arslan, Cagatay e11011, 

e11020 

Arslan, Deniz e14070 

Arsov, Christian e15195 

Artac, Mehmet e11008 

Artal, Angel e12000, 

e12012, e18011 

Arteaga, Carlos L. 510, 605, 

1024, 1054 

Arteta-Bulos, Rafael e21077 

Arthur, Chris 6559, 6627 

Arthur, Diane Carol e18568 

Arthur, Douglas W. TPS657 

Artigiani-Neto, Ricardo 

e14657 

Artignan, Xavier e15131 

Artioli, Fabrizio e11071 

Artioli, Grazia e12037 

Artru, Pascal 4018, e14129 

Artz, Andrew S. 6535^, 

6562, e13120^ 

Arun, Banu 1518, 1546, 

1549, e11090 

Arya, Monica 6561 

Arya, Nikita 8518 

AS, Kirthi Koushik e11536 

Asaad, Razan e14704 

Asad, Sultan 6612 

Asada, Yukinori e16020 

Asahina, Hajime 7086, 

e18135 

Asami, Kazuhiro 7521, 

10577 

Asano, Michio TPS10632 

Asanuma, Hiroshi 9569 

Asanuma, Taku e14011 

Asatiani, Ekatherine TPS3118 

Asch, Adam Steven e17008 

Asch, Steven M 6105 

Asche, Carl V e14106, 

e14141, e14146, e15183, 

e18097 

Asche, Julia 4115 

Aschebrook-Kilfoy, Briseis 

8072 

Aschele, Carlo e17533 

Ascherman, Jeffrey 6118 

Ascierto, Maria Libera 8576, 

10565 

Ascierto, Paolo Antonio 8501, 

8502^, 8511, 8513, 8517, 

8518, 8529, 8539, 8573, 

8581, 10565, e19034 

Asero, Salvatore e15544 

Ashcroft, John 8015 

Ashfaq, Raheela 1040, 

10630, e13571 

Ashkenazi, Avi 3543, 3552 

Ashkenazi, Karin 10528, 

10575, e21008 

Ashley, David M 9519 

Ashley, Pandora e11069 

Ashley, Sue 10086 

Ashman, Jonathon 6108 

Ashraf, Noman e14715 

Ashton-Prolla, Patricia 1522, 

10593, e13546, e21042 

Ashur-Fabian, Osnat e19573 

Ashworth, Alan 3050, 5035 

Asin, Gemma e14057 

Askenazi, Manor 6136 

Askin, Dudu e11008 

Asmis, Timothy R. e14154 

Asnacios, Amani 4018 

Asrari, Fariba 1128 

Assadourian, Sylvie 3579 

Assaker, Richard 2070 

Asselain, Bernard 8546 

Asselin, Barbara 9504 

Assenat, Eric 3633, 4032 

Assikis, Vasily J. 4550 

Assis, Joana e15532 

Assmann, Gunter 1523 

Assmus, Joerg 4015 

Assouline, Sarit E. 2547, 

8064 

Astl, Dorothea e13040 

Astolfi, Annalisa 10087 

Astone, Antonio e14156 

Astudillo, Horacio e11565, 

e15584 

Astudillo, Julio 7011 

Ata, Alper e15104 

Ataee, Mari 6556 

Ataergin, Selmin 6550 

Atagi, Shinji 7003, 7017, 

10577, e19556 

Atallah, Ehab L. 6582 

Ataman, Ozlem e14015 

Atanackovic, Djordje 2573^, 

4095^, 7013 

Atasever Akkas, Ebru e16005, 

e19575 

Atasoy, Beste Melek e16015 

Atassi, Bassel e16019 

Atefi, Mohammad e13045 

Atencio, Liezl 1592 

Ates, Can e20000 

Athanatou, Evangelia e19610 

Atherton, Pamela J. 6108, 

6133, e16572 

Atias, Dikla e14646 

Atif, Hesham 5557 

Atilgan, Alev e11023 

Atkins, Barbara McCormick 

7531 

Atkins, James Norman 

LBA506, TPS657, 

LBA1000, 3545 

Atkins, James LBA4007 

Atkins, Michael B. CRA2509, 

4500, 4505, 4543, 4606, 

4635, 8504, 8516, 8527, 

8569 

Atkinson, Bradley J. 4615 

Atkinson, Thomas Michael 

9144, e19633 

Atluri, Prashanti e13109 

Atmaca, Akin e14557 

Atmadini, Maizaton e15091 

Atreya, Chloe Evelyn 3517 

Attal, Michel 8009 

Attar, Eyal C. 6526, 6606, 

6617, 6618, 6621, 6629 

Attard, Gerhardt 4553, 

e15134, e15136 

Attassi, Mared e14565 

Attiyeh, Edward F. 9533 

Attner, Per e16048 

Attwood, Kristopher e11563, 

e15042, e15204, e19568 

Atwal, Siminder e21122 

Atwan, Manal e14117 

Atwood, Todd 10629 

Atzema, Clare 6039 

Au, Joseph Siu-kie 1534 

Au-Yeung, George e15541 

Aubry, Regis e19623 

Auby, Dominique 3506 

Auchus, Richard J 4645 

Aucoin, Nathalie LBA3500^ 

Audet, Robert e21099 

Audhuy, Bruno 6633 

Audigier-Valette, Clarisse 

TPS7112 

Audretsch, Werner e11556 

Auerbach, Martin 10012 

Auerbach, Michael e19609 

Auger, Nathalie 10556 

Augustin, Doris 552, 1072, 

1081 

Augustine, Christina K. 

10563 

Augustine, Titto A e14019 

Auliac, Jean Baptiste e16560 

Auliac, Jean-Bernard 1574 

Ault, Patricia e19589 

Aumont, Maud 2082 

Aung, Fleur M 6622 

Aung, LeLe e20003 

Aung, Thinzar 3589, e14155 

Aura, Claudia 509, 566, 

1011, 3014, 7041, 10511 

Aurer, Igor 8002 

Auriemma, Alessandra 

e14661 

Aurilio, Gaetano 546, 1049, 

1115 

Aussilhou, Beatrice 3609 

Aust, Daniela Ellen 4053 

Austin, Frances e14184 

Austin, J. Max e13087 

Austin, Melissa 5515 

Austin, TaShara e14617 

Autier, Philippe 1509 

Autio, Karen A. 4517 

Autran, Didier 2060 

Auziere, Sebastien e15198 

Avallone, Antonio e14040 

Avancha, Kiran Kumar 

Venkata Raja e15107, 

e16525 

Avella, Antoni e11036 

Avenia, Bettine TPS6638 

Averbook, Bruce Jeffrey 8522 

Avery, William 4056 

Avet-Loiseau, Herve 8014 

Avgerinos, Costas e14625 

Aviles-Salas, Alejandro 

e18028 

Avino, Robert J. 6079 

Avisar, Noa 9125 

Avivi, Camila e14646 

Avril, Marie-Françoise 8578, 

e21014, e21046 

Avritscher, Rony 10559, 

e14664 

Avsar, Emin 7543 

Avuzzi, Barbara e21118 

Awad, Ola 10025 

Awada, Ahmad 535, TPS652, 

TPS1140^, 3018^, 

e13594, e13605 

Awais, Omar 7074 

Awan, Farrukh Tauseef 6573, 

8108 

Awan, Tashfin 6612 

Awane, Hiroaki e14518 

Awasthi, Sanjay e13557 

Axelrod, Rita 7512, TPS7619 

Axelson, Magnus 7539 


Axiotis, Constantine A 

e18504 

Ayala, Francisco 4587, 

e11024 

Ayala-Ramirez, Montserrat 

4641 

Ayan, Inci 9567 

Ayanian, John 6006 

Aydin, Kubra e14698 

Aydogan, Fatma e14628 

Ayello, Janet e13022, 

e21150 

Ayers, Mark 3531, 3587, 

4054 

Ayerza, MIguel Angel 10074 

Ayhan, Ali e15572, e15573 

Aykan, Faruk e14628 

Ayuso Sacido, Angel 3601, 

e14093, e14144 

Ayuso, Juan Ramón 3536, 

e14097 

Ayyildiz, Veysel e11509 

Azad, Abul Kalam 1535, 

6005, 7586, 10522 

Azad, Nilofer Saba 2517, 

2545, 3009, 3016, 3020, 

TPS3117, 3616 

Azada, Michele e18140 

Azam, Faisal e11053 

Azar, Catherine A. LBA506, 

LBA1000 

Azar, Riad e14584 

Azaro, Analia 2042, 3005, 

3014 

Azcona, Eider e18031 

Azer, Mary W. F. 8558 

Azevedo, Carolina e14183 

Azevedo, Isabel 5567 

Azevedo, Renata Guise Soares 

e19552 

Azevedo, Sergio Jobim 

TPS4135 

Azim, Hamdy A. e18570 

Azinovic, Ignacio e16000 

Aziz, Noreen 6006, 6008, 

9130 

Aziza, Richard 4618 

Azizi, Amedeo A. TPS9596 

Azizi, Michel 1095, 5067 

Azkona, Eider e11525, 

e21009 

Aznab, Mozaffar 6556 

Aznar, Marianne Camille 

e18527 

Azodi, Masoud 5099, 

e13125, e15526, e15581 

Azuma, Haruhito e15000, 

e15048 

Azuma, Koichi e18060 

Azuma, Mizutomo 4026, 

4088 

Azzarello, Giuseppe 5513 

Azzoli, Christopher G. 7010, 

7014, 7052, 7066, 7527 

Alvarez Gallego, Jose Valero 

e11081 

B 

Baar, Joseph TPS655 

Baas, Paul 7081 

Baba, Hideo 3558, 10523, 

e13553, e21084 

Baba, Tomohisa e19583 

Baba, Yoshifumi 10523, 

e13553 

Babacan, Nalan Akgul 

e16005, e19575 

Babacan, Taner e11026, 

e11080 


Babakoohi, Shahab 7087 

Babal, Pavel e15027 

Babb, Sheri 1520 

Babich, John W. e13592 

Babiera, Gildy 594, 1028, 

1102 

Babigumira, Joseph e14525 

Babirak, Loren 6617, 6618 

Babu, Thambidurai Ganesh 

e13002 

Bacanu, Florin 9046 

Baccarani, Michele 6503, 

6504, 6513, 6531, 6596, 

6604 

Baccelli, Irene 1090 

Bach, Bruce A. 5504^ 

Bach, Ferdinand 2033, 2515 

Bach, Peter 6101 

Bacha, Jeffrey A. e13123 

Bachelot, Thomas Denis 

TPS646 

Bachelot, Thomas 10562 

Bachet, Jean Baptiste 10078 

Bachet, Jean-Baptiste 2537^, 

e14059 

Bachir, Jeanette TPS9596 

Bachleitner-Hofmann, Thomas 

3510, TPS10632 

Baciewicz, Frank e17528 

Back, Anthony 9008, 9101, 

9139 

Back, Michael e12507 

Back, Ronald R e14505 

Backen, Alison e14015 

Bacon, Ludwing e12027 

Bacus, Sarah S. e21120 

Badalamenti, Giuseppe 

LBA10008, 10063 

Badarinath, Suprith 

TPS3635^ 

Badger, Heath D. TPS1136 

Badgwell, Brian D. e19563 

Bading, James R 639 

Badoual, Cecile 5554, 

e13578 

Badoux, Xavier C. 6516^ 

Badovinac Crnjevic, Tanja 

e21126 

Badreldin, Waleed 4529 

Badri, Nadia 10047 

Badros, Ashraf Z. 8086, 

e19565 

Badurak, Pawel e12011 

Badve, Sunil S. 505, 1005, 

1021, 7032, 7106, 7107, 

7108, 10628 

Badwe, Rajendra A. 1108, 

e11552 

Bae, Jeong Mo 3624 

Bae, Kyun Seop 3592 

Bae, Kyun-Seop e13104, 

e13560 

Bae, Sang Byung e19554 

Bae, Sang-Byung e14688 

Bae, So Hyun 2041 

Bae, Sung Hwa e14570 

Bae, Susie e16516 

Bae, Woo Kyun e14649 

Bae-Jump, Victoria Lin 2591, 

5009, 5050, 5092, 

e15511 

Bae-Jump, Victoria e13063 

Baehner, Frederick L. 1005, 

1021 

Baek, HeeJong e17523 

Baek, Jeong-Heum e14137 

Baek, Ji Yeon e14072 

Baek, Jin Ho 6536, 6538, 

e18533 

Baek, Sun Kyung e14128 

Baena, Jose Manuel 10608, 

e11535, e21088 

Baer, Maria R. 6611, 

e16519, e16537 

Baerlocher, Gabriela M 6510 

Baertschi, Daniela 3595 

Baez-Diaz, Luis LBA506 

Baeza, Mario R. e14002 

Baffert, Sandrine TPS667 

Bagal, Bhausaheb Pandurang 

9559, e17003 

Bagalà, Cinzia e14156 

Bagatell, Rochelle 9500, 

9540 

Bagga, Dilprit 595 

Baggerly, Keith 1047 

Baghmar, Saphalta e18573 

Baglin, Anne Catherine 

e16013 

Baglioni, Michele 3061 

Bagnardi, Vincenzo 546, 

1049, 1115 

Bago-Horvath, Zsuzsanna 

10570, e21033 

Bague, Silvia 10052 

Bahary, Nathan 3545, 4022 

Bahassi, El Mustapha e16017 

Bahl, Ankur 5540 

Bahleda, Rastilav 3080, 4614 

Bahleda, Rastislav 3000, 

3012, 3104 

Bahlis, Nizar J. 6548, 8035 

Bahn, Duke e15212 

Bahrami, Armita e13544 

Bai, Hua 7537, 7545, 

e18022, e18035 

Bai, Li-Yuan e17014 

Bai, Shuang 2567, e13000 

Bai, Wei e14009 

Bai, Yuxian 4008 

Baichwal, Vijay R. e13581 

Baig, Hana e19015 

Baiget, Montserrat e14104, 

e18057 

Bailador, Gonzalo 1570 

Baile, Walter F. 9049 

Bailey, Clyde 8041 

Bailey, Howard Harry 520, 

9039 

Bailey, Leighann 2090^, 

2094^ 

Bailey, Stuart 7543 

Bainbridge, Daryl 6035 

Bains, Manjinder e15189 

Bains, Manjit S. 4061 

Bains, Puneet 6572 

Bains, Sarina e19641 

Baiocchi, Robert A. e18508 

Bair, A H. 4503 

Baird, Kristin 9545 

Baird, Richard D 3100 

Bajetta, Emilio LBA4001 

Bajor, David e18529 

Bajorin, Dean F. 4527, 

4581^, 4592, TPS4673, 

e15022 

Bajpai, Jyoti e13068 

Bajrami, Ilirjana 5035 

Bak, Sharon 6097 

Baka, Margarita e20002 

Bakacs, Tibor e13102 

Bakalarski, Pamela 4098 

Bakalian, Silvin e13017 

Baker Neblett, Katherine 

e15085 

Baker, Dave 9533 

Baker, Jackie S. 4077 

Baker, Kevin Scott e16502 

Baker, Marshall e14642 

Baker, Sharyn D. 2549 

Bakhru, Arvind 5055 

Bakhshi, Sameer 9549, 

9551, 9580 

Bakkar, Rania 10510 

Bakkum-Gamez, Jamie 

Nadine 5004 

Bal, Wieslaw e14159, 

e21049 

Balaa, Fady e14154 

Balabanov, Stefan 4590 

Balakrishnar, Bavanthi 550 

Balana, Carmen 2045, 

10079, e12504 

Balar, Arjun Vasant 4581^ 

Balasa, Balaji 8087 

Balasubramaniam, Sanjeeve 

2548, 2553 

Balasubramanian, Sohail 

3533 

Balasubramaniyan, 

Veerakumar 2002 

Balboni, Michael J. 9116, 

9132 

Balboni, Tracy A. 5579, 

9116, 9132 

Balcaitis, Stephanie 2585 

Balch, Glen C. e14165 

Balchin, Katelyn 6083, 

e19527 

Balci, Derya e18552 

Balci, Pinar e11507 

Balcueva, Ernie P. 9001 

Baldassarre, Randall L 7043 

Baldassarri, Paolo e14096 

Baldazzi, Valentina e15185 

Baldelli, Anna Maria 4084 

Baldelli, Elisa e18101, 

e21094, e21096 

Baldeos, Raquel e19636 

Balderi, Segio e18096 

Baldi, Giacomo G. 10063 

Baldi, Giacomo 10053, 

10065 

Baldini, Capucine e11070 

Baldini, Federica e19035, 

e19036 

Baldino, Giovanni e14094 

Baldotto, Clarissa Serodio Da 

Rocha 7506 

Baldotto, Clarissa Serodio 

e17548 

Baldueva, Irina Alexandrovma 

e13059 

Baldus, Stephan e11556, 

e14527 

Baldwin, Gouri e13507 

Baldwin, Graham e15117 

Bale, Allen E 1540 

Balen, Enrique e14057 

Balint, Joseph 2585 

Balis, Frank M. 9500, 9576 

Balk, Steven P. 4520, 4521 

Balko, Justin M. 510, 1024 

Ball, David 3590, e16538 

Ball, Douglas Wilmot 3020, 

TPS3117, 5508, 5518, 

5591 

Ball, Graham 1098 

Ball, S e13522 

Ballal, Shaila TPS3634 

Ballard, David 1046 

Ballatore, Valentina e15073, 

e15133 

Ballatore, Zelmira e21070 

Balleine, Rosemary L 550 

Balleisen, Leopold 6610 

697s

Ballen, Karen K. 6606, 6617, 

6618, 6621, 6629 

Ballester Navarro, Inmaculada 

4587 

Balleyguier, Corinne 5028, 

10098 

Ballman, Karla V. 4565, 

6015, 7008 

Ballo, Harald 3 

Ballot, Josephine 615 

Bally, Olivia 8068 

Balmaña, Judith 509, 566, 

619, 1009, 1011 

Balogh, Agnes 8508 

Balsells, Josep e21035 

Balser, Christina 3 

Balusu, Ramesh 10549 

Balvers, Melan 3059 

Balzarini, Luca 2580 

Bamberg, Michael e16033 

Bambury, Ian Garfield 5032 

Bambury, Richard Martin 

2062, e11569, e15078, 

e16506 

Bambury, Richard e19059 

Bamia, Christina e15040 

Bamias, Aristotelis 4524, 

4577, LBA5002^, 5033, 

e15040 

Bamlet, William R e14594 

Bampo, Chiara e21118 

Banasiak, James 6088 

Banat, Andre G. 3 

Banavali, Shripad 9559 

Bancroft, Elizabeth 1545, 

4653 

Banda, Deliya e16543 

Bandali, Nesan e15177^ 

Bandekar, Rajesh 2583, 

8018^ 

Bandman, Olga TPS4699 

Bando, Etsuro e14635 

Bando, Hideaki 3079, 

e14038 

Bando, Inmaculada e14147 

Bandos, Hanna LBA506, 

TPS1615 

Bandres, Eva e14057 

Banek, Severine e15195 

Baneke, Alex e14696 

Banerjee, Mousumi 6056 

Banerjee, Nila 10508 

Banerjee, Prajna 10513 

Banerjee, Susana N. 3048, 

5012, 5022 

Banerji, Aleena e18520 

Banerji, Udai 3004, 3022, 

10525 

Banez, Lionel Lloyds 4670 

Bang, Bhavesh Amarnath 

e12014 

Bang, Hyun J e15081 

Bang, Yung-Jue 3076, 3624, 

4081, 4118, 4124, 7508, 

e14136, e14572 

Bangerter, Markus TPS3639 

Banks, Phillip Lee 4085, 

e14564 

Bannan, Michael 8589 

Banni, Sebastiano e19634 

Bannykh, Serguei I. 2080 

Bansal, Anuj Kumar 9549, 

9551 

Banwait, Ranjit 8043 

Banys, Malgorzata 5042, 

e21003 

Banzet, Michelle 1562 

Bao, Ting 1039, 9103, 

10572 

Bao, Weichao 2543 

Bapsy, P P e21132 

Bar Yehuda, Sara e14731 

Bar, Jair e13541, e17509 

Bar-Ad, Voichita e19507 

Bar-Hanna, Micha e18511 

Bar-Joseph, Hadas e13080 

Bar-Sela, Gil 9052 

Barabe, Frederic 634 

Baracos, Vickie E. 4621, 

5569 

Baracos, Vickie E e13118 

Barahona, Nancy 4006 

Baranda, Joaquina Celebre 

4010 

Baranger, Bernard e15524 

Baranzelli, Marie-Christine 

2070 

Barash, Steven 9125 

Barath, Sandor e21140 

Barbachano, Yolanda 

LBA4000, e14088 

Barbareschi, Mattia e21102 

Barbas, Coral e15111 

Barbazan, Jorge 10534 

Barbee, Meagan Spencer 

e18553 

Barber, Beth e19043, 

e19044, e19045, e19060 

Barber, Emma L. 5039 

Barber, Jim 4509 

Barber, Kenya TPS4698^ 

Barbera, Lisa Catherine 6039 

Barberi, Simona e11514 

Barberis, Massimo 4120, 

7023 

Barbi, Stefano 4076 

Barbieri, Antonio e11052, 

e13539 

Barbieri, Elena 614, 631 

Barbieux, Hubert 1574, 

TPS7111 

Barboriak, Daniel TPS10635 

Barbour, Andrew TPS4145 

Barboza Quintana, Oralia 

e15525 

Barbui, Tiziano 6514^, 

6625^, 6626^ 

Barbuto, Anna Maria 3559 

Barcenas, Carlos Hernando 

612 

Bardia, Aditya 1122, 9103 

Bareiss, Petra M. e15577 

Barfield, Michael E. e14724 

Barg, Frances K e19531 

Bargallo Rocha, Enrique 

e11016, e12027 

Bargfrede, Michael 4656 

Barginear, Myra F. 1046 

Bargou, Ralph 6500^ 

Barham, Ruth e19543 

Bariani, Giovanni Mendonca 

6055, e20502 

Barile, Carmen e15160 

Barinoff, Jana 556, 1023 

Barista, Ibrahim 6550 

Barkan, Guliz e15014 

Barkauskas, Deborah Sim 

9520 

Barker, Christopher Andrew 

8549 

Barker, Peter 3055 

Barlesi, Fabrice TPS7111, 

7543, 7574, e13113 

Barletta, Giulia 7577, 

e21065 

Barlev, Arie e16512 

Barlogie, Bart 8041, e18548, 

e18576 

Barlow, William e16524 

Barnadas, Agust 1001, 1120, 

4079, 5590, 5595, 10555, 

10616, e11545, e14104, 

e14552, e15159, e18057 

Barnato, Sara E. TPS1134 

Barnes, Edward K. 7035 

Barnes, Jeffrey A. e18520 

Barnes, Tanganyika e14124, 

e14125, e14727 

Barnett, Anne Elizabeth 9039 

Barnett, Gene H. 2018, 

2076, 2100 

Barnett, Stephen e17539 

Barnett-Griness, Ofra 1578 

Barney, Brandon M. e14507 

Barnhart, Kerry M. 3060 

Barnholt, Kimberly E 10097 

Barnholtz-Sloan, Jill 1603 

Barnhurst, Kelly 2555 

Barni, Sandro 1073, 4627, 

7550, e19612 

Barnosky, Andrew R 9121 

Baron Toaldo, Marco 3061 

Baron, Andre T. e21000 

Barón, Anna E. 7601 

Barón, Anna E 10580 

Baron, Ari David e15115 

Barón, Francisco J. e19505 

Barone, Carlo 3502, e14113, 

e14156, e16553 

Barone, Julie 10554 

Barosi, Giovanni 6514^, 

6625^, 6626^, TPS6642^ 

Barr, Frederick G. 9535 

Barr, John e19635 

Barr, Paul M. 6515^, 8032, 

8080 

Barr, Ronald 6011 

Barrack, Evelyn R e15174 

Barrajon, Enrique 4587, 

e16025 

Barranco, Charles TPS8116 

Barrellier, marie-Therese 

1580 

Barrera, Juan 1015 

Barret, Maximilien 9026^ 

Barretina Ginesta, Maria Pilar 

1588 

Barrett, Cris e19522 

Barrett, John A e13040 

Barrett, Olivia Claire e15502 

Barrie, Maryline 2060 

Barrientos, Jacqueline Claudia 

6515^, 6518^ 

Barriere, Jerome 2600 

Barrios, Carlos H. TPS670, 

7503, 7506, 7512, 

e11087 

Barriuso, Jorge 3601, 3618, 

10546, 10547, e13085, 

e14093 

Barron, Thomas Ian 521, 

2599, e13096 

Barroso, Ana e18111 

Barrow, David A. e13063 

Barry, Michael J 9004 

Barry, William Thomas 

CRA1002 

Barshack, Iris 10528, 

e14646 

Barta, Stefan K. 8005 

Barth, Juergen 3 

Barth, Matthew John e18537, 

e18539 

Barth, Neil M. 2569 

Barthelemy, Philippe 636 

Bartido, Shirley TPS2619, 

TPS4700 

Bartlett, Cynthia Huang 7596, 

7598, 7599, 7600 

Bartlett, David L. e14184 

Bartlett, John M. S. 516, 

517, TPS665 

Bartlett, John M.S. TPS1144 

Bartlett, John 6102 

Bartlett, Nancy 8000, 8027, 

8060, 8070 

Bartoli, Claudia 5546 

Bartolini, Stefania 2057, 

2061 

Bartolome, Adela e15033 

Bartolotti, Marco 2061 

Bartolozzi, Carlo TPS4148 

Barton, Debra L. 1557, 9001, 

9075 

Barton, John H. 1086 

Bartos, Claudia I. 5592 

Bartsch, Rupert 2053, 

e21033 

Bartzi, Valentina 5574 

Baruzzi, Agostino 2057 

Baryshnikov, Anatoly Y. 2524 

Barzi, Afsaneh 1514, 4088, 

e14031 

Bas, Carlos Arturo e15570 

Basak, Jayasri e18043 

Basaran, Gul e16015 

Basaria, Shehzad e15139 

Basch, Ethan M. 9042, 

9047, 9104, 9144, 

e19633, e19647 

Bascioni, Romeo 9098 

Baselga, José LBA1, 508, 

509, 512, 533^, 539, 540, 

551, 559, 566, 597^, 

598^, 1009, 1011, 2042, 

2567, 2568, TPS3118, 

e11055^, e13048 

Basen-Engquist, Karen 

e11090 

Bashir, Omer e15140 

Bashir, Qaiser 6546, 8040, 

8102 

Basic Koretic, Martina 

e21126 

Basik, Mark TPS1139 

Basile, Assunta e13098 

Basirat, Farnoosh 9098 

Basiricò, Marco 10066 

Baskin-Bey, Edwina S. 

TPS4698^ 

Bass, J. David 1018 

Bass, Joyce 6528 

Bassett, Mitchell 4670 

Bassett, Roland 4533, 6540, 

e19009, e19014 

Bassi, Claudio e14625 

Bassi, Fabio 519 

Bassim, Carol 4569 

Basso, Enrico e11039, 

e11514, e12510, e19620 

Basso, Michele e14156, 

e16553 

Basso, Umberto e15160 

Bassot, Karine 636 

Bast, Martin 8047 

Baste, Neus 1588 

Basterretxea, Laura TPS4685 

Bastholt, Lars 8545 

Bastian, Boris 10524 

Bastie, Anne e14129 

Bastie, jean Noel 6523 

Bastien, Berangere TPS7610 

Bastos-Rodrigues, Luciana 

e13008 

Basu, Bristi 3004 


Basu, Gargi D. 1040, 10630, 

e13571, e15209 

Basu, Partha 5106, e15546 

Basu, Sanjib 7067, e16503, 

e18117, e21069 

Bataille, Vincent e19019 

Batchelor, Tracy 2005, 2009, 

2010, 2012, 2025, 3036 

Bates, Andrew T. 8056 

Bates, Gleneara e13067 

Bates, Susan Elaine 2548, 

2553, e13122 

Batist, Gerald 1099, 

TPS1139, e14020 

Batista, Norberto e15149 

Batista, Ranyell Spencer 

Sobreira 10069 

Batistatou, Anna 592 

Batra, Surinder e17549 

Bats, Anne-Sophie 5098, 

e15558 

Battaglia, Leslie 5523 

Battaglia, Luigi e21118 

Battaglia, Tracy Ann 6097 

Battista, Kristina 3082 

Battista, Marco Johannes 

5087 

Battista, Michle e12514 

Battley, Jodie E 2062, 

e11569, e14666, e14687, 

e15078, e19059 

Battolla, Enrico e17533 

Batty, Nicolas 8067, e15042, 

e18538 

Batus, Marta 7067, e18117 

Baudin, Eric 4014, 4071, 

5569 

Baudrin, Laurence e18089 

Baudry, Elodie e18505 

Bauer, Hillevi 6583 

Bauer, Joseph E. 1608 

Bauer, Juergen 8526 

Bauer, Kenneth S e13075 

Bauer, Maret 1084 

Bauer, Sebastian 10032^, 

10033, 10046 

Bauerfeind, Ingo 1114 

Bauersachs, Rupert 

TPS9149^ 

Bauerschlag, Dirk Olaf 

e13503 

Bauerschlag, Dirk 556 

Baujat, Bertrand e16013 

Bauknecht, Thomas 1059 

Baulieu, Jean-Louis TPS646 

Baum, George e11090 

Bauman, Glenn 6130 

Bauman, Jessica R e16062 

Bauman, John W. 5065 

Bauman, Julie E. 3009, 

5503, 5515, 5549, 5566, 

TPS5602, 7029, e13101 

Baumann, Klaus H. 5005, 

5007 

Baumann, Sybille e19530 

Baumgart, Megan Ann 5529, 

5532 

Baurain, Jean-Francois 5038, 

8532, 8539 

Bausela, Cristina e14147 

Bautista, Dolores e14116 

Bavbek, Sevil E. e15112 

Baxevanis, Constantin N. 

e15125 

Baxi, Shrujal S. 5514, 6001 

Baxley, Allison Ashley e17001 

Baxter, Nancy N. 6027 

Baxter-Lowe, Lee Ann 6537 


Bay, Jacques-Olivier 4625, 

6527, 6542, 10020, 

10035, 10042, 10078 

Bayer, Charlene W. 7048 

Baylin, Stephen 7006, 

e18147 

Baylon, Sheley M e16523 

Bayman, Neil e18095 

Bayo Calero, Juan Lucas 

e11081 

Bayo, Juan L. 10608, 

e11075, e11535, e21088 

Baz, Rachid C. 8016, 8017 

Bazeos, Alexandra 10550 

Bazhenova, Lyudmila 2052, 

7030, e16535, e21074 

Bazin, Igor e14623 

Bazolli, Barbara 1115 

Bazzi, Mouhamad e13075 

Bazzola, Letizia e11546 

Beach, Douglas Francis 

e12008 

Beadle, Beth Michelle 5561, 

5589 

Beadling, Carol 10591 

Beale, Philip James 3531, 

9021, 9087, 9126 

Beaney, M. P. e14022 

Bear, Harry Douglas LBA506, 

10565 

Bearden, James D. 9047 

Beardslee, Brian e11529 

Beare, Sandra 4004, 4029 

Bearelly, Smitha 6561 

Bearss, David 10549 

Beart, Robert W. TPS10632 

Bearzi, Italo e14561, e21070 

Beato, Carlos Augusto de 

Mendonça 7506 

Beatson, Melony 4569 

Beatty, Gregory Lawrence 

2500^ 

Beau-Faller, Michele 10507 

Beaubien, Ron 10587 

Beauchemin, Michel 634 

Beauchene, Suzanne e15206 

Beaumont, Hubert e13547 

Beaumont, Jennifer L 6092 

Beaunoyer, Mona 9563, 9570 

Beausoleil, Michel S 4535 

Beaussant, Yvan e19623 

Bebb, D. Gwyn e14073, 

e18110, e21083 

Bebek, Gurkan 5573 

Becchimanzi, Cristina 8066 

Becerra Ramirez, Henry 

Alberto e18114 

Becerra, Carlos 508, 2516, 

3023, TPS3111 

Becerra, Henry A. e12039 

Bechade, Dominique e14017, 

e14023 

Bechstein, Wolf 3508, 

TPS3641^ 

Bechter, Oliver Edgar e14719 

Beck, Christian 6584 

Beck, J Robert 6021 

Beck, J. Thaddeus LBA4, 

530, 539, 8511 

Beck, Mo Youl 10085 

Beck, Robert J e14021 

Beck, Rodney A. 516 

Beck, Susan L. 9137 

Beck, Thomas 1600^ 

Becker, Daniel Jacob 6114, 

e18139 

Becker, Dorothea 8528 

Becker, Gerd 5512 

Becker, Heinz 3600, e14161, 

e14167 

Becker, Jürgen C. 8517 

Becker, Robert 3074 

Becker, Shawn 10584 

Becker-Hapak, Michelle 2525 

Beckers, Marielle e13062 

Beckett, Brooke 10011^ 

Beckett, Laurel 7582, 7594, 

e13550 

Beckjord, Ellen Burke 9136 

Beckman, Robert A. 7536, 

e14617 

Beckmann, Matthias W. 554, 

1600^, 1602, 10540 

Becouarn, Yves e14017, 

e14023 

Becq, Jennifer 544 

Bedair, Ahmed e16002 

Bedard, Philippe 3003, 

3082, 4535, e13001, 

e19616 

Bedenne, Laurent LBA4003 

Bedetti, Benedetta 10080 

Bedikian, Agop Y. 8514, 

8587, e19009, e19014, 

e19039 

Bedke, Jens 4530 

Bedognetti, Davide 8576, 

10565 

Bedoya, Ivan Dario e14714 

Bedrosian, Isabelle 1102 

Beebe-Dimmer, Jennifer 

e14609, e15147 

Beecham, Kwamena e15163 

Beeker, Aart TPS4692^ 

Beelen, Karin J. 562 

Beer, David G. 10587 

Beer, Tomasz M. 4522, 

4525, TPS4691 

Beeram, Muralidhar 2512, 

2555, 3001, 3019, 

e13025, e13602, e13604 

Beg, Muhammad Shaalan 

TPS3116, e14165 

Begbie, Stephen e19642 

Begg, Colin B. CRA9513 

Beghelli, Stefania 4076 

Begin, Marie Josee 2102, 

e18120 

Begna, Kebede 6614 

Begnami, Maria D. e14728 

Beguin, Yves 6534 

Begum, Rubina 4004, 4029 

Begum, Tahmina e11539 

Beham-Schmid, Christine 

e18525 

Behera, Digambar e18009 

Behera, Madhusmita 7059 

Behera, Manoj Kumar e11082 

Behl, Ajay S e14160 

Behlendorf, Timo e19579 

Behr, Spencer 8580 

Behren, Andreas 8542 

Behrendt, Carolyn E. e19644 

Behrens, Carmen 7023 

Behrens, Robert J. TPS657 

Behringer, Dirk M. 4083 

Behrns, Kevin TPS4136 

Beijert, Max L 8039 

Beijnen, Jos H. 2550, 2596, 

e13028 

Beiko, Jason 2019 

Beissbarth, Tim 3600, 

e14161, e14162 

Beitler, Jonathan Jay 5560, 

5570, 7059, e21161 

Bejanyan, Nelli 8055 

Bekaii-Saab, Tanios B 4099 

Bekaii-Saab, Tanios S. 4039, 

4043, TPS10102^, 

e14169, e14170 

Bekers, Dave J. 10091 

Beksac, Meral 8095, 

e18572^, e21006 

Bekyashev, Ali H. e19012 

Belanger, Karl 2102 

Belani, Chandra Prakash 

TPS1138, 2553, 3049, 

3054, 7040, 7054, 7055, 

7512, 7551, e17560, 

e18138 

Belau, Antje 522, 624, 5031 

Belda-Iniesta, Cristobal 3068, 

3601, e13085, e14093, 

e14144 

Belderbos, Jose 7019 

Belghiti, Jacques 3609, 

e14553 

Belitsis, Kenneth 1540 

Belizna, Cristina 1580 

Belka, Claus TPS7617, 

e16033 

Belknap, Steven M 2532, 

4063, 6623 

Belkoff, Laurence 4550 

Bell, Melanie 6111, e16507 

Bell, Richard 502, 513, 

TPS670 

Bell, Ronny A. 6127 

Bell, Sue E 8015 

Bella, Santiago Rafael 

e21025 

Bellati, Filippo 5070 

Belldegrun, Arie S. e13045 

Belleannee, Genevieve 4129 

Bellera, Carine 9012 

Bellet, Meritxell 509, 566, 

619 

Belletier, Christine e11542 

Bellevicine, Claudio e19038 

Bellew, Kevin M. 3003, 3023 

Bellezza, Guido e21094, 

e21096 

Belli, Carmen 4017 

Belli, Susana e14598 

Bellin, Lisa Sheri e11550 

Belliveau, James e13561 

Bellizzi, Keith M 9130 

Bellmunt, Joaquim TPS4674, 

TPS4693, e15007, e15111 

Bello, Carlo e18093 

Bello, Celeste M. 2099, 

6568, 8065, 8084, 

e18503, e18506, e18509, 

e21123 

Bellon, Jennifer Ruth 6022 

Belloni, Benedetta 8563, 

e19017 

Belloni, Carlo 1500 

Belluco, Claudio e14151 

Belmans, Ann 1020 

Belmar, Nicole 8087 

Belmont, Laure e18075, 

e18102 

Belotti, Alessandro 3570 

Belounis, Assila 9563, 9570 

Belousova, Elena 4632, 

10619 

Beltran, Himisha 4649 

Beltran, Michel e16044, 

e16055 

Beltran, Miguel 1588, 

e15144 

Belvederesi, Laura e14561, 

e15074 

Belvin, Marcia 2566 

Ben, Yong LBA4537 

699s

Ben-Aharon, Irit 548, 2556, 

e13080 

Ben-David, Merav A. e14143 

Ben-Josef, Edgar e14603 

Ben-Or, Sharon e17550 

Benaim, Ely 2597, 3010, 

5021, TPS8109, TPS8110 

Benakanakere, Indira 6561, 

e11031 

Benali-Furet, Naoual e21014, 

e21046 

Benassi, Maria Serena 10066 

Benazzouna, Rana 9560 

Benboubker, Lotfi 8009, 

8014, 8020 

Benbrahim, Zineb e11502 

Bencardino, Katia 3570, 

TPS3637 

Benchimol, Daniel 5075 

Bendahmane, Belguendouz 

CRA3503 

Bendell, Johanna C. 2566, 

3006^, 3008, 3021, 3033, 

3041, 3067, 3097, 

TPS3118, LBA3501, 3543, 

3631, TPS3640, 4027, 

4127, e13076 

Bender, James 2087 

Bender, Ryan P 10630, 

e15209 

Bendszus, Martin 2034 

Bene, Marie C. 8026 

Benecchi, Sara e18039 

Benedetti Panici, Pierluigi 

LBA5003, 5070, 5093, 

5094, e15547, e15550, 

e15551, e15553 

Benedetti, Antonio e14561 

Benedetti, Fabio M. 3631 

Benedetti, Jacqueline K. 

4019 

Benedetti, Jacqueline 4010 

Benedikova, Andrea e14556 

Benes, Cyril 1055 

Benevelli, Carlotta 627 

Benevides, Carlos Frederico 

Lopes 643 

Benezery, Karen 5521, 

e16044, e16051, e16055 

Benfante, Antonina e21095 

Bengrine-Lefevre, Leila 4071 

Benhadji, Karim Adnane 

2554, 3005 

Benhaim, Leonor 3584, 

3597, 3604, 3615, 3622, 

4026, 4088, e11018, 

e14034, e14052 

Benhammane, Hafida e11516 

Benhar, Itai e13018 

Benitez, Julio 4620 

Benito, Juliana M. 6585 

Benizri, Emmanuel 5075 

Benjamin, Hila 10528, 

10575, e21008 

Benjamin, Kamlakshi Esther 

e19622 

Benjamin, Robert S. 10021, 

10071, e19520 

Benjaminov, Ofer e14731 

Benlloch, Susana 4068, 

10596, e14521, e18130, 

e18131, e18137, e18143 

Bennati, Chiara e18023, 

e18101 

Bennett, Antonia V 9144 

Bennett, Barbara Kaye 9044 

Bennett, Cathryn M. 

TPS10103 

Bennett, Charles L. 6044, 

9143, e19639 

Bennett, Dimitri e12001 

Bennett, Kathleen 521, 

2599, e13096 

Bennett, Kristi L 5573 

Bennett, Lee 539 

Bennett, Michael WIlliam 

e14666, e14687 

Bennis, Robyn 10574 

Bennouna, Jaafar 3010, 

CRA3503, LBA7500, 7557, 

7575, TPS7612, e13009, 

e13010, e18005 

Bensaid, Benoit 10049 

Bensaid, Cherazade 5098, 

e15558 

Bensfia, Samira e15112 

Bensinger, William 8034 

Bensink, Mark Eliot 6077 

Benson, Al B. e14542, 

e14551, e14610 

Benson, Al Bowen 3605, 

4030, 4102, 4126 

Benson, Brad e16502 

Benson, Charlotte 10038, 

10039, 10060 

Benson, Mitchell C. 2516, 

e15021 

Benteyn, Daphné 2507 

Bentley, David 544 

Bentley, John e16527 

Bentley, Tanya G. 3626, 

6057 

Benton, Christopher Brent 

6576 

Bentrem, David J. e14642 

Bentrem, David J 3608 

Benyunes, Mark 533^, 

e11055^ 

Benz, Christopher 10586 

Benz, Matthias R. 10012 

Benzel, Heather 9110 

Bepler, Gerold 2559, 7063, 

7593, e15005 

Beppu, Yasuo 10009, 10067 

Berahovich, Robert D. 2043 

Berano-Teh, Jennifer 1592, 

8038 

Berard, Henri e16560 

Berard, Paul e18558 

Berardi, Rossana 4627, 

10063, e21070 

Berardi, Simona 9059 

Berchmans, Emmanuel 6575 

Berdeja, Jesus G. 8033, 

TPS8115 

Berdel, Wolfgang E. 6610, 

e15026 

Bereder, Jean Marc 5075, 

e15574 

Berek, Jonathan S. 5065, 

TPS5113 

Berenguel, Maria e19636 

Berenson, James R. 8034, 

8098, e18549, e18558 

Beretta, Giordano D. 623, 

7082, TPS9155 

Berg, Deborah 8017, 8033, 

8034, 8064 

Bergagnini, Isabella 7033 

Bergamini, Cristiana 5555 

Bergamo, Francesca 3555, 

3585, 4017, 9090 

Berge, Eamon M 7504 

Berge, Eamon 7601, e21120 

Berge, Victor e15194 

Berge, Yann 3026, 3104, 

5522, 10027 

Bergelson, Ilana e20008 

Berger, Allison 3077 

Berger, Andre K e15060 

Berger, Andreas TPS1612, 

TPS3636 

Berger, Lars Arne 4597 

Berger, Markus 5047 

Berger, Michael F. 4604, 

5030, 10524 

Berger, Michael F 4527 

Berger, Raanan 535, 3027, 

4619, e14143, e14646, 

e15058 

Bergerot, Cristiane Decat 

e19504 

Bergethon, Kristin 7508 

Bergfeldt, Kjell 5052 

Bergh, Jonas 10083, e11510 

Berghmans, Thierry e18006 

Berghoff, Anna Sophie 2053, 

e21033 

Berghout, Koralee 10620 

Bergman, Bengt 7001 

Bergmann, Lothar e15044 

Bergnolo, Paola 10055 

Bergqvist, Michael 7539 

Bergqvist, Peter e15199^ 

Bergsagel, Leif 8043 

Bergsagel, P. Leif 8010 

Bergsland, Emily K. 4085, 

4126, e13000, e14542, 

e14551 

Bergstralh, Eric J. 4565 

Bergstrom, Donald Alan 

10573 

Bergstrom, Kimberly A. 

e14118 

Bergström, Stefan 7539 

Berigaud, Sylvie e18505 

Berille, Jocelyne LBA4003 

Berinstein, Neil Lorne 2588 

Berk, Lawrence B. TPS9150 

Berk, Veli e14089, e14670 

Berkenblit, Anna 4501 

Berking, Carola 8511 

Berkovcova, Jitka e19020 

Berkowitz, Alison e19647 

Berkowitz, Noah C. 1017 

Berlin, Jordan 2595, 3532, 

4052, e13606, e14503 

Berloco, Pasquale 4110 

Berman, Arlene W 7033, 

7103 

Berman, David M. 4577, 

4580, 4582 

Berman, David Mark 8541, 

8593 

Berman, David Monty 4585 

Berman, Ellin 6613, 9088 

Berman, Russell S. 8550, 

8557, 8565, 8589, 

e19003 

Berman, Tara 5078 

Bermejo, Begoña 1074, 

10500, 10616, e11523 

Bermejo, Justo Lorenzo 1096 

Bermingham, Niamh 2062, 

e11569 

Bernabé, Reyes 1531, 

e11075 

Bernales, Sebastián 3072 

Bernard, jean-Louis 5075 

Bernard, Laurence 3539, 

7090 

Bernard, Paquito 9074 

Bernard, Paula J e14075 

Bernard, Philip Seth 1008 

Bernard, Stephen A. 6042 

Bernardi, Daniele 586 

Bernardini, Marcus 5026 

Bernardo, Antonio 589 

Bernardo, Giovanni 589 

Bernards, Karen e13542 

Bernards, Rene’ 3065 

Berneman, Zwi N. 2506, 

e13051 

Bernemann, Christof e11534 

Bernhard, Helga 2573^ 

Bernhard, Juerg 9022 

Bernhardt, Christiane 3550 

Berno, Elisa 10055 

Berns, Els M. 526 

Bernsen, Hans J.J.B. 2 

Bernshaw, David e15541 

Bernstein, Jonine L. CRA9513 

Bernstein, Lori J 5587 

Bernstein, Mark L. 9503, 

9537, 10081 

Bernstein, Melanie 4552 

Bernstein, Sarah 2577 

Bernstein, Steven H. e18536 

Bernstein-Molho, Rinat 10043 

Beroukhim, Rameen 2020 

Berreho, Mohamed Amine 

e11502 

Berremili, Toufik 1580 

Berretta, Massimiliano 

e14040 

Berriolo-Riedinger, Alina 

TPS646 

Berrocal, Alfonso e19023 

Berros, Jose Pablo e18044, 

e19023 

Berruti, Alfredo 4627 

Berry, Allen 7072^ 

Berry, Donna Lynn 4571, 

9008, e19586, e19637 

Berry, John S. 625 

Berry, Kristin 6077 

Berry, Lynne D 7589 

Berry, Mark Francis e14562 

Berry, Scott R. e14171, 

e15177^, e16558 

Berry, William R. TPS4697 

Berryman, Robert B. e13079 

Bersani, Maurizio TPS9155 

Bersani, Samantha 4076 

Bertagnolli, Monica M. 3517, 

10017 

Bertelli, Gianfilippo 1094 

Bertelsen, Caitlin 1065 

Bertero, Luca 2037, 2075 

Berthelet, Eric 7020 

Berthet, Pascaline e12502 

Berthod, Grégoire e19050 

Bertolaso, Laura e13019 

Bertoldo, Francesco 9005, 

10063 

Bertolini, Francesco 2083 

Bertolini, Stephane V. 

TPS8111 

Berton-Rigaud, Dominique 

5018, e13095^, e13097^, 

e13108^, e15535 

Bertoni, Ramona e11546 

Bertorelle, Roberta 2049 

Bertossi, Monica 2580 

Bertran-Alamillo, Jordi 7522, 

10596, e14521, e18131, 

e18143 

Bertrand, Claude e14148 

Bertrand, Yves TPS9594 

Bertschinger-Ehrler, Julian 

2575 


Bertucci, François 1047, 

10014, 10023, 10042, 

10056, 10078, 10092, 

10095, TPS10102^, 

e21010 

Bertulli, Rossella TPS9155, 

10053, 10065 

Berube, Jayne 549^ 

Berwick, Marianne 8574 

Berz, David 4098 

Besse, Benjamin 7543, 

7599, 10507, 10556, 

e18071 

Besson, Caroline 8046 

Besson, Nadine 6511 

Bessudo, Alberto 2579, 

e13101 

Best, Kate e17519 

Bestani, Claudia e14598 

Besterman, Jeffrey M. 3039, 

e13602, e13604 

Bestoso, Elena e13098 

Betancur, Carlos Alberto 

e19604 

Betensley, Alan e12019 

Beteta, Carmen Rosa e19597 

Bethe, Ullrich 5516^ 

Bethel, Kelly e21074 

Bethke, Kevin P. TPS1134 

Betsuyaku, Tomoko e18058 

Betta, Pier Giacomo 7084 

Bettelli, Stefania Raffaella 

631 

Betticher, Daniel C. e19648, 

e18012 

Bettini, Anna LBA7501 

Bettis, Claudette 8524 

Betts, Kelly 9103 

Beumer, Jan H. TPS1138 

Beumer, Jan Hendrik 1070, 

2533, 2553, 3031, 3037, 

3049, 3054, 7022, 

TPS8606 

Beuthien-Baumann, Bettina 

10068 

Beutler, Thomas e14045 

Beuzeboc, Philippe 1095, 

LBA4567^, 4583, 5067, 

e15535 

Bevan, Catherine e15501 

Bevan, Paul 1092 

Beveridge, Roy A. 6109, 

e16536 

Bevers, Michael W. 9134 

Bevilacqua, Generoso 629 

Bevis, Kerri S. 5060 

Bex, Axel 4611 

Bexon, Alice Susannah 

e18047 

Beyeler, Michael 9059 

Beyer, Joerg 4597, 4600, 

e15026 

Beygi, Hooman e13081 

Beyne-Rauzy, Odile 6523 

Beyssac, Richard e14023 

Bezerra, Stephania 643 

Bhakta, Radhe S. 2581 

Bhalla, Kapil N. 10549, 

10605, e13568 

Bhalla, Megha e21047 

Bhamidipati, Pavan Kumar 

6597 

Bhangu, Aneel e14132 

Bhardwaj, Nina 2570, 2589, 

8571, e21081 

Bhardwaj, Vikas 7096 

Bhargava, Pankaj 4112, 4132 

Bhargava, Ranjana S. 1039 


Bhargava, Rohit 1038, 1085, 

e15560 

Bharthuar, Anubha e19607 

Bhat, Ashwini 10037 

Bhat, Krishna 2002 

Bhat, M L e19516 

Bhat, Neal 5088 

Bhathena, Anahita e13583 

Bhatia, Jasmine 5043 

Bhatia, Ravi 1592 

Bhatia, Smita 1592, 8038, 

9505, 9512, CRA9513 

Bhatla, Neerja 5104 

Bhatnagar, Aseem Rai 

e16012 

Bhatnagar, Bhavana 6611, 

e19565 

Bhatt, Aashish D. e21072, 

e21144, e21149 

Bhatt, Astha e14689 

Bhatt, Geetika e21072, 

e21144, e21149 

Bhatt, Niraj 2592 

Bhattacharya, Sudin 2581 

Bhattacharyya, Anirban 

TPS10631 

Bhattacharyya, Helen 6092 

Bhattacharyya, Pritish e18507 

Bhimani, Chandar 7059 

Bhor, Menaka e15063 

Bhora, Faiz Y. e18139 

Bhosale, Priya 4054 

Bhutani, Divaya 6549 

Bhutani, Manisha 8088, 

8104, e18568 

Bhutani, Manoop S. 4069, 

4078, 4086, e14547, 

e14548, e14669 

Bhutta, Usman e17012 

Bi, Feng LBA4537, 4638 

Bi, Nan e14511 

Biagetti, Simona e14086, 

e14561, e21070 

Biaggi, Christine 10033 

Biagi, James Joseph 3632, 

5019 

Biagini, Matteo 4015 

Biagioni, Francesca 3521 

Biakhov, Mikhail 7090 

Bian, John 6044 

Bianca, Ralph e19609 

Bianchetti, Sara e14082, 

e18065 

Bianchi, Andrea 8077 

Bianchi, Maria Paola e17006, 

e18563, e18566 

Bianchini, Carlo e19612 

Bianchini, Diletta 4553, 

e15134, e15136 

Bianco, Roberto e13509 

Biancon, Antonella e19595 

Bianconi, Fortunato e21094, 

e21096 

Bianconi, Maria Ines e15521 

Bianconi, Maristella e14086, 

e14561, e14663, e15074 

Biankin, Andrew Victor 

TPS4137 

Bias, Peter 9125, e19587 

Biasco, Guido 10087, 

e14647 

Bibbo, Marluce 10528 

Bibby, David C. 4603, 7079^ 

Bibeau, Frédéric 10505, 

TPS10632, e14059 

Bible, Keith Christopher 5544 

Bichev, Dmitry TPS4138 

Bickel, Hubert 10570 

Bickell, Nina e11004, 

e15513, e19621 

Bickerstaff, Matthew 8523 

Bickley, Thomas e15536 

Bidard, Francois-Clement 

8546 

Biddle, Andrea K 6096, 

e15184 

Bidoli, Paolo LBA4001, 

LBA7507, 7557 

Bie, Li 10543 

Bieber, Carolyn 5544 

Bieche, Yvan 10507 

Bielack, Stefan S. 9573, 

10081 

Bierman, Philip Jay 8047 

Biernat, Wojciech 505, 603, 

10561 

Biersack, Hans-Juergen 

e14565 

Biesma, Bonne 7554 

Biganzoli, Laura 530 

Bigbee, William L e14689 

Bigelow, Elaine e14585 

Biggi, Alberto 8077, e13093 

Biggs, David D. LBA1000 

Biggs, David e18122 

Biggs, Heather 544 

Biglia, Nicoletta 627 

Bignon, Emmanuelle e14168 

Bignotti, Eliana e15549 

Bihrle, Richard 4586 

Bijwaard, Karen 3074 

Bikov, Kaloyan A e14035, 

e14056 

Bilen, Mehmet Asim 6544, 

e13506 

Bilici, Mehmet e14526 

Bilim, Vladimir e15057, 

e15088 

Bilimaga, Ramesh s e19619 

Bilimoria, Karl Y. 3608 

Bilker, Warren B. 1503 

Bill, Matthew A e13549 

Billett, Amy 9502 

Billiter, David 9583 

Billmire, Deborah 9539 

Billups, Catherine 9502 

Bilotto, Anthony 2511 

Bilusic, Marijo 2526, 

TPS2617, TPS4701 

Binder, Claudia e15026 

Binder, Gary e18560, 

e18561 

Bines, Jose e11087 

Bingman, Anissa 4039 

Bingoel, Cigdem 4601 

Biniecka, Monika e21024 

Binmoeller, Kenneth e14546 

Binns, Shemeica N. 561 

Bintner, Marc 2048 

Biondani, Pamela e21118 

Biondi-Zoccai, Giuseppe 

e15192 

Biondo, Andrea 10525 

Biondo, Sebastiano 3571 

Biran, Haim e17509 

Birch, Kate E. 1502 

Bird, Brian Richard e14111 

Bird, Deborah TPS4150 

Bird, Ian M e15167 

Birgisson, Helgi 3576 

Birkemeyer, Elke 4015 

Birkhäuser, Frédéric D. 

e13045 

Birkmann, Josef 8031 

Birks, Peter Crawford 6085 

Birnbaum, Ariel E. e13124 

Birner, Peter 2053, e21033 

Bironzo, Paolo e15192 

Birrer, Michael J. 5029, 

TPS5112 

Birt, Michael 6077 

Birtwisle-Peyrottes, Isabelle 

10018 

Bischoff, Farideh Z. 584, 

10516, TPS10631 

Bischoff, Joachim 556, 624 

Bischoff, Sven 4044 

Biscotti, Tommasina e21070 

Bisen, Ajit e15121 

Bisgaier, Charles L. TPS3110 

Bishnoi, Sarwan K. e13007 

Bishop, Justin A. 5549 

Biskup, Karina 5047 

Bisovskaya, Yulia e14681, 

e14723 

Bissler, John 4632, 10619, 

e12042, e15096 

Biswas, Jaydip 2581 

Biswas, Tithi e17547, 

e17550 

Bitas, Christiana 10003 

Bitker, Marc-Olivier e15105 

Bitoun, Laurence 4036, 8591 

Bitran, Jacob D. e12002 

Bitting, Rhonda Lynn 10533 

Bittoni, Alessandro e14086, 

e14561, e14663, e15074 

Bitzer, Michael 4115 

Biville-Hedouin, Fabienne 

7575 

Bivona, Trever Grant 7522 

Bizieux-Thaminy, Acya 

e16560 

Bjarnason, Georg A. 4536, 

4538, 4613, 4633, 

TPS4683, 10622 

Bjelic-Radisic, Vesna 514 

Bjerregaard, Jon Kroll 

e14517, e14633 

Bjordal, Kristin 6002 

Bjorkholm, Magnus 8074 

Bjurlin, Marc e15119 

Blachar, Arye 1564 

Black, Amanda 4646 

Black, Amber A. e21090 

Black, Keith L. 2080, 2084, 

2087 

Black, Peter C. 4565 

Blackford, Amanda L. 6026 

Blackhall, Fiona Hellen 

e18095 

Blackstein, Martin E. 

LBA10008 

Blackwell, Kimberly L. LBA1, 

1006 

Blackwell, Kimberly TPS1148 

Blade, Joan 8018^ 

Blaes, Anne Hudson 4659, 

e15169, e16502 

Blagden, Sarah Patricia 2608, 

3000, 3022, e13033 

Blais, Normand e17507, 

e18120, e18136, e19591 

Blaise, Didier e18526 

Blakaj, Dukagjin e16058 

Blake, Monika 7068 

Blake, Robert L. e19617 

Blakeley, Jaishri O’Neill 2042 

Blakemore, Stephen 3077 

Blakesley, Rick E. 6509^ 

Blana, Andreas e15194 

Blanc, Ellen 4614, 4625 

Blanc, Jean-Frédéric 4032, 

TPS4146, 9012 

Blanc-Bisson, Christele 9012 

701s

Blancas, Isabel e11535, 

e11545, e21088 

Blanchard, Pierre 4554 

Blanchard, Raymond K 

e21011 

Blanchard, Rita A. e21076 

Blanchard, Suzette 1070 

Blanchard, Veronique 5047 

Blanchet, Benoit e13056 

Blanchon, Francois 1574 

Blanco Codeisido, Montse 

e14058 

Blanco, Esperanza e11074 

Blanco, Monsterrat 3022 

Blanco, Remei 1531, e18053 

Blanco-Calvo, Moisés e14595, 

e21002 

Blanco-Codesido, Montserrat 

3030 

Blandino, Giovanni 3521 

Blaney, Susan 9500, 9540, 

9541, 9581 

Blank, Christian U. 4611, 

LBA8500^, 8511, 8517 

Blank, Sima e14583, e14656 

Blank, Stephanie V. 5016, 

5054 

Blanke, C. D. 4010, 4019, 

4113, 10088 

Blasco, Ana 7058, 7060, 

10594, e12012 

Blaszkowsky, Lawrence Scott 

4021, 4112, e14615 

Blau, Gary E e18555 

Blau, Igor Wolfgang e18552 

Blay, Jean-Yves 1567, 1568, 

10005, 10006, 10007, 

LBA10008, 10009, 10010, 

10013, 10014, 10020, 

10027, 10035, 10049, 

10056, 10062, 10067, 

10078, 10089, 10092, 

10095, TPS10101, 10562, 

e13519, e13600^ 

Blaydorn, Lisa e19048^ 

Blazar, Bruce R. 6539 

Blazeby, Jane M TPS4143 

Blazer, Dan G. e14724 

Bleckmann, Annalen 3600, 

e14167 

Bleeg, Mary Lou e19588 

Bleicher, Jamie F. e21048 

Bleicher, Richard J. 6061 

Bleif, Martin 5512 

Bleijenberg, Gijs 9070 

Blenkinsop, C TPS1144 

Blesius, Aurore 4554, 10007, 

10033, 10044 

Blettner, Maria 1082, 

e11040^ 

Bleuse, jean-Pierre 3633 

Blevins, Richard 1040, 5523, 

e13571 

Blieden, Clifford 595 

Bligny, Dominique e15131 

Blin, Nicolas 8009 

Blinder, Victoria Susana 6073 

Blinman, Prunella Louise 

e16501 

BLISS, R e13522 

Bliss, Robin L. e16502 

Blobe, Gerard C. 2585, 

10563 

Block, Andreas e13095^ 

Block, Anne Marie W. 6565 

Block, Matthew Stephen 

5076 

Block, Norman L. e15153 

Block, Susan 9139 

Bloecher, Andrew 3587 

Blohmer, Jens U. 541, 1023 

Bloma, Marianne TPS4694 

Blondin, Beth A e21111 

Blons, Helene 2537^, 5554, 

10507 

Bloom, Gregory C 10048 

Bloom, Kenneth J. 516 

Bloomfield, Clara D. 6526 

Bloomston, Mark 4126, 

e14542, e14551 

Blough, David K 6007, 

e14068, e16524 

Blue, Michael e21066 

Bluemn, Eric Gregory 4669 

Blum, David e19648 

Blum, Joanne Lorraine 547 

Blum, Kristie A. 6507, 6508, 

8000, e18508 

Blum, Mariela A. 4069, 

4078, 4086, e14547, 

e14669 

Blum, Ronald H. 6114 

Blum, William G. 2533, 6526 

Blumberg, Joelle TPS4153 

Blumenschein, George R. 

2567, 2568, 3023, 5592, 

e13048 

Blumenthal, Susan e21022 

Blumetti, Jennifer e14590 

Bluth, Mark J. 8549, 8598 

Boachie-Adjei, Kwadwo 

e11057 

Boame, Nana e14154 

Bobadilla, Luz 8591 

Bobba, Ravi Kiran 1586, 

6561 

Bobek, Vladimir e21051 

Bobek-Billewicz, Barbara 

e21049 

Bobiak, Sarah 4126, e14542, 

e14551 

Bobos, Mattheos 573, 592 

Boc, Marko e14083 

Boccardi, Lidia 645 

Boccardo, Francesco e15185 

Bocchia, Monica TPS6640 

Bocci, Guido 3518, e11061 

Boccia, Ralph V. 6518^, 

8098, 10530, e18558, 

e21023 

Boccone, Paola e15192, 

e20512 

Bochicchio, Anna Maria 

LBA4001 

Bochner, Bernard 4527, 

4581^ 

Bociek, Gregory 8047 

Bock, Meredith 9107 

Bockorny, Bruno 6555, 

e18543 

Boddy, Alan V. 9542 

Bodenner, Donald 5518, 

5591 

Bodmann, Joanna e14611, 

e14665 

Bodmer, Alexandre 9059, 

e11048 

Bodnar, Carolyn 6077 

Bodoky, Gyorgy 4042 

Bodrogi, Istvan TPS4683 

Bodurka, Diane C. 5012, 

9134 

Bodurtha, Joann 1563 

Body, Jean-Jacques e19514 

Boeck, Stefan Hubert 4023, 

4041, 4072 

Boegemann, Martin 4590 

Boehler, Geir 4066 

Boehlke, Brittani e21022 

Boehm, Andreas e16016 

Boehm, Daniel 10551 

Boehme, Michael 624 

Boehrer, Simone 6523 

Boelke, Edwin e11556, 

e14527, e16033 

Boellaard, Ronald 7603 

Boer, Hink 4528, e15035 

Boerman, Otto C. 3035, 

e13111 

Boers-Sonderen, Marye 2593, 

5061 

Boezen, H. Marike 1502 

Bogaerts, Jan 1022, 10602 

Bogale, Solomon Desalegne 

580 

Bogani, Paola 9005 

Bogart, Jeffrey e16047 

Bogatch, Kita 8575 

Bogenrieder, Thomas 3092 

Boggio, Gaston Federico 

10074 

Boggio, Lisa N e16503 

Boglione, Antonella 10055 

Bogner, Paul e17535 

Bogner, Wolfgang 10570 

Bohanes, Pierre Oliver 3584, 

3597, 3604, 3615, 3622, 

4026, 4088, e11018, 

e14031, e14034, e14052 

Bohnen, Daniela TPS4138 

Bohr, David 8598 

Boice, John D. CRA9513 

Boiche, Julie 9074 

Boige, Valerie 3547, 

LBA4003 

Boileau, Jean-Francois 616 

Boise, Lawrence 8100, 8101 

Boisselier, Blandine 2023 

Boitier, Francoise e21014, 

e21046 

Bojar, Hans e11556 

Bojic, Marija e15090 

Bok, Robert A. 4660 

Bokemeyer, Carsten 3539, 

3562, 3574, 3591, 4095^, 

4597, 9114, e13097^, 

e13108^, e15026, e15168 

Boku, Narikazu 4002, 4031, 

4035, 4046, 4082, 

e14510 

Boland, Amy L 4531, 

TPS4681 

Boland, William e18110 

Boles-Ponto, Laura e15143 

Boleti, Ekaterini 4611 

Bolgeri, Marco e15100 

Bolina, Marina Borges 

e13008 

Bollag, David T. LBA5002^, 

5017^ 

Bollag, Gideon 8503^ 

Bolli, Geremia 1509, 1510 

Bollig-Fischer, Aliccia 7063 

Bolling, Joan e18550 

Bologna, Serge 6633, 8002 

Bolondi, Luigi 3061, 

TPS4151 

Bolt-de Vries, Joan 10504 

Bolten, Wolfgang W. e11040^ 

Bolton, Damien M e15117 

Bolton, Susan 1560 

Bolwell, Brian James 8055 

Bomalaski, John S. e17558 

Boman, Bruce M. TPS1615 

Bomba, Darrin e13077 

Bombard, Yvonne e11000 

Bombí, Josep Antoni 3536 

Bompas, Emmanuelle 10010, 

10014, 10020, 10056, 

10092, 10095 

Bomprezzi, Chiara 2037 

Bona, Eleonora 629 

Bona, Francesco e20512 

Bonamino, Martin H e14101 

Bonanni, Bernardo 519, 1500 

Bonanno, Laura e18130 

Bonapace, Ian Marc 4661 

Bonaventura, Antonino 3572, 

e14166, e15152 

Bonavida, Benjamin e18549 

Bond, Mary 9547, e18522 

Bondar, Vladimir e13095^, 

e13097^, e13108^ 

Bondarde, Shailesh Arjun 

2592, e13127 

Bondarenko, Igor N. 4501, 

7558, e15037 

Bondarenko, Igor 7551, 

8512, 9125, e19587 

Bondra, Kathryn 9544 

Bonebrake, Albert J. 5015 

Bonehill, Aude 2507 

Bonekamp, Susanne 4114 

Bonetti, Andrea 5513 

Bonfill, Teresa TPS4674 

Bonfils, Claire 3039 

Bong, Chin Wei 4106 

Bongaerts, A. H.H. 10581 

Bongero, Danielle e13569 

Bongu, Navneeth Rao 8047 

Boni, Corrado LBA5003 

Boni, Ermenegilda e11546 

Boni, Luca e18074 

Boni, Valentina 3005, 10512, 

10595 

Bonifacio, Cristina 2580 

Bonini, Chiara 6541 

Boniol, Mathieu 1509, 1510 

Bonizzoni, Erminio e19612 

Bonnefoi, Herve R. TPS667, 

1011 

Bonner, James A. 621 

Bonner, William 2553, 3031 

Bonner-Ferraby, Phoebe 8566 

Bonnet, Fabrice 8046 

Bonnet, Isabelle 1580 

Bonnet, Nathalie 8555 

Bonnetain, Franck TPS667, 

1584, LBA3500^, 3506, 

4018, 4053, 4091, 

e18005 

Bonneterre, Jacques 2070, 

e11012, e11049, e11070, 

e11500, e12506 

Bonneviale, Paul 10076 

Bonnin, Nathalie e15009 

Bono, Petri 507, CRA4502 

Bonomi, Maria 630 

Bonomi, Philip D. 7067, 

e18117, e21069 

Bonomi, Philip LBA4 

Bonomo, Guido e14607 

Bononi, Antonio e13019 

Bonotto, Marta 1044, 

e13058, e13070 

Bonsing, Bert A 4053 

Bonta, Dacian e21076 

Bonta, Ioana e21076 

Bontempo, Kelly M. 9584 

Bonthapally, Vijayveer 570, 

e12515, e16571 

Bonura, Salvatore 586 

Bonvalot, Sylvie 10016, 

10017, 10044, 10096 

Bonzano, Alessandro e15073 


Bookman, Michael A. 5041, 

5056, 5057 

Boolbol, Susan K. e11057 

Boominathan, Rengasamy 

10533 

Boone, Jonathan David 5060 

Boonstra, Philip S e12031 

Boonyaphiphat, Pleumjit 

e14639 

Boorjian, Stephen A. 4526, 

4657 

Booser, Daniel J. 515, 527, 

10613 

Booth, Christopher M. 1583, 

3632, e14003, e15177^ 

Boraas, Marcia 6061 

Borad, Mitesh J. 2579, 

e13052 

Borah, Bijan J 5004 

Boral, Anthony 3007, 9562 

Borbath, Ivan 4006, 4118 

Borchiellini, Delphine 

e16044, e16055 

Borczuk, Alain C. e13067 

Bordeaux, Jennifer 573 

Bordignon, Claudio 2580, 

5059, 6541, 7076, 7085, 

7581 

Bordogna, Walter 10596 

Bordonaro, Roberto e14040, 

e15544, e18026, e18096 

Bordonaro, Sebastiano 

e18002 

Bordoni, Rodolfo TPS7619 

Boren, Todd Patrtick e15501 

Borg, Martin e17544 

Borgato, Lucia 5078, e12037 

Borger, Darrell R. 4021, 

5029, 6606, 8522, 

e14615 

Borges, Eric 3092 

Borges, Virginia F. 9100 

Borget, Isabelle 5569, 9560, 

e16560 

Borghaei, Hossein 2595, 

e13606 

Borgia, Jeffrey Allen 7067, 

e21069 

Borgia, Jeffrey A e18117 

Borgida, Ayelet 4058 

Borker, Rohit e16573, 

e20510 

Bornemann, Antje 8526 

Borner, Markus 9059 

Borowski, Laurel e16532 

Borquez-Ojeda, Oriana 

TPS2619, TPS4700 

Borra, Anna 8077 

Borreani, Claudia 9120 

Borrello, Ivan e18561 

Borriello, Maria Rosaria 9098 

Borsatti, Eugenio 8046 

Borsu, Laetitia 10524 

Bortesi, Beatrice e14042 

Borthakur, Gautam 6528, 

6558, 6585, 6587, 6589, 

6592, 6597, 6603, 

TPS6635 

Bortolin, Michela e19595 

Bortoluzzi, Stephanie 8528 

Boruban, Melih Cem e11008 

Boruta, David M. 5029, 

e15545, e15568 

Borzelleca, Joseph 1563 

Bos, Marc Christiaan Allardt 

1533, 3044, TPS3115, 

7603, 10526, CRA10529 

Bos, Monique M.E.M. 4539 

Bosa, Chiara 2075 


Bosch, Ana 1074 

Bosch, Joaquim 7522, 

e18137, e18143 

Bosco, Jaclyn Lee Fong 9008 

Bose, Ron 503 

Boshoff, Chris 7538, 7562 

Bosl, George J. 4532 

Bosly, Andre 8021 

Bosman, Fred 3509, 3511, 

3575 

Bosomworth, Mike e13083 

Bosquee, Lionel LBA7000, 

7013, 7544 

Bosserman, Linda D. 1018, 

e11562, e13003 

Bosset, Daphne 8540 

Bossevot, Rachel TPS9154 

Bossi, Alberto 4554, 

TPS4689, TPS4691 

Bossi, Paolo 5555 

Bosson, Jean-Luc 1580 

Bossou, Ayoko R 5544 

Bossuyt, Veerle 1045, 10508, 

10558 

Bostrom, Bruce C. 9546 

Boswell, Erica 8043 

Bote, Josiah T. 3594 

Botero, Maria Luisa 10596 

Bott, Matthew Joseph 1541 

Botta, Cirino e13098, 

e14577 

Botta, Mario 7082, 7084 

Botteman, Marc 553, e15189 

Botteri, Edoardo 1049, 1115, 

e19036 

Botti, Gerardo 8581 

Bottini, Alberto 579, 1059, 

e11546 

Botto, Henry e15145 

Bottomley, Andrew 6002, 

6090, 7607 

Bottomley, David LBA4512, 

4551 

Bouabdallah, Kamal 8026, 

TPS8118 

Bouabdallah, Reda TPS1613, 

e18526 

Bouattour, Mohamed 2557, 

e14553, e14660 

Boucard, Celine 2060 

Bouchahda, Mohamed 3547 

Bouchal, Jan 1087 

Bouchalova, Katerina 1087 

Bouche, Olivier 3502, 3507, 

LBA4003, 10007, 10078, 

10089, TPS10102^, 

e14059 

Boucher, Eveline 4032, 

10078, e14148 

Boucher, Jean e19637 

Boucher, Kenneth M. 4525, 

e14177 

Boucher, Yves 1026 

Bouda, Damien 3063, 

e18071 

Boudahna, Lamie e11516 

Boudou-Rouquette, Pascaline 

10042, e13056 

Boue, Francois 8005 

Bouffet, Eric 9519 

Bouganim, Nathaniel 10620 

Boughan, Kirsten Marie 6590 

Boughey, Judy Caroline 1107 

Bougie, Olga 5032 

Bougnoux, Philippe TPS646 

Bouleuc, Carole e19623 

Boumedien, Feriel e13027 

Bounous, Valentina Elisabetta 

627 

Bouquier, Julie 5098 

Bourahla, Khalil TPS646 

Bourgeois, Hugues Pierre 

5018 

Bourgier, Céline 3063 

Bourgouin, Patrick P e17507 

Bourhis, Jean TPS5599 

Bourne Branchu, Veronique 

10006 

Bouros, Demosthenes e17553 

Bourquelot, Priscille M. 

e18572^ 

Bourre, Ludovic e15161 

Bourredjem, Abderrahmane 

3507, 7007 

Boursi, Ben 1507, 1564, 

4619, e15058 

Boussion, Helene 6110 

Boussioutas, Alex TPS4141 

Bouteille, Catherine e21056 

Boutros, Paul C e17539 

Boutsicaris, Christina e15585 

Bouvet, Michael 2044, 

10072, e14014 

Bouyahia, Nezar e11502, 

e11516, e14725, e14726 

Bover, Isabel 5031, 5068, 

7095, e12012, e15575 

Bowen, Deborah 1563, 

e13517 

Bowen, Kristina E. 571 

Bower, Mark 8046, e14574 

Bowes, Barbara e15118 

Bowles, Daniel W. 3017 

Bowling, Mark e17547, 

e17550 

Bowman, Doug 3077 

Bowman, Jill 2500^ 

Bowman, Kevin 2500^ 

Bowman, Lee 1068, 7075, 

e18138 

Bowser, Jessica e13516 

Bowtell, David 5073 

Bowyer, Samantha Elizabeth 

e16004 

Boy, Davide 1073 

Boy, Sandra 7105 

Boyar, Michelle S. 4057 

Boychak, Oleksandr 

Volodymyrovych e14687, 

e19059 

Boyd, Kevin 1535, 7586, 

8015 

Boyd, Leslie R. 5016, 

e15548 

Boyd, Thomas E. 3069, 

6518^, e18047 

Boye, Mark e18138 

Boyer, Michael J. 7079^, 

LBA7500, 7511, TPS7615, 

e19642 

Boyer-Chammard, Agnes 

TPS1613 

Boyette-Davis, Jessica A. 

9082 

Boyiadzis, Michael 6563 

Boyko-Fabian, Mariya e16018 

Boyle, Frances M. TPS1136 

Boyle, Frances 596, 604 

Boyle, Helen Jane 4614, 

e15009 

Boyle, Peter 1509, 1510 

Boyle, Terence 1543, e12038 

Bozcuk, Hakan Sat e11008, 

e14070 

Bozec Le Moal, Laurence 

5505 

Bozec, Alexandre 5521, 

e16044, e16055 

Bozkurt, Mustafa e14698 

Bozzarelli, Silvia e14672 

Bracarda, Sergio 4541, 4627, 

e15112, e15185 

Brach del Prever, Elena Maria 

10055 

Brachman, David 2008b, 

2047 

Brachtel, Elena F 10588 

Brack, Simon 2575 

Bradbear, Joseph e19598 

Bradbury, Angela R. 6095, 

6128 

Bradbury, Penelope Ann 

7093, 7511, e18079 

Brade, Anthony M. 2013 

Bradford, Carol Rossier 

e16014 

Bradford, Chad e13581 

Bradford, Leslie e15545, 

e15568 

Bradley, Cori e13584 

Bradley, Victoria e14574 

Bradley-Garelik, M. Brigid 

6504, TPS9594 

Brady, Anna K. 7595 

Brady, Claire e11569, 

e15078 

Brady, John C e21038 

Brady, Mary Susan 8583 

Brady, Rachel 4125 

Braghiroli, Maria Ignez Freitas 

Melro e12513, e14702 

Brahmbhatt, Himanshu 

e13054 

Brahmer, Julie R. CRA2509, 

2510, TPS2615, 7509, 

7531, 7541 

Brahmi, Sami Aziz e11502, 

e11516, e14725, e14726 

Braicu, Elena Ioana 5070 

Braicu, Elena Ioana 5047, 

5080 

Braicu, Ioana 5034, 5053, 

5058, 5071, e15520, 

e15531 

Braik, Tareq 8085, 9085, 

e18534 

Brain, Etienne TPS662, 

TPS667 

Braiteh, Fadi S. 3023, 3069, 

TPS3111 

Brakchi, Zahir 3052 

Brakemeier, Susan 4632 

Braly, Patricia S. 5012 

Brambilla, Christian 7529 

Brambilla, Elisabeth 7007, 

7529 

Brames, Mary J. 4534, 4598 

Bramhall, Simon R e14625 

Brammer, Melissa G. 1037, 

e11076, e19633 

Brammer, Melissa e11063, 

e11077 

Bramuglia, Guillermo Federico 

e18114 

Bramuglia, Guillermo e14109 

Brana, Irene 2042, 3014, 

3027, 3059, e13001 

Brand, Andrew e21091 

Brand, Lana 1608 

Brandao, Guilherme e18061 

Brandeis, Alison Emily 

e15576 

Brandenburg, Nancy A. 

e18559 

Brandes, Alba Ariela 2, 2057, 

2061, TPS2104, 7550 

703s

Brandes, Johann Christoph 

7048, 10625 

Brandi, Mario e21113, 

e21134 

Brandt, Amanda C. 1513, 

1518, 1520, 1546 

Brandt, Mark 6528 

Branham, Donna 5015 

Brannigan, Robert E 2532 

Branscum, Adam J. e21000 

Brar, Amarpali e15097 

Brase, Jan C. 542 

Brasnu, Daniel 5554 

Brastianos, Priscilla Kaliopi 

2020 

Brat, Daniel 3055 

Bratslavsky, Gennady 

TPS4680 

Bratthall, Charlotte e14531 

Braun, Ada H. TPS670, 

e16528 

Braun, Christian 2000 

Braun, Denis TPS7111 

Braun, Donald Peter 5049, 

e14012 

Braun, Eduardo 572, e21069 

Braun, Jonathan 1052 

Brautigan, David L 8530 

Bravaccini, Sara 10601 

Braverman, Albert S. e18504 

Bray, Emma 10550 

Braylan, Raul 8088 

Braziel, Rita M 8001 

Brazil, Kevin 6035 

Breathnach, Oscar S. e19059 

Breda, Enrico LBA5003 

Bredel, Markus 2001, 2035 

Bredella, Miriam A. 6136 

Breder, Valeriy Vladimirovich 

e14723 

Breen, Laura e15126 

Breen, Stephen TPS5600 

Breen, Timothy 4586 

Brega, Nicoletta 2610 

Brehar, Oana 8057 

Breitbach, Caroline TPS4152, 

e13044, e14566 

Breithaupt, Kirstin TPS4138 

Brekken, Rolf A. e13563 

Bremnes, Roy M. 7027 

Breneman, John C. 9509 

Brenin, Christiana 3047 

Brennan, Cameron W 2028 

Brennan, Michael 9024 

Brennan, Murray F. 10001, 

10015 

Brennan, Rachel Christine 

e13544, e13584 

Brennan, Tina 3533 

Brenner, Adrienne A 3528 

Brenner, Andrew Jacob 

TPS10099 

Brenner, Arnold e14704, 

e18574 

Brenner, Baruch e14067, 

e14571 

Brenner, David J. e15162, 

e17562 

Brenner, Dean E. e18118 

Brenner, Malcolm K. 2558 

Brentjens, Renier J. 2586, 

TPS2619, 6613 

Breslin, Susan 617 

Breslin, Tara M. 1125 

Bressan, Alexsander Kurowa 

10069, e14119 

Bressel, Mathias 3629 

Bressler, Linda R. 2073 

Bretcha, Pere 3064 

Breuer, F. e13100^ 

Breunig, Ian Michael e14522, 

e14626, e14638 

Brew, Christine Taylor 

e13577 

Brewer, Cathy J. 2018 

Brewer, Janice e12507 

Brewer, Jerry D 6571 

Brewer, Katherine e15046 

Brewer, Molly e15563 

Brewer, Takae 1047 

Brewster, Michael 6591 

Brewster, Wendy R. 2591, 

5050, e13063 

Brezden, Christine B. 9111 

Bria, Emilio 630, 4076, 

4541, TPS7109, e14661 

Briani, Chiara 9090 

Briasoulis, Evangelos C. 

e18567 

Brice, Pauline 8002, 8027 

Brichard, Vincent G. 7013, 

7056 

Brichkova, O. e11528 

Brickhouse, Alise 2027, 

2074^ 

Bridge, Julia Ann 9535 

Bridgewater, John A. 

TPS3637 

Brienza, Silvano 3026 

Briere, Josette 8048 

Briggs, Kathryn Jane 

TPS4140 

Brighenti, Matteo 4097, 

e19612 

Bright, Mary Anne 6086 

Briley, Linda P. 10532 

Brill, Yolanda e16035 

Brilliant, Kate E. e21116 

Brindle, James 5102 

Brinkman, Tara M. 9531 

Brisbin, Lori e15209 

Briscoe, Karen P. e19642 

Brissy, Sophie 8555 

Britan, Laura e15187 

Brites, Patricia Chaves 

e14597 

Brito, Rose- Marie 9563, 

9570 

Britten, Carolyn D. 508, 3003 

Britton, David J. e21091 

Brixner, Diana I. 6583 

Broadbridge, Vy e19513 

Broaddus, Russell 1513, 

10510, e13516 

Brocard, Anabelle e19019 

Brocia, Christine 8557 

Brock, Malcolm 1573, 

10625, e17552, e18147 

Brockmann, Michael 1533, 

10526, CRA10529, 

e18000 

Brockmeyer, Norbert 8505 

Brockstein, Bruce 5500, 

10003, 10028 

Broder, Michael S. 3626, 

6057, e14610 

Brodeur, Garrett M. e20008 

Brodie, Seth 10625 

Brodin, Patrik Nils e18527 

Brodowicz, Thomas 3574 

Brodsky, Jeffrey 8577 

Brody, Ed e21012, e21142 

Brody, Joshua 2513 

Broggini, Massimo LBA7501 

Brogi, Edi 557 

Bromberg, Michael e16022 

Bron, Dominique 8048 

Brondfield, Samuel Craig 

e15137 

Brooks, Barry Don 6109 

Brooks, Gabriel 6003 

Brooks, James D 10513 

Brooks, Robert J. 547 

Brooks, Roserika 3081 

Brooks, Sandra Elane 1512 

Broom, Reuben James 

e15050, e15054 

Brose, Marcia S. 5508, 5547 

Brossoie, Susan M 5577 

Brostjan, Christine e14095, 

e14099 

Brouchet, Anne 10076 

Brough, Rachel 3050, 5035 

Brouste, Veronique 9012, 

10035, e14017 

Brouwers, Adrienne H. 10581 

Brouwers, Barbara 1020 

Brown, Andrew M. K. e13107 

Brown, Brita e13581 

Brown, Camille D. 9565 

Brown, Chris 7079^, e16501, 

e19642 

Brown, Christopher 5517 

Brown, Damien e21037 

Brown, Dennis e13123 

Brown, Eric e14642 

Brown, Erika N. 537 

Brown, Gina 3586, e14088, 

e14097, e14132 

Brown, Holly M. 3531, 3587 

Brown, Janet Elizabeth 4642, 

e16528, e19514 

Brown, Jennifer R. 6515^, 

8032 

Brown, Jennifer 3000 

Brown, Jillian e15012 

Brown, John V. e15500 

Brown, Jubilee 5027, 9134 

Brown, Laura E. 9095 

Brown, Martin e13580 

Brown, Michael Paul 8517 

Brown, Monica 4607 

Brown, Myles 576 

Brown, Patrick Andrew 9548 

Brown, Paul D. 2031, 8584 

Brown, Peter D. 3052, 6513, 

6596, 6604 

Brown, Robert S 4101 

Brown, Stephen CW e15194 

Brown, Tanya Renae 9529 

Brown, Tiffany 2052 

Browne, Brigid 617, 633 

Browne, Sarah K 7033 

Brozos Vazquez, Elena Maria 

e14733 

Bruce, Can 10558 

Bruce, Justine Yang 4549, 

4568, 4654 

Bruce, Richard 10574 

Bruchovsky, Nicholas e15201 

Bruckner, Howard e14729, 

e14732, e15576 

Brue, Thierry 8568 

Brueckl, Wolfgang M. e17536 

Bruegl, Amanda S. 1513 

Brueilly, Kevin E e17002 

Bruera, Eduardo 9002, 9023, 

9025, 9049, 9062, 9063, 

9065, 9069, 9096, 9127, 

e19528, e19584, e19599, 

e19603, e19613, e19643 

Bruera, Gemma e14010 

Brufsky, Adam LBA506, 

LBA1000, 1085, 1526, 

1589 

Brugarolas, A. 3064, e16000 

Brugarolas, James 4616, 

TPS4678, e15066 

Brugel Ribere, Lydia 5505 

Brugger, Wolfram 3 

Brugiatelli, Maura 8006, 

e18564 

Brugnara, Sonia e14711 

Brugnatelli, Silvia e13103 

Brugni, Manuela 9098 

Bruins, Harman Maxim 4588, 

e15060 

Brulard, Celine 9536 

Brummendorf, Tim H. 5516^, 

6511, 10552, e19610 

Bruna, Jordi 9090 

Brundage, Michael Donald 

4509 

Brune, Frederique 5069 

Brunelle, Serge e15155, 

e19539 

Brunelli, Alessandro e21070 

Brunello, Antonella 586, 

e13019 

Brunet, Joan 1588 

Brunet, Rene e14023 

Brunetto, Algemir Lunardi 

10593 

Brunetto, Andre 3030 

Bruneu, Yvane 8578 

Bruneval, Patrick 5554, 

e13578 

Brunner, Andrew Mark 6617, 

6618 

Bruno Da Costa, Ligia e14673 

Bruno, Margarita 1060, 

e11015, e18547 

Bruno, Onorina e14553 

Bruns, Rolf TPS4139 

Brunson, Ann 3566 

Brunsvig, Paal 7027 

Brusa, Federica e15192 

Brusquant, David LBA3500^, 

3506 

Brustugun, Odd Terje 7027 

Brutcher, Edith e14614, 

e14692 

Bruzzi, Paolo 1073 

Bryant, Donna M. 9047, 

e16532, e16561 

Bryant-Comstock, Lynda 6060 

Bryla, Christina 2553 

Brünner, Nils 3576 

Bshara, Wiam e11563 

Buadi, Francis 8010, 8035, 

8092, 8096, 8105, 

TPS8116 

Buanes, Trond e14637 

Bubenheim, Michael 8026 

Bubis, Jeffrey Alan e14514 

Bubis, Jeffrey TPS4696^ 

Bubley, Glenn J. 4521 

Buchanan, Adam 1520 

Buchbinder, Aby 1017 

Bucheit, Amanda Dawn 8584 

Buchholz, Thomas A. 594, 

600, 1029, 1032, 1104, 

7062 

Buchler, Markus W e14625 

Buchner, Anton 9125, 

e19587 

Buchner, Thomas 6610 

Buchschacher, Gary L. 

e16031 

Buck, Martin LBA5000 

Buck, Steven e13089 

Buckley, Julliette M 1122 

Buckley, Sarah A e16052 

Buckner, Jan C. 2008b, 

2004, 2031, 2032, 6133 


Buclin, Thierry e11048 

Budach, Volker 5512, 

e16018, e16033 

Budach, Wilfried 5512, 

e11556, e14527, e16033 

Budakoglu, Burcin e11540 

Budd, G. Thomas 620, 

TPS655, TPS10103 

Buddavarapu, Kalyan 3630 

Budde, Klemens 4632, 

10619 

Budha, Nageshwar e13114 

Budihardjo-Welim, Henry 

7056 

Budinska, Eva 3511, 3575 

Budman, Daniel R. 1046 

Budrukkar, Ashwini 

Narsingrao e16021 

Buduhan, Gordon e14695 

Buehring, Hans-Joerg e15577 

Buekers, Thomas E. e15512 

Buelga, Paula e11517 

Buening, Barbara 5082^ 

Buerger, Horst 10627 

Buerki, Christine 4565 

Buettner, Reinhard 1533, 

10526, CRA10529 

Bufalino, Rosaria TPS9155 

Buffoli, Alberto 5513 

Buffon, Rosana e19036 

Bugat, Roland e19640 

Bugdahn, Tim e18565 

Buges, Cristina 3093, 7522, 

7540, 7542, 9129, 

e18137 

Buglioni, Simonetta 1050 

Bui Nguyen, Binh 9536, 

10005, 10006, 10007, 

10009, 10010, 10014, 

10020, 10023, 10027, 

10033, 10035, 10056, 

10057, 10067, 10089, 

10092, 10095, TPS10101, 

TPS10102^, e13600^ 

Bui, Binh 10062 

Bui, Marilyn M 10048, 

10070 

Bui, Son 5543 

Buisan, Oscar 4579 

Bujosa, Juan Ramon e12000 

Bulanov, Anatoly e15025 

Bulgrin, Angela e16549 

Bull, Christian R F 8563 

Bull, Janet 9002 

Buller, Harry e13062 

Bulley, Sue 7562 

Bulone, Linda 9004 

Bulotta, Alessandra 7076 

Bumb, Caroline 1048 

Bumgardner, William Mark 

3005 

Bunge, Sofia 9063 

Bunn, Paul A. 7526, 7532, 

7589, e18077 

Bunnell, Craig A. e16515, 

e16559 

Bunskoek, Sophie 4528 

Bunworasate, Udomsak 

6509^ 

Buonamici, Silvia 9562 

Buosi Silva, Thiago e19528, 

e19584 

Bupathi, Manojkumar 6521 

Buque, Aitziber e17522, 

e21009 

Burandt, E C 10501 

Burattini, Luciano e15074 

Burch, Patrick A. e14594 


Burel-Vandenbos, Fanny 

e12502 

Burg, Kenda CRA6009 

Burger, Jan Andreas 6507, 

6515^, 6517, 6558, 6598, 

TPS6635 

Burger, Renate e18565 

Burgett, Monica 2014 

Burgio, Marco Angelo e17546 

Burgio, Salvatore Luca 

e17546 

Burgos, Emilio 3618, 4089, 

10547 

Burgues, Octavio 1015, 

10500, 10616 

Burhenne, Juergen 10041^ 

Burillon, Jean-Philippe 

e13036 

Burke, James M. TPS4152, 

e13044 

Burke, James 4593, e14566 

Burke, John M. 3069, 

e18522 

Burke, Joseph Malachy 7526 

Burke, Lillian P. e13012 

Burke, Meghan 6606 

Burke, Rachel e14172 

Burke, Thomas W. e16574 

Burke, Wendy 3004, 3048, 

3051 

Burke, William M. 6078 

Burkey, Brian 5573 

Burkhard, Roger 10033 

Burkhardt, Carmen 8059, 

e18532 

Burkholder, Iris 3541 

Burma, Sandeep 10624 

Burmeister, Bryan TPS4145 

Burmeister, Lynn A. 5591 

Burmester, James e14008 

Burn, Timothy 6514^ 

Burnett, Bruce K. 2585 

Burnett, Omer L. e15502 

Burnett, Terrilea 3567 

Burnight, Timothy 9029 

Burningham, Zachary 9525 

Burns, Karen Cristly e20007 

Burns, Kathleen H. 6629 

Burns, Lisa 1559 

Burns, Matthew 7107, 7108 

Burr, Laura 3057 

Burrafato, Giovanni e15544 

Burri, Ryan J. e15162 

Burris, Howard A. 508, 512, 

535, 539, 540, 551, 559, 

618, TPS648, 1018, 1086, 

TPS2621, 3008, 3023, 

3033, 3041, 3067, 3097, 

3102, TPS3118, 7035, 

7100, 7567, 7587, 8510, 

e13076, e13077 

Burris, Howard 3062 

Burris, Patricia 6108 

Burrows, Francis 6577 

Burrows, Jon e21068 

Burstein, Harold J. 6089, 

e16515 

Burt, Michael e14632 

Burt, Paul e18095 

Burtness, Barbara 5566, 

5576, TPS5599, e13504 

Burton, Allen W, e19578 

Burton, Elizabeth M 6587 

Burton, Eric Christopher 

e17019 

Burton, Gary Von e11541 

Burton, Jill K. 5544 

Burton, Jon N 5564 

Bury, Martin J. 6054, 8521 

Bury, Martin Joseph 1025, 

7517, 9113 

Burzawa, Jennifer K. e13516 

Burzykowski, Tomasz 

TPS7610 

Busam, Klaus J. 8586 

Busby, Leslie T. 6109 

Buscariollo, Daniela L. 6019 

Busch, Steffi e19540 

Bush, Nigel 9008 

Bushmakin, Andrew G. 6092, 

e16530 

Bushnell, David L e14600 

Bushunow, Peter Walter 

e17535 

Buso, Marco Murilo e19504 

Busowski, Mary T e16030 

Busque, Lambert 6605 

Busse, Paul M. 5579, 5594, 

e16059 

Bussink, Jan e13111 

Bustami, Rami e19057 

Busteros, Jose Ignacio 4089 

Buta, Eugenia 5532 

Butaney, Mohit 7547, 7588, 

10592 

Butcher, Eugene e21071 

Butera, Alfredo e18002 

Buti, Sebastiano e15160 

Butler, Rachel TPS10633^ 

Butler, Robert W. 2040 

Butler, Steven M 1005 

Butori, Catherine 7591 

Butow, Phyllis Noemi 6111, 

e16507 

Butowski, Nicholas A. 2026 

Butrynski, James E. 1547 

Butt, Nadeem e14703 

Butterfass-Bahloul, Trude 

10081 

Butterfield, Lisa H. 8533 

Button, Anna M 8061, 

e14620, e15580 

Butts, Charles Andrew 

LBA7000 

Buturovic, Ljubomir J 10576 

Buxbaum, James e14679 

Buxhofer-Ausch, Veronika 

e14087 

Buxo, Maria 1588 

Buys, Saundra S. 1502, 1521 

Buyse, Marc E. 611, TPS648, 

1025, 3557, e13055 

Buyse, Marion e13056 

Buyukafsar, Kansu e15104 

Buyukberber, Suleyman 3565, 

e14526, e15047, e19024, 

e20514 

Buyukunal, Evin 3565, 

e21143 

Buzaglo, Joanne S. 9048 

Buzdar, Aman 596, 604 

Buzoianu, Manuela e18073 

Bychkov, Mark B. e19012 

Büchler, Markus W. 4095^ 

Bye, Tyler e13537 

Byer, Jennifer e14519 

Byers, Lauren Averett 7096, 

10612 

Bylicki, Olivier 7574 

Bylow, Kathryn A. 4603 

Byrd, John C. 6507, 6508, 

e13568, e18508 

Byrne, Clare 3613 

Byrne, Jennifer 6512, 8015 

Byrum, Stephanie D. e21039 

Byström, Styrbjörn 6557 

Bytautas, Jessica Peace 

e19616 

Büttner, Reinhard 3550, 

7603 

Böckenhoff, Annette 4628 

Böning, L. e14140 

C 

C. Roach, Emir e11509 

Caballero, Cristina 5068, 

e15575 

Caballero, Hector M e15527 

Caballero, Rosalia 10500, 

10616 

Cabanillas, Fernando 1060, 

8084, e11015, e18547 

Cabanillas, Maria E. 5518, 

Cabanne, Ana 

5547, 5591 

e14598 

Cabel, Luc 6110 

Cabeza Rodriguez, Maria 

Angeles e15033 

Cabibbo, Giuseppe TPS4151 

Cabrera, Antonio 1111 

Cabrera, Paula e15122 

Cabri, Jan 9033 

Cabrita, Fernanda e14673 

Cabuk, Devrim e14618, 

e16015 

Caceres, Jaime e12041 

Cachin, Florent TPS646 

Cadeddu, Christian 9006 

Cadeddu, Jeffrey 4616 

Cadenas, Christina 10551 

Cadiot, Guilaume 4071 

Cadoo, Karen Anne 1543 

Cadore, Anne Claire 10027 

Cadranel, Jacques 10507, 

e18075, e18089, e18102 

Cadron, Isabelle 5034, 5071 

Cafà , Ester Valentina 5093, 

e15547, e15551, e15553 

Caffo, Orazio 7550, e14711, 

e15160 

Caggiano, Vincent 1582, 

1606 

Caglio, Silvia 4122 

Cagney, Jennifer M. e18029 

Cagnon, Laurene e19050 

Cagossi, Katia e11071 

Cahana, Ayelet 559 

Cahill, Daniel P. 2019 

Cahova, Dana e14556 

Cai, Fan e13538 

Cai, Guoxiang 3551 

Cai, Hongyan 4055 

Cai, Jian-Chun e14629 

Cai, Jie 4576, 4588, 4589, 

e13531 

Cai, Ju-Fen e17512 

Cai, Ling 9103, e18121 

Cai, Ruigang e11025 

Cai, SanJun 3551 

Cai, Shirong 3047 

Cai, Wenli 6136 

Cai, Xiaohong e18033 

Cai, Xun e14508 

Cai, Xuwei e21115 

Caillot, Denis 8002, 8009 

Caimi, Paolo Fabrizio 8080 

Cain, Suzanne e19009 

Cainap, Calin 3532 

Caires, Inacelli Queiroz de 

Souza e15562 

Caires-Lima, Rafael e15562 

Cairncross, J. Gregory 2008b, 

TPS2104 

Cairo, Mitchell S. 6537, 

9501, e13022, e21150 

Cajal, Rosana e12000 

Cajfinger, Francis 1580 

705s

Cakir, Betul 9567 

Calabek, Bernadette 2071 

CALABRESE, BERNADETTE 

e12511 

Calabrese, Giuseppe e14042 

Calabrese, Pasquale 2040 

Calabro, Fabio e15003 

Calabuig, Silvia 10079 

Calatrava, Ana M 3618, 

10547 

Calcagnile, Selma e19532, 

e19533 

Calcedo, Maria Celia e12033 

Caldara, Alessia 586, 

e14711, e21102 

Caldas, Carlos 544, TPS1144 

Calderero, Veronica e15144 

Caldes, Trinidad e14147 

Caldito, Gloria e11541 

Caldwell, Imogen Rose 

e15050 

Caleffi, Maira 606, 1522 

Calemma, Rosa 8083 

Califano, Joseph A 5528 

Califf, Robert M 6047 

Caligiuri, Philip e13548 

Caliogna, Laura e13103 

Caliolo, Chiara 630 

Calise, Fulvio 4110 

Calistri, Daniele e18045 

Call, Jason Andrew e14555 

Call, Timothy e13517 

Callacondo, David e15036 

Callado, Rodrigo Barbosa 

e14183 

Callahan, Margaret 2521, 

8515, 8549, 8575 

Calleri, Angelica 2083 

Calles, Antonio 2567, 2568, 

3059, 3066, 3068, 

e13048, e18055 

Callies, Sophie 2554 

Callister, Matthew 6108 

Calmon, Raphael 9517 

Calogero, Raffaele A e13527 

Calvani, Nicola e11001, 

e11547 

Calvert, Paula 2609 

Calvetti, Lorenzo 3555, 

e14040 

Calvo, Alejandro R. e17506 

Calvo, Alfonso e15041 

Calvo, Begoña e17522, 

e21009 

Calvo, Elena Galve 10512, 

10595 

Calvo, Emiliano 3005, 3059, 

3066, e15111 

Calvo, Ezequiel 10583 

Calvo, Felipe A. e12003 

Calvo, Isabel 602, e11006, 

e11517 

Calvo, Katherine R. 8088, 

8104, e18568 

Calvo, Lourdes 1001, 10500, 

10616 

Calvo, Ovidio Fernández 

e15067, e15076, e15077 

Camacho, Ignacio e15171 

Camacho, Luis H. 2510, 

e13040 

Camacho, Mercedes 5590 

Camara, Oumar e15566 

Camargo, Veridiana Pires De 

e20502 

Cambois, Anne 3052 

Cambon, Alex e21144 

Camci, Celalettin 3565 

Camerini, Andrea e18074 

Cameron, David A. 502, 513, 

TPS660, TPS665, 

TPS1144, 6091 

Cameron, Silke e13039, 

e14707, e21128 

Camey, Suzi Alves 1522, 

10593 

Camidge, D Ross 7508, 7601 

Camidge, D. Ross 3007, 

7504, 7526, 7532, 7534, 

7589, 7596, e21120 

Caminiti, Caterina 9120 

Camitta, Bruce M. 9504 

Camoriano, John Kelly 8043, 

8053 

Camp, Aaron C 4108 

Camp, Melissa 1122 

Campagnolo, Marta 9090 

Campana, Davide e14647 

Campanella, Delia e20512 

Campanha, Daniel e14680 

Campassi, Cristina 10572 

Campbell, Alicyn TPS7615 

Campbell, Fiona e14625 

Campbell, Jenny 4061 

Campbell, Michelle M. 587 

Campbell, Nancy 9084 

Campbell, Olivia M. 10563 

Campbell, Steven C. e15095 

Campbell, Toby Christopher 

9039 

Campbell-Baird, Cynthia 

e14520 

Campbell-Hewson, Quentin 

9542 

Campelo, Rosario Garcia 

1531 

Campenni, Giuseppe e18065 

Campian, Jian Li e17552 

Campion, Loic e11551 

Campitelli, Maura e15535 

Campone, Mario 530, 532, 

540, 551, 559, 2082, 

3052 

Camporeale, Jayne 6093 

Campos Balea, Begoña 

e15067, e18040, e18146 

Campos, Angel 5520, 

e14147, e15094, e18069, 

e18106, e21015 

Campos, Arinilda Silva 

e16568 

Campos, Begoña e18070 

Campos, Conceicao Souza 

e15509 

Campos, France 636 

Campos, Marta Carmona 

e14733, e19505 

Campos, Tiffany 4125 

Campos-Parra, Alma Delia 

e18114 

Camps, Carlos 7058, 7060, 

10594, e18131, e18137, 

e18143 

Camuset, Juliette 1580 

Canadas, Carmen 5520, 

e15094, e18069, e18106, 

e21015 

Canal, Barbara 7585, e18104 

Canamares, Irene 4620 

Canar, Jeff 572 

Cancian, Maurizio e19592 

Candamio, Sonia 10534, 

e14733, e19505 

Candelaria, Myrna 6599 

Candeloro, Giampiero e11041 

Canela, Mercedes 7041 

Canessa, Pier Aldo e17533 

Canet, Ramon e11036 

Cañete, Adela TPS9596, 

10082 

Canfield, Angela C. e15179 

Cangiarella, Joan e11010 

Cangir, Ayten Kayi 1596 

Canil, Christina M. e15537 

Cannell, Amanda 10050 

Canney, Peter TPS665 

Cannita, Katia e14010 

Cannon, Donald Maurice 

e13537 

Cannon, George M. TPS9152, 

e13537 

Cano, Oscar D. 10628 

Cano, Stefan 9042, 9043 

Canon, Jean-Luc e14044, 

e14060, e19511 

Cañon, Rosa e16000 

Canonici, Alexandra 632, 

e13520 

Canter, Daniel e15006 

Canter, Robert J. e19013 

Cantin, Guy 8002 

Cantore, Maurizio 10611 

Cantos, Blanca e11035, 

e12012, e18521 

Cany, Laurent 9012, e14023 

Canzler, Ulrich 5005, 5031 

Cao, Gabriel e19569 

Cao, Junning 3038 

Cao, Liang 7033 

Cao, Lulu e21116 

Cao, Yabing e18517 

Cao, Yang 8042, 8106, 8107 

Cao, Yen Thi Kim Hong 

e13588 

Capaldi, Antonio e15133 

Capanu, Marinela 3577, 

4061 

Capasso, Immacolata e11052, 

e13539 

Capdevila, Enric 1120 

Capdevila, Jaume 3014, 

3571, 4119, 4122, 10546, 

TPS10632, e14088, 

e14671, e21021 

Capdevila, Laia 7540, 9129, 

e12504, e15001, e18131, 

e18143 

Capellades, Jaume 2045 

Capelletti, Marzia 7510 

Capelletto, Enrica e18103 

Capelli, Francesca e14094 

Capelli, Laura e18045 

Caplen, Natasha 9511 

Caplin, Martyn E 4123, 

TPS4153, e14696 

Caplin, Martyn 4121, 

e17543, e19581 

Capo, Adolfo Miguel e11087 

Capobianco, Gaetana 8066, 

8083 

Capozza, Scott TPS669 

Capozzi, Federica 10066 

Cappelleri, Joseph C 6092, 

e16530 

Cappelletti, Mariarosa e11546 

Capper, David 6519 

Cappetta, Alessandro e12037 

Cappuzzo, Federico 3521, 

e21018, e21095 

Capri, Giuseppe 3080 

Capriglione, Stella 5093, 

5094, e15547, e15550, 

e15551, e15553 

Caprino, Massimo TPS9154 

Caprio, Giuliana e11514 

Caprio, Kimberly Anne 1109 

Capuano, Loreto Giovanni 

e19002 

Capussotti, Lorenzo 4110, 

e14113 

Caraco, Corradina e14130, 

e19034 

Caraco, Corrado 8573, 8581, 

e19034 

Caramanti, Miriam e21070 

Carames, Cristina 5520, 

e14147, e15094, e18069, 

e18106, e21015 

Carapella, Carmine Maria 

2037, 2085 

Carasi, Stefania 1007 

Caratu, Ginevra 10511 

Carayol, Marion 9074 

Carballido, Estrella M. 5564, 

6568, 6608 

Carballido, Marcela e14521 

Carballo, Mar e11028 

Carberry, Mary 4111 

Carbone, Antonino 7585, 

e18104 

Carbone, David Paul 6038, 

7094 

Carbone, David P 7568 

Carbone, Giuseppina 4661 

Carbone, Salvatore Francesco 

e13098 

Carboni, Joan M. e15151 

Carcas, Antonio e13085 

Carcereny Costa, Enric 7540, 

7542, e18131, e18137, 

e18143 

Carcereny, Enric 1531, 3093, 

7522, 9129 

Carde, Patrice P. 8002 

Cardellino, Giovanni 3612 

Cardenal, Felipe 7522, 

e18137, e18143 

Cardenas, Andres e21000 

Cardenas, Jessica C e14505 

Cardenas, Joel e15556 

Cardenas, Jose M e11517 

Cardenes, Higinia Rosa 

e14683 

Cardillo, Giuseppe e19033 

Cardillo, Thomas M. 3091 

Cardin, Dana Backlund 

e14503 

Cardona Zorrilla, Andres 

Felipe e12039, e18114 

Cardona, Jose Vicente 

e18031, e18055 

Cardonick, Elyce 1127 

Cardoso, Fatima TPS661, 

1022, 9022 

Cardoso, Mauro 9557 

Cardozo, Timothy 9507 

Carducci, Michael Anthony 

2042, 3009, 3020, 

TPS3117, 4511, 4550, 

4559, 4564, 4619, 4642, 

4654, 4655, 4663, 4667, 

TPS4687, 6026, 10503, 

e15058, e15188 

Carella, Angelo Michele 2539, 

8006 

Carelli, Bruno e19552 

Carew, Jennifer S. 3073 

Carey, Brittany 10588 

Carey, George e17549 

Carey, Lisa A. TPS656, 

CRA1002, 1006, 1008, 

1524, 10515 

Carey, Thomas E e16014 

Carinelli, Silvestro 5090 

Caristi, Nicola e11056 


Carles, Joan LBA4518, 4574, 

TPS4692^, e15001, 

e15041, e21021 

Carlile, David 7544 

Carlo, Victor 1060, e11015 

Carlomagno, Chiara e13509 

Carlotti, Agnes e21014, 

e21046 

Carlotti, Carlos Gilberto 

e12512 

Carlson, Dawn M. 3532, 

7512, e13583 

Carlson, Heather R. 4130, 

4131 

Carlson, Josh John 560 

Carlson, Julie R. e19515 

Carlson, Rachel 4565, 

e15132 

Carlson, Robert O. e13581 

Carlson, Robert W. 2514 

Carmack, Condie Edwin 

10598 

Carmichael, Courtney e15084, 

e15178, e16563 

Carmichael, Lakeesha 3101 

Carmona, Maria Soledad 

e11035 

Carnaghi, Carlo 623 

Carneiro, Bruno Gustavo 

Muzzi Carvalho e12018 

Carnero Moya, Amancio 

e16037 

Carneseca, Estela C. e14599 

Carney, Desmond e19632 

Carney, Walter P. e15062, 

e15121, e21146 

Carnio, Simona 5546, 5548 

Carolan, Hannah 7020 

Caroli, Manuela 2037 

Caron, Huib 9517 

Caron, Philip 4057 

Caron, Whitney Paige 2591, 

5050 

Carpanese, Livio e14654 

Carpenito, Jennifer 4662 

Carpenter, Christopher L. 

e13601 

Carpenter, Christopher 4605, 

e15059 

Carpenter, Janet S 525 

Carpenter, John T. 10509 

Carpenter, William Ruffin 

5539, 6104, e15184 

Carr, Brian I. e14720 

Carr, Ruth Elizabeth e13522 

Carrasco, Eva Maria 1001, 

10500, 10616 

Carrasco, Javier e14044, 

e14060 

Carrasquillo, Jorge A. 

TPS4694, TPS9595 

Carrato, Alfredo TPS4135, 

e12033, e16029, e19590, 

e21104 

Carré, Typhanie 8568 

Carreca, Ignazio Ugo e14676 

Carreno, Beatriz M 2525 

Carreño, MariCruz e12015 

Carrera, Sergio e11525, 

e17522, e18031, e21009 

Carrere, Sebastien 3633 

Carrigan, Angela e16561 

Carrillo-de Santa Pau, Enrique 

e15191 

Carroll, Andrew J 9548 

Carroll, June e12034 

Carroll, Mary I. 639, 3108 

Carroll, Paul A. 1511 

Carroll, Peter 2564 


Carroll, William L. 9507, 

CRA9508, 9543, 9548 

Carson, Kenneth Robert 

4594, 8080 

Carteni, Giacomo TPS4151, 

4627, TPS4683, e15185 

Carter, Corey Allan 7033, 

7103 

Carter, David 2552 

Carter, Ebony B. 5063 

Carter, Jeanne 9104 

Carter, John A. e15189 

Carter, Kirsten 3003 

Carthon, Bradley e15006 

Cartmel, Brenda TPS669, 

TPS1614 

Cartmill, John TPS9153 

Cartron, Guillaume 8026 

Cartwright, Thomas H. 3522, 

3523, 3525, 3626, 6109, 

e16536 

Caruntu, Irina Draga e15032 

Carus, Andreas e21110 

Caruso, Melania e15544 

Caruso, Michele 623, e18002 

Carvajal, Lucas E. 4660 

Carvajal, Richard D. 3016, 

8507, 8515, 8549, 8575, 

8598, 10004, 10019, 

TPS10103 

Carvalho, Adriana Camargo 

e14150 

Carvalho, Andre Lopes 

e16046 

Carvalho, Benilton e16041 

Carvalho, Carlos 3547 

Carvalho, Heloisa de Andrade 

e15562 

Carvalho, Rafael Augusto 

Ribeiro e12018 

Casadei, Riccardo e14647 

Casadei, Virginia 4084 

Casadio, Rita 10087 

Casado, Antonio LBA5000, 

5038, 5087, 10052, 

10079, e20513 

Casado, Enrique 1570, 9073, 

e11028 

Casado, Esther 4079 

Casado, Luis Felipe 6512 

Casado, Victoria 5520, 

e15094, e18069, e18106, 

e21015 

Casagrande, Mariaelena 3612 

Casal Rubio, Joaquin e17545, 

e18040, e18146 

Casali, Paolo Giovanni 

TPS9155, LBA10008, 

10009, 10013, 10017, 

10022, 10026, 10053, 

10065, 10067, 10079, 

10096 

Casali-da-Rocha, Jose Claudio 

e14027 

Casalonga, François e19539 

Casanova, Claudia 5513 

Casanova, Michela 9517, 

9519, TPS9597^ 

Casares, Carolina 1608 

Casares, Maria de los Angeles 

10534 

Casaretti, Rossanna LBA4001 

Casas, Ana Maria 1011 

Casas, Maria Isabel 1001, 

10616 

Casasnovas, Olivier 8068 

Casassus, Philippe 8014 

Casbourne, Daniela 8101 

Cascales, Almudena e15033 

Casciano, Roman e14525, 

e14627, e15043 

Cascinu, Stefano e14040, 

e14086, e14561, e14663, 

e15074, e21070 

Cascione, Luciano 1007 

Case, Ashley Stephens 5101 

Case, Emily Christine 9092, 

e19624 

Case, L. Doug 9108 

Casey, Michelle LBA8509 

Casey, Rory e13570 

Casher, Jennifer e11531 

Cashy, John 2532 

Casillas, Jacqueline N. 6030 

Casini, Beatrice 1050 

Caspar, Clemens B. e19648, 

9059 

Cassano, Alessandra e14156, 

e16553 

Cassar, Alexia 10013, 10062 

Cassells, Lucinda Jane 

e19543 

Cassier, Philippe Alexandre 

3022, 10027 

Cassier, Philippe A 4614, 

10005, 10006, 10033, 

10078 

Cassinello, Javier e11074 

Cassingena, Andrea 3570 

Cassivi, Stephen David 4062 

Casso, Deborah 1590, 1591 

Castagneris, Nicolas e11044, 

e11501, e18125 

Castagneto, Bruno e14676 

Castaing, Denis 3547 

Castaldo, Noemi e11052 

Castaneda Altamirano, Carlos 

2097 

Castañeda, Carlos 642 

Castaño, Patricia e11024 

Castelao, Jose E 4575 

Castellana, Ramon 4122 

Castellano, Daniel E. 4118, 

4119, 4584, 4620, 

TPS4674, TPS4685, 

10546, e15001, e15041, 

e15149 

Castells, Antoni 3536, 3553 

Castelo, Beatriz 10546 

Castelvetere, Marina e21092 

Castera, Laurent e14553 

Castex, Marie Pierre 10076 

Castiglione, Monica M. 504 

Castillo, Javier Omar e15570 

Castillo, Jorge J. 8045 

Castillo-Martin, Mireia 

e14552 

Castillo-Tong, Dan Cacsire 

5034, 5071 

Castonguay, Vincent 5022 

Castro Gomez, Enrique 

e18040 

Castro Junior, Dalvaro Oliveira 

e16046 

Castro, Carlos e12039 

Castro, Elena 1545, 4653 

Castro, Gilberto 5588, 

e20502, e21040 

Castro, Javier e18011 

Castro, Kathleen M. 6086, 

9047, 9144, e16532, 

e19633 

Castro, Rafael amaral de 

e14173 

Catala, Mauricio 2515 

Catalan, Gustavo e11074 

Catalano, John V. 6624 

Catalano, Paul J. 4030 

Catalano, Vincenzo 4084, 

e14135 

Catalan, Gustavo e11081 

Cataldo, Francesco e19036 

Catane, Raphael e14143 

Catapano, Carlo 4661 

Catchatourian, Rosalind 

e18534 

Catenacci, Daniel Virgil 

Thomas 2561, 4022 

Cates, Joe e14632 

Cathomas, Richard 3595, 

e19648 

Catoira, Isabel e11523 

Caton, John Robert 7502 

Catot, Silvia 5068, e12012, 

e15575, e18053 

Cattaneo II, Richard e15512 

Cattani, Fabio 2085 

Catton, Charles N 9131, 

10050 

Catton, Pamela 9131 

Cau, Maria Chiara e19634 

Cauchy, Francois 3609 

Caudle, Abigail Suzanne 1130 

Caudwell, Beth e15050 

Caulin-Glaser, Teresa 9115 

Causeret, Sylvain 1584 

Cauvin, Cecile e19539 

Caux, Christophe 10562 

Cavalcante, Ludimila 7049 

Cavaletti, Guido 9089, 9090 

Cavallero, Erica e15192 

Cavallo, Federica e13527 

Cavallo, Michele 2057 

Cavanagh Podesta, Mercedes 

e12003 

Cavanna, Luigi 2057 

Cavenagh, James D. 8018^ 

Cavic, Milena e12020 

Cavicchiolo, Tina e15056 

Cavina, Raffaele 7085, 7585, 

e18104 

Cawkwell, Lynn e13554 

Cayir, Kerim e14526 

Cayre, Anne 1051, 10507 

Cayre, Yvon E e21014, 

e21046 

Cazaly, Angelica 8566 

Cazap, Eduardo L. e16505 

Cazes, Aurelie e18102 

Cazin, Lionel e21156 

Cazzaniga, Marina Elena 

9090 

Cazzaniga, Massimiliano 519, 

1500 

Ceacareanu, Alice C. e15042 

Cease, Kemp Bailey e18118 

Cebon, Jonathan S. 8542, 

e17539 

Cebrian, Juan Luis e20513 

Ceccaldi, Joel 9012 

Ceccarelli, Matteo 1073 

Cecconetto, Lorenzo e11054 

Cecere, Fabiana Letizia 

e18074 

Cechini, Luis 4579 

Cedres, Susana 7041 

Cehelsky, Jeffrey 3062 

Cejas, Paloma 3618, 10547 

Celik, H.Eray e21050 

Celik, Ismail e19024 

Celio, Luigi 9133 

Celis, Aneska e20502 

Celiz, Pamela 4579 

Cella, David CRA4502, 6092, 

6117, 8054, 9020, 9056, 

9099, 9112, 9532, 

e16530 

707s

Ceraulo, Domenica 4017 

Cerbone, Linda e15003 

Cercek, Andrea 3577, 

e14112 

Cereda, Stefano 4017 

Cerello, Piergiorgio e13093 

Ceresoli, Giovanni Luca 7082 

Cerfolio, Robert 7008 

Cerhan, James R. 6571, 

8061, 9057 

Cerillo, Ivana 1554 

Cermak, Jaroslav 6559 

Cerny, Jan 6569 

Cerny, Thomas 9045, e14544 

Cerrato, Sebastian e12511 

Cerullo, Vincenzo e13035 

Cervantes, Francisco 6505^, 

6514^, 6625^, 6626^, 

TPS6639 

Cervantes-Ruiperez, Andres 

2567, 2568, 3021, 3062, 

3535, TPS3637, e13048, 

e13095^, e13097^, 

e13114, e14088, e14589 

Cervera Grau, J. M. 4587 

Cervera Grau, Jose Manuel 

e15144, e16025 

Cervio, Andres e12511 

Cesar, Isabela Costa e13008 

Cesaretti, Jamie A. e15162 

Cescutti, Jessica 3018^ 

Cesne, Axel Le 10010, 

10095 

Cesta Incani, Ursula e13512, 

e13572 

Cesta, Alisia e11041 

Cetin, Bulent e14526 

Cetin, Karynsa 1581, 4659, 

e15147, e15169 

Cetina, Lucely e15569 

Cevik, Duygu 3565 

Ceyssens, Sarah 3559 

Cha, Edward 8580, e19046 

Cha, Joo Hee e11508 

Chabaud, Sylvie 10027, 

10092, 10095, 10562, 

e16036, e16560 

Chabolle, Frederic e16013 

Chabot, John A e14708 

Chachoua, Abraham e18139 

Chacko, Celin 1126 

Chacko, Raju Titus e15082 

Chacon Lopez-Muniz, Jose 

Ignacio 10500, 10616, 

e11074 

Chacon, Jose Ignacio e11543, 

e19596 

Chacon, Matias e14598 

Chad, Amine Mohammed 

e11516, e14725, e14726 

Chadha, Manpreet 3060 

Chadjaa, Mustapha 

TPS4692^, e15115 

Chae, Jung Min e14128 

Chae, Yee Soo 3554, 6536, 

6538, 8023, e14074, 

e14570, e18533 

Chae, Young Kwang 537 

Chae, Young K 536 

Chaft, Jamie E. 7014, 7580, 

10560 

Chagnon, Sophie 8540 

Chagpar, Anees B. 1109, 

1121, 1571, 1595, 

e16511 

Chai, Akiko 6591 

Chai, Christy Yoon-Hee 10070 

Chai, Feng 4117, 4545, 

8519 

Chai, Li e13505 

Chaib, Iman 4579 

Chaïbi, Pascal 6110, e18505 

Chaigneau, Loic 10014, 

10020, 10023, 10078, 

TPS10102^ 

Chaix, Marie 10014 

Chakraborty, Amitava 2581 

Chakraborty, Nitya e21135 

Chakravarti, Arnab 2001, 

e19040, e21044 

Chakravartty, Arunava e13583 

Chalabi, Nassera 1051 

Chalas, Eva e15504 

Chalela, Patricia e16566 

Chaleteix, Carine 8014 

Challapalli, Amarnath e21093 

Chalmers, Jeffrey J. e21124 

Chamberlain, Marc C. 2046 

Chambers, Glenda 3025 

Chambers, Mark Steven 

e19520 

Chamorey, Emmanuel e16051 

Champ, Colin E. e11505 

Champeny, Torie L 6063 

Champion, Laurence TPS646 

Champlin, Richard E. 4533, 

6501, 6529, 6540, 6546, 

6551, 8040, 8102 

Chan, Adrien M. 6049 

Chan, Alexandre 9041, 

e13023, e18546 

Chan, Amy e12017 

Chan, Annie W 5579, 5594, 

e16059 

Chan, Anthony T. C. 5502, 

5511, e14085, e14528, 

e15110 

Chan, Ching-Wan 1064 

Chan, Dan e18077 

Chan, Daniel Boon Yeow 

2551, e13002 

Chan, Edward Michael 3001, 

3008 

Chan, Emily 3535, e14503 

Chan, Eric Chun Yong 

e13023 

Chan, Esther 6130 

Chan, Geoffrey 6584 

Chan, Godfrey Chi Fung 

e12006 

Chan, Iris Tan-Chi 2566 

Chan, Jennifer A. 4027, 

4125, e19586 

Chan, John K. 3058, e13078 

Chan, Keith S. e15002 

Chan, Kelvin K. e14003, 

e14532, e16558 

Chan, Kelvin 5587, e14171 

Chan, Kenjey e14020 

Chan, Matthew 6018 

Chan, Megan 2525 

Chan, Pierre e14545 

Chan, Sabrina e13583 

Chan, Stephen E 2564 

Chan, Stephen Lam e14528 

Chan, Stephen 1013, 1014, 

1098 

Chan, Susanne M. 4613, 

4633 

Chan, Timothy An-thy 7052 

Chan, Yiong Huak e18528 

Chanan-Khan, Asher Alban 

Akmal 8035 

Chance, Lacey 4574 

Chand, Gyan e16023 

Chand, Vikram K. 7557, 

7558, e13011 

Chandarlapaty, Sarat 10618 

Chander, Sarat 3629 

Chandiwana, David e15189 

Chandler, G. Scott e13000, 

e13113 

Chandler, James 2035, 

TPS2107 

Chandler, Jason Claud 

TPS1143 

Chandra, Anita e19518 

Chandra, Subhash 5104 

Chandra, Sunandana 8589 

Chandramouleeswaran, 

Sindhu 5577 

Chandramouli, Gadisetti V.R. 

e13045 

Chandramouli, Nitin B. 

TPS2103 

Chandran, Raj e13583 

Chandrashekar, A e15003 

Chandrinos, Vassilis 7564 

Chandwani, Kavita Dayal 

9009, 9010, 9028, 9141, 

9142 

Chang, Andrew C. 7037 

Chang, Anne L. S. e19048^ 

Chang, Bill H. 9555 

Chang, Chien-Hsing e13005, 

e18513 

Chang, Daniel Tandel 4045 

Chang, Ellen T. 6050 

Chang, Eunice 3626, 6057 

Chang, Gee-Chen TPS7614 

Chang, George J. 3556, 

3598, 4060, TPS10632 

Chang, Heung-Moon e13104 

Chang, Howard T. 2056 

Chang, Hyun e14559, 

e18092 

Chang, Ilsung e13000, 

e13113 

Chang, Joe Y. 7062 

Chang, Jose 4660 

Chang, Julie E. 8064 

Chang, Kay W 5525 

Chang, Kenneth J. 4055, 

e14546 

Chang, King-Jen 1043 

Chang, Martin 1019 

Chang, Mike e15117 

Chang, Monica 10586 

Chang, Sei-Kyung e18501 

Chang, Susan Marina 2026, 

2101 

Chang, Tung-Chieh e16050 

Chang, Twan Ying 1061 

Chang, Victor Tsu-Shih 

e14727, e19638, e19639 

Chang, Victor T e14124, 

e14125, e18516, e19606 

Chang, Yao-Yin 1043 

Chang, Yen-Hwa e15064 

Chang, Yu-Lin 8035 

Chang, Yuan 8577 

Chang, Yuchiao 9004 

Chanthawong, Suthan e13023 

Chantrathammachart, Pichika 

e14505 

Chao, Angel 5109 

Chao, Bo H. e13537 

Chao, Calvin 549^, 3626 

Chao, David 7562 

Chao, Herta H. 6033 

Chao, Jeff 6615 

Chao, Joseph e13116, 

e14182 

Chao, Ju-Hsien e16533 

Chao, K. S. Clifford 7050, 

e15162, e17562, e21097 

Chao, Richard C. 4118 

Chao, Samuel T. 2018, 2076, 

2092, 2100 

Chao, Samuel 4106 

Chao, Ta-Chung 1079 

Chao, Yee 4108, e14605 

Chapman, Judy-Anne W. 500, 

501, 538, 561, e11005 

Chapman, Paul B. LBA8500^, 

8501, 8502^, 8515, 8549, 

8598 

Chapman, Robert e12019 

Chapotot, Louis 4618 

Chappell, Bridget e15056 

Charalambous, Charis e15030 

Charamis, Helen 1099 

Chari, Ajai e21006 

Charif, Mahmoud TPS3116 

Charlot, David e21047 

Charlot, Marjory 6097 

Charlson, John A. 555, 563, 

6063 

Charnsangavej, Chusilp 3544 

Charpentier, Danielle 3504 

Charpentier, Eric 1011 

Charpentier, Julie e15161 

Charpentier, Kevin 4098 

Charpentier, Monica e21079 

Chasalow, Scott D. 8593 

Chase, Dana Meredith 6132 

Chastek, Benjamin e14013, 

e14016 

Chateau, Marie-Christine 

10018 

Chatelut, Etienne 2549, 4614 

Chatfield, Mark D. 4531, 

TPS4681, 5081 

Chatman, David 3015 

Chatta, Gurkamal S. 2588 

Chatterjee, Anirban LBA4001 

Chatterjee, Aradeep 2581 

Chatterjee, Ashim Kumar 

2581 

Chatterjee, Nilanjan 1521 

Chatterton, Robert T. 518 

Chaturvedi, Pankaj 5585, 

e16021 

Chau, Ian LBA4000, 

TPS4146, e14088 

Chau, Noan Minh 3098 

Chau, Noan-Minh e16024 

Chau, Quincy 8028 

Chau, Zeling 4059, e14691 

Chaubet Houdu, Marie 

e18071 

Chaudhary, Imran 3093, 

e14019 

Chaudhary, Rekha T. 

TPS3116 

Chaudhri, Shalini e11062 

Chaudhry, Arvind 2585 

Chaudhry, Muhammad Ali 

4045 

Chaugule, Shraddha e18097 

Chauhan, Bharat 5585 

Chauhan, Cynthia 6133 

Chauhan, Lata e13568 

Chauhan, Nikhil 6530 

Chauhan, Sanket e15171 

Chauhan, Shailendra 

TPS4136 

Chaukar, D. 5585 

Chaussy, Christian G e15194 

Chauvie, Stephane 8077, 

e13093 

Chavarri-Guerra, Yanin 524, 

596 

Chaves-Conde, Manuel 

e16037 

Chavez, Jose Fortino e11565 


Chavez, Julio C. 6568, 6575, 

6588, 6608, 8084 

Chavez-Gallegos, Silvia 9554 

Chavez-Mac Gregor, Mariana 

537, 600, 1104 

Chawla, Sant P. 3015, 

10009, 10010, 10013, 

10036, 10067, TPS10100, 

TPS10101 

Chay, Christopher H. e13109 

Chay, Wen Yee e16024 

Chayahara, Naoko e16034 

Che, Yebin e14716 

Cheadle, Jeremy 3516 

Cheang, Maggie Chon U. 

1008, 3628 

Chebib, Amale 6110, e18505 

Checka, Cristina e11064 

Cheedella, Naga K Sucharita 

4086 

Cheema, Faisal N. e11541 

Cheerva, Alexandra C 6537 

Chehab, Nabil 4577 

Chekerov, Radoslav 5031, 

5034, 5044, 5053, 5064, 

5070, 5071, 5080, 

e15520, e19558 

Chekmasova, Alena A. 2586 

Chelis, Leonidas e14567 

Chellini, Federico e13098 

Chemler, Joseph A. e12026 

Chen, Albert 4660 

Chen, Alice P. 1010, 

TPS1138, 3049, 3054, 

3087, 5020, e19633 

Chen, Alice 3031, 9144 

Chen, Allen C. 7584 

Chen, Amy Y. 5560, 5570 

Chen, Bang-Bin 1079 

Chen, Beiyun 1083 

Chen, Bingshu E 2547, 

4509, TPS5600 

Chen, Bo e14511 

Chen, Caroline 8587 

Chen, Charles 3032 

Chen, Chun e18013 

Chen, Chun-yan 5535 

Chen, Clara A 6097 

Chen, Clara 2526, 4569, 

e20510 

Chen, Clark 2101, 10553 

Chen, Cong 2512 

Chen, Connie e15061 

Chen, Daniel S. e13000, 

e13113 

Chen, David 3578, 4526, 

10596, 10619 

Chen, Diana M e19048^ 

Chen, Dongfu e14511 

Chen, Eric Xueyu 3082, 

5587, 7511, e14524 

Chen, Frank 5007 

Chen, Gong e13583, e14674 

Chen, Gongyan 7520, 7548 

Chen, Haiming e18549 

Chen, Han Yang e19030 

Chen, Hao 6066 

Chen, Heidi 7008 

Chen, Helen X. 534, 3020, 

7033 

Chen, Helen 4047, 4639 

Chen, Herbert e14554 

Chen, Homer e13555 

Chen, Hong 2520^ 

Chen, Hongbin 7541, e17535 

Chen, Hui-Ling e14516 

Chen, Huiqin 1054 

Chen, Isan 4548, 4644, 

TPS4697 


Chen, James Lin 4617 

Chen, James e13123 

Chen, Jen-Shi 4118 

Chen, Jianhua 7559 

Chen, Julianne 6529 

Chen, JUN e17514 

Chen, Ken 503 

Chen, Kezhong e21103 

Chen, Kuen-Feng e14516 

Chen, Kuo-Hsing e18034 

Chen, Lee-may 5022 

Chen, Lei 6583, 6594, 6600, 

7520 

Chen, Leo 6069 

Chen, Li-Tzong TPS4149 

Chen, Lieping 2514, 5506 

Chen, Ling Y. 9105 

Chen, Ling 6079, 6081, 

e19593 

Chen, Lu 9524 

Chen, Min Hua e14701 

Chen, Minshan 4033 

Chen, P.C. e11561 

Chen, Pei Xian 1538 

Chen, Pei-Jer 4033, 4108, 

e14516 

Chen, Peng-Yu e11526 

Chen, Ping 7091, 8074 

Chen, Robert W. 8027, 

e13079 

Chen, Ronald C. 4647, 4658, 

6032, 6037, 6093, 6107, 

e15184 

Chen, Shang-Hung TPS7614 

Chen, Shiuan e15114 

Chen, Siyu e13526 

Chen, Stephanie 3058 

Chen, Steven L. 1035, 1117 

Chen, Sting e20507 

Chen, Susan 3077 

Chen, Suzie TPS3112 

Chen, Tai-Tsang 8539 

Chen, Wallace Jian Jun 

4100^, 5551 

Chen, Wallace 5580 

Chen, Wei e17528 

Chen, Wei-Wu 1061, 1079, 

e14576 

Chen, Weidong 4092, 

e14575 

Chen, Wengen e13075 

Chen, Wenming 8095, 8097 

Chen, Xi 7532 

Chen, Xiang 9518 

Chen, Xiangai 2598 

Chen, Xiaoxia 7535, 10527, 

e18123 

Chen, Ya-Fang e16050 

Chen, Yao-Tseng e17539 

Chen, Yen-Lin 10058 

Chen, Yi-Bin Albert 6606, 

6617, 6618 

Chen, Ying 4503 

Chen, Yingbei 4604 

Chen, Yinpu 4006 

Chen, Yongshun e14645 

Chen, Yuh-Min 7519^, 7557, 

e18132 

Chen, Zhengjia 2576, 5560, 

7059, 7097, e14169, 

e14170, e14614 

Chen, Zhengyi 1569 

Chen, Zhi-Yu 3598 

Chen, Zhihong 7039, 

e13510, e18090 

Chen, Zhiwei 7091 

Chen, Zhong-pin e18121 

Chen, Zhong-ping e12503 

Chen, Zhuo Georgia e13110, 

e21161 

Chen, Zhuo 1535, 7586, 

10522 

Chen-Kiang, Selina 8036 

Cheng, Ann-Lii 1061, 1079, 

4035, TPS4147, e14516, 

e14576, e14617 

Cheng, Ashley Chi Kin 4105, 

5511, TPS7614 

Cheng, Catherine e14586 

Cheng, Dangxiao 1535, 7586, 

10522 

Cheng, HC 5511 

Cheng, Hsiao-Wang 8592 

Cheng, Hua e13510 

Cheng, Huan 573, e21106 

Cheng, Jason C. e14576 

Cheng, Jonathan D. 3027, 

e13598 

Cheng, Jushun e13542 

Cheng, Ke 4638 

Cheng, Kit 1046 

Cheng, Lee e16574 

Cheng, Liang 4586 

Cheng, Lucy e14727 

Cheng, Michael 8575 

Cheng, Phillip e13084 

Cheng, Qiao-Yuan e17512 

Cheng, Shih-min 5510 

Cheng, Shin-June e16050 

Cheng, Simon 7050, e17562, 

e21097 

Cheng, Skye H Hong-Chun 

e11526 

Cheng, Steven Kunyuan 

6047, 6051 

Cheng, Ying LBA4537, 7559 

Chenna, Ahmed 608 

Chenna, Sumana 1587 

Cheong, David 10048, 10070 

Cheong, Dennis 1064 

Cheong, Jae-Ho e14504, 

e14652 

Cheong, Pei Fen e13002 

Chepeha, Douglas Brian 

e16014 

Cher, Michael L. 1560, 4571 

Chera, Bhishamjit S. 5539 

Cherbavaz, Diana B. 4560 

Chereguini, Maria F e11517 

Cherepanov, Dasha 6057, 

e14610 

Cherian, Anish Jacob e19562 

Cherif, Amani 9572 

Cherkasova, Marina Valerievna 

e15543 

Chernick, Michael R e19519 

Chernovskaya, Tatiana V. 

9060 

Cherry, Benjamin M. 8088, 

8104 

Cherry, Mohamad Ali e17012 

Chervenick, Paul A. e18503, 

e18506 

Cheshire, Sprague 2074^ 

Cheson, Bruce D. 8000, 

8001, 8065 

Chester, John D. 4531 

Chetaille, Bruno e18526 

Chetty, Runjan e13587 

Cheung, Foon Yiu 4105 

Cheung, Nai-Kong V. 

TPS9595 

Cheung, Veronica e21047 

Cheung, Wing Kui 3099 

Cheung, Winson Y. 3527, 

3560, 3610, 6006, 6014, 

6018, 6064, 6066, 6085, 

9078, e14048, e14532, 

e14537, e14588, e19547 

Cheung, Yin Ting 9041 

Chevalier, Soazig 3579 

Chevez-Barrios, Patricia 9515 

Chevreau, Christine 4625, 

10006, 10020, 10027, 

10035, 10056, 10062, 

10076, 10092, 10095 

Chew, Helen K. 1010, 3054 

Chew, Jenny e18063^ 

Chew, Sin Chi 2598 

Cheze, Stephane 6523 

Chhabra, Akansha e11522 

Chi, Andrew S. 2009 

Chi, David 576 

Chi, Dennis 5056, 5057, 

5108 

Chi, Kim N. 4514, 4519^, 

4558, TPS4675^ 

Chi, Yihebali e14606, 

e14668 

Chi, Zhi Hong 8506, 8561, 

8562, e15051, e15052 

Chia, Stephen K. L. 549^, 

582, 1008, 1036 

Chia, Yen Lin 5048 

Chiado’ Cutin, Simona 10055 

Chianese-Bullock, Kimberly A. 

8530, e19028 

Chiang, C L 4105 

Chiang, ChienWei 2601 

Chiang, Wendy M. 4117, 

4545, 10579 

Chiao, Judy H. 3053, 6520 

Chiappori, Alberto 2559, 

7065, e17559 

Chiara-Bruneaud, Claire 

e15535 

Chiarella, Michael 6601 

Chiarelli, Anna M. e12034 

Chiari, Rita e18023, e18101, 

e21094 

Chibaudel, Benoist 2537^, 

LBA3500^, 3506 

Chibon, Fred 9536 

Chibout, Salah-Dine 9562 

Chicata, Victor e14057 

Chidambaramurthy, K N 

e11511 

Chidiac, Tarek 8525 

Chieco, Pasquale 3061 

Chigurupati, Sravanthi 

e13516 

Child, J. Anthony 8015 

Childs, Barrett H 1021 

Childs, Jennifer 5082^ 

Childs, Timothy 5032 

Chilson, Kate 9139 

Chim, James 8097 

Chin, Francis 10051, e20509 

Chin, Keisho 10541 

Chin, Kevin M. TPS4689, 

TPS4691, 8512, 8539, 

e19010 

Chin, Lynda 1055, e15200 

Chin, Melvin T.M. e13585 

Chin, Motoaki 9574 

Chin, Ng Soo e18528 

Chin, Suet-Feung 544 

Chinchon Espino, David 

e16037 

Chindavijak, Somjin e16040 

Chinen, Ludmilla T. D. 

e14680 

709s

Chinen, Ludmilla T.D. 

e16046 

Chinen, Ludmilla Thome 

e21073 

Chinn, Danielle C. e17537 

Chinn, Steven Bennett 

e16014 

Chinnaiyan, Arul e15205 

Chinot, Oliver L. 2023, 2060 

Chintagumpala, Murali M. 

9515 

Chintu, Chifumbe 9558 

Chiorean, E. Gabriela 3034, 

4049 

Chiorrini, Silvia e21070 

Chiparus, Ovidiu 2603 

Chipeta, James 9558 

Chiriboga, Luis 2589 

Chirikov, Viktor e14522, 

e14626, e14638 

Chiriva-Internati, Maurizio 

e21105 

Chirivella, Isabel 1074, 

e11523 

Chirpaz, Emmanuel 2048 

Chiruzzi, Chiara e21118 

Chirwa, Thabiso W. 10530, 

e21023 

Chisesi, Teodoro 8006 

Chishima, Takashi 2044, 

e14014 

Chisholm, Gary B. 1102, 

9049, 9065, 9069, 9096, 

e19528, e19584, e19603, 

e19613 

Chisholm, Julia C. 9510, 

9519, TPS9597^ 

Chisti, Mohammad Muhsin 

628, e17015 

Chitale, Dhananjay 1560 

Chitsazzadeh, Vida 8537 

Chittawatanarat, Kaweesak 

e18538 

Chittenden, Eva 9049 

Chittoor, Sreenivas 7502 

Chiu, Brian C-H 8072 

Chiu, Chang-Fang e17014 

Chiu, Connie Ging Ting 2519 

Chiu, Joanne e14545 

Chiu, Ken e14182 

Chiu, Kung Y. e11068 

Chiu, Sophia e21016 

Chiuri, Vincenzo Emanuele 

e18048 

Chkadua, George Z. 2524 

Chlebowski, Rowan T. 1501, 

e14005 

Chlenski, Alexandre 9534 

Chmielik, Ewa e21049 

Chmielowski, Bartosz 3015, 

8587, 10003, TPS10099, 

TPS10103 

Chmura, Steven J. e11512 

Chng, Wee Joo 8097 

Chng, WeeJoo 8095 

Cho, Byoung Chul e14559, 

e18080, e18092 

Cho, Chie-Hee 5512 

Cho, Daniel C. TPS4686, 

8516, 8569 

Cho, Eun Kyung TPS7614, 

e14137, e14685, e18050 

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Cho, Hirotomi e11564 

Cho, Jae Yong e14580 

Cho, Kyung Sam e14128 

Cho, Kyung-Ja 4093, 5586 

Cho, Michael e19639 

Cho, Mong e14566 

Cho, Myung Mi 1587 

Cho, Nam-Yun 3624 

Cho, Nariya e21160 

Cho, Sang-Hee e14649 

Cho, Soo-Jeong 4028 

Cho, Steve Y. 4654, e13116 

Cho, Su-Hee e16003, 

e18148 

Cho, Yoon Young 6536 

Cho, Young-Seok e14634 

Cho, Yukiko 8094 

Chodacki, Ales LBA4512, 

4551 

Chodak, Gerald 4648 

Chodon, Thinle e13045 

Choe, Kyuran Ann e14714 

Choi, Audrey 1031 

Choi, Chang-Min e13104, 

e18052 

Choi, Eugene A. 10090 

Choi, Eun Kyung 7004, 

e18501 

Choi, Hye Jin 4103 

Choi, Il Ju 4028 

Choi, Jin-Hyuk e11559, 

e18519 

Choi, Jun Young 3554, 6536, 

e18533 

Choi, Kee Don 4093 

Choi, Kyoung-Soo 10609 

Choi, Mehee 1069 

Choi, Mihee 4028 

Choi, Minsig e14163, 

e14519, e14609 

Choi, Moon Ki e13094 

Choi, Seung-Ho 5586 

Choi, So-Jung 7053, e18083, 

e21062 

Choi, Walter e18139 

Choi, Young 574, e11029 

Choi, Yunsuk 6564 

Choksi, Janak K. 7002 

Chollet, Philippe J. M. 1051 

Chomat-Neyraud, Muriel 9080 

Chomy, François 9012 

Chon, Hye Sook TPS3114 

Chone, Carlos Takahiro 

e16041 

Chong, Dawn Qingqing 3098, 

e14155 

Chong, Kelly 2519 

Chong, Marc 4105, e14706 

Choo, Richard 4595 

Choo, Su Pin 4100^ 

Choong, Nicholas W. e17555 

Chopra, Akhil e15045, 

e15107 

Chopra, Mona 8564 

Chopra, Rajesh 3006^ 

Chopra, Shamit e19607 

Choquet, Sylvain 2023, 8030 

Choti, Michael A. 3596, 

3616, 4126, e14542, 

e14551 

Chotirosniramit, Anon e13061 

Chou, Joanne F. 3577, 

4581^, 8598, CRA9513 

Chou, Takaaki 8097 

Chouahnia, Kader e18003, 

e18020 

Chouaid, Christos 6058, 

7574, e16560, e18005, 

e18102 

Chouaki, Nadia LBA7507 

Choucair, Ali K. 2058 

Choudhary, Vidhu e16549 

Choudry, Haroon e14184 

Choueiri, Toni K. TPS2613, 

4504, 4505, 4522, 4525, 

4536, 4538, 4543, 4577, 

4582, 4585, 4635, 

TPS4686, e15007, e21016 

Choufi, B 6523, 8026 

Choussy, Olivier 5565 

Chovanec, Michal TPS4677, 

e15027, e15028 

Chow Maneval, Edna 4548 

Chow, Annabelle e15177^ 

Chow, Diana 2098 

Chow, Laura Q. 2510, 

TPS2615 

Chow, Oliver e14656 

Chow, Warren Allen 3108 

Chowbay, Balram 2598, 3098 

Chowdhary, Rajesh 2532 

Chowdhary, Sajeel A. e12500 

Chowdhury, Simon 4529, 

4611 

Chowdry, Rajasree Pia 7097 

Choy, Edwin 10058 

Choy, Hak 7002 

Choyke, Peter L. TPS4701, 

10589, e18568 

Chrétien, Anne-Sophie 10517 

Chrischilles, Elizabeth A. 

6034 

Chrisofos, Michael e15040 

Christakidis, Evagelos e14567 

Christensen, Ib Jarle 3576, 

8545 

Christensen, James G. 8520 

Christensen, Kevin e15119 

Christensen, Rene dePont 

3513, 3573 

Christgen, Matthias 552 

Christian, Beth e18508 

Christiani, David C. 3594 

Christians, Kathleen K. 

e14613 

Christiansen, Hans e13039, 

e21128 

Christiansen, Jason 517 

Christman, Lori e21066 

Christmas, Timothy e16501 

Christner, Susan M. 2533 

Christodouleas, John Paul 

7098, e17534 

Christodoulou, Marianna 

e21027 

Christodoulou, Sophie 9126 

Christopherson, Cindy 10586 

Christopherson, Kent W. 6552 

Christophi, Christopher 

TPS3643 

Christophyllakis, Charalampos 

e18105 

Christos, Paul J. e18029 

Chronowski, Christopher 9544 

Chu, Alice e19058 

Chu, Chia Lin 4056 

Chu, Christina 5065 

Chu, Chun Hung e12006 

Chu, CM e15110 

Chu, Edward TPS1138, 

2553, 3037, 3049, 3054 

Chu, Franklin 4665 

Chu, Hui-May 8541 

Chu, Kyung e14708 

Chu, Laura 1590, 1591, 

4092, e14575 

Chu, Luis TPS657 

Chu, Peiguo e21019 

Chu, Quincy 3013, e13011 

Chu, Quyen e11541 

Chu, Ray M 2084, 2087 

Chu, Tianqing e18088 

Chu, Yaya e13022 

Chua, Clarinda Wei Ling 8078 

Chua, Mei-Sze e14037 

Chua, Melvin 10626 

Chua, Victoria S 3015, 

10036 

Chua, Yu Jo TPS4137, 

e14088, e14703 

Chuah, Benjamin 2551, 

3002, e13002 

Chuah, Charles 6503 

Chuang, Eric Y 1043 

Chuang, Linus T. e15556 

Chuang, Tony 8524 

Chudzik, Malgorzata 603 

Chugh, Rashmi 3025, 10028, 

TPS10103 

Chui, Stephen Y. e11042 

Chui, Wai Keung 9041 

Chulikavit, Maruit e14525, 

e14627 

Chuma, Stacey 8043 

Chumsri, Saranya 1039, 

9103, 10572 

Chunda-Liyoka, Catherine 

9558 

Chung, Cathie T. 1105 

Chung, Christine H. 5549, 

5566, e16061 

Chung, Chung Taik e16047 

Chung, Doo Hyun 7566 

Chung, Gina 1045 

Chung, Harold M. e18550 

Chung, Hsingwen e15089 

Chung, Hyun Cheol TPS4142 

Chung, Hyun Cheol 3606, 

e14084, e14652 

Chung, Ik-Joo e14649, 

e15064 

Chung, Jo L e14037 

Chung, Jooseop e15064 

Chung, Karen e12024, 

e15172, e15197, e16512, 

e16528, e18107, e19630 

Chung, Peter W. M. 4535 

Chung, Vincent M. 3078, 

3108, e14182 

Chupreta, Sergey 10587 

Church, David N. 4599 

Church, Frank C e14505 

Church, Terry 1124, e19506 

Churilla, Thomas M. 6031 

Churilova, L. e11528 

Chyou, Po-Huang e14008 

Ciafone, Denise 6108 

Ciancola, Fabrizio e14082 

Cianfrocca, Mary E. 610 

Cianni, Roberto e14654 

Cianniello, Daniela 630 

Ciardiello, Fortunato 7550 

Ciarlo, Andrea LBA4001 

Cibula, David 5001 

Cibull, Michael e15578 

Ciceri, Fabio 6541 

Cicetti, Moreno 4084 

Cicolin, Alessandro e11524 

Cid, J.I. 4630 

Cierna, Zuzana e15027 

Cigler, Tessa 1010 

Cihon, Frank 3502 

Ciliberto, Domenico e14577 

Cillan, Elena e15159 

Cillero, Lourdes e14147 

Cilli, Fiona 9024 

Cillo, Umberto 4115, e14563 

Cinefra, Margherita e11001, 

e11547, e18048 


Cinieri, Saverio LBA5003, 

e11001, e11547, e18026, 

e18048 

Cioffi Lavina, Maureen 608 

Cioffi, Angela 10022, 10023, 

10044, 10057, 10089 

Cioffi, Gianni 645 

Ciombor, Kristen Keon 

e14503 

Cione, Charlotte 4526 

Ciosek, Stephanie L. 1539 

Cipolla, Bernard G e15131 

Cipone, Mario 3061 

Cipriano, Toni 6137 

Ciprotti, Marika e15056 

Cirkel, Geert A. 2596 

Cirrincione, Constance 

CRA1002, CRA9013 

Ciruelos Gil, Eva Maria 

e11081 

Ciruelos Gil, Eva Maria 642 

Ciruelos, Eva M. 10608, 

e11535, e15552, e21088 

Citron, Marc L. 532 

Cittadini, Antonio e11052 

Cittelly, Diana M. 564 

Citterio, Giovanni 7581 

Ciuffreda, Libero e15192 

Ciuffreda, Ludovica e13512, 

e13572 

Ciuleanu, Tudor-Eliade 

LBA7000 

Ciuraru, Noa e14731 

Ciurea, Ana 8537 

Ciurea, Stefan O. 6546 

Civelek, Ali Cahid e21072, 

e21144, e21149 

Civelek, Burak e13031 

Clack, Glen e21037 

Claes, Bart 507 

Clapisson, Gilles 10562 

Clark, Amy Sanders 6000 

Clark, Ann Lau e16027 

Clark, Emma 533^, 597^, 

598^, e11055^ 

Clark, Jeffrey W. 3053, 4021, 

7508, e14615 

Clark, John Ross 5579, 5594, 

e16059 

Clark, Joseph 4546, 5501, 

e16027 

Clark, Karen L 9048 

Clark, Katherine TPS9153 

Clark, Leslie Horn 5009, 

5092, e15511 

Clark, Matthew M. 1610 

Clark, Melanie e15008 

Clark, Rachel Marie e15545, 

e15568 

Clark, Sarah Victoria 6623 

Clark, William B. e18550 

Clark, William R. 4550, 4656 

Clark-Langone, Kim 3512 

Clarke, Blaise A 5019 

Clarke, Blaise 5010, 5026, 

5105 

Clarke, Jennifer Leigh 2026 

Clarke, Michael F. 2514 

Clarke, Noel W e15141 

Clarke, R. M. 1543 

Clarke, Roisin e12038 

Clarke, Stephen John 4644, 

9021 

Clarke-Pearson, Daniel L. 

2591, 5050, e13063 

Clarkson, James E. TPS9150 

Classe, jean Marc e11551 

Claudio, Martin MARCELO 

e18114 


Clausen, Cathy L TPS9150 

Clauser, Eric e21014 

Clauser, Steven B. 6046, 

6086, 9047, 9144, 

e16532, e19633 

Claussen, Christina e19502 

Clay, Timothy M. 2585 

Cleary, James F. 9039, 

TPS9152, e16010 

Cleary, James M. 3021, 

3028, 3039, 3053 

Cleary, Sean F TPS9150 

Cleary, Sean P 4109, e14592 

Cleeland, Charles S. 5561, 

5589, 6002, 6551, 8091, 

9047, 9072, 9081, 9082, 

9083, 9099, 9106, 9112, 

9118, 9140, e11051, 

e15173, e19589 

Clegg, Eericca e15536 

Clemens, Michael R. 552 

Clemens, Michael 4023, 

10540 

Clement, Paul M. 5516^ 

Clemente, Claudio e14042, 

e18021 

Clemente, Gemma e11036 

Clementi, Regina 9547 

Clements, Arthur e19011 

Clements, June 4041 

Clemenzi-allen, Angelo 8072 

Clemons, Mark J. 587 

Clemons, Mark 6083, 9111, 

10620 

Clerici, Thierry 8540 

Clerkin, Barbara M. e14582 

Clerkin, Kara M. e14582 

Cleveland, Barbara 9085, 

e14186 

Cleverly, Ann 2042 

Cliby, William 5076 

Cliffe, Bettina e19648 

Clifton, Guy T. 625, 2508, 

2529 

Climent Duran, Miguel Angel 

TPS4672, TPS4674, 

TPS4688, e15041 

Climent, Miguel Angel 

TPS4685 

Cline, Kathryn J. 6049 

Clingan, Philip 7511 

Clisant, Stephanie 10020, 

e11012, e14560 

Clive, Sally 2583 

Clotet, Montserrat 10555 

Cloughesy, Timothy Francis 

2005, 2101 

Cloutier, Martin e16571 

Clynes, Martin 2536, e15126 

Cmelak, Anthony 5502, 5566 

Co, Chloe e13516 

Coakley, Fergus V. 8580 

Coan, April D. 2027, 2090^, 

2094^ 

Coate, Linda 2063 

Coates, Alan Stuart 504, 

9022 

Cobleigh, Melody A. 572, 

TPS657 

Cobo, Manuel 7011, 7540, 

7558, e18015, e18131 

Cobos, Everardo e15103, 

e21105 

Coca, Pragnya 6554, e18544, 

e18545 

Coche, Jean-Charles e14060 

Coche, Thierry 7056, e13061 

Cochet, Alexandre TPS646 

Cochrane, Dawn R. 564 

Cocker, David j e13073 

Cocorocchio, Emilia e19036 

Codacci Pisanelli, Giovanni 

e12510 

Codes, Manuel 10608, 

e11535, e21088 

Codignola, Claudio e14018 

Codina, Gomez 6633 

Codreanu, Ion 6555, e18543 

Codrington, Henk 7019 

Coeffic, David Emmanuel 

TPS646 

Coelho, Ana e15532 

Coelho, Luiz Gonzaga e13008 

Coelle, Celine 7591 

Coenen, Marieke J.H. 10077 

Coens, Corneel LBA5000, 

6002, 6090, 7607 

Coeshott, Claire TPS3638, 

e14501 

Coffin, Robert TPS8604, 

e14546 

Cogan, Chad 5088 

Cognetti, Francesco 630, 

1073, 4541, e13512, 

e13572, e14113, e14661 

Cogswell, Janet e14727, 

e18516, e19638 

Cohen, Adam D. TPS8111, 

e19580 

Cohen, Alice J. e16565 

Cohen, Deirdre Jill 4022 

Cohen, Edward P. e13034 

Cohen, Evan N. 8091, 9081, 

9083, e13582 

Cohen, Ezra E. W. 5500, 

5508, 5517, TPS5598, 

TPS5599, e13106 

Cohen, Harvey Jay 6015 

Cohen, Jack A. e18502 

Cohen, Jonathan M. e13034 

Cohen, Kenneth Stuart 8075 

Cohen, Lorenzo 6054, 9029, 

9031 

Cohen, Marlene Z. 9096 

Cohen, Orit 10034 

Cohen, Pamela TPS6639 

Cohen, Richard F. e16052 

Cohen, Roger B. 2595, 7092, 

7595, e13606 

Cohen, Samantha 5079 

Cohen, Shira e14731 

Cohen, Stephen M TPS10632 

Cohen, Steven J. 2583, 

3590, 3605, 4052 

Cohen, Victor e18061, 

e18098, e19626 

Cohen, Yoram e18511 

Cohen, Zvi R 2078 

Cohen-Jonathan Moyal, 

Elizabeth Laurence 10076 

Cohn, Allen Lee TPS3111, 

LBA3501, 4007, 7502, 

e18558 

Cohn, Allen TPS3638, 

e14501 

Cohn, David E. 1519, 5101, 

e15585 

Cohn, Michael 3590 

Cohn, Susan Lerner 9516, 

9533, 9534, 9583 

Cohn-Cedermark, Gabriella 

4508 

Coiffier, Bertrand 8002, 

8057, 8063 

Coimbra, Felipe José 

Fernandez e14728 

Coindre, Jean-Michel 9536, 

10018, 10035, 10056 

Coit, Daniel G. 8583, 8586 

Cojocarasu, Oana 9011 

Cok, Jaime e12041 

Colak, Havva e14557 

Colantonio, Ida TPS7109 

Colantuoni, Giuseppe 1073 

Colao, Annamaria 1604, 

e19038 

Colbeck, Margaret e19513 

Colcher, David 639 

Colchon, Paulo Henrique 

e12035 

Colditz, Graham A. e18551 

Coldwell, Douglas M. 3590 

Cole, John T. 6580 

Cole, Sarah 4096, e13084 

Coleman, Morton 8036, 

e21006 

Coleman, R. Edward e13592 

Coleman, Robert Edward 502, 

511, 513, TPS670, 1094, 

LBA4512, 4551 

Coleman, Robert L. 5015, 

5021, 5027, TPS5114, 

e15578 

Coletti, Gino e14010 

Colevas, A. Dimitrios 2514, 

5525, 5566, 9024 

Colevas, Electra A 5525 

Colevas, Kara 2028 

Colicchio, Lynn e16515 

Collard, Olivier 10020, 

10078 

Collecchi, Paola 629 

Colleoni, Marco 504 

Collette, Laurence 4053 

Collichio, Frances A. 6093 

Collignon, Marie-Anne 

e15558 

Collin, Christine 3520 

Collin, Francoise 10018 

Collins, Brian Timothy 2091 

Collins, Connie TPS4687 

Collins, Denis 637, 2536 

Collins, Helen e19511 

Collins, Ian M. 1502 

Collins, Jerry M. 3087 

Collins, LaTonya R 6505^ 

Collins, Sara 2534 

Collins, V. Peter TPS10633^ 

Collinson, Fiona Jane e13083 

Collisson, Eric Andrew 3058 

Colman, Howard 2002, 2003 

Colmenero, Maria e15033 

Colo, Anna Estela Luiza 

e11059 

Colom, Bartomeu e11036 

Colom, Helena 3096 

Colombini, Sonia e19549 

Colombino, Maria 8581, 

e14094 

Colombo, Chiara 10000, 

10016, 10017 

Colombo, Massimo 4033 

Colombo, Nicoletta LBA5000, 

5001, 5090, e13095^, 

e13097^ 

Colombo, Renata e15562 

Colomer, Anna e14552 

Colon-Otero, Gerardo 2015 

Colorito, Maria Luisa e21095 

Colucci, Silvia e13525 

Columbo, Laurie Ann 4045 

Comandone, Alessandro 

10055 

Comas, Carmen 1570 

Combemale, Patrick 10049 

Comber, Harry 2609, 6036, 

e16514 

711s

Come, Steven E. 9071, 9100 

Comis, Silvia 4122 

Commo, Frederic 10556 

Company, Maria 4089 

Compton, Carolyn C. 3517 

Compton, Kathryn 3103 

Conan, Anne-Hélène 9563 

Conces, Madison 7032, 

7107, 7108 

Concha, Angel 4089 

Concin, Nicole 5071, 5111 

Conde, Esther 3068 

Conde, Sara e18111 

Condello, Caterina 1554, 

e15034 

Condemi, Giovanni e14676 

Condori, Dhiossett e15159 

Condy, Mercedes M 10002, 

10004 

Cone, Christina 2074^ 

Conforti, Rosa 1091 

Cong, Xiangyu e14534 

Cong, Xiuyu Julie TPS5598 

Cong, Ze e15172, e16528 

Conill, Carles 3536 

Conings, Godelieve 9035 

Conklin, James J e13082 

Conkling, Paul TPS3111, 

e18047 

Conkright, William A. e15115 

Conley, Anthony Paul 10048, 

10070, 10094, e20511 

Conley, Barbara A. 5020 

Conley, Christoher R 8053 

Conley, Jennifer e13592 

Conlon, Susan e21147 

Connault, Jerome 1580 

Connell, Jacqueline e14015 

Connell, Louise Catherine 

e19632 

Connelly, Mark C. 7092, 

10533 

Conner, Kathy 8075 

Conner, Michael G. 5036, 

e15502 

Conner, Thomas 1502 

Connery, Cliff P. e18139 

Connolly, E. M. 1511, 1543 

Connolly, Elizabeth M. 

e12038 

Connolly, Elizabeth e18095 

Connolly, Gregory Clayton 

6059 

Connolly, John 3098 

Connolly, Roisin M. 10509 

Connor, James e14520 

Connor, Michael e14632 

Connors, Joseph M. 8049 

Conort, Pierre e15105 

Conrad, Charles A. 2003, 

2029^, 2036, 2064 

Conradi, Lena-Christin 3600, 

e14161, e14162, e14167 

Conrads, Thomas P e15560 

Conroy, John D. e19544, 

e19567 

Conroy, Thierry 1584, 

LBA4003, 4053 

Considine, Michael 5549 

Constantinidou, Anastasia 

10086 

Constenla, Manuel e18011 

Constine, Louis S. 9524 

Conte, Pier Franco 631 

Conte, Pierfranco 614 

Contel, Estela e11523 

Contentin, Nathalie 6542 

Conter, Henry Jacob 6529 

Conti, Alessandro e15074 

Conti, Laura e13527 

Conti, Peter 639 

Contreras, Ana Cecilia 

e11517 

Contreras, Ana C e11006 

Contu, Antonio Silverio 

e14094 

Cook, Gordon 8015 

Cook, Michele 5073 

Cook, Robert W. 7106, 8543 

Cooley, Timothy Patrick 4030 

Cools, Nathalie 2506 

Coombes, Charles e21093 

Coombes, Kevin R. 7096, 

10612 

Coombes, R. Charles e21137 

Coombs, John e15043 

Cooney, Kathleen A. e15205 

Cooney, Matthew M. 

TPS10099, e15208 

Cooper, Gregory 1569 

Cooper, Joseph 569, 571, 

6098, e11002, e16540, 

e16552 

Cooper, Laurence 6540 

Cooper, Matthew 6091, 

e16007 

Cooper, Robert Michael 9588 

Cooper, Tiffiny 621 

Coopey, Suzanne 1122 

Cooray, Prasad 3629, 

e14644, e14718 

Cope, Frederick Oliver 

e21066 

Cope, Reed e14632 

Copelan, Edward Alan 8055 

Copeland, Larry J. e15585 

Copetti, Massimiliano e21092 

Copley-Merriman, Kati 6626^ 

Coppola, Carmela e11052, 

e13539 

Coppola, Sara 10017 

Copreni, Elena LBA7501 

Copur, Mehmet Sitki 9110 

Corallo, Salvatore e16553 

Corazzelli, Gaetano 8066, 

8083 

Corben, Adriana 10618 

Corbishley, Catherine M 4640 

Corcoran, Claire 617 

Corcoran, Ryan Bruce 3528 

Cordeiro De Lima, Vladmir 

Claudio 643, e21073 

Cordeiro, Peter 9043 

Cordero Franco(1), Nazaret 

e11543, e19596 

Cordio, Stefano Sergio 

LBA4001, e14040, 

e15544, e18026 

Cordova, Sharon e15094, 

e18069, e18106, e21015 

Coriat, Romain 2557 

Corless, Christopher L. 4586, 

TPS7609, 10591 

Corman, John M 2564 

Cormio, Gennaro LBA5003 

Corn, Paul G. 4513, 4523, 

4549, 4615, e15092 

Cornelio, Gerardo H. 1534 

Cornelison, Terri L 520 

Cornelius, Lynn 2525 

Cornely, Oliver A. 9067 

Cornillon, Jerome 6534 

Cornu, Jean-Nicolas e15105 

Corona Villalobos, Celia 

Pamela 4114 

Corona, Rosalie 1563 

Coronado, Cinthya 3093, 

e15001 

Coronado, Monica e13085 

Corpening, Jennifer C. 

e16561 

Corradetti, Michael Nino 

7050, 7098, e17534 

Corradini, Nadege 9517, 

10014 

Corradini, Paolo e18572^ 

Corradino, Irene e19549 

Corrado, Claudia TPS8118 

Corral Jaime, Jesus 2530, 

LBA7507, 10525 

Corral, Mitra 5533, e16053 

corrales-Alfaro, Carmen 6599 

Corrales-Rodriguez, Luis 

e18136 

Corre, Romain 7574 

Correa, Arlene M 4078, 

4086, 7043 

Correa, Denise 2006, 2008 

Correa-Gallego, Camilo 3620 

Correale, Pierpaolo e13098, 

e14577 

Correll, Judy e20007 

Corrie, Philippa 4121, 

TPS8605, e14625 

Corsi, Domenico C. e14082 

Cortes, Javier 509, 566, 

597^, 598^, 619, TPS652, 

1032, TPS1140^, 10511 

Cortes, Jorge E. 6501, 6503, 

6504, 6506, 6511, 6513, 

6525, 6528, 6544, 6558, 

6578, 6585, 6587, 6589, 

6596, 6597, 6601, 6603, 

6604, 6605, 6607, 

TPS6635, TPS6636, 

TPS6639, TPS6641, 

e19589 

Cortes, Matias Nicolas 

e11044, e11501, e18125 

Cortes-Funes, Hernan 642, 

4620, e11074, e15033, 

e15552 

Cortes-Gonzalez, Ruben 

e11098 

Cortesao, Emi-lia e12040 

Cortesi, Enrico e18065 

Cortessis, Victoria K 4575 

Cortez, Brandon 8580 

Cortez, Czrina 2518 

Corthals, Jurgen 2507 

Cortinovis, Diego Luigi 9090 

Cortot, Alexis B. e18006, 

e18066 

Cosaert, Jan TPS4675^ 

Coscas, Yvan 1567, 1568 

Cosentino, Sebastiano 

e18096 

Cosgrove, David 3020, 

TPS3117, 3596, 4114 

Cosimelli, Maurizio e14082 

Coskinas, Xanthi 7079^ 

Coskun, Hasan Senol e14070 

Coskun, Ugur 638 

Coso, Diane TPS1613, 6633, 

e18526, e19539 

Cossor, Furha Iram e14005 

Cossu, Antonio 8581, 

e14042, e14094 

Costa, Bruno M 2026 

Costa, Carlota 4068, e14521, 

e18130, e18131, e18137, 

e18143 

Costa, Daniel Botelho 7523, 

7579 

Costa, Felipe D’Almeida 643 

Costa, Fernando Ferreira 

e16041 

Costa, Luciano 8010 

Costa, Luis 607 

Costa, Serban Dan 541 

Costa, Wilson Luiz e14728 

Costantini, Chiara 4081 

Costantino, Joseph P. 

LBA506, 538, LBA1000, 

TPS1142 

Costello, Brian Addis 4657, 

5077, e13052 

Costello, Joseph F 2026 

Costello, Rene 8088, 8104, 

e18568 

Costes Martineau, Valerie 

e16013 

Cote, Marc-Andre 634 

Cote, Michele L 7063, 7593 

Cote, Richard J 4575, 4663, 

10503 

Cotreau, Monette M. 4132, 

e13041 

Cotrell, Aaron e17015 

Cotter, Maura B. 1042 

Cotter, Ryan 5578 

Cottini, Silvia e14661 

Cottler-Fox, Michele e18576 

Cotto, Elise e18505 

Cottu, Paul H. 601, e15524 

Cottura, Ewa 10020 

Coudert, Bruno P. TPS646 

Coughlin, Christina Marie 

3016 

Coukos, George 5065 

Coulson, Luke C 9127 

Coulter, Sally 550 

Counago, Felipe 1111 

Counsell, Nicholas 7538 

Countouriotis, Athena Maria 

6512 

Coupkova, Helena e18062 

Coupland, Sarah 8523, 8564, 

TPS8605 

Courbon, Frederic 9517 

Couriel, Daniel R. 8011 

Cournoyer, Sonia 9563, 9570 

Courtier, Anais 10562 

Cousin, Sophie 10013, 

10014, e13118 

Cousson-Gelie, Florence 9074 

Couto, Rosario e15532 

Coutre, Steven E. 6502, 

6507, 6518^, 8012 

Couture, Felix 3504 

Couvelard, Anne 4129, 4133 

Couvillon, Anna TPS4701 

Cova, Agata 5555 

Cova, Dario e14676 

Covello, Kelly L. 5533 

Cowan, Kenneth H. 1538 

Cowan, Richard 4509 

Cowey, C. Lance TPS4686 

Cowey, Charles Lance 4603, 

8503^, 8567 

Cowie, Julie e19617 

Cox, David TPS1145 

Cox, Donna S 3023, 4108 

Cox, James D. e14548 

Cox, Nancy J 9516 

Cox, Trevor F e14625 

Coxon, Fareeda Y LBA4000 

Coxon, Katy Marie 6115 

Coyne, James C. 9145 

Crabtree, Carol 6113 

Craft, Paul Stanley e15152 

Crago, Aimee Marie 10015 

Craig, Adam 6513, 6596, 

6604, TPS6637 

Craig, Michael TPS6637 

Craighead, Peter S TPS5116 


Cramer, Laura D. 4651 

Crane, Christopher H. 4051 

Crane, Gemma Louise 4599 

Crane, Heidi TPS3634 

Cranmer, Lee D. 10010 

Crawford, Beth e16510 

Crawford, Brooke S. e18508 

Crawford, E. David 4, e15176 

Crawford, Jeffrey 1062, 6129, 

9135 

Crawford, S. Michael 5046 

Crawley, Freya 587 

Craxi, Antonio TPS4151 

Crea, Francesco 10611 

Creekmore, Allison N 3047 

Creelan, Ben C. 2559 

Cremolini, Chiara 3518, 

3540, 3546, 3549, 3555, 

3585, 3597 

Crequit, Jacky 7574 

Crescentini, Robert M. 6568, 

6575, 6588, 6608, 8084 

Crespo Massieu, Carmen 

e11081 

Crespo, Aurora e16000 

Cress, Rosemary 6052 

Cresti, Nicola 3100 

Cretella, Elisabetta e13019 

Cretin, Elodie e19623 

Cretin, Jacques 9011 

Crevenna, Richard 2071 

Creveuil, Christian TPS7112 

Crew, Katherine D. 9018, 

10516 

Criado, Ernesto 1570 

Crida, Benedetta e18103 

Crighton, Emilia M 3599 

Crino, Lucio 1604, 3521, 

5513, 7503, 7531, 7533, 

7550, 7600, e18021, 

e18023, e18101, e19038, 

e21018, e21094, e21096 

Cripe, Timothy P 9509 

Crippa, Flavio 4507, e21118 

Cripps, M. Christine e19527 

Crisan, Anamaria 4565 

Crisci, Stefania 8083 

Crisi, Girolamo 2057 

Crispens, Marta A. e15582 

Crispo, Anna 1554 

Crist, Wendy A LBA8509 

Cristea, Mihaela C. 3108, 

5025, 7518, 9068 

Cristin, Antonio 3612 

Cristofanilli, Massimo 531, 

577, 594, e13582 

Critchfield, Jeffrey J e14609 

Crivello, Margaret Lord 6061 

Crockard, M. A. e14022 

Crocker, Theresa e21155 

Crombet Ramos, Ofelia 6580 

Crombet Ramos, Tania 2515, 

2527 

Crombie, Catherine e16501 

Cromer, Jamie TPS650 

Cromwell, Ian 549^ 

Crona, Daniel James e15086 

Cronin, Beth 5100 

Cronin, Maureen T. 1015, 

3533, 4649, 7510, 7529, 

10524, 10559, 10590, 

e17541, e19004 

Cronk, Michelle F. 3572, 

TPS4137 

Crook, Tim e18567 

Cropet, Claire 10006 

Cros, Jerome F 5554 

Cros, Jerome 4133 


Cros, Sara 7540, 9129, 

e12504, e18131, e18143 

Crosara, Marcela Alves 

Teixeira 2038 

Crosby, Thomas TPS4143 

Crosby, Tom David Lewis 

LBA4000 

Crosby-Thompson, Allison 

e18530 

Crouzet, Sebastien e15194 

Crow, Jaime 1028 

Crowley, John CRA6009, 

8041 

Crowley, Michael J e21011 

Crown, John 581, 615, 617, 

622, 632, 633, 637, 1042, 

2536, e13520, e19059 

Cruciani, Giorgio 7550, 7584 

Cruickshank, Scott 567 

Crump, Barbara e14124, 

e18516, e19606, e19638 

Cruz Mora(1), Miguel Angel 

e11543, e19596 

Cruz, Cristina 3014, e13605 

Cruz, Crystal M 2589 

Cruz, Felipe Melo e16568, 

e19537, e19552 

Cruz, Josefina 10079 

Cruz, Marcelo Rocha De 

Sousa e11058, e18078 

Cruz-Borja, Primo 9554 

Cruz-Munoz, William e11061 

Cryer, Sarah K 7579 

Csajka, Chantal e11048 

Csapo, Kimberly A. e16561 

Cseh, Jozsef 2522, 3530 

CsToth, Ingrid e18006 

Cuadra, Jose Luis 4579, 

e12504 

Cuartero, Julie 5105 

Cuatrecasas, Miriam 3536, 

3553, e14041 

Cubedo, Ricardo 10079, 

e21088 

Cubelli, Marta e13057 

Cubero, Daniel de Iracema 

Gomes 5588 

Cubero, Daniel Iracema 

e16568, e19537, e19552 

Cubillo, Antonio 3066, 

TPS3637, 4040, e15111 

Cucchi, Silvia e13105 

Cuccuini, Wendy 8048 

Cuéllar Ponce de león, Luis 

Ernesto e18524 

Cueva Banuelos, Juan 

Fernando e14733 

Cufer, Tanja 558, 7081, 

e16505 

Cuff, Justin 6072 

Cuffe, Sinead 1535, 6005, 

7586, 9032 

Cui, Chuan Liang 8506, 

8554, 8561, 8562, 

e15051, e15052 

Cui, Kemi 2098 

Cui, Yonggang e21026 

Cuillerot, Jean-Marie 

TPS4689, TPS4691, 

TPS7113, TPS7611 

Cuinet, Marie 4618 

Cuisenier, Jean 1584 

Culakova, Eva 6129, 9135 

Culbertson, Richard e15130 

Culine, Stephane 4583 

Culliney, Bruce 5531, 5559, 

5581 

Cultrera, Jennifer L. 6568, 

6608, 8084, e18503, 

e18506, e18509, e21123 

Cummings, Francis J. e13126 

Cummings, Francis e13124 

Cummings, K. Michael 1529 

Cummins, Michelle M 7079^ 

Cunanan, Josephine e13117, 

e15008 

Cunha, Geraldo Felicio 

e13008 

Cunha, Isabela Werneck 

e11058, e20506 

Cunningham, David 3531, 

3587, LBA4000, 4004, 

4029, 4121, TPS4139, 

TPS4143, e13541, 

e14088, e14132, e14625 

Cuorvo, Lucia Veronica 

e21102 

Cupissol, Didier 10035, 

10092, 10095 

Cuppini, Lucia 2083 

Curiel, David T e13087 

Curiel, Tyler J. 3073 

Curigliano, Giuseppe 546 

Curley, Steven A. 4116 

Curley, Tracy 4548, TPS4697 

Currà, Maria Francesca 

e18023, e18101 

Curran, Emily 6582 

Curran, John 10590 

Curran, Walter J. 2001, 

2008b, 2013, 5583, 7059 

Curran, Walter John 7097 

Currin, Erin-Siobhain R. 1088 

Currow, David C 2604, 9128, 

TPS9153 

Curry, Jonathan 8537 

Curry, Richard Charles 2006 

Curry, Saundra e15021 

Cursio, Elisabetta e14156 

Curti, Alessandra 4097 

Curti, Brendan D. TPS2613, 

3032 

Curtin, John Patrick 5016 

Curtin, Karen 9525, 9561 

Curtis, Alexandra e15203, 

e15204 

Curtis, Kelly Kevelin 3060, 

8053 

Curve, Herve LBA5000 

Curvietto, Marcello 8573, 

e19034 

Cushen, Samantha 1559 

Cusi, Maria Grazia e13098 

Cusnir, Mike e19646 

Cussenot, Olivier e15105 

Custodio Cabello, Sara 

e12003, e14058 

Custodio, Ana 3618, 10547, 

e12033, e13085 

Cusumano, Pino 10554 

Cuynet, Patrice e19623 

Cuyun Carter, Gebra 5533, 

e16053 

Cvancarova, Milada 4066, 

4637, 9590, e14053 

Cwiertka, Karel 1087 

Cynober, Luc e13056 

Czapiewski, Piotr 10561 

Czapski, Natalie e12024, 

e15197, e18107, e19630 

Czarkowski, Andrea e19028 

Czartoryska-Arlukowicz, 

Bogumila 505, 603 

Czechura, Tomasz 1033, 

6040 

Czerkawski, Barbara 549^ 

Czerlanis, Cheryl M. e13121 

Czernin, Johannes 10012 

Czerwinski, Debra 2514 

Czito, Brian G. e14724 

Czok, Sarah e15548 

Czuczman, Myron Stefan 

8001, e18530, e18537, 

e18538, e18539 

Czuczman, Natalie e18537 

D 

D Arlhac, Michel 1574 

D’Achille, Anna Maria e19002 

D’Adamo, Stefania 3061 

D’Addetta, Carmela e21092 

D’Agostino, Diego 7056, 

e13061 

D’Aiuto, Giuseppe 1500 

d’Amato, Claudia e13509 

D’Ambrosi, Rafael e15033 

D’Ambrosio, Consuelo 5513 

D’Ambrosio, Lorenzo 10066, 

e15192, e20512 

D’Ambrosio, Paul 4662 

D’Amico, Anthony Victor 6121 

D’Amico, Thomas A. 7008, 

e14562, e18018 

D’Amore, Francesco 8051 

D’Andrea, Gabriella 1016, 

10514 

D’Angelica, Michael Ian 

3577, 3620 

D’Angelo, Sandra P. 8549, 

8575, 8598, 10004, 

10019 

D’Arcangelo, Manolo e21095 

d’Ario, Giovanni 3575 

D’Ascenzo, Fabrizio e15192 

D’Auria, Kevin 8597 

D’Avella, Domenico 2049 

D’Cunha, Nicholas C. e21105 

D’Cunha, Ruth e21105 

D’Emidio, Silvia 4084 

D’haens, Jean 2050 

D’hondt, Veronique e13594 

D’Incalci, Maurizio 10047 

D’Incecco, Armida e21018 

d’Journo, Xavier 4091 

D’Souza, David 6130 

D, Madhusudan e19619 

Da Corte, Donatella e13019 

da Costa, Alexandre Andre 

Balieiro 643 

DA Silva, Guedes e14673 

da Silva, Joao Santana 

da Silva, Marcelo Gurgel 

1075 

Daaboul, Hamid Elia 

e15509 

e20500 

Dabakuyo, Tienhan Sandrine 

1584 

Dabney, Raetasha Sheavette 

625, 2508, 2529 

Dabrow, Michael B. e19519 

DaCosta Byfield, Stacey 

e16539 

Dad, Shakeela e14079 

Dadaev, Tokhir 1545 

Dadduzio, Enzo e14156 

Dadras, Soheil Sam e21135 

Dafni, Urania 592 

Daga, Haruko e18036, 

e18042 

Dagoglu, Nergis 9567 

Dahan, Laetitia 4087, 4091 

Dahiya, Saurabh e19543 

Dahl, Olav 4508 

Dahlberg, Suzanne Eleanor 

7516, 7553 

Dahle-Smith, Asa LBA4001 

713s

Dahlheimer, Tambra 2546 

Dahmane, Elyes e11048 

Dahut, William L. 2526, 

3043, 4569, TPS4701, 

10589 

Dai, David 3007 

Dai, Jie 8561 

Dai, Luyan TPS5599 

Dai, Qun e18574 

Dai, Shuqin e11091 

Dai, Wei 5582 

Daignault, Stephanie 2602, 

4506 

Daignault-Newton, Stephanie 

4591, e18118 

Daigo, Yataro e13552, 

e13565 

Dailey, Seth H e16010 

Daily, Maureen 6054 

Dakheel, Omar 2577 

Dakhil, Shaker R. 551, 1083, 

6591, 7002, 7590, 7592, 

TPS7618, 9001, 9014, 

e15115 

Dal Bello, Maria Giovanna 

7577, e21065 

Dal Canton, Orietta 10055 

Dal Mas, Antonella e14010 

Dal, Pinar e11045 

Dalac-Rat, Sophie 8591 

Dalal, Jay S. e16027 

Dalal, Mehul 6059 

Dalal, Shalini 9002, 9025, 

9049, e19584 

Dalasanur Nagaprashantha, 

Lokesh Prasad Gowda 

e13557 

Dalbagni, Guido 4581^ 

Dalban, Cecile 3506, 9026^ 

Dale, David C. 1062, 6129, 

9135 

Dalen, Egbert J. van e19560 

Dalgleish, Angus George 8534 

Dalia, Samir 6568, 6575, 

6588, 6608, 8084 

Dalkin, Bruce L. 4521 

Dall’Occa, Patrizia 2061 

Dalla Palma, Maurizia 

e12037 

Dalla Pria, Alessia e14574 

Dallas, Nikolaos Andreas 

1130 

Dallinger, Claudia e15037 

Daly, Andrew 6548 

Daly, Corinne 6027 

Daly, Mary Beryl 1502, 1550 

Daly, Peter e12038 

Damaj, Gandhi Laurent 6534, 

6542, 8026 

Damast, Shari 9104 

Damato, Bertil 8523, 8564, 

TPS8605 

Damber, Jan-Erik 4550 

Damian, Silvia 3080 

Damiani, Patrizio 5093, 

5094, e15547, e15550, 

e15551, e15553 

Damiano, Vincenzo e13509, 

e15034 

Damião, Ronaldo 4510, 4642 

Damjanov, Nevena 4111 

Damjanovic, Svetozar e21136 

Damm, Robert e14630 

Danaee, Hadi 2597 

Danaei, Mahmoud 10600 

Dancey, Janet 3047, e13049, 

e13107, e19616 

Dane, Faysal 3565, e14526, 

e16015 

Danenberg, Kathleen D. 7582 

Danenberg, Kathleen D 1040, 

10630 

Danenberg, Kathleen 7594 

Danenberg, Peter V. 7066 

Danese, Mark e15172 

Danesh Manesh, Amir 

Hossein 6557 

Daneshmand, Manijeh 3515 

Daneshmand, Siamak 4576, 

4578, 4586, 4588, 4589 

Danesi, Hassan 1016, 3085, 

4077 

Danesi, Romano 10611, 

e13057 

Dang, Chau T. 532, 6025, 

10514 

Dang, Ha 9539 

Dang, Long H. TPS4136, 

4603, TPS10099 

Dang, Nam H. 8081 

Dangi-Garimella, Surabhi 

e14515 

Daniel, Catherine 1095, 5067 

Daniel, Davey B. 7035, 7100, 

7567 

Daniel, Hubert D 3616 

Daniele, Bruno 4006, 

TPS4151 

Daniele, Gennaro 3030, 

TPS4151, e14130 

Daniels, Dianne 2078 

Daniels, Gregory A. 10539 

Daniels, Molly S 1513, 1518, 

1520 

Danila, Daniel Costin 4548, 

4562, TPS4697 

Danilov, Alexey Olegovich 

e13059 

Danilova, Anna Borisovna 

e13059 

Danjoux, Marie 4129 

Dannenberg, Andrew J 10514 

Danova, Marco 4017 

Dansey, Roger D. 4510 

Dansin, Eric 7575 

Danso, Michael A. TPS658 

Danson, Sarah 6113, 7081, 

TPS8605 

Dantonello, Tobias M. 9573 

Dantzer, Jessica 525 

Dao, Fanny 5030 

Daoudi, Khaoula e11502, 

e11516, e14725, e14726 

Daponte, Antonio 8573 

Dar, Lalit 5540 

Darb-Esfahani, Silvia 522, 

523, e15531 

Darby, Charles Harris e13588 

Darcourt, Jacques TPS646, 

8077 

Darendeliler, Emin 9567 

Darfler, Marlene e21068 

Darkow, Theodore e17009 

Darling, Gail Elizabeth 1583, 

10522 

Darloy, Franck e16051 

Darnell, Colleen Marie 

e16017 

Daroqui, Cecilia e14019 

Darvin, Maxim E. 5064, 

e19558 

Darvishian, Farbod 2589, 

8550, 8589, e19003 

Darwish, Alaa Eldin e15530 

Darwish, Mona 9547, e18522 

Das Gupta, Soumyasri 

e13568 

Das, Asha 1591 

Das, Mayukh 7583 

Das, Millie Snigdha 10574 

Das, Prajnan 4060, 4641 

Dasanu, Constantin 6555, 

e18543 

Dascalu, Bogdan e19547 

Dascola, Isabella 2057 

Dasgupta, Roshni e20007 

Dasgupta, Swati e13030, 

e18043 

Dashkoff, Cyd 9019 

Daskalova, Anastassia 3594 

Dasoula, Aggeliki e18567 

Dassonville, Olivier 5521, 

e16044, e16051, e16055 

Datar, Ram H 4575, 10503 

Dauba, Jérôme LBA3500^, 

9012, e14023 

Daud, Adil 3058, 3102, 

8510, 8531, 8580, 

TPS8602, e13596, e19046 

Daugaard, Gedske e15115 

Daugherty, Christopher 6117, 

9586, e13026 

Daugherty, Claire 6530 

Dauplat, Marie-Melanie 1051 

Davar, Diwakar TPS8606 

Dave, Manish J e18117 

Daver, Naval Guastad 6544, 

6558, 6578, 6592, 6597, 

6607 

Daver, Roshni 6597 

Davey, Monica e19580 

Davi, Maria Vittoria 1604 

Davicioni, Elai 4565 

David, Alice K. TPS658 

David, Philippe 7057 

Davidenko, Irina 5504^ 

Davidoff, Amy J. 6028, 6060, 

6075, 6131, e16519, 

e16537 

Davidson, Ashley 582 

Davidson, Christian 2010 

Davidson, Cynthia 3057 

Davidson, Dirk C. e11562, 

e13003 

Davidson, James Ashley 549^ 

Davidson, John Andrew 

e16004, e19642 

Davidson, Nancy E. 1005, 

1021, 1027 

Davidson, Wendy Louise 

e19550 

Davies, Andrew John 8056 

Davies, Angela M. 4052 

Davies, Anthony 637 

Davies, Claire 502 

Davies, Faith 8015 

Davies, Janine Marie e14073 

Davies, Marianne 5529, 5532 

Davies, Michael A. 8501, 

8584, e19009, e19039 

Davila, Jessica 3542 

Davila, Marco L. TPS2619 

Davis, Aretha Delight 9004 

Davis, Brian 4595 

Davis, Darren W. e13500, 

e13562, e13575, e13577, 

e15124, e21028, e21029 

Davis, Darren e21058 

Davis, Gerard e13583 

Davis, Ian D. TPS4681, 

TPS4690, 8542, e15056 

Davis, James W. e19051 

Davis, John D 2567 

Davis, John W. 4556, e15181 

Davis, Keith L. 7101, e15165 

Davis, Mellar P. 6092 

Davis, Rihan 2039 

Davis, Samantha e11529 

Davis, Thomas A. TPS2103 

Davis, Thomas W. e13588 

Davis, Warren e15203 

Davis, Yolanda M. 4055 

Davison, Jon M. e14689 

Davol, Pam e13124 

Davos, Marine 2060 

Davoudianfar, Mina LBA4001 

Daw, Hamed e15023, 

e18046 

Dawar, Richa e18538, 

e18539 

Dawe, David e17518 

Dawood, Shaheenah S. 1032 

Dawsey, Scott 4506 

Dawson, Laura A. 4109, 

e14592 

Dawson, Nancy Ann 4, 4569 

Dawson, Sarah-Jane 544 

Day, Bann-Mo 8567 

Day, Fiona Lee 3623 

Day, Kathleen C. 4506, 4573 

Day, Mark L. 4506, 4573 

Day, Rena e15181 

Dayao, Zoneddy Ruiz 1558 

Dayes, Ian S. 6049 

Dayyani, Farshid e15151 

Dazzi, Claudio 2057 

Dcruz, A. K. 5585, e16021 

de Aguirre, Itziar 7540, 

10596 

De Albuquerque Ribeiro, 

Ronaldo 7506, e14183 

de Almeida Leite, Raphael 

e19528, e19584 

de Andrade, Jurandyr Moreira 

1075 

de Andrade, Mariza 1610 

de Angelis Nascimento, Maria 

Salete e19528, e19584 

De Angelis, Carmine 1554 

De Angelis, Verena e18101 

De Azambuja, Evandro 

e12035 

De Baere, Thierry 3547 

De Benedittis, Caterina 6531 

De Benedittis, Daniela 

e17006, e18563, e18566 

De Boer, Carla 3059 

De Boer, J. P. 8039 

De Bono, Johann Sebastian 

2530, 4513, 4515, 

LBA4518, 4519^, 4553, 

TPS4692^, TPS4693, 

5022, 10525, e13599, 

e13601, e15134, e15136 

De Braud, Filippo G. 3578, 

4507, 4629, e21118 

De Braud, Filippo 2595, 

e13606 

De Buck, Stefan S. 3003 

De Camargo Cancela, 

Marianna 6036, e16514 

De Carvalho Bittencourt, 

Marcelo e12506 

De Castro, Javier 3618, 

7522, 7542, TPS7612, 

10547, e12000, e12012, 

e13085, e18015, e18055 

De Celis Ferrari, Anezka 

Carvalho Rubin 6055 

De Censi, Andrea 519, 1500 

De Cicco Nardone, Carlo 

e15547, e15551, e15553 

De Conti, Ronald C. 5564, 

8534 

De Correia Pereira, Marta 

Isabel e12040 


De Coster, Sandra 4622 

De Cre, Mireille e13073 

De Cremoux, Hubert e18102 

DE Cremoux, Patricia 10507 

de Crespigny, Alex 2566 

De Faverge, Geoffroy 1574 

De Filippi, Rosaria 8066, 

8083 

De Filippis, Lucilla e14096 

DE Fraipont, Florence 10507 

De Geeter, Patrick 4601 

de Geus- Oei, Lioe-Fee 

e13111 

De Giorgi, Ugo CRA4502, 

TPS4683 

De Giorgi, Valeria 8576 

De Giorgi, Vincenzo 8581 

De Gramont, Aimery 2537^, 

LBA3500^, 3506, 4053 

De Gregorio, Nikolaus 5005, 

5007 

De Greve, Jacques 5022, 

9035 

De Groot, John Frederick 

2003, 2011, 2029^, 2036, 

2064 

de Groot, Steffen 1080 

de Gruijl, Tanja 2562 

de Haas, Sanne 10581 

de Herder, W.W. 4122 

De Jong, Floris Aart e16526 

de Jong, Igle J. 10581 

De Jong, Johan R 10581 

De Jonge, Maja J. 2593 

de Jongh, Felix E 10504 

De Juan, Ana 10079, 10512, 

10595 

de La Bourdonnaye, 

Guillaume 5516^, e18047 

de la Cruz, Juan J e11006 

De la Cruz, Maxine e19613 

de la Fouchardière, Arnaud 

e14730 

DE LA Fouchardiere, 

Christelle 4032, e14730 

De La Garza, Jaime G. 1607, 

e18028 

De la Haba Rodriguez, Juan 

R. TPS654^ 

De la Haba- Rodriguez, Juan 

10608, 10616, e11535, 

e21088 

de la Hoya, Miguel e14147 

De la Mata, Dolores 7068, 

e19618 

de la Morena, Pilar e11024 

de la Motte Rouge, Thibault 

641, 6110 

De La Orden, Margarita 

e16526 

de la Riba Alvarez, Ines 

10047 

De la Rochefordiere, Anne 

e15535 

de la Rosa, Federico 4584, 

4620 

de la Torre, Martha e19594 

De Las Casas, Luis e14098 

de las Heras, Begona 3030 

de las Penas, Ramon 1531 

De Laurentiis, Michele 630, 

1073 

de Lavallade, Hugues 10550 

de Leon, Cristina 2569 

de Leon, Maria e15581 

de Liguori Carino, Nicola 

e21037 

de Lima Araujo, Luiz 

Henrique 7506, e17548 


De Lima, Marcos J.G. 6529, 

6540, 6544 

De Lisa, Maria Grazia e21070 

De Lorenzo, Claudia e11052, 

e13539 

De Lorenzo, Francesco 

e19592 

De Los Santos, Jennifer F. 

e15502 

de Luque, V. 4630, e14115 

De Lutio, Elisabetta e14130 

De Maglio, Giovanna 3612, 

e18021 

de Maio, Ana Paula e13509 

De Manzoni, Giovanni 4076 

de Marco, Luiz e13008 

De Maria, Andrea 10565 

De Maria, Ruggero e13512 

De Marinis, Filippo LBA7507, 

7522, 7540, 7542, 7550, 

7557, 7558 

de Martino Lee, Maria Lucia 

TPS9594 

De Mattos -Arruda, Leticia 

10511 

De Mattos-Arruda, Leticia 

509, 566, 619 

De Mello, Ramon Andrade 

e15532 

De Mesmaeker, Peggy 

e13605 

de Miguel Luken, Maria Jose 

e16037 

de Miguel Luken, Veronica 

e16037 

De Miguel, Bernardo 2539, 

3093 

De Minicis, Samulele e14561 

de Muga, Silvia 4580 

De Nictolis, Michele 4084 

De Oronzo, Maria Antonietta 

5094, e15550, e15553 

De Pas, Tommaso M 7581 

De Pas, Tommaso Martino 

3007, 7013, 7533, 7596 

De Pascale, Antonella e19549 

De Pasquale, Maria e11001 

De Piaggio, Marina e16025 

de Pinho, Marcos Barcelos 

e14101 

De Placido, Sabino 1073, 

1554, e13509, e15034 

de Pril, Veerle TPS7113 

de Rink, Iris 3065 

de Romeuf, Christophe 5069 

de Roquancourt, Anne 568^ 

De Rossi, Costanza e19595 

De Sanctis, Rita e16025 

De Santis, Maria 4539 

De Sarro, Giovambattista 

e21113 

De Schaetzen, Gaetan 8532 

De Signoribus, Giorgio 9098 

De Snoo, Femke 577, 1022, 

10545, 10554, 10597, 

e21013 

de Sousa Alves, Pedro 7013 

De Souza Lawrence, Lana 

Maria 1128 

De Souza, Bradley 6005 

De Souza, Caio Silverio 

e12021 

De Souza, Carmino 6505^, 

TPS9594 

De Souza, Paul L. LBA4518, 

e13585, e15152 

De Stefano, Alfonso e13509 

de Torres, Ines e21021 

De Troia, Beatrice 10026, 

10053, 10065 

De Vega, Josep M. 5590, 

5595 

De Velasco, Guillermo 4620, 

e15033, e15149, e15552 

De Vicente, Emilio 4040 

De Vincenzo, Fabio 2580, 

e21139 

De Vincenzo, Rosa 5059 

De Vita, Fernando 546, 3546 

De Vos, Sven 6518^, 8081 

de Vries, Elisabeth G. E. 

e15035 

De Vries, Elisabeth 4528, 

10581, 10602 

de Vries, Jolanda 9070 

de Vries, Petrus 4632 

de Waard, Jan Willem 

TPS10632 

De Wit, Maike 9033 

De Wit, Ronald 4570 

De, Pradip 626, e13579 

De-Montserrat, Helene 3104, 

e13009, e13010 

Deady, Sandra 2609 

Deal, Allison Mary TPS656, 

1524, 6042, 6107 

Deal, Ken e11000 

Deal, Meredith 6042 

Dealis, Cristina 2037 

Dean, Andrew Peter e14644, 

e14718 

Dean, Cheryl A. e21090 

Dean, Emma Jane 3004, 

3030, 3051 

Dean, James P. e15206 

Dean, James T 563, 6063 

Dean, Robert M. 8055 

Dean-Colomb, Windy Marie 

10613 

Deandreis, Desiree 5083, 

5509^ 

DeAngelis, Carlo e15180 

DeAngelis, Lisa Marie 2006, 

2008 

DeAngelo, Daniel J. 6526, 

6621 

DeAngelo, Daniel J 6503, 

8043 

Debernardi, Felicino e20512 

DeBernardo, Robert 5102 

Debiec-Rychter, Maria 9536, 

10030, 10538 

Debieuvre, Didier 1574, 

TPS7111 

Deblasio, Weiping Xu 8547 

Debled, Marc 601, TPS667 

Debois, Muriel 7013 

Debourdeau, Philippe 1580, 

e13062 

Debra, Rowett 2604 

Debruyne, Philip R. 4622 

Debska, Sylwia e21099 

Deburr, Tawania L 8514, 

e19009, e19014 

Debus, Jürgen 2034, e16033 

DeCamp, Malcolm M. 7040, 

7054, 7055 

Decano, Julius L e13574 

Decarli, Nicola L e21102 

DeCastro, Guarionex e15018, 

e15019, e15021 

Decatris, Marios P. e15030 

Decaux, Olivier 8014 

Deck, Kenneth B. 10554 

Decker, Brian 9095, e12500 

Decker, David A. 9095 

Decker, Paul A. 4062, 7008 

Decker, Paul D e12500 

Decker, Roy H. 5529, 5532 

Decker, Thomas 3588 

Deconinck, Eric 6542, 

e19623 

Decordova, Shaun 3022 

Decoster, Lore 9035 

Decosterd, Laurent e11048 

DeCourtney, Christine 6126 

Dedieu, Jean-Francois 

e15116 

Dediu, Mircea LBA7507 

Deeb, George 6565 

Deeg, H Joachim 6522 

Deeken, John F. 2590, 3095 

Dees, Elizabeth Claire 

TPS656, 9020, 10515, 

e13596 

DeFord-Watts, Laura M 6524^ 

Defrein, Anne Marie 615 

Deftereos, Savas e14567 

Degendorfer, Pamela 3013 

Degenhardt, Tom 552 

Degheidy, Heba A 6581 

Degiovanni, Daniela 7084 

Degnim, Amy C. 10586 

Degos, Francoise 4033 

Deguiral, Philippe e14148 

DeGuzman, Angel e13583 

Dehesdin, Daniele 5565 

Dehghan-Paz, Irene 572 

Dehle, Francis 7604 

Dehner, Louis P 9521, 9522 

Dei Tos, Angelo Paolo 10009, 

10053, 10063 

Deighan, Clayton e21124 

Deininger, Michael W.N. 

6624 

Deitel, Wayne 6027 

Dejardin, David 6504, 6506 

DeJesus, Yvette e16574, 

e19625, e19629 

Dejoie, Thomas e21117 

DeJoubner, Nutan Jyothi 

e21045 

Dekeyser, Josh 3580 

DeKoven, Mitch 570 

del Barco, Sonia e11545, 

e19542 

Del Bene, Gabriella e14096 

del Carmen, Marcela G 5029, 

e15545, e15568 

del Cerro, Elia 1111 

Del Conte, Gianluca 3080 

Del Curatolo, Anais e13512, 

e13572 

Del Fabbro, Egidio 9062, 

9127, e19528, e19584, 

e19643 

Del Giglio, Adriana Braz 

e19552, e21151 

Del Giglio, Auro 5588, 

10568, e11059, e13016, 

e16568, e19537, e19552, 

e21151 

Del Marmol, Veronique 

e19026 

Del Mastro, Lucia TPS653, 

1073 

Del Prete, Michela e14086, 

e14561, e14663, e15074 

Del Priore, Giuseppe e15514, 

e15561 

Del Re, Marzia e13057 

Del Rio, Elisabeth e18057 

Del rio, Maguy 10505 

Del Vecchio, Michele 8513, 

8517 

Delabie, Jan 8074 

715s

DeLacure, Mark D. e16052 

Delage, Judith e21156 

Delaloge, Suzette TPS652, 

1011, 1091, 1601 

Delande, Stephanie 4622 

Delaney, Colleen 6631 

Delaney, Joseph e21159 

DeLaney, Thomas F. 4021, 

10058, e16059 

Delarochefordiere, Anne 

e15524 

Delarue, Richard 8021, 8063 

Delasalle, Kay 8093 

Delattre, Jean-Yves 2 

Delattre, Olivier 9510 

Delaunay, Jacques 6523, 

6559, 6632 

Delaunoit, Thierry 3559, 

e14060 

Delavault, Patrick TPS4153 

Delbecque, Laure e12515 

Delbeuck, Xavier e11012 

Delea, Thomas E. e11067 

Delee, Maxon 7601 

deLeon, Maria 5099 

Deleporte, Amélie 3559 

Delfanti, Sara e13103 

Delgado, Francois-Michel 

6110 

Delgado, Juan Ramon 1041 

Delgado, Lucia Beatriz 

e16505, e19007 

Delgado, Salvadora 3536, 

3586 

Delgado-Guay, Marvin Omar 

9002, 9063 

Delios, Anna Maria 2028 

Delioukina, Maria L. 6545 

Delisle, Marie-Bernadette 

10076 

Deliveliotis, Charalambos 

e15199^ 

Dell’ Aglio, Carmine 10066 

Dell’Orto, Patrizia 1022 

Dell, Sharon 9591 

Della Puppa, Alessandro 2049 

Dellinger, Andrew e13589, 

e21038 

Delman, Keith A. 8543 

Delmar, Paul 5522 

Delmore, James Edwin 5015 

DeLongis, Susan e19588 

Delord, Jean-Pierre 2605, 

3026, 3104, 5516^, 5522, 

e13009, e13010, e13594 

Delorenzi, Mauro 3509, 

3511, 3575, 9510 

Delourme, Julie e18066 

Delpech, Yann 612 

DelPriore, Guiseppe 5107 

Delrio, Paolo e14130 

Deluca, Jill 7040 

Delva, Remy LBA4567^, 

4625 

Delwail, Vincent 2023 

Demanse, David 508, 3003, 

e13605 

Demarchi, Martin LBA4007 

Demas, William F. TPS9150 

DeMatteo, Ronald P. 3577, 

3620 

DeMers, April e14503 

Demers, Brigitte 3080 

Demers, Eric 634 

Demetri, George D. 1547, 

LBA10008, 10010, 10013, 

10061, 10067, 10097, 

TPS10101 

Demeure, Michael J. 4013 

Demian, Gerges Attia 9566 

Demicco, Elizabeth G 10071 

DeMichele, Angela e19531 

Demidov, Lev V. 2524, 

LBA8500^, LBA8509, 

e19005 

DeMie, Lynn e13581 

Deming, Dustin A. 3103 

Deming, Richard L. e16572 

Demir, Gokhan e14698, 

e19024 

Demir, Lutfiye 638 

Demirag, GÃƒÂ 1 ⁄4zin e14107 

Demirdjian, Sylvie 9572 

Demirelli, Fuat e21143 

Demiri, Stamatina e11519 

Demirkan, Hatice Mirac 

Binnaz e11507 

Demirkazik, Ahmet 1572, 

1596 

Demkow, Tomasz 4606 

Demmy, Todd L. 1529, 

e17535 

Demolin, Gauthier 3559 

DeMoor, Patricia A e16535 

Demura, Yoshiki 7561 

Demuth, Tim e13598 

den Hollander, Martha 

Willemine 4132 

Den, Robert Benjamin 

e15012, e19507 

Denda, Tadamichi TPS3642, 

e14510 

Denduluri, Neelima TPS1148 

Denehy, Linda e19605 

Deng, Jie e16038 

Deng, Li e16017 

Deng, Qiaolin 10539 

Deng, Qiqi e13011 

Deng, Wei 5110 

Deng, Xingming 7059, 7097 

Deng, Yanhong 6033, 

e14153, e21106 

Deng, Yongchuan 9017 

Deng, Zhuoxia 5558 

Dengel, Lynn Thacher e19062 

Dengler, Jolanta 6510 

Denham, Fiona e19008 

Denholm, Katie Ann 2530, 

10525 

Denicoff, Andrea 9047, 

9144, e16561, e16569, 

e19633 

Denis, Marc G. 2082, 

e21117 

Denisova, Elena e15025 

DeNittis, Albert S. e14157 

Denitz, Jordan e16026 

Deniz, Ferhat 4641 

Deniz, Kemal e14089, 

e14670 

Denkert, Carsten 522, 523, 

1023, 4020, 10627, 

e15531 

Denlinger, Crystal Shereen 

TPS3111 

Denmeade, Samuel R. 4550, 

4559 

Denoux, Yves 543 

Denslow, Sheri 5063 

Dent, Louise 8056 

Dent, Rebecca Alexandra 

1032, 9041 

Dent, Susan Faye 587 

Dent, Susan 1036 

Denton, Brian 10015 

Denzlinger, Claudio TPS3639 

Deo, S. V. S e11013, e17505 

Deonarain, Mahendra e13525 

Depenni, Roberta 2057 

Depierre, Alain 7057 

Deplanque, Gael LBA4007, 

LBA4567^, 4583, 9011 

Deppen, Stephen A 7008 

DePriest, Carol 2569 

Der, Sandy 10522 

Deray, Gilbert 1095, 5067 

Derbel, Olfa e14730 

Derdel, Jerry TPS9150 

Derenne, Laurent e14148 

Dering, Judy 8592 

Derks, Maarten e15166 

Derollez, Marc TPS7111 

Deroma, Laura e15091 

DeRoos, Anneclaire 1527, 

6560 

Derr, Alan G 1057 

Dervenis, Christos e14625 

Des Guetz, Gaetan e18003, 

e18020 

Desai, Ami V. 9576 

Desai, Amishi e18554, 

e21114 

Desai, Anant e13507 

Desai, Arati Suvas e16062 

Desai, Bhardwaj 2013 

Desai, Jayesh 3623, e13054, 

e16516 

Desai, Mihir e15060, e15171 

Desai, Neelam Vijay 

TPS4136, e14612 

Desai, Palak 572 

Desai, Pankaj B TPS3116 

Desai, Sangeeta 1108 

Desai, Sonal 7582, 7594, 

e13526 

Desal, Hubert 2082 

Desantis, Mariangela e15574 

Desantis, Mariangella 5075 

Desar, Ingrid 5061 

Desbiens, Christine TPS1139 

Deschler, Daniel G. e16059 

Deshmukh, Chetan Dilip 

2592, e13127 

Deshmukh, Sanjay P e11506 

Deshpande, Hari Anant 5529, 

5532 

Deshpande, Rahul e21037 

Deshpande, Vikram 4021 

Desideri, Giovambattista 

e11041 

DeSilva, Ashley A 2026 

DeSilvio, Michelle TPS658 

Desjardins, Annick 2027, 

2074^, 2090^, 2094^, 

2095^, TPS2103 

Desjardins, Laurence 8546, 

9538, e13017 

Desmedt, Christine 515, 

e21010 

Desmoulins, Isabelle 10062 

Desolneux, Gregoire e14017 

DeSon, Amanda 4102 

Desruennes, Eric 1580 

Dessanti, Paolo e17533 

Desseigne, Françoise e14730 

Dessi’, Mariele 9006 

Dessureault, Sophie 2559 

Dessypris, Nick e20002 

Desta, Zeruesenay 525 

Destaillats, Alice 3026 

Destro, Anna e18104 

Destro, Annarita 7061, 7585 

Desutter, Petra 1097 

Detjen, Katharina M 4128 

Dettino, Aldo A. e14728, 

e18078 

Detweiler-Short, Kristen 8011 

Detzler, Taylor 4591 

Deutsch, Alexander Josef 

e18525 

Deutsch, Eric 3063 

Deutsch, Jeremy Michael 

3056 

Dev, Rony 9062, 9127, 

e19528, e19584, e19643 

Deva, Sanjeev e15054 

Devanarayan, Viswanath 

e13583 

Devarajan, Karthik 1550 

Devery, Aoife 2536 

Devesa, Manuel e21104 

Devgan, Vikram e21011 

Devi, Gayathri 2585 

Devidas, Meenakshi 9504, 

CRA9508, 9537, 9543, 

9546, 9548 

Deville, Anne e20006 

Devin, Etienne TPS7111 

Devine, Katie 9113 

Devine, Steven M 2533 

Devins, Gerald M. 2063 

Devito, Vikki 7078 

Devitt, Bianca Alix e16562 

Devlin, Sean 6532 

Devlin, Susan 6508 

Devore, Nathan 1569 

Devos, Annick 9517 

Devos, Patrick 2070 

DeVries, Todd e15120 

Dewas, Sylvain e14560 

Dewdney, Alice e14088 

Dewhirst, Mark W e21119 

Dewi, Sagita e11022 

Dewitt, William 10516 

Dewji, Mohamedraza 10009, 

10067 

Dey, Jyotirmoy 9519 

Dey, Nandini 626, e13579 

DeYoung, Barry e15580 

Dezentje, Vincent O. 526 

Dezerlle, Martine 9080 

Dhage, Shubhada e11064 

Dhakal, Binod e17555 

Dhalluin, Christophe 

TPS9597^ 

Dhalluin, Xavier e18066 

Dhanda, Rahul e15063, 

e15089, e20510 

Dhangada Majhi, Prabin 

e17549 

Dhani, Neesha C. e14535 

Dhanvijay, Sushant e15011 

Dhar, Arindam TPS2614 

Dharsee, Moyez 10622 

Dhermain, Frederic 3063 

Dhesy-Thind, Sukhbinder K. 

6049, e14001 

Dhillon, Haryana M. 9021 

Dhillon, Navneet 8543 

Dhinakaran, Mullai e19622 

Dhindsa, Navreet TPS663 

Dhobe, Poornima 3011, 3013 

Di Bacco, Alessandra 3077, 

8017, 8033, 8034, 8064, 

e13603 

Di Bartolomeo, Maria 

LBA4001, e21118 

Di Battista, Monica 2061 

Di Biasi, Brunella e14018 

Di Blasi, Concetta e15544 

Di Cocco, Barbara e19501 

Di Cosimo, Serena 619, 1011 

Di Costanzo, Francesco 

LBA4001, e18074 

Di Costanzo, Giovan Giuseppe 

TPS4151 


Di Emma, Veronica e19002 

Di Fabio, Francesca LBA4001 

Di Filippo, Franco 1050 

Di Filippo, Simona 1050 

Di Giacomo, Anna Maria 

8513, 8529 

Di Giacomo, Daniela e14010 

Di Giannatale, Angela 9517 

Di Lascio, Simona e14156 

Di Lecce, Valentina e21113 

di Legge, Alessia 5059 

Di Leo, Angelo 1008, 1012 

Di Lorenzo, Giuseppe 

e15034, e15043, e15112, 

e15185 

Di Loreto, Carla e15091 

Di Lucca, Giuseppe 4017 

Di Lullo, Gloria A. 6135 

Di Maio, Massimo TPS4151, 

e18021, e19592 

Di Marco, Marco e14096 

Di Marco, Mariacristina 

e14647 

Di Narzo, Antonio Fabio 

3509, 3575 

Di Pace, Raffaella 1500 

Di Palma, Mario 4554, 4621, 

e15049 

Di Raimondo, Francesco 8006 

Di Salvatore, Mariantonietta 

e14156 

Di Sanza, Cristina e13572 

Di Stasi, Savino Mauro 4572 

Di Stefano, Mirella 5059 

Di Tommaso, Luca 623 

Di, Genhong e11567 

Di, Yang e14651 

Diaconu, Iulia e13035 

Diamond, Jennifer Robinson 

3017 

Diane, Goere e14158 

Diao, Lixia 7096, 10612 

Dias, Lauren Elizabeth 

e14615 

Dias, Nathalie 9517 

Dias-Santagata, Dora 7532 

Diasio, Robert B. 3564, 

3617, 4009, 4075 

Diaz Paniagua(1), Laura 

e11543, e19596 

Diaz Pena, Elena e16037 

Diaz Rubio, Eduardo 10564 

Diaz, Angelica 2587 

Diaz, Enrique Gallardo 

TPS4672 

Diaz, Gema e17503 

Diaz, Jose 10061 

Diaz, Jr., Luis A. 3068 

Diaz, Luis A. 2517, 3016, 

3596, 3616, 4045, 4114 

Diaz, Nieves e11545, e15144 

Diaz, Robert 10082 

Diaz, Zuanel TPS1139, 

e14108 

Diaz-Flores, Ernesto 6582 

Diaz-Gavela, Ana 1111 

Diaz-Montero, C Marcela 

9565 

Diaz-Padilla, Ivan 5019 

Diaz-Rubio, Eduardo e14147, 

e20513 

Dib-Faria, Luiza e14702 

DiBenedetto, Joseph e19615 

DiCarlo, John e21011 

Dicato, Mario-A e14180 

Dichmann, Robert 8098 

Dicker, Adam P. 4041, 

e11505 


Dicker, Adam e15012, 

e19507 

Dicker, David e11544 

Dickinson, Kim e21111 

Dickinson, Kimberly M. 5040 

Dickler, Maura N. 575, 

10514 

Dickman, Eileen D. e13568 

Dickow, Brenda e15081 

Dickson, Mark Andrew 8549, 

8575, 8598, 10002, 

10004, 10019, TPS10103 

Dickson, Mike 9143 

Die Trill, Javier e21104 

Diebold, Marie Danielle 

e14059 

Diebolder, Herbert e15566 

Dieci, Maria Vittoria 631 

Dieckmann, Karin 2071 

Dieleman, Edith 7019 

Dienstmann, Rodrigo 509, 

566, 2567, 2568, 3014, 

e13048 

Dieras, Veronique LBA1, 

TPS662, e13017 

Dierckx, Rudi A 10581 

Dierickx, Daan 8030 

Dietel, Manfred e18016^ 

Dieterle, Nelli 10054 

Dietlein, Markus 3044, 7603, 

8079 

Dietrich, Daniel 10033 

Dietrich, Mary S. e16038, 

e19559 

Dietrich, Sascha 6519, 

10040 

Dietz, Allen 2546 

Dietz, Andreas e16016 

Dietzfelbinger, Hermann F. 

3588 

Dieudonné, Anne-Sophie 

1020 

Diez, Blanca D. e12511 

DiGianni, Lisa 1547 

DiGiovanna, Michael 1045 

Dignan, Mark e11097, 

e12004 

Digumarthy, Subba 7524 

Digumarti, Raghunadharao 

6554, e16505, e18544, 

e18545 

Dikalioti, Stavroula e20002 

Dilawari, Asma Ali e11010 

Dileo, Palma 10063 

Diller, Lisa CRA9513 

Dillies, Anne-Francoise 5505 

Dilling, Thomas J. 7065, 

e17559 

Dillinger, Jennifer 9132 

Dillman, Robert Owen 2569 

Dillon, Patrick Michael 

e19028 

Dilts, David M. 6047, 6051, 

e16569 

Dimitriadis, George e21027 

Dimitrov, Todor e13505 

Dimitrova, Desislava 5053, 

5070 

Dimitrova, Nevenka 10508 

Dimond, Eileen P. 6086, 

e16561 

Dimopoulos, Meletios A. 

5033, 8018^, TPS8112, 

TPS8113, e15040, 

e18572^ 

Dimopoulos, Prokopios 

e14567 

Dinan, Michaela A 1525 

Dinardo, Courtney Denton 

6579 

Dincaslan, Handan e20000 

Dincer, Murat e21050 

Ding, Hao e18088 

Ding, Ke-Feng e14024 

Ding, Keyue TPS2104, 7511 

Ding, Li 503, 9518 

Ding, Michelle e13600^ 

Ding, Robert Phooi Huat 

4106 

Ding, Wei e13517 

Ding, Xian e14642 

Ding, Xiaoyan e11538 

Ding, Yan 4646 

Ding, Yi tao e14509 

Ding, Yi 8589 

Ding, Zhenyu e18086 

Dingemans, Anne-Marie C. 

TPS7612 

Dingli, David 8092, 8096, 

8105, TPS8116, e21006 

Dinh, Yvonne 8040, 8102 

Dinhof, Carina 2053 

Diniz, Alessandro Landskron 

e14728 

Dinjens, Winand N.M. 2 

Dinkel, Andreas e15157 

Dinkel, Carina 554 

Dinney, Colin P.N. 4523 

DiNofia, Amanda 9587 

Diodati, Francesca 9120 

Diong, Colin e18528 

Dionigi, Paolo e13103 

Diorio, Caroline 634 

Diorio, Dawn TPS655 

Dip Borunda, Abdel Karim 

e15567 

DiPaola, Robert S. 2526, 

4500 

DiPasquale, MariaChiara 

e14711, e21102 

DiPersio, John F. 6624 

DiPersio, John F 6503 

Dirix, Luc Yves 516, 517, 

e13605 

Dirix, Luc 532, 2583, 8579, 

10504 

Dirksen, Uta 10080 

Dirlea, Mihaela 9131 

Dirven, Hubert 6619^ 

Disalvatore, Davide 546 

Disci, Rian e14628 

DiSiena, Michael Ross 

e13561 

Disilvestro, Paul 1519 

DiSipio, Theresa C. 9576 

Disis, Mary L. 5082^ 

Diskin, Sharon 9516 

Dispenzieri, Angela 8043, 

8092, 8096, 8105, 

TPS8116 

Dispersyn, Garance TPS9154, 

e14006 

Dito, Elizabeth 4048 

Ditsch, Nina 1114 

Ditto, Antonino 5096 

Dive, Caroline e14015, 

e15141, e21037 

Divekar, Ganesh 2592, 

e13127 

Diwakar, Ravi B 1093, 

e11511, e12030, e14721 

Dixon, Margie e13026 

Dizdar, Omer e11011, 

e11023, e11026, e11045, 

e11515, e14174, e15572, 

e15573 

Dizdar, Yavuz 9567 

Dizon, Don S. 5100 

Djaladat, Hooman 4576, 

4589 

Djanani, Angela e14719 

Djordjevic, Bojana 1513 

Dmitriev, Igor e13087 

Dmitrovsky, Ethan 7022, 

e13567 

Do, An 5575 

Do, Chuong B 10097 

Do, Ingu e13094 

Do, Khanh Tu 3087, 3529 

Do, Kim-Anh 1054, e15092 

Do, Young Rok e14570 

Doat, Solene e14065 

Dobbin, Zachary C. 5036 

Dobi, Albert e15207 

Dobi, Erion e11019 

Dobrilla-Dintinjana, Renata 

9097 

Dobrovic, Alexander 8520 

Dobs, Adrian e19582 

Dobson, Lisa TPS8605 

Dobson, Nicky 9589 

Dockx, Yanina 1129 

Dodd, Anna 9021 

Dodion, Pierre F. 10010 

Dodson, Shontelle e19582, 

e19585 

Dodwell, David John 502 

Doebele, Robert Charles 

7504, 7526, 7531, 7534, 

7601, e21120 

Doehn, Christian e15044 

Doerfel, Steffen TPS3641^, 

5031 

Dogan, Semih 1601 

Dogan, Snjezana 10524 

Dogan, Yasemin TPS4138 

Doger de Speville, Bernard 

Gaston e11035, e11527, 

e12015, e17502, e17503, 

e17515, e18521 

Dogliotti, Luigi e15185 

Doherty, Gerard M 6056 

Doherty, J. E. e14022 

Doherty, Mark e17561 

Dohner, Hartmut 6567 

Dohner, Konstanze 6567 

Dohollou, Nadine 5018 

Dohrenwend, Eric 10002 

Doi, Ryuichiro e14506 

Doi, Seiji 7569 

Doi, Toshihiko 3079 

Doihara, Hiroyoshi 1119, 

TPS1147 

Doimi, Franco F. 1024 

Doimi, Franco e11066 

Dokmak, Safi 3609 

Dolan, James e15138 

Dolan, M. Eileen 9516 

Dolinsky, Jozef e19020 

Doll, Donald C. e17525 

Dollinger, Matthias M. 4115 

Dolloff, Nathan G 8090 

Domanska-Czyz, Katarzyna 

e18512 

Domas, Jean TPS7111 

Domchek, Susan M. 1506 

Domenech, Montserrat 

TPS4674, e15144 

Domenichini, Enzo e14598 

Domerg, Caroline 7007 

Domine, Manuel 1531, 5520, 

7095, e15094, e18011, 

e18015, e18055, e18069, 

e18106, e21015 

Domingo, Gelenis C. 6608 

717s

Domingo, Gelenis 6568, 

6575, 6588 

Domingues, Pedro Masson 

e17548 

Dominguez Franjo, 

Purificacion e11028 

Dominguez Hormaetxe, Saioa 

e21089 

Dominguez, Rafael 2515 

Dominici, Fernando e19569 

Dominioni, Lorenzo 1532 

Domino, Marisa E 6029 

Domling, Alexander 8577 

Dommermuth, Alena e14131 

Domont, Julien 3063, 10005, 

10007, 10016, 10020, 

10027, 10033, 10044, 

10089, 10092, 10095 

Donachie, Paul 9539 

Donahue, Amy 3533 

Donahue, Timothy R. e14582 

Donald, Emma 1548 

Donaldson, Kirsteen 3100 

Donaldson, Sarah S. 9502, 

9537 

Dondero, Richard TPS8116 

Dondi, Alessandra 8006 

Done, Susan 1019, 1123 

Donehower, Ross C. 2535, 

2594, 3020, 3616, 4005, 

4055 

Donepudi, Sreekanth 10614 

Dong, Bin 538 

Dong, Hongshan e21080 

Dong, Mei e14662 

Dong, Song e13510 

Dong, Wei 1590, 1591, 

4092, e14575 

Dong, Yu e18038 

Dongre, Amol 9559, e17003 

Donia, Marco 2565, 2574 

Donini, Maddalena 4097 

Donnadieu, Anne e11070 

Donnellan, Paul P. LBA1000, 

e19059 

Donnelly, Bryan J 4 

Donnelly, Kerri e13588 

Donnelly, Patrick E. 6031 

Donner, Allan 9003 

Donnini, Alessia e15011 

Donovan, Jenny TPS665 

Donovan, Sean 8590 

Donskov, Frede 4536, 4538, 

e21110 

Doolin, Elizabeth E. 4603, 

7079^ 

Doolittle, Nancy Diane 2040, 

2077 

Doot, Robert K 1088 

Dorantes, Yuzmiren e19618 

Doratotaj, Behzad e21082 

Dorca Ribugent, Joan 1001 

Dorent, Richard 1095, 5067 

Dorff, Tanya B. e13084, 

e13531, e15005, e15153 

Dorff, Tanya B TPS4679 

Dorin, Ryan Paul 4588 

Dorkhom, Stephan Joseph 

6544, 6607 

Dorkin, Maurizio e19002 

Dorlhiac-Llacer, Pedro E 

6505^ 

Dormans, John P. 9537 

Dorn, Paige L. e11512 

Doros, Leslie Ann 9521, 

9522 

Dorosario, Andrew 8552 

Doroshow, James H. 3031, 

3087, 3529, 5020, 10603 

Dorta, Javier 1531 

Dorta, Miriam e15033 

Dorvault, Nicolas 10556 

dos Santos, Renata e19528, 

e19584 

Dosa, Edit 2040, 2077 

Doshi, Sameer 2535, 2594 

Doshi, Simit e15181 

Dotan, Efrat e14021 

Dotson, Emily K. e18508 

Dotti, Katia F e21118 

Doubet, Ellen e15012 

Douce, Thomas B e13581 

Douek, Michael 1131 

Douer, Dan 6532 

Dougherty, Patrick M. 9082, 

9140 

Douglas, Jeremy 9019 

Douillard, Jean Yves e14148 

Douillard, Jean-Yves 3507, 

3581, LBA4003, 7007, 

7013 

Doung, Yee-Cheen 10011^ 

Dourthe, Louis-Marie e11019 

Doussau, Adelaide 4053 

Doval, Dinesh e15082 

Dove, Lorna 4101 

Dowden, Scot D. e14073 

Dowdy, Sean Christopher 

5004, 5087 

Dowell, Barry e13583 

Dowell, Jonathan 7518 

Dowlati, Afshin 7087, 

e17563, e18046 

Dowling, Ryan JO 1019 

Downing, James 9518 

Downing, Sean 3533, 4649 

Downs, Melinda 3020, 

TPS3117 

Dowsett, Mitchell 9103 

Doyle, Catherine 3572 

Doyle, L. Austin 4639, 6582, 

8598, 9541, 9581, 

e14586 

Doyle, Laurence A. 8075 

Doyle, Laurence A 3020, 

3103, 3529 

Doyle, Yvonne e15534 

Doz, Francois P. 9538 

Drabick, Joseph J. 8090 

Dracopoli, Nicholas J e17541 

Draetta, Giulio Francesco 

e15200 

Dragnev, Konstantin H. 7022, 

e14514 

Drake, Catherine 2062, 

e16506 

Drake, Charles G. CRA2509, 

TPS2613, 4505, TPS4689, 

5506 

Drakes, Maureen e13121 

Dranitsaris, George e18562, 

e18567 

Dranoff, Glenn 2502 

Drape, Jacqueline 8060 

Drapkin, Benjamin Jacob 

6617, 6618 

Drappatz, Jan 2009 

Drayson, Mark 8015 

Dreger, Peter 6543, 8004 

Dreher, Cara 1512 

Dreicer, Robert 4609, 4650, 

4662, TPS4684, TPS4693, 

e15095, e15208 

Drengler, Ronald L. e13025 

Drengler, Ronald 2512, 2555 

Dreno, Brigitte 8559, 8591, 

e19019 

Dresser, Mark J. e13114 

Dressler, Lynn G. 6042 

Drevs, Joachim e13508, 

e13597 

Drew, Yvette 3048, 3051 

Dreyer, Chantal 2557, 

e14553, e14660 

Dreyer, Nancy A. e11051 

Dreyer, ZoAnn Eckert 9548 

Dreyfus, Brigitte 6584 

Dreyfus, Francois 6523 

Dreyling, Martin H. 8030, 

8031 

Drilon, Alexander Edward Dela 

Cruz 7052, 7066, 7527, 

7578, 7580 

Driol, Pamela 1044, e13058, 

e13070 

Drobish, Amy 10515 

Drobniene, Monika 9046 

Droege, Cornelia M. e18012 

Drolsum, Anders e14637 

Drooz, Alain 3590 

Dropulic, Boro TPS1616 

Drosik, Kazimierz 4606 

Drouet, Alain 10049 

Drouet, Ludovic e21156 

Drouin, Michel A. 3039, 

e13602, e13604 

Drouin, Sarah e15105 

Drovetto, Nicholas Alan 

e21148 

Droz, Jean Pierre 5028, 

e15009 

Droz, Jean-Pierre e15122 

Drozdowskyj, Ana 7522, 

7540, 7542 

Drucker, Aaron Mark 9088 

Druker, Brian J. 9555 

Drullinsky, Pamela 8054 

Drumm, William e13542 

Dry, Sarah M 10012, 10588 

Du Bois, Andreas 5005, 

5007, 5051 

Du Four, Stephanie 2050, 

e19026, e19027 

du Manoir, Jeanne Michelle 

e15020 

Du, Feng e14606 

Du, Min e14593 

Du, Nan 7036 

Du, Weidong e18088 

Du, Xiang 3551 

Du, Yuhong 3094 

Dua, Rajesh 2585 

Duan, Jianchun 7537, 

e18022, e18035 

Duan, Qiuli 6548 

Duan, Xiuzhen e15538 

Duan, Zhigang 3542 

Duarte, Jose 4584 

Duarte, Lupe 8089 

Dubel, Gregory 4098 

Dubey, Sarita 2535, 2594, 

4005 

Dubinett, Steven M. 7518, 

7532 

Dubois, François 2070 

DuBois, Kara S e14566 

DuBois, Steven G. 3058, 

9537 

Dubost, Emilie e19555 

Dubovsky, Jason A. 6575 

Dubowy, Ronald L. 3019, 

e13576 

Dubreuil, Olivier 4018 

Dubrow, Robert 1591 

Dubsky, Peter Christian 514, 

542, 10570 

Ducassou, Marie 10042 

Duch, Joan 1120 

Ducharme, Murray P 6619^ 

Duchesne, Gillian M. 

TPS4690 

Duchnowska, Renata 505, 

603, e21099 

Ducimetiere, Francoise 10056 

Duckworth, Lizette Vila 

e14612 

Ducolone, Alain 7057 

Ducreux, Michel 3507, 3535, 

3547, 4032, 4036, 4053, 

4071, e14129 

Duda, Dan G. 1026, 2010, 

4112 

Duddalwar, Vinay 4096 

Dudgeon, Deborah Jane 6039 

Dudley, Mark E. 8576, 

e14179 

Dudnik, Elizabeth 9052 

Dudnitchenko, Alexander Serg 

e13095^, e13097^, 

e13108^ 

Dueck, Amylou C. 6108, 

6133, 8010, 8053, 9047 

Duehrsen, Ulrich 8030 

Dueland, Svein 4015 

Dueñas Porto, Marta 4584 

Duerinck, Johnny 2050, 

e19027 

Duerk, Heinz A. 3 

Duffaud, Florence 10005, 

10006, 10023, 10027, 

10056, 10078, 10092, 

10095 

Duffey, Steven e15054 

Duffield, Amy 6629 

Duffner, Jay 4056 

Duffy, Alison P 6611 

Duffy, Austin G. 3103, 

10566, e14064 

Duffy, Deirdre 6537 

Duffy, Mary e16538 

Duffy, Michael J. 622, 1042 

Duffy, Regan M. TPS7609 

Duffy, Steven 6572 

Dufour, Christelle 9560, 

9572 

Dufour, Jean-Francois 4107 

Dufour, Patrick Regis 636 

Dugan, Margaret Han 2603 

Duggal-Beri, Priya 6111 

Duggan, Peter 6548 

Dugo, Nella 5094, e15547, 

e15550 

Dugué, Pierre-Antoine e14006 

Duh, Mei Sheng 10061 

Duhamel, Alain 2540, 6534, 

6542 

Duhamel, Jean-Paul 

TPS7112, e18089 

Dujon, Cecile e16560 

Dukelow, Karen e17558 

Duman, Berna Bozkurt 

e11088, e13523 

Dumez, Herlinde 3018^ 

Dummer, Reinhard 8076, 

8502^, 8505, LBA8509, 

8511, 8526, 8563, 

e19017 

Dumont, Amaury Gerard 

e13519 

Dumont, Frédéric e14158 

Dumont, Patrick TPS7111 

Dumont, Sarah N. e13519 

Dumstorf, Chad A 8082 

Dunbar, Erin M. TPS2103 

Duncan, Gail 4526 

Dunet, Vincent 10033 


Dunleavy, Kieron 2528, 

8005, 8051 

Dunlop, Alison 10039, 10060 

Dunlop, Joanna 1094 

Dunn, Ian F. 2020 

Dunn, Janet A TPS660, 

TPS665, TPS1144, 5046, 

e16042 

Dunn, Sandra E. e13123 

Dunne, Grainne 2536 

Dunning, Bernadine 

TPS5114, TPS10635 

Dunning, Mark 544 

Dunnwald, Lisa K 1088 

Dunphy, Frank e13032 

Dunson, William A. 9137 

Duong, Vu 2099 

Dupont, Jakob 3025 

Dupont-Gossard, Anne Claire 

4018 

Dupre, Pierre-Francois 

TPS646 

Duprez, Thierry 5519 

Dupuis, Charlotte e16044, 

e16051, e16055 

Dupuis, Jehan 8057 

Dupuis, Lee 9556 

Dupuis, Olivier LBA3500^, 

e14148 

Dupuy, Danielle 1553, 6120, 

e16531 

Dupuy, Evelyne e21156 

Duque, Cristiano Guedes 

e14027 

Duque, Lourdes e14727, 

e18516, e19638 

Durak, Merih e11507 

Duran, Hipolito 602 

Duran, Ignacio 3005, 3066, 

4119, TPS4672, e15111 

Duran, Jose e11036 

Durand, Jean-Bernard e13506 

Durand, Jean-Philippe 

e13056 

Durando, Antonio 1073 

Durando, Xavier 8532, 

e13108^ 

Durant, Cecile 1580 

Durante, Emilia e13019 

Durante, Michael e13596 

Duranti, Simona e18023, 

e18101 

Durastante, Vittorio 3612 

Durci, Michael e17524 

Durie, Brian G. 8037, 8095, 

8097, e18556, e18561 

Durosinmin, Muheez e11554 

Dursun, Polat e15572, 

e15573 

Duruisseaux, Michael e18075, 

e18102 

Dutcher, Janice P. 4500, 

4504 

Dutel, Jean Luc 3506 

Dutt, Neelam e15554 

Dutta, Anindya 8597 

Dutton, Susan LBA4001 

Duval, Vincent e13605 

Duval-Modeste, Anne 

Benedicte 8591 

Duvic, Madeleine 8537 

Duvillard, Pierre 4129, 5028, 

10098 

Duvillie, Ladan 6512 

Duvvuri, Seshagiri TPS6635 

Dwivedi, Alok kumar e14714 

Dworacki, Grzegorz 10536 

Dwyer, David 8537 


Dy, Grace K. 4117, 4545, 

7073, 7555, 7605, 8519, 

e13006, e13101, e17535, 

e18118 

Dy, Irene Ang 6595 

Dy, Philip 6582 

Dyer, Martin J. S. 6584 

Dyer, Michael A. e13544, 

e13584 

Dyer, Richard e11066 

Dykas, Dan 1540 

Dykema, Karl 4624 

Dyla, Alicja e21049 

Düran, Andreas 2560 

Dyson, Greg e14163 

Dyson, Gregory e14609, 

e16019 

Dyster, Lyn M. 4654 

Dyszkiewicz, Wojciech 10536 

Dytfeld, Dominik 8011 

Dzhabarov, Farkhad e19049 

Dziadziuszko, Rafal 7597 

Dziewirski, Wirginiusz 8548 

Dzodic, Radan e21136 

Dörken, Bernd 4020, 4044, 

e14533, e15053 

E 

E, Mingyan e14511 

Ea, Roth TPS8602 

Eaby-Sandy, Beth e18032 

Eagle, Ralph 9515 

Eakle, Janice F. 512, 3545 

Eap, Chin-Bin e11048 

Eapen, Ann e21076 

Earashi, Mitsuharu 1119 

Earl, Helena Margaret 

TPS660, TPS665, 

TPS1144 

Earl, Julie e12033 

Earle, Craig 6006, 6026, 

6039, 7606, e11050 

Early, Dayna S e14584 

Earnest, Arul 5553 

Earwood, Chris 4127 

Eary, Janet F. TPS3109 

Easaw, Jacob C. e14073, 

e21044 

Eastham, James Andrew 4552 

Easton, Doug 1545 

Easton, John 9518 

Eastwood, Daniel e17555 

Eaton, Anne 557, 575, 9104, 

e11531 

Eaton, Keith D. 2610, 5503, 

5515 

Ebb, David 9503 

Ebbinghaus, Scot 7531, 

10010 

Ebeid, Emad Nabil 9566 

Ebeling, P. e13100^ 

Eberhardt, Wilfried Ernst 

Erich e18016^, e18100 

Eberhardt-Wetherington, Berit 

e19502 

Ebert Motara, Maja e14083 

Ebos, John M. e15042 

Ebrahim, Jalal 6084, 9111 

Ebsworth, Karen e13580 

Eccher, Claudio e21102 

Echaburu, Juan Virizuela 

TPS4672, TPS4674 

Echalier, Ben R. 520 

Echarri, Mari-a Eugenia 8572 

Echenique, Miguel M. 1060, 

e11015 

Echeveste, Jose Ignacio 8572, 

e18008 

Echt, Katharina V e15187 

Eckardt, Jeff J. 10012 

Ecke, Thorsten 4524 

Eckel, Robert H e15192 

Eckermann, Simon 2604, 

TPS9153 

Eckert, Robert 7572 

Eckhardt, S. Gail 3017, 

e13006, e14071 

Economopoulos, Theofanis 

e21027 

Ecsedy, Jeffrey 2597 

Ecstein-Fraïssé, Evelyne B 

4570, e15112 

Eddy, Sean e14164 

Edelman, Gerald 7514, 8531 

Edelman, Martin J. 4022, 

6131, 7546, TPS7616 

Edelmann, David 10034 

Edelsberg, John e12024, 

e15197, e18107, e19630 

Edelstein, Kim 2063 

Edenfield, Jeff TPS3111 

Edesa, Wael e15530 

Edge, Stephen B. 1033, 

1125, 6088, e19568 

Edge, Stephen B e11563 

Edgerton, Susan e21099 

Ediebah, Divine Ewane 6002, 

6090, 7607 

Edil, Barish H 3596, 4045, 

e13559, e14585 

Edington, Howard 8533, 

TPS8606 

Edmonston, Tina B 10528 

Edmundowicz, Steven 

Alphonse e14584 

Edsgard, Daniel 10521 

Edwards, Beatrice J. 2532, 

4063, 6623 

Edwards, Connla 637 

Edwards, Joanne E. e14054, 

e14110 

Edwards, Susan e13084 

Eeles, Ros A. 1545, 4653 

Efremidis, Anna P. e11519 

Efstathiou, Eleni 4556, 

e15122 

Egan, Barbara 9094 

Egawa, Shin e15127 

Egawa, Shinichi 4035, 

e14011 

Egberts, Friederike e19031 

Egerer, Gerlinde 10040, 

10041^ 

Egger, Matthias 4083, 4090 

Eggermond, Anja M 8039 

Eggermont, Alexander M. 

8535, e19022 

Eggers, Carrie 5560 

Eggmann, Nina e19017 

Eghan, Naa 6021 

Egleston, Brian 6021, 6061, 

6095, 6128 

Eglitis, Janis 9046 

Egorin, Merrill J. 2533 

Egorova, Natalia e15513 

Egrot, Christophe e15105 

Eguchi, Kenji 1530, e19556 

Ehinger, Mats 10024 

Ehlers, Shawna L. 9057 

Ehmann, W. Christopher 8090 

Ehninger, Gerhard 10068, 

10552 

Ehrenstein, Vera 1579, 

e12023 

Ehrenwald, Edward 3590 

Ehrlich, Peter 9524 

Ehrnrooth, Eva TPS5598, 

TPS5599 

EI-Khoueiry, Anthony e14031 

EI-Khoueiry, Rita e14031 

Eichelberg, Christian 4539 

Eichenauer, Dennis A. 8079 

Eichhorn, Christoph e19031 

Eichler, April F. 2009, 9004 

Eichler, Katrin e14131 

Eickhoff, Jens C. 3101, 

3103, TPS9152, e19047 

Eid, Toufic e20004 

Eidtmann, Holger 522, 541, 

1023 

Eiermann, WOLFGANG 1023 

Eigentler, Thomas K. 8526, 

e19031 

Eilber, Frederick C. 10000, 

10012 

Eilber, Frederick R. 10000 

Eilender, David S. 3619, 

e15554 

Eimermacher, Hartmut 6610 

Ein-Gal, Shlomit Y. 8524 

Einefors, Rickard 1594 

Einhorn, Jan e14125, 

e19606, e19638 

Einhorn, Lawrence H. 4534, 

4596, 4598 

Einsele, Hermann 6500^, 

e18572^ 

Einstein, Mark H. 5025 

Eisbruch, Avraham e16014 

Eiseman, Julie 2553, 3031 

Eisen, Andrea 1555, e12034 

Eisen, Tim 4501, e15037, 

e18100 

Eisenberg, Marcia 614 

Eisenberg, Rosana 6038 

Eisenberger, Mario A. 4506, 

4559, 4564, 4568, 4570, 

4619, 4665, TPS4692^, 

e15058, e15188 

Eisenbruch, Maurice 6111, 

e16507 

Eisenhauer, Anne 5019 

Eisenhauer, Elizabeth A. 

1036, 2051, 5010 

Eisenhauer, Eric Lawernce 

5101, e15585 

Eiser, Christine 6113 

Eisinger, Francois 1567, 

1568, TPS1613 

Eisner, Florian e14066 

Eisner, Joel Robert 4671, 

e15167 

Eisterer, Wolfgang 4074, 

e14103, e14719 

Eito, Clara e14057 

Ejaz, Shamim 4641 

Ejlertsen, Bent 596, 604 

Ekenel, Meltem e14628 

Ekinci, Ahmet Siyar e14526 

Eklund, Martin e16504 

Ekman, Simon 7539, 7597 

Eksborg, Staffan 7539 

El Ashry, Mohamed S e15129 

El Cheikh, Jean 6534, 6542 

El Ghali, Ilham 10600 

el Ghandour, Ashraf e18572^ 

El Ghazaly, Hesham e17556 

EL Haoudi, Khalid e14726 

El Mekkeoui, Zineb 

Benbrahim e18124 

El Mesbahi, Omar e11502, 

e11516, e14725, e14726, 

e18124 

El Messaoudi, Safia 10505 

El mrabet, Fatima Zahra 

e11516 

El Sadda, Wael M e15129 

719s

El Sherbeiny, Esam e15129 

El-Deiry, Mark 5570 

El-Deiry, Wafik e11544 

El-Gehani, Faraj e15540 

El-Hariry, Iman TPS7613^ 

El-Hashimy, Mona 512, 2543 

El-Jawahri, Areej 6106, 9004 

El-Khoueiry, Anthony B. 

3078, 3584, 3604, 3615, 

3622, 4096, 4099, 4113, 

e13084, e14581, e14679 

El-Khoueiry, Rita 3540, 

3546, 3549, 3584, 3597, 

3604, 3622, 4026, 4088, 

4096, e11018 

El-Modir, Ahmed e15534 

El-Naggar, Adel K. 5524, 

5592 

El-Osta, Hazem Edmond 

3106 

El-Rayes, Bassel F. 3094, 

e14169, e14692, e14736 

El-Rayes, Bassel F 2576, 

e14170, e14512, e14614 

El-Serag, Hashem 3542 

El-Shikh, Wafaa 4116 

El-Shinawi, Mohamed e21055 

El-Tamer, Mahmoud 557, 

1118 

Elaesser, Reiner e19587 

Elagoz, Sahande e11083 

Elaidi, Reza-Thierry e15040 

Elashoff, David 2519 

Elashoff, Robert M. 7518 

Elashoff, Robert 8534 

Elatre, Wafaa 4010 

Elbadawy, Samy 9566 

Eldon, Michael A. 5048 

Eleftheraki, Anastasia G 5033 

Elena Vaja, Elena Vaja 5574 

Elez, Elena 2583, 3539 

Elfakharany, Mohamed 3619 

Elfring, Gary L. e13588 

Elia, Loredana 6531 

Elias, Anthony D. 528, 564, 

TPS668, TPS10099, 

TPS10103 

Elias, Dominique 3507, 

e14158 

Elias, E. George e13129 

Eliott, Jaklin A. e19553 

Elisei, Rossella 5508, 5591 

Elkin, Elena B. 6001, 6073, 

6101 

Elkiran, Emin Tamer 638 

Elkiran, Tamer 9050 

Ellard, Susan 549^, 582, 

1036, 4514 

Ellberg, Carolina 1594 

Ellebaek, Eva 2565, 2574 

Ellezam, Benjamin 2022 

Ellimoottil, Chandy e16544 

Elling, Dirk 624 

Elliott, Brian M e21006 

Elliott, Martin 9542 

Elliott, Michelle A. 6614 

Elliott, P. Anthony e15141 

Elliott, Richard 3050 

Ellis, Alison 7030 

Ellis, Catherine Elizabeth 

TPS658 

Ellis, Ian O. 1013, 1014, 

1098 

Ellis, Matthew J. TPS664, 

1048, 3047 

Ellis, Matthew James 503, 

534, 1008 

Ellis, Peter Michael 7093, 

7511, e17532 

Ellis, Robin Anne 2569 

Ellis, Sarah Gabrielle 8566 

Ellis, Steve 1545 

Ellis, Sue 6113 

Ellis, William J 4520 

Ellison, Christie e16561 

Ellison, David W. 9518 

Ellsworth, Eric M. e21048, 

e21121 

Ellwanger, Kristina 8059 

Elmesidy, Salah Eldeen 

e18001 

Elmishad, Amira e13121 

Elramsisy, Adam 2080 

Elsass, Karen E. 9575 

Elsayed, Yusri A. 3059 

Elsayegh, Nisreen 1546, 

1549 

Elsayem, Ahmed F. 6125 

Elserafy, Mostafa M. e20514 

Elshaikh, Mohamed A. 5088, 

e15512 

Elson, Paul 2018, 2076, 

2096, 4609, TPS4679, 

TPS4684, 6521, e15095, 

e15208, e18046 

Elston-Lafata, Jennifer 

e18144 

Elstrom, Rebecca L. 8054 

Elter, Thomas 7603, 8031 

Elting, Linda S. 600, 6124 

Elvin, Paul 3561 

Elving, Lammy 9070 

Ely, Benjamin 4547, 4571, 

4663, 10503 

Ely, Scott 8036 

Elyan, Firas 10034 

Emadi, Ashkan 6629 

Emami, Marjan 1535, 7586 

Emanuelsson, Olof 10521 

Emblem, Kyrre E. 2009 

Embree, Elizabeth 10533 

Embree, Heather TPS1616 

Emerick, Kevin S. e16059 

Emerson, Ryan 6631 

Emi, Manabu e14636 

Emi, Yasunori 3558 

Emile, Jean-François 8540, 

e14059 

Emmanuel, Romala 4063, 

e18571 

Emmel, Ann E. 6074 

Emmenegger, Urban 

e15177^, e15180 

Emmons, Gregory Scott 

e19543 

Emond, Jean 4101 

Emoto, Shigenobu e14530 

Endell, Jan 6574 

Enderica Gonzalez, Sergio 

5077 

Endlicher, Esther 4034 

Endo, Itaru 2044, e14014, 

e14047, e14050, e14624 

Endo, Kojin e14011 

Endo, Masahiro 7088, 

e21007 

Endo, Takashi 10531 

Eng, Cathy LBA3501, 3544, 

3556, 3598, 4060 

Eng, Charis 1508, 1516, 

5573 

Eng, Dawn Fun TPS6638 

Eng, Lawson 1597, 9032 

Eng, Yoko 4098, e16058 

Engel, Christoph 3550 

Engel, Erik e14138 

Engel, Jessica Marie 555, 

563, 6063, e14160 

Engel, Juergen e15153 

Engel, Jutta 1114 

Engel-Riedel, Walburga 1533, 

7001, 7603, CRA10529, 

e18000 

Engelen, Kristel 1022 

Engell-Noerregaard, Lotte 

2574 

Engellau, Jakob 10024 

Engelman, Eric Steven 

e14600, e14620 

Engelman, Jeffrey A. 7508 

Engels, Eric A. 6070 

Engelstaedter, Verena e15529 

Engenhart-Cabillic, Rita 5512 

Engert, Andreas 8079, 

e13079 

Engle, Robert e13081 

English, Patricia A e13606 

Engracia, Ruth Ginger 

e15571 

Enis, Marguerite 1019 

Enk, Alexander 4034, 8505 

Enke, Aaron S. TPS7613^ 

Enkemann, Steven 10048 

Ennis, Marguerite 2572 

Enomoto, Takahiro e19583 

Enos, Rebecca A. e16561 

Enrech, Santos e11074 

Enright, Katherine e14003 

Ensminger, William D. 

e14603 

Ensor, Joe 594, e14664 

Enting, Roelien H. 2 

Enzinger, Peter C. 4027, 

e19586 

Eoli, Marica 2083 

Eom, Hyeon Seok 8023 

Epenetos, Agamemnon A. 

e13525 

Epner, Elliot E 6616, e18500 

Epstein, Andrew S. 9004, 

9105 

Epstein, Joel Brian 5528 

Epstein, Jonathan I 4570 

Epstein-Peterson, Zachary 

9116 

Eramo, Adriana e13512 

Erasmus, Jeremy J. 4069, 

4078 

Erba, Harry Paul 6502, 6582, 

TPS6637 

Erben, Philipp 6510 

Erbs, Philippe 2605 

Erbstoesser, Erhard 1023 

Ercan, Dalia 7510 

Ercolano, Elizabeth TPS669, 

TPS1614 

Ercoli, Alfredo e12037 

Erdag, Gulsun 8530 

Erdem, Dilek e14107 

Erdmann, Michael e19032 

Erdozain, Jose Carlos 1570 

Eremin, Dmitry 6088 

Eren, Mehmet Fuat e16005, 

e19575 

Eren, Onder Orhan e11008 

Eren, Tulay e11011 

Erfán, Jozsef 5516^ 

Ergin, Melek e11088 

Ergun, Aydin e11026 

Erho, Nicholas 4565 

Erickson, Beth e14613 

Erickson, Julie e21129 

Ericson, Solveig 6594, 6605, 

TPS6636, TPS6638 

Eriksson, Andre Huss e19056 

Eriksson, Jennifer 6058 

Eriksson, Mikael 8074, 

10081 

Erill, Nadine e14552 

Erin, Nuray e21130 

Erinjeri, Joseph Patrick 

10004 

Erismis, Betul e14174 

Erkmen, Cherie Parungo 7022 

Erlander, Mark G. 561, 

10530, 10588, e21019 

Erler, Brian 1540 

Erlichman, Charles 534, 

3001, 4047, 4099, 5020, 

5025, 5544, 6570, 8013, 

e13052, e13517 

Ermacora, Paola 3612 

Ermani, Mario 2057, 2061 

Ernest, Mary Lou 9107 

Ernst, Brenda e16030 

Ernst, Christine 2584 

Ernst, D. Scott 8587, e19616 

Ernstoff, Marc S. TPS2614 

Eroglu, Celalettin e14526, 

e14670 

Ersahin, Cagatay e15538 

Erten, Mujde Z. 6060, 6075 

Ertl, Linda S e13580 

Ervin, Thomas J. LBA3501, 

TPS3640, e13113 

Esaki, Taito 3045, 4002 

Escalante, Carmelita P. 9072 

Escallon, Jaime 1019 

Escalon, Juliet 2589 

Escande, Fabienne 10507 

Escano, Crystal 2589 

Escarzaga, Diana e18117 

Escriu, Carles 8523 

Escudero, M. Pilar 3571 

Escudero, P. 4119 

Escudero, Pilar 3553 

Escudier, Bernard J. 

CRA4502, 4540, 4546, 

4554, 4614, 4621, 4625, 

TPS4683, e15049 

Escuin, Daniel 10555 

Eser, Markus 8059 

Eskens, Ferry 2593, 4132 

Esmay, Paula 5523 

Espadana, Ana e12040 

Esparaz, Benjamin 9028 

Espat, Joseph 4098 

Esperide, Barbara 9098 

Espie, Marc TPS652 

Espino, Guillermo e13604 

Espinosa, Enrique 8517, 

e19023 

Espinosa, Iñigo e14104 

Espinoza Venegas, Macarena 

Paz 4587, e16025 

Espinoza, Anne Marie 4038 

Espinoza, Ramiro 6599 

Espinoza-Delgado, Igor 

TPS4687 

Espirito, Janet L. 6109 

Esplen, Mary-Jane 3567 

Esposito, Angela 1049, 1115 

Esposito, Assunta 8573, 

e19034 

Esquerdo, Gaspar 4587, 

e16025, e18049, e18053 

Esser, Regina 3574 

Esserman, Laura 9107, 

10586, e16504 

Esteban Esteban(1), Carmen 

e11543, e19596 

Esteban, Emilio TPS4683, 

TPS4685, e15041, 

e15067, e15149, e18044 

Esteban, Isabel e11028 


Esteller, Manel 3570 

Esterni, Benjamin LBA4567^, 

e18526, e19539 

Estes, Jacob Michael 5062^, 

e13087, e15502 

Esteva, Francisco J. 527, 

612, 10613 

Estevan, Rafael 3586 

Esteves, Brooke 4132, 4501, 

e15082 

Esteves, Jorge e14673 

Esteves, Susana e13119 

Estevez-Diz, Maria Del Pilar 

e15562 

Estorch, Montserrat 1120 

Estrella, Heather 3509 

Estrella, Timothy e21155 

Estrov, Zeev 6517, 6528, 

6589 

Esumi, Hiroyasu 1552 

Eswarvee, Chinnamani 

e15128, e15135, e18068 

Etchin, Julia e13586 

Etemadi, Hooman e17521 

Etemadmoghadam, Dariush 

5073 

Etienne, Pierre-Luc LBA4003 

Etienne-Grimaldi, 

Marie-Christine 2537^, 

2600 

Etiz, Durmus e21050 

Eto, Hidehiro e15533 

Eto, Masatoshi e15048 

Etoh, Tsuyoshi 3569 

Ettl, Johannes 556 

Ettore, Giuseppe e15544 

Ettrich, Thomas TPS1612, 

TPS3636 

Etxaniz, Olatz 4579, e12504, 

e15001 

Etzioni, Ruth D 4557 

Eubanks, Susan e17547, 

e17550 

Eucker, Jan 8031 

Eulenburg, Christine 5058 

Eustace, Alex J. 633 

Eustaquio, Joy e19570 

Eustermann, Heidi 640 

Evans, Andrew 4633, 

e15118, e18139 

Evans, Arthur T 9085 

Evans, Douglas B. 4013, 

4051, e14613 

Evans, Erica 8032 

Evans, Kenneth R. 10622 

Evans, Kenneth 7020 

Evans, Laura 9019 

Evans, Linda TPS4143 

Evans, Steven e14075 

Evans, T.R. Jeffry 2552, 

3000, TPS4134, TPS8605, 

TPS10633^ 

Evans, Tracey L. 7092, 7098, 

7533, 7546, 7595, 7596, 

e18032 

Evans, William K. 6049 

Evaul, Kristen 4645 

Evelhoch, Jeffrey L. 10573 

Even, Caroline 5028 

Even-Shoshan, Orit 6000 

Evens, Andrew M. 8060, 

8072, 8080 

Everaert, Hendrik 2050 

Evers, Kathryn 6061 

Evoy, Denis 1042 

Evrard, Serge e14017 

Evren, Sevan e15118 

Ewald-Riegler, Nina 5005 

Ewend, Matthew G. 2091 


Ewer, Michael 533^, e13506 

Ewesuedo, Reginald 2534, 

e13074 

Extermann, Martine 6100, 

7065, e17559 

Extremera, Sonia TPS652, 

2539 

Ey, Frederick S. e11042 

Eymard, Jean-Christophe 

e15142 

Ezaoui, Sarah e21046 

Ezeife, Doreen 6082 

Ezeome, Emmanuel e19572 

Ezewuiro, Obiageli 9571 

Ezhilarasan, Ravesanker 2002 

Ezziddin, Samer e14565, 

e14654 

F 

F. Blaine Hollinger, F. Blaine 

e17016 

Fabarius, Alice 6510 

Fabbri, Francesca 10615 

Fabbri, Maria Agnese e12514 

Fabbri, Maria Agnese 

LBA7501, e14082, e18065 

Fabbro, Michel 5018, 

e15535 

Fabi, Alessandra 1073 

Fabian, Carol J. 520, 9000 

Fabian, Thomas 7024 

Facanha, Adriana e14183 

Facchini, Gaetano e15160 

Facchini, Thomas TPS4692^ 

Fackler, Mary Jo 518 

Fackrell, David Gareth 

e15534 

Facon, Thierry 8009, 8020, 

TPS8112, TPS8113, 

TPS8114 

Fadare, Oluwole e15582 

Faderl, Stefan 6501, 6517, 

6528, 6544, 6558, 6578, 

6585, 6589, 6592, 6597, 

6603, 6607 

Fadhel, Ehab 6084, 9032 

Fadul, Camilo E. CRA9013 

Faedi, Marina 2037, 2057, 

e11054 

Faehling, Martin 7572 

Fagan, Dedra H. e13590 

Faggiano, Antongiulio 1604, 

e19038 

Fagin, James A. 5509^, 5514 

Fagnani, Daniele 9120 

Fagniez, Nathalie 8057 

Fagundes, Renato Borges 

e14597 

Fahey, Thomas J e21011 

Fahl, William E TPS9152 

Fahrig, Antje e17516 

Fainstein, Igor e15029 

Fairbairn, Elliann 6115 

Fairchild, Justin P. TPS4691, 

TPS7113 

Fairey, Adrian Stuart 4563, 

4576, e15171 

Fairooz, Puthiyapurayil M 

9568 

Faivre, Sandrine J. 2554, 

2557, 3609, 4032, 5504^, 

e13594, e14553, e14660 

Faivre, Théa TPS3118 

Faivre-Finn, Corinne 7538, 

e18095 

Faivre-Pierret, Matthieu 2070 

Fajardo, Julieta e19528, 

e19584 

Fakhro, Summer A 3036 

Fakhry, Nicolas e16055 

Fakih, Marwan 3582 

Fakiris, Achilles 7040 

Falandry, Claire TPS667, 

8068, 9011, 9079, 9080 

Falchero, Lionel e18005 

Falchi, Lorenzo 6516^ 

Falchook, Gerald Steven 

3102, 3106, 3107^, 3528, 

5021, 8510, 8551, 8594, 

10510, 10607, e13020, 

e13506, e13595, e13596, 

e19004 

Falci, Cristina e13019 

Falcone, Alfredo 629, 3502, 

3518, 3540, 3546, 3549, 

3555, 3585, 3597, 

e13057, e14040, e14113 

Falcone, Italia e13512, 

e13572 

Falcone, Katherine e15565 

Faletti, Carlo 10055 

Falge, Christiane 6510 

Falk, Martin H. TPS4701, 

LBA7000 

Falk, Roni 1521 

Falk, Stephen LBA4000, 

LBA4001, TPS4143, 7562 

Falkowski, Slawomir 8548, 

10538 

Fallai, Carlo 5555 

Faller, Douglas V. e14591 

Fallowfield, Lesley 5527 

Faloppi, Luca e14086, 

e14561, e14663, e15074 

Falusi, Adeyinka e11554 

Faluyi, Olusola Olusesan 

4058 

Falzarano, Sara Moscovita 

4560 

Falzone, Rick 3062 

Fan, Alice C. 10513 

Fan, Jia e14538 

Fan, Kang-Hsien e14503 

Fan, Lin 9009, 9014, 9091 

Fan, Lu e13002 

Fan, Qingxia e18033 

Fan, Sheung Tat e14545 

Fan, Songhua 3038 

Fan, Tiffany 7049 

Fan, Timothy M. e21145 

Fan, Xuemo 2087 

Fan, Ying e11025, e11538 

Fan, You Hong 5524, 10612 

Fan, Yunhua 1576 

Fan, Zhongyi 7036 

Fanale, Michelle A. 6116, 

8027, 8065 

Fanciulli, Giuseppe 1604 

Fanelli, Marcello Ferretti 643, 

e14680, e14728, e18078 

Fanelli, Marcelo e11087 

Fang, Cheng 10500 

Fang, Erica 10598 

Fang, Hui e14511 

Fang, Liang LBA1 

Fang, Min e15207 

Fang, Qin 7034 

Fang, Xiang e16554 

Fang, Xue-Feng e14026 

Fang, Yong 4092, e14575 

Fanica, Daniela 4018 

Fann, Jesse R 9008 

Fanta, Paul Timothy 2052, 

e14069, e14078, e14079 

Fantasia, John e16026 

Fanti, Stefano e21006 

Fantin, Bruno 9067 

Fantini, Simona e21118 

Farace, Françoise 3080 

Faraggi, Marc e15558 

Farah, José Francisco de 

Mattos e14657 

Farah, Michelle de lima 

e21151 

Farah, Naim e15024 

Farassati, Faris e13535 

Farber, Charles Michael 6122 

Farbstein, Motti e14731 

Fareed, Jawed e13115, 

e13117, e15008 

Farfalli, German 10074 

Farfan, Carlos Alberto 4620 

Farge, Dominique 1580, 

e13062 

Farges, Olivier 3609 

Farhadian, Joshua Andrew 

8544, 8565 

Farhat, Rawad e20004 

Faria, Claudio e16521 

Farias, Caroline Brunetto de 

e13546 

Faricy-Anderson, Katherine E. 

4098 

Fariello, Anna Maria e12514 

Faries, Mark B. 8534, 

e19029 

Farina, Gabriella LBA7501, 

9005 

Farina, Patrizia 2049 

Faris, Jason Edward e14615 

Farmer, Pat 1036 

Farol, Len 8089 

Farolfi, Alberto e11054 

Faron, Matthieu 3507 

Farooq, Aamer e17535 

Farouk, Fatma e15129 

Farragher, Susan 3516 

Farrar, John T e19531 

Farrar, William Blair LBA506 

Farre, Jose 3064 

Farre, Nuria 5590, 5595 

Farrell, Brian T. 2077 

Farrell, Michael P. 1543, 

e12031, e12038 

Farsi, Fadila e19640 

Fartoux, Laetitia 4032 

Farver, Carol e18085 

Fasching, Peter A. 541, 

TPS1146, 10599 

Fasciano, Karen 9015 

Fasola, Giampiero 1604 

Fasola, Gianpiero 1044, 

3612, 7013, 7550, 

e13058, e13070, e14040, 

e15091 

Fassunke, Jana CRA10529 

Fast, Loren e21116 

Fatato, Penny Marie 7030 

Fathallah, Hassana TPS3116 

Fathi, Amir Tahmasb 6606, 

6617, 6618, 6621, 6629 

Fauci, Janelle M. 5060 

Faure, Gilbert e12506 

Fausel, Christopher A. 

e18555 

Fautrel, Alain e19037 

Favaretto, Adolfo G. 7082, 

7550, 7575, e18130 

Favier, Bertrand e16036 

Favier, Laure LBA5000 

Favret, Anne 1018 

Fawcett, Jonathan TPS3643 

Fawole, Adewale Alade 2076, 

2093 

Fawzy, Mahmoud 5557 

Fay, Angela Musial 1540 

Fay, Michael F. TPS2104 

721s

Fayad, Luis 6501, 8067 

Fayette, Jerome 5505, 

e16036 

Fazal, Salman 6620 

Fazekas, Belinda 2604 

Fazio, Nicola 4120 

Fazio, Vito Michele e21092 

Fecher, Leslie Anne 8518 

Fedarko, Neal e13042 

Fedele, Palma e11001, 

e11547 

Fedele, Roberta e18564 

Fedeli, Anna e11054 

Fedeli, Franco e17533 

Federico, Massimo 8006 

Federico, Piera e15034, 

e19038 

Federico, Sara Michele 

e13584 

Federico, Victoria 9144, 

e19633 

Federspiel, Birgitte 4015 

Federspiel, Jerome J e15184 

Fedorenko, Catherine R. 6007 

Fedyanin, Mikhail e15025, 

e15029, e15082 

Fee-Schroeder, Kelliann C. 

9075 

Feeback, Jennifer Wanpen 

e14632 

Feely, Homira 2052 

Feeney, Kendra J. e19016 

Fegely, Maryellen e15565 

Feghaly, Julien e20004 

Fegueux, Nathalie 6534 

Feher, Olavo 2038, e12513, 

e16046 

Fehm, Tanja N. 1023, 1067, 

1090, TPS1146, 1602, 

5042, 10599, e15577, 

e21003 

Fehrenbacher, Louis LBA506, 

LBA1000, 1025, TPS1142, 

7517 

Fehrmann, Rudolf S. N. 

e15035 

Fei, Kezhen e11004, e19621 

Fei, Shi-Jiang e13510 

Feigenberg, Steven J. 10572 

Feigin, Kimberly 1006 

Feiglelson, Heather S e14160 

Feilotter, Harriet 5032 

Fein, Francine 4018 

Fein, Luis Enrique 9077 

Fein, Luis 7029, e11087 

Feinberg, Bruce A. 569, 571, 

6098, e11002, e16540, 

e16552 

Feinberg, Zachery e14185 

Feinmesser, Meora 10528 

Feinstein, Stuart e19571 

Feit, Kevie e18063^ 

Feith, Marcus e14527 

Fekrazad, M Houman 5549 

Feld, Ronald 1535, 7029, 

7586, e14524 

Feldberg, Edit e19529 

Feldman, Darren Richard 

4532 

Feldman, Eric Jay 6525, 

6601, TPS6637 

Feldman, Lawrence Eric 5528 

Feldman, Mark 10037 

Feldman, Max e14579 

Feldman, Rebecca A e15209 

Feldman, Tatyana e18507, 

e19641 

Feldman-Moreno, Rebecca 

Anne 5523 

Felger, Jennifer 9122 

Felici, Alessandra 4541 

Feliciano, Josephine Louella 

6131 

Felip, Enriqueta 1531, 3007, 

7041, 7522, 7542, 7543, 

7544, e12000, e12012 

Feliu, Jaime 1570, 3586, 

3618, 4079, 10547, 

e13085, e14097 

Féliz, Luis Roberto 3536, 

e13540 

Fellague-Chebra, Rafik 

TPS8111 

Fellenz, Lori 6054 

Fellman, Bryan 6054 

Felsberg, Joerg 2067 

Felsher, Dean W. 10513 

Fenaux, Pierre 6522, 6523, 

6534 

Fencl, Pavel e14631 

Fend, Falko e15577 

Feng, Gansheng e14605 

Feng, Guosheng e16054 

Feng, Janine D. 4041 

Feng, Ji Feng 7520, 7557, 

7559 

Feng, Lei 4641, 5524, 5592, 

8067 

Feng, Mary Uan-Sian e14603 

Feng, Ping bo 4073 

Feng, Rentian 8099 

Feng, Shibao 1526, 

TPS3635^, e19048^ 

Feng, Yan TPS2622, 8541, 

e18085 

Feng, Yang 3605 

Fengler, Ruediger 9573 

Fenig, Eyal e14571 

Fennell, Dean Anthony 7583, 

TPS7613^ 

Fennell, Mary 6086 

Fennell, Thomas e17015 

Fennelly, David William 

e13570 

Fennelly, David e21024 

Fenner, Martin 4631, e15190 

Fenton, Dave 7511 

Fenton, Mary Anne 1045 

Fenwick, Stephen W 3613 

Fergus, Karen e19545 

Ferguson, Maree e19550 

Ferguson, Mark K. 4062 

Ferguson, Sarah E 5026 

Ferhanoglu, Burhan 6550 

Ferland, Emery e14020 

Ferlay, Celine 4614, 4625, 

7574 

Ferme, Christophe 8002 

Fern, Lorna Anne 6115 

Fernandes, Annemarie 7098, 

e17534, e18032 

Fernandes, Donald Jerald 

5526 

Fernandes, Gabriela 1522 

Fernandes, Kimberly A. 6087 

Fernandes, Recidia Rayane 

Reboucas e12512 

Fernandez Abad, Maria 602, 

e11006, e11517 

Fernandez Calvo, Ovidio 

e18040, e18146 

Fernandez Franco(1), Lourdes 

e11543, e19596 

Fernández Gabriel, Elena 

e15067 

Fernandez Montes, Ana 

e18040 

Fernandez Parra, Eva e11075 

Fernandez, Antonio e19576 

Fernandez, Beatriz 10534 

Fernandez, C. 4630 

Fernandez, Carmen Gomez 

595, 608 

Fernandez, Cristian 7029 

Fernandez, Lita 3015 

Fernandez, Maria Elena Elez 

3014 

Fernandez-Acenero, Maria 

Jesus e15094, e18069, 

e18106, e21015 

Fernandez-cruz, Laureano 

e21035 

Fernandez-del Castillo, Carlos 

4021 

Fernández-Esparrach, Gloria 

3536 

Fernandez-Garcia, Eva 

TPS652, 2539 

Fernandez-Martos, Carlos 

3586, 3618, 10547, 

e14041, e14097 

Fernandez-Morejon, Francisco 

Jose 3064 

Fernando, Indrajit Nalinika 

5046, e15534 

Ferolla, Piero 1604, e19038 

Ferone, Diego 1604, e19038 

Ferrajoli, Alessandra 6516^, 

6517, 6587, 6598 

Ferrandez, Dolores e14147 

Ferrandina, Gabriella 

LBA5003 

Ferrandino, Michael 4670 

Ferraresi, Virginia 10006, 

e14661 

Ferrari, Alessia e11071 

Ferrari, Anna C. e15191 

Ferrari, Antonella e17006 

Ferrari, Daris 5513 

Ferrari, Laura 3612, 4017 

Ferrari, Stefano 10022, 

10079 

Ferrarini, Ilaria 629 

Ferrario, Cristiano 1099 

Ferraro, Giuseppa e11056 

Ferraro, John TPS3638, 

e14501 

Ferrarotto, Renata 3544 

Ferraù, Francesco 7550 

Ferraz, Marcio R. e11513 

Ferre, Malena e14552 

Ferre, Pierre e13036 

Ferreira, Ana Carolina e21073 

Ferreira, Carlos G. M. 7506, 

e14101 

Ferreira, Fabio Oliveira 

10069, e14119 

Ferreiro, Jose Luis e21158 

Ferreiro, Josefa e11525 

Ferrell, Betty R. 9068, 

e16563, e19563 

Ferrer Lopez, Pablo 1574 

Ferrer, Ana Isabel e19576 

Ferrer, Milagros 10564 

Ferrer-Lozano, Jaime 1015 

Ferreri, Andres J. 8058 

Ferreri, Andres 8006 

Ferrero, Annamaria LBA5000 

Ferrero, Jean Marc LBA4567^ 

Ferrero, Jean-Marc TPS646, 

TPS654^ 

Ferretti, Gabriele 7084 

Ferretti, Gianluigi 1050 

Ferretti, Vincent e13107 

Ferreyros, Greenlandia 

e11518 

Ferri, Ivana e21094 

Ferri, Marco e14018 

Ferris, Robert L. 5528, 5566 

Ferro, Alfredo 1007 

Ferro, Antonella 586, 

e14711, e21102 

Ferro, Paola e17533 

Ferrone, Cristina 4021 

Ferrone, Marcus 4660 

Ferrone, Soldano 8528, 

10614 

Ferru, Aurelie 3520 

Ferrucci, Pier Francesco 

8513, 8529, e19035, 

e19036 

Ferrusi, Ilia L e11050 

Ferry, David Raymond 

LBA4000, e13007 

Ferry, David R 3505, 

LBA4001 

Fersching, Deborah e21067 

Fersis, Nikos 624 

Ferte, Charles 4540 

Fertig, Elana J. 5549 

Fertil, Bernard 8578 

Feser, William 10580 

Fesl, Christian 514 

Festiccia, Claudio e15200 

Fetsch, Patricia e14179 

Fetterly, Gerald J. 3029, 

4117, 4545, 4654, 8519, 

e13006, e14690 

Fetting, John H. 1128, 

10509 

Feusner, James Henry 9553 

Feyer, Petra C. 5512, 9033, 

e19540 

Feyerabend, Susan e15195 

Feyler, Sylvia 8015 

Fhied, Cristina e21069 

Ficarra, Guido 631 

Ficker, Joachim H e17536 

Ficorella, Corrado e14010 

Fidias, Panos 4027, 7099 

Fidler, Mary J. 7067, 7546, 

e18117, e21069 

Fiduccia, Pasquale 2049 

Fiedler, Walter M. 2504 

Fiel, M. Isabel e14583 

Field, Jeff e21152 

Field, Kathryn Maree e16516 

Fiellin, Martha TPS669 

Fietkau, Rainer 7001 

Figarella, Dominique 2060 

Figarella-Branger, Dominique 

2023 

Figg, William Douglas 3042^, 

3043, 4569, 4671 

Figlin, Robert A. 7518, 

e15059, e15084 

Figueira, Alicardo Cesar 606 

Figueiredo-Pontes, Lorena 

Lobo de 7523 

Figueras, Joan e14120 

Figueredo, Javier 2515 

Figueroa, Angelica e14595, 

e21002 

Figueroa, Salvador 1531, 

e12012 

Figueroa, Santiago 7058, 

10594 

Figurin, Konstantin e15025, 

e15029 

Filanovsky, Kalman e19529 

Filbet, Marilene 9049, 9080, 

e19578 

Filiberti, Silvia 9120 

Filicko-O’Hara, Joanne E. 

e16548 

Filidei, Mario 629 


Filipazzi, Paola 5555 

Filipits, Martin 542, 7007, 

10501 

Filippi, Luca e19002 

Filippi, Marie-Helene e11019 

Filleron, Thomas 10076 

Filleul, Bertrand 3559 

Filleur, Stephanie e15103 

Finas, Dominique e13100^ 

Findlay, Brian Peter 3572 

Findlay, Michael P. N. 

e15054 

Fine, Barbara e16515 

Fine, Robert e14708 

Finelli, Antonio e15118 

Fingert, Howard 2597 

Fink, James R TPS10635 

Fink, Karen L. 2008b, 

TPS2107 

Fink, Louis M. 10503 

Fink, Stephanie 4565 

Finkelstein, Daniel TPS3117 

Finkelstein, Dianne M 596, 

604, TPS670 

Finkelstein, Julia e15021 

Finkelstein, Marsha J 9521 

Finkelstein, Sydney D. 

e21048, e21121 

Finley, David J. 7024 

Finley, Richard 7020 

Finn, Kathleen T. 6054 

Finn, Richard S. 8592 

Finnern, Henrik W. 6058 

Finney, Lindsey H. 618 

Finocchiaro, Gaetano 2083 

Finocchiaro, Giovanna 7061, 

7585, e18104 

Fins, Joseph J 9121 

Fintak, Patricia A 5082^ 

Fioravanti, Antonella e13098 

Fioravanti, Suzanne 3103 

Fioraventi, Suzanne 10566 

Fiore, James 8547 

Fiore, John Joseph 7052 

Fiore, Marco 10016, 10017, 

10053 

Fiorentini, Giammaria 4084 

Fiorentino, Stefania e15075 

Fioretti, Agnese Maria 645 

Fiorica, James TPS5113 

Fiorio, Elena 586 

Firdaus, Irfan LBA3501, 

4127 

Firvida Perez, Jose Luis 

e18146 

Firvida Perez, Jose Luis 

e15076, e15077, e18040 

Firvida, Jose-luis e15067, 

e17545 

Fiscella, Kevin 9091 

Fisch, Michael 2003, 6054, 

6076, 6080, 9016, 9061, 

9099, 9106, 9112, 

e15173, e19631 

Fischbach, Wolfgang 4090 

Fischer von Weikersthal, 

Ludwig 3519^, 3541, 

3588, TPS3639, e17516 

Fischer, Anna e15577 

Fischer, Christian 4128 

Fischer, Johannes C. e21017, 

e21020 

Fischer, Lars 8031 

Fischer, Mary 3620 

Fischer, Patricia 4532 

Fischer, Peter 2024 

Fischer, Thomas 6511 

Fischer, Victoria 6620 


Fischer-Valuck, Benjamin W 

e17524 

Fishel, Jean 3016 

Fisher, Barbara 6130 

Fisher, Brian 1504 

Fisher, Cyril 10038, 10060 

Fisher, David 3516, 3530 

Fisher, Deborah 6044 

Fisher, Douglass 3567 

Fisher, George A. e14610 

Fisher, Maxine e11063 

Fisher, Richard I. 8001, 

e18536 

Fisher, Richard TPS4690, 

5571 

Fisher, Rosalie Anne 

TPS4679 

Fisher, Sheila e16007 

Fisher, William E. e14501 

Fishman, David 5016 

Fishman, Mayer N. TPS2613, 

4503, e15010 

Fishman, Peter 553, e15189 

Fishman, Pnina e14731 

Fishman, Sari e14731 

Fiskus, Warren 10549, 

10605 

Fithian, Andrew 10535 

Fitilev, Sergei B. 9060 

Fitoussi, Olivier 8014 

Fitzgerald, Barbara e19522 

Fitzgerald, Catherine A. 6071 

FitzGerald, David JP 2503^ 

Fitzgerald, Kristina e12515 

Fitzgerald, Meghan 569, 571, 

e11002 

FitzGerald, S. P. e14022 

Fitzmaurice, Thomas F. 

TPS4689 

Fizazi, Karim 4510, 

LBA4518, 4519^, 4540, 

4554, 4558, LBA4567^, 

4574, 4621, 4642, 

TPS4689, TPS4691, 

TPS4693, 5028, e15049, 

e19514 

Flacco, Antonella e18023, 

e18101, e21094, e21096 

Flahavan, Evelyn e13096 

Flaherty, Keith T. 4056, 

4500, 8502^, 8503^, 

LBA8509, 8510, 8516, 

8526, 8561, 8562, 8567, 

8569 

Flaherty, Lawrence E. 8504, 

8521, 8525, 8527, 8567 

Flamaing, Johan 9035 

Flamen, Patrick 3559 

Flammiger, Anna e15168 

Flanagan, Louise 1042 

Flanigan, Robert Charles 

e15014 

Flavin, Aileen e14666 

Flechl, Birgit 2071 

Flechon, Aude e15009 

Flechtner, Henning 6002, 

6090, 7607 

Fleisher, Martin 4516, 4548, 

4562 

Fleishman, Stewart Barry 

CRA9013 

Fleming, Deborah L. e16561 

Fleming, Gini F. 534, 1010, 

5012, 5019, 5020 

Fleming, Mark T. 4586 

Fleming, Natanya e21022 

Fleming, Ronald Alan 3000 

Fleming, Saroj e16546 

Fleming, Steven 6052 

Fleming, Stewart e15078 

Flentje, Michael 5512, 7001 

Fleshner, Neil Eric 9131, 

e15118 

Fletcher, Julie 5046 

Fletcher, Kalen M 9037 

Fletcher, Sarah e15582 

Fleury, Joel e11019 

Flickinger, John Charles 

7040, 7054, 7055 

Flinn, Ian W. 6122, 6507, 

6509^, 6515^, 6518^, 

TPS6636, 8081 

Flinois, Alain e15198 

Flockhart, David A. 525 

Flohr, Penelope 10525 

Floquet, Anne 5018, 5028, 

9012, e15535 

Flor, Maria Jose 10052 

Flora, Douglas B. 4127, 

7100, 7567 

Florance, Allison M. TPS661, 

10532 

Florero, Marilyn e11032 

Flores, Aurea M. 5065 

Flores, Elsa 8537 

Flores, Jacklyn J e19625, 

e19629 

Flores, Lucia Edith e15569 

Flores, Maria Regina C. 

e18047 

Flores, Natasha 505 

Flores, Rafael 6088 

Flores, Ronald A. e13591 

Flores-Estrada, Diana 7068 

Florescu, Anca e21092 

Florescu, Marie 2102, 

e17507, e18120, e18136 

Florez, Maria del Pino 4089 

Floriani, Irene LBA4001, 

5513, LBA7501 

Floris, Giuseppe 10030 

Flowers, Christopher 6122 

Flowers-Poole, Dava 10508 

Floyd, Leroy Cordero e18516, 

e19638 

Fluge, Oystein 8074 

Flugelman, Anath 1578 

Flynn, Jayme e14503 

Flynn, Joseph M. 6508, 

e18508 

Flynn, Patrick J. 1025, 2031, 

LBA4007, 6570, e14501 

Flörcken, Anne 4539, 

e15053 

Fløtten, Øystein 7027 

Foa, Paolo 5504^, 5513, 

7550, e14676 

Foà, Robin 6531 

Focan, C. N. J. 3547, 

e14006 

Fode, Kirsten 8545 

Foekens, John A 10504 

Foerster, Frank Gerhard 1077 

Fogelman, David R. 4038, 

4054 

Fogli, Laura K e13569 

Fojo, Antonio Tito 2548, 

e13122, e14064 

Fokt, Izabela e18557 

Folin, Annika 10083 

Folkerd, Elizabeth 9103 

Follana, Philippe LBA5002^ 

Folprecht, Gunnar 3530, 

3562, 3574, 3591 

Foltran, Luisa 3612, e14040 

Foltz Boklage, Susan H 

e14106, e14141, e14146, 

e15183, e18097 

Fomin, Svetalna 1540 

Fonck, Marianne 9012, 

e14017, e14023 

Fong, Alan M. 2591 

Fong, Erika e13571 

Fong, Lawrence 2563, 2564, 

4593 

Fong, Mei Ka e14712 

Fong, Peter C.C. 5022, 

e15050, e15054 

Fong, Yuman 3577, 3620 

Fonkem, Ekokobe e18541 

Fonsatti, Ester 8513 

Fonseca, Eileen e16512 

Fonseca, Fernando L. A. 

e11059 

Fonseca, Rafael 8037, 

e18556 

Font Pous, Albert 4579, 

TPS4672, TPS4674, 

e15001 

Font, Albert 7095 

Fontaine, Jacques 10070 

Fontana, Andrea 629, 4627 

Fontana, Vincenzo e17533 

Fontanella, Caterina e13058, 

e13070 

Fontanelli, Rosanna 5096 

Fontanini, Gabriella 3521, 

3585, e14042 

Fontayne, Alexandre 5069 

Fontein, Duveken 10518 

Fontela, Antoinette e13585 

Foo, Leon Siang Shen 10051, 

e20509 

Fora, Ahmad Ali 3582 

Fora, Gianluca 5546, 5548 

Foran, James M. 8032 

Forastiere, Arlene A. 5576, 

e13504, e16061 

Forbes, John F. TPS1136 

Ford, Charles N e16010 

Ford, Daniel TPS4692^ 

Ford, Eric C 2017 

Ford, Hugo e14100 

Ford, James 10619 

Ford, Jennifer 9586 

Ford, Kathy e13592 

Ford, Kendra e13568 

Ford, Laurie Ann 6565, 6602 

Foreman, Trudi e21142 

Forero, Andres 8065 

Forero-Torres, Andres 510, 

1006, 3069, 8027, 

e13079 

Forest, Valerie e15202 

Forestieri, Valeria 1554 

Forgeson, Garry e15054 

Forget, Frederic 9117 

Forgey, Robert TPS3110 

Formaker, Carl 2564, 4664 

Forman, Lora W. e14591 

Forman, Stephen J. 1592, 

6545, 6547, 8038, 8089, 

e18542 

Formenti, Silvia e11010, 

e11064, e11529 

Formento, Jean-Louis 2537^ 

Formento, Patricia 2537^ 

Formica, Serena 10087 

Formiga, Maria Nirvana 

e14728 

Formisano, Barbara e21118 

Formisano, Luigi e13509, 

e15034 

Fornarini, Giuseppe e15185 

Fornaro, Lorenzo 3555, 3585 

Forner, Dirk 5005 

Fornier, Monica Nancy 10514 

723s

Foroni, Chiara e11546 

Foroni, Letizia 10550 

Foroutan, Parastou 10084 

Forsberg, Goran 4550 

Forschner, Andrea 8526 

Forse, Armour R. e16554 

Forshew, Tim 544 

Forstbauer, Helmut 1072, 

1602 

Forster, Lourdes 9565 

Forstpointner, Roswitha 4072 

Forsyth, Michael T. e15089 

Forsyth, Peter A. J. 2099 

Forsythe, Laura Pence 9130 

Fort, Pauline e19555 

Fortin, Andre 5502, 5530 

Fortpied, Catherine 8002 

Fossa, Sophie D. 1536, 

LBA4512, 4551, 4637 

Foster, Julia 6606, 6621 

Foster, Matthew Charles 

e13074 

Foster, Nathan R. 7073, 

7605 

Foster, Richard 4586 

Foszczynska-Kloda, 

Malgorzata e21099 

Fotheringham, Lori e13581 

Fotis, Michael A 2532 

Fotopoulou, Christina 5005, 

5034, 5053, 5070, 5071, 

5080, 5087, e15520, 

e15531, e19597 

Fotovati, Abbas e13123 

Foucher, Pascal TPS7111 

Fougeray, Ronan 4522, 4525, 

e15007 

Foukakis, Theodoros 10083, 

e11510 

Fouladi, Maryam 9541, 9581 

Foulis, Alan K e14117 

Foulon, Veerle 4622 

Fountzilas, George 573, 592, 

5033, 10575, e15040, 

e21018 

Fourchotte, Virginie e15524, 

e15535 

Fourme, Emmanuelle TPS662 

Fournel, Marielle e13602, 

e13604 

Fournel, Pierre 7574, e16560 

Fournel-Frederico, Cécile 

2605 

Fournier, Charles 10020, 

e11012, e11049, e14560 

Fournier, Marion e13007 

Fournier, Nathalie 5069 

Fourrier-Réglat, Annie e14168 

Fouyssac, Fanny 9517 

Fowler, Jeffrey e15585 

Fowler, Nathan Hale 6518^ 

Fox, Catharine e19522 

Fox, Elizabeth 9500, 9576 

Fox, Floyd E. TPS4675^ 

Fox, Josef J. 4517, 4548 

Fox, Judith Ann TPS6637 

Fox, Kevin R. 6000 

Fox, Paul e14574 

Fox, Richard TPS4150 

Fox, Stephen B. TPS1136, 

8520, e21111 

Fox, Tara 7536 

Foxhall, Lewis E e19625, 

e19629 

Foxwell, Tyler e14689 

Fra, Joaquin 10052 

Fracasso, Paula M. 3047 

Fraccon, Anna Paola e13019 

Fradique, Antonio CALDEIRA 

e14673, e14713 

Fragandrea, Ioanna e20002 

Fram, Robert J 3539 

Frame, Sheelagh 3053 

Frampton, Garrett 1015, 

4649, 7529, 10524 

Franasiak, Jason 5009, 5092 

Franc, Benjamin L. e21026 

Franceschi, Enrico 2057, 

2061, 4017 

Franceschini, Maria Cristiana 

e17533 

Francesconi, Alessandra 

Bastian 8538 

Francescutti, Valerie e14172 

Francese, Valentina e11524 

Franchi, Giulia Maria 1604 

Franchina, Tindara e11056 

Francia, Giulio e11061 

Francis, Adele TPS665, 

e11062 

Francis, Prudence A. 

TPS1136 

Francis, Stephen 8512, 

8539, TPS8603 

Francisco, Federico e14075 

Francisco, Liton 1592, 9505 

Franck, Anne 8089 

Franco, Maria Isete Fares 

e14657 

Franco, Rebeca e11004, 

e15513, e19621 

Franco, Vito 8006 

Franco, Vivian I 9530 

Franco-Lie, Isabel e14637 

François, Eric e14168 

Francois, Sylvie 6534 

Franekova, Veronica e18077 

Frangou-Plemenou, M e13556 

Frank, Douglas TPS5601, 

e16026 

Frank, Konrad 1533, 10526, 

CRA10529 

Frank, Steven J. 5561, 5589 

Franke, Fabio A. 7503, 7506 

Frankel, Arthur E. 2505 

Frankel, Paul Henry 1010, 

2538, 3108, 10545, 

10574, e14182, e15114, 

e16563 

Frankel, Stanley 2504 

Franklin, Wilbur A. 7504, 

7532, 7534, 7552, 7589, 

10580 

Frankum, Jessica 3050 

Frantziyantz, Elena e19049 

Franz, Bettina 2502 

Franz, David Neal 10619 

Franzem, Melanie e14138 

Franzen, Lars e14531 

Fraser, Alison M 9561 

Fraser, Christopher 9547 

Fraser-Browne, Carol 

TPS4690 

Frassica, Deborah Anne 1128 

Frassineti, Luca LBA4001 

Frassoldati, Antonio TPS4151 

Frati, Luigi e14096 

Frattini, Mark G. TPS2619, 

6613 

Frattini, Milo e21018 

Frattini, Silvia 645 

Frazer, J. Kimble 9501 

Frazier, A. Lindsay 9523, 

9539 

Frazier, Kenneth 4085, 

e14564 

Frear, Meghan e15154 

Freas, Elizabeth 3017 

Frébourg, Thierry e14010 

Fredeking, Arden e19000 

Frederick, Mitchell J. 5524 

Fredrickson, Jill O. e13000 

Freedland, Stephen J. 4670 

Freedman, Matthew L 4543 

Freedman, Matthew 4635 

Freedman, Rachel A. 1100 

Freeman, Burgess B. e13584 

Freeman, Carol e14098 

Freeman, Daniel J. 3580 

Freeman, Marc 6049 

Freemantle, Sarah J. e13567 

Frees, Melanie 3056 

Fregnani, José Humberto 

e20506 

Freiberg-Richter, Jens 

TPS3639 

Freier, Werner 4539, e14138 

Freilich, Bradley L e14632 

Freilone, Roberto 8006 

Freiman, Joel 4085, e14564 

Freitas, Paulo Henrique Aires 

643, e18078 

Freixenet, Jorge 7011 

Freixinos, Víctor e15575 

Frenay, Marc 2, e12502, 

e20006 

French, Audrey L. 1611, 

8085 

French, Pim 2 

Frenel, Jean-Sebastien 601, 

2082 

Frenkel, Eugene P. 2077, 

3100 

Frenken, Bettina 10600 

Fresno-Vara, Juan Angel 

e11081 

Freter, Carl 1586, 6561, 

e11031 

Fretwell, Jo 9589 

Freund, Karen M 6097 

Frey, Noelle V. 6579, e18540 

Freyer, Craig e18509 

Freyer, Gilles 529, 636, 

8068, 9011, 9079, 9080, 

e15182 

Frezza, Anna Maria 10063, 

e14135 

Friard, Sylvie TPS7112, 

e18089 

Frias, Jesus e13085 

Friberg, Gregory R. 3009 

Friboulet, Luc 10556 

Frick, Kevin D. 6026 

Fricke, Harald 2034 

Fricke, Lothar 9033 

Frickhofen, Norbert e15026 

Fridrik, Michael A. 4074 

Fried, Daniel B. e17550 

Fried, Daniel B e17547 

Friedberg, Jonathan W. 

6515^, 8001, TPS8109, 

e18530 

Friedbichler, Katrin 3092 

Friedland, Julie C 3090 

Friedlander, Michael 3048, 

4531, 5001, 5022, 5081, 

TPS5116, 9044 

Friedlander, Terence W. 4593 

Friedman, Allan H. 2090^, 

2094^, 2095^ 

Friedman, Danielle Novetsky 

CRA9513 

Friedman, Debra L. 9558 

Friedman, Erica Brooke 8565, 

e19018 

Friedman, Henry S. 2027, 

2074^, 2090^, 2094^, 

2095^ 

Friedman, Kent P e11522 

Friedman, Sue 1608 

Friedmann, Alison M. 9502, 

9585 

Friedrich, Matthias 2504 

Friend, Julia C. TPS4680 

Friese, Klaus 554, 1072, 

1081, 1114, e15529 

Friesland, Signe e14531 

Friess, Helmut e14625 

Frigeri, Ferdinando 8066, 

8083 

Frimodt-Moller, Bente 7554 

Frisbee-Hume, Susan 9002, 

9023, 9025, e19599 

Frisinghelli, Michela e14711 

Frizziero, Melissa 4076, 

e14661 

Froehling, Stefan 6519 

Frohlich, Mark Walter e15120 

Froim, Doriana 1055 

Frost, Debra 1545 

Frost, Gregory I 2579 

Frost, Michael 4632, 10619 

Fruchart, Christophe 6633 

Fruehauf, John P. 8521, 

8524 

Fruehauf, S. e13100^ 

Fruth, Briant 5025, 8013 

Frutiger, Yvette M. e18534 

Fryar, Beverly B. 3085 

Frydenberg, Mark TPS4690 

Frye, Sasha TPS3111 

Fryer, Christopher 9529 

Frödin, Jan-Erik 7539 

Fu, Cheng 4628 

Fu, De Liang e14651 

Fu, Haian 3094 

Fu, Jack Brian e19509 

Fu, Jing 8099 

Fu, Ling 5575 

Fu, Maofu e13545 

Fu, Maoyong 1052 

Fu, PingFu TPS655, 

TPS1616, 7087 

Fu, Qiang e14716 

Fu, Rochelle 2040 

Fu, Shi-bo e13558 

Fu, Siqing 3106, 3107^, 

4639, 8551, 10510, 

10607, e13020, e13101, 

e13506, e13595 

Fu, Zhen-fu e13558 

Fucek, Ivica 8059, e18532 

Fuchs, Barry e19641 

Fuchs, Charles S. 3537, 

4027, 4042, 4112, 4125, 

TPS4135, e19586 

Fuchs, Eva-Maria 607 

Fuehrer, Kim e16549 

Fueki, Naoto e18037 

Fuentes Pradera, Jose 

e11075 

Fuentes, Eloisa 10576 

Fuentes, M Josefa 10555 

Fuentes, Stephane e19539 

Fuerhauser-Rappaport, 

Christine 1537 

Fuerst, Sophie 5007 

Fugazza, Clara 4017 

Fuhr, Uwe 3044 

Fujii, Hirofumi 5542 

Fujii, Kazuhiko e18059 

Fujii, Masato 5542 

Fujii, Satoshi 585, e14038 

Fujii, Shinji e13072 


Fujii, Shoichi 3569, 3607, 

e14047, e14050, e14624 

Fujii, Yasuhisa e15038 

Fujiki, Yoshitaka e11017 

Fujimori, Minoru e13037 

Fujimori, Tamaki e14635 

Fujimoto, Chinatsu 3045 

Fujimoto, Hiroyuki e15098 

Fujimoto, Junya 7023, 7078 

Fujimoto, Yasushi e16032 

Fujimoto, Yoshiya e14145 

Fujimoto-Ouchi, Kaori 

e13502, e18064, e18091 

Fujino, Katsuki 3079 

Fujioka, Tomoaki 10520 

Fujisawa, Masato e15048 

Fujisawa, Tomomi TPS1147 

Fujita, Shiro 7528, 10610, 

e18025, e18134 

Fujita, Tomoyuki e13037 

Fujita, Yuka 7561, 7571, 

e18135 

Fujitani, Kazumasa 4002 

Fujiwara, Keiichi 3084, 

5087, 5103 

Fujiwara, Toshiyoshi 1063 

Fujiwara, Yasuhiro 3084, 

10519, e11065, e19535 

Fujiwara, Yoshiro e18027 

Fujiwara, Yutaka e16034 

Fujiyama, Shigetoshi e14622 

Fuke, Satoshi e18135 

Fuks, David 3609 

Fukuda, Haruhiko 3524, 

5542, 6112, 7003, 7017 

Fukuda, Masaaki 7515 

Fukuda, Minoru 7569 

Fukuda, Satoko e15065 

Fukuda, Shunichi 7080 

Fukuda, Takahiro 6533 

Fukui, Iwao e15038 

Fukumura, Dai 1026 

Fukunaga, Yosuke 3625, 

e14145 

Fukuoka, Junya TPS659, 

e17540 

Fukuoka, Kazuya 7031, 7080 

Fukuoka, Masahiro 7521 

Fukushima, Hiroki e19583 

Fukushima, Julia Tizue 

e15562 

Fukushima, Masao e21031 

Fukutomi, Akira 4031, 4035 

Fuller, Clifton David 5561, 

5589 

Fuller, Courtney 9110 

Fuller, Greg 2011 

Fulp, William J 6100, 7024 

Fumagalli, Caterina 4120 

Fumagalli, Debora 507, 

e21010 

Fumagalli, Elena 10053 

Fumoleau, Pierre 596, 604, 

3026 

Funahashi, Yasuhiro 5518, 

5591, e13511, e19055 

Funakoshi, Akihiro 4035 

Funakoshi, Tohru 10578 

Funakoshi, Yohei e16034 

Funchain, Pauline 5573 

Fung, Chunkit 1536 

Fung, Henry C. 6552, 

e16503 

Fung, Hua TPS1616 

Funke, Roel Peter TPS2616, 

e13000, e13113, e13114 

Furge, Kyle A. 4624 

Furini, Lara e12037 

Furlanetto, Jenny 630 


Furman, Richard R. 6507, 

6518^ 

Furman, Wayne Lee 9534 

Fursse, Jo TPS9154 

Furugaki, Koh e18091 

Furukawa, Masayuki 4031 

Furuse, Junji 4031, 4035, 

4046 

Furuya, Kenichi e15579 

Furuya, Luis e12043 

Furuyama, Hiroaki e14518 

Fury, Matthew G. 5509^, 

5514, 5537, 5545^ 

Fusco, Anne 8598 

Fuse, Nozomu 3079, e14510 

Fusi, Alberto 5572, e18010 

Fuss, Martin 5596^ 

Fuste, Pere e13540 

Fuster, Jose 4119 

Futagawa, Shunji e14004 

Futran, Neal 5503 

Fuwa, Nobukazu 5556 

Fuxius, Stefan e15520 

Fyfe, David Walter LBA4001 

Färnegårdh, Katarina e13518 

G 

G, Janaki M e11536 

G, Rajeev A e11536 

Gaafar, Rabab Mohamed 

7081 

Gaal, Karl e18542 

Gabarre, Jean 8058 

Gabbanini, Massimo 5096 

Gaber, Germaine 1069 

Gabitzsch, Elizabeth 2585 

Gabow, Aaron e19647 

Gabrail, Nashat Y. e15557 

Gabram, Sheryl G. A. 7048 

Gabriele, Pietro e15133 

Gabrielson, Edward 10509 

Gabril, Manal Y. 4613, 4633 

Gabrilove, Janice Lynn 8032 

Gadaleta, Caldarola Gennaro 

e21113 

Gadaleta, Cosmo Damiano 

e21113, e21134 

Gadaleta, Gabriella e19641 

Gadaleta-Caldarola, Gennaro 

e21134 

Gadashova, Ayten e13535 

Gadbaw, Brian Christopher 

e19047 

Gadd, Michele 1122 

Gadellaa-van Hooijdonk, 

Christa G.M. 2596 

Gadgeel, Shirish M. 2081, 

7005, 7063, 7593, 

e17528, e21057 

Gadi, Vijayakrishna K. 

TPS3109 

Gadisseur, Alain P. 2506 

Gafford, Philip e14045, 

e14046 

Gagliato, Debora De Melo 

643, e18078 

Gagnier, Paul TPS4689, 

TPS4691 

Gagnon, Bruno e18098 

Gagnon, Patrick James 5596^ 

Gagnon, Robert C. 4605, 

8518 

Gago, Jose Luis 4579 

Gagua, Irina Rezo e15506 

Gahramanov, Seymur 2077 

Gaiger, Alexander 2071 

Gaillard, Isabelle 8002 

Gaines, Natalie e15103 

Gaion, Fernando 9005 

Gaita, Fiorenzo e15192 

Gajate, Pablo e20513 

Gajavelli, Srikanth e14019 

Gajdosik, Martina Srajer 

e21116 

Gajendra, Smeeta 6593 

Gajewski, Thomas 2500^, 

2561, 2582, 8525, 8547 

Gajjar, Amar J. 9518, 9531 

Gajra, Ajeet 6572, 9034, 

9109, 9123, e16047, 

e18133, e18535 

Gakis, Georgios e19021 

Gal, Anthony A 7097 

Gal, Jocelyn 6633, e16044 

Gal, Tamas e21000 

Gal, Thomas e16035 

Gala, Marianna e11052, 

e13539 

Galais, Marie-Pierre LBA4003 

Galamaga, Robert W. e12002 

Galan, Antonio 7095, 10608, 

e11535, e21088 

Galanina, Natalie 10558 

Galanis, Evanthia 2004, 

2031, 2032 

Galant, Christine e21010 

Galazan, Lior 1564 

Galcheva-Gargova, Zoya 4056 

Gale, Davina 544 

Galetta, Domenico 7023, 

7550 

Galiauskas, Raimundas 

e14111 

Galibert, Marie-Dominique 

e19037 

Galicia, Ignacio e13085 

Galicier, Lionel 8005 

Galimberti, Fabrizio 7022 

Galimberti, Sara 8006 

Galizia, Danilo 10066, 

e15073, e20512 

Galizia, Eva e14663 

Gall, Valerie e19502 

Gallach, Sandra 7058, 7060, 

10594 

Gallagher, David James 

e19601 

Gallagher, David J 1543, 

e12031, e12038, e15022 

Gallagher, Emily R. 6004, 

6048, 6062, 6106, 9030, 

9101 

Gallagher, Fergal e12038 

Gallagher, Maryann 4596 

Gallagher, Robert E e15191 

Gallamini, Andrea 8077, 

e13093 

Gallarati, Chiara 3003 

Gallardo Rincon, Dolores 

e15527 

Gallardo, Elena e14733 

Gallardo, Enrique 4580, 

4582, 4585, e15041 

Gallardo, Humilidad F. 2518, 

8583 

Galle, Peter Robert TPS3641^ 

Gallego Jimenez, Inmaculada 

e11075 

Gallego Plazas, Javier 3571, 

10547 

Gallego Rubio, Oscar 5590, 

5595 

Gallego, Javier 3618, e14041 

Gallego, Oscar 2045, 10052 

Gallego, Rosa 3536, 3553, 

4079 

Gallegos Sancho, Isabel 

e11074 

Gallegos, Jessica 9134 

Gallen, Manuel 3586, 

e14097 

Gallenstein, Donna 8582 

Galleta, Laura 5073 

Gallez-Hawkins, Ghislaine 

8089 

Gallick, Gary E. 3561, 

e15151 

Galligioni, Enzo LBA5003, 

e14711, e15160, e21102 

Gallinger, Steve 5026 

Gallinger, Steven 3567, 

4058, 4109, e14535, 

e14592 

Gallinson, David H. TPS3640 

Gallo, Aly e11066 

Gallo, Ciro TPS4151, 

LBA5003 

Gallo, Enzo 1050 

Gallo, Giuseppe Alberto 

e18564 

Gallois, Anne 2570, 8571, 

e21081 

Gallop-Evans, Eve 8056 

Gallot, Lillia 8080 

Galloway, Thomas J 10064 

Galmarini, Carlos 10047 

Galmarini, Felipe e13105 

Galmiche, Marie e11048 

Galsky, Matt D. 4516, 4522, 

4524, 4525, 4586, 4603, 

4623, TPS4676, 6065, 

e21016, e21032 

Galtes, Susana e15111 

Galve Calvo, Elena e11074 

Galvez, Jose 2531 

Gamazon, Eric R 9516 

Gambacorti-Passerini, Carlo 

6503, 6511, 6512 

Gambara, Guido e15549 

Gambardella, Antonio e14676 

Gambaro, Alessandra 3570 

Gamble, Mary 4101 

Gamble, S. Ellen 9575 

Gambol, Teresa E 4557 

Gamerman, Victoria e19054 

Gámez-Pozo, Angelo e11081 

Gammaitoni, Loretta 10066 

Gammoh, Emily 2578 

Gample, Tina LBA4001 

Gamucci, Teresa e12514, 

e14082, e18065, e18072 

Gamulin, Marija e15031 

Gan, Christine M. e15514, 

e15578 

Gan, Gregory 7526 

Gan, Hui Kong 3000, 5587 

Gan, Jacek e19047 

Ganai, Sabha 10090 

Ganapathi, Ram N. 5034, 

5070 

Gandara, David R. 1010, 

3023, 3078, 5020, 7005, 

7018, 7083, 7517, 7552, 

7570, 7582, 7594, 7599, 

TPS7619, e17537 

Gandhi, Ajeet 2072 

Gandhi, Arpita e14124, 

e14727 

Gandhi, Jitendra G. 4656 

Gandhi, Leena 3028, 3053, 

TPS3118, 7099, 7509, 

7543 

Gandhi, Varsha 6528 

Gandikota, Neetha 5578 

Gandini, Sara 519, e19035, 

e19036 

Gane, Nicolas 9080 

725s

Gang, Wu 7091, e14511 

Gangaram, Anjali e21069 

Gangopadhyay, Sudeshna 

e13030, e13533, e18043 

Ganguli, Arijit e12515, 

e13038 

Ganguli, Sushila 10060 

Ganguly, Siddhartha 10549, 

10605, e13568 

Ganjoo, Kristen N. 8081, 

10036 

Ganly, Ian 5545^, 5562 

Gannon, Philippe O. e15202 

Gano, Katherine 8053 

Ganschow, Pamela 1553 

Ganser, Arnold e15190 

Ganten, Tom M 4115 

Ganti, Apar Kishor e17549 

Ganz, Patricia A. TPS1142, 

3545, 6006, e11003 

Ganzer, Roman e15194 

Ganzinelli, Monica LBA7501 

Gao, Bo 550 

Gao, Chong e13505 

Gao, Feng 1048, 3077, 

5013, 5101, e14584, 

e15528 

Gao, Guanghui e18123 

Gao, Harry 10545 

Gao, Hui e13582 

Gao, Jianfei 9017 

Gao, Jianjun 2520^ 

Gao, Jing e14122, e14604 

Gao, Li 5535 

Gara, Michelle TPS4134 

Garambois, Veronique 5069 

Garassino, Isabella M.G. 7585 

Garassino, Isabella e18104 

Garassino, Marina Chiara 

LBA7501 

Garay, Carlos A. 4608 

Garbay Decoopman, Delphine 

10057 

Garbe, Claus 4034, 8502^, 

LBA8509, 8512, 8517, 

8526, e19031 

Garber, Judy Ellen 576, 

1009, 1506, 1547, 10097 

Garbo, Lawrence E. 3023, 

TPS3111, 7502 

Garcia Alfonso, Pilar e14058, 

e14671 

Garcia Alonso, Mirta TPS4672 

Garcia Aranda, Mariola 602 

Garcia Arroyo, Francisco 

Ramon 8062 

Garcia Carbonero, Iciar 

e11545, e15144 

Garcia de Santiago, Clara 

e11028 

Garcia del Muro, Xavier 3096, 

TPS4672, TPS4674, 

TPS4685, 10052 

Garcia Escudero, Ramon 

4584 

Garcia Gerardi, Carlos 

e15507, e15508 

Garcia Gonzalez, Maria 

10512, 10595 

Garcia Lopez, Maria Jose 

e11074 

Garcia Nieto, Sandra e19576 

Garcia Palomo, Andres 

e11074 

Garcia Sanchez, Jose e17545, 

e18049, e18053 

Garcia Valdecasas, Barbara 

10555 

Garcia, Agustin 1010, 1065, 

3054, TPS3111, e13084, 

e13531 

Garcia, Alicia e18030 

Garcia, Antonia e15111 

Garcia, Beatriz 2527 

Garcia, Camilo 3559 

Garcia, Damian 1570, 3586 

Garcia, Helena 10608 

Garcia, Jorge A. 4609, 

TPS4684, e15095, e15208 

Garcia, Jose e19643 

Garcia, Katherine e15571 

García, Lina 4040, e11517 

Garcia, Olga 8005 

Garcia, Reynaldo e13074 

García, Yolanda 5068, 

e15575 

Garcia-Albeniz, Xabier 3536, 

3553, 4079, e14041 

Garcia-Alonso, Angel 

LBA4001, e14587 

Garcia-Blanco, Mariano 

10533 

Garcia-Bueno, Jose Maria 

e18015 

Garcia-Caballero , Tomas 

4089 

Garcia-Campelo, M. Rosario 

e12012, e18131 

Garcia-Carbonero, Rocio 

TPS3637, 4119 

Garcia-Donas, Jesus 

TPS4674, TPS4685, 

TPS4688, 5068, 10546, 

e15041, e15575 

García-Estevez, Laura 602, 

e11006, e11517 

Garcia-Foncillas, Jesus 4079, 

5520, 10512, 10595, 

e14057, e14147, e15094, 

e18069, e18106, e21015 

García-García, Elena 4040 

Garcia-Garre, Elisa e11024 

Garcia-Gomez, Ramon 

e18011, e18015 

Garcia-Gonzalez, Araceli 

e19589 

Garcia-Grossman, Ilana 

Rebecca 4581^, e15022 

Garcia-Hernandez, Carmen 

TPS6640 

Garcia-Hernandez, Jorge 

4123, e19581 

Garcia-Manero, Guillermo 

6520, 6544, 6558, 6578, 

6587, 6597, 6603, 6607 

Garcia-Martinez, Elena 

e11024, e21088 

Garcia-Pinon, Francisco 

e18053 

Garcia-Ribas, Ignacio 1011 

Garcia-Vargas, Jose E. 

LBA4512, 4551 

Garcias-Espana, Carmen 

e11036 

Garde, Javier 4587, e18049, 

e18053 

Garden, Adam S. 5561, 5589 

Garden, Benjamin C e18571 

Garderet, Laurent 8014 

Gardiman, Marina Paola 2049 

Gardin, Claude 6523 

Gardiner, Stuart K 9019 

Gardizi, Masyar 1533, 3044, 

TPS3115, 10526 

Gardner, Brian 7518 

Gardner, Ginger J. 5108 

Gardner, Lesa R. LBA3501 

Gardner, Lisa 6131 

Gardner, Olivia S. 3023, 

5065 

Gardner, Thomas 4650 

Garfield, David H. e18123, 

e19573 

Garg, Karuna 5030, 5043 

Garg, Madhur 4030, e16058 

Garg, Mandeep K e18009 

Garg, Naveen e19645 

Garg, Vishvas 2532, 4063 

Garibaldi, Elisabetta e15133 

Garin, Avgust e15025, 

e15029 

Garin, M. e11528 

Garino, Astrid 9108 

Garje, Rohan e15023 

Garland, Linda L. 7083 

Garlipp, Benjamin e14630 

Garmire, Lana 3630 

Garner, Elizabeth e14625 

Garnier, Alice 6534, 6542 

Garnier, Frederico 6534 

Garofalo, Amanda TPS658 

Garofalo, Rosemary 1132 

Garon, Edward B. LBA4, 

7002, 7543, 7589 

Garonzik, Samira Merali 2603 

Garosi, Vittorio Luigi 4050 

Garralda, Elena 3068 

Garraway, Levi A. 10502 

Garrett, Chris R. 3544, 

e13599, e19645 

Garrett, Karen 9019 

Garrett, Leslie A. e15545, 

e15568 

Garrett, William M. 

TPS6643^ 

Garrido López, Pilar 1531, 

7540, e12000, e12012, 

e16029, e18055 

Garrido-Laguna, Ignacio 3057 

Garrison, Louis P e14525 

Gartrell, Benjamin Adam 

4623, TPS4676, 6065 

Garufi, Carlo e14661 

Gary, Kristen 9105 

Garza, Miguel e13500 

Garzaro, Massimiliano 5546, 

5548 

Garzon, Felix Tomas e18063^ 

Garzotto, Mark 4511, 4663, 

10503 

Gasbarra, Rita e19033 

Gasbarrini, Antonio 4006, 

TPS4151 

Gasco, Amaya 7540, 7542, 

e18137, e18143 

Gascon, Pedro e13540 

Gascoyne, Randy D. 8003, 

8007, 8049 

Gasiorowski, Lukasz 10536 

Gaska, Tobias 8022 

Gaspar, Laurie E. 7018, 7526 

Gasparetto, Cristina 8012, 

8037, e18556 

Gasparini, Daniele e14654 

Gasparini, Giampietro e19612 

Gasparini, Mauro e15192 

Gasparini, Pierluigi 1007 

Gasparri, Mario e17555 

Gasparro, Donatello e15185 

Gass, Jennifer S. 1045 

Gass, Margery 1501 

Gastier-Foster, Julie M 9535 

Gat-Charlap, Amira 1564 

Gatalica, Zoran 1040, 4013, 

5523, 10630, e20507 

Gately, Kathy 637 

Gates, Mary R. 2566 

Gatica, Gabriela e15570 

Gato-Weis, Cara e14098 

Gatto, Lidia 10087 

Gattoni, Elisabetta 7084 

Gattuso, Paolo 572 

Gaucher, Alison 8530 

Gaucher, Christine 5069 

Gauchez, Philippe 2048 

Gaudet, Mia e15022 

Gaudy-Marqueste, Caroline 

8555, 8568, 8578 

Gaughan, Elizabeth Mary 

7579 

Gaughan, John P. e16022 

Gaulard, Philippe 8048 

Gauler, Thomas C. 4023, 

5516^, e15026 

Gaur, Rakesh 4019 

Gautam, Ajay 5526 

Gautam, Shiva e18541 

Gauthier, Eric 10020 

Gauthier, Genevieve 10094, 

e11076, e16571, e20511 

Gauthier, Marie-Pierre 8532 

Gauthier, Mélanie 1584, 

4018 

Gautschi, Oliver 2068, 3595 

Gava, Alessandro 5513 

Gavila, Joaquin 1011 

Gavina, Belen e14147 

Gavine, Paul 4124 

Gavrilovic, Dusica e21030 

Gavrilovic, Igor T. 2008 

Gawade, Prasad Laxman 9527 

Gawande, Jayant Shankar 

9559 

Gawel, Susan e13583 

Gay, E. Greer 6046, 6088 

Gaylor, Shari TPS3110 

Gazawi, Nidal e19540 

Gazial-Sovran, Avital e19015 

Gazzah, Anas 3012 

Gazzaniga, Paola e14096 

Geary, David e13106 

Geater, Sarayut Lucien 

LBA7500, TPS7614, 

TPS9151, e18063^, 

e19608 

Gebauer, Gerhard e21003 

Gebbia, Vittorio 7554, 

e18002 

Geberth, Matthias 1077, 

e19540 

Gebhardt, F e13597 

Gebhardt, Mark C. 9537 

Geboers, Inge 1129 

Gebski, Val 550, TPS1136, 

TPS3643, TPS4137, 

TPS4141, 4531, TPS4681, 

TPS5116, e13007 

Geddings, Julia E e14505 

Gee, Adrian P. 4643 

Geentjens, Kristof e13073 

Geffken, Mareike 10046 

Geffriaud-Ricouard, Christine 

e15161 

Gehl, Julie 2069 

Geho, David e13600^ 

Gehrig, Paola A. 2591, 5009, 

5050, 5063, 5092, 

e13063, e15511 

Gehrke, Flavia de Sousa 

e11059 

Gehrmann, Mathias 10551 

Geiger, Jessica L. 8060 

Geisel, Juergen 4107 

Geiss, Romain 6110 


Geissler, Benjamin e15109, 

e21056 

Geissler, Michael 4023, 

4072, TPS7109 

Gelber, Richard D. 504, 9022 

Gelber, Shari I. 9100 

Gelber, Shari 9071 

Gelderblom, Hans 526, 

10006, LBA10008, 10009, 

10067, 10077, 10081, 

10518, e16526 

Gelet, Albert e15194 

Gelibter, Alain e14661 

Gellert, Klaus 4020 

Gellert, Lan L. 8003 

Gellhaus, Katharina 5053 

Gellrich, Sylke 8076 

Gelmon, Karen A. 538, 549^, 

582 

Gemba, Kenichi 7560 

Gemignani, Mary 575, 

e11531 

Gemma, Akihiko 7515, 7561, 

7563, 7565, e18129 

Gemma, Donatello e14082 

Gencer, Deniz 3541 

Genden, Eric 5578 

Genega, Elizabeth M. 4521 

Generali, Daniele Giulio 579, 

e11546 

Genestie, Catherine 641, 

e11551 

Genestreti, Giovenzio 7550, 

e17546 

Genin, Pascal 10517, 

TPS10634 

Gennari, Alessandra 519 

Gennari, Paolo e15550, 

e15553 

Gennatas, Konstantinos 

e13556 

Genova, Carlo 7577, e21065 

Gentilcore, Giusy 8573 

Gentile, Michelle Sara 

e18523 

Gentles, Andrew e21071 

Gentzler, Ryan D. e16548 

Genyk, Yuri e14679 

Geoerger, Birgit 9517, 9519, 

TPS9597^ 

Geoffrois, Lionnel 4625 

Geoffroy, Francois J. 2032 

George, Ben e14613 

George, Binsah 3544 

George, Claude Paul e13588 

George, Daniel J. 4513, 

4549, 4550, 4612, 4655, 

4667, 10533, e15061, 

e15120 

George, Goldy 8551 

George, James N e17001 

George, Saby TPS4687, 

10609, e15042 

George, Suzanne 1547, 

5090, 10017, TPS10103 

George, Thomas J. TPS4136, 

e14612 

George, Timothy e18509 

Georgoulias, Vassilis 7564, 

e18105 

Geraci, Joseph 10622 

Geraldes, Catarina e12040 

Gerber, Bernd 541, 1023 

Gerber, David E. e13563, 

e18076 

Gerber, Linda 6123 

Gerber, Naamit Kurshan 9104 

Gerber, Peter Arne e11556 

Gercheva, Liana 8018^ 


Gercovich, Daniela 9038 

Gercovich, Felipe G. 9038, 

e11037, e15507, e15508 

Gercovich, Natasha e15508 

Gerdemann, Ulrike 2558 

Gerecitano, John F. 8054, 

9092 

Geredeli, Caglayan 638 

Geretti, Elena TPS663 

Gerger, Armin 3584, 3597, 

3604, 3622, 4026, 4088, 

e11018, e14034, e14052 

Gergich, Kevin 2512 

Gerigk, Ulrich 1533, 10526, 

CRA10529 

Gerken, Guido 4115 

Gerl, Arthur 4602 

Germano, Serena 617 

Germanos, Peter 7604 

Germaschewski, Fiona 5065 

Germenis, Anastassios 

e20002 

Gernone, Angela e15160 

Gerotzafias, Grigoris 1580 

Gerrard, Gareth 10550 

Gerratana, Lorenzo 1044, 

e13058, e13070 

Gerritsen, Winald R. 2562, 

TPS4689, TPS4691, 

e15112 

Gerry, Arianna Aldridge 9051, 

e16564 

Gerschenson, Mariana 9530 

Gershenson, David Marc 

1518, e15583 

Gershenwald, Jeffrey E. 8530, 

8536 

Gerson, Stanton TPS1616 

Gerstenblith, Meg R. 1603 

Gerstner, Elizabeth Robins 

2009, 2012, 2025, 2059, 

3036, TPS10635 

Gerstner, Gregory James 

e17021 

Gertz, Erik 4547 

Gertz, Morie A. 8043, 8092, 

8096, 8105, TPS8116 

Gerunda, Giorgio Enrico 4110 

Gervais, Radj 7522, 7542, 

7574, e18089 

Geschwind, Jean-Francois 

4114, e14581 

Gessert, David e18502 

Gettinger, Scott N. CRA2509, 

TPS2615, 7509, 7531, 

7533, 7599, e21106 

Getz, Gad 2020, 10502 

Geubels, Barbara M. 4528 

Geva, Ravit 1507, e21018 

Gewandter, Jennifer S. 9010, 

9014, 9028, 9113, 

e16056 

Gewirtz, Alexandra N. 3577 

Geye, Heather M e16010 

Geyer, Charles E. LBA506, 

LBA1000, 1025, TPS1142, 

9020 

Geyer, Mark B 6537 

Geyer, Susan Michelle 4039, 

6508 

Geynisman, Daniel M. 2561 

Gezgen, Gamze e11509 

Ghadessi, Mercedeh 4565 

Ghadimi, B. Michael 3600, 

e14161, e14167 

Ghai, Vikas e18500 

Ghalib, Mohammad Haroon 

3093, e14019 

Ghaneh, Paula 8564 

Ghanem, Hady 8103 

Ghanem, Ismael 642, 

e15001, e15552 

Ghazal, Hassan e18558 

Ghazalpour, Anatole 1040, 

10630, e15209, e20507 

Ghebremichael, Musie S. 

e13504 

Gherardi, Giorgio LBA7501 

Ghesquieres, Herve 2023 

Ghi, Maria Grazia 5513 

Ghim, Byoung-Chul 7053 

Ghinea, Nicolae e21138 

Ghio, Domenico 7076 

Ghiotto, Cristina e12037 

Ghnassia, Jean-Pierre e11542 

Ghobrial, Irene M. 8043 

Gholam, Pierre Michel 

e14581 

Ghonimi, Elham 8067 

Ghosh, Jaya e13068 

Ghosh, Sarbani Laskar 

e16021 

Ghosh, Sunita e15540 

Ghossein, Ronald A. 5514 

Ghushchyan, Vahram e16550 

Giacchetti, Sylvie e14006 

Giaccia, Amato 10629 

Giaccone, Giuseppe 7033, 

7103, TPS7609 

Giacobbe, Felicia 3570 

Giacomantonio, Carman A. 

e21090 

Giacomazzi, Juliana 1522, 

10593, e21042 

Giacomi, Nora e14598 

Giagini, Athina 5574 

Giagounidis, Aristoteles 6522, 

6527, 6610 

Giaj Levra, Matteo e18103 

Giamas, Georgios 3546, 

3597, 4088, e11018 

Giammarile, Fransesco 10049 

Giammicchio, Karen e16510 

Giampaglia, Marianna e18048 

Giampaolo, Bianchini 545, 

1012 

Giampieri, Riccardo e14040, 

e14086, e14561, e14663, 

e15074 

Gian, Victor 7035, 7567, 

7587, TPS8115 

Giani, Jorge e19569 

Giannarelli, Diana 630, 4541, 

8513 

Giannatempo, Patrizia 4507 

Gianni, Alessandro M. 4507 

Gianni, Lorenzo 9005 

Gianni, Luca LBA1, 532, 

545, e18096 

Giannini, Caterina 2031, 

2032 

Giannini, Edoardo G 4115 

Giannini, Giuseppe e14042 

Giannitto-Giorgio, Carmelo 

e18026 

Gianoncelli, Letizia 7061, 

7585, e18104 

Giantonio, Bruce J. 3614, 

4111, 6000 

Giardina, C 10554 

Giardini, Roberto e11546 

Gibbon, Darlene 3054, 

TPS3112 

Gibbons, Jay 3041 

Gibbs, John F. e14610 

Gibbs, Peter 3515, 3623, 

e16516 

Gibori, Hadas e14067 

Gibson, Diana 3000 

Gibson, Jeffrey B e17531^ 

Gibson, Laura TPS655 

Gibson, Michael K. 5528, 

5541, e14689 

Gich, Ignasi 10555, e14104, 

e14552 

Gichuru, Gladwell Wantiru 

e20504 

Gierszewska, Magdalena 4562 

Giese, K. e13597 

Giessen, Clemens Albrecht 

3519^, 3603, TPS3639 

Gietema, Jourik A. 4132, 

4528, 10581, e15035 

Gietema, Joyce Q. 4528 

Gifoni, Markus e14183 

Giglio, Pierre 2003 

Gignac, Gretchen e15139 

Gigot, Jean Francois e14044 

Giguere, Jeffrey Kent 9061, 

9108 

Gil Deza, Ernesto 9038, 

e11037, e15507, e15508 

Gil Gil, Miguel J. 502, 2045 

Gil, I e19023 

Gil, Marta 3096 

Gil, Miquel 10608, e11535, 

e21088 

Gil, Roberto de Almeida 

e14027 

Gil, Thierry 3018^, 

TPS4692^ 

Giladi, Moshe e14616 

Gilbert, Jill 5566 

Gilbert, Judith A. e13086 

Gilbert, Mark R. 2001, 2003, 

2019, 2029^, 2030, 2036, 

2064 

Gilbert, Ralph William 

TPS5600 

Gilbertson, Richard J. 9518 

Gilcrease, Glynn Weldon 

e14090 

Giles, Francis J. 3073, 

6619^, e15126 

Gill, Amandeep 3566 

Gill, Inderbir S e15060, 

e15171, e15212 

Gill, Ritu R. 10592 

Gill, Rosalynn D e21012, 

e21142 

Gill, Sandeep 5046 

Gill, Sharlene 6014, e14568, 

e14588 

Gillen, Jessica e15103 

Gillenwater, Heidi H. e13077 

Gillespie, Marion Boyd 5528 

Gillespie, Theresa Wicklin 

e15187 

Gillett, Cheryl 10586 

Gillies, Richard e13587 

Gillies, Robert 10084 

Gillies, Stephen e19047 

Gilligan, Timothy D. TPS4684 

Gillio, Alfred P 6537 

Gillis, Theresa A. 9047 

Gillison, Maura L. 5530, 

5566 

Gilman, Paul CRA9013 

Gilmore, James W. 569, 571, 

e11002, e14106, e14141, 

e14146, e15183, e18097 

Gilmore, Katherine R. 8091, 

9081 

Gilmore, Steven e19565 

Gilson, Eric 9011 

Gilts, Chelsea D. 9031 

727s

Gimenez Capitan, Ana 4068, 

10596, e14521, e18130, 

e18131, e18137, e18143 

Gimenez, Alejandra 10082 

Gimotty, Phyllis A. e19054 

Gimpel, Petra 10563 

Gimsing, Peter 8019 

Giner, Vicente e17545, 

e18049 

Ginés, Alba 9129 

Ginés, Àngels 3536 

Gingerich, Joel Roger 4514 

Gingrich, Jeffrey R. 4550 

Gino, Giancarlo 10055 

Ginsberg, Lawrence E. 5592 

Ginsberg, Michelle S. 3563, 

7052, e19647 

Ginsburg, Elizabeth S 9071 

Ginther, Charles 8592 

Giobbie-Hurder, Anita 8569, 

9084 

Giommoni, Elisa e18074 

Giordani, Erika e11039, 

e11514, e12510, e19620 

Giordani, Paolo 4084 

Giordano, Alessandra e11524 

Giordano, Antonio e13582 

Giordano, Carlo 5546, 5548 

Giordano, Laura 7061, 7585, 

e14672, e18104, e21139 

Giordano, Pasqualina e14130 

Giordano, Sharon Hermes 

537, 600, 612 

Giorgi, Francesca 9098, 

e14086 

Giotis, Angie e15180 

Giotta, Francesco 645 

Gioulbasanis, Ioannis e18098 

Giovannetti, Elisa 10611 

Giovanni, Antoine e16044, 

e16055 

Giovannini, Catia 3061 

Giovannini, Monica 7581 

Giovannoni, Mariella 3612 

Giovannucci, Edward 4555 

Giovinazzo, Hugh 5050 

Giralt, Jordi 5502 

Giralt, Sergio 6529, 6544, 

6546 

Giranda, Vincent L. TPS1138, 

2013, 3049, 3054 

Girard, Luc 7096, 10612, 

e18077 

Girard, Philippe TPS7111 

Girardi, Fabio e19595 

Girgis, Afaf 9128, e16507 

Giri, Dilip D. 1006 

Giri, Nagdeep e18093 

Giri, Neelam 5563 

Giri, Uma 10612 

Giri, Veda N. 1517 

Girodet, Didier e16036 

Girones, Regina e15144, 

e17545 

Giroux Leprieur, Etienne 

e18075, e18102 

Girre, Veronique TPS667 

Gisleskog, Per Olsson 2535, 

2594 

Gisselbrecht, Christian 8048 

Gisslinger, Heinz 6514^, 

6625^, 6626^, TPS6640, 

TPS6642^ 

Gitlitz, Barbara Jennifer 

TPS7619, e13084 

Giubellino, Elena 10055 

Giudice, Aldo e11052, 

e13539 

Giuffrida, Dario 1604 

Giuliani, Costanza e18074 

Giuliano, Armando E. 1105 

Giulini, Stefano Maria 4110 

Giurescu, Marius 4050 

Giusca, Simona Eliza e15032 

Giustini, Lucio 9098, e14086 

Given, Barbara Ann e12500 

Given, Charles W e12500 

Gizzi, Marco e14044 

Gkiozos, Ioannis e17508, 

e17557 

Gladieff, Laurence 5017^ 

Gladkov, Oleg 531, 7090, 

9125, e19587 

Gladson, Candece 2014 

Glantz, Michael J. TPS2107, 

e11544, e12005 

Glanz, Karen 1503 

Glare, Paul A. 9087, 9094, 

e19566 

Glas, Annuska 3065 

Glasberg, Joao e16568 

Glasgow, Amanda L. 9087 

Glaspy, John A. e19511 

Glass, Andrew e12024, 

e15197, e18107, e19630 

Glass, Bertram 6543, 8004 

Gleason, Charise 8100, 8101 

Gleave, Martin Edwin 4514, 

TPS4695 

Gleissner, Jochen e15195 

Glenjen, Nils e14531 

Gligorov, Joseph 568^, 641, 

1051, 1095, 5067 

Glimelius, Bengt 3508, 3538, 

3548, 3576, 4053, 8002, 

TPS10632, e14053, 

e14088 

Glimm, Hanno 6519 

Glisson, Bonnie S. 5592, 

7096, 7597 

Glitza, Isabella Claudia 9069 

Globig, Cordula e19579 

Glogowska, Iwona 10582 

Glogowski, Maciej e12011 

Gloor, Beat e14544 

Glover, Curtis L e15565 

Gluck, Iris e14143 

Gluck, Stefan 10597, 

e15107, e16525 

Gluz, Oleg 552 

Glynn, Sharon A. e15126 

Glynne-Jones, Robert 4004, 

4029 

Gnad-Vogt, Ulrike Senta 

2573^ 

Gnani, Alessandra 6531 

Gnant, Michael 512, 514, 

539, 540, 542, 551, 559, 

10501 

Gnjatic, Sacha 2589, 

TPS8111, e11563 

Gnocchi, Chiara 10087 

Go, Mylene Sy e15522 

Go, Ronald S. 6074, e16555, 

e16561 

Gobet-Bourcelot, Sophie 9080 

Goda, Hiroyuki 5584 

Godard, Aurelie e19623 

Godbold, James H. 4524, 

6065, e21032 

Goddard, Karen 7020 

Goddard, Katrina e14160 

Godefroy, Emmanuelle 2570, 

e21081 

Godette, Karen D. 9122 

Godfrey, CJ 8541 

Godfrin, Yann e14650 

Godinez-Puig, Victoria 2532, 

4063, 6623 

Godley, Lucy A. 6562 

Godley, Paul Alphonso 4647, 

4658 

Godoy-Scripes, Paola e16058 

Godwin, John E. 6502 

Goebeler, Marie-Elisabeth 

2504, 6500^ 

Goebell, Peter J. 4539, 

e15044 

Goehler, Thomas 640 

Goehring, Gudrun 6510 

Goekbuget, Nicola 6500^ 

Goekkurt, Eray 2573^, 10552 

Goel, Ajay e14029 

Goel, Rakesh 1025 

Goel, Sanjay 3093, e14019, 

e14682 

Goel, Shom 1026 

Goeminne, Jean-Charles 

4622, e14060 

Goessl, Carsten Dietrich 

4510, 4642, e15172, 

e19514 

Goettel, Rainer 6566 

Goetz, Marlies 6567 

Goetz, Matthew P. 534, 

3001, 10509, e13086 

Goez, David 2078 

Goff, Barbara Ann 5021, 

5054, 5082^ 

Goff, Laura Williams 2595, 

4117, 4545, 8519, 

e13606, e14503 

Goffard, Nicolas 10553 

Goffin, John R. e18079 

Goffredo, Veronica e21113, 

e21134 

Gogas, Helen 592, 8505 

Gogia, Ajay 6593, e11013 

Gogoi, Radhika e15536 

Goh, Alvin e15060, e15171 

Goh, Boon C. 1064, 2551, 

3002, 4100^, 5544, 

e13002 

Goh, Chee Leng 1545 

Goh, Jeffrey C. TPS5113 

Goh, Wee Lee e18528 

Goiffon, Reece J. 503 

Gok Durnali, Ayse 638 

Gokmen, Erhan e19024 

Gokmen-Polar, Yesim 505, 

7106, 10628 

Goksu, Sema Sezgin e14070 

Golan, Talia 3027, e14143, 

e14646 

Golant, Mitch 9048 

Gold, Anne TPS4682 

Gold, David V. 3091, 4043 

Gold, Heather Taffet 6628 

Gold, Kathryn A. 7047 

Gold, Michael e15582 

Goldberg, Jeffrey M. 1512 

Goldberg, John M. 9565 

Goldberg, Judith D. 5016, 

e11010, e11064 

Goldberg, Richard M. 3502, 

3514, 3517, 3532, 3617 

Goldberg, Sarah B. 7524, 

7525 

Goldberg, Stacie 2510 

Goldberg, Stuart 6509^, 

6520, 6525, TPS6636, 

e19641 

Goldberg, Zelanna 7530 

Goldemberg, Alberto e14657 

Goldenberg, Alec e14581 

Goldenberg, David M. 3091, 

4043, e13005, e18513 

Goldfarb, Paul M. TPS10632 

Goldfarb, Shari Beth 575, 

9104, 10514 

Goldgar, David 1538 

Goldhirsch, Aron 504, 546, 

1049, 1115, 9022 

Goldim, Jose Roberto 1522, 

10593 

Goldin, Jonathan G. 4566 

Golding, Sophie 5522, 7544 

Goldinger, Simone M. e19017 

Goldkorn, Amir 4511, 4563, 

4663, 10503 

Goldmacher, Gregory V. 

e13082 

Goldman, Bryan H. 4019, 

e18536 

Goldman, Cecilia e19552 

Goldman, John M. 10550 

Goldman, Jonathan Wade 

3032, 3034, 3042^, 

e13000 

Goldman, Stanton 9501 

Goldman, Stewart 9532 

Goldschmidt, Jerome H. 3069 

Goldschmidt, Pablo e13105 

Goldsmith, Stanley J. e13592 

Goldsmith, Tessa A. e16059 

Goldstein, Bram e15500 

Goldstein, Daniel A. 10514 

Goldstein, David P. 9032 

Goldstein, David P 10522 

Goldstein, David TPS3643, 

TPS4137, 6111, 9044, 

9087, e16507 

Goldstein, Lori J. 1021, 1092 

Goldstein, Matthew 2514 

Goldstein, Scott 3621 

Goldstein, Steven C. e18540 

Goldstein, Theodore C. 503 

Goldsweig, Howard TPS8604, 

e14546 

Goldwasser, Francois 1095, 

2557, 4583, 5067, 

e13056 

Goldwasser, Meredith 3007 

Golfieri, Rita e14654 

Golfinos, John e19015 

Gollerkeri, Ashwin 3032 

Gollins, Simon e14587 

Gollob, Jared 3062 

Gollub, Marc 3563, 3583 

Golomar, Wilson e13105 

Goloubeva, Olga G. 10572, 

e19565 

Gombos, Andrea 3018^ 

Gomella, Leonard G. e15012, 

e15120 

Gomes, Monica e15532 

Gomez de Liaño, Alfonso 

e15159 

Gomez Dorronsoro, Maria 

Luisa e14057 

Gomez Dorronsoro, Marisa 

e14120 

gomez Lopez, Cesar 9073 

Gomez Ordonez, Silvia 

e15033 

Gomez Raposo, Cesar 1570, 

e11028 

Gomez, Alexandra e12039 

Gomez, Ana 10564 

Gomez, Auxiliadora 3571 

Gomez, Daniel Richard 6124, 

7062 

Gomez, David e17503 

Gómez, Francisco 3072 


Gomez, Henry Leonidas 531, 

1024, 2097, e11087, 

e11518 

Gomez, Henry e11066, 

e15036 

Gomez, Javier 10013 

Gomez, Jorge E. e17564 

Gomez, Lourdes 4089 

Gomez, Nerea 8572 

Gomez, Patricia 619 

Gomez, Rosa Maria Sanchez 

10512, 10595 

Gomez, Scarlett Lin 6050 

Gomez-Abuin, Gonzalo 

e15570 

Gómez-Codina, Jose 7011, 

7095, 8062 

Gomez-Martin, Carlos 3068 

Gómez-Pardo, Patricia 509, 

566 

Gomez-Pinillos, Alejandro 

e15191 

Gomez-Roca, Carlos Alberto 

2539 

Gomez-Roca, Carlos 5522 

Gomez-Tato, Antonio 10534 

GonÃƒÂ�aves de Freitas 

Seriaco, Fabiola de Lourdes 

e19528, e19584 

Goncalves, Anthony 529, 

e19539 

Goncalves, Margarida Brito 

e13119 

Goncalves, Marina Sahade 

e20502 

Goncalves, Priscila Hermont 

e14519 

Gondek, Lukasz 6521 

Gonen, Mithat 3583, 3620, 

10015 

Gong, Cynthia e15154 

Gong, Gyungyub e11504, 

e11508 

Gong, Jifang 3040, e14604 

Gong, Jing TPS3117 

Gong, Ke-Wei 8592 

Gong, Yun 515, 594 

Gongora, Celine 10505 

Gonsalves, Wilson I. 8092 

Gonschior, Ann-Katrin 

e13095^ 

Gonzague, Laurence 

TPS1613, e19539 

Gonzales, Alicia 1592 

Gonzalez de Castro, David 

LBA4000, TPS10633^, 

e14088 

Gonzalez del Alba, Aranzazu 

TPS4672, TPS4674, 

e15041, e15144 

Gonzalez Gordaliza, Cristina 

e12033 

Gonzalez Griego, Martha 2515 

Gonzalez Guerrero, Juan 

Francisco e15525 

Gonzalez Larriba, Jose Luis 

10564, e18055 

Gonzalez Vela, Jose Luis 

e15525 

Gonzalez, Adriana 6038 

González, Alan e14104 

Gonzalez, Alberto 2023 

Gonzalez, Arancha TPS4685 

Gonzalez, Carmen E. 6125 

Gonzalez, Encarnacion 

10608, e11535, e21088 

Gonzalez, Federico 1111 

Gonzalez, Gisela 2527, 2531 


Gonzalez, Joseph 1006, 

TPS1143 

Gonzalez, Manuel Sureda 

3064, e16000 

Gonzalez, Maria Magdalena 

e16561 

Gonzalez, Melanie L. e14124, 

e14125, e14727, e18516, 

e19606, e19638 

Gonzalez, Michael 3004 

Gonzalez, Ramon 3064 

Gonzalez, Rene 3102, 8510, 

8567 

Gonzalez, Ricardo Jorge 

10048, 10070 

Gonzalez, Sonia 1001 

Gonzalez, Xavier e11081 

Gonzalez-Angulo, Ana M. 537, 

1015, 1029, 1032, 1054, 

1104, 9072 

Gonzalez-Billalabeitia, 

Enrique 4587, 7095 

Gonzalez-Carrero, Joaquin 

4089 

Gonzalez-Cortijo, Lucia 1111 

Gonzalez-Huarriz, Marisol 

e14057 

Gonzalez-Larriba, Jose-Luis 

7011, e12012 

González-Martín, Antonio 

5017^, 5031, 5068, 

e15575 

Gonzalez-Santiago, Santiago 

1011 

Gonzalo, Nuria 3096 

Gonzalvez, Maria Luisa 

e11545, e15144 

Goodall, Shannon e15180 

Goode, Ellen L. 5077 

Goodhand, James e19581 

Goodheart, Michael J e15580 

Goodman, Aaron 7097 

Goodman, Andrew TPS8605 

Goodman, Annekathryn 5029, 

e15545, e15568 

Goodman, Karyn A. 3583, 

4045, 4061, e14555 

Goodman, Michael 5570, 

e14512, e15187 

Goodman, Oscar B. 4558, 

e15210 

Goodman, Simon L. 2055 

Goodman, Vicki L. 

LBA8500^, 8501, 8518 

Goodwin, Neal TPS3110 

Goodwin, Pamela Jean 1019, 

9111 

Goodwin, Rachel Anne 1036 

Goodyer, Ian 9589 

Gooley, Theodore 5082^ 

Gooskens, Saskia 8535 

Gopal, Ajay K. 8027 

Gopal, Arun e15140 

Gopalakrishna, Prashanth 

2552, e18063^ 

Gopaluni, Srivalli e11089, 

e18535 

Gopinath, Kodaganur 

Srinivasachar 1093, 

e11511, e12030, e14721 

Goranova-Marinova, Vesselina 

8018^ 

Gorbach, Sherwood 9067 

Gorbunova, Vera A. 3532, 

7512, e15543, e19012 

Gorbunova, Vera LBA7500, 

e14723 

Gordon, Leo I. 8003, 8080, 

e18530 

Gordon, Lynn K 1052 

Gordon, Michael Alexander 

4010 

Gordon, Michael S. e13077 

Gordon, Michael S. 3023, 

3032, 3034, 3042^, 4513, 

7514, 8531, e13000 

Gordon, Nicolaus e19040 

Gordon, Ryan Robert 4669, 

e15207 

Gordon, Stephen e13007 

Gordon, Stuart R. e14514 

Gore, Lia 3017, TPS9594, 

e13600^ 

Gore, Martin Eric 5012, 

5017^, 5022 

Gore, Steven e16519, 

e16537 

Gorey, Tom 1113 

Gorgun, Omer 9567 

Gori Savellini, Gianni e13098 

Gori, Stefania e19592 

Gorin, Sherri Sheinfeld 3567 

Gorlia, Thierry 2 

Gorlick, Richard Greg 9503 

Gorman, Greg e15515, 

e19006 

Gornet, Terrie 10613 

Gornick, Michele Caroline 

1515 

Gorritz-Kindu, Magdaliz 

e14028, e14030 

Goryca, Krzysztof 10561 

Gos, Aleksandra 8548, 

e19022 

Gosiengfiao, Yasmin C. 9534, 

e20001 

Gospodarowicz, Mary K. 4509 

Goss, Glenwood D. 7093, 

7511, TPS7613^, 10620, 

e13541, e18079 

Goss, Paul Edward 500, 501, 

524, 561, 596, 604, 

TPS670, e11005 

Goswami, Chirayu Pankaj 

505, 7106, 10628 

Goswami, Trishna 8065 

Gotay, Carolyn 6002, 7607 

Goteke, Vamshi Krishna 

Reddy e18545 

Gotlib, Jason R. 6624 

Goto, Ayumu e14047, 

e14050, e14123 

Goto, Hidemi e14596 

Goto, Koichi 1552, 7044, 

e17513, e17526, e17554, 

e18054, e18064 

Goto, Tomoko 5037, e15579 

Gotoh, Masahiro 3088^ 

Gotoh, Mitsukazu e13015 

Gottardis, Marco M. e15151 

Gotte, Martin e21041 

Gottfried, Maya 4564, 4619, 

e15058, e18108 

Gottlieb, Linda TPS1614 

Gotto, Geoffrey 4552 

Gou, Hongfeng 4638 

Goubar, Aicha 543, 1091, 

1601 

Gough, Karla 9124, e19605 

Gouin, Francois 10056 

Goulart, Bernardo H.L. 6007 

Gould, Jeff 9103 

Gouldesbrough, David e16042 

Gounant, Valérie TPS7112, 

e18075 

Gounder, Mrinal M. 3016, 

3062, 10004, 10019 

Gourdin, Theodore Stewart 

6611 

Gourevitch, David e13507 

Gourgou-Bourgade, Sophie 

LBA4003 

Gourin, Christine Gail e16061 

Gourley, Charlie 3048, 5022 

Gousia, Anna 10575 

Gouy, Sebastien 5083, 

10098 

Govil, Sushama 1540 

Govindan, Ramaswamy LBA4, 

2610, 3046, 7006, 7010, 

7002 

Govindan, Serengulam V. 

3091 

Govindarajan, Mallarajapatna 

e11027, e14675, e14721, 

e19619 

Govindarajan, Rangaswamy 

6099 

Govindasami, Koveela 1545 

Gowdar, Indraneel e12004 

Gowdra Halappa, Vivek 4114 

Goy, Andre e18507, e19641 

Goyal, Abhishek 4101 

Goyal, Gautam 9559 

Goyal, Ravi K. 6017, 6029, 

e15184 

Goyal, Shikha 2072 

Goydos, James S TPS3112 

Graaf, Winette T.A. Van der 

10067 

Grabellus, Florian 10032^, 

10046 

Grabsch, Heike 4124, 

TPS4143 

Grabska, Joanna 6555, 

e18543 

Grabulovski, Dragan 2575 

Gracia, Jose Manuel e18044 

Gracien, Edith 7558 

Gradishar, William John 596, 

604, 610, TPS1134, 2532, 

6623 

Gradishar, William TPS661 

Grados Sanchez, Oswaldo 

Abelardo e12041 

Graeber, Stefan 1523 

Graesslin, Olivier 1584 

Graf von der Schulenburg, 

J.-Mathias e18016^ 

Graff, Jeremy Richard 8082 

Graff, John 6023 

Graham, Donna M. e16506 

Graham, Mark e21022 

Graham, Martin 3029 

Graham, Richard A. e13106 

Graham, Roger e11548 

Graham, Tracy 1555 

Gralla, Richard J. e19635 

Gralow, Julie TPS3109, 

e16524 

Gramantieri, Laura 3061 

Gramatzki, Martin 6543, 

8004, e18565 

Grambach, Jana 1084 

Graña, Begoña 1009 

Granados-Garcia, Martin 1607 

Granata, Roberta 5555 

Grande Pulido, Enrique 4119, 

10546 

Grande Ventura, Carlos 

e18040 

Grande, Enrique e14671 

Grande, Roberta e14082 

Grange, Florent 1566, 8601 

Granger, Catherine e19605 

Granito, Alessandro TPS4151 

729s

Granowetter, Linda 9537 

Grant, Barbara W. 2006, 

6507 

Grant, Cliona 2528, 8051 

Grant, Florence 3620 

Grant, Janice 6069 

Grant-Huerta, Yanina 1581 

grant-Kels, Jane e21135 

Grasela, Thaddeus 9547 

Graser, Anno 3603, e14043 

Grasic Kuhar, Cvetka 558 

Grasso, Luigi 3016 

Gratama, Jan W 10504 

Graudenz, Marcia S 1522 

Grauer, Matthias e15577 

Gravalos Castro, Cristina 3571 

Gravenor, Donald 7100 

Gravina, Giovanni Luca 

e15200 

Gravis, Gwenaelle LBA4567^, 

4583, 4606, 4625, 

e15155, e19539 

Gray, Angel e13115, e13117 

Gray, Heidi J. 5021, 

TPS5113 

Gray, Jhanelle Elaine 3027, 

7065, e17559, e21155 

Gray, Kathryn P. 4543, 4555, 

4635 

Gray, Robert James 1005, 

1021, 1027, 9020 

Gray, Sarah E 9064 

Graziano, Francesco 3518, 

3540, 4026, 4084, 

e14135 

Graziano, Joseph e13066, 

e13067 

Graziano, Paolo e18021 

Graziano, Stephen L. 7007 

Graziano, Steve e16047 

Grebennik, Dmitri O. 

TPS4675^ 

Greco, Frank A. 3097, 4130, 

7035, 7100, 7567, 7587, 

10530, 10584, e13076, 

e21023 

Greco, Luigi e19002 

Green, Andrew R. 1013, 

1014, 1098 

Green, Dan e11098, e15569, 

e19594 

Green, Daniel M. 9526 

Green, Jennifer A TPS2103 

Green, John LBA5000 

Green, Margaret 6582 

Green, Marjorie C. 527 

Green, Michael J e13026 

Green, Rebecca L. 6093 

Green, Sarah G. e14118 

Green, Stephen 3004 

Greenan, Caroline 10553 

Greenberg, James e18507 

Greenberg, Jonathan 7536, 

e14617 

Greenberg, Mark 6030 

Greenberg, Peter 6522 

Greenberg, Philip D 2523 

Greenberg, Richard Evan 

4526 

Greenberg, Richard H. 

TPS3635^ 

Greene, Jessica 6602 

Greene, John e19059 

Greene, Joshua B. e16027 

Greene, Mark H. 1519 

Greenhalf, William e14625 

Greeno, Edward e14610 

Greenup, Rachel Adams 1122 

Greer, Joseph A. 6004, 6048, 

6062, 6106, 9030, 9101 

Gregorc, Vanesa 7076, 7085, 

7544, 7581, TPS7619, 

e18096 

Gregori, Josep 10511 

Gregory, Stephanie A. 6552, 

8080, e16503, e18502, 

e18510 

Gregory, Walter 502, 513, 

8015, e13083 

Greig, Paul David 4109, 

e14592 

Greil, Richard 514, TPS1148, 

CRA3503, TPS3641^, 

4074, 10501 

Greillier, Laurent e16560 

Greimel, Elfriede 7607 

Greimel, Eva 6002, 6090 

Greiner, Jochen 6567 

Greisinger, Anthony 8543 

Grell, Peter e11072 

Gremillet, Eric e15109, 

e21056 

Gresham, Gillian e14154 

Greshock, Joel e13596 

Gressin, Remy 2023, 8026 

Greten, Tim F 4023, 4032 

Greten, Tim 3103, 10566 

Greulich, Heidi 4580 

Grever, Michael R. 6508 

Grewal, Jai TPS2107 

Grewal, Ravinder K. 5509^ 

Grey, Andrew e15054 

Greystoke, Alastair P 3004 

Greystoke, Alastair 3030 

Grgic, Mislav e15031 

Gribbin, Thomas Edward 

e16561 

Gribkoff, Greta TPS7611 

Gridelli, Cesare LBA7507, 

7550, TPS7612 

Griebel, Lis-Femke 5007 

Grier, Charles E. 3627, 

e13047 

Grier, Holcombe E. 9503, 

9537 

Griesinger, Frank TPS7612 

Griffin, Melissa e13596 

Griffin, Michael TPS4143 

Griffin, Nicole 10630 

Griffin, Thomas W. LBA4518 

Griffith, Kent A. 8011, 10028 

Griffiths, Elizabeth A. 6565, 

6602 

Griffiths, Michael TPS10633^ 

Griggs, Jennifer J. 6024, 

6056 

Grigiene, Ruta TPS661 

Grignani, Giovanni 10066, 

e15073, e15192, e20512 

Grigorieva, Julia e18096, 

e18100 

Grigsby, Perry Wayne e15514 

Grigull, Joerg 4633 

Grijuela, Barbara 5096 

Grill, Jacques TPS9596 

Grilley-Olson, Juneko E. 3046 

Grillo, Federica e19038 

Grillo, Tarin 4021 

Grimaldi, Antonio M 8573, 

e19034 

Grimaldi, Franco 1604, 

e19038 

Grimison, Peter S. 4531, 

TPS4681 

Grimison, Peter 9126 

Grimm, Christoph 5111 

Grimm, Sean Aaron 2006, 

2035 

Grimminger, Peter Philipp 

e12007 

Grinblatt, David L. 6122 

Griner, Paula L. 1018 

Grinsted, Lynda 3004, 7503 

Grisham, Rachel Nicole 5030, 

5043 

Grisold, Wolfgang 2 

Grissom, Daniel e14177 

Grist, William 5560, 5570 

Grivas, Petros 4506, 4573 

Grivaux, Michel 1574 

Grives, Audrey 10562 

Grob, Jean Jacques 8518, 

8568, 8578, 8591 

Grob, Jean Jacques 

LBA8500^, 8555, 8559 

Grober, Yuval 2078 

Groen, Harry J.M. 7543 

Groeschel, Andreas 2573^ 

Grogan, Eric L. 7008 

Grohe, Christian TPS7109 

Grollier, Chrystelle e14148 

Groman, Adrienne E. 3582, 

e14690, e19041 

Grommes, Christian 2008 

Gronbaek, Henning 4015 

Gronchi, Alessandro 10000, 

10016, 10017, 10022, 

10026, 10065, 10079, 

10096 

Gros, Alena e14179 

Grosch, Kai 3099 

Grosh, William W. 8530 

Groshen, Susan G. 2538, 

4563, 4575, 8073, 

e13531, e15153 

Gross, Anne e16515, e16559 

Gross, Cary P. TPS669, 

1030, 1595, 4651, 6019, 

6628, 9034, 9109, 9123, 

e15150, e18133 

Gross, David 4014 

Gross, Gerald G. 1083 

Gross, Neil D. e16045 

Grossbard, Michael L. 6114, 

e18139 

Grosser, Susanne 4034 

Grosshans, David 9585 

Grossi, Francesco 7081, 

7085, 7550, 7558, 7577, 

7581, TPS7612, e21065 

Grossman, H. Barton 4523 

Grossman, Mary e19626 

Grossman, Stuart A. 2017, 

e17552 

Grosso, Federica 7082, 7084, 

10053, e19549 

Grosso, Marco 8529 

Grothey, Axel 1557, 3502, 

TPS3634 

Grotz, Travis Edward 8600 

Grotzinger, Kelly LBA8500^, 

e12001 

Grove, Laurie E. 8027, 8070 

Grover, Surbhi 7098, 

e12009, e12508, e17534, 

e18032 

Groves, Morris D. 2003, 

2029^, 2036, 2064 

Growcott, Jim W e15141 

Growdon, Whitfield Board 

5029, e15545, e15568 

Grubb, Robert L. 4594 

Grubbs, Elizabeth Gardner 

4641 

Grubbs, Stephen S. e18122 

Gruber, Harry E. 2101 

Gruber, Michael L. TPS2107 

Gruber, Stephan 10570 

Gruber, Stephen B. 1515, 

1578, e12026 

Grude, Francoise e14148 

Gruenberger, Birgit 4074, 

e14095, e14099 

Gruenberger, Thomas 3508, 

3613, e14095, e14099 

Grueneisen, Andreas 6610 

Gruenhage, Frank 1523 

Gruenwald, Frank e14565 

Gruenwald, Viktor 4631, 

e19502 

Grunberg, Steven M. 9061 

Grundy, Anna e17519 

Grupp, Stephan A. 9506 

Gruselle, Olivier 7056, 

TPS8111, e13061 

Gruttadauria, Salvatore 4110 

Grybowicz, L TPS1144 

Grycz, Krystyna 4660 

Grünwald, Viktor 4503, 4636, 

e15190 

Grzegorzewski, Kris e14525, 

e14627 

Grzesiczek, Anja 3595 

Gröpper, Stefanie 6527 

Grønberg, Bjørn Henning 

7027, 9040 

Gschwend, Juergen 4590 

Gschwend, Jürgen E. e15112, 

e15157, e15195 

Gu, Aiqin e18088 

Gu, Chu Shu e14001 

Gu, Chu-Shu 6049 

GU, Kangsheng 8554 

Gu, Xiaoling e18082 

Guan, Bin e14538 

Guan, Changjiang e14716 

Guan, Jilin e18090 

Guan, Ran e19030 

Guan, Wen xian e14509, 

e21034 

Guan, Zhongzhen 3614 

Guancial, Elizabeth Ann 

4577, 4582 

Guaraldi, Monica 5513 

Guardado, Sandra e15033 

Guardino, Ellie LBA1, 528, 

1037 

Guarducci, Cristina 1012 

Guarino, Lorena e11052 

Guarino, Michael J. 4043, 

e18122 

Guarneri, Valentina 614, 631 

Guastafierro, Anna 8577 

Guastalla, Jean Paul 

e13095^, e13097^ 

Guba, Susan C. LBA4 

Gucalp, Ayca 1006 

Guchelaar, Henk-jan 526, 

10077, 10518 

Guckert, Mary E. LBA8500^, 

8501 

Guderian, Gernot e15044 

Gudikote, Jayanthi 10612 

Guelfucci, Bruno e16044, 

e16051, e16055 

Guenther, Georg 6566 

Gueorguieva, Ivelina 2042 

Guerci-Bresler, Agnes 6505^, 

6522, 6523 

Guerif, Stephane e15199^ 

Guerin, Annie 1037, 6594, 

10094, e11076, e16571, 

e20511 


Guerin-Meyer, Veronique 

e14148 

Guerra Alia, Eva e15575 

Guerra, Eva 5068 

Guerrero, Carmen T e12033 

Guerrero, David e14057 

Guerrero, Javier 3072 

Guerrero, Lisa 9534 

Guerrieri-Gonzaga, Aliana 519 

Guerry, DuPont e19054 

Guglielmi, Alfredo 4110 

Guglin, Maya 2612 

Guha, Chandan e16058 

Guha, Udayan 7103 

Guhlke, Stefan e14565 

Gui, Jiang e14514 

Guidelli, Giacomo e13098 

Guidoboni, Massimo 8513 

Guiducci, Graziano 2057 

Guigay, Joel 5505 

Guijarro, Ricardo 7058, 

7060, 10594 

Guiles, Fran 3621 

Guilhot, Francois 6506 

Guillem, Jose G. 3563, 3583 

Guillemaut, Severine 10006 

Guillemet, Cecile 10035, 

10056 

Guillemin, Françis 1584 

Guillemot, Didier e14065 

Guillen, Carmen 1531 

Guillen-Ponce, Carmen 

e12033, e19590 

Guillen-Rodriguez, Jose 

e18534 

Guillot, Bernard 8591 

Guillot, Eugenie e11551 

Guimaraes, Alexander R 

2012, e14615 

Guimbaud, Rosine 3547, 

4091 

Guinan, Emer M. 1511 

Guinan, Patrick e13513, 

e13532, e15119 

Guindalini, Rodrigo Santa 

Cruz 2038 

Guinebretiere, Jean-Marc 

10554 

Guitart, Joan e18523 

Guiu, Michel e14129 

Guivarch, Laurent e14148 

Guix, Marta 4582, TPS4688 

Gujja, Swetha 6099 

Gul, Naheed 10025 

Gulati, Roman 4557 

Gulaya, Sachin 6121 

Gulbas, Zafer e21050 

Gulec, Seza A 4043 

Gulenchyn, Karen Y. 6049 

Guller, Ulrich e14544 

Gulley, James L. 2526, 

TPS2617, 3043, TPS3638, 

4569, TPS4701, 10589 

Gullo, Giuseppe 615, 623, 

e13520 

Guminski, Alexander David 

e19042 

Gumus, Mahmut e14618 

Gumusay, Ozge 638 

Gunaldi, Meral e13523 

Gunchenko, Alexandra 3027 

Gundacker, Holly 4010, 6502 

Gundeti, Sadashivudu 6554, 

e18544, e18545 

Gunduz, Seyda e14070 

Gunn, Gary Brandon 5561, 

5589 

Gunn, Shelly e13025 

Gunnarsson, Orvar e15139 


Gunson, Diane E 9562 

Gunter, Marc J e14005 

Gunturi, Anasuya 8569 

Gunturu, Krishna Soujanya 

e14534 

Gunzer, Katharina TPS662 

Guo, C.H. e11561 

Guo, Chengye e18033 

Guo, Fuchun e18051 

Guo, Huiqin e18087 

Guo, Jun LBA4537, 4628, 

8506, 8554, 8561, 8562, 

e15051, e15052 

Guo, Min Amy 6583, 6600 

Guo, Rong e19588 

Guo, Shuliang 7091 

Guo, Wei 5593, e14645 

Guo, Xiang e13021 

Guo, Xiaotao e13064 

Guo, Yantong e13526 

Guo, Ye 8552, e16039 

Guo, Ying 3055 

Guo, Yongli e13567 

Guo, Zhanfang 534, 3047 

Gupta, Ashok Kumar 

CRA2509, 2510, 2521, 

TPS2613, TPS2622, 4505, 

7509, 8507 

Gupta, Avinash 3051 

Gupta, Charu 4666 

Gupta, Digant 5049, e14012, 

e14697 

Gupta, Gopal Nand e15014, 

e16544 

Gupta, Ira 6584 

Gupta, Monica e19619 

Gupta, Neeraj 3077, 8017, 

8033, 8034, 8064, 

e13603 

Gupta, Nilesh 1560, e15174 

Gupta, Pankaj e18513 

Gupta, Rajeev e19516 

Gupta, Rajesh 3083 

Gupta, Rajnish K. e16551 

Gupta, Ritu 6593, 9549, 

9551, 9580 

Gupta, Rohan 10071 

Gupta, Shachi e15123 

Gupta, Shivani e16012 

Gupta, Shweta 1611, 8085, 

e14590 

Gupta, Sudeep 1032, 3011, 

e11552, e13068 

Gupta, Tejpal e16021 

Gupta, Vikas 6624, TPS6640 

Gupta, Vishal e13500, 

e13562, e21028, e21029 

Gur, Eyal 1564 

Gurbuz, Yesim e14618 

Guren, Marianne Gronlie 

4015 

Guren, Tormod Kyrre 3531, 

3548 

Gurevich, Pavel 2567 

Gurion, Ronit 8069 

Gurkan, Emel 6550 

Gurney, Howard 550, 4531 

Gurney, James G. 9526, 

9531 

Guron, Gunwant K. e12025 

Gurpide, Alfonso 7095, 8572, 

e15041, e18008 

Gurski, Carol Ann 4566 

Guru, Khurshid e15204 

Gury, Jean-Pierre 1574 

Gusella, Milena e13019 

Guset, Valentin 6123 

Gustafson, Eric e13561 

Gustafson, Michael 2546 

Gustafsson, Goran 9590 

Gustavson, Mark 517 

Gusyatin, Oleg e21146 

Guth, Amber Azniv e11010 

Guth, Dagmar e19540 

Guthoff, Rainer 2054 

Guthrie, Graeme JK e14054 

Guthrie, Katherine 6631 

Gutierrez Restrepo, Eduardo 

e18044 

Gutierrez, Antonio 10079 

Gutierrez, Benjamin e15165 

Gutierrez, Martin 2610, 8073 

Gutierrez, Maya TPS662 

Gutierrez-Barrera, Angelica M. 

1546, 1549, e11090 

Gutierrez-Gutierrez, Gerardo 

9073 

gutierrez-Hernandez, Olga 

6599 

Gutin, Alexander 7023 

Gutin, Philip H. 8583 

Gutkind, Jorge Silvio 5541 

Gutkind, Silvio e16061 

Gutzmer, Ralf LBA8500^, 

8505, 8559, e19031 

Guy, Michelle 1545 

Guyetant, Serge 4129 

Guyon, Frederic e15535 

Guzzo, Federica 5093, 5094, 

e15547, e15550, e15551, 

e15553 

Gwede, Clement 6100 

Gyan, Emmanuel 2023, 

2539, 8026 

Gyimesi, Edit e21140 

Gynnild, Mari Aas 9040 

Günther, Andreas e18565, 

e18572^ 

Gyorffy, Balazs 10571, 

e21005 

Gyorffy, Steve e13011 

Gyorki, David E. 8583 

Gyotoku, Hiroshi 7569 

Gyure, Maria 1563 

H 

Ha, Caroline Ann 9065 

Ha, Jeslin 8078, e18515 

Ha, Tam Cam 1593, e18546 

Haab, Francois e15105 

Haag, Georg Martin 4083 

Haagsma, Ben e15517 

Haaland, Benjamin 5580, 

e15045 

Haalck, Thomas 8505 

Haanen, John B. A. G. 4611, 

8502^ 

Haas, Jonathan A. e15504, 

e21114 

Haas, Lindsey R 5004 

Haas, Michael 4023, 4072 

Haas, Naomi B. 4500, 4513, 

e13604 

Haasbeek, Cornelis J 7009 

Haasler, George e17555 

Haass, Nikolas 8553 

Habbous, Steven 1597, 9032 

Haber, Daniel A. 4566 

Haberal, Nihan e15572, 

e15573 

Haberl, Christopher 3588 

Habermann, Elizabeth Butzer 

6016 

Habermann, Thomas Matthew 

9057 

Habertheuer, Karlheinz 

e14087 

Habets, Leo 10600 

Habib, Nabil e20500 

Habib, Sharifa 9076 

Habib, Stefanie e18066 

Habibian, Muriel LBA4567^ 

Habr, Dany 2543 

Habra, Mouhammed Amir 

4639, 4641 

Habuchi, Tomonori 10520 

Hack, Stephen Paul TPS3640 

Hacker-Prietz, Amy 4045 

Hacking, Nigel TPS4150 

Hackl, Monika 2053 

Hackl, Wolfgang 508 

Hackshaw, Allan 7538, 7562 

Haddad, Abdo S. e18046 

Haddad, Fabio Jose e21073 

Haddad, Housam 4609, 

TPS4684 

Haddad, Mojgan 603, 608, 

614 

Haddad, Riad 1578 

Haddad, Robert I. 5501, 

5579, 5582, TPS5598, 

9024, e16060 

Haddad, Vincent 4042, 

TPS4135 

Haddad, Zaid 4565 

Hadeiba, Husein e21071 

Hadenfeldt, Rebecca 9110 

Hadengue, Alexandra 3506 

Hadji, Peyman e11040^ 

Hadler, Dietrich 7536 

Hadoux, Julien 10098 

Hadziahmetovic, Mersiha 

9544 

Haefner, Mark Dieter e19648 

Haenel, Mathias 8025, 8031 

Haeusler, Christa e14103 

Haferlach, Claudia 6510, 

6610 

Haffty, Bruce George e13543 

Haga, Shunsuke 1112 

Hage, Georges e20500 

Hagemann, Andrea R. 5013 

Hagemeister, Erin e16515 

Hagemeister, Fredrick B. 

8067 

Hagen, Steinar 6619^ 

Hagenbeck, Carsten 

TPS1146, 1602 

Hager, Gudrun 5058 

Hager, Henrik e21110 

Haggman, Michael 4550 

Hagiwara, Eri e19583 

Hagiwara, Koichi 7563, 

e18129 

Hagiwara, May e16573 

Hagiwara, Sachiko 10604, 

e18004, e18014, e18017 

Hagleitner, Melanie M. 10077 

Hah, Jeong-Hun 5552 

Hahn, Astrid e15157 

Hahn, Elizabeth A 6092 

Hahn, Lars 1077 

Hahn, Markus 1067, 1090, 

e21003 

Hahn, Noah M. 4524, 4586, 

4603, TPS4676, e15179, 

e15213, e21016 

Hahn, Seung Shin e16047 

Hahn, William C 2020, 4585, 

5011 

Haidau, Augustin e18534 

Haie Meder, Christine 10098 

Haie-Meder, Christine 5083 

Haigentz, Missak e16058 

Haim, Nissim 9052 

Hainaut, Pierre 1522, 7007, 

10593, e13546 

731s

Hainsworth, John D. 618, 

1018, 1086, 4014, 4130, 

7035, 7100, 7567, 7587, 

8556, 8567, 10530, 

10584, e21023 

Hainsworth, John D 8579, 

e19048^ 

Haioun, Corinne 8021, 8057 

Haislip, Sally 569, 571, 

e11002, e14106, e14141, 

e14146, e15183, e18097 

Haitao, Ma e18013 

Haiying, Nan 1094 

Hajage, David 9538 

Hajdenberg, Julio e15010, 

e15102 

Hajduch, Marian 1087, 

e14556 

Hajek, Roman 8095 

Hakamada, Kenichi e14709 

Hakansson, Ulf 4508 

Hakim, Khaldoun 1574 

Hakimi, Abraham A. 4604 

Halabi, Susan 4515, 4592, 

4655, 4667 

Haldeman, Jennifer e19047 

Hale, Christopher e19003 

Hale, Diane F 625, 2508, 

2529 

Hale, Juliet 9539 

Hale, Katherine Stemke 

1015, 4131 

Halene, Stephanie 6628 

Haley, Sherri 2517 

Halfdanarson, Thorvardur 

Ragnar 6034, e14594, 

e14600, e14620, e15580 

Halford, Sarah E. R. 9542 

Hall, Brett 2583 

Hall, Carolyn S. TPS10631, 

e21107 

Hall, Chad A 8082 

Hall, Geoff e13083 

Hall, Junior 9506 

Hall, MacLean S 2511 

Hall, Marcia LBA5000 

Hall, Michael J. 1544, 1550, 

e14021 

Hall, Peter TPS665 

Hall, Philip S 4610 

Hall, Robert 7029 

Hall, Simon 4623 

Hall, Stacy e19528, e19584 

Hall, Suzanne P 4557, 

e15206 

Hallberg, Kenth e13518 

Hallemeier, Christopher Leigh 

4595 

Haller, Daniel G. 3522, 

3523, 3525, 3578 

Haller, Nairmeen Awad 

e17004 

Halling, Kevin C 1083 

Hallmeyer, Sigrun 8567 

Hallock, Abhirami 2081 

Hallquist, Allan e11562, 

e13003 

Halluard, Céline 2605 

Halm, Melissa e15089 

Halmos, Balazs 3024, 

e17563 

Halpenny, Barbara 9008 

Halperin, Marc e15172 

Halpern, Allan C. e19052 

Halpern, Anna 6562 

Halpern, Marisa e14067 

Halpern, Michael T. 6046 

Halpern, Wendy 2567 

Hals, Petter-Arnt 6619^ 

Halton, Elizabeth 6613 

Haluska, Frank G. 6503, 

8504, 10010 

Haluska, Paul 534, TPS2618, 

3001, 3027, 5012, 5073, 

5077 

Halvorsen, Tarje Onsoien 

7027 

Halyard, Michele Y. 6108, 

e16572 

Ham Guo, Maung Shwe 9041 

Ham, Hye Seon e14136 

Hamada, Akinobu e13072 

Hamada, Chikuma 3607 

Hamadani, Mehdi 8065 

Hamaguchi, Masanari e18056 

Hamaguchi, Tetsuya 3524, 

e14126 

Hamakawa, Hiroyuki 5584 

Hamaker, Marije 1080 

Hamalidou, Eleni Kyrillos 

e14567 

Hamamoto, Yasuo 4002, 

4031, e14123, e14510 

Hamatake, Motoharu 3045 

Hamberg, Paul 2593, 10504 

Hamdan, Shadi E. e15123 

Hameed, Meera 10001, 

10015 

Hamid, Omid 2510, 3528, 

8502^, 8508, 8510, 8518, 

8567, e13101, e19048^ 

Hamidou, Zeinab 1584 

Hamilton, Ann S. 6023, 9130 

Hamilton, Audrey M. 8054 

Hamilton, Bronwyn E. 2077 

Hamilton, Mark e21044 

Hamilton, Michael 2577 

Hamilton, Olivia 6021 

Hamilton, Robert James 

e15022 

Hamilton, Ronald H. 8528 

Hamilton, Stephanie A. 3627, 

e13047 

Hamlin, Paul A. 8054 

Hammel, Pascal LBA4007, 

4032, 4053, 4133, 

e14660 

Hammer, Liat 9052 

Hammerer, Peter e15195 

Hammerman, Peter S. 7006 

Hammers, Hans J. TPS2614, 

4549, 4564, 4619, 

TPS4694, e15058 

Hammers, Hans TPS4687 

Hammond, Sue CRA9513, 

9528 

Hamoir, Marc 5519 

Hampshire, Margaret K. 6135 

Hampson, Grace 8056 

Hamza, Mohamed Ali 2030, 

2064 

Han, Baohui 1551, e12010, 

e12013, e13528, e17551, 

e18013, e18038, e18088, 

e21001 

Han, Chen 1066 

Han, Chun 4073 

Han, Dale 10048 

Han, Dolly 6084, 9111 

Han, Gang 2544, 10048 

Han, Guohong e14605 

Han, Heather TPS2620 

Han, Hye-Suk e19538 

Han, Hyo S. 1585, 2534 

Han, Jae Ho e18519 

Han, Ji-Youn 7089, 7533, 

7596, e18119 

Han, Jung Woo 3606 

Han, Lei 500, 561 

Han, Leona C. 4657 

Han, Mark e21080 

Han, Misop e15214 

Han, Myung Woul 5586 

Han, Qinghong 1063 

Han, Sae-Won 1003, 3076, 

3624, e14136 

Han, Tae H. e13079 

Han, Wei e14716 

Han, Wonshik 1056, 1133, 

10621, e11532, e21160 

Hanafi, Widayana 10051, 

e20509 

Hanagiri, Takeshi 10585 

Hanai, Nobuhiro e16032 

Hanash, Alan M. 6539 

Hanby, Andrew TPS10633^ 

Hancock, John F. e13516 

Hancock, Michael L. e19582, 

e19585 

Hande, Kenneth R. 10003 

Handgretinger, Rupert 9573 

Handisides, Damian 6585 

Handorf, Elizabeth e18032 

Handy, Beverly Carol 10613 

Haney, Patricia LBA8500^ 

Haney, Sophie 2552 

Hanfstein, Benjamin 6510 

Hangauer, David G. 4654 

Hanin, Francois-Xavier 5519 

Hank, Jacquelyn A e19047 

Hanker, Lars Christian 5044, 

e15520 

Hanks, Brent Allen 10563 

Hanmod, Santosh S. 9578 

Hanna, Ehab Y. 5561, 5589 

Hanna, Glenn 5582 

Hanna, Michelle 6130 

Hanna, Nader 1039, e14035, 

e14056, e14522, e14626, 

e14638 

Hanna, Nasser H. 4534, 

7516 

Hanna, Wedad 1123 

Hanna, William e21047 

Hannah, Alison L. TPS4695 

Hanneken, Jan M 7608 

Hanniford, Douglas 8550, 

8565 

Hannig, Carla 4065 

Hanning, Fritha J. e15054 

Hannon, Breffni e16567 

Hanrahan, Aphrothiti 4527 

Hans, Stephane 5554, 

e13578 

Hansen, Lisa 9018 

Hansen, Morten 2565 

Hansen, Nora M. TPS1134 

Hansen, Olfred 7001 

Hansen, Torben 3513, 3573 

Hanson, Jennifer 3515 

Hanson, Sven e13503 

Hansra, Damien Mikael 

e18109 

Hansson, Johan 8517, 8588, 

10521 

Hao, Desiree 3013, e18110 

Hao, Si Jie e14651 

Hao, W-H e14699 

Haq, Rashida 3515, 9111 

Haqq, Christopher M. 4521, 

4558 

Haque, Sofia 5514, 5545^ 

Har-Noy, Michael e13013 

Hara, Hiroki 4031 

Hara, Kazuo e14540 

Harada, Masao 7017, 7028, 

7070, 7086, 7561 

Harada, Naoki e13502 

Harada, Toshiyuki 7563, 

7565, 7571, e18135, 

e19556 

Haraf, Daniel J. 5500 

Haralambakis, Nick 5574 

Haraldsdottir, Sigurdis 

e14178 

Harari, Paul M. e16010 

Harasymczuk, Malgorzata 

8528 

Harb, Wael A. 7556, 8032, 

e13040, e18558 

Harbeck, Nadia 552, 556, 

TPS649, 1072, 1081, 

1092, 1114, e11040^, 

e13605 

Harbison, Christopher 3615 

Harbom, Kirsten e18147 

Hardacre, Jeffrey M 4049 

Hardenbergh, Patricia H. 

6094 

Hardesty, Rosemarie A. 2590, 

3095 

Hardikar, S. 4107 

Harding, Gale e18556 

Harding, James J. 8515, 

8575 

Hardingham, Jenny 3534 

Hardj, Marjie e13120^ 

Hardt, Molly 9034, 9109, 

9123, e18133 

Hardwicke, Fred L. e21105 

Hardy, Janet 2604 

Hardy, Richard 4121 

Hardy-Bessard, Anne-Claire 

TPS4692^, 5018 

Hare, Elethea e13064, 

e13067 

Hare, Ryan B e19041 

Haregewoin, Abebe 3627, 

e13047 

Hargrave, Darren R 9519, 

9542, TPS9596 

Hari, Parameswaran 8033 

Harich, Hanns-Detlev 640 

Hariprasad, Gururao e15510 

Hariprasad, Roopa e15510 

Harita, Shingo 7042 

Harkin, D. Paul 10553 

Harlacker, Kathleen e13602, 

e13604 

Harland, Luke 9032 

Harland, Stephen John 4529, 

4558 

Harle, Alexandre TPS10634 

Harman, Dennis 6088 

Harmenberg, Johan 7539 

Harmenberg, Ulrika 4561 

Harmon, David C. 10058 

Harms, JAN-Dirk 2048 

Harness, Jay K. 6086, 9047 

Harnicar, Stephen 6613 

Haro, Akira e13090 

Harold, Michael e16516 

Harold, Nancy 2571 

Haroun, Iman 1555 

Harpaz, Zivit e14731 

Harpole, David 7008 

Harr, Jodi L. e16561 

Harrell, Frank E e14501 

Harrelson, Robin 6524^ 

Harrington, Elizabeth 3004 

Harrington, Kevin J. 2530 

Harris, Adrian L. 1066 

Harris, Anne 9521, 9522 

Harris, Brianna 8043 

Harris, Dean Laurence 

e15054 


Harris, Ella 1113 

Harris, Gordon J 6136 

Harris, Jonathan 5530, 5583 

Harris, Lyndsay 1045, 10508, 

10558 

Harris, Pamela Jo 2606, 

5544 

Harris, Wayne A C e21045 

Harris, Wayne 2576, e15006 

Harrison, Claire N 6514^, 

6625^, 6626^, TPS6639, 

TPS6642^ 

Harrison, Evan 5055 

Harrison, Lauren 6537, 9501 

Harrison, Louis Benjamin 

5531, 5559, 5581, 6114, 

e15138 

Harrison, Marilynn e19008 

Harrison, Mark LBA4001 

Harrison, Michael Roger 

4654, e15061 

Harrison, Timothy 10553 

Harrow, Kimberly 3041 

Harshman, Lauren Christine 

4536, 4538, 4610, 10513, 

e15005 

Hart, Eric M 3083 

Hart, Lowell L. 512, 

TPS8115 

Harter, Philipp 5007, 5031, 

5051, e15520 

Hartford, Alan 4568 

Hartig, Gregory K e16010 

Hartkopf, Andreas D. 1067, 

1090, 5042, e21003 

Hartley, John Anthony 4123 

Hartley, Lynne 5073 

Hartmann, Arndt 4590 

Hartmann, Holger e14138 

Hartmann, Joerg Thomas 

4090, e15026 

Hartmann, Lynn C. 5076 

Hartmann, Michael 4530 

Hartner, Lee 9117 

Hartshorn, Kevan L. 9004 

Harun, Nusrat 7078 

Harunal Rashid, Mohamad 

Farid Rin 10051, e20509 

Harustiak, Tomas e14631 

Harvey, Christopher 2502 

Harvey, Jimmie Huling 6624 

Harvey, R Donald 2576, 

3049, 3094, e13026, 

e18569 

Harvey, R. Donald 3055, 

e18553 

Harvey, Vernon J. 9022 

Harwin, William N. 1086, 

7567, e18560, e19615 

Harza, Mihai 4501 

Harzstark, Andrea Lynne 

4513, 4660, e15137 

Hasan, Baktiar 7081, 8076 

Hasan, Farah 2589 

Hasan, Yasmin 1101, 1116, 

e11512 

Hasanali, Zainul 6616, 

e18500 

Hasani, Ekta 6005 

Hasanovic, Adnan 7505, 

7578 

Hase, Kazuo 3625 

Hasegawa, Dave e13500, 

e21029 

Hasegawa, Hirotoshi 10531, 

e14091 

Hasegawa, Junichi 3607 

Hasegawa, Kiyoshi 4104 

Hasegawa, Koki 10519 


Hasegawa, Seiki 7031, 7080, 

10585 

Hasegawa, Takeo e13015 

Hasegawa, Yasuhisa 5542, 

e16032 

Hasegawa, Yoshie TPS1141 

Hasegawa, Yoshihiro e15098 

Hasegawa, Yoshikazu 7000, 

e18128 

Hasegawa, YUkihiro 7086 

Hasenbach, Kathy 2055 

Hasenburg, Annette 516, 517 

Hasenkamp, Justin 6543, 

8004 

Hasford, Joerg 6510 

Hashemi Sadraei, Nooshin 

2014 

Hashemi-Sadraei, Neda 2076, 

2093, 2096, 2100 

Hashiguchi, Yojiro 3625 

Hashimoto, Kenji e19535 

Hashimoto, Kenkichi e14722 

Hashimoto, Kiyoshi e21053 

Hashimoto, Kohei 7038 

Hashimoto, Masaki 7080, 

10585 

Hashimoto, Yutaka e13072 

Hashine, Katsuyoshi e15127 

Hasija, Nalini 2099 

Haslinger, Michelle e14172 

Hasrouni, Edy 6521 

Hass, Holger 3519^, 3588 

Hass, Tomas e14621 

Hassan Hamed, Ali e15561 

Hassan, Andrew Bassim 

10006 

Hassan, Manal 4116 

Hassan, Muhammad Radzi 

Abu 4106 

Hassan, Raffit 7030 

Hassel, Jessica C. LBA8509, 

e19031 

Hassell, Robert 569, 571, 

e11002 

Hassett, Edel e14111 

Hastings, B Taylor 6103 

Hata, Akito 7528, 10610, 

e18025, e18134 

Hata, Hiroyuki 8097 

Hata, Taishi TPS3642 

Hata, Yoshinobu e18127 

Hatabu, Hiroto 7553 

Hatake, Kiyohiko 10541, 

e19512 

Hatanaka, Kazuteru 3593, 

e14062 

Hatano, Koji e15065 

Hatch, Stephanie e13587 

Hatcher, Helen 3100, 9589 

Hatfield, James 9578 

Hatlevoll, Ingunn e14531 

Hatori, Masahito 9574 

Hatori, Takashi 4035 

Hatse, Sigrid 1020 

Hatsuse, Kazuo 3625 

Hattermann, Valerie 1067 

Hatton, Matthew 6113, 7562 

Hattori, Michiyo e18036, 

e18042 

Hattori, Minoru e14091 

Hattori, Yoshihiro e18060, 

e18134 

Hatzidaki, Dora 7564 

Hatzimichael, Eleftheria 

e18567 

Hatzimouratidis, Constantinos 

e15040 

Hatzis, Christos 515 

Hauber, A. Brett 4608 

Hauck, Adina 4602 

Hauge, Petra Weber e14637 

Hauge, Truls e14637 

Haugnes, Hege Sagstuen 

4508 

Hauke, Ralph J. 4603, 

TPS4676, TPS4697, 8556 

Hauns, Bernhard 4115 

Haupt, Eric C. 4517 

Hauptmann, Steffen 5005 

Haura, Eric B. 2544, 2559, 

7065, 7589, e17559, 

e21155 

Hauschild, Axel LBA8500^, 

8501, 8502^, 8505, 8511, 

8517, 8579, 8585 

Hauser, Stefan 4636 

Hausman, Diana Felice 3024 

Hauss, Pierre-Alexandre 1574 

Haustermans, Karin 4053, 

TPS4141 

Hautaniemi, Sampsa 8074 

Hautefeuille, Agnes e13546 

Hautmann, Matthias 5512 

Havel, Libor 7575 

Havelange, Violaine TPS6637 

Havlik, Roman e14556 

Havsteen, Hanne e13108^ 

Hawaldar, Rohini W 1108, 

e11552 

Haward, Robert 6091 

Hawes, Debra 4575, e15005, 

e15153 

Hawk, Natalyn Nicole 2576, 

e14614 

Hawker, Gillian e19522 

Hawkes, Claire 1014 

Hawkes, Eliza Anne 3587 

Hawkins, Douglas S. 1576, 

9509, 9535 

Hawkins, Elma S. 2087, 

TPS2107 

Hawkins, Robert E. CRA4502 

Hawks, Geri TPS4680 

Hawks, Laura 10514 

Hawley, Sarah T. 6023, 6024 

Haworth, Annette TPS4690 

Hawryluk, Elena B. 8552 

Hawthorne, Ben e17529 

Hay, John TPS5600 

Hayakawa, Kazushige e15533 

Hayashi, Hidetoshi e18060 

Hayashi, Katsuhiro 10072, 

10075, e20505 

Hayashi, Kazuhiko e21108 

Hayashi, Michio 10610 

Hayashi, Mina e18081 

Hayashi, Mitsuhiro TPS1141 

Hayashi, Naoki 590, 1012 

Hayashi, Ryuichi 5542 

Hayashi, Tatsuro e17517 

Hayashi, Yuji 613 

Hayashi, Yuki e14547 

Hayashida, Tetsu 10531, 

e11060 

Hayat, Henry 4619, e15058 

Hayden, James B. 10011^ 

Haydon, Andrew Mark 3504 

Haydu, Lauren 8558, e19011 

Hayeems, Robin Zoe e19616 

Hayenga, Jon e17529 

Hayes, Daniel F. 525, 9020 

Hayes, David N. 5503, 5515, 

5533, 5539, 5577, 7006 

Hayes, Malcolm 549^ 

Hayes, Monica Prasad 

e15513 

Hayes, Teresa Gray 4643 

Hayes-Jordan, Andrea Anita 

9509, 10021 

Hayes-Lattin, Brandon M. 

9136, e19503 

Haylock, Brian e14587 

Hayman, Suzanne R. 8013, 

8043, 8092, 8096, 8105, 

TPS8116 

Haymart, Megan Rist 6056 

Hayn, Birgit 10526 

Hayn, Matthew H. e15046, 

e15203 

Haynes, Hilda e16058 

Haynes, Kevin 1503 

Hayran, Mutlu 9050 

Hays, John L. 2545 

Hays, Rita 9110 

Hayter, Charles 4509 

Hayward, Larry 511, 

TPS1144 

Hayward, Michele C 5577 

Haz-Conde, Mar e14595, 

e21002 

Hazarika, Diganta e11043 

Hazlett, Allison e18550 

Hazra, Saswati 10535 

He, Aiwu Ruth 2590, 3095, 

TPS3638, e14009, 

e14569, e14658 

He, Bing e14523 

HE, Chengcheng 5558 

He, Chunyu e14645 

He, Hang e14651 

He, Housheng Hansen 576 

He, Kuanglin e15565 

He, Miaoling e15178 

He, Ren 6105 

He, Shui TPS6643^ 

He, Suqin 3090 

He, Xi C e14153 

He, Xin 1508 

He, Yulei 1605 

He, Zijing 9082 

Headly, Anna e14175 

Heale, Esti e12034 

Healey, Diane I. 6506 

Healey, John H. 9537 

Healy, Laura 1511, 1559 

Healy, Patrick N. 2602, 4591 

Heaney, Mark L. 6609, 6613 

Heath, Elisabeth I. 1560, 

4654, 4656 

Heaton, Simon 3022 

Hebbar, Mohamed 3506, 

3547, LBA4007 

Hebden, Tony e17009 

Hebert, Christophe 5521 

Heck, Matthias e15195 

Heckel, Martha L. TPS10635 

Heckler, Charles E. 9028 

Heckler, Charles E 9010, 

9014, 9027, 9113, 9141, 

9142, e19510 

Hedley, David W 4109, 

e14524, e14535, e14592 

Hedley, Mary Lynne 9077 

Hedlund, Åsa 7539 

Hedrick, Eric 6507, 6508, 

6515^ 

Hedrick, Nancy A. 2040 

Hedvat, Cyrus 10524 

Hee, Kim-Hor e13002 

Heeger, Steffen 3591 

Heemers, Hannelore e15204 

Heenan, Sue 4640 

Heerema, Nyla A. 6507, 

6508, 9548 

Heeren, Timothy C 6097 

Heeroma, Dr Karin 1534 

733s

Heerschap, Arend e13111 

Heersink, Mila J e11505 

Heery, Christopher Ryan 

2526, TPS2617, TPS3638, 

TPS4701 

Heese, Oliver 2034 

Heffner, Leonard T. 8100, 

8101 

Heflin, Jon e17506 

Hegarty, Sarah e15163 

Hegde , Aparna 4037 

Hegde, Priti e13000, e13113 

Hegde, Upendra P. e21135 

Hege, Kristen 2562, 3006^ 

Hegewisch-Becker, Susanna 

TPS3641^, 4023, 4065 

Hegi, Monika 2001 

Heguy, Adriana TPS4144, 

4527, 7052 

Hehlmann, Rudiger 6510 

Hei, Tom K e21097 

Hei, Yong Jiang 7549 

Heiba, Sherif 5578 

Heidecke, Cordula 7542 

Heidenreich, Axel 4530, 

TPS4698^, e15112, 

e15122, e15195 

Heider, Ulrike e18552 

Heigener, David Felix e18100 

Heijmen, Linda e13111 

Heike, Michael TPS3641^, 

8022 

Heil, Gerhard 3 

Heilbrun, Lance K. 1560, 

5534, e15081 

Heilbrun, Marta Elise e13548 

Heimberger, Amy B. 2011 

Heimburger, Douglas C. 9558 

Heinecke, Achim 6610 

Heinemann, Volker 3519^, 

3541, 3588, 3603, 

TPS3639, TPS3641^, 

4023, 4041, 4050, 4072, 

e11528, e14043 

Heinrich, Bernhard 1092, 

e11528 

Heinrich, Daniel LBA4512, 

4551 

Heinrich, Georg 1602, 

10540, e15520 

Heinrich, Michael C. 10591 

Heirman, Carlo 2507 

Heiskanen, Raita e13035 

Heist, Rebecca Suk TPS3118, 

7010, 7099, 7513 

Heitjan, Daniel 7077 

Hejduk, Karel e18062 

Hejna, Matthew e13115 

Hejna, Michael 4074 

Hekmat, Khosro 1533, 

10526, CRA10529 

Helal, Rafaela Cordeiro 

e14101 

Helbich, Thomas 10570 

Helbling, Daniel 3595 

Held, Gerhard 8022, 8024, 

8025 

Held, Swantje 4072 

Held-Warmkessel, Jeanne 

e19580 

Helenowski, Irene B. 1561 

Helfrich, Barbara 7534 

Helft, Paul R. 6095, 6128 

Helgadottir, Hildur 10521 

Helias-Rodzewicz, Zofia 8540 

Hellborg, Henrik 4561 

Heller, Glenn 4517 

Heller, Michael J e21047 

Hellerstedt, Beth A. 3069, 

TPS3111, 7514 

Hellman, Andrzej 6584 

Hellriegel, Edward 9547, 

e18522 

Hellstrom, Anita e18551 

Hellwig, Birte 10551 

Helman, Lee J. 9511 

Helms, Hans-Joachim e14167 

Helvaci, Kaan e11540 

Hembrough, Todd A. e21068 

Hemminki, Akseli e13035 

Henary, Haby Adel 8551 

Hendershott, Karen 1127 

Henderson, Ben e11541 

Henderson, David Andrew 

3012, 3046 

Henderson, Les 4022 

Henderson, Tara O. CRA9513, 

9586 

Hendifar, Andrew Eugene 

3015 

Hendifar, Andrew 10036 

Hendlisz, Alain 3559 

Hendrick, Franklin e16519, 

e16537 

Hendrickx, Tine 4622 

Hendriks, Bart TPS663 

Hendriks, T 3576 

Hendrikx, Jeroen 2550 

Hendrix, Laura H 4647, 

4658, 6037 

Heng, Daniel Yick Chin 4536, 

4538, 6082, e14073, 

e21083 

Hengstler, Jan G 10551 

Henin, Emilie e15182 

Henke, Corinna C. 9033 

Henke, Michael 5502, 

e16033 

Henner, William David 

10576, 10584 

Hennessy, Sean e19531 

Henning, Jan-Willem 6548 

Henriksson, Anders e19532 

Henriquez Cooper, Hoover 

Rodyl e15556 

Henriquez, Alexandra 1111 

Henry, David H. 1577, 4030 

Henry, Elizabeth e19588 

Henry, Norah Lynn 525, 

e16524 

Henry, Stefanie 5505 

Henschen, Stephan 552 

Hense, Joerg 2086 

Hensing, Thomas A. e18117 

Hensley, Kenneth e14098 

Hensley, Martee Leigh 5090, 

TPS10103 

Hentic, Olivia 4133, e14660 

Hentrich, Marcus 4602, 8046 

Hentsch, Bernd 4115 

Heo, Dae Seog 5552, 7566 

Heo, Jeong 4103, e14566 

Heon, Stephanie 7525, 7547, 

7553, 10592 

Hepburne-Scott, Henry 8566 

Hepp, Philip Gm 1072, 

e21020 

Heras, Javier e11028 

Heras, Lucia e18030 

Herbert, Robert J. 6026 

Herbst, Roy S. 5529, 5532 

Hercbergs, Aleck A e19573 

Herder, Judith 6058 

Heriot, Alexander Graham 

3629 

Herkommer, Kathleen e15157 

Herman, Christine e21060, 

e21111 

Herman, Dominique 1574 

Herman, Gary A. 10573 

Herman, James Gordon 

10625, e18147 

Herman, Joseph M. 3596, 

4045, 4055, e14585 

Hermann, Jacques TPS7111 

Hermann, Robert C. LBA4, 

e13113 

Hermans, Chris A.M. e19560 

Hermine, Olivier LBA4007, 

10007, 10089, 

TPS10102^ 

Hernan, Carranza e12039 

Hernandez, Claudia 6580 

Hernandez, Elvin e16523 

Hernandez, Irene e14057, 

e14120, e21086 

Hernandez, Liza e13088, 

e15010 

Hernandez, Rohini Khorana 

1579, 1581, e12023 

Hernandez, Susana 10564 

Hernandez-Cortes, Gines 

1111 

Hernandez-Ilizaliturri, 

Francisco J. e18537, 

e18538, e18539 

Hernandez-Losa, Javier 566, 

3014, 7041 

Hernando, Blanca 10512, 

10595, e11074 

Hernando, Cristina 7058, 

10594 

Hernando, Eva 8550, 8565, 

e19015, e19018 

Hernando-Trancho, Florentino 

7011, 10564 

Herndon II, James E 2074^ 

Herndon, Betty e21085 

Herndon, James Emmett 

2027, 2090^, 2094^, 

2095^ 

Herold, Stefanie 10536, 

10537 

Herr, Harry W. 4581^, 

e15022 

Herrel, Lindsey Allison 

e15187 

Herremans, Catherine e13605 

Herrera Gomez, Angel 1607 

Herrera, Alex Francisco 

e18530 

Herrera, Javier e21086 

Herrera, Jorge Eduardo 

e11565 

Herrera, Luis A e12027 

Herrera, MaryTere e15527 

Herrera, Victoria L.M. e13574 

Herrero, Ana 1570 

Herrero, Joaquin 8062 

Herrero, Mercedes 602, 

e11517 

Herrin, Jeph 1030, 4651 

Herrmann, Edwin e15044 

Herrmann, Ken 10012 

Herrmann, Richard e19648 

Herschbach, Peter e15157 

Herschberger, Amber B 

TPS3114 

Hersey, Peter 8503^, 

LBA8509, 8553 

Hersh, Evan 8534 

Hershman, Dawn L. TPS669, 

CRA6009, 6078, 6118, 

9018, 10516 

Herskovic, Arnold M. e18502 

Hertenstein, Bernd 6543 

Hertz, Daniel Louis 10515 

Hertz-Eichenrode, Martin 

Michael 1077 

Hertzog, Antoine e19555 

Herve, Christian e19640 

Herwig, Martina 2054 

Herzog, Thomas J. 5087, 

6078, e15578 

Heskamp, Sandra 3035 

Hesketh, Paul Joseph 7570 

Heslop, Helen E. 2558 

Hess, Dagmar e13605 

Hess, Georg 4128, 6543, 

6584 

Hess, Gregory P. e16512 

Hess, Kenneth R. 527, 612, 

2003, 2029^, 2036, 

10613, 10627, e13020 

Hesse, Sylvie 8555 

Hessel, Colin 5508 

Hetherington, John 4509 

Heublein, Sabine e15529 

Heuck, Christoph J. e18548 

Heuck, Christoph Johann 

8041 

Heudel, Pierre 10562, 

e14730 

Heukamp, Lukas Carl 1533, 

7603, 10526, CRA10529 

Heussen, Nicole 10552 

Hevessy, Zsuzsanna e21140 

Hew, Karina E 5055 

Hexner, Elizabeth O. 6579, 

6624 

Heyburn, John 7030 

Heymach, John 3598, 7096, 

7567, 10612, e15075, 

e15085, e15087 

Hibler, Lauren Marie 1571 

Hickish, Tamas TPS651, 

TPS9148 

Hickman, Theresa TPS4152, 

e14566 

Hickson, Ian e15166 

Hida, Naoya e18099 

Hida, Toyoaki 7003, 7028, 

e17510, e18145 

Hidaka, Noriaki 10073 

Hidalgo, Manuel 602, 2567, 

2568, 3066, 3068, 4040, 

e11006, e11517, e13048, 

e15111 

Hidalgo, Rosa 4101 

Hiddemann, Wolfgang 6610 

Hieken, Tina J. e19061 

Higaki, Kenji 588 

Higano, Celestia S. 4, 4511, 

4513, 4557, 4571, 4663, 

10503, e15201, e15206 

Higgins, Brian Patrick 

e19570 

Higgins, Doreen 5082^ 

Higgins, Helen B TPS660, 

TPS665, TPS1144, 5046 

Higgins, Kristin 7059 

Higgins, Linda C TPS4678 

High, Hilda Anne 5022 

Highsmith, W Edward 10588 

Higuchi, Mitsunori e13015 

Hijazi, Hussam 10042 

Hijazi, Youssef 2504 

Hijikata, Yasuki e13014 

Hijioka, Susumu e14540 

Hijiya, Nobuko TPS9594 

Hijri, Fatima Zahra e11502, 

e11516, e14725, e14726 

Hilden, Joanne M. 9548 


Hilf, Norbert 3530 

Hilfenhaus, Georg 4128 

Hilfrich, Joern 1023 

Hilger, James D. 8098 

Hilger, Ralf A. 2086, 10032^ 

Hill, Andrew e15152 

Hill, Brian Thomas 8055 

Hill, D Ashley 9521, 9522 

Hill, Dawn 3025 

Hill, Jamie 3062 

Hill, Jerrold W. e16512 

Hill, Kimberley 1542 

Hill, Mark 3578 

Hill, Richard P e14535 

Hill-Kayser, Christine E. 6135 

Hille, Elysee T.M. 526 

Hillemanns, Peter 5007 

Hiller, Louise TPS660, 

TPS665, TPS1144 

Hillmen, Peter 6584 

Hilpert, Felix LBA5002^, 

5005, 5007, 5031 

Hils, Rita 5051 

Hilton, Christie 6620 

Hilton, Nancy e16515 

Hiltz, Andrea Clare 4509 

Himmetoglu Ussakli, Cigdem 

e15207 

Himsl, Isabelle Katrin 1114 

Hindenburg, Hans-Joachim 

5044, e11040^, e19540 

Hinder, Vicky e15054 

Hindi, Nadia 3618, e13085 

Hines, Oscar J e14582 

Hinke, Axel 640, 3 

Hino, Masayuki TPS8118 

Hinoi, Takao e14091 

Hinotsu, Shiro e15004, 

e15106 

Hiotis, Spiros P. e14583, 

e14656 

Hirai, Fumihiko 3045 

Hirai, Takashi 3607 

Hirakawa, Akihiro e19535 

Hirakawa, Hitoshi e16032 

Hirakawa, Masakazu e13014 

Hirama, Hiromi e15127 

Hirashima, Tomonori 7521, 

e18036, e18042, e18141 

Hirashita, Teijiro e14722 

Hirata, Akira 10531 

Hirata, Kazuto e17538 

Hirata, Yoshito e15201 

Hirchaud, Edouard 8048 

Hiret, Sandrine e21117 

Hirmand, Mohammad 4519^ 

Hiro, Junichiro e14039, 

e14541, e21053 

Hironaka, Shuichi 4002 

Hirose, Kenzo 3596, 3616 

Hirose, Shigemichi e11060 

Hirose, Takashi e13029 

Hiroshige, Shoji e14722 

Hirota, Makoto 5556 

Hirsch, Bradford Richard 

6041, 6047, 6051 

Hirsch, Fred R. 7516, 7517, 

7552, 7597, e18077 

Hirsch, Jennifer e15103 

Hirsch, Michelle S. 4543, 

4582, 4635, 5011 

Hirschfeld, Azriel e14729, 

e14732, e15576 

Hirsh, Vera LBA7500, 7511, 

7590, 7592, TPS7618 

Hirte, Hal W. 3082, 5001, 

5019, e13011, e19616 

Hisamatsu, Kazufumi e11503 


Hisamoto, Akiko 2607, 7045, 

7576, e18027 

Hishida, Tomoyuki e17554 

Hishiki, Tomoro 9577 

Hitre, Erika 2522, 3530 

Hitz, Felicitas 9045 

Hixson, Douglas C. e21116 

Hiyama, Eiso 9577 

Hjelm-Eriksson, Marie 4561, 

TPS4696^ 

Hlavata, Zuzana e19020 

Hlubocky, Fay J. 6117, 

e13026 

Ho, Adelyn 9043 

Ho, Alan Loh 5509^, 5514, 

5545^ 

Ho, Albert 8596 

Ho, Alice Y. 1118 

Ho, Anthony D. 6519 

Ho, Anthony D 10040, 

10041^ 

Ho, Cheryl 7020, e18079 

Ho, Gui Yi e19523 

Ho, Gwo Yaw e19598 

Ho, Han Kiat e13023 

Ho, Linus 4051, e14548 

Ho, Maria Yi 3610, e14588 

Ho, Seong-Hyun e19574 

Ho, Steffan Nicholas 2610 

Ho, Thai Huu 4624 

Ho, Xuan Dung 641 

Hoang, Anh 4556, 4624 

Hoang, Tien e16010 

Hoang-Xuan, Khê 2, 2023 

Hobbs, Adele e15164 

Hobday, Timothy J. 4047, 

e14594 

Hobeika, Amy 2585 

Hoch, Ute 5048, e13577 

Hochberg, Ephraim P. 

e18520 

Hochberg, Fred 2009 

Hochberg, Jessica e13022 

Hochhaus, Andreas 3541, 

6504, 6506, 6509^, 6510, 

6511, TPS6641, e21063 

Hochman, Jimena e19007 

Hochman, Tsivia e11010, 

e11064 

Hochster, Howard S. e14534 

Hochwald, Steven N. 

TPS4136 

Hodge, James W. 2526 

Hodge, Rachel 10009 

Hodges, David e11069 

Hodgson, Darren R e15141 

Hodgson, David C. 9524 

Hodgson, John Graeme 3509, 

3511, 3575 

Hodgson, Lydia 7513 

Hodi, F. Stephen 2502, 

CRA2509, 8507, 8508, 

8516, 8569, TPS8603 

Hoefler, Gerald e14066 

Hoehler, Thomas 2522, 

3530, 3539 

Hoejberg, Lise 8545 

Hoelscher, Arnulf e14527 

Hoelzer, Dieter 6500^ 

Hoenigschnabl, Selma 

e14087 

Hoering, Antje 3078, 8041 

Hoerring, Antje 8095 

Hoersch, Dieter 4118 

Hoersch, Silke 3578 

Hoeyer-Hansen, Maria Helena 

e19056 

Hofer, Silvia 2067 

Hoff, Paulo M. e15562, 

e20502 

Hoff, Paulo Marcelo 6055 

Hoff, Paulo Marcelo 2038, 

e11513, e12513, e14702, 

e21040 

Hoff, Paulo 3544, 3598 

Hoffman, Arnold e19565 

Hoffman, Eric W. 8547, 

e17558 

Hoffman, Karen Elizabeth 

e15181 

Hoffman, Robert M. 1063, 

2044, 10072, e14014, 

e14700, e21051 

Hoffman-Censits, Jean H. 

4526, e15012 

Hoffmann, Andreas-Claudius 

2086 

Hoffmann, Chen 2078 

Hoffmann, Isabell 1082 

Hofheinz, Ralf 3541, 4083, 

4090 

Hofman, Paul 7591 

Hofman, Veronique 7591 

Hofmann, Hans-Stefan 7105 

Hofmann, Lawrence V 

e21153 

Hofmann, Marco H. 3092 

Hofmann, Susanne 6567 

Hofmeister, Craig C. e16027 

Hofsli, Eva 4015 

Hofstetter, Gerda 5111 

Hofstetter, Wayne Lewis 

4069, 4078, 4086, 

e14547, e14548, e14669 

Hofstädter, Ferdinand e16520 

Hogan, Katherine e14179 

Hogan, Laura E. 9507 

Hogan, William J. 6614, 

8092 

Hogarth, Linda 3100 

Hogendoorn, Pancras C. W. 

10081 

Hogeveen, Sophie 6084, 

9111 

Hogg, David 8502^, 8517 

Hogge, Donna 6601 

Hohenberger, Peter 

LBA10008, 10009, 10031, 

10067, 10096, TPS10101 

Hohenberger, Werner 10031 

Hohl, Raymond J. 3056 

Hohloch, Karin 8052 

Hoiczyk, Mathias 10032^, 

10046 

Hoiom, Veronica 8588, 

10521 

Hojat Farsangi, Mohammad 

6557 

Holbrechts, Stephane 3559 

Holbrook, Jaimee S 4063, 

6623 

Holcombe, Randall F. e21109 

Holcroft, Christina e14020 

Holden, Debra J. 6046 

Holden, Scott N. 2567 

Holder, Chad A 3055 

Holder, Dara Denise e15018, 

e15019 

Holdhoff, Matthias 2042 

Holen, Kyle D. 3101, 

e14554, e16571 

Holes, Leanne 6518^ 

Holinski-Feder, Elke 3550 

Holla, Soumya e14710 

Holland, Jaymes 4504 

Holland, John M 5596^, 

e16045 

Holland, William S. e17537 

Hollander, Thomas e14584 

Hollebecque, Antoine 3000, 

3021, 3026, 3104, 4614, 

e13118 

Hollema, Harry 10581 

Holleran, Julianne L. 2533, 

3031 

Hollowell, Courtney M.P. 

e13513, e13532 

Holman, Allison e16059 

Holman, Laura L. 1518 

Holman, Rose Marie 2589 

Holmberg, Leona 4533 

Holmes, Frankie Ann 547, 

1017 

Holmes, Holly Michelle 9072 

Holmström, Benny 4668 

Holodny, Andrei 7052 

Holst, Frederik 10501 

Holt, Abby E 6099 

Holt, Cheryl L e16543 

Holt, Nanna 4015 

Holtan, Shernan G. 8599 

Holte, Harald 8074 

Holten-Andersen, Mads 3576 

Holter, Jennifer L. e17001, 

e17010 

Holter, Spring 3567, 4058 

Holtorf, Megan L. 10011^ 

Holtzhausen, Alisha 10563 

Holtzman, Matthew Peter 

e14184 

Holzer, Alison K e21071, 

e21153 

Holzhausen, Hans-Juergen 

522 

Holzmann, David 8563 

Homann, Nils 4080, 4083, 

4090 

Homayounfar, Kia 3600, 

e14161, e14167 

Homerin, Michel 2605, 

TPS4152 

Homma, Akihiro 5542 

Homma, Sakae e18127 

Homma, Shigenori 10578 

Hommura, Fumihiro 7571 

Hon, Henrique 6005, 6084, 

9032 

Hon, Jeremy K. 7590, 7592, 

TPS7618 

Honarpishe, Helen 1109 

Honavar, Santosh 9515, 

9568 

Honda, Yoshihiro e19521 

Honecker, Friedemann 4590, 

4597, 9114 

Honegger, Juergen Bernd 

8526 

Honey, R. John 4633 

Hong, Dae Sik e14688, 

e19554 

Hong, David S. 3106, 3107^, 

3598, 4639, 8551, 8594, 

10510, 10607, e13020, 

e13506, e13595, e19004, 

e19055 

Hong, Dr Shengyan e18073 

Hong, Fangxin 8007, 9008 

Hong, Ji Hyung e14558, 

e19614 

Hong, Jun Hyuk e15080 

Hong, Jung Yong e13094 

Hong, Junshik e14137 

Hong, Junsik e14685 

Hong, Ruey-Long e16050 

Hong, S. Peter 9575 

Hong, Seung-Hyun 7089 

735s

Hong, Seung-Mo 3568 

Hong, Sook Hee e14558, 

e18050 

Hong, Sung Joon 4628 

Hong, Sung-Hyeok 9575 

Hong, Theodore S. 4021, 

e14615 

Hong, Waun Ki 5524, 7078 

Hong, Yong Sang 3568, 

3592, e13104, e13560, 

e14072 

Hong, Young Seon e14558 

Hongo, Fumiya e15055, 

e15099 

Honisch, Ellen 5097, e21020 

Honma, Rio e17520 

Honma, Yoshitaka e14126 

Honoré, Charles e14158 

Honoré, Stéphane 2060 

Honovic, Lorena 9097 

Hood, Brian L e15560 

Hood, Deborah D. 6086 

Hood, Nicky 1019 

Hooda, H.S. e16002 

Hoog, Jeremy 3047 

Hoogerbrugge, Peter 9550, 

10077 

Hook, Jane 10081 

Hooker, Craig 1573, e17552 

Hooley, Regina 1109 

Hoon, Dave S. B. 2519 

Hooper, Catherine L. e19637 

Hooshmand, Susanne M. 

3594 

Hope, Andrew J. 5587 

Hopkins, Jenny R e16569 

Hopkins, Judith O. 9014 

Hopkins, Wendie e15056 

Hopman, Wilma e19541 

Hoppe, Stephanie 9012 

Hoppenreys, Laurent 9012 

Hoppensteadt, Debra e13115, 

e13117, e15008, e15538 

Hopper, John L. 1502, 3567 

Hoppo, Toshitaka e14689 

Hoque, Ehteshamul e11533 

Hor, Pooja e13030 

Horai, Takeshi 10604, 

e18004, e18014, e18017 

Horak, Christine E. e13504 

Horak, Mary 8533 

Horard, Béatrice 9011 

Horchani, Ali e15122 

Horenblas, Simon 4611 

Horgan, Anne 4109, e14524, 

e14592 

Horgan, Meaghan e12034 

Horgan, Paul G 3599, 3611, 

e14054, e14092, e14110, 

e14117 

Horger, Marius 4115 

Hori, Mitsuo 8094 

Horie, Hisanaga e14091 

Horiguchi, Jun 540, 613, 

TPS1141 

Horiike, Atsushi 10569, 

10604, e18004, e18014, 

e18017 

Horinouchi, Hidehito 7070 

Horinouchi, Takashi 1103 

Horio, Yoshitsugu e17510, 

e18145 

Horn, Leora 6068, 7094, 

7509, 7568, 7589 

Hornberger, John C. 10584 

Horndler, Carlos 3553, 

e14041 

Horne, Heather 4043 

Hornedo, Javier 1111 

Horneffer, Yvonne 3529 

Hornicek, Francis J 10058 

Hornick, Jason L. 10029 

Horning, Sandra J. 8003, 

8007 

Hornslien, Kjersti 7027 

Horowitz, David Paul 7050, 

e15162, e17562 

Horowitz, Laurie 10528, 

e21008 

Horowitz, Neil S. 5063 

Horowitz, Nina Ruth 1109 

Horowitz, Peleg 2020 

Horrigan, Stephen 10605, 

e14090 

Horsman, Janet M 6113 

Horst, Heinz-August 6500^ 

Hortobagyi, Gabriel N. 512, 

515, 527, 537, 539, 540, 

551, 559, 600, 612, 1012, 

1029, 1047, 1102, 1104, 

9018, 10613, e13582 

Horwitz, Eric M. 5530, 5583 

Horwitz, Steven M. 8060, 

8063, 8069 

Hoshi, Manabu 10073 

Hoshino, Mika e13015 

Hoshino, Mirei 2519 

Hoshino, Yoshinori 10531 

Hosing, Chitra 6546, 6622, 

8040 

Hoskin, Peter LBA4512, 

4551 

Hosnii, Shama 1098 

Hosokawa, Ayumu e14062 

Hosokawa, Masahito e21007 

Hosomi, Yukio 7012, e18099 

Hosonaga, Mari 635 

Hospital, Valerie 8591 

Hossain, Akm Mosharraf 1586 

Hossain, Mohammed S 2576 

Hotko, Yevhen 3535 

Hotta, Katsuyuki 2607, 7045, 

7576, e18027 

Hotta, Tomomitsu 8050 

Hotte, Sebastien J. 3082, 

4514, 5502, e13011, 

e19616 

Hou, Jeannie 8579, 8585 

Hou, Jian 8097, e18572^ 

Hou, Jing-Zhou 6563 

Hou, Mei e18033 

Hou, Ming-Feng 1043 

Hou, Ningqi 1101, 1116 

Hou, Shengcai e18013 

Hou, Steve j 10528 

Hou, Wei TPS4136, e14612 

Hou, Yijuan 3093 

Houbiers, Ghislain 3559 

Houck, William A. TPS658 

Houede, Nadine 9012, 

e13594, e15142 

Hough, Holly 6054 

Houghton, Peter 9541, 9544, 

9581 

Houk, Alice 6103 

Houlgatte, Remi 8048 

Hountis, Panagiotis e17553 

Houot, Roch 2514, 8057 

Hourdequin, Kathryn 

Cunningham 6013 

House, Larry 2611 

Housset, Martin e13578 

Houston, Kathleen Emilie 

Mary 8538 

Houston, Nicole D. 2545 

Houston, Stephen 511, 8539 

Houston, Teresa 1529 

Houts, Arthur C. 5014 

Houtsma, Daniel 10518 

Houweling, Leanne e16526 

Hoverman, J. Russell 6109, 

e16536 

Hovey, Elizabeth J. e15152 

Howard, Dianna S. 6502 

Howard, Jason 5549 

Howard, Leslie M. e19543 

Howard, Margaret e16543 

Howard, Scott C. 6530, 9502 

Howard-McNatt, Marissa 

Michelle 6127 

Howe, Erin N. 564 

Howell, Doris 6035, 6039, 

9131 

Howell, Elizabeth A. e15513 

Howitt, Brooke E 5011 

Howitt, John 614 

Hoyle, Martin 3602 

Hoyos, Sergio 642 

Hozaeel, Wael 4083, 4090 

Hrinczenko, Borys e21133, 

e21154 

Hristova, Gergana 2547 

Hromas, Robert TPS5602 

Hrstic, Irena 9097 

Hruby, Gregory e15019, 

e15021 

Hsia, Te-Chun 7549, 

TPS7614 

Hsiao, Chao e15542 

Hsiao, Wendy C. 6057 

Hsieh, H Ben 10574 

Hsieh, James 4604 

Hsieh, Susie 6132 

Hsieh, Wen Chuan e11068 

Hsieh, Wen Son 4103, 8003 

Hsing, Ann W 4646 

Hsu, Cheng-Lung e16050 

Hsu, Chih-Hung e14576 

Hsu, Chiun 1061, 4103 

Hsu, CS e14699 

Hsu, Feng-Ming e14576 

Hsu, Frank James 7077 

Hsu, Jack e16047 

Hsu, Joann e15084 

Hsu, Karl TPS3118, 

TPS6641 

Hsu, Limin 1029, 1104 

Hsu, Shiaowen David 2585 

Hsu, Tina e16558 

Htut, Myo 8038, 8089 

Hu, Adriana e12017 

Hu, Beihong 8593 

Hu, Boyu 8595 

Hu, Chao-su 5535 

Hu, Chaosu e16039 

Hu, Cheng-ping 7091, 7520 

Hu, Chunhong 7091, 7559 

Hu, Eddie e12017 

Hu, Jethro Lisien 2080, 2084 

Hu, Jing TPS6642^ 

Hu, Kai e16054 

Hu, Kaiji e13123 

Hu, Kenneth 5531, 5559, 

5581, 9024 

Hu, Leijun 2516 

Hu, Qiong 10527, e18123 

Hu, Xi-Chun 10567, e11567, 

e11568 

Hu, Xioaping P 3055 

Hu, Yi e13521 

Hu, Zhihong e15538 

Hu, Zhihuang e13021 

Hu, Zhiquan 4628 

Hu, Zhiyuan 1027 

Hua, Emily 505 

Hua, Guoqiang 6539 

Hua, Zhaolai e14539 

Huang, Alex Yee-Chen 9520 

Huang, Alexander 2525 

Huang, Baisong 4033 

Huang, Bee-Yau e13088, 

e15010 

Huang, Bin 5095 

Huang, Bo 5558 

Huang, Chao Hui e13551 

Huang, Chao H 5500, 

e13535 

Huang, Cheng 3040, 7091, 

7548 

Huang, Chiun-Sheng TPS649, 

TPS651 

Huang, Chu-Chun 5109 

Huang, Chunzi 2576 

Huang, Eric 7066, 7582, 

7594, e12007 

Huang, James 7043, e17015 

Huang, Jianan 7520 

Huang, Jing e13110, 

e14502, e14734 

Huang, Kun e19053 

Huang, Lily 1569 

Huang, Lingkang e15059 

Huang, Lyen C. 6010 

Huang, Meijuan e14648, 

e18033 

Huang, Pei-Ming e14576 

Huang, Peng 518, e15188 

Huang, Ruili 10025 

Huang, Shang-Yi 8097 

Huang, Sharon 2519 

Huang, Sherry e21148 

Huang, Shiang-Fu e16050 

Huang, Shu-Min 1061, 1079 

Huang, Susie Yi 2059 

Huang, Ta-Chen e14576 

Huang, Wei 10011^ 

Huang, Weidong 603, 608, 

614 

Huang, Wenmei TPS2618, 

8065 

Huang, Xuan 4569 

Huang, Yajue 10528, e21008 

Huang, Yan e13021 

Huang, Ying e18090, e18517 

Huang, Yingjie 604, TPS661 

Huang, Yiran LBA4537, 4628 

Huang, Yong 4102 

Huang, Yuan-Shung 1504 

Huang, Yuhui 2010 

Huang, Zhimin e18090 

Huber, Rudolf M. 7001, 

TPS7617 

Huberman, Kety H 7052 

Hubert, Catherine e14044 

Hubner, Richard LBA4001 

Huchot, Eric 1574 

Hucke, Christian 8079 

Hudes, Gary R. TPS2613, 

TPS2614, 4526, 4605, 

TPS4686, e15070, e19580 

Hudis, Clifford 557, TPS668, 

CRA1002, 1006, 1016, 

TPS1143, TPS1145, 6015, 

10514, 10618 

Hudson, Christopher 8542 

Hudson, Lori L. 2021, 

e15061 

Hudson, M’Liss A. 4594 

Hudson, Malcolm e16501 

Hudson, Melissa M. 6030, 

9502, 9505, CRA9513, 

9526, 9527, 9531 

Huebner, Alexander e21044 

Huebner, Kay 1007 

Huellein, Jennifer 6519 

Huelsewig, Carolin e11534 


Hueltenschmidt, Beatrix 5512 

Huelves, Miriam e11035, 

e11527, e12015, e17502, 

e17503, e17515, e18011, 

e18521 

Huether, Robert 9518 

Huettmann, Andreas 8030 

Huges, Elisha 7023 

Huggins-Puhalla, Shannon 

Leigh TPS1138, 3054 

Hughes, Andrew M. e15141, 

e21037 

Hughes, Brett Gordon Maxwell 

7079^, 8538, e16501, 

e19642 

Hughes, David J. e12031 

Hughes, Kevin S. CRA1505 

Hughes, Lorie L. 1005 

Hughes, Lucinda 1517 

Hughes, Melissa E 599, 1125 

Hughes, Nicholas Peter 1066 

Hughes, Steven TPS4136 

Hughes, Timothy P. 6505^, 

6509^ 

Hughes-Davies, Luke TPS665 

Hugosson, Jonas 4668 

Huh, Joo Ryung e18501 

Huh, Sang Y. TPS3635^, 

7035 

Huh, Warner King TPS5115, 

e13087 

Hui, Ai-Min 8017, 8033, 

8034, 8064 

Hui, David 9002, 9023, 

9025, 9049, 9062, 9065, 

9069, e19528, e19584, 

e19602, e19603, e19613 

Hui, Edwin P. e14528 

Hui, Edwin Pun 5511 

Hui, Joyce e14528 

Hui, Pei 5099, e15581 

Hui, Rina 550 

Hui, Siu e16557 

Hui, Zhouguang e14511 

Huidobro Vence, Gerardo 

e18040, e18146 

Huijbers, Anouck e14151 

Huillard, Olivier e13017 

Huitema, Alwin D. R. e13028 

Huitema, Alwin D.R. 2550, 

2596 

Huizing, Manon Thirza 1129, 

e13051 

Hulin, Cyrille 8009, 8014 

Hulkki Wilson, Sanna e14088 

Hulshof, Maarten C. 4094 

Humblet, Yves 3502, 

e14044, e14060 

Humm, John 4517 

Hummel, Horst 8079 

Hummelen, Paul Van 5011 

Humphray, Sean 544 

Humphrey, TIM e13587 

Hundemer, Michael 6519 

Hunder, Naomi N. H. e13079 

Hung, Arthur 10011^ 

Hung, Mien-Chie 4624 

Hung, Shih-Kai e16008 

Hunger, Stephen 9506, 

9507, CRA9508, 9543, 

9548 

Hungria, Vânia Tietsche de 

Moraes 8095, e18572^ 

Hunt, Joanne 4553 

Hunt, Kelly 503, 1028, 

1102, 1107, 1130 

Hunt, Wendy 3039, e13604 

Hunter, Deborah S. 6514^ 

Hunter, Krystal 1127 


Hunter, Robert F. e14102 

Hunter, Terri B. 2559 

Hunter, Zachary R 8042, 

8106, 8107, e18575 

Hunter-Merrill, Rachel 4557 

Huntsman, David e14568 

Huo, Dezheng 1033, 1101, 

1116, 6040 

Huo, Lei 594, 1102 

Huober, Jens Bodo 523, 

1023 

Huppert, Nelly e11064 

Hur, Hyuk e14084 

Hur, Min Hee 1053 

Hurd, David Duane 6524^ 

Hurd, Ralph E. 4660 

Hurh, Eunju 9519 

Hurley, Judith 595, 608, 

1071, e11038 

Hurley, Laura 614 

Hurria, Arti 1010, 1070, 

6015, 9034, 9109, 9123, 

e18133, e19586 

Hurst, Deborah 6591 

Hurtubise, Brenda e19641 

Hurvitz, Sara A. TPS648, 

TPS649, 1037, 9144 

Hurwitz, Herbert 3039, 

3042^, 3614, e13589, 

e21038 

Husain, Amna 6039 

Husain, Amreen 5054 

Husain, Juhi e18535 

Husband, David J. e18068 

Huschens, Susanne 9114 

Huse, Jason T. 2028 

Hussain, Arif e13075, 

e15108, e15146, e15148 

Hussain, Maha 4, 4506, 

4511, 4513, 4547, 4549, 

4571, 4573, 4663, 10503 

Hussain, Raza e16043 

Hussein, Hany 9566 

Hussein, Hussein Soudy 

e15530 

Hussein, Lily 9085 

Hussein, Mohamad A. 8011, 

8016 

Husseini, Faress 2605 

Hussey, Juliette M. 1511 

Husson, Marie TPS10634 

Hutchison, Anne Smith 7094 

Hutchison, Robert E. 9524 

Huth, James F. 8534 

Hutson, Thomas E. 4501, 

4603, TPS4676, TPS4682, 

TPS4686, e15063, 

e15070, e15089 

Hutterer, Markus 2053 

Hutzschenreuter, Ulrich 

e14138 

Huyghe, Ivan 1129 

Huynh, Anne 6534 

Huynh, Hung The 4100^ 

Huynh, Thanh Khoa 10078 

Hwang, Clara 1560, e14160, 

e15174 

Hwang, Deok Won 7104, 

e16003, e18148 

Hwang, Eu-Chang e14649 

Hwang, In Gyu 4064 

Hwang, Jessica 9072, 

e19631 

Hwang, Jimmy J. 2590, 

3095, TPS3638, e14009, 

e14569, e14658 

Hwang, Jimmy 4102, e19046 

Hwang, Jin Wook e17523 

Hwang, Jun-Eul e14649 

Hwang, Larn e15542 

Hwang, Michael e14069, 

e14078 

Hwang, Rosa F. 1028 

Hwang, Scott N 3055 

Hwang, Seong-Geun e14504 

Hwang, Siok Gek Jacqueline 

5551, 5580 

Hwang, Tae-Ho e14566 

Hwang, Tsann-Long e20514 

Hwang, Wei-Ting 4596 

Hwang, Wenke 6052 

Hwang, William e18528 

Hwu, Patrick 2510, 8514, 

8551, e19009, e19014, 

e19039 

Hwu, Wen-Jen 2510, 8508, 

8514, e19009, e19014, 

e19039 

Hyland, Andrew 1529 

Hyland, John e13570, 

e21024 

Hylands, Lucy e13601 

Hyman, David Michael 5030, 

5043 

Hymes, Kenneth B. e21082 

Hyodo, Ichinosuke 4002 

Hyoju, Sanjiv Kumar e11094 

Hyseni, Entela 5093, 5094, 

e15551 

Hysert, Pat 1529 

Hyslop, Terry e15163 

Hyun, Eric D. 8584 

Hyung, Woo Jin e14504, 

e14652 

Hölscher, Arnulf H 4090 

Hölzle, Erhard 8505 

Hörsch, Dieter 4122, e14513 

I 

Iaccarino, Giancarla 8083 

Iacobucci, Ilaria 6531 

Iacono, Rosanne e11505 

Iacovelli, Roberto 4621, 4629 

Iadanza, Manlio e11071 

Iaffaioli, Rosario Vincenzo 

e14130 

Iaffaioli, Rosario Vincenz 

e11052, e13539 

Iafrate, A. John 6606, 7508, 

7589, 8522 

Iafrate, Franco e14096 

Iaiza, Emiliana 3612 

Iannacone, Claudio 7550 

Iannessi, Antoine e13547 

Iannone, Robert 10573, 

e13598, e13601 

Iannotti, Nicholas e13113, 

e18063^ 

Iasonos, Alexia 5030, 5090, 

5108 

Iau, Philip 1064 

IbañezdeCáceres, 

Inmaculada 3601, e14093, 

e14144 

Ibanez Martinez, Jose 4089 

Ibanez, Carlos E. 2101 

Ibarz, Luis 4579 

Ibeas, Patricia e11035, 

e11527, e12015, e17502, 

e17503, e17515, e18521 

Iberico, Carlos 2531 

Iborra, Severine 5007 

Ibrahim, Azman e18068 

Ibrahim, Fady 2098 

Ibrahim, Nageatte 8569 

Ibrahim, Nuhad K. 10613 

Ibrahim, Ramy A. 2503^ 

Ibrahim, Sherif Abdelaziz 

e21041 

Ibrahim, Toni 4627, 9005, 

10615, e11054 

Ibrahimi, Adil e14726 

Ibsen, Per 2069 

Ibusuki, Mutsuko e11017 

Ichida, Takafumi 4104 

Ichihara, Eiki 2607, 7576, 

e18027 

Ichikawa, Kimihisa e14516 

Ichikawa, Wataru 4012 

Ichikawa, Yasushi e14047, 

e14050 

Ichinose, Yukito 6112, 7003, 

7045, TPS7110, 7549 

Ichiyanagi, Osamu e15057, 

e15088 

Ichiyasu, Hidenori e18059 

Icli, Fikri 1572, 1596 

Ictech, Sandra 2029^, 2036 

Ida, Kohmei 9577 

Ida, Satoshi e13553 

Idbaih, Ahmed 2023 

Idelevich, Efraim e14571, 

e19529 

Idoate, Miguel A. 8572, 

e18008 

Idowu, Michael O 10565 

Idrees, Kamran e14184 

Ieguchi, Makoto 10073 

Iganej, Shawn e16031 

Igarashi, Kentaro 10075, 

e20505 

Igarashi, Seiji 7021 

Iglesias Dios, Jorge Luis 3093 

Iglesias, David A. e13516 

Iglesias, Lara 5516^ 

Iglesias, Mar 4089 

Ignatiadis, Michail 515 

Iguchi, Haruo 4031 

Iizasa, Toshihiko e21054 

Ijichi, Kei e16032 

Ikai, Iwao e14518 

Ikeda, Hideko e17540 

Ikeda, Masafumi 4031, 4042 

Ikeda, Norihiko 7012 

Ikeda, Satoshi e19583 

Ikeda, Takaya 7569 

Ikeda, Tetsuo e14536 

Ikeda, Yuji 5037, e15579 

Ikegame, Kazuhiro 6533 

Ikegami, Toru e14536, 

e14602 

Ikemura, Shinnosuke e18058 

Ikezawa, Kenji e14518 

Ikhlaque, Nadeem 4085 

Ikpeazu, Chukwuemeka 

e16001 

Ilagan, Venus M 8091, 9081 

Ileana, Ecaterina 4554 

Ilhan-Mutlu, Aysegul 2024 

Ilie, Marius 7591 

Illarramendi, Jose J. 10512, 

10595 

Illerhaus, Gerald 2040, 4090, 

8031 

Illidge, Timothy M 8056 

Ilson, David 4057, 4061, 

TPS4144 

Im, Annie P. 6563 

Im, Hae Kyung 9516, 

e11554 

Im, Ra Joo 1053 

Im, Seock-Ah 597^, TPS649, 

1003, 2542, 3076, 3624, 

4124, 10621, e11532, 

e14136, e21160 

737s

Im, Young-Hyuck 598^, 644, 

TPS649, 1003, 2542, 

e11055^ 

Imada, Toshio 4070 

Imai, Yukihiro 7528 

Imamura, Fumio 7028, 

e18007, e18025, e18134, 

e18141, e19556 

Imamura, Hiroshi 4012 

Imamura, Jun e14622 

Imamura, Takahisa e21084 

Imamura, Yoshinori e16034 

Imaoka, Hiroshi e14540 

Imbeaud, Sandrine e14059 

Imbert, Yves 9012 

Imbevaro, Silvia e15072 

Imoto, Shigeru 1106, 1119 

In, Reika 590 

Ina, Kenji TPS3642 

Inaba, Masaaki 1106 

Inaji, Hideo 540 

Inal, Ali 638, e14526 

Inamine, Morihiko 5086 

Inanc, Mevlude 638, e14089, 

e14526, e14670 

Inatani, Hiroyuki 10075 

Inatani, Michiyasu 3022 

Inauen, Roman Ignaz 3595, 

10033 

Inazawa, Johji 10520 

Incio, Jaoa 1026 

Inclan, Alejandro A. 1086 

Inculet, Richard I. 6049 

Indio, Valentina 10087 

Indresh, Desai e14675 

Indushekar, Subbanna 

e14721 

Infante, Jeffrey R. 2579, 

TPS2621, 3006^, 3008, 

3023, 3033, 3041, 3062, 

3067, 3077, 3097, 3102, 

TPS3118, 3528, 8510, 

8556, e13076, e13077, 

e13603 

Infante, Maurizio 7061 

Infanzon, Erick e12043 

Ingaramo, Maria Clara 

e13042 

Ingle, Ashish M 9500, 9540, 

9541, 9581 

Ingle, James N. 1005, 1006, 

10586, e13501 

Ingrosso, Antonella 7551 

Ingui’, Manuela 10055 

Inic, Momcilo e21136 

Inic, Zorka Momcilo e21136 

Inman, Brant Allen 4670 

Innocenti, Federico e13120^, 

e15086 

Innominato, Pasquale F. 

3547, TPS9154, e14006 

Inomata, Masafumi 3569 

Inou, Takashi e14004 

Inoue, Akira 7086, 7515, 

7563, 7565, 7571, 

e18129 

Inoue, Hiromi 4634 

Inoue, Hiroyuki e13014 

Inoue, Junichiro e17020 

Inoue, Kenichi 613 

Inoue, Masanori 7038 

Inoue, Takahiro 10520 

Inoue, Takayo 3086 

Inoue, Tomio 4626 

Inoue, Yasuhiro e14029, 

e14039, e14541, e21053 

Insa, Amelia 1074 

Intra, Mattia 1115 

Inukai, Michio TPS3642 

Inwards, David James 9057 

Inzerillo, John J. e13109 

Ioakimidis, Leukothea I 

e18575 

Ioffe, Olga B. 1519, 10572 

Ioka, Tatsuya 4031, 4035, 

e14518 

Ionescu, Diana 549^, 7020 

Ionta, Maria Teresa e14094 

Iop, Aldo 586, e11071 

Ippolito, Massimo e18096 

Iqbal, Hassan e16043 

Iqbal, Mudassar 6612 

Iqbal, Omer M. e15538 

Iqbal, Sheikh Usman 3602, 

e14028, e14030, e14061 

Iqbal, Syma 3584, 3622, 

4019, 4096, 4113, 

e13084, e14031, e14679 

Iqbal, Zafar 6612 

Irmscher, Romy e14630 

Iro, Heinrich 5512 

Irrera, Giuseppe e18564 

Iruarrizaga, Eluska e11525, 

e17522, e18031 

Irvin, William Johnson 

TPS656 

Irwig, Michael 2532 

Irwin, Blair Billings 6041 

Irwin, Melinda TPS669, 

TPS1614, 9007 

Isa, Luciano 9120 

Isa, Shunichi 7000, e18126, 

e18128 

Isaacs, Claudine 1521 

Isaacson, Jeffrey D. 4041, 

e13028 

Isabel Gil Garcia, Maria 

e14097 

Isacoff, William H. e14582 

Isada, Akira e18135 

Isaka, Keiichi 10557 

Isakoff, Steven J. 508, 510, 

1006, 1009, 1026, 3021 

Isambert, Nicolas 3026, 

10014, 10020, 10042, 

10056, 10062, 10078, 

TPS10102^, e13009, 

e13010 

Isdale, Debora 4098 

Isenberg, Gerald 3621 

Isenring, Elizabeth e19550 

Ish-Shalom, Maya 4564, 

4619, e15058 

Isham, Crescent R 5544 

Ishibashi, Olivia 9557 

Ishida, Hiroo e13029 

Ishida, Tadashi 7528, 

e18025 

Ishida, Takanori e11530 

Ishida, Tsuyoshi 9574 

Ishido, Kenji 4046 

Ishigami, Hironori e14530 

Ishiguro, Hiroshi e21052 

Ishihara, Shinichi e18037 

Ishii, Genichiro 1552, 7044, 

e17554, e18064 

Ishii, Hiroshi 4031, e14506, 

e14677 

Ishii, Mari 10577 

Ishii, Takeshi 9574 

Ishii, Yoshiki 7561 

Ishii, Yoshiyuki 10531 

Ishikawa, Takashi TPS1141, 

e14047 

Ishikawa, Toshiaki e14127 

Ishikawa, Yuichi 3625, 

10541, e18017 

Ishikura, Satoshi 7017, 

7028, 8050 

Ishimori, Ayako e18019 

Ishimoto, Osamu 7086, 

7561, 7565, e19521 

Ishimoto, Takatsugu 10523, 

e13553 

Ishioka, Chikashi e19611 

Ishioka, Kouta e18058 

Ishioka, Tatsunari e13076 

Ishitobi, Makoto 1103 

Ishizawa, Kenichi 8029, 

8050 

Ishizuka, Naoki 8050, 

e15004 

Isidoro, Miguel e13119 

Isikdogan, Abdurrahman 638, 

e14526 

Isla, Dolores 1531, 7095, 

e12000, e12012, e18055, 

e18131 

Islam, Nahida 8080 

Islam, Rezwan e14008 

Ismaeel, Fakher e19597 

Ismael, Gustavo e11087 

Ismail, Jeffri R. M. e16506 

Ismail-Khan, Roohi 1585, 

TPS2620 

Isobe, Hiroshi 7070, 7515, 

7571, e18129, e18135 

Isobe, Kazutoshi e18127 

Isobe, Takeshi e13072 

Isobe, Yasushi 8050 

Isogai, Pierre K e15180 

Isonishi, Seiji 5003 

Israel, Robert Joseph 4662 

Issa, Amalia M. 6005 

Issa, Djamila e16526 

Issa, Jean-Pierre 5524 

Issels, Rolf D. 10054 

Istomin, Yuriy e20514 

Isu, Kazuo 9574 

Itakura, Haruka e21153 

Itakura, Meiji e21054 

Italiano, Antoine 9536, 

10005, 10006, 10014, 

10023, 10027, 10035, 

10042, 10057, 10062, 

10078, e13594 

Itano, Osamu e14080 

Itano, Satoshi e14080 

Ito, Kenichiro 7571 

Ito, Tatsuo 7578 

Ito, Tomoaki e14139 

Ito, Toshikazu 1119 

Ito, Yoshinori 540, TPS659, 

e19512 

Itoga, Sakae 7046 

Itoh, Kuniaki 585, 8050 

Itoh, Kyogo e13046, e13050 

Itoh, Norimasa e18126 

Itokazu, Gail 8085 

Itri, Loretta 1016, 2555, 

4077 

Itsura, Peter 5107 

Ittmann, Michael M. 4643 

Iturbe, Julian e11021 

Itwaru, Sandy Ann e15140 

Itzhaki, Aviran e14616 

Ivancic, David 518 

Ivanov, Krasimir e21100 

Ivanov, Roman A. 9060 

Ivanov, Sergey TPS4692^ 

Ivanova, Anastasia e13074 

Ivanova, Ivayla 10521 

Ivanovic, Marija 5050 

Ivanyi, Philipp e15190 

Iversen, Helle K. 2069 

Iversen, Trine Zeeberg 2565, 

2574 

Ives, Denise I. e14611, 

e14665 

Iveson, Timothy 2535, 2594, 

LBA4000, 4005 

Ivey, Alison TPS4136, 

e14612 

Ivy, S. Percy 2009, 2606, 

3078, 3082, 3101, 5019, 

10004 

Iwae, Shigemichi 5542 

Iwagami, Shiro 10523, 

e13553 

Iwai, Toshiki e18091 

Iwai, Toshinori 5556 

Iwakuma, Nobutaka e13046, 

e13050 

Iwamoto, Shigeyoshi TPS3642 

Iwamoto, Takayuki 545, 

1012, 1047 

Iwanaga, Ichiro e14062 

Iwasa, Satoru e14126 

Iwasaki, Masashi e21004 

Iwasaku, Masahiro 7528, 

e18025, e18134 

Iwasashi, Hajime e19508 

Iwase, Hiroaki e14596 

Iwase, Hirotaka 540, e11017 

Iwata, Hiroji 512, 540, 

TPS661, TPS670 

Iwatani, Tsuguo 591 

Iwatsuki, Masaaki 10523, 

e13553 

Iyengar, Neil M. 6582, 

10618 

Iyer, Gopa 4527, 4581^, 

5030 

Iyer, Renuka V. 4038, 

e14610, e14659, e14690 

Iyer, Shrividya 7533, 7596, 

e16570 

Iza, Estibaliz e17522 

Izarzugaza, Yann 5520, 

e15094, e18069, e18106, 

e21015 

Izetti, Patricia e13546 

Iznaga, Normando 2515 

Izquierdo, Angel 1588, 

e12012 

Izrailov, Roman e14717 

Izumi, Namiki 4104 

Izumi, Tetsuta 1103 

Izumi, Yotaro 7038 

Izzo, Francesco e14130, 

e14654 

J 

Jabbour, Abdo e20500 

Jabbour, Elias 6501, 6527, 

6544, 6577, 6585, 6587, 

6589, 6592, 6594, 6597, 

6603, 6607, TPS6635 

Jabbour, Melhem Salim 9110 

Jabbour, Nicola e11097 

Jabbour, Salma e14555 

Jabel, Nicole e16565 

Jac, Jaroslaw TPS1143, 

e13040 

Jaccard, Arnaud 8026 

Jacene, Heather A. 8552 

Jackisch, Christian 640, 

1023, e11040^ 

Jackman, David Michael 

7524, 7525, 7547, 7553, 

7556, 7579, 7588, 10592 

Jackson, Alan e14015 

Jackson, Erica TPS2620 

Jackson, Gilchrist L. 8543 


Jackson, Graham H. 8015 

Jackson, Jessica 4085, 

e14564 

Jackson, Marianne 6093 

Jackson, Nadine 4027 

Jackson, Vicki A. 6004, 

6048, 6106, 9004, 9101 

Jacob, Linu Abraham TPS649 

Jacob, Rojymon e14555 

Jacob, Simon 634 

Jacobi, Oded e13018 

Jacobs, Andrew 9113 

Jacobs, Benjamin e16022 

Jacobs, John Robert 5534, 

e16019 

Jacobs, Linda A. 9145 

Jacobs, Lisa K. 518, 1128 

Jacobs, Paula M. 2077 

Jacobs, Samuel A. 611, 1025 

Jacobs-Small, Mona 4111, 

7077 

Jacobsen, Anne-Birgitte 

e14531 

Jacobsen, Britta M. 564 

Jacobsen, Tove Flem 6619^ 

Jacobson, Kristine B e21060, 

e21111 

Jacobus, Laura S. 8061 

Jacobus, Susanna J. e15170 

Jácome, Alexandre A.A. 

e14599 

Jacot, William 568^ 

Jacquemier, Jocelyne 543 

Jacquet, Alexandra 5069 

Jadhav, Nitin 3011 

Jaeckle, Kurt A. 2004, 2015, 

2031, 2032, e16569 

Jaeger, Bernadette Anna 

Sophia 554, TPS1146, 

1602, 10540 

Jaeger, Ulrich 8058 

Jaekel, Nadja TPS6642^ 

Jaen, Ana 10608, e11535, 

e21088 

Jaen, Juan C. 2043, e13580 

Jaffa, Ariel J. 1564 

Jaffa, Zachary 5582 

Jaffe, Elaine S. 2528, 8051 

Jaffee, Elizabeth M. e14585 

Jafferji, Insiya e13500, 

e21029 

Jafri, Syed Faisal e14632 

Jafri, Syed Hasan Raza 

e16009 

Jagannath, Sundar 8011, 

8016, 8020, 8035, 

e21006 

Jagdt, Bjoern e14103 

Jager, A. 10504, e16526 

Jagiello Gruszfeld, Agnieszka 

I. 10582 

Jaglal, Michael 2099, 

e21123 

Jaglowski, Samantha Mary 

6508 

Jagtap, Deepa e17528 

Jahagirdar, Balkrishna N. 

5566 

Jahan, Thierry Marie 3058, 

7030 

Jahanzeb, Mohammad 605, 

TPS1137 

Jahn, Franziska e19579 

Jahn, Thomas Michael 6518^ 

Jahng, Patrick e16523 

Jahnke, Kristoph 2040, 2054 

Jaimes, Natalia e19052 

Jain, Alka e13042 

Jain, Amit 4598 


Jain, Kunal e19550, e19622 

Jain, Minish Mahendra 2592, 

3011, e13127 

Jain, Nitin 6535^, 6582, 

e14609 

Jain, Pooja e18068 

Jain, Prantesh 1611 

Jain, Rakesh K. 1026, 2009, 

2010, 2012, 2025, 4112 

Jain, Salvia Sanjay 5016 

Jain, Shivi 8085, e14186, 

e14590 

Jain, Supriya K. e11512 

Jain, Vinay Kumar 8081 

Jaiyesimi, Ishmael A. 628, 

e14608, e17015 

Jajac Brucic, Lana e15031 

Jajeh, Ahmad e18510 

Jakesz, Raimund 514, 10501 

Jakic Razumovic, Jasminka 

e21126 

Jakkoju, Rakesh 8536, 

e15181 

Jakob, Andreas e15044 

Jakob, Augustinus TPS4148 

Jakob, John Andrew 8584 

Jakobsen, Anders Kristian 

Moeller 3513, 3573, 5052, 

e14134 

Jakobsen, Erik 7026 

Jakobsen, Jan Nyrop 7001 

Jakovljevic, Ksenija e12020 

Jakowatz, James G. 8524 

Jakubowiak, Andrzej J. 8011, 

8020, 8035, TPS8114 

Jakubowski, Loni 3057 

Jalal, Prasun 4116 

Jamal, Rahima 2547 

Jamal-Hanjani, Mariam 3100 

Jamaluddin, Muhammad 

Faisal e14687, e19059 

Jamaluddin, Nimah e15528 

James, Danelle Frances 6507, 

6508, 6515^ 

James, Iain 10553 

James, Katherine 6126 

James, Michelle D 3516 

James, Nicholas David 

e15091 

James, Ralph e21026 

James, Roger 4004, 4029 

James, Samuel e15582 

Jameson, Gayle S. 2516 

Jameson, Michael B. e15054 

Jamieson, Rebekah 10563 

Jamoul, Corinne 8559 

Jamshed, Arif e16043 

Jamshed, Saad e18558 

Janakiraman, Manickam 4527 

Janas, Mette S. TPS9149^ 

Janelsins, Michelle Christine 

9009, 9010, 9028, 9141, 

9142 

Janevski, Angel 10508 

Janeway, Katherine A. 9503 

Jang, Geundoo 4093 

Jang, Hee-Jin e16534 

Jang, Raymond Woo-Jun 

e14003 

Jang, Se Jin 3568 

Jang, Sekwon e19000, 

e19025 

Jani, Ashesh B. e15006 

Janik, John E. 8051 

Janjigian, Yelena Yuriy 4057, 

4061, TPS4144, 7580, 

9105, e14586 

Jankilevich, Gustavo e15521 

Jankovic, Radmila e12020 

Jankowitz, Rachel Catherine 

611 

Jankowski, Janusz LBA4001 

Jankowsky, Rüdiger 4115 

Janku, Filip 3023, 3106, 

3107^, TPS3117, 8551, 

10510, 10607, e13020, 

e13534, e13595 

Janne, Pasi A. 7010, 7503, 

7547, 7588, TPS7615, 

e18093 

Janne, Pasi Antero 7007, 

7510, 7530, 7553, 10592 

Janni, Johann Wolfgang 

TPS1146, 5097, e11556 

Janni, Wolfgang 554, 1072, 

1081, 1090, 1600^, 1602, 

10540, 10599, e21020 

Janot, Francois e16013 

Jansen, Jeroen P. e19010 

Janson, Eva Tiensuu 4015 

Janssen, Eva e19031 

Janssen, Jan e15044 

Janssen, Marc e15166 

Jantus-Lewintre, Eloisa 7058, 

7060, 10594 

Janus, Cecile P 8039 

Janus, Nicolas 1095, 5067 

Janz, Nancy K. 6023, 6024 

Jara-Sanchez, Carlos e11535 

Jarabo, Jose Ramon 10564 

Jarboe, Jamie 4117, 4545 

Jardel, Henry 8014 

Jardine, Victoria L e18100 

Jares, Pedro 3553, e14041 

Jariwala, Krutika e16527 

Jarkowski, Anthony e19041 

Jarlenski, Donna 4056 

Jarnagin, William R. 3577, 

3620 

Jarner, Mikala F. TPS9149^ 

Jarosz, Bozena 603 

Jarosz, Mirna 3533 

Jarrar, Doraid 7051 

Jarrett, Lee Ann e16038 

Jarzab, Barbara 5508, 5518, 

5591, e14159 

Jarzab, Michal e14159, 

e21049 

Jaskowiak, Nora T. 1101, 

1116 

Jaspan, Tim 9517, TPS9596 

Jasra, Sakshi e16565 

Jassem, Ewa 10561 

Jassem, Jacek 505, 603, 

TPS649, 4050, 9046, 

10561, e21099 

Jasso Mosqueda, Juan 

Guillermo e14061 

Jatoi, Aminah 5076, 7605 

Java, James 5056, 5057 

Javed, Yasir Ahmed TPS1137 

Javle, Milind M. 4038, 4054, 

e19645 

Javvadi, Prashanthi 10624 

Jaw-Tsai, Sarah e13028 

Jawed, Irfan e14064 

Jawlekar, Gajendra 3013 

Jaworska, Magdalena e21099 

Jayabalan, David 8036 

Jayachandran, Aparna 8542 

Jayakumar, Arumugam 

e18557 

Jayanti, Venkata K e14640 

Jayaprakash, Nalini 6530 

Jayaram, Anuradha e14687, 

e19059 

Jayasekera, Jinani e15146 

Jayasuriya, Chami e16567 

Jayson, Gordon C. e14015 

Jean, Annie 564 

Jeannet, Laëtitia 8089 

Jeannin, Gaelle 7503 

Jeannon, Jean-Pierre 5522 

Jedrzejczak, Wieslaw W. 

e18572^ 

Jeffers, Michael 3019, 

e13576, e18100 

Jefford, Michael 3504, 6111, 

9087, e16507 

Jego, Virginie 3107^ 

Jehn, Christian e14140 

Jelaca-Maxwell, Kathy 4568 

Jelinek, Jaroslav 5524 

Jelovac, Danijela 5062^ 

Jemal, Abdusebur 9555 

Jemming, Chloé 2605 

Jenkins, Emily Oldham 1524 

Jenkins, Marjorie e21105 

Jenkins, Robert B. 2008b, 

4009, 4565 

Jenkins, Valerie A 5527 

Jennings, Dominique 2009, 

2025, 3036 

Jenny, Matthias e13508 

Jensen, Anni Ravnsbæk 

e14063, e14105 

Jensen, Brett T e15124 

Jensen, Gail e18144 

Jensen, Helle Anita e14517 

Jensen, Kristian e21129 

Jensen, Kurt S. 2069 

Jensen, Lindsay G e14555 

Jensen, Roxanne E 9130 

Jensen, Steen Lindkaer 

e11022 

Jeon, Eun Kyoung e14634, 

e18050 

Jeon, Justin Y e14114 

Jeon, Mijin 6564 

Jeon, Ung Bae e14566 

Jeon, Yoon-Kyung 7566 

Jeon, Young Woo e19554 

Jeong, Deok Hyun e14114 

Jeong, Jae-Heon e14128 

Jeong, Jong-Hyeon TPS1142 

Jeong, Seong Hyun e18519 

Jeong, Seung-Yong 3624 

Jephcott, Catherine Rachel 

e14100 

Jerin, Lems 9097 

Jerkeman, Mats 8074 

Jeruss, Jacqueline Sara 

TPS1134 

Jeschke, Udo e15529 

Jeter, Stacie 518, 9103, 

10509 

Jethwa, Alexander 6519 

Jett, James R. 7605 

Jeung, Hei-Cheul e14652 

Jewell, Andrea e15548 

Jewett, Michael A. S. 4500, 

4633, e15118 

Jewett, Michael A 4535 

Jewitt, Natalie C. 2063 

Jeyabalan, Neera e14001 

Jeziorski, Arkadiusz e19022 

Jha, Gautam Gopalji e15211 

Jhaveri, Komal L. 10618 

Ji, Fei 2503^, TPS2621 

Ji, Jianfei 2087 

Ji, Jiuping Jay 3031, 5020 

Ji, Jun Ho e14072, e16003, 

e18148 

Ji, Lingyun 1065, 1124, 

e13084, e19506 

Ji, Qinghai e16039 

Ji, Rui-Ru 8593 

739s

Ji, Yongling e17527 

Jia, Jingquan e13589 

Jia, Wang Xiao e17512 

Jia, Xiaoyu 4517, 4532 

Jia, Zhen 10567, e11567, 

e11568 

Jian, Hou 8095 

Jian, Weiguo e15002 

Jiang, Bin 9017 

Jiang, Brittany 5575 

Jiang, Chen 2533 

Jiang, Chunsheng 1091, 

e21146 

Jiang, Dingfeng 6034 

Jiang, Guanchao e17504, 

e21103 

Jiang, Haiyan 9131 

Jiang, Haoyuan 7548 

Jiang, Jing 7062 

Jiang, Ming e18514 

Jiang, Ping 2579 

Jiang, Qin 3090 

Jiang, Su 9017 

Jiang, Wen-chang e14668 

Jiang, Xuejuan 4575 

Jiang, Yixing TPS1138, 2553, 

3049, 3054 

Jiang, Yizhou 2535, 2594, 

4005 

Jiang, Yong Jian e14651 

Jiang, Yuqiu 10504 

Jiang, Zefei e13036 

Jiang, Zhi-Qin 3561, 3598, 

e14071 

Jiao, Wei e13107 

Jiao, Xiaolong 570 

Jibara, Ghalib e14656 

Jibb, Lindsay 9556 

Jie, Fei 8587 

Jie, He e14502, e18013 

Jilla, Swapna 9055 

Jillella, Anand P. 6573, 8108 

Jimenez, Camilo 4641, 

e13592 

Jimenez, Connie R. e18094 

Jimenez, Joaquin J e14593 

Jimenez, Jose 7041 

Jimenez, Laura 3096 

Jimenez, Marta 10035 

Jimenez, Paula TPS4685, 

TPS4688, 10546, e14671, 

e15144 

Jimenez, Rachel e16500 

Jimenez, Ulpiano 7011 

Jimenez, Valerie 8089 

Jimenez-Baranda, Sonia 8571 

Jimeno, Antonio 2567, 2568, 

3017, 3024, LBA5000, 

e13048 

Jin, Bo e18038 

Jin, Chen e14651 

Jin, Denise 2567 

Jin, Feng 5535 

Jin, Kate 7519^ 

Jin, Mei Hua 8099 

Jinno, Hiromitsu 1106, 

10531, e11060, e14080 

Jirillo, Antonio e15072 

Jitawatanarat, Potjana 

e18538 

Jo, Booil 9051 

Jo, Deog Yeon e14529 

Jo, Jungmin e11508 

Jobe, Blair A e14689 

Jobkar, Terri L. 8011 

Jobo, Toshiko 5003 

Jodrell, Duncan Ian 3100 

Joe, Andrew K. 8502^, 

8503^, TPS8603 

Joe, Teresa 4643 

Joens, Thomas e15531 

Joensuu, Heikki 507, 

TPS647, LBA10008 

Joensuu, Timo K. e13035 

Joergensen, Jens Christian 

Riis e14134 

Joergensen, Stine 3513 

Joffe, Steven 1605 

Johal, Balvindar Singh 

e14176 

Johannessen, Dag Clement 

LBA4512, 4551 

Johansen, Cathrine e14637 

Johansen, Julia S. 3548, 

8545 

Johansson, Carolina 8588 

Johansson, Harriet Ann 519 

John, Esther M 1502 

John, Sonia e17010 

John, Tom e17539 

John, William J. LBA4, 1068, 

7075, LBA7507, e18138 

Johne, Andreas 3107^ 

Johns, Amanda L. 5014 

Johnson, Amy J 6507, 6508 

Johnson, Ana TPS5600 

Johnson, Brendan Mark 9117 

Johnson, Bruce E. 7525, 

7588, 7589, 10592 

Johnson, Bruce E 7099, 

7547, 7553 

Johnson, Candace S. e18118 

Johnson, Catherine 1013, 

1098 

Johnson, Dave 6518^ 

Johnson, David B. 6133 

Johnson, David H. 6068, 

7094, 7568 

Johnson, Derek Richard 2065 

Johnson, Doug 6102 

Johnson, Frank E. 6079, 

6081, e15528, e19593 

Johnson, Jeffrey L. 6526, 

8000 

Johnson, John R 3074 

Johnson, Jonas Talmadge 

8533 

Johnson, Karen 1501, 

e14005 

Johnson, Laureen 3013 

Johnson, Maureen 6086 

Johnson, Melissa Lynne 3083, 

7580 

Johnson, Nathalie 9019 

Johnson, Peter W. M. 8056, 

TPS10633^ 

Johnson, Philip James 4033, 

TPS4150, e13507 

Johnson, Russell F. e16513 

Johnson, S e13522 

Johnson, Valen E. 8091, 

9081, 9083 

Johnson, William 593 

Johnsson, Anders 3573 

Johnston, Claire 2552, 3030 

Johnston, Curtis 5523 

Johnston, Donna 9556 

Johnston, Gregory 3619, 

e14046 

Johnston, Mary Ann e19582, 

e19585 

Johnston, Patrick B. 8028 

Johnston, Richard 4669, 

e15207 

Johnston, Stephen R. D. 531, 

TPS661, TPS666, 

TPS10633^ 

Johnston, Tammie e21026 

Johnston, Taren A 5027 

Johnstone, David 7022 

Jolivet, Jacques 4105, 

e14706 

Jolly, Damien 1584 

Jolly, Douglas J. 2101 

Joly, Bertrand 8026 

Joly, Florence 636, 2583, 

LBA4567^, LBA5000, 

e14650, e15535 

Joly, Katelle e11019 

Jonak, Zdenka 5065 

Jonasch, Eric 4503, 4609, 

4615, 4624, 9029, 

e15075, e15092 

Jonat, Walter 1084, e13503 

Jones, Cheryl 2566 

Jones, Chris TPS9596 

Jones, Daniel 8596 

Jones, David R 7008 

Jones, David 3057 

Jones, Dennie V. 5549 

Jones, Desiree 6551, 9118 

Jones, Emma 3008 

Jones, Frank 2585 

Jones, Glenn e19570 

Jones, Heather L e14184 

Jones, Howard e15582 

Jones, Jeffrey Alan 6508, 

e18508 

Jones, Jennifer M 9131 

Jones, Jeremy e15084, 

e15178 

Jones, Julia J 10050 

Jones, Keith 3022 

Jones, Kimberly 4048 

Jones, Louise K. TPS10633^ 

Jones, Mark M. 6559, 6627, 

6632 

Jones, Mary Elizabeth 3027 

Jones, Natalie Beckman 1125 

Jones, Richard 7562 

Jones, Robert J. 4558 

Jones, Robert Peter 3613 

Jones, Robert T. 2020 

Jones, Robin Lewis 10011^, 

10039, 10086, TPS10099 

Jones, Roy B. 4533, 8102 

Jones, Sarah TPS8605 

Jones, Siân 3068 

Jones, Suzanne Fields 3008, 

3033, 3041, 3067, 3097, 

e13076 

Jones, Suzanne 3006^, 3021 

Jones, Tamekia 9548 

Jones, Terence 5543 

Joniau, Steven e13061 

Jonker, Derek J. 3504, 3515, 

3572, e14154 

Jonnalagadda, Sreenivasa 

e14584 

Jonsson, Håkan 4668 

Jonsson, Olafur G. 9590 

Jonstam, Gustaf 4561 

Joo, Jungnam e16534, 

e18119 

Joo, Sam e17009 

Jooss, Karin 2562 

Joosten, J J.A. 7009 

Jordan, Berit e19579 

Jordan, Emmet 1543, 

e21147 

Jordan, Karin e19579 

Jordan, Mary Ann e19571 

Jorgensen, Jeffrey L. 6501 

Jorissen, Robert N 3623 

Jose, Chakiath TPS4690 

Joseph, David John TPS4690 

Joseph, Kathie-Ann P. 

e11004 

Joseph, Kurian e15540 

Joseph, Lindsay J. TPS2621 

Joseph, Loren 6562 

Joseph, Mathew John 7035 

Joseph, Richard Wayne 8590 

Joseph, Vijai e15022 

Joshi, Alaknanda 10532 

Joshi, Amit 5585, e16028, 

e17500 

Joshi, Brijen L 6067 

Joshi, Monika e17560 

Joshi, Nikhil Purushottam 

2072 

Joshi, Rohit e19513 

Joshua, Anthony Michael 

4514, e15118 

Joshua, Anthony TPS4695 

Jotereau, Francine 2570 

Jotte, Robert M. LBA4, 3023, 

7541 

Jouannaud, Christelle 1051, 

1095, 5067 

Jouary, Thomas LBA8500^, 

8532, 8559, 8591 

Joubert, Warren Lance 3572 

Joulain, Florence 3602 

Jouravleva, Elena e13562, 

e21058 

Jouret-Mourin, Anne e14044, 

e14060 

Jouvet, Anne 2023 

Jouybari, Touraj 6556 

Jovanovic, Borko 8080 

Jove, Jeremy e14168 

Jovic, Gordana 10081 

Jozefara, Jolanta 1127 

Jozwiak, Sergiusz 10619 

Ju, Gui-zhi e13558 

Ju, Melody e12009 

Ju, Xiaoming e13545 

Ju, Yan 10543 

Juan Vidal, Oscar 4587, 

e15144, e17545, e18049 

Juan, Gloria 3580 

Juan, Oscar e18015, e18053 

Juarez, Eva e19594 

Jubb, Adrian M. 1066 

Juckett, Mark 6570 

Judde, Jean-Gabriel e15161 

Judge, Joshua Marshall 

e19062 

Judson, Benjamin 5529, 

5532 

Judson, Ian Robert 10009, 

10013, 10038, 10039, 

10060, 10067, 10086 

Judson, Patricia Lynn 5054 

Judy, Brendan 7595 

Jueckstock, Julia Kathrin 

1081, 5007 

Juergens, Herbert 10080 

Juergens, Rosalyn A. e18147 

Juez, Ignacio 4079 

Juhasz-Boess, Ingolf 1523 

Juhn, Frank 3533 

Julian, Jim A LBA1031, 6049 

Julian, Thomas B. TPS657, 

1025 

Julier, Patrick LBA4001 

Julka, Pramod Kumar 2072, 

e11082, e15518 

Juma, Matthews TPS6638 

Jumonville, Alcee 6074, 

6570 

Jumper, Cynthia A. e21105 

Junecko, Beth Fallert 8528 

Jung, Ah Rang 6564 


Jung, Andreas 3519^ 

Jung, Eun-Jung 4124 

Jung, Hwoon-Yong 4093 

Jung, Hyun Ae e16003 

Jung, Kyung Hae 1003, 

2542, e11504, e11508, 

e13104 

Jung, Minkyu TPS4142, 

e14137, e14652, e14685 

Jung, Sin-Ho 8000 

Jung, Su Yon 1085, 1589 

Jung, Yun Hwa e14558 

Jungberg, Peter e19540 

Jungbluth, Achim A 2589, 

TPS8111, e17558 

Junker, Niels 2574 

Junqueira, Manuela Jacobsen 

575 

Junqueira, Maribel e15114 

Jurado, Josefina Cruz 10052 

Jurcic, Joseph G. 6609, 6613 

Jure-Kunkel, Maria CRA2509, 

2511, 2521, TPS2613, 

8593 

Juretic, Antonio e21126 

Juretic, Manuela 3039 

Juric, Dejan 2567, 2568, 

e13048 

Jurkowska, Monika 8548, 

e19022 

Jusko, William J e13006 

Just-Landi, Sylvaine e15155 

Justus, Jacob 1562 

Juvekar, S 5585, e16028 

Juwara, Lamin 3529 

Jürgensmeier, Juliane M 

e13541 

Jäger, Elke 4080, 4083, 

4090, e14557 

Jäger, Michael 2584 

Jänicke, Martina e14138 

Jöhrens, Korinna e15053 

Jönsson, Mattias e13518 

K 

K, Jagannathrao Naidu 

e12501 

Kaasa, Stein e19648, 9040 

Kaatsch, Peter 9573 

Kabata, Hiroki e18058 

Kabbinavar, Fairooz F. 

e13045 

Kabbinavar, Fairooz 3614, 

TPS4683, TPS4686 

Kaburagi, Takayuki 7012 

Kaburaki, Kyohei 10569, 

10604, e18004, e18014, 

e18017 

Kacan, Turgut e16005, 

e19575 

Kacel, Elizabeth L 9146 

Kachnic, Lisa A. 4030, 

TPS9150 

Kadalayil, Latha 4004, 4029 

Kadambi, Ananth 6553 

Kadan-Lottick, Nina 9546 

Kadar, Lianna e14531 

Kadia, Tapan M. 6517, 6528, 

6558, 6587, 6589, 6592, 

6597, 6607, TPS6635 

Kadlec, Adam e16544 

Kadlec, Bohdan e18062 

Kadlubek, Pamela CRA1505, 

e16532 

Kadowaki, Shigenori e14038 

Kadowaki, Tadashi 5518, 

e13511, e19055 

Kaechele, Volker 4065 

Kaeding, Allison 9548 


Kaehler, Katharina K. 4034 

Kaempgen, Eckhart 8532, 

e19032 

Kaen, Diego e14521 

Kaen, Luis Alberto e14521 

Kafka-Ritsch, Reinhold 

e14719 

Kafri, Zyad 5534 

Kaga, Kichizo e17520 

Kagami, Yoshikazu 8050 

Kager, Leo 10081 

Kageyama, Shinichi e19546 

Kahan, Zsuzsanna TPS661, 

9046 

Kahatt, Carmen Maria 

TPS652, 2539, e15001 

Kahl, Brad S. 8003, 8007 

Kahlert, Steffen 1114 

Kahn, Daniel e13117, 

e15008 

Kahraman, Deniz 3044, 7603 

Kai, Kazuharu 1047 

Kai, Yuki e13072 

Kaidar-Person, Orit e18511 

Kaira, Kyoichi e18037 

Kaiser, Brianne e13025 

Kaiser, Karen 9056 

Kaiser, Ulrich 3 

Kaji, Reiko 7528, 10610 

Kajiura, Shinya e14038 

Kajiura, Yuka 590 

Kakehi, Yoshiyuki e15127 

Kakeji, Yoshihiro 3558, 

e14033, e14601 

Kakizume, Tomoyuki 3088^ 

Kaklamani, Virginia G. 610, 

TPS1134, 1561 

Kako, Severine e21018 

Kakolyris, Stylianos e14567, 

e17553 

Kakudo, Yuichi e19611 

Kakumanu, Ankineedu 

Saranya 2051 

Kakuske, Jennifer C e16010 

Kalac, Matko e13569 

Kalachand, Roshni Deepa 

e15016 

Kalambakas, Stacey 9519 

Kalanovic, Daniel 4631, 

e19502 

Kalaw, Emarene 8078, 

e18515 

Kalaycio, Matt E. 6509^, 

8055 

Kalbacher, Elsa 10042 

Kalbakis, Kostas e18105 

Kaldate, Rajesh R. 1550, 

3627, e13047 

Kale, P. 3089^ 

Kale, Sule e21130 

Kalebic, Thea 3077, e13603 

Kalemkerian, Gregory Peter 

e18018, e18118 

Kaley, Thomas Joseph 2008 

Kalfin, Michael e16515, 

e16559 

Kalfoglou, Creton 10619 

Kalhor, Neda 7023 

Kalil, Karime 3544 

Kalinka-Warzocha, Ewa 603 

Kalinowski, Katherine H 

2074^ 

Kalinsky, Kevin 584, 8522, 

10516 

Kalirai, Helen 8523, 

TPS8605 

Kalkavan, Halime 2086 

Kalle, Christof V. 6519 

Kallen, Karl-Josef 2573^ 

Kallenberg, Kai 2079 

Kallender, Howard 4108 

Kalli, Kimberly 5076 

Kallur, Kumar G e11027, 

e12030, e14675, e14721 

Kalmadi, Sujith R. e18046 

Kalmanti, Maria e20002 

Kalnicki, Shalom e16058 

Kalofonos, Haralabos 9090 

Kalogeras, Konstantine T. 

592, e21018 

Kalpathy-Cramer, Jayashree 

2012, 2059 

Kaltman, Rebecca Davidson 

e11084 

Kam, Michael K. 5511, 

e15110 

Kamada, Yoshihiko e11530 

Kamai, Takao e15048 

Kamal, Arif e16556 

Kamal, Muna e15540 

Kamalakaran, Sitharthan 

10508 

Kamat, Ashish M. 4523 

Kamata, Minoru e14500 

Kamatani, Naoyuki 10520 

Kamba, Tomomi e15048 

Kambhampati, Suman 

e13568 

Kamdar, Manali K. e17008 

Kamei, Haruhito 7560 

Kamel, Ihab R. 4114 

Kamel-Reid, Suzanne 2051, 

5010, 5105 

Kamen, Charles e16564 

Kami, Kenjiro e14635 

Kamijo, Izumi e13508 

Kamimatsuse, Arata 9577 

Kaminski, Mark Stefan 8001, 

8011, e18530 

Kaminsky, Anna 1038 

Kaminsky, Michael S 1037 

Kamiyama, Toshiya 10578 

Kamiyama, Yukari 7021 

Kammerer, Klaus Peter 

e19533 

Kamp, Torsten G. 7572 

Kamphuisen, Pieter W 

TPS9149^ 

Kampletsas, Eleftherios 592 

Kampmann, Eric 10054 

Kamsu-Kom, Nyam e19022 

Kamura, Toshiharu 5006, 

5085 

Kanaan, Mohammed Nawaf 

3619, e14045, e14046, 

e15554 

Kanaan, Zeyad e17004 

Kanagavel, Dheepak e14623, 

e15029 

Kanai, Fumihiko e14622 

Kanai, Masashi e14518 

Kanakry, Jennifer Ann 8003 

Kanan, Sadhana e17003 

Kanani, Samir 3590 

Kanarek, Norma 1573 

Kanayama, Hiro-Omi e15068 

Kanazu, Masaki 10577 

Kanbara, Hisashige e21007 

Kanda, Jossi Ledo 5588 

Kandalaft, Lana 5023 

Kandasamy, Ravichandran 

e19524, e19526 

Kandilakis, Giannis 9033 

Kandrnal, Vit e11047, 

e11072 

Kane, Christopher J 4500 

Kane, John Michael e14172, 

e19041 

Kane, Michael P. TPS3112 

Kaneda, Hiroyasu e18060 

Kaneko, Masahiro 1530 

Kanemitsu, Yukihide 3524 

Kanerva, Anna e13035 

Kaneta, Toshikado 3088^ 

Kanetsky, Peter A. 1539 

Kang, Byung Woog 3554, 

6536, 6538, e14074, 

e14580, e18533 

Kang, Eunyoung 1056 

Kang, Gyeong Hoon 3624 

Kang, Haiyan 4008 

Kang, Hye Jin e14072, 

e14580 

Kang, Hyunseok e13110, 

e21045 

Kang, Jin Hyoung TPS7614, 

e13061, e14558, e14580, 

e18050 

Kang, Jung Hun 4064, 9065, 

e19603, e19613 

Kang, Min H 8073 

Kang, Moon Chul e17523 

Kang, Myoung Joo e14543 

Kang, Sanghee 2036 

Kang, Seok Yun 1003, 2542, 

TPS4142, e11559, e18519 

Kang, Soonmo Peter 2512, 

e13106 

Kang, Su-yi e14668 

Kang, Sung-Soo 1053 

Kang, Tae Ho 1053 

Kang, Tongjun 1592, 8038, 

9512 

Kang, Un-Beom 10621 

Kang, Won Ki 4011, 4064 

Kang, WonKi 10535, e13094 

Kang, Xinmei e11095 

Kang, Yoon-Koo 4082, 

LBA10008, 10085, 10093, 

e13092, e13104, e14543, 

e14617 

Kang, Young-Ah 6564 

Kangasniemi, Lotta e13035 

Kanji, Zaheer 4058 

Kankasa, Chipepo 9558 

Kankesan, Janarthanan 1583 

Kann, Lisa M. 3068 

Kannan, Sadhna 9559 

Kanner, Andrew TPS2106 

Kanno, Hitoshi e21108 

Kannourakis, George 

TPS4681 

Kano, Jessica e19570 

Kantarjian, Hagop 6501, 

6503, 6504, 6506, 6509^, 

6513, 6516^, 6517, 6520, 

6525, 6527, 6528, 6544, 

6558, 6559, 6576, 6578, 

6585, 6587, 6589, 6592, 

6596, 6597, 6603, 6604, 

6607, 6624, 6627, 6632, 

TPS6635 

Kantelhardt, Eva Johanna 580 

Kantoff, Emily 3105, 4048 

Kantoff, Philip W. 4543, 

4585, 4635, 4648, 4655 

Kantoff, Philip 4516, 4521, 

4582, 4662, 4667, 

e15170 

Kantor, Andrea TPS8602, 

e19046 

Kantor, Evan e14621 

Kanujia, Arti e13068 

Kanz, Lothar e15577 

Kanzler, Stephan TPS3641^ 

Kao, Johnny e15162 

Kapadia, Nirav S. 7037 

741s

Kaparelou, Maria 583 

Kapaun, Christine 3519^ 

Kaphan, Regis 6633 

Kaplan, Ellen B 4515 

Kaplan, Henry G. 6560 

Kaplan, Joseph 7587 

Kaplan, Lawrence D. 8005 

Kaplan, Muhammed Ali 

e14526 

Kaplan, Muhammet Ali 638 

Kaplan, Richard S. 3516, 

6091 

Kaplon, Rita 9544 

Kapoor, Nimmi S. 1105 

Kapoor, Prashant 8105 

Kapoor, Rahul e12014 

Kapoun, Ann 3025 

Kapp, Amy V. 3543, 3552 

Kapp, Daniel Stuart 10576 

Kapp, Kerstin 4636 

Kappauf, Herbert W. 3588 

Kappeler, Christian 4103 

Kappelmayer, Janos e21140 

Kapur, Payal 4616 

Kar, Niladri 2014 

Kar, Siddhartha P. 4054 

Kara, Ismail Oguz e13523 

Karaboué, Abdoulaye 3547, 

e14006 

Karaca, Halit e14089, 

e14670 

Karachaliou, Niki e18137 

Karagkounis, Georgios 3616 

Karahan, Vladislav B. e19012 

Karakasis, Katherine 5010 

Karakitsos, Petros e17553 

Karakousis, C. P. 8534 

Karakousis, Giorgos 

Constantine e19054 

Karam, Andre 3039, e13602, 

e13604 

Karamchandani, Jason 2043 

Karameris, Andreas e21098 

Karamlou, Kasra e11042 

Karampeazis, Athanasios 

7564 

Karanes, Chatchada 8038, 

8089 

Karanth, Siddharth 4130, 

4131 

Karaoglu, Aziz e15006 

Karapanegiotou, Lena 2530 

Karapetis, Christos Stelios 

3504, 3515, 3532, 

TPS4137, e13007, 

e17544, e19550 

Karaszewska, Boguslawa 9117 

Karavasilis, Vasilios e15040 

Karayan-Tapon, Lucie 3520 

Karayiannakis, Anastasios 

e14567 

Karcaaltincaba, Musturay 

e11509 

Kardinal, Carl G. 1586 

Kareb, Jacalyn e19588 

Karginova, Olga TPS656 

Karim, Shanaz e11533 

Karimi, Misagh e11562, 

e13003 

Karjalainen-Lindsberg, 

Marja-Liisa 8074 

Karkada, Mohan 2588 

Karl, Alexander 4530 

Karlan, Beth 5072 

Karlberg, Mia 3538 

Karlin, Nina J. 5544 

Karlov, Petr A 4503 

Karmakar, Parimal e13533 

Karmali, Rashida A. e15515, 

e19006 

Karmali, Reem e21069 

Karne, Sheetal 6615 

Karnes, R. Jeffrey 4565, 

4657 

Karol, Michael D. 3094 

Karp, Daniel D. 7608 

Karpov, Andrei 6064 

Karr, George e11569 

Karra Gurunath, Ravichandra 

8532 

Karrasch, Matthias 8002, 

8076 

Karrison, Theodore 2561, 

4022, 5500, 8075, 

e13106 

Karsh, Lawrence Ivan 4642 

Kartashov, Alex e11067 

Karthaus, Meinolf e11528 

Karthikeyan, Venkat 5540 

Karuturi, Meghan Sri e19603, 

e19613 

Karve, Sudeep 7101 

Karyakin, Oleg TPS4692^ 

Karzai, Fatima H 3043 

Kasahara, Kazuo e17540 

Kasahara, Takashi e15071 

Kasai, Takashi 7021 

Kasamatsu, Takahiro 5085 

Kasatkin, Vadim e20503 

Kaseb, Ahmed Omar 4116, 

e13020, e14664 

Kashani-Sabet, Mohammed 

8534 

Kashigar, Aidin 9032 

Kashiwa, Miyuki e17020 

Kashtan, Hanoch e14571 

Kashyap, Trinayan 1055, 

e13549 

Kasiborski, Fabrice 3052 

Kasimir-Bauer, Sabine 5042, 

10599 

Kasimis, Basil e14124, 

e14125, e14727, e18516, 

e19606, e19638 

Kasper, Hallie Bieber 9585 

Kasper, Stefan TPS3641^ 

Kasperzyk, Julie 4555 

Kasprowicz, Nikola S. 1072, 

1602, e21020 

Kass, Samantha Lindsay 

e19647 

Kassam, Alisha 9076 

Kassam, Zahra 6084 

Kassarjian, Ara 6136 

Kassem, Mohammed Azher 

9085 

Kassem, Nader e20500 

Kassem, Neemat e18570 

Kasseroler, Marie-Therese 

e14719 

Kaste, Sue 9527 

Kasubhai, Saifuddin M. 3543 

Kasuga, Akiyoshi 4046 

Kasymjanova, Goulnar 

e18061, e18098, e19626 

Katabi, Nora 5545^ 

Katagiri, Katsunori e16020 

Katai, Hitoshi 4012 

Kataja, Vesa V 507, 

TPS4696^ 

Katakami, Nobuyuki 7515, 

7521, 7528, 10610, 

e18025, e18134, e19556 

Kataoka, Akihiko 10578 

Kataoka, Tomoko e16034 

Katashiba, Yuichi e18081 

Katato, Khalil 7102 

Katay, Ildiko 3044 

Katayama, Hiroshi 3569, 

6112 

Katayama, Naoyuki e19546 

Katayose, Yu e14011 

Kates, Max 4623 

Kates, Ronald E. 552 

Katheria, Vani 9034, 9109, 

9123, e18133 

Kathman, Steven 2535, 2594 

Kathpal, Madeera 2039 

Kato, Jason e13573 

Kato, Ken e14126 

Kato, Kengo e16020 

Kato, Koji 6533 

Kato, Shunsuke e19611 

Kato, Takashi 3593, e14062 

Kato, Takeshi 3524 

Kato, Terufumi 7012, 

LBA7500, e19583 

Kato, Tomoaki 4101 

Kato, Tomoyuki e15057, 

e15088 

Kato, Yuka 7576, e18099 

Katre, Ashwini A. 5036 

Katsanis, Emmanual e13013 

Katsaounis, Panagiotis 5574 

Katsaros, Dionyssios 

LBA5000, LBA5003 

Katsumata, Noriyuki 3084, 

5003, 5006, e19535, 

e19557 

Katsura, Yukitaka 8094 

Katsuura, Yutaka 7571 

Kattan, Michael W. 1514, 

4552, 4570, 4652, 5562, 

e15070 

Katurakes, Nora C. 6086 

Katz, Artur e11014, e12513 

Katz, Daniela 10034 

Katz, Deborah e19543 

Katz, Jessica 2521 

Katz, Leah M. 4516 

Katz, Sanford R. e17524 

Katz, Seth 1016 

Katz, Steven J. 6023, 6024 

Katz, Terry 7502 

Kaubisch, Andreas 4022, 

4047, 4098, 4099, 5025, 

e14019, e14682 

Kaubitzsch, Sabine 2504 

Kauff, Noah D. 1519, 5043 

Kauffman, Michael 1055, 

4634, e13549, e13586, 

e15200 

Kauffman, Tia N e14160 

Kaufman, Bella 5022 

Kaufman, Howard 2588, 

TPS8604 

Kaufman, Jonathan L. 8086, 

8100, 8101, e18553, 

e18569 

Kaufman, Peter Andrew 529, 

1526, e11051 

Kaufmann, J. e13597 

Kaufmann, Manfred 596, 

604, 1023 

Kaufmann, Scott H 5073 

Kauh, John S. 3077, 3094, 

4043, e13603, e14614, 

e14692 

Kauh, John S 2510, 2576 

Kaul, Karen 577 

Kaun, Stephan 2007 

Kauppinen, Sakari e13567 

Kaur, Harmeet e19645 

Kaur, Jyotdeep e18009 

Kaur, Paramjit e13028 

Kaur, Sukhwinder e17549 

Kaura, Satyin e18562 

Kaushal, Aradhana TPS4701 

Kaushal, Sunil e14046 

Kaushik, Amit e15510 

Kaushik, Rucha Vishal 1108, 

e11552 

Kavan, Petr 9557, e14020 

Kavanagh, Brian D. 7526 

Kavcic, Marko 1504 

Kavianimoghadam, Kaveh 

6556 

Kawabata, Hidetaka 591 

Kawabata, Hugh e17009 

Kawabata, Izumi 3100 

Kawabe, Takumi 7029 

Kawachi, Mark H. e15178 

Kawaguchi, Koji e16049 

Kawaguchi, Tomoya 7000, 

10577, e18126, e18128 

Kawaguchi, Yasuo e14091 

Kawahara, Masaaki 7017, 

7028 

Kawai, Hiroki e14510 

Kawai, Norisuke e15098 

Kawai, Yasutaka e18135 

Kawai, Yuki e11564 

Kawakami, Yukikiyo e11560 

Kawamoto, Hiroshi 9574 

Kawamura, Masafumi 7038 

Kawamura, Mikio e14541, 

e21053 

Kawamura, Shigeyuki e13076 

Kawamura, Taiichi e14635 

Kawano, Hiroyuki e14601 

Kawano, Yoshifumi 9574 

Kawano, Yuko 10604, 

e18004, e18014, e18017 

Kawasaki, Hitoshi e14709 

Kawase, Akikazu 1552 

Kawase, Ichiro e18056, 

e18141 

Kawashima, Atsunari e15065, 

e15069 

Kawashima, Osamu 7012 

Kawashima, Toana 9514 

Kawashima, Yousuke e19521 

Kawasugi, Kazuo 9053 

Kawate, Takahiko 10544 

Kawazoe, Hisashi e15057, 

e15088 

Kay, Neil E 6122, e13517 

Kaya, Serap e14618 

Kaya, Yalcin e11083 

Kayaleh, Omar 4113 

Kaye, James A. e15165 

Kaye, Stanley B. 2540, 3048, 

3051, 5022, 5035, 10525, 

e13601 

Kayitalire, Louis 3052 

Kayser, Clarissa e19610 

Kayser, Jacques e14180 

Kazama, Toshifumi e18037 

Kazanjian, Kevork 1587 

Kazanov, Diana 1564 

Kazanov, Dina 1507 

Kazeem, Gbenga 1059, 1073 

Kazim, Abdul Latif 10609 

Kazumoto, Tomoko e15533 

Ke, Chunlei TPS670 

Ke, Xuehua 6028, 6075 

Keam, Bhumsuk 5552, 7566 

Kean, Yin 9067 

Keane, Maccon M. 502 

Keane, Maccon TPS661 

Kearney, Jill TPS666 

Kearney, Nora e19617 

Kearns, Pamela TPS9594 

Keating, Anne Therese 8587 

Keating, Karen E 10553 


Keating, Michael J. 6122, 

6516^, 6517, 6598 

Keating, Nancy Lynn 1100, 

6045 

Kebenko, Maxim 2504 

Kebriaei, Partow 6501, 6540 

Kebudi, Rejin 9567 

Keck, Michaela K. 5517 

Keedy, Vicki Leigh 7094, 

7568 

Keegan, Patricia 3074 

Keeler, Elizabeth 1518 

Keeler, Emmett B. 6057 

Keeling, Peter e21158 

Keenan, Kathleen 10514 

Keenan, Robert 7008 

Keeney, Gary L. 5004 

Keessen, Marianne 2550 

Kefford, Richard 550, 3102, 

8501, 8510, 8518, 8558, 

e13594, e19011 

Kehoe, Siobhan Marie 

e15501 

Kehrer, Diederik F. S. 10504 

Keikavoussi, Petra e19032 

Keil, Felix 4074 

Keil, O. e13597 

Keilani, Mohammad 2071 

Keilholz, Ulrich 2523, 

5516^, 5572, 8532, 

e16018, e18010 

Keir, Christopher Hunt 

10088, 10094, e20511 

Keizman, Daniel 4564, 4619, 

e15058, e18108 

Kelchner, Vanessa 10587 

Keldsen, Nina 3548, 5052 

Kell, M. R. 1543 

Kell, Malcolm R. 1113, 

e12038 

Kelleher, Fergal C 8520 

Kelleher, William Peter 9103 

Keller, Jason 8041 

Keller, Ulrich 8025, e19031 

Kelley, Mark C. 8534 

Kelley, Robin Katie 3006^, 

3105, 4007, 4102 

Kelley, Stacey 6126 

Kellman, Robert e16047 

Kellock, Trenton Tyler 

e14048 

Kellokumpu-Lehtinen, 

Pirkko-Liisa 507 

Kelly, Anne e16515 

Kelly, Catherine M. 581, 

e21147 

Kelly, Catherine Margaret 

e19632 

Kelly, Catherine M 545 

Kelly, Ciara Marie 581 

Kelly, John 8520 

Kelly, Karen 7005, 7018, 

e13551, e17537 

Kelly, Kevin R. 8032, 

TPS8109 

Kelly, Maria e16514 

Kelly, Mary A TPS6635 

Kelly, Tracy R. e14613 

Kelly, Virginia 6511 

Kelly, William Kevin 4526, 

4655, 4667, e15012 

Kelsen, David Paul 4061, 

TPS4144, 9094, 9105, 

e14586 

Kelvin, Joanne Frankel 575 

Kemal, Yasemin e14107 

Kemeny, Gabor 10533 

Kemeny, Margaret 529, 

6073, 9004 


Kemeny, Nancy E. 3577, 

3620 

Kemkes, Ariane C. 5523 

Kemp, Charisse N. 6509^ 

Kendle, Ryan F. 8575 

Kendra, Kari Lynn e13549 

Kenis, Cindy 9035 

Kenmotsu, Hirotsugu 7088, 

e21007 

Kennecke, Hagen F. 3527, 

3628, 4118, 6014, 6069, 

e14176, e14588, e19547 

Kennedy, Andrew S. 3590 

Kennedy, Breandan e13570 

Kennedy, John 1511, e13520 

Kennedy, Kelly Marie e21119 

Kennedy, M. John 1543, 

e12038 

Kennedy, Richard D. 10553 

Kennedy, Victoria 9048 

Kenney, Kara 518 

Kenney, Richard T. e19058 

Kenny, Lizbeth M. 5571, 

8538 

Kenny, Ursula 1559 

Kenouchi, Ouarda 10517 

Kent, Debra A. 9552, e20007 

Kentepozidis, Nikolaos K. 

e18105 

Kentsis, Alex e13586 

Keogh, Louise A. 3567 

Keogh, Mary 1046 

Keohan, Mary Louise 10002, 

10004, 10019, 10057, 

TPS10103 

Keohane, Catherine 2062, 

e11569 

Kerbel, Robert S. e15177^, 

e19015 

Kerbel, Robert S e11061 

Kerbrat, Pierre 5028, 10056, 

e11012 

Kereakoglow, Sandra 9100 

Keresztes, Roger 7546 

Kerger, Joseph N. 5505 

Kerkhoven, Ron M 3065 

Kerns, William D e14731 

Kerr, Christine e15535 

Kerr, Keith M 7583 

Kerr, Phil e21135 

Kerr, Sarah E 10588 

Kerrou, Khaldoun TPS646 

Kershenbaum, Anne 1578 

Kersten, Christian 3538, 

4066 

Kersual, Nathalie 5069 

Kesari, Santosh 2052, 2101, 

TPS2106, TPS2107 

Keshari, Rajiv Prasad e14674 

Keskin, Muge e21050 

Keskin, Serkan e14628 

Keskin, Özge e11020 

Kesler, Kenneth 7032, 7106, 

7108 

Kesmodel, Susan 10572 

Kessler, Joerg 8079 

Kessler, Luisa e11510 

Ketchens, Charlean e13531 

Ketchum, Steven B TPS6637 

Ketterling, Rhett 6614 

Kettlety, Timothy R e15565 

Kettner, Erika 4023 

Keung, Emily 5090, 9086 

Keung, Yi-Kong e12017 

Key, Nigel e14505 

Keyver-Paik, Mignon-Denise 

5005 

Khabele, Dineo e15582 

Khabra, Komel 10060 

Khader, Jamal e15024 

Khadija, Kalai 10556 

Khair, Tina Ashley e11057 

Khajavi, Mehrdad e15075 

Khaled, Hussein Mustafa 

8002 

Khalid, Sanaullah 6620 

Khalifa, Rania H e18570 

Khalife, Riad e20500 

Khalil, Ahmed LBA3500^, 

3506 

Khalil, Iya G. e19055 

Khammari, Amir e19019 

Khan Manji, Samira 6615, 

e14185 

Khan, Atif J. e13543 

Khan, Awais M. 6586 

Khan, Cyrus 6620 

Khan, Ghulam 6123 

Khan, Hussein e13117 

Khan, Iftekhar 7562 

Khan, Jamal Anono e13071^ 

Khan, Khurum Hayat e13599 

Khan, Mohammad K. e15006 

Khan, Mohid Shakil 4123 

Khan, Muhammad Atif 6099 

Khan, Qamar J. 9000 

Khan, Sadya CRA4502 

Khan, Saira 9584, e20008 

Khan, Salam 6557 

Khan, Seema Ahsan 518, 

TPS1134, 2532 

Khan, Shah Alam 9580 

Khan, Shaheer A. 8549 

Khan, Zeba M. 6122, 

e18556, e18560, e18561 

Khan, Zubair 5528 

Khandekar, Alim e17531^ 

Khanin, Raya 7578 

Khanna, Anchit e13566 

Khanna, Rahul e16527 

Khanna, Samir e15101 

Khanna, Sarika e19025 

Khanshour, Ammar e12019 

Kharaishvili, Gvantsa 1087 

Kharfan-Dabaja, Mohamed A. 

6586 

Kharkevitch, Dmitri D. 

e19058 

Kharofa, Jordan e14613 

Khatcheressian, James L. 

8567 

Khater, Leticia e16041 

Khatkov, Igor e14717 

Khatri, Vijay P. 3566 

Khattri, Arun 5517 

Khattry, Navin 9559, e17003 

Khawaja, Osmaan e16513 

Khayat, David 641, 6110, 

e11551 

Khazan, Mikhail e12016 

Khazanov, R. e11528 

Khder, Yasser e15037 

Khelif, David Hamid 2048 

Khella, Heba WZ 4633 

Kheoh, Thian San LBA4518, 

4521, 4558 

Khetan, Vikas 9515 

Khillan, Ratesh e15097 

Khin, Sonny 3087, 3529 

Khleif, Samir 2577, 2578 

Khoa, Mai Trong 1534 

Khoja, Leila e21037 

Khokhlova, Svetlana 

Victorovna e14723, 

e15543 

Khong, Hoa e11050 

Khoo, Lay Poh 8078, e18515 

Khoo, Stella 2538 

Khoo, Vincent e15199^ 

Khorana, Alok A. 6059, 

TPS9149^ 

Khouri, Issa F. 6529, 6544 

Khouri, Nagi 518, 10509 

Khoury, Hanna Jean 6503, 

6511, 6577 

Khoury, Nabil e20004 

Khozin, Sean 7033, 7103 

Khrebtukova, Irina 10539 

Khurana, Monica 9553 

Khuri, Fadlo Raja 2576, 

3094, 5501, 5560, 5570, 

7048, 7059, 7097, 7589, 

10625, e13026, e21045, 

e21161 

Khushalani, Nikhil I. e19041 

Kiatsimkul, Porntip 7534 

Kibel, Adam Stuart 4570 

Kichenadasse, Ganessan 

e19550 

Kida, Hiroshi e18056 

Kidner, Travis Brad e19029 

Kieback, Dirk Guenter 516, 

517 

Kiechle, Marion 1072, 1081 

Kiefer, Amy K 10097 

Kiehl, M. e13100^ 

Kiel, Krystyna D. 1069 

Kiel, Nancy e19588 

Kiel, Patrick e18555 

Kiely, Belinda E. TPS1136, 

9087, 9126 

Kier, Peter e14087 

Kieran, Mark W. 9519 

Kies, Merrill S. 5583, 5592 

Kiesel, Brian 3049, 3054 

Kiesel, Ludwig 10627, 

e11534, e21041 

Kiessling, Peter 4034 

Kieszkowska-Grudny, Anna 

e19561 

Kiewe, Philipp M. 2007 

Kigawa, Junzo 5103 

Kigin, Mackenzie 9586 

Kii, Takayuki 3088^ 

Kijima, Takashi e18007, 

e18056, e18141 

Kikuchi, Eiji 9569 

Kikuchi, Eiki 7571 

Kikuchi, Ryoko e15579 

Kikuchi, Yoshihiro 5037, 

e15579 

Kikuhara, Yoshihito e21007 

Kikuta, Atsushi 9574 

Kiladjian, Jean-Jacques 

6514^, 6625^, 6626^, 

TPS6641, TPS6642^, 

TPS6643^ 

Kilgore, Kelly L. e19528, 

e19584 

Kilgour, Elaine 4124 

Kilic, Diclehan 9050 

Kilic, Leyla e14628 

Kilickap, Saadettin 3565, 

9050, e11083, e16005, 

e19575 

Killelea, Brigid K. 1030, 

1109, 1595 

Killian, Keith TPS7609 

Killick, Emma 4653 

Kilpatrick, Deborah 4526 

Kim, Benjamin 6105 

Kim, Bong-Seog TPS4142 

Kim, Bonglee e13514 

Kim, Byung Chul 7053 

Kim, Byung Sik 10093 

Kim, Chae-yong 2041 

Kim, Chan Gyoo 4028 

743s

Kim, Chan Kyu e14688 

Kim, Chang Won e14566 

Kim, Choung-Soo e15080, 

e15122 

Kim, Da Rae e18092 

Kim, Dae Joon e14559 

Kim, Dae-Eun e14649 

Kim, Dae-Young 6564 

Kim, Dong Kwan e14573 

Kim, Dong-Sik e19574 

Kim, Dong-Wan 3007, 3076, 

5552, 7530, 7533, 7543, 

7566, 7596, 7599, 7600, 

10009, e12029 

Kim, Dong-Wook 6503, 6506 

Kim, Edward S. 5524, 7023, 

7047, 7502 

Kim, Eun-Hye 7053 

Kim, George P. 4038, 

e13052 

Kim, Gun Min 3606, e18092 

Kim, Gyu IM e14580 

Kim, Gyunji 4628 

Kim, Hadong 574, e11029 

Kim, Hae Rin e14537 

Kim, Hak-Hee e11508 

Kim, Han Jo e19554 

Kim, Han Sang 3606, 

e14559, e18080 

Kim, Hanjo e14688 

Kim, Hark K. e21043 

Kim, Harold 5530, 5534, 

e16019 

Kim, Hee Jeong 578, e11508 

Kim, Hee Young e13094 

Kim, Heeyoung 9512 

Kim, Ho Young e12029 

Kim, Ho-Sook 3592 

Kim, Hwa Jung 3568 

Kim, hye Jin 578 

Kim, Hye Ryun 2542, 

e14652 

Kim, Hyeon Chang e16529 

Kim, Hyeong Ryul 4093, 

e14573 

Kim, Hyeong Ryul 7510 

Kim, Hyo Song e12029, 

e14652 

Kim, Hyo-Jin e14686 

Kim, Hyoung-Il e14504, 

e14652 

Kim, Hyun Jeong e14136 

Kim, Hyun Jung e14688, 

e19554 

Kim, Hyun Ki e14559 

Kim, Hyun Sik e14734, 

e14736 

Kim, Hyun Sue 1017 

Kim, Hyun-Jung e13065 

Kim, Hyung Lae e15046, 

e15203 

Kim, Hyunsoo e14164 

Kim, Hyunsung e14181 

Kim, Isaac Yi e15214 

Kim, Ja Young e18501 

Kim, Jae Hoon e15503 

Kim, Jae Hyun e17523 

Kim, Jae Weon e15503 

Kim, Jang Hee e18519 

Kim, Jee Hyun 1003, 3076 

Kim, Jenny J. TPS2613 

Kim, Jenny e19570 

Kim, Jeong Eun 3568, 

e11504 

Kim, Jeong-Eun e11508 

Kim, Jeong-Oh e18050 

Kim, Jeri e15181 

Kim, Jhingook 7053, 7510, 

e18083, e21062 

Kim, Ji sun 1133, e21160 

Kim, Ji Yeon 4544^ 

Kim, Jin Cheon 3568 

Kim, Jin Seok 8097, 

TPS8118 

Kim, Jin Young 7089, 

e14570 

KIM, Jiyoun 4093, 5586 

Kim, Jong Gwang 3554, 

6536, 6538, e14074, 

e14570, e18533 

Kim, Jong Hoon 4093, 

e18501 

Kim, Jong-Hyeok e15559 

Kim, Jong-Mook e19574 

Kim, Jongphil 2544, 7065, 

10070, e17559 

Kim, Joo-Hang 7549, 7557, 

7558, e14559, e18092 

Kim, Joon-Hyung J. 5587 

Kim, Joseph W. 2526, 

TPS2617, TPS4701, 

10589 

Kim, Ju Young e14580 

Kim, Julian 1031, 8595 

Kim, June e16052 

Kim, Jung-AH e16047 

Kim, Jung-Young 2074^ 

Kim, Kenneth H. 5062^, 

e13087 

Kim, Kevin B. 8503^, 8510, 

8514, 8536, 8537, 8551, 

e19009, e19014, e19039 

Kim, Ki Hyang TPS4142 

Kim, Ki Won e14583, 

e14656 

Kim, Ki-Han e14686 

Kim, Ki-Hun 10093 

Kim, Kihyun 8097 

Kim, Koen Kook e14685 

Kim, Ku Sang 578, 2542, 

e11559 

Kim, Kwang Hyun 5552 

Kim, Kwang Pyo e21043 

Kim, Kyoung Ha e19554 

Kim, Kyoung-Mee 4011, 

10535 

Kim, Kyoungha e14688 

Kim, Kyu-Pyo 3568, 3592, 

e11504, e13104, e13560, 

e14072 

Kim, Kyu-Rae e15559 

Kim, Kyung Min e14504 

Kim, KyungMann 555, 563, 

6063, e13537, e19047 

Kim, M. K. e14610 

Kim, Mi-Jung e14136 

Kim, Michelle e21109 

Kim, Min Chan e14686 

Kim, Min Kyoung e14570, 

e19538 

Kim, Miranda 7098, e17534 

Kim, Nam Kyu 3606, 

e14081, e14084, e14114 

Kim, Noe Kyeong 4028 

Kim, Philip 4563 

Kim, Phillip Sangwook 4011, 

10535, 10536, 10537, 

e14584, e21017 

Kim, Richard D. e14519, 

e14715 

Kim, Roger Hoon e11541 

Kim, Ryan 2052 

Kim, Samyong e14529 

Kim, Sang Yoon 5586 

Kim, Sang-We 7004, 7543, 

7549, TPS7614, e13104, 

e18052 

Kim, Se Hyun e14081, 

e14084, e18092 

Kim, Se Hyung e14136, 

e14688, e19554 

Kim, Se Won 1053 

Kim, Seok Jin 8023 

Kim, Seung Il 2542 

Kim, Seung Jin TPS1141 

Kim, Sharon 1031, e19580 

Kim, Si-Young e14128 

Kim, Simon P. 4657, 6126 

Kim, Sinil 4503, LBA4537, 

4546, 7551 

Kim, So Yeon 1577 

Kim, Sook-Young 7089 

Kim, Stefano Chong Hun 

e14007 

Kim, Sun Hyun e19613 

Kim, Sun Young 3531, 3587, 

e14072 

Kim, Sung Hoon e13514 

Kim, Sung Hyun 4028 

Kim, Sung 4011 

Kim, Sung-Bae 578, 1003, 

2542, 4093, 5586, 

e11504, e11508, e13104 

Kim, Sung-Doo 6564 

Kim, Sung-Hyun e14686, 

e18083, e21062 

Kim, Sung-Won 1056 

Kim, Sungjin 5560, 7059, 

7097, e14614 

Kim, Sunyoung e19574 

Kim, Tae IL e14081, e14084 

Kim, Tae Min 2041, 3076, 

4544^, 5552, 7566, 

e12029 

Kim, Tae Soo 3606 

Kim, Tae Won 3531, 3532, 

3568, 3587, 3592, 

e13104, e13560, e14072 

Kim, Tae Yong e14580 

Kim, Tae-Hoon 574, e11029 

Kim, Tae-Yong e14136 

Kim, Tae-You 3076, 3531, 

3587, 3624, e11532, 

e14136, e14580, e21160 

Kim, Won Seog 8023, 8029, 

e18528 

Kim, Woo Ho 4124 

Kim, Yeong 1538 

Kim, Yeul Hong e14580 

Kim, Yong Hee 4093 

Kim, Yong-Hee e14573 

Kim, Yong-Man e13104 

Kim, Yookyung e16500 

Kim, Young Ae 9066 

Kim, Young Hwan e21043 

Kim, Young Woo 4028 

Kim, Young-Hoon 2041 

Kim, Yu Jung 2041, 3076 

Kim, Yu Min e14504 

Kim, YuJung 4544^ 

Kimball, Amy Sarah 8075 

Kimberg, Cara I. 9531 

Kimbler, Kimberly D. e21000 

Kimbro, Lisa e16510 

Kimler, Bruce F. 520, 9000 

Kimlin, Michael e19550 

Kimmick, Gretchen Genevieve 

6015, 6052 

Kimmig, Rainer 5042 

Kimura, Eizo 5003 

Kimura, Hideharu TPS659 

Kimura, Hiroaki 2044, 

10072, 10075, e20505 

Kimura, Takayuki e13511 

Kimura, Tatsuo 7003, 

e17538 

Kimura, Yasunori e15055, 

e15099 

Kinarsky, Yulia 1538 

Kinders, Robert J. 3031, 

3087, 3529 

Kindler, Hedy Lee 2561, 

3105, 4022, 4047, 7029, 

7030, 7077 

Kindler, Manfred e15044 

Kindler, Thomas 6511 

King, Dennis e21066 

King, Erin Rebecca e15583 

King, Gentry T 536 

King, Karen 10532 

King, Madeleine TPS5116, 

6002, 6111, 7607, 

e16507 

King, Robin 1520 

King, Stephanie e15522 

King, Tari A. 10618 

King, Thomas 6530 

Kingham, T. Peter 3577, 

3620 

Kingsley, Edwin e18558 

Kingswood, Christopher 4632, 

10619 

Kinhult, Sara 10024 

Kink, John A. TPS3113 

Kinoshita, Hidefumi e15071 

Kinoshita, Ichiro 7571, 

e17520, e18135 

Kinoshita, Rumiko e15533 

Kinoshita, Takayuki TPS1147 

Kinoshita, Tomohiro 8050 

Kintzinger, Clement 2048 

Kinugasa, Yusuke 3569, 

3607 

Kinzig, Martina 3044 

Kioi, Mitomu 5556 

Kipps, Thomas J. 6122, 8032 

Kira, Yukimi e17538 

Kirby, Chaim 9583 

Kirchhoff, Tomas 8557 

Kirchner, Sandra 9019 

Kirchner, Thomas 3519^, 

4041, 10054 

Kirichenko, Alexander V. 

e21036 

Kirita, Keisuke e17526 

Kirk, Dylan T e18549 

Kirkbride, Peter 4509 

Kirkpatrick, John 2090^, 

2094^ 

Kirkpatrick, Nathaniel D. 

2010 

Kirkwood, John M. 8501, 

8504, 8522, 8527, 8528, 

8533, 8547, 8559, 

TPS8606 

Kirn, David H. TPS4152, 

e13044, e14566 

Kirsa, Sue e16538 

Kirschbaum, Mark H. 6582 

Kirshner, Jeffrey J. 9141, 

9142, e19510 

Kish, Julie Ann 5564, 6100 

Kishi, Hiroto e13072 

Kishi, Kazuma 7012 

Kishimoto, Hiroyuki e14014 

Kishimoto, Junji 7045, 

e13014 

Kishimoto, Takashi K 4056 

Kishine, Kennji e14004 

Kishino, Daizo 7042 

Kiss, Alex e19545 

Kissane, David W 9121 

Kistangari, Gaurav e15023 

Kit, Oleg I e11558, e20503, 

e21101 


Kita, Aya e21059 

Kita, Tsunekazu 5037, 

e15579 

Kitada, Koji 4012 

Kitagawa, Ryo 5006 

Kitagawa, Yuko 10531, 

e11060, e14045, e14080 

Kitaichi, Masanori e18126 

Kitajima, Masaki 1106 

Kitajima, Masayuki e14004 

Kitamura, Hideya e19583 

Kitano, Atsuko 590 

Kitano, Seigo 3569 

Kitano, Shigehisa 2518 

Kitao, Akihito 5045, e19548 

Kitayama, Joji e14142, 

e14530 

Kitsios, Petros e15030 

Kitsukawa, Shinichi e15038 

Kittas, Christos e21098 

Kittel, Kornelia e19540 

Kitto, Alex e18549 

Kitzweger, Elvira e14087 

Kiura, Katsuyuki 2607, 7042, 

7045, 7560, 7576, 7602, 

e18027 

Kivett, Valerie A 2026 

Kiyici, Aysel e11008 

Kiyohara, Meagan 1052 

Kiyota, Hidemi e18060 

Kiyota, Naomi 5542, e16034, 

e17020 

Kizilarslanoglu, Cemal 

e11080, e11509 

Kizilbash, Sani Haider 

e14608 

Kjaer-Frifeldt, Sanne 3513 

Kjellén, Elisabeth 10024 

Kjellman, Anders 4508 

Klaase, Joost TPS10632 

Klaassen, Robert 6103 

Klaisuban, Wipawi e14051 

Klamt, Fábio e21042 

Klapman, Jason 4055 

Klappers, Petra 6500^ 

Klare, Peter 5031, e15520, 

e19540 

Klasen, Hermann A. 2007 

Klassen, Anne 9042, 9043 

Klautke, Gunther 7001 

Klee, George G. 4565 

Kleha, Joseph Francis 

e13596 

Klein Connolly, Hannah 

e11096 

Klein, Eric A. 4560 

Klein, Pamela 567 

Klein, Paula e11057 

Klein, Peter e11040^ 

Klein, Stefan 3588, 4023 

Kleinberg, Lawrence 2013, 

2017 

Kleinfield, Robert 2597 

Kleinman, Shlomi 1564 

Klem, Robert E. e15113 

Klemp, Jennifer R. 9000 

Klener, Pavel e18539 

Klepin, Heidi D. 6015, 9034, 

9109, 9123, e18133 

Kleski, Amy 9115 

Klevesath, Manfred B 3107^ 

Kliesch, Sabine 4530 

Klimberg, V. Suzanne e19563 

Klimovsky, Judith 4014, 

4632, e14621 

Klimowicz, Alexander C. 

2001, e21083 

Klimstra, David 10524 

Kline, Justin Paul 8075 


Kline, Zoe e18077 

Klingbiel, Dirk 3595, 

e19648, 9045 

Klingebiel, Thomas 9573 

Klinghammer, Konrad 

Friedrich 5572 

Klingler, Christoph e15090 

Klingler, Sophie 10517 

Klinkhammer-Schalke, Monika 

e16520 

Kloecker, Goetz H. e16517, 

e16533, e16545, e21072, 

e21149 

Klos, Dusan e14556 

Kloss, Susanne e15044 

Kloth, Jacqueline S.L. 2596, 

10091 

Klouvas, George 5033 

Kluetz, Paul Gustav 4569 

Klug, Evelyn 542 

Kluger, Harriet M. 7514, 

8531 

Klughammer, Barbara 10596 

Klumpen, Heinz-Josef 

TPS4148 

Klumpp, Bernhard 8526 

Kluschke, Franziska 5064, 

e19558 

Knackmuss, Stefan 8059, 

e18532 

Knapen, Marie Claire 9035 

Kneebone, Andrew TPS4690 

Knezevic, Dejan 4560 

Knigge, Ulrich 4015 

Knight, Alastair D. e19544, 

e19567, e19578 

Knight, Julie A 1502 

Knight, Robert D. 607, 

e15170, e18559 

Knight, Simon e17539 

Knight, Tyler e18559 

Knobler, Robert 8076 

Knoedler, Maren 5572 

Knoefel, Wolfram Trudo 

e14527, e21020 

Knol, Anne-Chantal e19019 

Knol, Jaco C e18094 

Knoops, Laurent 6514^, 

6625^, 6626^ 

Knop, Stefan 8095 

Knopf, Kevin B. 6553, 

e13081 

Knott, Adam 597^, 598^, 

e11055^ 

Knox, Chetaye CRA9013 

Knox, Jennifer J. 4099, 

4109, 4536, 4538, 

TPS4686, 10522, e14524, 

e14592 

Knudsen, Kraig J. 1598 

Knusli, Claudio 10033 

Knuth, Alexander 2573^ 

Knutsen, Raymond 1587 

Ko, Andrew H. 3105, 4038, 

4048, 4102 

Ko, Clifford Y. 3545, 3608, 

6057 

Ko, Emily Meichun 5009, 

e15511 

Ko, Emily 5092 

Ko, Jennifer TPS648 

Ko, Jenny J 6014 

Ko, Ryo e18019 

Ko, Sanghwa e14121, 

e14181 

Ko, Seung Sang 1053 

Ko, Wan-Seng e11561 

Ko, Yon-Dschun 1533, 

10526, CRA10529 

Ko, Yoo-Joung 4522, 4525, 

e14171, e15177^ 

Ko, Yoon-Ho e14634 

Koay, Eugene Jon 8584 

Koba, Hayato e17540 

Kobayashi, Kazuma 3558 

Kobayashi, Kunihiko 7515, 

7561, 7563, e18129 

Kobayashi, Masashi e18036, 

e18042 

Kobayashi, Nozomi 10578 

Kobayashi, Susumu 7523 

Kobayashi, Takao e19521 

Kobayashi, Toshimitsu 

e16020 

Kobayashi, Yasuyuki e15068 

Kobayashi, Yukio 8050 

Kobe, Carsten 3044, 7603 

Kobs, Christina L. 9575 

Kobyakov, Grigory 2034 

Koc, Basak 9567 

Koca, Dogan 638 

Kocak, Ivo TPS4696^ 

Kocak, Necmettin 6550 

Kocáková, Ilona 3539 

Kocaman, Gokhan 1596 

Kocaturk, Celalettin 7024 

Kocer, Murat 638 

Koch, Michael O. 4586 

Koch, Sven D. 2573^ 

Kocherginsky, Masha 5500 

Kockx, Mark 8503^ 

Kocs, Darren M. 1017 

Koczwara, Bogda e19550, 

e19553 

Koczywas, Marianna 3108, 

7029, 7518, 9068, 

e18018 

Kodaira, Makoto 10519, 

e19535 

Kodaira, Takeshi e14500, 

e15533 

Kodali, Swati e16060 

Kodama, Kotaro e13511 

Kodama, Shoji 5003 

Kodama, Tetsuro 7021 

Kodera, Yasuhiro 3558 

Koeberle, Dieter 3595, 

e19648, 9045, 10033, 

e14544 

Koechlin, Alice 1509, 1510 

Koehler, Astrid 8503^ 

Koehler-Santos, Patricia 1522 

Koelbl, Heinz 10551 

Koeller, Jim M. e16522 

Koenig, Kimberly 

Higginbotham 527 

Koenig, Nelly e18505 

Koenig, Ronald J 6056 

Koenigsberg, Tova 1126 

Koenigsmann, Michael 4083 

Koepfgen, Kathryn M. e15137 

Koepl, Lisel 6007, e14068 

Koepnick, Sven 3550 

Koeppel, Marie-Christine 

8555 

Koeppen, Susanne 2086 

Koerber, Wolfgang 10600 

Koestler, Wolfgang 607 

Kofahl-Krause, Dorothea 3 

Koga, Hirofumi e15127 

Koga, Rintaro e14506 

Kogan, Mikhail 4501 

Kogler, Ulrika 1594 

Kogut, Neil Martin 6545 

Koh, Sung Ae e19538 

Koh, Tong San 1064, 4100^ 

Koh, Wee Yao 2016, 5553 

Koh, Yasuhiro e21007 

Koh, Yin Ling e18546 

Koh, Youngil 4544^, 5552 

Kohen, Nelson e15507 

Kohler, David R. 3043 

Kohler, Racquel Elizabeth 

6017, 6029 

Kohli, Antia e13042 

Kohli, Manish e15132 

Kohlmann, Wendy 9525, 

9561 

Kohn, Elise C. 2545 

Kohne, Claus-Henning 3562, 

3591 

Kohno, Mikihiro e13090 

Kohno, Norio 635, TPS1141 

Kohno, Shigeru 7569 

Kohnoe, Shunji e14033 

Kohrman, Michael 1609, 

e12042, e15096 

Kohrogi, Hirotsugu e13072, 

e18059 

Kohrt, Holbrook Edwin 2043, 

2513, 2514, e13555, 

e21071 

Koie, Takuya e15068 

Koike, Teruaki 7012 

Koike, Yukihiro e14622 

Koivula, Satu 8074 

Koizumi, Fumiaki 10519, 

e11065 

Koizumi, Tatsuhiko e19521 

Koizumi, Toshiyuki 5556 

Koizumi, Wasaburo 4026, 

4088, e14510 

Kojima, Hiroshi 8094 

Kojima, Hiroyuki e14500 

Kojima, Tetsuya e18135 

Kojouharoff, Georgi 4023 

Kok, Victor C. e11561 

Kokorsch, Philipp e15577 

Kokudo, Norihiro 4104 

Kokx, Patricia 6054 

Kolar, Zdenek 1087 

Kolarevic, Daniela e21030 

Kolatkar, Anand e21074 

Kolb, Brigitte 8009, 8014 

Kolek, Vitezslav e18062 

Kolesar, Jill 3101, 3103, 

7516 

Kolesnick, Richard 6539 

Kolev, Nikola e21100 

Kolhe, Ravindra 6573, 8108 

Kolitz, Jonathan E. 2533, 

6525, 6526, 6601 

Kollar, Attila 3595 

Kollender, Yehuda 10043 

Koller, Josef 8505 

Koller, Michael 6090, 

e16520 

Kollia, Georgia CRA2509, 

TPS2622, 4505, 7509, 

8507 

Kolligs, Frank T 4006, 

e14654 

Kollmannsberger, Christian K. 

TPS2614, 3039, 4536, 

4538, e14537, e14568 

Kollmeier, Jens 7001, 7575 

Kollmeyer, Thomas M. 4565 

Kolman, Petr 7512 

Kolodziej, Ilka TPS5116 

Kolodziej, Michael A. 6109 

Kolodzieyski, Lev 3086 

Kolostova, Katarina e21051 

Komaki, Ritsuko e14548, 

e14669 

Komarnitsky, Philip B 7090 

Komarova, Ekaterina e19049 

Komatsu, Shigeru e19583 

745s

Komatsu, Yoshihiro e14689 

Komatsu, Yoshito 3593, 

e14062 

Komeno, Takuya 8094 

Kometani, Takuro 3045 

Kommoss, Friedrich 5005 

Kommoss, Stefan 5005 

Komori, Takahide e16034 

Komrokji, Rami S. 3081, 

6568, 6575, 6586, 6588, 

6608 

Komuta, Kiyoshi e18007, 

e18056, e18141 

Kondadasula, Sri Vidya 

e13089 

Kondalsamy-Chennakesavan, 

Srinivas e15541 

Kondi-Pafiti, Agathi e13556 

Kondo, Chiaki e17510, 

e18145 

Kondo, Nobuyuki 7080, 

10585 

Kondo, Satoshi 9577 

Kondo, Shinya e14540 

Kondo, Tsunenori e15068, 

e15071 

Kondoff, Matt R 1608 

Kondoh, Chihiro e14500 

Kondziolka, Douglas 8528 

Konety, Badrinath e15211 

Kong, Anthony 530 

Kong, Feng-Ming (Spring) 

7037, e17530, e21115 

Kong, Li-Ren 3002 

Kong, Ling-Yuan 2011 

Kong, Sun-Young 4028 

Kong, Weidong 1583 

Kong, Yan 8561, 8562 

Kong, Yana e11091 

Konias, Marina e19540 

Konicek, Bruce W 8082 

Konigsberg, Robert 514 

Konishi, Fumio 3569 

Konishi, Tsuyoshi 3625 

Konkankit, Veerauo V 8592 

Konkashbaev, Anuar 9516 

Konno, Satoshi e18135 

Kono, Hidaka 9569 

Kono, Scott A. 5560, 5570, 

e21045 

Kono, Scott Arthur 7048 

Konopleva, Marina 6558, 

6576, 6585, TPS6635 

Konopski, Zbigniew e14637 

Konski, Andre A. e17528 

Konstantinopoulos, Panagiotis 

8528 

Konto, Cyril 8512, 8539, 

TPS8603 

Kontopodis, Emmanouil 

e18105 

Kontoyiannis, Dimitrios P 

e17016 

Koo, Yang Seo e14685 

Kooby, David A. e14692 

Koock, Ulrike 4083 

Koolen, Stijn 2550 

Koon, Henry B. 8595 

Koong, Albert 4045 

Koornstra, Rutger H.T. 562 

Kopcewicz, Katarzyna 3055 

Kopetz, Scott 3528, 3544, 

3556, 3561, 3598, 

e14071 

Kopit, Justin TPS8112, 

TPS8113, TPS8114 

Kopp, Joachim e15053 

Kopp, Lisa M. 9503 

Koppe, Fredirike 7019 

Koraa, Emad e17556 

Korc-Grodzicki, Beatriz 5108 

Korcum, Aylin Fidan e21130 

Korczak, Bozena 9119 

Korde, Neha 8088, 8104, 

e18568 

Kordes, Sil 4094 

Korfel, Agnieszka 2007, 

2040, 2054, 8031 

Koritzinsky, Marianne e15118 

Korman, Alan CRA2509 

Korn, Michael 3006^ 

Korn, Wolfgang Michael 4102 

Kornacker, Martin 3012, 

3046 

Kornblith, Alice B. 6015 

Korogi, Yohei e18025, 

e18134 

Koroukian, Siran M. 1598 

Korphaisarn, Krittiya e14051 

Korte, Susan H. 5514, 5545^ 

Korth, Christopher Charles 

e13040 

Kortylewski, Marcin e15178 

Koru-Sengul, Tulay 1572 

Korves, Caroline 10061 

Korytowsky, Beata 4542, 

6092, e15061, e16530 

Kos, Fahriye Tugba e13031 

Kosaka, Takashi e14624 

Koscielniak, Ewa 9573 

Koscielny, Serge 4618, 

e13118 

Kose, Kenan e20000 

Kosel, Matthew L. e13086 

Kosela, Hanna 10538 

Koshikawa, Kayoko e13037 

Koshiol, Jill e18128 

Koshrawipour, Tanja 10059 

Kosik, Kelly e13121 

Koski, Anniina e13035 

Kosloff, Rebecca A. 7587 

Kosmider, Suzanne e16516 

Kosovec, Juliann e14689 

Koss, Juliane 1084 

Kossoff, Ellen e15042, 

e19568 

Kostakis, Ioannis e21098 

Kostakoglu, Lale 5578, 

e13592, e21006 

Kostashuk, Edward 4509 

Kosten, Scott e14501 

Kostjakova, Ljudmila e15029 

Kostlevy, Jordan e19047 

Kostouros, Efthimios e15040 

Kosuge, Tomoo e14506 

Kosugi, Hiroshi 8097 

Kosztyla, Daniel 9573 

Kota, Vamsi 6573, 8108 

Kotani, Yoshikazu 7003, 

e18134 

Kotapati, Srividya e19010 

Kotasek, Dusan e19511 

Kotchko, Nancy 1608 

Kote-Jarai, Zsofia 1545, 4653 

Kotecki, Nuria 2070, 10035, 

e11049 

Kotkova, Tatjana N. e11086 

Kotoula, Vassiliki 573, 592, 

10575 

Kotowski, Adam S. e14659 

Kotsakis, Athanasios 

Panayotis 5541, e18105 

Kottschade, Lisa A. 1557, 

8600 

Kotzerke, Joerg 10068 

Kouakam, Claude e11049 

Koubkova, Leona e18062 

Kouchner, Pierre e11551 

Koudelakova, Vladimira 1087 

Koufopoulos, Nektarios 

e11519 

Koumakis, George e11519 

Koumarianou, Anna e21027 

Koussis, Haralabos 5513, 

e12037 

Koustenis, Andrew 7002 

Kouta, Hiroko 5037, e15579 

Koutcher, Lawrence 5537 

Koutras, Angelos 573 

Kouwenhoven, Mathilde C.M. 

2 

Kovac, Suzana e15117 

Kovach, Barbara 10596 

Kovacsovics, Tibor 6601 

Koval, Greg 6582 

Kovalenko, Nadezhda 

TPS651, 5017^ 

Kovel, Svetlana 4564, 4619, 

e15058 

Kowal, Monika e21049 

Kowalczyk, Anna 603 

Kowalska, Malgorzata e21049 

Kowalski, Dariusz M e12011 

Kowalski, Luiz Paulo e16046 

Kowalsky, Richard J. 5050 

Kowalyszyn, Ruben Dario 

e14521 

Koya, Richard C. e13045 

Koyama, Hiroki 1103 

Koyanagi, Nozomu 3084 

Kozloff, Mark 3543, 3552, 

TPS3637, 6122 

Kozlowski, Piotr 6584 

Kozma, Sara TPS3116 

Kozuki, Toshiyuki 7576, 

e18099 

Kozyreva, Olga N. e15123 

Kraan, Jaco 10504 

Krabisch, Petra 552 

Kracht, Karolyn 4606 

Kraemer, Dale F. 2040 

Kraemer, Sandrine 4071 

Kraetschell, Robert W. 5087 

Kraft, Andrew S. 10003 

Kraft, Walter K e16548 

Krahn, Thomas 10536, 

10537, e21017, e21020 

Krailo, Mark D. 9503, 9537, 

9539, 10081 

Krajcsi, Peter e21140 

Krakobsky, Vanesa e11555 

Krakowski, Ivan LBA4567^, 

e19640 

Kramar, Andrew 2540, 

e11070 

Kramer, Daniel 7090 

Kramer, Gero e15090 

Kramer, Melissa 4562 

Kranenburg, Britte 8018^ 

Kranenburg, Tanya 9518 

Krasin, Matthew J. 9502 

Krasna, Mark 1540 

Krasner, Carolyn N. 5029 

Krasnik, MARK 7026 

Krasnozhon, Dmitriy e19609 

Kratz, Christian 9521 

Kraus, Dennis 5537, 5545^ 

Kraus, Dietmar e17536 

Kraus, Sarah 1507, 1564 

Krause, Stefan W. 6510 

Krauss, John C. 8007 

Krauss, Juergen 5516^ 

Krauze, Michal Tadeusz 8528 

Krawczyk, Natalia 5042, 

e21003 

Kreahling, Jenny 10084 

Krebs, Matthew 3004, 3030, 

3048 

Krege, Susanne 4524, 4530 

Kreienberg, Rolf 1078, 1082, 

e11040^ 

Kreilick, Charles e14106, 

e14141, e14146, e15183, 

e18097 

Kreipe, Hans Heinrich 552 

Kreischer, Nathan e13601 

Kreissl, Michael 5508 

Kreitman, Robert J. 2503^ 

Krekow, Lea 547 

Krell, Jonathan e21137 

Krell, Robert Wallace 6020 

Kremmidiotis, Gabriel 4603, 

7079^ 

Krenn, Markus e14103 

Krestin, Gabriel P. 10091 

Kreutz, Werner e13508 

Kreys, Eugene e16522 

Kridel, Steven 6524^ 

Kriegel, Irene 1580 

Krikelis, Dimitrios 10086, 

10575 

Krikov, Maxim e14152 

Kris, Mark G. 3083, 7014, 

7052, 7066, 7505, 7527, 

7530, 7532, 7580, 7589, 

10560, e19647 

Krishna, Sai Sakktee 5551, 

5580 

Krishnamoorthy, Saravanan 

e13064 

Krishnamurthy, Savitri 

TPS10631, e13582 

Krishnamurthy, Vikram 

e19061 

Krishnan, Amrita Y. 6547, 

8038, 8089, e18542 

Krishnan, Monica Shalini 

6022 

Krishnan, Rajaram e21047 

Krishnan, S. 3089^ 

Krishnan, Shobha e12009 

Krishnan, Sunil 4116 

Krishnasamy, Meinir e19605 

Krishnatry, Rahul e16021 

Krissel, Heiko 4103 

Krist, Alex 1563 

Kristensen, Gunnar 

LBA5002^, 5008 

Kristjansdottir, Kolbrun 9584, 

e20008 

Kristopaitis, Theresa e19588 

Kristopher, Attwood e15039 

Krivak, Thomas C. e15560, 

e15578 

Krivokuca, Ana e12020 

Krizman, David e21068 

Krocker, Jutta 624 

Kroeger, Nils e13045 

Kroep, Judith R. 10006 

Kroepil, Feride e14527 

Krogh, Merete 8545 

Krogsgaard, Michelle 8589 

Kroiss, Regina 1537 

Krol, Augustinus 8039 

Kroll, Stew TPS10100 

Kroll, Stewart 6585 

Kroll, Torsten 10600 

Kronborg, Camilla J S 

e14063, e14105 

Kronenwett, Ralf 522, 523, 

542 

Kroog, Glenn Scott 8020, 

TPS8112, TPS8114 

Krop, Ian E. 508, TPS663, 

1026 


Krop, Ian E LBA1, 528, 532, 

10558 

Kros, Johan M 2 

Kroschinsky, Frank 10068 

Krouse, Robert S. e19563 

Krucker, Thomas 9562 

Kruczek, Kimberly R. 8072 

Krueger, Colin 4095^ 

Krueger, Darcy A. 9541 

Kruer, James A e15179 

Krug, Lee M. 1541, 7014, 

7029, 7052, 7527, 

e17558 

Krug, Utz 6610 

Kruger, Darcy 1609 

Krukemeyer, Manfred Georg 

e13091 

Krull, Kevin R. 9531, 9532 

Kruper, Laura 1035, 1117 

Kruse, Edward J. e14694 

Kruse, Janice 6108 

Kryukov, Gregory 10502 

Krzakowski, Maciej Jerzy 

LBA7000, 7090, 7536, 

7575, e12011 

Krzyzanowska, Monika K. 

2572, 3632, 6087, 9003, 

9131, e14003, e14524, 

e14592 

Kröning, Hendrik 4065, 

e14140, e14152 

Ku, Yonson 4104 

Kuang, Peng 10527 

Kuang, Qin 1535, 7586 

Kuang, Yukang e18013 

Kuba, Maria Gabriela 510, 

1024 

Kubal, Timothy Edward 

e18503, e18506 

Kube, Stefanie 9573 

Kube, Ulrich e15044 

Kubicka, Stefan CRA3503 

Kubin, Thomas 4072 

Kubo, Akihito 7000, 10577, 

e18126, e18128 

Kubo, Kazuyuki 613 

Kubo, Michiaki 10520 

Kubo, Yoshiro 3524 

Kubota, Akira 5542 

Kubota, Kaoru 7028, 7515, 

7549 

Kubota, Yoshihiro e11564 

Kubota, Yoshinobu 4626 

Kucera, Stephen e14714 

Kuchimanchi, Mita 5072 

Kuchroo, Vijay 8571 

Kucuk, Omer 4656, 5534, 

e15006, e16019, e20000 

Kucuk, Ozlem e21006 

Kucukoner, Mehmet 638, 

e14526 

Kucukoztas, Nadire e11011, 

e11023, e11026, e11045, 

e11515, e14174, e15572, 

e15573 

Kuczyk, Markus 4530, 

e15195 

Kuda, Tomoya 7571, e19521 

Kudaka, Wataru 5086 

Kudchadkar, Ragini Reiney 

3102, 8510, 8582, 8587 

Kuderer, Nicole Maria 6129, 

9135 

Kudo, Daisuke 8094 

Kudo, Keita 10569, 10604, 

e18004, e18014, e18017 

Kudo, Kenichiro 7576 

Kudo, Masatoshi 4033, 4104, 

e14617 


Kudo, Mineo 3593 

Kudo, Toshihiro e18060 

Kudoh, Kazuya 5037, 

e15579 

Kudoh, Shinzoh 7521, 

e17538 

Kudoh, Shoji 7515 

Kudrik, Fred J. 8567 

Kudrimoti, Mahesh R. 

e16035 

Kuebler, J. Phillip LBA506 

Kuehne, Reto 3595 

Kuemmel, Sherko 556, 624 

Kuemmerlen, Verena e18010 

Kuenzel, Heike TPS7617 

Kuerer, Henry Mark 1028, 

1102, 1130, 1549, 

TPS10631 

Kufer, Peter 2504 

Kugler, John William 7073 

Kuhn, Christina e15529 

Kuhn, Peter 4102, e21074 

Kukla, Andrea K. 5544 

Kukreti, Vishal 8035 

Kukura, Vlastimir e12505 

Kulakodlu, Mahesh e14013, 

e14016 

Kulanthaivel, Palaniappan 

3001 

Kulig, Kimary 2021 

Kulikov, Evgeny TPS4696^ 

Kulita, Patrycja e19561 

Kulkarni, Raghav e16042 

Kulkarni, Sujay 3011, 3013 

Kulkarny, Vibhati 1558 

Kulke, Matthew 3594, 4085, 

4125, 4126, e14542, 

e14551 

Kuller, Anne 4011 

Kuller, Lewis H 1501 

Kullmann, Frank TPS3641^, 

4072 

Kullmann, Verena 5051 

Kulma-Kreft, Monika e21099 

Kumagai, Toru e18025 

Kumaki, Nobue 565 

Kumanogoh, Atsushi e18007, 

e18141 

Kumar, Aalok 3527, e14568 

Kumar, Chandan 4591 

Kumar, K. Sunesh 5104 

Kumar, Kirushna 9117 

Kumar, Lalit 5104, 6593, 

e15510, e18518, e18573 

Kumar, Mukesh 8101 

Kumar, Nagi B. e21155 

Kumar, Pankaj 5540 

Kumar, Parag 2591, 5050, 

e13063, e13074 

Kumar, Pavan e19055 

Kumar, Priya 5500, 5544 

Kumar, Rachit e19025 

Kumar, Sanjeev e19516 

Kumar, Satish TPS8605 

Kumar, Shaji 8033, 8034, 

8092, 8095, 8096, 8105, 

TPS8116, e13517 

Kumar, Sunesh e15518 

Kumatani, Youji 1103 

Kumbhaj, Prashant e16012 

Kume, Makoto e14518 

Kummar, Shivaani 3031, 

3087, 3529, 5020, 8073 

Kumosa, Lucas e21047 

Kun, Larry E. 9531 

Kundel, Yulia e14067, 

e14571 

Kung, Andrew L. e13586 

Kung, Ling e16523 

Kunieda, Katsuyuki 3607, 

TPS3642 

Kunimasa, Kei 7528, 

e18025, e18134 

Kunisaki, Chikara 4070, 

e14624 

Kunitoh, Hideo 7012, 7515 

Kuniyoshi, Renata Kelly 

e11059 

Kunju, Priya 4591 

Kunkel, Lori A. 8035 

Kunnavakkam, Rangesh 

2561, 6582 

Kunnavakkum, Rangesh 6562 

Kunos, Charles 5089, 5102 

Kunst, Peter W.E. 7019 

Kunst, Tricia 7103 

Kuntz, Karen M 6016 

Kunz, Claudia 2034 

Kunzmann, Volker 4072, 

e13100^ 

Kuo, Han Pin TPS7614 

Kuo, Kevin F 4557 

Kuo, R-Y e14699 

Kuo, Wen-Hung 1043 

Kuom, Sabine 7572 

Kupershmidt, Ilya e21159 

Kupersztoch, Yankel M 

e16500 

Kupets, Rachel 6134 

Kupka, Markus 554 

Kurachi, Yoshitaka TPS3642 

Kurahashi, Issei 4012 

Kuramochi, Hidekazu e21108 

Kuraoka, Kazuya 5084 

Kurata, Takayasu 7000, 

e18060, e18128 

Kurbacher, Christian M. 

e13100^ 

Kurdziel, Karen A 10589, 

e18568 

Kure, Elin 3548 

Kurek, Ralf e15191 

Kurhanewicz, John V. 4660 

Kurian, Seira 9505 

Kurihara, Hiroaki 10519 

Kurihara, Laurie 10587 

Kurkjian, Carla 3008, 3041, 

3067, 3097, e17012 

Kurkure, Purna Arun 9559 

Kurland, Brenda F 1088, 

TPS3109, 5503, 5515 

Kurland, John F. TPS8603 

Kurmasheva, Raushan 9544 

Kuroda, Ken e19577 

Kuroda, Nobukazu e14518 

Kuroi, Katsumasa 540 

Kurokawa, Koji e17540 

Kurokawa, Mineo 6533 

Kurosaka, Masahiro e17020 

Kurosumi, Masafumi 613 

Kurozumi, Sasagu 613 

Kursar, Jonathan D. 3008 

Kurt, Hakan e15104 

Kurtagic, Elma 4056 

Kurtin, Sandra E 3028 

Kurtz, Jean Emmanuel 636 

Kurtz, Jean-Emmanuel 2605, 

4071, 10056 

Kurzeder, Christian 5031 

Kurzrock, Razelle 535, 2583, 

3003, 3078, 3106, 3107^, 

TPS3117, 3528, 4639, 

5021, 8531, 8551, 8594, 

10510, 10607, e13020, 

e13506, e13534, e13595, 

e13596, e13600^, 

e19004, e19055 

Kusche, Manfred 10600 

Kuschel, Petra 10046 

Kushi, Lawrence H e14160 

Kushnir, Michal e14067 

Kuss, Iris LBA10008 

Kussman, Ashleigh M. 

e14098 

Kusuhara, Masatoshi e14635 

Kusumoto, Masahiko 1530 

Kusumoto, Sojiro e13029 

Kusumoto, Tetsuya e14722 

Kusunoki, Masato e14029, 

e14039, e14541, e21053 

Kusunoki, Yoko 10577 

Kutateladze, Tatiana G. 7504 

Kuten, Abraham e18511 

Kutikov, Alexander 4526 

Kutluk Cenik, Bercin e13563, 

e18076 

Kutscheidt, Andreas 1077 

Kutscher, Sarah 2522 

Kuttruff, Sabrina 2522, 3530 

Kutwak, Flavia 7049 

Kuvshinoff, Boris W. e14659 

Kuykendal, Adam Rea 4647 

Kuzel, Timothy e13088, 

e18523 

Kuzman, James A e15580 

Kuznetsov, Galina 3030 

Kvale, Elizabeth 6080 

Kvikstad, Anne 9040 

Kvols, Larry 4125, e14579 

Kwa, Maryann e11010 

Kwak, Eunice Lee 2566, 

3053, 3528, 4021, 4027, 

7508, e14615 

Kwak, Larry W. 2528, 8067 

Kwan, Min-Fun Rudolf 4654 

Kwan, Sherry e15154 

Kwari, Monica 6501 

Kwiatkowski, David J. 7589 

Kwiatkowski, Fabrice 1051 

Kwo, Paul e14683 

Kwoh, T. Jesse e13562 

Kwok, Chloe 4105, e14706 

Kwok, Mary 8088, 8104, 

e18568 

Kwok, Shirley 10586 

Kwon, Deukwoo e16001 

Kwon, Hyuk-Chan e14686 

Kwon, Jung Hye 9065, 

e19599, e19603, e19613 

Kwon, Tack-Kyun 5552 

Kwon, Woo Sun 3606 

Kwong, Philip 4105 

Ky, Bonnie 4500 

Kühne, Thomas 10081 

Kyle, Robert A. 8105 

Kyriakopoulos, Christos 1071, 

e11038 

Kyuichi, Kadota 7052 

König, Jochem 1082 

König, Klaus e11040^ 

L 

L’Heureux, Darryl TPS5114, 

TPS10635 

La Delfa, Anthony 9032 

La Quaglia, Michael P. 8586, 

TPS9595 

La Russa, Francesca 4541 

La Spina, Chiara Maria 7082 

La Torre, Ignazia 1073 

La Verde, Giacinto e17006, 

e18563, e18566 

La-Beck, Ninh My 2591, 

5050 

La-Touche, Susannah 4640 

Laack, Eckart LBA7507 

747s

Laack, Nadia N. 2032, 

e14507 

Laadem, Abderrahmane 607, 

e15170, e19609 

Labadie, Julia 1100 

labardini-Mendez, Juan 6599 

Laberge, Francis 7511 

Labianca, Roberto LBA4001, 

4053, LBA7501, TPS9155, 

e19549, e19612 

Labiano, Tania 8572, e18008 

Labidi-Galy, Sana Intidhar 

10562 

Labonte, Melissa Janae 3540, 

3546, 3584, 3604, 3622, 

4026, 4088, e11018, 

e14034, e14052 

Labouba, Ingrid e15202 

Labow, Daniel M. e14656 

Labrie, Fernand 10583 

LaCasce, Ann S. e18530 

Lacave, Roger e18075, 

e18089 

Lachance, Daniel Honore 

9075 

Lack, Carole 9589 

Lackey, Jacqueline 4568 

Lackner, Mark e21122 

Lacombe, Denis A. 2, 2540 

Lacombe, Sophie 4018 

Lacoste, Gisele TPS7610 

Lacour, Valerie 4622 

Lacouture, Mario E. 8515, 

9088, 9092, e13591, 

e18571, e19052, e19624 

Lacroix, Joëlle 4618 

Lacroix, Ludovic 10556 

Lacroix, Magali TPS667 

Lacroix-Triki, Magali 543 

Lacy, Antonio 3536 

Lacy, Cindy 2077 

Lacy, Jill e14534 

Lacy, Martha 8043, 8092, 

8096, 8105, TPS8116 

Lad, Thomas E. 9085 

Ladabaum, Uri 6077 

Ladanyi, Marc 1541, 7505, 

7532, 7578, 7580, 7589, 

10524, 10560 

Ladekarl, Morten e21110 

Lademann, Juergen 5064, 

e19558 

Ladha, Abdullah e19627 

Ladner, Robert D. 3584, 

3622 

Ladrera, Guia Elena 7519^ 

Lae, Marick 10018 

Lafitte, Jean-Jacques 

TPS7111, e18006, e18066 

Laflamme, Christian 634 

Lafleur, Josiane TPS1139 

LaFrance, Norman David 

e13592 

Lagarde, Pauline 9536 

Lage, Agustin 2527 

Lagerwaard, Frank J 7009 

Lagier, Robert 10586 

Lagrone, Lore 2003 

Laguerre, Brigitte LBA4567^ 

Laheru, Dan 3596, 4045, 

4055, e14585 

Lahn, Michael M. F. 2042 

Lahogue, Annick TPS649 

Lahuerta, Ainhara 10512, 

10595 

Lahuerta, Juan José 8095 

Lai, Cheng e13101 

Lai, Chyong-Huey 5109 

Lai, Dominic W. e16052 

Lai, Jin-Shei 9532 

Lai, Lily L. e14182 

Lai, Maria 4105, e14706 

Lai, Pamela 6083 

Lai, Rose 2006 

Lai, Ruay-Sheng TPS7614 

Lai, Siang Hui 2066 

Lai, Wei-Chu V 5078 

Lai, Xin e14706 

Lainas, Ioannis TPS6634, 

TPS8603 

Laine, Fabrice 8057 

Lainez Milagro, Nuria 

TPS4672, TPS4674, 

TPS4688 

Lainez, Jose Miguel e18555 

Laird, A. Douglas 8531 

Laird, Glen 7584 

Lakdawalla, Darius 4666, 

e15186 

Lake, Diana 10514 

Lake, Jessica 7054, 7055 

Lakomy, Radek 3505, 3579 

Lakshmanan, Imayavarambam 

e17549 

Lal, Anita 10576 

Lal, Priti 4596 

Lal, Rohit 7562 

Lalet, Caroline e14023 

Laliberte, Julie 9500, 10587 

Laliberte, Robert e13101 

Lall, Terrance e21026 

Lalla, Deepa 1037, 9144, 

e11063, e11076, e11077, 

e19633 

Lallas, Costas D. 4526, 

e15012 

Lallemant, Benjamin e16044, 

e16051, e16055 

Lally, Brian E. e16518 

LaLonde, Michelle 9115 

Lam, Elaine Tat 3017 

Lam, Paula 2066 

Lam, Raymond 10573, 

e13598 

Lam, Wayne 4640, e15100 

Lamanna, Nicole 6122, 

6609, 6613 

Lamar, Maria 4006, 4117, 

4545, 8519 

Lamar, Ruth E. 618, 

TPS8115 

Lamarca, Angela 10547, 

e13085 

Lambert, John M. 8057 

Lambiase, Antonio 2580, 

5059, 6541, 7076, 7085, 

7581 

Lambrechts, Diether 507, 

1020 

Lambrechts, Sandrina 5058 

Lamerato, Lois e12024, 

e15147, e15197, e18107, 

e19630 

Lamm, Donald L. 4593 

Lammers, Philip Edward 

6038 

Lammertsma, Adriaan A. 

7603 

Lamont, Elizabeth B. 1605 

Lamont, J. V. e14022 

Lamparella, Nicholas E. 

e15062 

Lampe, Dieter 624 

Lampron, Megan 4543, 4635 

Lamy, Aude 5565, e14010 

Lamy, Pierre-Jean 10505 

Lamy, Thierry 8026 

Lan, Guiping 5558 

Lan, Lan 1605 

Lan, Yun 4005 

Lancaster, Johnathan M. 

1585 

Lance, Ray 4586 

Lancelotta, Mary Pat 10590 

Lancet, Jeffery 6588 

Lancet, Jeffrey E. 3081, 

6568, 6586, 6601, 6608, 

TPS6637 

Lanchbury, Jerry S. 7023 

Lanctot, Jennifer 9526 

Lanczky, Andras 10571 

Land, Stephanie R. TPS1142 

Land, Susan 7063 

Landa, Jonathan 4548, 

10002 

Landau, Danny e15010, 

e15102 

Landaverde, Denis e16547 

Landeiro, Luciana Garcia 

5588 

Landen, Charles N. 5036 

Lander, Thomas 2573^ 

Landers, Mark 1058 

Landesman, Yosef 1055, 

4634, e13549 

Landgren, Ola 8088, 8104, 

e18568 

Landi, Bruno 10078 

Landi, Lorenza 3521, 

LBA4001, e21018, e21095 

Landier, Wendy 9505 

Landolfi, Joseph C. TPS2107 

Landolfi, Stefania 4089, 

e21021 

Landreneau, Joshua P 7071 

Landreneau, Rodney Jerome 

7071, 7074 

Landry, Jerome Carl 3605 

Landsman, Keren 1578 

Landsman-Blumberg, Pamela 

593 

Lane, Alex R. e15116 

Lane, Ashley R. 9543 

Lane, Dorothy S 1501 

Lane, Kathleen A. e16557 

Lane, Sharon e16515, 

e16559 

Lang, Amy 2555 

Lang, Evan Z. 4127 

Lang, Forrest TPS9147 

Lang, Frederick F. 2019 

Lang, Hauke TPS3641^ 

Lang, Jin Yi 5597 

Lang, Jin-yi 5535 

Lang, Katherine 1563 

Lang, Kathy 9144, e19633 

Lang, Melanie e19502 

Lang, Roland 8563 

Lang, Wenhua 5524 

Langdon, Robert M. 4085, 

TPS7619 

Lange, Georgia 1028 

Lange, Joan E e16053 

Lange, Julie R. 1128 

Lange, Paul H. 4520 

Langer, Christiane TPS3635^ 

Langer, Claus 10031 

Langer, Corey J. 5583, 7077, 

7092, 7098, 7590, 7595, 

TPS7612, TPS9150, 

e16062, e18032 

Langer, Seppo W. 4015 

Langer, Stefan 10059 

Langholz, Bryan 9515 

Langleben, Adrian 1099 

Langley, Emma J. e14584 

Langley, Ruth E TPS4143 

Langridge, Carolyn I 5527 

Langston, Amelia A. 8101 

Lani, Elisa e21095 

Laniado, Michael 10068 

Lanier, Keith S. e16561 

Lanigan, Christopher 620, 

e18085 

Lankeit, Henrike Katharina 

8052 

Lankheet, Nienke A.G. 2596 

Lann, Danielle 1540 

Lannin, Donald R. 1045, 

1109, 1121 

Lannoy, Valerie e14044 

Lannutti, Brian Joseph 6518^ 

Lanoy, Emilie 4621, 10044, 

e18071 

Lantzsch, Tilmann 624 

Lanuti, Michael 7010 

Lanza, Giovanni 3510 

Lanzalone, Silvana 7533 

Lanzardo, Stefania e13527 

Lanzetta, Gaetano 4627 

Lanzirotti, Antonio e13067 

Lanzos Gonzalez, Eduardo 

e15033 

Lanzotti, Victor J. 6054 

Lao Romera, Juan e11081 

Lao, Christopher D. 8521 

Lao, Juan 10512, 10595 

Lao-Sirieix, Si-houy 4121 

Lapadula, Vittoria 9133, 

e14096 

Laperriere, Normand 2008b, 

TPS2104 

Lapique, Nicolas 3511 

LaPlant, Betsy 6570, 8013, 

8043 

Lapolla, Assunta Maria 

e11001 

Laporta, Rosalia e12015 

Lapunzina, Pablo 3618, 

10547 

Lara, Gisell Anaid 1607 

Lara, Jonathan F. 614 

Lara, Miguel Angel e11074 

Lara, Primo 3566, 4511, 

4547, 4607, 4663, 7514, 

10503, e17537 

Lara-Medina, Fernando 

e12027 

Larbi, Emmanuel Douglas 

e15517 

Lardelli, Pilar TPS652, 

TPS10101 

Largillier, Remy 568^, 

e11019 

Lariou, Maria Stella e20002 

Larkin, James M. G. 

TPS4679, TPS4682, 

8502^, LBA8509, 8517, 

TPS8605, 10038 

Larkins, Gail 8016 

Larocca, Luigi Maria e14042, 

e18021 

LaRocca, Renato V. TPS2107 

Larry, Wang 9564 

Larsen, Eric 9502, CRA9508 

Larsen, Julie S. TPS666 

Larsen, Linda 1124 

Larsen, Stig Einride e11022 

Larsimont, Denis 507, 

e21010 

Larson, Melissa L. e18510 

Larson, Peder E. 4660 

Larson, Richard A. 2533, 

6509^, 6526, 6562, 6582 

Larson, Robin Joyce 6013 


Larson, Steven M. 3563, 

4517, 4548, 5509^ 

Larsson, Olle 7539 

Larue, Christine 10098 

Lasalvia-Galante, Eduardo E. 

e13105 

Lasalvia-Prisco, Eduardo M. 

e13105 

Lasch, Kathryn Eilene 

e12515 

Laser, Benjamin S. 5088 

Lash, Alex e19647 

Laskin, Janessa J. 7020 

Lasley, Foster D e14683 

Lassau, Nathalie 3080, 4618 

Lasso, Roberto 10079 

Last, David 2078 

Lastiri, Jose Maria 10074 

Lastoria, Secondino e14130 

Lastoria, Secondo e19034 

Lata, Suman 531 

Lathan, Christopher S. 

e18067 

Lathia, Chetan D. e13576, 

e18100 

Latiano, Tiziana Pia e21092 

Latiano, Tiziana e19035 

Latif, Asma e21032 

Latif, Marcia e19647 

Latif, Rabia e18504 

Latko, Ewa 9026^ 

Latorre, Claudia Grandino 

e19552 

Latorzeff, Igor LBA4567^ 

Latouche, Aurelien TPS667 

Latreille, Jean LBA3500^ 

Latronico, Antuono 1500 

Lattanzio, Laura 2600 

Latten, M. J. e14022 

Latteri, Fiorenza e18026, 

e18096 

Lau, Anthea 7606 

Lau, Clayton e15178 

Lau, Derick 7517 

Laubacher, Barbara A. 

e21107 

Laubender, Ruediger Paul 

3541, 3588, 3603, 4023, 

e14043 

Lauderdale, Katharine E 9132 

Lauer, Richard C. 4603 

Lauer, Ulrich M 4115 

Laughlin, Anne 3082 

Launay-Vacher, Vincent 1095, 

5067 

Launchbury, Francesca 4653 

Laura, Perelli e11044, 

e11501, e18125 

Lauratet, Betty e11551 

Laurent, Dirk 3502, 

LBA10008 

Laurent, Louise C. 10539 

Laurent-Puig, Pierre 2537^, 

5098, 5554, e14059, 

e14129 

Lauria, Rossella 1554, 

LBA5003 

Lauricella, Calogero 3570, 

LBA7501 

Laurie, Scott Andrew 

TPS2615, 7093, 7511 

Laurino, Mercy 3567 

Lauseker, Michael 6510 

Lausoontornsiri, Wirote 4108, 

e13013, e16040 

Lautenschlaeger, Tim e21044 

Laux, Douglas Earl 3056 

Lauzier, Sophie 9138 

LaVallee, Theresa TPS2618 


Lavelle, Aonghus e19601 

Lavenia, Giuseppe e15544 

Laver, Joseph H. 9526 

Lavergne, Emile e15009 

Laverman, Peter e13111 

Lavery, Hugh J. e15164 

Lavey, Robert S 10048 

Lavole, Armelle e16560, 

e18075, e18102 

Lavolle, Armelle 7574 

Lavori, Philip W. 5525 

Lavranos, Tina C. 4603, 

7079^ 

Law, Linda 4085, e14564 

Law, Wai Lun TPS10632, 

e14032 

Lawal, Olukayode O e11554, 

e12022 

Lawal, Taoreed O e14734, 

e14736 

Lawrence, Donald P. 

CRA2509, 8503^, 8507, 

8510, 8516, 8522, 8569 

Lawrence, H. Jeffrey 10596 

Lawrence, Scott M 3031 

Lawrence, Theodore Steven 

e14603 

Lawrence, Yaacov Richard 

e14143 

Lawson, David H. 2576, 

8543, 8567, e13088 

Lawton, Thomas J. 516 

Lax, Sigurd e14066 

Lay, Harry H 2074^ 

Lay, John C. 2591 

Layman, Rachel M. CRA1002 

Layne, Tracy Melissa e16511 

Lazar, Vladimir 7529 

Lazaridis, George 592, 

e15040 

Lazaro Quintela, Martin 

TPS4672, e12012, 

e15067, e15076, e15077, 

e18040, e18146 

Lazarus, Hillard M. TPS1616 

Lazaryan, Aleksandr 8055 

Lazovich, DeAnn 8574 

Lazzarelli, Silvia 4097 

Lazzaretti, Maria Grazia 

e11071 

Lazzari, Chiara e18096 

Lazzeroni, Matteo 519, 1500 

Le Beau, Michelle M. 6562 

Le Boulicaut, Julie 10089 

le Caer, Herve 7574, e16051 

Le Cesne, Axel 10005, 

10006, 10007, LBA10008, 

10009, 10013, 10016, 

10017, 10020, 10023, 

10027, 10033, 10044, 

10056, 10062, 10067, 

10078, 10089, 10092 

Le Chevalier, Thierry 7007 

Le Corre, Delphine e14059 

le Coutre, Philipp D. 6503, 

6512, TPS6640 

Le Deley, Marie-Cécile 9517, 

TPS9596 

le Frere-Belda, marie-Aude 

5098, e15558 

Le Gall, Fabrice e18532 

Le Gall, Francois e19037 

Le Gouill, Steven 8026 

Le Guellec, Sophie 10076 

Le Loupp, Anne-Gaelle 2082, 

e21117 

Le Maignan, Christine 10042, 

e11019 

Le Monies, Alise e14168 

Le Page, Cécile e15202 

Le Pechoux, Cécile 10016, 

10044, e18071 

Le Rhun, Emilie TPS662, 

2070, e11012, e12506 

Le Teuff, Gwenael 3063, 

7007 

Le Tourneau, Christophe 

e13017 

Le, Anh T 7504 

Le, Dung Thi 4045 

Le, Lisa W. 7606 

Le, Lisa e16567 

Le, Lyly H. 6071 

Le, Ngocdiep T. 3003 

Le-Petross, Huong T. 594, 

1107 

Lea, Jayanthi e13078, 

e15501 

Leach, Laura M. 9115 

Leahey, Ann 9515 

Leahy, Michael Gordon 

LBA10008, TPS10101 

Leahy, Terri 2013 

Leak, Ashley Nicole 6119 

Leal, Alessandro e11513 

Leal, Alexis D. 9057 

Leal, Jeffrey P 4045, 10509 

Leandro-Garcia, Lj 10546 

Leary, Colleen e14549, 

e14550 

Leary, Sarah 9519, 9581 

Leasure, Justin 9544 

Leasure, Nick C. TPS657 

Leath, Charles A. e15578 

Lebbe, Celeste 1566, 8512, 

8518, 8591, 8601, 10056, 

e13594 

Lebedinsky, Claudia 

TPS6639, TPS6641 

Leber, Brian 6505^ 

Lebitasy, Marie Paule 

TPS7111 

Leblanc, Eric 5083 

LeBlanc, Michael Leo 8001 

Leblond, Veronique 8030 

Leboeuf, Rebecca 5509^ 

Lebot, Marie-Annick e14148 

Leboulleux, Sophie 5569 

Lebourgeois, Paul A. 3630 

Lebovic, Daniel 8011 

Lebowicz, Yehuda Z. 

TPS5601 

Lebrec, Jeremie 10619 

Lebret, Thierry e15145 

Lebrun, Christine e12502 

Lebrun-Jezekova, Daniela 

9079 

Lebrun-Ly, Valerie 10078 

Lebwohl, David Edward 512, 

559 

Leccia, Marie Thérèse 8591 

Lechuga, Carmen e15033 

Lechuga, Mariajose 4644 

Leclercq, Nathalie e18006 

Lecomte, Thierry 3520, 4018 

Lecumberri, Ramon 7095 

Lecuru, Fabrice 5098, 

e15558 

Ledermann, Jonathan A. 

4004, 4029 

Ledesma, Wendy M. 555, 

563, 6063 

Lee, Adam 3564, 3617 

Lee, Adrian Pak Siu e12507 

Lee, Adrian e19042 

Lee, Agnes Y. TPS9149^ 

Lee, Ann Sing 4105, e14706 

Lee, Annette 1046 

Lee, Belinda e21137 

Lee, Bong-Jae e18501 

Lee, Bonnie e16523 

Lee, Brian 9553 

Lee, Byeong IL e14580 

Lee, Byung-In 1058, e14164 

Lee, Changsuk e14543 

Lee, Charlene e15042 

Lee, Chee 3534, 5081 

Lee, Ching-Chih e16008 

Lee, Christina R. e15177^ 

Lee, Christopher W. 7511 

Lee, Clara Inkyung e19011 

Lee, Conrad 4105, 5511 

Lee, Dae Ho 7004, e13104, 

e15080, e18052 

Lee, Dana e16533 

Lee, Dennis J e15060 

Lee, Donghoon e18119 

Lee, Edmund Jon Deoon 

2598 

Lee, Edward James 6591 

Lee, Eudocia Quant 2005 

Lee, Fook Thean e15056 

Lee, Geon Kook e21043 

Lee, Geun Dong e14573 

Lee, Gil Yeon e14128 

Lee, Gin-Hyug 4093 

Lee, Grace Lauren e13084 

Lee, Guek Eng 3098, 3589 

Lee, Guk Jin e14558, 

e19614 

Lee, Gwo-Shu Mary 4516, 

4543, 4635 

Lee, Hae Won e17523 

Lee, Haekyung 1053 

Lee, Hee Jin e11504 

Lee, Hee Seok e21043 

Lee, Hee Yeon e14558, 

e19614 

Lee, How-Sung e13002 

Lee, Hun Ju 6598 

Lee, Hwang-Jae e19574 

Lee, Hye Yoon 2542 

Lee, Hyo Jin e12029, 

e14529 

Lee, Hyun Woo e14580, 

e18519 

Lee, Hyun-Ju 2541 

Lee, Hyun-Jung 3624, 

e14136 

Lee, Hyun-Sung e16534 

Lee, J. Jack 5524, 7047, 

7078 

Lee, Jae Cheol e18052 

Lee, Jae Hoon 8095, 8097, 

e14137, e14685, e18572^ 

Lee, Jae Seok 6564 

Lee, Jae-Lyun 3568, 3592, 

4536, 4538, 4544^, 4628, 

e13104, e13560, e15080 

Lee, Jang-Ming e14576 

Lee, Jay Ted e19509 

Lee, Je-Hwan 6564 

Lee, Jeanette Y 4030, 8005 

Lee, Jeeyun 4011, 4064, 

10067, 10535, e12029, 

e13044, e13094, e14072 

Lee, Jeffrey Edwin 4051, 

8534, e14548 

Lee, Jeffrey H. 4051 

Lee, Jeffrey H 4069, 4078, 

4086, e14547, e14669 

Lee, Jennifer TPS4134 

Lee, Jeong-Ok 7566 

Lee, Jerry 1058 

Lee, Ji Hyun 1053 

Lee, Ji Hyun e14686 

Lee, Ji Yean e16003, e18148 

749s

Lee, Ji-Hyun TPS3114, 6100 

Lee, Jihye e13044 

Lee, Jill Lunsford e16502 

Lee, Jin Soo 7089, 7519^, 

e18119 

Lee, Jin e19611 

Lee, Jinseon 7053, e18083, 

e21062 

Lee, John Muzi 9019 

Lee, John e19580 

Lee, Jong Won e11508 

Lee, Jong Yeul 4028 

Lee, Jong-Eun e13065 

Lee, Jong-Seok 3076, 

TPS7614 

Lee, Ju Ruey-Jiuan 10596 

Lee, Ju-Whei 5566, 5576 

Lee, Jun Ho 4028 

Lee, Jun Woo e14566 

Lee, Jung Shin 3592, 7004, 

e18052 

Lee, Jung-Hee 6564 

Lee, Jung-min 2545 

Lee, Jungsin e13061, 

e13104 

Lee, Kang Young e14081, 

e14084 

Lee, Keun Seok 2542 

Lee, Keun Wook e14580 

Lee, Keun-Seok TPS649, 

1003 

Lee, Keun-Wook 3076, 

e14572 

Lee, Khai Mun 5553 

Lee, Ki Hyeong LBA7500 

Lee, Kichun Sky 7048 

Lee, Kyoo-Hyung 6564 

Lee, Kyu Seop e14529 

Lee, Kyu Taek e14688, 

e19538, e19554 

Lee, Kyung Hee TPS4142, 

e14570, e14572, e19538 

Lee, Kyung-Hun 2542, 3624, 

5552, e14136 

Lee, Kyung-Min 1056 

Lee, Lawrence Soon-U 

e13002 

Lee, Lip e18095 

Lee, Louis e15110 

Lee, Luen F. 3522, 3523, 

3525 

Lee, Lynette e14155 

Lee, Mark 3512, 4560 

Lee, Michele 1118 

Lee, Michelle Mei Lin 4106 

Lee, Min Mi 2041 

Lee, Min-Jung 3087, 7033 

Lee, Moon Hee 1003, 

TPS4142 

Lee, Myung Ah e14558, 

e14634, e19614 

Lee, Myung Kyung 9066 

Lee, Namsu e14688, e19554 

Lee, Nancy Y. 5537, 5545^ 

Lee, Patrick W. e21090 

Lee, Peter 3010, TPS8109 

Lee, Po-Huang e13061, 

e20514 

Lee, Richard J. 4566 

Lee, S. Ming 7538 

Lee, Sandra J. 8522 

Lee, Sang Cheol e19554 

Lee, Sang-Cheol e14688 

Lee, Sang-Joon 5549, 

TPS5602 

Lee, Sang-wook 5586, 

e18501 

Lee, Se-Hoon 4544^, 5552, 

7004, 7566, e15047, 

e15064 

Lee, Shih-Yuan 4549 

Lee, Shing Mirn 2541 

Lee, Simon Craddock e19536 

Lee, Siow-Ming 7562 

Lee, Soo Jung 3554, 6536, 

6538, e14074, e18533 

Lee, Soo-Chin 530, 1064, 

1575, 2551, 3002, 

e13002, e19523 

Lee, Soohyeon 1003, 2542, 

e16529 

Lee, Soonil 4064 

Lee, Stephanie 6103, 9139 

Lee, Su Jin 644, 7104 

Lee, Suee e14686 

Lee, Sun Ah e14570 

Lee, Sunmin 3087 

Lee, Susanna TPS5114 

Lee, Sze Ting e15056 

Lee, Sze Xian e21078 

Lee, Tani Ann T. 4011 

Lee, Theresa 1521 

Lee, Ting Yim TPS5114 

Lee, Victor 5511, 7519^, 

e18063^ 

Lee, William 3086 

Lee, Won Chan 570 

Lee, Won-Suk e14137 

Lee, WY e15110 

Lee, Yeon-Su 7089 

Lee, Yihua 4007, 4504, 

4513, 5547 

Lee, Yin Leng 1593 

Lee, Yong Chan e14559 

Lee, Yoo Jin 6536, e18533 

Lee, Young Joo e18119 

Lee, Young-Shin 6564 

Lee, Yu-Chin e18132 

Lee, Zi-jia e11068 

Leen, Ann M. 2558 

Leer, Jan Willem 9070 

Lees, Michael e19010 

Leeuwen, Frank van 9550 

Lefebvre, Caroline 530 

Lefesvre, Pierre e14044 

Lefeuvre, Delphine 3063 

Lefeuvre-Plesse, Claudia 

e11012 

Lefevre, Arthur e12506 

Lefranc, Anne 10027 

Lefranc, Jean-Pierre 641, 

e11551 

Legare, Robert Duffy 1045 

Legouffe, Eric 4625, 

TPS4692^, 9011 

Legoux, Jean-Louis 3506 

Legrier, Marie-Emmanuelle 

e15161 

Legros, Laurence 6523 

Lehman, Robert TPS1145 

Lehmann, Frederic 7013, 

7056 

Lehmann, Karl M 5051 

Lehmann, Sylvia 10552 

Lehmkuhl, Hans 8030 

Lehner, Julia e21067 

Lehners, Nicola 6519 

Lehnert, Manfred 2512 

Lehtimaki, Terho e15564 

Lei, Junying 1508 

Lei, Lei e17512 

Lei, Xiudong 537, 1029, 

1104 

Leibold, Tobias 3563 

Leibovich, Bradley C. 4657 

Leiby, Benjamin E e16548 

Leichman, Lawrence P. 4052 

Leigh, Bryan R. 3034, 

3042^, e21038 

Leigh, Meggan TPS661 

Leighl, Natasha B. 1535, 

6005, 7541, 7586, 7606, 

9003, 9032, 10522, 

e11000, e11050, e16505, 

e18079 

Leighton, John Charles 

e16561 

Leijen, Suzanne e13598 

Leinwand, Joshua e13064, 

e13066, e13067 

Leinweber, Clinton 2032 

Leip, Eric 6511 

Leis, Jose Francisco 8053 

Leisen, Margarete 10041^ 

Leisenring, Wendy M. 6030, 

9505, CRA9513, 9514, 

9528 

Leitao, Mario M. 9104 

Leitch, A. Marilyn 503, 1107 

Leitzel, Kim 501, 607, 614, 

e14520, e15062, e15121, 

e15170, e21039 

Lekakis, Lazaros e11519 

Leleu, Xavier 8009, 8014, 

8095 

Lema, Mauricio e19604 

Lemare, Francois 9560, 9572 

Lemarié, Etienne e18100 

Lemas, M. Victor 8003 

Lemech, Charlotte Rose 

e13585 

Lemech, Charlotte 3000 

Lemieux, Julie 634, 9138 

Lemke, Klaus 6026 

Lemke, Sheila M. e11089 

Lemoine, Antoinette e14521 

Lemonnier, Christine 1574 

Lena, Hervé TPS7112, 7584 

Lenain, Pascal 8014 

Lencioni, Monica 4006 

Lencioni, Riccardo 4108, 

TPS4152 

Lendinez, Alberto e14147 

Lendvai, Nikoletta TPS8111 

Lengerke, Claudia e15577 

Lengfelder, Eva 6610, 8024 

Lenhard, Miriam Susanne 

1114 

Lennes, Inga Tolin 6048, 

6062, 6106, 7524, 9030 

Lensing, Janet 3001 

Lentzsch, Suzanne 8099 

Lenz, Cosima 3584 

Lenz, Felicitas 3584 

Lenz, Guido e13546 

Lenz, Heinz-Josef 3078, 

3502, 3518, 3540, 3546, 

3549, 3584, 3597, 3604, 

3615, 3622, TPS3635^, 

4010, 4019, 4022, 4026, 

4047, 4049, 4088, 4096, 

4113, e11018, e14031, 

e14034, e14052, e14679 

Lenzi, Renato 4130, 4131 

Leo, Ermanno e21118 

Leo, Silvana Assunta e18048 

Leon Mateos, Luis TPS4674, 

TPS4688, e15067, 

e15076, e15077 

Leon Rodriguez, Eucario 

e15567 

Leon, Ana 5520, e14147, 

e15094, e18069, e18106, 

e21015 

Leon, Larry 7573 

Leon, Luis TPS4685, e19505 

Leon, M. 4630 

Leon, Paola Beatriz 4089 

Leon, Xavier 5590, 5595 

Leon-Ferre, Roberto e14620 

Leonard, David e19536 

Leonard, E. Jane TPS8109, 

TPS8110 

Leonard, Gregory e14687 

Leonard, John 6518^, 8000 

Leonard, Robert C. F. 1094 

Leone, Alvaro e19033 

Leone, Bernardo Amadeo 

e11021 

Leone, Francesco 4110 

Leone, Jose Pablo e11021 

Leone, Julieta e11021 

Leong, Lambert T 1599 

Leong, Lucille A. 3108 

Leong, Stephen 3017 

Leong, Swan e16024 

Leong, Trevor 3629, 

TPS4141 

Leong, Wey 1019 

Leongamornlert, Daniel 1545 

Leontovich, Alexey A 8599 

Leopold, Lance 2500^ 

Lepage, Come 4129 

Lepère, Céline 3547, 4036 

Lepeu, Gerard 6633 

Leporati, Meri e11071 

Leppa, Sirpa 8074 

Leppert, John 10513 

Lera, Andrea Thaumaturgo 

e19552 

Lerchenmuller, Christian A. 

556, 4065, 4539 

Lerda, Daniel e21025 

Lerma, Enrique 1120, 10555 

Lerner, Seth P. 4586, 

TPS4673, TPS4678, 

e15002, e15003 

Lerner, Susan 6122, 6517, 

6598 

Lerner, Tatiana Goberstein 

e19552 

Leroux, Agnès 10517 

Lerro, Catherine C. 6008, 

6011 

Lerut, Evelyne e13061 

Lerzo, Guillermo Luis e11087 

Leschinger, Monika Iris 7554 

Lesho, Patricia 8075 

Lesimple, Thierry 8591, 

e13594, e19037 

Lesinski, Gregory B. e13549 

Leslie, Scott 4589, e15060, 

e15212 

Lesniak, Maciej S. 2014 

Lesnick, Connie E e13517 

Lesnikoski, Beth-Ann 1030 

Lesnock, Jamie L e15560 

Lesoin, Anne LBA5000, 5018 

Lesokhin, Alexander M. 2518 

Lesovoy, Vladmir 4501 

Lespagnol, Alexandra e19037 

Lessa, Rafael Costa 643, 

e18078 

Lessard, Laurent e15202 

Lesser, Glenn Jay TPS2107, 

9108 

Lester, Jason 6058 

Lestuzzi, Chiara 645 

LeTarte, Nathalie 2073, 

e13027, e19591 

Letendre, Louis 6614 

Leteurtre, Emmanuelle 4129 

Lethert, Kristine H. e11042 

Letocha, Henry e14531 


Letrent, Stephen P. 7530, 

TPS7615 

Letson, Douglas D 10048, 

10070 

Leunen, Karin 3048 

Leung, Abraham C. F. 5048 

Leung, CM e15110 

Leung, K C 4105 

Leung, Marco 8537 

Leung, Mova e19570 

Leung, Roland Ching-Yu 

e14545 

Leung, Sing Fai 5511, 

e15110 

Leuschner, Carola 3060 

Leuschner, Ivo 9573 

Leux, Christophe 2082 

Lev, Dina 10000 

Levchenko, Eugeny 8559 

Levenback, Charles 5027 

Levers, Marloes 9550 

Leverson, Glen e14554 

Levi, Edi 9578 

Levi, Francis 3547, 

TPS9154, e14006 

Levigne, Frederic e15109 

Levillain, Pierre 3520 

Levin, Glenn N e15192 

Levin, Tomer 9004, 9105 

Levin, Victor A. 2003, 2036 

Levin, Wendy J. 4010 

Levine, Douglas A. 5030, 

5043 

Levine, Edward A. LBA1000 

Levine, Edward Allen 6127, 

TPS10632 

Levine, Ellis Glenn 4506 

Levine, Mark Norman 

LBA1031, 6049 

Levine, Ross L. 6606, 9507 

Levinson, Adam W. e15164 

Levit, Claudio e15507 

Levitan, Denise A. 6524^ 

Levitsky, Hyam I. 2513 

Levitt, Amanda e18061 

Levitt, Daniel 10036 

Levitt, Jonathan M. e15002 

Levra, Matteo G. 7085 

Levy, Antonin e15049 

Levy, Benjamin 3024, 6114, 

e18139 

Levy, Christelle e11019 

Levy, Richard S. 6626^ 

Levy, Robert M. 2035 

Levy, Ronald 2513, 2514, 

e13555 

Levy-Gabriel, Christine 9538, 

e13017 

Lew, Danika 9018 

Lewandowski, Jennifer Ann 

6115 

Lewanski, Conrad R. 7538, 

7562 

Lewin, Sharyn Nan 6078, 

e13066 

Lewinshtein, Daniel 4669, 

e15207 

Lewis, Andrea L. 1512 

Lewis, Colleen Margaret 

2576, 3094 

Lewis, Jacqueline S e21137 

Lewis, James D. 1503 

Lewis, Jason S. TPS9595 

Lewis, Jen Kate 10525 

Lewis, Joe e15126 

Lewis, John D. e21090 

Lewis, Karl D 3102, 8503^, 

8510, 8579 

Lewis, Lionel D. 2533 


Lewis, Marina T 10580 

Lewis, Mark 4075 

Lewis, Samantha 3028 

Leyland-Jones, Brian 626, 

1027, e13579, e21099 

Leynia, Pierre e14148 

Leyvraz, Loredana e19050 

Leyvraz, Serge 8532, 10033, 

e11048 

Lezama -Valle, Pablo e20005 

Lezon-Geyda, Kimberly 10508 

Lhomel, Christine 1566, 

1567, 8601 

Lhomme, Catherine 5028, 

10098 

Lhommel, Renaud 3559, 

5519 

Li Destri, Marta 5093, 5094 

Li, Aiwu e18123 

Li, Ang e17018 

Li, Baoping e13069 

Li, Benjamin Xiaoyi 9017 

Li, Benjamin e11541 

Li, Bing 7535 

Li, Chenghong 9526 

Li, Chunde 4561 

Li, Chung-I 7094, 7568 

Li, Claire 2601 

Li, Dan e18051 

Li, Daneng 5108 

Li, Dechuan e14049 

LI, Fang 1097 

Li, Gang e13045 

Li, Gavin 1583, 3632 

Li, Ge 10625 

Li, Gu e21060, e21111 

Li, Guisheng e16054 

Li, Hailun 8003 

Li, Hairong 8596 

Li, Haiyan e13589 

Li, Hanzhong 4628 

Li, Haojie 4092, e14575 

Li, Hong e21156 

Li, Jennifer 5019, e18549 

Li, Ji e14651 

Li, Jian e14604 

Li, Jianbin e11520, e11521, 

e13524, e13529, e13530 

Li, Jiayu 7535, 10527 

Li, Jie e14604 

Li, Jieran 10622 

Li, Jin 3038 

Li, Jing 1560 

Li, Jingjin TPS6643^ 

Li, Jinhui 4558 

Li, Jun 1515, 1561, e14024 

LI, Kai 7548 

Li, Lang 505, 525, 2601 

Li, Li 1569, 10532 

Li, Ling 6003 

Li, Lingheng e14153 

Li, Longjiang 5507 

Li, Lu 7091, e14648, 

e18033 

Li, Marilyn M. 10598 

Li, Mingjie e18549 

Li, Mo-Dan e14026 

Li, Ning 9544, e14511, 

e14539 

Li, Qiang 7559, e18013 

Li, Qing e11025, e11538 

Li, Qiyu 9045 

Li, Qunna e21045 

Li, Robin 10539 

Li, Rong 1551, e12010, 

e12013, e17551 

Li, Rubi 7549 

Li, Rui 4645 

Li, Sandra e13585 

Li, Shan 3623 

Li, Sheng 9507 

Li, Shirley e18542 

Li, Shirong 8099 

Li, Shuhong 6581, e21079 

Li, Shukuan 1063 

Li, Shuling 4659, e15169 

Li, Si Ming 8506, 8562, 

e15051, e15052 

Li, Sierra Mi 10545 

Li, Sonia Patricia 1066 

Li, Szu-Chin e16008 

Li, Tao e14511 

Li, Tianhong 7582, 7594, 

e13526 

Li, Tianyu e14021 

Li, Wei 7091 

Li, Wen e21004 

Li, Wenhui e18033 

Li, Xi e18142 

Li, Xia e14511 

Li, Xiang 4638 

Li, Xiao e17504 

Li, Xiao-Feng e21072, 

e21144, e21149 

Li, Xiaochun 5016 

Li, Xiaosong 7036 

Li, Xiaoyu e14508 

Li, Xiaoyun 7531 

Li, Xiuli 8089 

Li, Xuan e16521 

Li, Xuefei 7535, 10527 

Li, Yan e14604 

Li, Yanchun 10598 

Li, Yi 5507 

Li, Yimei 1504 

Li, Yisheng 510 

Li, Yuelin 9105 

Li, Yufeng e15502 

Li, Zejian e18087 

Li, Zhenghong 9527 

Li, Zhiyong e13538 

Li, Zhong-Qian e15565 

Li, Zujun 5531, 5559, 5581 

Liaaen, Erik Dyb 7027 

Lian, Bin 8506 

Lianes, Pilar e12012 

Liang, Chris 3041 

Liang, Hong e16549 

Liang, Jane Q TPS7615 

Liang, Ji 2011 

Liang, Jun e14511 

Liang, Long 8561 

Liang, Meina TPS2621 

Liang, Min Rui e14651 

Liang, Raymond 8097 

Liao, Chun-Ta e16050 

Liao, Jason e18500 

Liao, Jay Justin 5503, 5515 

Liao, Kai-Ping Eric 6124 

Liao, Laura e15193 

Liao, Meilin 7519^ 

Liao, Riqiang 7039 

Liao, Wei-Li e21068 

Liao, Winston W. P. e21097 

Liao, Yuqian e11538 

Liao, Zhongxing X. 4073, 

e14548, e14669 

Liau, Linda M. 2101 

Liauw, Winston S. 3504, 

e13585 

Libby, Edward N. 8010 

Libener, Roberta 7084 

Liberati, Emanuele 4572 

Liberman, Eliezer 1507, 

1564 

Libertini, Michela 10065 

Libertino, John A e15196 

Liboy, Idalia 8084 

LiButti, Daniel 9530 

Lich, Kristen Hassmiller 

6017, 6029 

Licht, Thomas 10031 

Lichtenegger, Werner 1600^, 

1602, 5070, 5087, 10540 

Lichter, Peter 1096 

Lichtiger, Benjamin 6622 

Lichtman, Stuart M. 5056, 

5057, 5108, 9034, 9109, 

9123, e18133 

Licitra, Lisa F. 5504^, 5508, 

5518, 5555, 5591, 

TPS5598, TPS9155 

Liddle, Chris 550 

Lie, Wen-rong 2525, e21069 

Lie, Yolanda 603, 608, 614 

Liebaert, Francois e14059 

Liebert, Monica 4591 

Liebman, Hannah M. 3594 

Liebner, David A. e19053 

Liebrich, Clemens 5044 

Liede, Alexander 1579, 1581, 

4659, e12023, e15147, 

e15169 

Liederer, Bianca M. e13114 

Liedke, Pedro E.R. 596 

Liedke, Pedro Emanuel 

Rubini 524 

Liedtke, Bernd 552 

Liedtke, Cornelia 552, 

10627, e11534 

Liem, Giok Siong e14085 

Lienard, Danielle e19026 

Liens, David e14650 

Liersch, Torsten 3600, 

e14161, e14162, e14167 

Lieser, Elizabeth Ann Teresa 

8599 

Lieu, Christopher Hanyoung 

3017, 3598, e14071 

Lievens, Johanna Caroline 

e13073 

Lièvre, Astrid e14129 

Liew, Choong-Chin 4106 

Ligeza-poisson, Catherine 

TPS7112 

Light, Emily e16014 

Lightsey, Judith L. TPS4136 

Ligibel, Jennifer A. TPS669, 

1026, TPS1614, 9084, 

e14114 

Ligon, Keith 2020 

Liguigli, Wanda 4097 

Lih, Chih Jian 3529 

Lih, Chih-Jian 5020 

Lilenbaum, Rogerio 7506 

Liliac, Ludmila e15032 

Lilja, Hans 4668, e15113 

Lillie, Sarah E 6023 

Liloglou, Triantafilos 5543 

Lim, Adrian K. e21137 

Lim, Allison 9576 

Lim, Chun Ren 4106 

Lim, Dean 3108, e14182 

Lim, Do Hyoung 4064 

Lim, Elgene 576 

Lim, Ho Yeong 4064, 4103, 

TPS4147, 4544^, e13044, 

e14617, e15064 

Lim, Howard John 549^, 

3527, 3610, 6014, 

e14176, e14532, e14537, 

e14568, e14588, e19547 

Lim, Hoyeong e13094 

Lim, Hyeong-Seok e13092 

Lim, Joline Sijing e13505 

Lim, Joo Han e13065 

Lim, Keith Hsiu Chin 2016 

751s

Lim, Kian-Huat e14584 

Lim, Kiat Hon 3589 

Lim, Megan S 9500 

Lim, Siew Eng 2551 

Lim, Soon Thye 1593, 8078, 

10051, e18515, e18528, 

e18546, e20509 

Lim, Sun Min e14559, 

e16529 

Lim, Tee TPS4690 

Lim, Wan-Teck 2598, 3098, 

5544, 5551, 5580, 7549, 

e16024, e18063^ 

Lim, Xn-Yii 2551 

Lim, Yoojoo 5552 

Lima, Aldo Angelo Moreira 

e14183 

Lima, Alessandro e14119 

Lima, Carmen Silvia Passos 

e16041 

Lima, Geraldine Eltz 643, 

e18078 

Lima, Roberto Cesar e14183 

Lima, Vladmir C. e11058, 

e18078 

Limacher, Jean-Marc 2605, 

TPS4152, e19019 

Limareva, Svetlana 

Vladimirovna e15543 

Limaye, Maneesha R 4045 

Limaye, Sewanti Atul 5501, 

5582, 9024, e16060 

Limburg, Paul J. 3526 

Limentani, Steven A. 611 

Limesand, Dianne L e16513 

Limmroth, Christina 8024 

Limon, Jesus e11016 

Limonero, Joaquin T. e19542 

Limor, Sora 6525 

Limwongse, Chanin e14051 

Lin, Albert Y. e14037 

Lin, Alexander e16062 

Lin, Boris K. 2516 

Lin, Charles 8538 

Lin, Cheng-Yao 4103 

Lin, Chia-Chi 4524, e14576 

Lin, Chiao-Yun 5109 

Lin, Chien-Yu e16050 

Lin, Chihche TPS4134 

Lin, Chii-Dean e14037 

Lin, Ching-Hung 1061, 1079 

Lin, Daniel W. 4520, 4650 

Lin, Daniel e14682 

Lin, Derrick T. e16059 

Lin, Edward H. 6077, 

e14153 

Lin, Felice 6605 

Lin, Heather 1546, 1549, 

7047 

Lin, Ho-Sheng e16019 

Lin, James e15018, e15019 

Lin, Jay 6059 

Lin, Jenny J e11004 

Lin, Jianqing 4526, 4656, 

e15012 

Lin, Jin-Ching e16006 

Lin, Lilie L. e12009, e17534 

Lin, Lilie e18032 

Lin, Meng-Chih TPS7614 

Lin, Nancy U. 599, 605, 

TPS658, 3036, 6089, 

9084 

Lin, Pin-Wen e20514 

Lin, Po-Han e17014 

Lin, Simon M 2532 

Lin, Steven H. 4069, 4078, 

4086, 7043, e14547, 

e14548 

Lin, T-H e14699 

Lin, Tasha e16014 

Lin, Tongyu 5535, TPS8118, 

8554, e18517 

Lin, Xun 4542 

Lin, Yan 3037, 3049, 3054, 

6563, 8533, 8547 

Lin, Ying e15085, e15087 

Lin, Yvonne Gail e13531, 

e19506 

Lin, Z-Ping e13125 

Linard, Pauline 7574 

Linardou, Helena 573, 

e15040 

Linares, Susana 1111 

Linari, Alessandra 10055 

Linciano, Francesca e15547, 

e15550 

Lincy, Jeremie 4632 

Lind, Charlotte TPS5599 

Lind, Joline S. e18094 

Lind, Michael J. e13554 

Lind, Pehr A. 5066 

Lindberg, Patricia e16520 

Lindebjerg, Jan 3513, 

e14134 

Lindeman, Neal Ian 7588, 

8042, 10592 

Lindemann, Kristina 5008 

Lindemulder, Susan Joy 9546 

Linden, Diana 8588 

Linden, Hannah M. TPS3109 

Linden, Ola 10024 

Lindenberg, Maria Liza 10589 

Linder Stragliotto, Christina 

10083 

Linder, Albert 7056, e13061 

Lindet, Clothilde 10018 

Lindh, Birgitta 3538 

Lindhofer, Horst 2584, 5080, 

e13108^ 

Lindner, Juha 2522 

Lindner, Lars 10054 

Lindor, Noralane M. 3567 

Lindquist, Deborah 547, 596, 

604 

Lindsay, Dianne Frances 

TPS1136 

Linehan, David e14584 

Linehan, W. Marston 

TPS4680 

Linette, Gerald P. 2525, 

8567 

Ling, Huichung Tina e11010, 

e11522 

Ling, Leona E. 10563 

Ling, Marilyn N 9027 

Ling, Winnie Hui Yee 1575, 

e13002, e19523 

Ling, Yi-He e18113 

Ling, Zhiqiang e21080 

Linga, Vijay Gandhi 6554, 

e18544, e18545 

Lingen, Mark W. 5517 

Lingle, Wilma L. 1083 

Lingua, Alejo e21025 

Link, Brian K. 8061, 9057 

Link, Charles J. 2501, 2571, 

4049, e19008 

Link, Jeanne TPS3109 

Link, Michael Paul 9502 

Link, Richard E TPS4678 

Linke, Rolf Gerhard 8567 

Linker, Charles A. 2533 

Linklater, Karen 7026 

Linn, Sabine C. 562 

Linnert, Mette 2069 

Linquist, Breanna M. 9001, 

9075 

Lins- Almeida, Thiago e12512 

Lion, Maeva TPS10634 

Liotta, Lance A. e14151, 

e15549 

Lioure, Bruno 6534, 6542 

Lipatov, Oleg N. 4501, 

e15082 

Lipitz Snyderman, Allison 

Nicole 6101 

Lipman, Andrew J. 7567 

Lipp, Eric S 2027, 2074^ 

Lippert, Hans e14630 

Lippman, Scott Michael 

5524, 5592, 7047, 7096 

Lippmann, Lynne T. 5101 

Lipscomb, Joseph 6044, 

e14608, e15187 

Lipshultz, Steven E. 9503, 

9504, 9505, 9530 

Lipsky, Michael e15021 

Lipson, Doron 3533, 4649, 

7510, 10524, 10559, 

10590 

Lipton, Allan 501, 607, 614, 

7054, 7055, e14520, 

e15062, e15121, e15170, 

e17560, e19514, e21039 

Lipton, Jeffrey H. 6513, 

6596, 6604 

Lipton, Jeffrey Howard 

6505^, 6512, 6605 

Lipton, Lara Rachel TPS4135 

Lira, Cynthia 6607 

Lira, Ruth R 5525 

Lis, Christopher G. e14697 

Lis, Rosina 4577, 4580 

Lisa, Donna M. 5545^ 

Lisano, Julie M. 7541 

Lisby, Steen 6584, 8019 

Liskova, Stefania TPS4677, 

e15028 

Lisovsky, Mikhail e14514 

Liss, Adam 7040 

Lissia, Amelia 8581 

List, Alan F. 3081, 6522, 

6586 

Lister, John 6620 

Lithwick Yanai, Gila 10528 

Lithwick-Yanai, Gila e14067 

Litière, Saskia 10602 

Litman, Thomas e19056 

Litrup, Peter e15081 

Litsas, Georgia 6089 

Litta, Pietro e12037 

Little, Anthony 9540 

Little, Melvyn 8059, e18532 

Little, Richard F. 8005 

Little, Shonda M 3528, 

8510, e19046 

Littler, John e18068 

Littman, Catherine 2568 

Litton, Jennifer Keating 537, 

1032, 1130, 1549, 6116, 

9002 

Litwin, Samuel e19580 

Litwiniuk, Maria Malgorzata 

e21099 

Litz Curry, Christine 

TPS3635^ 

Litzow, Mark Robert 6614 

Liu, Annie Y e15582 

Liu, Baorui 4068, 9017, 

e14509, e21034 

Liu, Biao 3029 

Liu, Cameron S. 4521 

Liu, Chen TPS4136 

Liu, Chun-Yu e14516 

Liu, Donglin e13005 

Liu, Fang 3551 

Liu, Fengjun e14643 

Liu, Fenlin 4092, e14575 

Liu, Geoffrey 1535, 1597, 

3007, TPS5600, 6005, 

6084, 7586, 9032, 10522 

Liu, Glenn 4, 3101, 3103, 

4656, TPS4697 

Liu, Guohui 8017, 8033, 

8034, 8064, e13603 

Liu, Han 4604 

Liu, Heshan 1083, 1557, 

9001, 9075 

Liu, Hongbing e18082, 

e18084, e18116 

Liu, Hongtao 6535^, 6562 

Liu, Hongyu e17514 

Liu, Hua 5021 

Liu, Huan 6104 

Liu, Jijun 8084 

Liu, Jinan 6600, e15130 

Liu, Jingyi LBA4 

Liu, Jinsong e14645 

Liu, Jiyan 4628, 4638 

Liu, Li 3023 

Liu, Limin 10535 

Liu, Liming 7541 

Liu, Lu 10041^ 

Liu, Luying e14049 

Liu, Meilian e16054 

Liu, Meng-zhong e18121 

Liu, Minetta C. 1006 

Liu, Mitchell 7020 

Liu, Nathan S. 4612 

Liu, Ping 8091, 8514, 9017, 

9081, 9083 

Liu, Qi 6030 

Liu, Ray 3077 

Liu, Shih-An e16006 

Liu, Songling 8580 

Liu, Stephen V. e15153 

Liu, Suiyang 6606 

Liu, Tian 9122 

Liu, Wanli e11091, e13021 

Liu, Wei 7548, 9531 

Liu, Wen e15124 

Liu, Wenchao 7548 

Liu, Wendy 8520 

Liu, Wenli 9072 

Liu, Xia 8042, 8106, 8107 

Liu, Xiangdong 2500^ 

Liu, Xiaohe 10574 

Liu, XiaoMei e15191 

Liu, Xiaoqing 7520, 7533, 

7548, 7557, 7559 

Liu, Xiaoxia 9086 

Liu, Xin 6616 

Liu, Xinjun 4011 

Liu, Xueli 8089, e15084 

Liu, Yi 626 

Liu, Ying 6039 

Liu, Yingmiao e21038 

Liu, Yong 3006^ 

Liu, Yongyu e18013 

Liu, Yuan 3086, 4605, 

e13026, e15085, e15087 

Liu, Zhanqi 8547 

Liu, Zhaoyu e14605 

Liu, Zhimei 1609, 4608, 

4612, e12042, e14525, 

e14627, e15063, e15096 

Liu, Ziyue 4586, e21016 

Livaudais, Jennifer C. e15513 

Liverani, Chiara 10615 

Livingston, Michael B. 

10003, TPS10099 

Livrati, Philippe e15155 

Liyange, Nilani TPS4153 

Lizard, Sarab 10507 

Ljungman, Gustaf 9573 


Ljungman, Mats 4591 

Llacer-Moscardo, Carmen 

LBA4003 

Llanos, Marta 8062 

Lledo, Gérard LBA3500^ 

Llombart Cussac, Antonio 

10512, 10595, e11545 

Llombart, Antonio 1011 

Llorca, Cristina e11074 

Llorca, Laurence 2537^ 

Llorente, Rosa M. e11074 

Lloreta Trull, Josep 4580, 

4585 

Lloyd, Andrew R. 9044, 

e15152 

Lloyd, Arwel e14587 

Lloyd, Shane 6019 

Lluch, Ana 1001, 1011, 

1015, 1074, 10500, 

10616, e11523 

Llugdar, Jose Roberto e21025 

Lo Nigro, Cristiana 2600 

Lo Re, Giovanni e15160 

Lo Russo, Chiara 7585, 

e18104 

Lo Russo, Giuseppe e11039, 

e11514, e12510, e19620 

Lo, Dennis YM 5511 

Lo, Nangi 5046 

Lo, Peter 7547 

Lo, Pu-Han 8542 

Lo, Shelly S. e19588 

Lo, Simon S. TPS1616 

Lo, Soo Kien 9041 

Lo, Yungtai e14682 

Loaiza, Sandra 10550 

Lobelle, Jean Pierre 9035 

Lober, William B 9008 

Loberiza, Fausto R. 9139 

Lobo, Christopher F. 7035 

Lobo, Francisco 5520, 8062, 

e15094, e18069, e18106, 

e21015 

Loboda, Andrey 3531, 3587 

Lobry, Celine 4018 

LoBuglio, Albert F. 621 

Lobur, David TPS8606 

Locati, Laura 5555 

Loch, Carolyn Sue 2029^ 

Loch, Michelle Marie e21076 

Locher, Chrystele 1574 

Lock, Victoria 3028, 9542 

Lockart, Barbara e20001 

Locke, Susan C. 2021 

Lockhart, A. Craig 3047, 

LBA3501, 4062 

Lockhart, Albert C. e15116 

Lockley, Michelle 4056 

LoConte, Noelle K. 3101, 

3103, 3105, e14554 

Loda, Massimo F. 4521, 

4555, 4577, 4582 

Loder, Charisse e15191 

Lodhi, Ashutosh TPS10631, 

e13582 

Loeb, David Mark 10025 

Loeb, Keith 2523 

Loeffler, Markus 8022 

Loehrer, Patrick J. 7032, 

7106, 7107, 7108, 

e16557 

Loembe, Arsene Bienvenu 

e15037 

Loertzer, Hagen e15158 

Loevendorf, Marianne Begtson 

e19056 

Loffreda, Massimiliano 

e12514 

Logan, Theodore 4603 


Loggers, Elizabeth T 9139 

Loghin, Monica Elena 2003, 

2036 

Loghman-Adham, Mahmoud 

1590 

Logothetis, Christopher 4513, 

LBA4518, 4521, 4556, 

4558, TPS4691, e15151 

Logue, John P. LBA4512, 

4551 

Loh, Elwyn 2535, 2594, 

4005 

Loh, Marie 2551 

Loh, Mignon L. 9506, 9548 

Lohneis, Philipp e18552 

Lohrisch, Caroline A. 549^, 

582 

Loi, Sherene 507, 515 

Loi, Shrushma TPS660 

Loibl, Sibylle 522, 523, 541, 

556, 1023 

Loizos, Nick TPS10099 

Lok, Anna e19631 

Lok, Edwin e18541 

Lokhorst, Henk M 8019 

Lolkema, Martijn P.J.K. 2596, 

4056, e13028, e13596 

Lolli, Cristian 10087 

Lombardi, Francesca 7023 

Lombardi, Giuseppe 2049, 

e14563 

Lombardo, Marco 8006 

Lombo, Liliana 5567 

Lonardi, Sara 3518, 3549, 

3555, 3585, e14040, 

e14563 

London, Karin 1117 

London, Wendy B. 9516, 

9533, 9534, 9583 

Long, Alison 4056 

Long, Elodie 7591 

Long, Georgina V. 3102, 

8501, 8503^, 8510, 8518, 

8558, e19011 

Long, Jessica B. 1030, 1595, 

6628 

Long, Mary Ann 1529 

Longauer Banholzer, Maria 

7544 

Longhi, Alessandra 10026 

Longhitano, Laura e15544 

Longmate, Jeff 2538 

Longo, Federico 10546 

Longo, Flavia LBA7501, 

9133, e14082, e14096 

Longo, Marina e18103 

Longo, Valter e13531 

Longpre, Lara TPS4152, 

e14566 

Longvert, Christine 8540 

Lonial, Sagar 2576, 8012, 

8017, 8020, 8033, 8035, 

8086, 8100, 8101, 

TPS8112, TPS8113, 

e18553, e18569, e18572^ 

Lonneux, Max 5519 

Look Hong, Nicole Jannelle 

10058 

Look, A. Thomas e13586 

Look, Maxime P 10504 

Look, Regan M. 9019 

Loong, Herbert e14085 

Loos, Walter J. 2593, 4132 

Lopa, Samia H. 3545 

Lopatin, Margarita 3512, 

3626 

Lopes, Ademar 10069, 

e14119 

Lopes, Antonio de Barros 

e14597 

Lopes, Gilberto de Lima 

e15045, e16525 

Lopes, Gilberto e15107 

Lopes, Vrishali 5100 

Lopez Ben, Santiago e14120 

Lopez Calderero, Iker 7544 

Lopez Criado, M Pilar 

TPS4672, e19023 

Lopez de Ceballos, Maria 

Helena e11545 

Lopez Gomez, Miriam 9073 

López Jiménez, Antonio 

e18049 

Lopez Ladron, Amelia e11075 

Lopez Lincuez, Maria Emilia 

10074 

López López, Rafael 530 

Lopez Ruitti, Paula e14109 

Lopez Vilaro, Laura 1120, 

10555 

Lopez Vivanco, Guillermo M 

7095 

Lopez, Antonio 4587 

Lopez, Christian TPS668, 

TPS4695 

Lopez, Ines e14057 

López, José Luis e14002 

Lopez, Jose e15103 

Lopez, Katrina e15500 

Lopez, Lenny 9004 

López, Maria e16029 

Lopez, Rafael 10534, 

e14733, e19505 

Lopez, Roberto e11035, 

e11527 

Lopez, Salvatore 5093, 

e15547, e15551, e15553 

López-Basave, Horacio Noe 

e15527 

López-Brea, Marta F. 

TPS4672 

López-Casas, Pedro P. 3066, 

3068 

Lopez-Chavez, Ariel TPS7609 

Lopez-Crapez, Evelyne 10505 

Lopez-Diaz, Christine 547 

Lopez-Gomez, Miriam 1570, 

e11028 

Lopez-Gonzalez, Ana e11035, 

e11527, e12015, e17515, 

e18521 

Lopez-Guerrero, Jose Antonio 

10079, e15575 

Lopez-Ilasaca, Marco e11066 

López-López, Carlos 3571 

Lopez-Macias, Constantino 

e15584 

Lopez-Martin, Jose A. 2583, 

10052, e19023 

Lopez-Mozos, Fernando 

e14589 

Lopez-Peñalver, Jesus 1041 

López-Picazo, José María 

e15041, e18008 

Lopez-Pousa, Antonio 5590, 

5595, 10052, 10079 

López-Ríos, Fernando 602, 

3066, 3068, 4040, 

e11006 

Lopez-Trabada Ataz, Daniel 

e12003 

Lopez-Vega, Jose Manuel 

TPS653, 1001, 10512, 

10595 

Lopez-Vivanco, Guillermo 

7011, e11525, e17522, 

e18031, e21009 

Loprinzi, Charles L. 1557, 

9001, 9075 

Loquai, Carmen 8505, 8517, 

e19031 

Lora, David 642 

Lorch, Anja 4597, 4600, 

e15026 

Lorch, Jochen H. 5501, 

5579, 5582, e16060 

Lord, Christopher J. 3050, 

5035 

Lord, Raymond S. 9141 

Lord, Sally 5081 

Lordick, Florian 3535, 

e13095^, e13097^, 

e13108^, e14167 

Loren, Alison W. 6579, 

e18529, e18540 

Lorence, Robert M. LBA7500 

Lorente, David 10082 

Lorente, Gustavo A. 6585 

Lorenz, Mario TPS4138 

Lorenz, Ralf 1602, 5044 

Lorenz, Wilfried e16520 

Lorenzen, Sylvie 4080 

Lorenzi, Elena 2580, e21139 

Lorenzo-Patiño, Maria J 

e21002 

Loretelli, Cristian e14086, 

e14561, e15074 

Lorf, Thomas e14167 

Lorigan, Paul 8502^, 

TPS8605, e19010 

Lorimer, Ian 3515 

Loring, Jeanne F. 10539 

Loriot, Virginie 3633, 10505 

Loriot, Yohann 4540, 4554, 

4574, 4621 

Lorsbach, Michael 8052 

Lortholary, Alain 5018 

Lorusso, Domenica LBA5003, 

5059, 5087, 5096 

LoRusso, Patricia 528, 

TPS663, TPS668, 2534, 

2566, 2579, TPS2618, 

3029, 3059, 3062, 4639, 

e19048^ 

Lorusso, Vito e18048 

Los, Maartje 4539 

Losa, Ferran 3571, e18030 

Losa, Raquel e18044 

Loscalzo, Matthew 9048 

Losem, Christoph 3 

Losonczy, Gyorgy e13113 

Losurdo, Agnese 623 

Lotan, Yair 4591, 4616, 

TPS4678 

Lotia, Mitesh e17019 

Lotz, Jean-Pierre 10035 

Lotze, Michael T. 3019 

Lou, CaiJin e17512 

Lou, Feiran 7043 

Lou, Pei-Jen e16050 

Lou, Yuqing 1551, e17551 

Louahed, Jamila 7013, 7056, 

e13061 

Loucaides, Eileen 6115 

Loucks, Aimee e15154 

Loud, Peter e19041 

Loughran, Thomas P. 6590, 

6616 

Louhimo, Riku 8074 

Louie, Alexander V. 6130 

Louie, Arthur Chin 6525, 

6601 

Loundou, Anderson 8555 

Lounsbury, Heather 8032 

753s

Loupakis, Fotios 3518, 3540, 

3546, 3549, 3555, 3585, 

3597, 3604, 3622, 4026, 

4088, 4096, e11018, 

e13057, e14031, e14034, 

e14040, e14052 

Lourenco, Gustavo Jacob 

e16041 

Loussouarn, Delphine 2082 

Louvet, Christophe 

LBA3500^, 3506, 4032 

Louwman, Marieke J. 8039 

Lovat, Francesca 1007 

Lovat, Katherine e19598 

Lovecchio, John L. 5056, 

5057 

Lovecek, Martin e14556 

Lovly, Christine Marie 7094, 

7532 

Low, Eng Joo 4106 

Low, Li shan 4100^ 

Low, Walter 2546, 3070 

Lowe, Ann M. 6508 

Lowe, Robert 10550 

Lowe, Val J. e21006 

Lowery, Jan 3567 

Lowery, Maeve A 4057 

Lowy, Andrew M. 4019, 

e14069 

Lowy, Israel 2562 

Loya, Asif e16043 

Loyer, Evelyn 3544 

Lozada, Claudia Patricia 2531 

Lozano, Guillermina 10506 

Lozano, Juan Jose 3553 

Lozano, Maria D. 8572, 

e15041, e18008 

Lozano, Nicolas TPS10634 

Lozanski, Gerard 6526 

Lu, Charles 5589, 5592, 

9118, 9518 

Lu, Dongrui (Ray) 4118 

Lu, Gary 8040 

Lu, Haolan TPS7611 

Lu, He e21156 

Lu, Hongyang e17512 

Lu, Jerry e21047 

Lu, Jiade Jay 2016 

Lu, Jianfeng 5072 

Lu, Jiangyang e18087 

LU, Jinlong 5558 

Lu, Karen H. CRA1505, 

1513, 1518, 1519, 1520, 

1546, 5027, e13516 

Lu, Kelley 1562 

Lu, Lanchun 9544 

Lu, Ligong 4008, e14605 

Lu, Lingeng 5099, e15581 

Lu, Michael W LBA1 

Lu, Ming e14604 

Lu, Minqiang 4008 

Lu, Ning e14511 

Lu, Shir Kiong 10060 

Lu, Shun 7091, 7520 

Lu, Sunny e11068 

Lu, Tai-xiang 5535 

Lu, Xian 7601 

Lu, Xiang e11003 

Lu, Xiaomin 9546 

Lu, Xuyang e13045 

Lu, Yen-Shen 1061, 1079, 

e11022 

Lu, You 4073, e14648, 

e18033, e18086 

Lu, Yu-Shiang 6078 

Lu, Yunhua e11567, e11568 

Lu, Zhen-Yi e17512 

Lu, Zhihao e14604 

Lu, Zhiqiang Kevin e19639 

Lu-Emerson, Christine 2010 

Luaces, Patrcia Lorenzo 2515 

Luan, Jennifer 3528, e19046 

Luan, Shen 3015, e14593 

Luan, Wei e14583 

Lub-de Hooge, Marjolijn N. 

10581 

Lubbe, Dirk 5007 

Lubben, Jade Marie 8010 

Lubner, Sam Joseph 3101, 

3103, e14554 

Lubow, Meredith A. 2040 

Lucas, Jared 4669, e15207 

Lucca, Joan Vern 7099, 

e19637 

Lucchesi, Sara 629, 3518, 

3546, 3549 

Lucchini, Eleonora e14661 

Lucci, Anthony 594, 1102, 

TPS10631, e13582, 

e21107 

Lucci, Joseph A. 5065 

Lucey, James e19601 

Luciano, Antonio e11052, 

e13539 

Luciano, Jason e14184 

Ludkovski, Olga 1036 

Ludovini, Vienna 3521, 

e14042, e18021, e18023, 

e18101, e21018, e21094, 

e21096 

Ludwig, David A. 9565 

Ludwig, Elizabeth e18522 

Ludwig, Joerg 2522, 3530 

Ludwig, Joseph A. 10003, 

10021, 10071, e19520 

Ludwig, Justin 6000 

Luebbe, Kristina 556, 

TPS661 

Luebke, Aaron Lynn e13548 

Lueck, Hans-Joachim 556 

Luecke, Klaus 10536, 10537 

Lueftner, Diana e14140 

Lueke, Matthias 2054 

Luengo, Maria Isabel e11024 

Luengo-Gil, Gines e11024 

Lueza, Beranger 10556 

Luger, Selina M. 6520, 6579 

Luger, Thomas 4034 

Lugowska, Iwona A. 10538 

Lugtenburg, Pieternella 8002, 

8039, e16526 

Luini, Alberto 519 

Luis, Ines Maria Vaz Duarte 

599, 6089 

Luisser, Irmard 542 

Lujan, Ramona 4096 

Lukawy, Jacek TPS6643^ 

Luke, Jason John 2606, 

8549, e13588 

Luketich, James D. 7071, 

7074, e14689 

Luknic, Alice Marie TPS657 

Luley, Kim Barbara 4083, 

4090 

Lum, Christopher A. 1599, 

e19051 

Lum, Lawrence G. e13089 

Lum, Lawrence G e13124 

Lumba, Sumit e19042 

Lumbroso, Jean 9560 

Lumbroso, Livia e13017 

Lumbroso-Le Rouic, Livia 

9538 

Lumgair, Heather e17543 

Luminari, Stefano 8006 

Luna Fra, Pablo 10079 

Luna, Hermenigilda 6108 

Luna, Yesenia L 4666, 

e15186 

Lunceford, Jared 3531 

Lund, Bente 5052 

Lund, Mary Jo B. 6052 

Lund, Peder 2514 

Lundeberg, Joakim 10521 

Lundgren, Lotta 10024 

Lungershausen, Juliane 6058 

Lunning, Matthew Alexander 

8060, 8063 

Luo, Jialing e14049 

Luo, Jingqin 503, TPS664 

Luo, Rongcheng e18033 

Luo, Shujun 10539 

Luo, Suhong 4594 

Luo, Yang e11025, e11538 

Luo, Yi 7091, 7520 

Luo, Yuling 5543 

Luo, Zhongyao e11557 

Luong, Richard 2513 

Luong, Tu Vinh 4121 

Lupi, Cristiana 3521, 3585 

Lupichuk, Sasha M. 1036, 

e14073 

Lupinacci, Lorena 10074 

Luppe, Denise 4098 

Luppi, Mario 6531 

Luptrawan, Anne 2084 

Luque Caro, Raquel TPS4672 

Luque, Manuel 2539, 

e15001 

Lurain, John Robert e15523 

Lusa, Amanda 7050 

Lusebrink, Jessica e18000 

Lusky, Monika TPS4152 

Lust, John Anthony 8096, 

8105, TPS8116 

Lustberg, Maryam B. e21124 

Lustig, Robert A. e12508 

Luthra, Rajyalakshmi 3106, 

10510, e13595 

Luthra, Rakesh e11063 

Lutke Holzik, Martijn 10554 

Lutrino, Stefania Eufemia 

3612, TPS3637, e14040 

Lutsyk, Miroslav e18511 

Luttgen, Madelyn 4102, 

e21074 

Lutz, Manfred P. 4053, 

TPS4140 

Luu, Dai Chu Nguyen e18018 

Luu, Thehang H. 1010, 

1035, 1070, 3108 

Luu-The, Van 10583 

Luukkaa, Marjaana TPS4696^ 

Luvero, Daniela 5093, 5094, 

e15547, e15550, e15551, 

e15553 

Luzi Fedeli, Stefano 4084 

Lv, Chentao e14575 

Lv, Fangfang e11568 

Lv, Jima e14511 

Lv, Meijun 7091 

Lv, Yanling e18116 

Lwin, Thuya Win 3002 

Lwin, Zarnie 6087 

Ly, Janey 10574 

Lybeert, Marnix L. 8039 

Lüchtenborg, Margreet 7026 

Lyerly, H. Kim 2585, 10563 

Lyerly, Susan 6524^ 

Lyford-Pike, Sofia 5506 

Lyle, Stephen 8543 

Lyman, Gary H. 1062, 1525, 

6129, 9135 

Lynch, Caroline Dorothy 5107 

Lynch, Henry T. 1538 

Lynch, Julie Ann e18067 

Lynch, Kristian 1608 

Lynch, Siobhan P. 1029, 

1104 

Lynch, Thomas James 7010, 

TPS7611 

Lynn, Audrey 1569 

Lyons, John F. 3028, 9542 

Lyons, Roger M. 6624 

Lyons, Tomas e19059 

Lypas, Georgios 1547 

Lüpfert, Christian e13594 

Lyss, Alan P. CRA1002 

Lyulko, Alexey A. 4501 

M 

M. Tirado, Oscar 3096 

Ma, Ai-Hong e13526 

Ma, Brigette 5511, e14085, 

e14528 

Ma, Cynthia X. 534, TPS664, 

1010, 1048, 3047 

Ma, Daniel 2031 

Ma, Fei e11025, e11538 

Ma, Jianhui 4628 

Ma, Junxun 7036 

Ma, Meili e12013 

Ma, Michelle W. 8557, 8565, 

8589, e19003 

Ma, Patrick C. e17563, 

e18046, e18085 

Ma, Shenglin e17527 

Ma, Shuo 8032 

Ma, Suyong e19574 

Ma, Tian 7022, e13567 

Ma, Wen Wee 3024, 3582, 

4117, 4545, 8519, 

e13006, e14659 

Ma, Xiao-Jun 5543 

Ma, Xiaomei 1595, 6628 

Ma, Xingqun e18116 

Ma, Yifei 6010 

Ma, Yu e18051 

Ma, ZhenLu e14716 

Maale, Gerhard 10037 

Maartense, Eduard 1080 

Maas, Paige 1521 

Maass, Nicolai 556, e13503 

Maazaz, Khalid e14726 

Maazen, RWM Van Der 8039 

Mabjeesh, Nicola J. 1564 

Mabro, May 2537^, 

LBA3500^, 3506 

Mac Mathuna, Padraic M. 

e12031 

Macak, Dusan e15027 

Macarulla, Teresa 3014, 

4053 

Maccario, Rita e13103 

Maccaroni, Elena e14086, 

e14561, e14663, e15074 

Macchini, Marina e14647 

Macciò, Antonio e19634 

MacConaill, Laura E. 5011 

MacDiarmid, Jennifer e13054 

Macdonald, David R. 2051 

Macdonald, John S. 4010 

MacDonald, Lisa 2588 

MacDonald, Neil e18098 

Macdonald, Orlan Kenneth 

e14507 

MacDonald, Shannon M. 

9585 

Macdonald, Theresa 4649 

MacDonald, Tobey 9519 

Mace, Joseph TPS8115 

Macedo, Gabriel de Souza 

e13546, e21042 

Macedo, Omar e19618 

Macfarlane, David e13128 


Macgregor, Tom e13587 

Machado Frascari, Luciana 

e19528, e19584 

Machado, Isidro e14041 

Machado, Karime Kalil 

e15562 

Machalekova, Katarina 

e15027 

Machavoine, Jean-Luc 9080 

Machida, Nozomu 4046 

Machiels, Jean-Pascal H. 

4583, 4622, 5505, 5519, 

TPS5598, e13605, 

e14060, e15115 

Machiels, Jean-Pascal 2583 

Machiorlatti, Michael e17012 

Machtay, Mitchell TPS1616, 

5530 

Maciá, Sonia 4587, 

TPS4674, e18053 

Macias, Ismael e15159 

Maciejewski, Jaroslaw P. 

6521 

Maciejewski, John Joseph 

6552 

Maciejewski, Paul K 9037, 

9146 

Macis, Debora 519 

Mack, Philip C. 4511, 4547, 

4663, 7018, 7552, 7582, 

10503 

Mack, Philip C 7005, 7083, 

7517, e13550, e17537 

Mackall, Crystal 9545 

Mackay, Helen 1597, 5001, 

5010, 5019, 5026, 5105, 

e14524 

MacKenzie, Mary J. 3013, 

4536, 4538, TPS4683 

Mackey, John Robert e14625 

Mackillop, William J. 1583, 

3632 

Mackley, Heath B. 7055 

Macklin, Eric e18520 

Macklis, Roger M. 10623 

Mackman, Nigel e14505 

MacLean, Anthony e14073 

MacLeod, Nicholas James 

e15037 

MacNeil, Mary Valeria 2051 

Macon, William R 9057 

MacVicar, Gary R. 4506 

Madadi, Anusha Reddy 

e16555 

Madajewicz, Stephan e14019 

Madan, Ravi A. 2526, 

TPS2617, 3043, 4569, 

TPS4701, 10589, e13122 

Maddala, Tara 4560 

Madden, Erik e18549 

Madden, Stephen F. 617, 

633 

Maddi, Rahul Narayan 6554, 

e18544, e18545 

Maddocks, Kami J. 6508, 

e13568 

Madeddu, Clelia 9006, 

e19634 

Madero, Rosario 3618, 

10547 

Madhuri, Thumuluru Kavitha 

e15517 

Madhusudan, Srinivasan 1014 

Madhusudanannair, Vinu 

3106 

Madi, Ayman 2552 

Madkour, Ashraf e17556 

Madoz, Juan 5520, e15094, 

e18069, e18106, e21015 


Madroszyk, Anne e19539 

Maeda, Atsuyuki 3607 

Maeda, Lauren Shizue 8060 

Maeda, Patricia Hikari 

e11059 

Maehara, Yoshihiko 3558, 

e13090, e14033, e14536, 

e14601, e14602, e14722 

Maekawa, Hiroshi e14139 

Maemondo, Makoto 7086, 

7561, 7563, 7565, 7571, 

e18129 

Maeng, Chi Hoon 644, 7104, 

e13094, e16003, e18148 

Maenpaa, Johanna e15564 

Maerten, Angela 4023 

Maertens, Johan TPS6637 

Maestri, Marcello e13103 

Maestu, Inmaculada 1531 

Maetzold, Derek 7106, 8543 

Magagna, Silvia e13057 

Magargal, Wells Wrisley 

e21131 

Magasi, Susan 9056 

Mager, Donald E. e14690 

Maggard Gibbons, Melinda 

6057 

Maggioni, Angelo e19036 

Maggiori, Leon e14158 

Maggiorotto, Furio 627 

Magi-Galluzzi, Cristina 4560 

Magidson, Jay 4516 

Magley, Andrea 10088 

Magliocca, Kelly R. 5560 

Magliocco, Anthony M. 2001, 

e21083 

Magliocco, Tony e21044 

Magneux, Celine 641 

Magnin, Valerie Florence 

2048 

Magometschnigg, Heinrich 

10570 

Magoon, Daniel 9548 

Magoski, Nadine M 3504 

Magremanne, Michele 5519 

Magro, Ana 1074 

Maguire, Aoife e21024 

Maguire, Roma e19617 

Mahadevan, Daruka 3028, 

8032 

Mahajan, Anita 2001, 9585 

Mahal, Lara K e19018 

Mahale, Parag e17016 

Mahalingam, Devalingam 

3073, 3078, e15116 

Mahamat, Abakar e15574 

Mahan, Meredith e15174, 

e15512 

Mahapatra, Manoranjan 

e17000 

Mahaseth, Hemchandra 

e14512, e14614 

Mahdavi, Khosrow 2569 

Mahe, Isabelle 1580 

Maher, Michael A. 1543, 

e19601 

Maher, Richard e19042 

Mahesh, Bandemegal e11027 

Maheshwari, Neelabh 7040 

Maheswaran, Shyamala 4566 

Mahlberg, Rolf 4083 

Mahler-Araujo, Betania 544 

Mahmud, Nadiya 10550 

Mahner, Sven 5001, 5005, 

5007, 5031, 5034, 5058, 

5071, 5087, e15520 

Mahon, Brett 7067, e18117 

Mahon, Garry e14180 

Mahoney Shannon, Kristen 

e16510 

Mahoney, Douglas W. e15132 

Mahoney, John Francis 4655, 

4667 

Mahoney, Martin 1529 

Mahoney, Michelle R. 3514, 

3617 

Mahoney, Sandy 8514, 

e19014, e19039 

Mai, Phuong L. 1519 

Maia, Joyce Maria L. e14680, 

e14728 

Maiello, Evaristo e21092 

Maier, Gal e15136 

Maier, Sabine TPS7113, 

TPS7611 

Maier, Thomas e14099 

Maillard, Natacha 6542 

Maillard, Sophie e15535 

Maillet, Denis e15182 

Mailliez, Audrey e11012, 

e11049, e11500 

Maimon, Natalie 4564, 4619, 

e15058, e18108 

Maimonis, Peter J. e21091 

Maindrault-Goebel, Frederique 

e19623 

Maines, Francesca 4541 

Mainwaring, Paul N. 

LBA4518, 4558, TPS4683, 

TPS4692^, TPS4696^ 

Maio, Michele 8502^, 8513, 

8529 

Maiolino, Angelo 8018^, 

8095 

Maiolino, Piera e14130 

Maire, Frederique 4133 

Mais, Anna 4115 

Maison-Blanche, Pierre 

e15115 

Maisonneuve, Patrick 1500 

Maitah, Main e21057 

Maithel, Shishir Kumar 

e14169, e14170, e14692 

Maiti, Baidehi e15095 

Maitland, Michael L. e13106 

Maitra, Radhashree e14019 

Maiya, Arun 5526 

Maizel, Abby e13124 

Majem, Margarita 1531, 

7522, 7542, e12000, 

e12012, e18057, e18130, 

e18131 

Majeske, Cindy e12500 

Majeti, Ravindra 2523 

Mak, Milena Perez e21040 

Makarenko, Serge 9078 

Makarov, Danil V. 6019 

Makarov, Vladimir 10587 

Makarova, Olga V e21079 

Makatsoris, Thomas 5033 

Makeyev, Yan G. 5016 

Makhson, Anatoly 7512 

Maki, Robert G. 10001, 

10003, 10004, LBA10008, 

10013, 10021, 10022, 

10057, 10097, TPS10103, 

e13600^ 

Makimoto, Atsushi 9574 

Makin, Guy 9542 

Makino, Haruhiko 10624 

Makino, Hirochika e14624 

Makiura, Daisuke e17020 

Makiya, Monica 10074 

Makiyama, Akitaka 3045 

Makrilia, Nektaria e17508 

Makris, Andreas TPS665, 

1066 

Makuuchi, Masatoshi 4104 

Mala, Carola 1092 

Malafa, Mokenge Peter 

e14715 

Malagola, Michele 6531 

Malamos, Nikolaos 583 

Malamou-Mitsi, Vassiliki 

10575 

Malangone, Elisabetta 

e14028, e14030 

Malapelle, Umberto e13509 

Malasse, Stephanie 7575 

Malatesta, Theresa Maria 

e19507 

Malats, Nuria e12033 

Malaurie, Emmanuelle 

LBA5003 

Malchiodi, Michael e21122 

Maldonado, Antonio 1111 

Maldonado, Xavier e15199^ 

Maleddu, Alessandra 10087 

Malek, Kamel TPS6643^ 

Malekzadeh, Katty 9517 

Malfertheiner, Peter TPS4148 

Malhi, Vikram e13114 

Malhotra, Jyoti CRA9513 

Malhotra, Usha e14712 

Malik, Hassan Zakria 3613 

Malik, Laeeq e14703 

Malik, Monica 9055, e12501 

Malik, Prabhat Singh e17505, 

e17511 

Malik, Shakun M. 3074 

Malik, Zafar I e15112, 

e15128, e15135, e18068 

Malin, Jennifer L. e14610 

Malin, Jennifer 6105 

Malin, Jessica e14175 

Malinoski, Frank J e16053 

Malinowski, Paige 4027 

Malisic, Emina e12020 

Malka, David 4018, 4032, 

9026^, e14158 

Malkowski, Bogdan 8077 

Mallet, Stéphanie 8555, 

8568 

Mallick, Atrayee Basu e14019 

Mallick, Rajiv 9056 

Mallick, Ranjeeta 10620 

Mallick, Supriya 2072 

Mallick, Ujjal e13522 

Mallikarjun, Priya e11097, 

e12004 

Mallmann, Peter 3044 

Mallon, Robert e13576 

Malmgren, Judith April 6560 

Malmstrom, Robert e15154 

Malone, Michael D e15141 

Maloney, David G. 8001 

Maltese, Mariangela 4097 

Maltoni, Roberta e11054 

Maluccio, Mary A. e14683 

Malvehy, Joseph 8578 

Maly, Joseph 609 

Malysa, Agnes 7593 

Malysz, Jozef 8090 

Mambo, Elizabeth 3630 

Mambrini, Andrea LBA4001, 

4017, 10611 

Mamedov, Alexandre e15180 

Mamet, Rizvan e18018 

Mamon, Harvey J. 4021 

Mamorska-Dyga, Aleksandra 

6123 

Mamounas, Eleftherios P. 

LBA506, LBA1000 

Mamounas, Eleftherios P 616, 

TPS657, 1025, TPS1142 

Mamtani, Ronac 1503 

755s

Man, Shan e11061, e15177^ 

Manaloor, Elizabeth 8108 

Manasanch, Elisabet E. 8088, 

8104, e18568 

Manca, Antonio e20512 

Mancao, Christoph TPS3637 

Mancari, Rosanna 5090 

Manceau, Gilles e14059 

Mancenido, Noemi 1570 

Manches, Olivier 2570, 

e21081 

Mancini, Andrea e15200 

Mancini, Julien 10078 

Mancini, Maria Laura e18072 

Mancini, Maria 5096 

Mancini, Raffaello e14082 

Mancuso, Andrea Petricca 

e19033 

Mancuso, Maurizio 7084 

Mancuso, Patrizia 2083 

Mandadi, Mounika e16517 

Mandal, Rakesh e17005 

Mandala, Mario e19549, 

e19612 

Mandalia, Amar e16001 

Mandat, Tomasz 603 

Mandel, Nil Molinas e19024 

Mandeli, John P e15191 

Mandolesi, Alessandra 

e14086, e14561, e21070 

Mandrekar, Sumithra J. 6133, 

7555, 7605 

Mandrioli, Anna 10087 

Mane, Anupama Dutt e11506 

Manegold, Christian 

TPS7109, TPS7613^ 

Manente, Liborio e19033 

Manente, Paolo e19595 

Manenti, Luigi TPS3637, 

5522, 7544 

Manetsch, Gabriela e19648 

Maneval, Daniel C. 2579 

Maneval, Edna Chow 4644, 

TPS4697 

Maney, Todd 4013 

Mangardich, Antranik 6123 

Mangili, Giorgia 5059 

Maniar, Manoj 3081 

Maniar, Tapan TPS670 

Manieh, Moustafa e20514 

Manikhas, Alexey 531, 1059, 

e11086, e19609 

Manji, Arif e13001 

Manji, Gulam Abbas 6615, 

e14185 

Manjili, Masoud 10565 

Manka, Lukas e15195 

Mankoff, David A. 1088, 

TPS3109, TPS10635 

Manley, Paul W. 10030 

Mann, Bhupinder Singh 

e16569 

Mann, Elaina e13028 

Mann, Susan e16515, 

e16559 

Manneh, Ray e15033, 

e15552 

Mannel, Robert S. TPS5114 

Manning Duus, Elizabeth 

e19577 

Manning, Robert J 8042, 

8107, e18575 

Mano, Max S. e11014, 

e11087, e11513 

Mano, Yohei e14536 

Manoharan, Prakash e14015 

Manola, Judith 4500, 6080, 

9016 

Manolis, Evangelos e21098 

Manrique, Gonzalo e19007 

Mansfield, Aaron Scott 

e21112 

Mansfield, David 2530 

Mansi, Janine 1094 

Mansmann, Ulrich Robert 

3588, 3603, 4023, 10054, 

e14043 

Manso, Luis 642, 1011, 

e11074, e11081, e11535, 

e15552, e21088 

Manson, JoAnn E 1501 

Manson, Stephanie 10061 

Mansoor, Atiya 10011^ 

Mansoor, Maryah e18574 

Mansoor, Wasat LBA4000, 

LBA4001, TPS4143 

Mansour, Marc 2588 

Mansourbakht, Touraj 9026^ 

Mansouri, David 3599 

Mansouri, Kambiz 1059 

Mansouri, Ladan 6557 

Mansouriah, Merad 5569 

Mansueto, Giovanni 9133, 

e12514, e18065, e18072 

Mansutti, Mauro 1044, 1073, 

e13058, e13070 

Manta, Carmen e17533 

Mantovani, Giovanni 5513, 

9006, e13098, e14577, 

e19634 

Mantovani, Lorenzo e14113 

Mantripragada, Kalyan C 

4098 

Mantry, Parvez e14581 

Manu, Michell 7103 

Manuaba, Tjakra e11022 

Manuel, Manuarii 10562 

Manuel, Megan 6524^ 

Manuguerra, Giovanna 623 

Manuyakorn, Ananya e14051 

Manyam, Madhavi e14045 

Manzano, Hermini e14041 

Manzano, Jose Luis 3571, 

e14671 

Manzoni, Marco 1604 

Manzoni, Mariangela e13103 

Manzullo, Ellen F. 9072 

Mao, Hui e13110, e14734 

Mao, Jun e19531 

Mao, Li Li 8506, e15051, 

e15052 

Mao, Li 5524 

Mao, Mao 3509 

Mao, Weimin e17512, 

e18013, e21080 

Mao, You-Sheng e14502 

Mapara, Markus Y. 8081 

Mapelli, Sergio 10022 

Maples, W. e14610 

Maples, William James 5544 

Maquilan, Genevieve e12508 

Mar, Victoria 8520 

Marabelle, Aurelien 2513, 

e13555 

Marabese, Mirko LBA7501 

Maragkos, Charilaos e17557 

Maragulia, Jocelyn 8069 

Maraldo, Maja Vestmo 

e18527 

Marandino, Ferdinando 1050 

Marasco, Antonella 8513 

Maraval-Gaget, Raymonde 

9011 

Marban, Patrick 3002 

Marcacci, Giampaolo 8066 

Marcaillou, Charles e14059 

Marcato, Paola e21090 

Marcello, Norina 2057 

Marchal, Frederic 10078, 

10517 

Marchello, Benjamin T. 3545 

Marchetti, Antonio e14042, 

e18021 

Marchetti, Paolo e15185 

Marchetti, Serena 2550 

Marchi, Enrica e13569 

Marchi, Paolo 1073 

Marchionni, Luigi 4585 

Marcial, Luisa Vanessa 1060 

Marciano, Roberta e13509 

Marciscano, Ariel e16052 

Marck, Brett 4520 

Marcom, P. Kelly 599 

Marcomigni, Luca e18023 

Marcos, Jean-Michel 1574 

Marcos, Manuel e11517 

Marcos, Rafael 1588 

Marcott, Valerie D. e15092 

Marcoux, J Paul 7588, 

e19637 

Marcucci, Guido 6526 

Marcucci, Lorenzo 629 

Marcus, Adam 5560 

Marcus, Elizabeth A. e16531 

Marcus, Karen Chayt 9502, 

9537, 9585 

Mardiak, Jozef TPS4677, 

9046, e15027, e15028 

Mardis, Elaine 503, 9518 

Mardjuadi, Feby I e14060 

Mardor, Yael 2078 

Maréchal, Raphael 3559, 

4050 

Marek, Billie J. 4085 

Marelli, Laura e17543 

Margalit, Danielle Nina 

e16060 

Margeli Vila, Mireia 1001, 

e11081 

Margeli, Mireia e11545 

Margenthaler, Julie A. 6079, 

6081, e19593 

Margery, Jacques TPS7112, 

e16560 

Marghoob, Ashfaq A. e19052 

Marginean, Celia 3515 

Margolese, Richard G. 

LBA506, 538 

Margolin, Kim Allyson 4533, 

8525, 8567, e16563 

Margolis, Jeffrey e17015 

Margono, Benjamin 7519^ 

Margulis, Vitaly 4616, 

TPS4678 

Mari, Ettore 7550 

Mari, Véronique 5018, 

e12502, e20006 

Mariadason, John e14019 

Mariani, Andrea 5004, 5076 

Mariani, Luca 627 

Mariani, Luigi 4507 

Mariani, Pascale 8546, 

e15524 

Mariani, Rachel e12002 

Maric, Irina 8088, 8104, 

e18568 

Mariconti, Luisa 7544 

Marien, Ann e15166 

Marienhagen, Joerg 7105 

Mariette, Christophe 4091, 

e14560 

Marin, Cristi 8540 

Marin, David 10550 

Marin, Jan e15195 

Marina, Neyssa 9503, 9537, 

10081 

Marinca, Andreea e15032 

Marinca, Mihai Vasile e15032 

Marincola, Francesco 8576 

Marincola, Franco 10565 

Marinello, Jorge Juan 2515 

Marineo, Giuseppe e19564^ 

Maringwa, John T 6002, 

7607 

Marinho, Simone e11513 

Marinko, Tanja 558 

Marino, Ana Luisa e19007 

Marino, Antonella e11001 

Marino, Gregory 6126 

Marinucci, Dena e21074 

Maris, John M. 9516, 9533, 

9576 

Maritaz, Christophe 9560, 

9572 

Mariucci, Sara e13103 

Marjanovic, Mira 10576 

Mark, Tomer Martin 8036, 

e21006 

Markert, James TPS2107 

Markey, Janell 6042 

Marki-Zay, Janos e21140 

Markin, Abraham 6016 

Markman, Ben TPS3637 

Markman, Maurie 5015, 

5049, e14697 

Markmann, Susanne 552 

Markopoulos, Christos 516, 

517, 583 

Markovic, Svetomir 8599, 

8600, e14507, e21112 

Markovich, Alla Anatolievna 

e19005 

Markovits, Judit E 9562 

Markow, Justin M. e18554 

Markowitz, Avi B. 5502 

Markowitz, Sanford D. 1569 

Marks, Charles e11569 

Marks, Gerald J. e14157 

Marks, John e14157 

Marks, Lawrence Bruce 6093 

Marks, Reinhard 6500^ 

Markulin-Grgic, Lijerka 

e12505 

Markus, Susan TPS3117 

Marley, Sarah E e15141 

Marme, Frederik 1090, 1096 

Marmissolle, Fabiana e14598 

Marmol, Maribel 3553 

Marolleau, Jean pierre 6534, 

8026 

Maron, Leeza M. 2040 

Marosi, Christine 2024, 

2053, 2071 

Maroto, José Pablo e15001, 

e15159 

Maroto, Pablo TPS4685 

Maroun, Christiane R. 3039, 

e13602, e13604 

Maroun, Jean Alfred 3578 

Marples, Maria 8523 

Marques, Dania Sofia e15532 

Marques, Daniel Fernandes 

2038 

Marques, Gilberto P e12040 

Marques, Mateus e14673 

Marquette, Charles Hugo 

7591 

Marquez, Cristina e11517 

Marquez, Diana 6132 

Marquez, I e19023 

Marquez, Mirari e12033 

Marquez, Raul 5068, e15575 

Marquez-Medina, Diego 7554 

Marquez-Rodas, Ivan e12003 

Marquina, Isabel 1570 

Marr, Brian 8598 


Marr, Tiffany e19570 

Marrapese, Giovanna 3570 

Marrari, Andrea 10026, 

10065 

Marreaud, Sandrine 10009, 

10067 

Marrero, Jorge A. e14581 

Marrinucci, Dena e21122 

Marrodan, Ines e11525, 

e17522, e18031, e21009 

Marsault, Blandine e19555 

Marschner, Ian 5081 

Marschner, Norbert e14138 

Marsh, Brian e19632 

Marsh, Robert de Wilton 

4022, e14642 

Marsh, Sharon 7586 

Marshall, Amy 7077 

Marshall, Andrea 5046 

Marshall, Ariela 1539 

Marshall, Deborah e11000, 

e11050 

Marshall, Ernest 7562, 8523, 

8532, 8564, TPS8605 

Marshall, Helen 502, 511, 

513 

Marshall, James Roger 

e15203 

Marshall, John 2590, 3095, 

TPS3638, TPS10632, 

e13116, e14009, e14569, 

e14658 

Marsiglia, Hugo e14002 

Marsoni, Silvia 2540, 

LBA7501, e19549 

Martel, Céline 10583 

Martel, Diane 4098 

Martel, Guillaume e14154 

Martel-Lafay, Isabelle 

LBA4003 

Martel-Planche, Ghyslaine 

1522 

Martell, Robert E. 4117, 

4545, e14005 

Martella, Francesca e18074 

Martelli, Olga LBA7501, 

e18065 

Marten, Angela TPS3636 

Marten-Mittag, Birgitt e15157 

Martens, John W.M 10504 

Martens, Tobias 2034 

Martens, Uwe Marc 3539, 

4050, 4090 

Martenson, James A. e16572 

Marth, Christian 514, 515, 

5031, 5042, 5052, 5071, 

5087, 5111 

Marthey, Lysiane 4018 

Marti, Gerald E 6581 

Marti, Roberto e14589 

Marti-Ciriquian, Juan Luis 

7095 

Marti-Marti, Francisca Elena 

e14015 

Martin Broto, Javier 10079 

Martin del Yerro, Jose Luis 

1111 

Martin Liberal, Juan 3096 

Martin Lorente, Cristina 

TPS4672, e15001, e15159 

Martin Reinas, Gaston 9038 

Martin Valades, Jose Ignacio 

5520 

Martin, Andrew J. 9087 

Martin, Anne-Laure 543 

Martin, Anne-Marie 3102, 

LBA8500^, 8501, 8518, 

e15085, e15087 

Martin, Antoine 8026 


Martin, Daniel 5541 

Martin, Dena e16047 

Martin, Eric 3509 

Martin, Francis 1574 

Martin, Jan 5004 

Martin, Jeremiah Thomas 

e14562 

Martin, John 1026 

Martin, Lainie P. 3029, 

5021, 8530 

Martin, Ludmila Katherine 

4039, e14169, e14170 

Martin, Marta e14041 

Martin, Michael Gary 3085 

Martin, Miguel 596, 604, 

TPS652, TPS670, 1001, 

1008, e12003, e14058 

Martin, Montse e18030 

Martin, Paloma 1074 

Martin, Peter 8064 

Martin, Petra e21024 

Martin, Robert C. G. e14581 

Martin, Stephane 2082 

Martin, Stuart S e21079 

Martin, Sue Ellen 4563 

Martin, Thomas 8035 

Martin-Algarra, Salvador 

8572, e18008 

Martin-Richard, Marta 3586, 

4079, e14097, e14104, 

e14552 

Martin-Valades, Jose Ignacio 

e14147, e15094, e18069, 

e18106, e21015 

Martinelli, Fabio 5096 

Martinelli, Francesca 6002 

Martinelli, Giovanni 6527, 

6531 

Martinez Banaclocha, 

Natividad 7011 

Martinez Cardús, Anna 9129 

Martinez Carrasco (1), Begona 

e11543, e19596 

Martinez de Vega, Vicente 

1111 

Martinez Garza, Laura Elia 

e15525 

Martinez Lago, Nieves 

e14733, e19505 

Martinez Marín, Virginia 

3618, 10547, e13085 

Martinez Marti, Alex 7041, 

7542 

Martinez Rodriguez, Jorge 

Luis e15525 

Martinez Sesmero (2), Jose 

Manuel e19596 

Martinez Villacampa, 

Mercedes 3571 

Martinez, Alberto J 8582 

Martinez, Alejandra 5083 

Martinez, Carmen 4089 

Martínez, Esther e15041 

Martinez, Gary 10084 

Martinez, Itzel Anahi 1607 

Martinez, Juan Carlos e21104 

Martinez, Manuel e12016 

Martínez, Miguel Angel 

e19007 

Martinez, Mireia e21009 

Martinez, Nieves 7058, 

10594 

Martinez, Noelia 602 

Martinez, Pablo 7041, 7544 

Martinez, Patricia e11523 

Martinez, Purificación 10512, 

10595 

Martinez, Raquel 3068 

Martinez, Steve R. e19001, 

e19013 

Martinez, Victor 4584 

Martinez-Amores, Brezo 3601, 

e14093, e14144 

Martinez-Balibrea, Eva 9129 

Martinez-Bueno, Alejandro 

e18137, e18143 

Martinez-Diaz, Francisco 

e11024 

Martinez-Fernandez, Monica 

4584 

Martínez-Galan, Joaquina 

1041 

Martini, Chiara 1604 

Martini, Thomas e15160 

Martinisi, Julia e19048^ 

Martinius, Holger e13108^ 

Martino, Massimo Vincenzo 

e18564 

Martino, Rosemary TPS5600 

Martino, Silvana 1021 

Martino, Tami 10622 

Martins Ferreira Castro, Ana 

Filipa 5567 

Martins, Flavia Linhares 

e13008 

Martins, Renato 5503, 5515, 

5518, 5591, 7530, 7600 

Martins, Sandro José e14657, 

e16046, e18078 

Martins, Suelen Patricia dos 

Santos e16568 

Martins, Yolanda 6103 

Martinsson, Jessica e13518 

Martoni, Andrea e15185 

Martorell, Miguel 7058, 

7060, 10594 

Martschick, Anja 5064, 

e19558 

Marttila, Timo e15112 

Martus, Peter 2007, 8031 

Martyn, Julie TPS5116 

Maru, Anish 3011 

Maru, Dipen M 3561, 4069, 

4078, 4086, e14071, 

e14547, e14548 

Marucci, Gianluca 2061 

Marulappa, Shashidhara Y. 

8081 

Marumoto, Tomotoshi e13014 

Marur, Shanthi 5566, 

e16061 

Maruyama, Kaoru 10577 

Maruyama, Satoru e15127 

Marven, Michelle 9124 

Marvin, Monica L. e12026 

Marx, Alexander 7105 

Marx, Gavin M. 4510, 

e15152 

Marynchenko, Maryna 6600 

Mas Estelles, Fernando 

e14097 

Mas Lopez, Luis Alberto 7531 

Más, Luís e15036 

Masalu, Nestory Andrew 

10601 

Mascarenhas, Leo 9564 

Mascaux, Celine e18006 

Maschek, Birgit J 4056 

Maschmeyer, Georg 3 

Masci, Giovanna 623 

Masciari, Serena 1547 

Masciullo, Valeria 5059 

Mase, Takahiro 588 

Masedu, Francesco 4572 

Maseki, Nobuo 8050 

Masi, Gianluca 3518, 3540, 

3549, 3555, 3585 

Masiero, Elena 3612 

Maskiell, Judith A 3567 

Maslak, Peter George 6609, 

6613 

Masny, Agnes e16510 

Mason, Cathleen 1046 

Mason, Christopher 9507 

Mason, James R. TPS5113, 

e21061 

Mason, Malcolm David 4509, 

TPS10633^ 

Mason, Malcom e15199^ 

Mason, Robert TPS4143 

Mason, Teresa e16045 

Mason, Warren P. 2051, 

2063, TPS2104 

Masood, Asif e16043 

Masroor, Sohaib 6005 

Masrorpour, Fatemeh 7096 

Mass, Robert D. 3067 

Massacesi, Cristian TPS648 

Massad, L. Stewart 5013, 

5101 

Massard, Christophe 3104, 

4554, 4642 

Massari, Francesco 630, 

4541, e14661 

Massett, Holly e16569 

Massey, Christine 2063 

Massey, Dan LBA7500 

Massey, Woody C 2027, 

2074^ 

Massi, Daniela 8581 

Massicotte, Marie-Helene 

5569 

Massidda, Bruno e14094 

Massie, Lisa 9002 

Massimino, Maura TPS9596 

Massin, Frederic e12506 

Massmanian, Lisa e13041 

Masson, Eric TPS2622, 8541 

Massopust, Kristy e13531 

Massuti, Bartomeu 7011, 

7095, 7522, 7540, 7542, 

e18055, e18130, e18131, 

e18137, e18143 

Masszi, Tamás 8018^ 

Master, Viraj A. e15006 

Masters, Gregg 2521 

Masters, Gregory A. e18122 

Masterson, Timothy A. 4586 

Mastrangelo, Michael J. 

8560, e19016 

Masuda, Aya 9569 

Masuda, Hiroko 1047 

Masuda, Munetaka 4070 

Masuda, Norikazu 540, 1106, 

TPS1147 

Masuda, Shinobu 565 

Masullo, Pietro 1500 

Masumori, Naoya e15071 

Matano, Alessandro 530 

Matano, Elide e15034 

Matasar, Matthew J. 2008, 

2089, 8054 

Matczak, Ewa 4542, 6092, 

e16530 

Mateescu, Cristian e14553, 

e14660 

Mateo, Joaquin 2530, 3021, 

3048, 10525 

Mates, Mihaela e19541 

Mathenge, Edward G. e21090 

Matheson, Alastair 3557 

Mathew, Josy e19627 

Mathew, Sherry 6613 

Mathews, John 10037 

Mathiason, Michelle A. 6074 

Mathieu, Luckson Noe 1573 

757s

Mathieu-Nicot, Florence 

e19623 

Mathijssen, Ron H.J. 2549, 

2596, 5001, 10091 

Mathios, Assefa 580 

Mathiot, Claire 8014 

Mathiot, Nathalie e18089 

Mathisen, Michael 6544, 

6597, 6607 

Mathonnet, Muriel 10505 

Mathoulin-Pelissier, Simone 

4053, 9012, 10035, 

e14023 

Matijevic, Mark 3030, 5518 

Matijevich, Karen 2582, 

8547 

Matin, Surena F. 4523, 

9029, e15075, e15092 

Mato, Anthony R. e18507, 

e19641 

Matono, Rumi e14536 

Matos Neto, Joao Nunes 606 

Matos, Leandro Luongo 5588, 

e16568, e21151 

Matous, Jeffrey 8027 

Matrana, Marc Ryan 4615 

Matro, Jennifer Madeline 

1544 

Matsubara, Akio e15048 

Matsubara, Nobuaki 585 

Matsubara, Nobumichi 7565 

Matsuda, Eisuke e17517 

Matsuda, Yoshinobu 10577 

Matsueda, Satoko e13046, 

e13050 

Matsuguma, Haruhisa 7021 

Matsui, Junji e13511, 

e19055 

Matsui, Kaoru 7028 

Matsui, Osamu 4104 

Matsui, Takanori e14510 

Matsui, Zenichi 9569 

Matsumoto, Hiroshi 613 

Matsumoto, Koji 5045, 

e19548 

Matsumoto, Seiji 7080, 

10585 

Matsumoto, Takeshi 7528, 

10610 

Matsumoto, Toshifumi 

e14722 

Matsumura, Akihide e18126 

Matsunaga, Tadashi e21007 

Matsuno, Yoshihiro e17520 

Matsuo, Keitaro 4067, 7560 

Matsuo, Takuji 9053 

Matsuoka, Lea e14679 

Matsusaka, Satoshi 10541, 

e14145 

Matsushita, Kazuyuki 7046 

Matsushita, Kohei e21053 

Matsuura, Hiroshi e14722 

Matsuura, Kazuto 5542 

Matsuura, Kentaro 3079 

Matsuura, Kuniomi e17538 

Matsuura, Yuka e18036, 

e18042 

Matsuyama, Yutaka 4104, 

e14506 

Matsuzaki, Akinobu 9574 

Matsuzaki, Hiroumi 5574 

Matta, Mona 2060 

Matta-Castro, Thalita e14027, 

e17548 

Matthaios, Dimitrios e17553 

Matthay, Katherine K. 9515, 

9533 

Matthews, John TPS4690 

Matthews-Smith, Velmalia 

6038 

Mattina, Marco e15544 

Mattioli, Sandro e18045 

Mattonet, Christian 3044, 

TPS3115, 7603, 

CRA10529 

Matulewicz, Theodore 1540 

Matulonis, Ursula A 5011 

Matulonis, Ursula 5012 

Matuschek, Christiane 

e11556, e14527, e16033 

Matushek, Paul E e21060 

Matveev, Vsevolod B. e15025 

Matza, Louis S. e16528 

Mau, Christine 541 

Mauch, Cornelia 8505 

Maude, Shannon L. 9506 

Mauer, Murielle E. 3508, 

4053, TPS4140 

Maughan, Benjamin 4525 

Maughan, Tim 2522, 3516, 

3530, 3574 

Maunsell, Elizabeth 9138 

Maurea, Nicola 645, e11052, 

e13539 

Maurel, Joan 3553, 4079, 

e14041, e21035 

Maurel, Juan 3536, 3586, 

3618, 10052, 10547, 

e14097 

Maurer, Barry 8073 

Maurer, Dominik 2522 

Maurer, Matthew A. 10516 

Maurer, Matthew J. 5077, 

9057 

Mauri, Davide 5066 

Mauri, Simonetta e19648 

Mauro, David J. 3531, 3587, 

4054 

Mauro, Lucia M e14593 

Mauro, Michael J. 6605, 

TPS6636 

Mauro, Virginie 7591 

Maus, Martin Karl Herbert 

3518, 3546, 3549, 7582, 

7594, e12007 

Mautner, Victor-Felix 6136 

Maverakis, Emanual e19001, 

e19013 

Mavis, Cory e18537, e18539 

Mavridis, Konstantinos 10606 

Mavroudis, Dimitrios e18105 

Maxim, Peter 10629 

Maximiano, Constanza 

e17502, e17503, e17515, 

e18521 

Maxson, DeLee 7534 

Maxuitenko, Yulia e15515, 

e19006 

May, Christoph 4122, 7105, 

e13503 

May, Kenneth F. 2502 

Mayer, Bhabita 9117 

Mayer, Deborah K. 6119 

Mayer, Erica L. CRA1002 

Mayer, FranÃƒÂ§oise 1051 

Mayer, Frank 2522, 2573^, 

3530, 4083, 7554, 

e14152, e15026 

Mayer, Ingrid A. 510, 605 

Mayer, Jiri 6559, 6584, 6627 

Mayer, Julie Ann 584, 

TPS10631 

Mayer, Musa 1526, e11051, 

e19633 

Mayer, Nicholas J. e15078 

Mayer, Robert J. 3517, 3631 

Mayer, Tina M. TPS2107 

Mayer, Wesley A TPS4678 

Mayer-Mokler, Andrea 2522, 

3530 

Mayerle, Julia TPS3639 

Mayne, Susan T e16511 

Mayo, Angela 8010 

Mayo, Clara 4068, 7522, 

10596, e14521, e18130, 

e18131, e18143 

Mayorga, Cheryl Ann 2569 

Mayr, Doris e15529 

Mays, Theresa A. e13025 

Mazard, Thibault 4087 

Mazer, Mia 2084, 2087 

Mazeron, Renaud 10098 

Mazhar, Danish 4529, 4531 

Maziere, Camille e14017 

Mazieres, Julien TPS7112, 

7584, e18089 

Mazorra, Zaima 2527 

Mazuir, Florent e15116 

Mazumdar, Jolly 3000, 8518 

Mazur, Grzegorz 6559, 6632 

Mazurenko, Natalia N. 

e20501 

Mazzanti, Chiara 629 

Mazzanti, Paola e21070 

Mazzanti, Roberto e14577 

Mazzara, Calogero 4627 

Mazzarello, Sasha 10620 

Mazzei, Maria Eugenia 

e19007 

Mazzer, Micol 3612 

Mazzocchi, Maria e14018 

Mazzola, Giuseppe e19595 

Mazzoni, Enrica e11547 

Mazzoni, Francesca e18074 

Mc Hugh, Kieran 9517 

McAfee, Steven L 6617, 

6618, 6621 

McAleer, Cecilia TPS4679 

McAleese, Fionnuala 8059 

McArdle, Stephanie 1013, 

1098 

McArthur, Grant A. 8502^, 

8503^, 8517, 8520, 

e13054 

McBride, Sean M 5594 

McBride, William H. e13045 

McCabe, Christopher TPS665 

McCabe, Mary S. 6073, 9121 

McCabe, Nuala 10553 

McCaffrey, John 581, 1543, 

e12038, e19601, e19632, 

e21147 

McCaffrey, Judith C 5564, 

5591 

McCaffrey, Thomas V 5564 

McCall, Linda Mackie 1107 

McCann, Georgia Anne-Lee 

e15585 

McCann, Lauren CRA4502, 

e15059 

McCanna, James e21047 

McCarter, Martin TPS10632 

McCarthy, Aoife e15078 

McCarthy, Bridget J. e12036 

McCarthy, Damian L. 3095 

McCarthy, Joy S. e11079 

McCarthy, Philip L. 6565 

McCarty, John e18550 

McCaskill-Stevens, Worta J. 

TPS657 

McCaskill-Stevens, Worta 

6086 

McCaughan, Georgia J. 9126 

McCaul, James Anthony 

e16042 

McCauley, Dilara 1055, 

e13586, e15200 

McClain, Jonathan e12005 

McClanahan, Pamela e14503 

McClay, Edward Francis 2569 

McCleary, Nadine Jackson 

4112, e19586 

McClelland, Michael 10543 

McCleod, Michael 4127 

McClish, Donna 1563 

McCloud, Philip 7604 

McClure, Bev 3629 

McClure, Candace e13078, 

e15578 

McCombie, William R. 4562 

McCook, John 3015, e14593 

McCormack, Peter 3048, 

3051 

McCormick, Beryl 1004 

McCormick, Kristen N. 7071 

McCormick, Lynn 6126 

McCready, David R. 1019, 

9131 

McCulloch, Leanne 8086, 

e18569 

McCulloch, Timothy M 

e16010 

McCulloch, William 567 

McCully, Katen C. 1544, 

1550 

McCusker, Margaret Elizabeth 

8585 

McCutcheon, Ian E. 2019 

McDade, Theodore P. 4059, 

e14691 

McDaniel, Kelly e16528 

McDermed, Jonathan E. 

e15113 

McDermott, David F. 

CRA2509, 4504, 4505, 

4543, 4617, 4635, 8507, 

8508, 8516, 8567, 8569 

McDermott, Enda 1042 

McDermott, Martina 617, 633 

McDermott, Raymond S. 

e14705, e15093, e17561 

McDermott, Raymond e15016 

McDermott, Shaunagh 

e14615 

McDevitt, Jennifer T. 

TPS2621 

McDonagh, Charlotte 

TPS3111 

McDonagh, Paul D. e19055 

McDonald, Alicia 6595 

McDonald, Angus 4531 

McDonald, Dan CRA2509, 

TPS2613, TPS2622, 4505, 

7509, 8507 

McDonnell, Felicity e14705, 

e15016 

McDonnell, Kevin e12026 

McDunn, Susan H. 9085 

McDyer, Fionnuala A 10553 

McElduff, Patrick e14166 

McElhinny, Abigail 4041 

McFarlane, Graham 6005 

McGaughey, Dean S. e13032 

McGee, Sharon F. 581 

McGinn, Travis W. 9001 

McGinniss, Matthew Jerome 

1040, 4013, 10630, 

e15209, e20507 

McGlone, Thomas e16513 

McGoldrick, Trevor 3048 

McGovern, Rachel TPS7611 

McGovern, Renee M. 9581 

McGowan, Margit e21075 


McGowan, Patricia M. 622, 

1042 

McGrath, Sophie e15517 

McGraw, Steven 2031 

McGree, Michaela 5004 

McGregor, John R. 10614 

McGregor, Kimberly 3057 

McGreivy, Jesse S. 4042, 

TPS4135 

McGuire, Brendan e14581 

McGuire, Kandace P 1038 

McGuire, William P. 5012 

McGuirk, Joseph 10605 

McHenry, Brent TPS4689, 

TPS4691 

McHugh, Deaglan e15016 

McHugh, Kelsey 9544 

McHUGH, Peter J e13587 

McIntosh, Christine e13569 

McIntosh, Lynn e18079 

McIntyre, John B. e21044 

McIntyre, Kristi 547, 3069 

McKay, Marie 8564 

McKee, Kathryn S. e15075 

McKee, Mark D. 3532, 7512, 

e13583 

McKeegan, Evelyn Mary 

e13583 

McKeever, Elizabeth 4109, 

e14524, e14592 

McKendrick, Joseph James 

3629, TPS3637, e16516 

McKendrick, Joseph J 3505 

McKenna, Aaron 2020 

McKenna, David 2546 

McKenna, Dorothy R 6013 

McKenna, Edward 3522, 

3523, 3525, e19048^ 

McKenney, Jesse e15005 

McKenzie, Meghan 2566 

McKeown, S. e14022 

McKibbin, Trevor e18553 

McKiernan, James M. 4593, 

e15018, e15019, e15021 

McKinlay, Mark A 3029 

McKinley, Marti 4052 

McKinney, Yolanda 10589 

Mckoy, June M. 4063, 6623 

McKoy, June M 2532 

McLachlan, Sue-Anne 

e16501, e16562 

McLaughlin, Brian Thomas 

6563 

Mclaughlin, Laurie e19598 

McLaughlin, Peter 8067 

McLean, Estelle 10553 

McLemore, Elisabeth Paul 

e14069 

McLendon, Roger E 2021 

Mcleod, David G. e15207 

McLeod, Howard L. 10515, 

e13109 

McLinden, Michelle 1094 

McMahon, Jeanne A 3582 

McMahon, Jeremy McMahon 

e16042 

McMahon, Pamela M 6004 

McMasters, Kelly M. 8534 

McMeekin, D. Scott 3008, 

3041, 3097 

McMenemin, Rhona e17519 

McMillan, Alex 8060 

Mcmillan, Donald C. 3599, 

3611, e14054, e14092, 

e14110, e14117 

McMillan, Robert 1118, 1541 

McMullin, Mary Frances 

TPS6642^ 


McNally, Diane L. e15146, 

e15148 

McNally, Orla 5073 

McNamara, Erica J. 6046, 

6088 

McNamara, Mairead Geraldine 

4109, e14524 

McNamara, Mairead e14592 

McNamara, Michael J. 

e14611, e14665 

McNeel, Douglas G. 

TPS2613, 4650 

McNeill, Jonathan D 7595 

McNulty, Ann M 8082 

McPherson, Christopher 

TPS3116 

McPherson, Eugene e17022 

McPherson, Monica e14124, 

e18516, e19638 

McQuade, Jennifer e18540 

McQueen, Robert Brett 

e16550 

McQueen, Teresa J TPS6635 

McSherry, Frances 2027, 

2074^ 

McSwain, Anita P. e11084 

McTiernan, Anne e14005 

McWalter, Gael 1548 

McWhirter, Elaine 3082 

McWilliams, Robert R. 3102, 

e14594 

Meade, Angela M. 3516 

Meadows, Anna T. 9515 

Meadows, Helen 4004, 4029 

Meagher, Alison e19568 

Meani, Francesco e15549 

Means-Powell, Julie Ann 

4117, 4545, 8519 

Meany, Holly Jane 9533 

Mebis, Jeroen 4622 

Medalia, Gal e14571, 

e14731 

Medeiros, Michelle 7546, 

9103 

Medeiros, Rui e15532 

Medford-Davis, Laura Nyshel 

7040 

Medina Sanson, Aurora 

e20005 

Medina Villaamil, Vanessa 

e14595, e15076, e15077, 

e15079, e21002 

Medina, Fernando Lara 1607, 

e11016 

Medlin, Stephen Charles 

8041 

Medlin, Stephen e18576 

Medvedev, Viktor 5508 

Meer, Laurens van der 9550 

Meershoek – Klein 

Kranenbarg, Elma 526 

Meert, Anne-Pascale e18006 

Meert, Nicolas e14060 

Meeus, Marie-Anne 3018^ 

Meeus, Pierre e14730 

Mefti, Fawzia TPS662 

Mega, Anthony E. 4662 

Megason, Gail C. 9547 

Mego, Michal TPS4677, 

e15027, e15028 

Mehan, Mike e21012, 

e21142 

Mehanna, Hisham e16042 

Mehedint, Diana e15039, 

e15046, e15204 

Mehmood, Tahir e16043 

Mehmud, Faisal CRA4502 

Mehnert, Janice M. TPS3112 

Mehra, Ranee 3007, 5500 

Mehran, Mariam 3039, 

e13602, e13604 

Mehran, Reza J. 4069, 4086, 

7078 

Mehring, Elmar 6567 

Mehrishi, Jitendra e13102 

Mehrotra, Bhoomi TPS5601, 

e16026 

Mehta, Ajay O. TPS649, 

TPS651, 3011 

Mehta, Cyrus R. TPS6637 

Mehta, Jayesh 6623, 8037, 

e18556 

Mehta, Keyur 522, 523 

Mehta, Maitrik e15505 

Mehta, Minesh P. 2008b, 

2001, 2013, 2047 

Mehta, Monal e13543 

Mehta, Shaveta 1066 

Mei, Baigen TPS3113 

Mei, Matthew 8038 

Mei, Qi 5097 

Meier, Friedegund Elke 8526 

Meier, Werner 5007, 5031 

Meijer, Coby 4528, e15035 

Meijer, Sybren L. 4094 

Meiler, Johannes 4083 

Mein, Charles 10550 

Meiri, Eti 10575, e21008 

Meisner, Angela W. 1558 

Meisner, Christoph 1067, 

2000 

Mekan, Sabeen Fatima 1046 

Mekata, Eiji e11564 

Mekhail, Tarek 7100, e13113 

Mel Lorenzo, Jose Manuel 

e18040 

Mel, Jose Ramón e11535, 

e18070, e21088 

Melamed, Jonathan e15191 

Melanson, Anne Marie 

e11548 

Melcher, Carola Anna 

TPS1146, 1602, 10540 

Meldgaard, Peter 7001 

Melegari, Elisabetta e11054 

Melemed, Allen S. 1068 

Melemed, Symantha 

LBA7507 

Melendez Asensio, Barbara 

10500 

Melhem-Bertrandt, Amal 527, 

537 

Melichar, Bohuslav 559, 

3010, LBA4007, 4503, 

e14556 

Melisi, Davide e14661 

Melisko, Michelle E. 9107 

Mell, Loren K. 6121, e14555 

Mellado, Begoña TPS4674, 

e15041 

Mellemgaard, Anders 7026 

Mello, Celso Lopes 10069, 

e14119, e14680, e14728 

Mellor, Dan e16538 

Mellstedt, Hakan 6557, 

e13518, e15531 

Melnikova, Vladislava O. 

e13500, e13562, e13575, 

e13577, e15124, e21028, 

e21029 

Melnikova, Vladislava e21058 

Melnychuk, David e14020 

Melo Mendes, Ana Valeria 

e12021 

Melosky, Barbara L. 7020 

Meltzer, Paul S. TPS7609 

Melville, Heather 3095 

Melville, Sharon K. 6070 

Melvin, Cathy 6017, 6029 

Memoli, Vincent 7022 

Memon, Muhammad e20508 

Men, Taoyan 7608 

Menard, Jean e15049 

Menasherov, Nikolai e14571 

Menda, Yusuf e15143 

Mendelson, David S. 3032, 

3034, 3042^, e13077 

Mendelson, Estella 6626^ 

Mendez Herrera, Maria del 

Carmen e15527 

Mendez Vidal, Maria Jose 

TPS4672, TPS4688 

Mendez, Eduardo 5503, 5515 

Mendez, Guillermo Ariel 

e14598 

Mendez, Jose Carlos e14041 

Mendez, Maria Jose TPS4685 

Mendez, Miriam e17502, 

e17503, e17515, e18521 

Mendez, Pedro 4579 

Mendiola Fernandez, Cesar 

1001 

Mendiola, Cesar 642, 

e11081, e15552 

Mendivil, Alberto e15500 

Mendonca, Eneida 9583 

Mendoza, Jose Francisco 

e15571 

Mendoza, Silvia 2527 

Mendoza, Tito R. 5561, 

5589, 6551, 8091, 9047, 

9072, 9081, 9082, 9083, 

9099, 9106, 9118, 9140, 

e15173 

Menefee, Michael E. 

TPS2618, 5544 

Menen, Rhiana e21051 

Menendez, Xiomara e13084 

Meneses, Abelardo 1607 

Menetrier-Caux, Christine 

10562 

Meng, Fanliang e15563 

Meng, Maxwell V. 4593 

Meng, Raymond D. TPS2616, 

9105, e13114 

Meng, Xia 3551 

Meng, Xue 4073 

Meng, Xuli e11566 

Menon, Hari e17003 

Menon, Jarayam 4106 

Menon, Mani 1560 

Menoyo Bueno, Alicia e16037 

Menten, Johan TPS2104 

Menzies, Alexander M. 550, 

8558, e19011 

Menzies, Alexander M 3102 

Menzin, Andrew 5056, 5057 

Meoni, Giulia e18074 

Merad, Mansouriah 4621 

Merante, Serena 6531 

Mercado, Gabriela e18028 

Mercaldo, Nathaniel D. 

e14501 

Mercatali, Laura 10615 

Mercer, Carol A TPS3116 

Merchant, Melinda S. 9545 

Merchant, Thomas E. 9531 

Mercier, Betty 9074 

Mercier, Mariette 1584 

Mercier-Blas, Anne e11019 

Mercill, Sharon L e13086 

Mercuro, Giuseppe 9006 

Merdek, Keith D. e21146 

Meredith, Judy e14098 

Meredith, Rhonda 1058 

Mergen, Noemi 6500^ 

759s

Mergenthaler, Hans-Guenther 

e15026 

Merghoub, Taha 2521 

Mergui-Roelvink, M. 2550, 

e13028 

Meria, Paul e15524 

Meric-Bernstam, Funda 1015, 

1029, 1054, 1104, 1130, 

e14662 

Merican, Ismail 4106 

Meriggi, Fausto e14018 

Merimsky, Ofer 10034, 

10043 

Merino, Maria 1570, 9073, 

e11028 

Merkelbach-Bruse, Sabine 

CRA10529 

Merker, Vanessa L. 6136 

Merkow, Ryan P 3608 

Merks, Johannes H. 

TPS9597^ 

Merla, Amartej e14019 

Merlano, Marco Carlo 2600, 

5502 

Merle, Patrick e18089 

Merlin, Jean-Louis 10517, 

TPS10634, e14129 

Merlo, Domenico Franco 

1073, e21065 

Mernaugh, Ray 628 

Meropol, Neal J. 605, 1514, 

6021, e14021 

Merrick, Daniel 10580 

Merriewether, A. Rene 2576 

Merriman, Kelly W. 6125 

Merseburger, Axel S. e15195 

Mertens, Ann 9505 

Mertens, Cecile 9012 

Mertens, Wilson C. e19543 

Mes-Masson, Anne-Marie 

e15202 

Mesa, Ruben A. 6624, 

TPS6641 

Meschino, Wendy e12034 

Meservey, Caitlin 610, 

TPS1134 

Meshref, Mohamed M. 

e16505 

Mesia, Ricard 5502, 5516^ 

Mesker, Wilma E e14151 

Mesnard, Nathalie TPS646, 

e11019 

Messa, Francesca 2600 

Messahel, Souad e15091 

Messam, Conrad A. 9117 

Messersmith, Wells A. 2567, 

2568, 3017, 3528, 3552, 

e13006, e13048, e14071 

Messina, Antonella 10026 

Messina, Caterina e15185 

Messina, Giuseppe e18564 

Messinger, Yoav H. 9521, 

9522 

Mester, Jessica 1508, 1516 

Mesti, Tanja e14083 

Met Domestici, Marie Amelie 

e12502, e20006 

Metges, Jean Philippe 

e14148 

Metheny, Trina 520 

Metrakos, Peter 4118, 

e14621 

Metran Nascente, Cristiane 

e20506 

Metro, Giulio e18023, 

e18101 

Metwalli, Adam R. TPS4680 

Metz, James M. 6135 

Metz, Wendy e21066 

Metzger, Brigitte e14180 

Metzger, Monika 9502 

Metzger, Otto e21010 

Metzger, Severine 4614 

Metzinger, Daniel 5095 

Metzner, Bernd 8031, 

e15026 

Metzner, Cornelia 4122 

Metzner-Sadurski, Joanna K. 

9061 

Meulemans, Bart 8076 

Meunier, Jérome 9011 

Meunier, Katy Luce e19500 

Mewawalla, Prerna 6555, 

e18543 

Meyer, Anne-Marie 5539, 

6104, e15184 

Meyer, Christian e17536 

Meyer, Christiane e19050 

Meyer, Frank e14630 

Meyer, Gary 3537, e14584 

Meyer, Guy TPS9149^ 

Meyer, James S. 9537 

Meyer, Janelle Marie 10011^ 

Meyer, Jeffrey John e14165 

Meyer, Julia 9507 

Meyer, Meghan E 9071 

Meyer, Michael e17529 

Meyer, Nicolas 8591, e13594 

Meyer, Tim 4121, 4123, 

TPS4150, e14696, e17543 

Meyer, William H. 9509 

Meyer-Sabellek, W e13597 

Meyer-ter-Vehn, Tobias 2054 

Meyerhardt, Jeffrey A. 3537, 

4112, 4125, e14114, 

e19586 

Meyers, Brandon M e14001 

Meyers, Bryan F 4062, 7008 

Meyers, Christina A. 9072 

Meyers, Jeffrey P 7555 

Meyers, Marlene e11529 

Meyers, Paul A. 9503 

Meyerson, Howard TPS655 

Meyerson, Matthew 7006 

Meyskens, Frank L. 9018 

Meza, Jane L 9509 

Mezhir, James J. 10015 

Mezquita, Laura 3601, 

e14093, e14144 

Mezynski, Janusz 4553, 

e13599 

Mhawech-fauceglia, Paulette 

5091 

Mhlanga, Joyce 10509 

Miah, Aisha 10060 

Mianowska, Marta e14159 

Miao, Sara 4632 

Micallef, Sandrine 3080 

Miceli, Rosalba 5555, 

10000, 10016 

Micetich, Kenneth C. 4113 

Micewicz, Ewa D. e13045 

Micha, John P. e15500 

Michael, Agnieszka e15517 

Michael, Michael 3629, 

TPS4141 

Michael, Shaunita A. 4117, 

4545, 8519 

Michaelides, Ioannis e15030 

Michaelidou, Kleita 10606 

Michaelson, James e18520 

Michaelson, M. Dror 4546, 

4549, 4566, 4644, 

TPS4682 

Michaelson, Richard 614 

Michailichenko, Tatyana 

e13059 

Michailidis, Prodromos 

e14567 

Michalaki, Vasiliki e13556 

Michallet, Anne-Sophie 8068 

Michallet, Mauricette 6534, 

6542 

Micheau-Bonnier, Douglas 

9011 

Michej, Wanda 8548, e19022 

Michel, Maurice Stephan 

4539 

Michel, Pierre LBA4003, 

TPS10102^ 

Michele, Antonio e15152 

Micheli, Rodrigo 1522 

Michelin, Odair Carlito 

e14173 

Michels, Jean-Jacques 10018 

Michelucci, Angela e13057 

Michener, Tracy 8508 

Michielin, Olivier e19050 

Michiels, Stefan 507, e21010 

Michimae, Hirofumi 5003, 

7515 

Michina, Zoya P. e19012 

Michl, Patrick 4050 

Michor, Franziska 4577, 

4585 

Michotte, Alex 2050 

Michoux, Nicolas 5519 

Middel, Peter 3600, e14162 

Middleton, Gary William 

LBA4000, TPS4143 

Middleton, Mark R. 3051, 

e13587, e14625 

Middleton, Steven e13600^ 

Midgley, Rachel A TPS10632, 

e13007 

Midgley, Rachel LBA4001 

Midthun, David E. 1610 

Miele, Evelina e12510 

Mielgo Rubio, Xabier e11074 

Mier, James Walter 8516 

Mierzwa, Michelle Lynn 

e14714 

Mietlowski, William Leonard 

2543 

Mietzel, Melissa A 8011 

Migdady, Yazan 1034 

Migden, Michael R 8579 

Miglianico, Laurent e15131 

Miguel, Ana 10608 

Mihalcioiu, Catalin Liviu 

Dragos TPS1139 

Mihalis, Eva 9107 

Mihic, Daniela 8563 

Mijatov, Branka 8553 

Mikami, Kazuya e15055, 

e15099 

Mikami, Tomomi 3002 

Mikhael, Joseph 8010 

Mikhail, Sameh e14009 

Mikhaylova, Irina N. 2524 

Mikheykin, Andrey 10587 

Miki, Izumi e19557 

Miki, Jun e15127 

Miki, Tsuneharu e15055, 

e15098, e15099 

Mikkelsen, Tom 2018 

Mikula, Lynn A 10050 

Mikus, Gerd 10041^ 

Mikuskova, Eva 9592 

Milam, Michael R. 5095 

Milandri, Carlo e18045 

Milani, Manuela e11546 

Milani, Richard V e15192 

Milano, Filippo 6631 

Milano, Gerard A. 2537^, 

2600 

Milano, Michael T 1536 

Milanowski, Janusz 7090 

Milas, Mira 1508 

Milbourne, Andrea 6116 

Milburn, Christy 8533 

Milecki, Piotr 4642 

Milella, Michele 4017, 4541, 

e13512, e13572, e14661 

Miles, Dale 4504, 5547 

Miles, David LBA1, TPS660, 

e11055^, e16547 

Miles, Joshua 639 

Miles, Lisa e14015 

Mileshkin, Linda R. TPS5116, 

9124, e15541, e16538, 

e16562, e19605 

Miletello, Gerald 1086 

Milhem, Mohammed M. 

3056, LBA8509, 10010, 

TPS10103, e13088, 

e15010 

Milione, Massimo e21118 

Miliotto, Anthony e11563 

Milisen, Koen 9035 

Millán, Isabel e18521 

Millar, Ewan K.A 504 

Millar, Jeremy TPS4690 

Millard, Frederick E. e15115 

Millenson, Michael Mark 

e18530 

Millenson, Michael M e19580 

Miller, Andrew H. 3055, 

6076, 9016, 9122 

Miller, Austin 5041 

Miller, Barry 2528 

Miller, Brandon L. e21124 

Miller, Carole Brennan 6605, 

6624, TPS6642^ 

Miller, Claire 3083, e19647 

Miller, Danielle TPS4141 

Miller, David Scott 5087, 

e15501 

Miller, Dustyn e15042 

Miller, Ehud 1564 

Miller, Elizabeth 2074^ 

Miller, Fiona Alice e19616 

Miller, Jessica 6054, 9014 

Miller, Kathy TPS663, 1027, 

6025, e21099 

Miller, Kenneth David 6067 

Miller, Kurt 4510, 4519^ 

Miller, Langdon L. 6518^ 

Miller, Laura Elizabeth 

7072^, e17531^ 

Miller, Lisa e13067 

Miller, Mark 9067 

Miller, Melissa F 9048 

Miller, Meredith Halks 10576 

Miller, Naomi 1123 

Miller, Paul J. E. e21077 

Miller, Paul 4056 

Miller, Robert C. e14507, 

e14555, e16572 

Miller, Robert Stephen 10509 

Miller, Rowan 5035 

Miller, Thomas P. 8001, 

e18534, e18536 

Miller, Todd W 1054 

Miller, Tracie L. 9530 

Miller, Vincent A. 3083, 

3533, 7527, 7529, 10590, 

e17541 

Miller, Wilson H. 1099 

Miller, York E 10580 

Milleron, Bernard 7057, 

e18075 

Millholland, Robert 563, 

6063 


Millikan, Randall E. 4523, 

4615 

Mills, David R. e21116 

Mills, Glenn Morris e14667, 

e16009 

Mills, Gordon B. 1015, 1054, 

4131 

Millward, Carl 3512, 4560 

Millward, Michael 3000, 

7079^, LBA8500^, 

e16501, e19642 

Milne, Ginger L 7518, 10514 

Milne, Roger L 1502 

Milner, Alvin e13594 

Milner, Ruth 9529 

Milojkovic Kerklaan, Bojana 

e13594 

Milosevic, Michael 5105 

Milowsky, Matthew I. 4527, 

4581^, 4592, e15022 

Milton, Ashley 2597 

Milutinovic, Aladin e21146 

Mimaki, Sachiyo 1552 

Mimidis, Kostantinos e14567 

Mims, Martha P. 4643 

Min, Byung Soh e14084 

Min, Chang Ki 8097 

Min, Trisha 4109, e14524, 

e14592 

Minami, Hironobu e16034, 

e16505 

Minami, Seigo e18007, 

e18056, e18141 

Minamimoto, Ryogo 4626 

Minardi, Daniele e15074 

Minasian, Lori M. 9018, 

9047, 9144, e19633 

Minato, Koichi 7003, 7012, 

7515, e18037, e19556 

Minato, Nagahiro e21004 

Minca, Eugen C. 620 

Minden, Mark D 6627, 6632 

Minegishi, Yuji 7563, 7565, 

e18129 

Miner, Thomas J. 4098 

Mineur, Laurent 3502, 3506, 

TPS10102^ 

Ming, Zhao e17501 

Minhans, Sachin e18041 

Minichillo, Santino e13057 

Minisini, Alessandro 1044, 

e13058, e13070 

Mink, Jennifer 8594 

Minn, Heikki 5502 

Minna, John D. 7096, 7589, 

10612, e18077 

Minni, Francesco e14647 

Mino, Emilio Araujo 1611 

Minomo, Shojiro 10577 

Minor, David R. 8508, 8518 

Minoshima, Yukinori e13511 

Minotti, Vincenzo e18023, 

e18101, e21094 

Minozzi, Marina e12510 

Minsat, Mathieu e15535 

Minton, Neil 8037, e18559 

Minton, Susan E. 1585, 

TPS2620 

Mintz, Arlan H. 8528 

Minuto, Francesco e19038 

Miquel, Catherine 2023 

Miquel, Rosa 3536 

Mir, Olivier 1095, 2557, 

5067, e13056 

Mirabel, Xavier e14560 

Mirabile, Aurora 5555 

Miraglio, Emanuela 2600 

Mirakhur, Beloo LBA8500^ 

Miralles, Ambrosio 9073 


Miramon Lopez, Jose e11081 

Miranda Rosales, Luis Miguel 

e18524 

Miranda, Andrea 5093, 5094, 

e15547, e15551, e15553 

Miranda, Christine e14102 

Miranda, Gus 4576, 4578, 

4588, 4589 

Miranda, Raelson Rodrigues 

e12021 

Miranda, Susana e13601 

Miranda, Vanessa Costa 

e14702 

Mirandola, Leonardo e21105 

Miro, Cristina e11517 

Miron, Lucian e15032 

Miron, Patricia 6569 

Miroshnichenko, Gennady 

6134 

Mirshahidi, Hamid R. e16523 

Mirshams, Maryam 10522 

Mirza, Mansoor Raza 1055, 

LBA5002^ 

Miscoria, Manuela e15091 

Misek, Glen I. e14640 

Mishima, Hideyuki 3524, 

3607, TPS3642 

Mishima, Yuji 10541 

Mishra, Anand Kumar e19516 

Mishra, Anjali 10587, 

e16023 

Mishra, Mark Vikas e11505 

Mishra, Pravas Chandra 

e17000 

Mishra, Priyankana 527 

Mishra, Saroj Kanta e16023 

Misino, Andrea e21113, 

e21134 

Misitzis, Ioannis 10606, 

e11073, e11519 

Miskovska, Viera TPS4677, 

e15027, e15028 

Misleh, Jamal Ghazi e18122 

Misra, Sumathi 9004 

Misra, Vivek e14015 

Missale, Gabriele TPS4151 

Misset, Jean-Louis 568^, 

5018 

Missiaglia, Edoardo 9510 

Mister, Donna 9122 

Mistry, Bipin 3030 

Mita, Alain C. 2610, 3073, 

3078, 7029, e15116, 

e18047 

Mita, Monica M. 3060, 3073, 

3078, e15116 

Mitchell, Aaron 6051 

Mitchell, Alan 8041 

Mitchell, Carmen 4586, 

e15003 

Mitchell, Edith P. 3621, 

4043 

Mitchell, Heather e21008 

Mitchell, Lada TPS653, 

TPS654^, 3614, 8517 

Mitchell, Paul 6058, 

LBA7000, 7079^, e17539 

Mitchell, Sandra A. 9047, 

9130, 9144, e19633 

Mitchell, Scott 10038, 

10039 

Mitchell, Susan L. 9004 

Mitchinson, Christy e21037 

Mitha, Nathalie e18505 

Mitikiri, Nirupama Devi 

e15108 

Mitin, Andrey e15029 

Mitra, Anirban Pradip 4565, 

4575, 4578 

Mitra, Dipendrea Kumar 

e17511 

Mitra, Nandita 1539, e18032 

Mitry, Emmanuel 4036, 

4071, 4087, e14065, 

e14168 

Mitsiades, Nicholas e17018 

Mitsudo, Kenji 5556 

Mitsudomi, Tetsuya TPS7110, 

7521, e18145 

Mitsuoka, Keisuke e21059 

Mitsuoka, Shigeki 6112, 

e17538 

Mitsuyama, Shoshu 1119 

Mitsuyasu, Ronald T. 4030 

Mittal, Bharat Bhushan 5500, 

e18523 

Mittar, Priyanka e11057 

Mittempergher, Lorenza 3065 

Mittendorf, Elizabeth Ann 

625, 1028, 1032, 1107, 

1130, 2508, 2529 

Mittermueller, Johann 3588 

Mittra, Arjun e19506 

Miura, Daishu 591, 1106, 

TPS1141 

Miura, Satoru 7561 

Miura, Yasushi e17020 

Miura, Yousuke e18037 

Miwa, Keisuke 3084 

Miwa, Shinji 10075 

Miyagishima, Takuto 3593 

Miyajima, Akira 9569 

Miyakawa, Hiroyuki 4031 

Miyake, Hideaki e15048 

Miyamoto, Atsushi e14518 

Miyamoto, David Tomoaki 

4566 

Miyamoto, Natsuko e18036, 

e18042 

Miyamoto, Yuji TPS3642, 

e13553 

Miyamura, Koichi 6533 

Miyashita, Minoru e11530 

Miyata, Jun e18058 

Miyata, Yoshihiro 7031 

Miyazaki, Jun e15004 

Miyazaki, Masaki e18058, 

e18060 

Miyoshi, Eiji e17520 

Miyoshi, Shinichiro e17517 

Miyoshi, Sosuke e21059 

Miyoshi, Yasuo e13037 

Mizoguchi, Akira e21053 

Mizoguchi, Kosuke 7569 

Mizumoto, Kazuhiro 4035 

Mizuno, Nobumasa 4042, 

e14540 

Mizuno, Ryuichi 9569 

Mizuno, Toshiro e19546 

Mizuno, Yoshio e11007 

Mizunoe, Tomoya 5084 

Mizunuma, Nobuyuki 10541, 

e14145 

Mizusawa, Junki 3524, 3569, 

4031, 5542, 6112, 7028, 

e14510 

Mizutani, Yoichi e15000 

Mjaaland, Odd 4066 

Mjaaland, Svein 4066 

Mladosievicova, Beata 9592 

Mlineritsch, Brigitte 514 

Mo, Frankie 5511, e14085, 

e14528 

Mo, Jinggang e14523 

Moachon, Gilbert 3052 

Mobley, Gary M. 9118 

Mocci, Evelina e12033 

Moccia, Alden A 8049 

Mocellin, Simone e12037 

Moch, Holger 2055 

Mochizuki, Hitoshi e14622 

Mocquery, Magali TPS9154 

Modak, Anil S e13086 

Modak, Shakeel TPS9595 

Modena, Yasmina e13019 

Modest, Dominik Paul 3519^, 

3588, TPS3639, 4023, 

e14043 

Modi, Shanu 528, 10514, 

10618 

Modi, Tejas e12025 

Modi, Yashpal e12025 

Modiano, Manuel R. 7541, 

7556 

Modonesi, Caterina e13019 

Moehle, Robert 2007, 8031 

Moehler, Markus Hermann 

TPS3641^, 4090, 

TPS4138, TPS4140 

Moenig, Stefan Paul 4090 

Moertel, Christopher L. 2546 

Moes, Johannes 2550 

Moeslein, Fred M 3590 

Mogal, Harveshp D. e19593 

Mogg, Robin 3531, 3587 

Mogha, Ariane e19037 

Moghadamfalahi, Mana 5095 

Moghaddamjou, Ali 6085 

Mognetti, Thomas TPS646, 

10049 

Mogushi, Kaoru e11065 

Mohamed, Amin Eltigani 

e15530 

Mohamed, Ateesha F 4608 

Mohamed, Hesham 6506 

Mohamed, Mohamed K. 7005 

Mohamed, Tarek Yakout 

e18570 

Mohammad, Helai P e18147 

Mohammad, Waleed e14154 

Mohammed, Tamer e17556 

Mohammed, Zahra MA 

e14054 

Mohan, Anant e17505 

Mohanti, B. K 5104, e11013, 

e17505 

Mohanti, BK 5540 

Mohar, Alejandro 1607, 

e12027 

Mohd Sharial, Mohd Syahizul 

Nuhairy e17561 

Mohile, Supriya Gupta 9009, 

9010, 9014, 9028, 9034, 

9091, 9109, 9113, 9123, 

9141, 9142, e18133 

Mohler, James e15203, 

e15204 

Mohr, Peter 8505, LBA8509 

Mohr, Raphael e12015 

Mohrbacher, Ann 8073 

Mohri, Yasuhiko e14029, 

e14039, e14541, e21053 

Mohrmann, Svjetlana e21020 

Mohty, Mohamad 6534, 6542 

Moinpour, Carol 4571, 

CRA6009, 9018 

Moiseyenko, Vladimir 

Mikhailovich 3505 

Moiseyenko, Vladimir e13059 

Mojtahedi, Golnessa 5026 

Mok, Tony LBA7500, 7519^, 

7530, TPS7614, TPS7615, 

TPS7616, e18063^ 

Mokhtari, Karima 2023 

Molchanova-Cook, Olga 

e13075 

Molderez, Christoph 1129 

761s

Molero, Xavier e21035 

Moles-Moreau, Marie-Pierre 

8026 

Moley, Jeffrey F. 2525 

Molhoek, Kerrington R. 8530, 

8597 

Molica, Carmen e18023, 

e18101 

Molica, Stefano e18564 

Molife, L Rhoda 2530, 3021, 

3030, 3048, 3051, 3080, 

10525 

Molina, Ana M. 4542, 

TPS4682 

Molina, Arturo TPS666, 

LBA4518, 4521, 4556, 

4558, 4664, e15137 

Molina, Ashley 1608 

Molina, Franck 10505 

Molina, Julian R. 1565, 

3001, 5544, 7073, 7555, 

7605 

Molina, Matias e11044, 

e11501, e18125 

Molina, Thierry Jo 8021 

Molina-Garrido, MJ e12033, 

e19590 

Molina-Vila, Miguel Angel 

4068, 7522, e14521, 

e18130, e18131, e18143 

Molinaro, Annette M 2026 

Moline, Teresa e21021 

Molinier, Oliver 7057, 

TPS7112, LBA7507 

Molino, Annamaria 586 

Molinolo, Alfredo e16061 

Molins, Carmen 4587 

Molins, Joaquim Bellmunt 

4522, 4525, 4577, 4580, 

4582, 4585, e15001, 

e15041 

Molkenboer-Kuenen, Janneke 

D.M. 3035 

Mollee, Peter 8030 

Mollema, R 7009 

Moller, Jakob M. 2069 

Mollevi, Caroline 10505 

Molnar, Erin 6508 

Moloney, Julie 3537 

Molteni, Agostino e21085 

Momen, Lamia 1006 

Momiyama, Masashi 2044, 

10072, e14014 

Mon, Yin Yin e11078 

Monaco, Francesco e18039 

Monarca, Bruno e17006, 

e18563, e18566 

Monasterolo, Gabriella 10055 

Monclair, Tom 9583 

Mondejar Solís, Rebeca 

e14058 

Monden, Kazuya 7528, 

10610, e18134 

Monden, Nobuya 5542 

Monestier, Sandrine 8555, 

8568, 8578 

Monfardini, Lorenzo e14607 

Monfardini, Silvio e14607 

Monforte, Joseph 1058, 

e14164 

Monga, Dulabh K. e21036 

Monges, Genevieve 4129 

Mongort, Cristina e14589 

Mongoue-Tchokote, Solange 

e16045 

Monica, Valentina TPS7109 

Monika, Brueggemann 6500^ 

Monjazeb, Arta 3566 

Monk, J. P. 4511, 4655, 

4663, 4667, 10503 

Monnereau, Alain e14168 

Monnet, Elisabeth 7057 

Monnet, Isabelle TPS7112, 

7574, e18089, e18102 

Monnier, Justin e21071 

Monreal, Mayte 7095 

Monroe, Philip J. 9575 

Monson, Kathryn 5527 

Montagna, Daniela e13103 

Montagut, Clara e15111 

Montalar, Joaquin 10082 

Montañana, Myriam 8572 

Montanari, Bruno 1115 

Montandon, Nicole e19050 

Montaner, David 7060 

Montas, Sacha M 9121 

Montazeri, Amir H e15128, 

e15135, e18068 

Montbarbon, Xavier e16036 

Montcuquet, Philippe e11019 

Montefusco, Mary 2521, 

8549, 8598 

Montemurro, Michael 10033 

Montemurro, Severino e21134 

Montenegro, Alexander 

TPS5600, 7511 

Montera, Roberto 5093, 

5094, e15547, e15550, 

e15551, e15553 

Montero, Alberto J. 4043, 

9565, e11038, e15107, 

e16525 

Montero, Maria Angeles 7041 

Montero, Pablo H. 5562 

Montes, Ana 7544 

Montes, Marta e14057 

Montesa, A. 4630 

Montesarchio, Vincenzo 4115 

Montestruc, Francois 10007 

Monteverde, Martino 2600 

Montgomery, Robert B. 4520, 

4521, 4665, TPS4695 

Monti, Maria Gaia e11052 

Monti, Nadia 1500 

Montini, Enrica e13103 

Montironi, Rodolfo e15074 

Montone, Eva 5093, e15551, 

e15553 

Montoto, Silvia 8058 

Monzo, Mariano e13540 

Monzon, Federico A. 4624 

Monzon, Francisco e14057 

Monzon, Jose Gerard e13049 

Moo, Tracy-Ann 1118 

Mookerjee, Bijoyesh 

TPS6643^ 

Moon, Hyeong Gon 1133, 

e21160 

Moon, Hyeong-Gon 1056, 

10621, e11532 

Moon, James 5015, 7005, 

7018, 7083, 7517, 7552, 

7570, 8504, 8521, 8525, 

8527 

Moon, Joon Ho 3554, 6536, 

6538, e18533 

Moon, Woo Kyung e11532, 

e21160 

Mooney, Kathi 9137 

Moorahrend, Enno 4065 

Moore, Alexis 6017, 6029 

Moore, Amy Patricia 3058, 

e13000 

Moore, Andrew Jacob e19559 

Moore, Dan H. 9107, 10586 

Moore, David J e15141 

Moore, Dominic T 6107 

Moore, Halle C. F. 1076 

Moore, Joanne e19519 

Moore, Kathleen N. 3008, 

3041, 3067, 3097, 5012, 

TPS5116 

Moore, Malcolm J. 3082, 

3504, 3515, 3572, 4047, 

4058, TPS4134, TPS4135, 

4535, 9003, e14524, 

e14592, e19522 

Moore, Marietta L. e15179 

Moore, Nicholas e14168 

Moore, Nicola TPS9597^ 

Moore, Patrick S. 8577 

Moore, Rebekah 1516 

Moore, Sara 4058 

Moore, Theodore 6537 

Moore, Timothy David 

TPS3110 

Moore, William R 4671, 

e15167 

Moorman, Meredith e17001 

Moorthy, Ganesh TPS3116 

Mora, Serena 519 

Morabito, Fortunato 8083, 

e18564 

Moraco, Nicole H. 10001, 

10019 

Moral, Antonio 1120 

Morales La Madrid, Andres 

Eduardo 9534 

Morales Pancorbo, David 

e11075 

Morales, Rafael 2540, 

e15001, e21021 

Morales, Rita 10004 

Morales, Serafin 1011, 

10512, 10595, e11545 

Morales-Barrera, Rafael 

TPS4674 

Morales-Espinosa, Daniela 

e11098, e15569 

Morales-Vasquez, Flavia 

e15527 

Moran, Ann Marie e13574 

Moran, Cesar 7023 

Moran, Diarmuid M e21120 

Moran, Jon e17550 

Moran, Kirsty 10525 

Moran, Susan 4549, 4656 

Moran, Teresa 3093, 7011, 

7522, 7532, 7542, 7543, 

e18131, e18137 

Mordechovich, Daniel e14616 

Mordenti, Joyce TPS668 

Moreau, Michel 3559 

Moreau, Philippe 8009, 

8014, 8020, 8095, 

TPS8112, TPS8113, 

TPS8114, e18572^ 

Moreau, Sandrine e13605 

Moreau, Stephanie 8540 

Moreau, Thierry e14006 

Moreira, António e13119 

Moreira, Rubem e14027 

Morelli, Emanuela 8066 

Morelli, Franco 5513 

Morelli, María Pia 4040 

Moreno, Antonio e16000 

Moreno, Carolina 2612 

Moreno, Jesus Zamora 7068 

Moreno, Juan 3618, 10547 

Moreno, Lucas 9542 

Moreno, Ofir 3067 

Moreno, Victor 3051, 3080, 

3510, 3601, 3618, 10547, 

e13085, e13599, e13601, 

e14093 

Moreno-Aspitia, Alvaro 

CRA1002, 1083, 6570, 

e13501 

Moreno-Eutimio, Mario Adan 

e15584 

Moreno-Fernandez, Debora 

3014 

Morere, Jean F. 1095, 1567, 

1568, 5067, e18003, 

e18020 

Morero, Jose Luis 7029 

Moretto, Patricia e15537 

Morgades, Mireia 8005 

Morgan, Adrienne TPS665 

Morgan, Gareth J 8015, 8095 

Morgan, Jeffrey A. 1547 

Morgan, Jessica 575 

Morgan, John 1587 

Morgan, Michael A. e15190 

Morgan, Paul TPS9596 

Morgan, Richard 4653 

Morgan, Robert 3054, 3108, 

5020, 5025 

Morgan, Shethah 4124, 

e13541 

Morgan, Susan Kay 1018 

Morgans, Alicia Katherine 

6045 

Morgenfeld, Eduardo L. 9038, 

e11037, e15507, e15508 

Morgenstern, Sara e14067 

Morgensztern, Daniel 5529, 

5532 

Morgenthaler, Nils G. 10536, 

10537 

Mori, Kiyoshi 7017, 7021, 

7070 

Mori, Masahide e18007, 

e18025, e18134 

Mori, Tsuyoshi e11564, 

e13559 

Mori, Yoshiaki 7565 

Morice, Philippe 5028, 5083, 

10098 

Morikawa, Naoto 7086, 7561, 

7563, 7565, e19508 

Morimoto, Masami e11560 

Morimoto, Yuhki e21053 

Morin, Franck TPS7111, 

TPS7112, 10507, e18089 

Morioka, Junko e18059 

Morioka, Toru 565 

Morishima, Yasuo 6533 

Morishita, Naoko e18036, 

e18042 

Morita, Craig T e21004 

Morita, Kazutoyo e14602 

Morita, Masaru e14601 

Morita, Satoshi 1106, 4002, 

7521, 9574, e14123, 

e18007, e18025, e18060, 

e18129 

Morita, Shane Young e19051 

Morita, Yoshitaka TPS3642 

Moriwaki, Toshikazu 4002 

Moriya, Yoichiro e18091 

Moriya, Yoshihiro 3524, 3569 

Morizane, Chigusa 4031 

Morland, Bruce 9542 

Moro-Sibilot, Denis TPS7112, 

7533, e18089 

Morosi, Carlo 4507, 10026 

Morosky, Anne e13599 

Moroso, Stefano 1044 

Morote, Juan 4510 

Morozov, Alexei 5012 

Morrell, Glen 3057 

Morris, Carol 10022 

Morris, David E. 2091 


Morris, David e18098 

Morris, Donald e18110 

Morris, Elizabeth Ann e11531 

Morris, G. Stephen e17002 

Morris, Jackie e14587 

Morris, Jeffrey 3598, 4116 

Morris, John Charles 2571, 

e21064 

Morris, Karen e21037 

Morris, Michael J. 4517, 

4548, 4568, 4655, 4667, 

TPS4694 

Morris, Patrick Glyn 2006, 

10514 

Morris, Shannon Renae 

e13596 

Morris, Stephan 3090 

Morris, Van Karlyle 3561 

Morrison, Carl D e11563, 

e15203 

Morrison, Debra J. 9507 

Morrison, Devi 6573 

Morrison, Jodie 4665 

Morrison, P. J. 1543 

Morrison, Rosemary 2552 

Morrison, Tara e11085, 

e12509 

Morrison, William H. 5561, 

5589 

Morrissey, Stephanie 4504 

Morrone, Robert j 2587 

Morrow, Gary R. 9009, 9010, 

9014, 9027, 9028, 9113, 

9141, 9142, e16056, 

e19510 

Morrow, Kevin 6580 

Morrow, Phuong Khanh H. 

9061, 9072 

Morschhauser, Franck 8002, 

8030, 8057 

Morse, Linda K. 7099 

Morse, Michael 2517, 2585, 

2588, 10563 

Morsi, Amr M. e19015 

Mortarotti, Joan 6108 

Mortensen, Deborah 3006^ 

Mortensen, Michael Bau 

e14633 

Mortier, Laurent 1566, 8559, 

8591, 8601 

Mortimer, Joanne E. 639, 

1010, 1070, e13116, 

e19644 

Mortimer, Peter 4549 

Morton, Donald L. 2519, 

8534, e19029 

Morton, Ronald A. e19582 

Morvan, Francois e16044 

Morvillo, Manfredi 3555 

Moscetti, Alessandro e17006, 

e18563, e18566 

Moscetti, Luca e12514, 

e18065 

Moschos, Stergios J. 8533, 

8547 

Moschos, Stergios J 8503^, 

8528 

Moschovi, Maria e20002 

Moscinski, Lynn e18503, 

e18506 

Moscol, Giancarlo 7051 

Mosconi, Massimo e19035, 

e19036 

Moseley, Jennifer L. e15116 

Moseley, Paul 1013, 1098 

Mosenkis, Jeffrey 9104 

Moser, Barry K 6526 

Moser, Lutz 5512 

Moser, Rachel 6091, e16007 


Moshfegh, Ali 6557 

Moshier, Erin L. 4524, 6065, 

e21032, e21109 

Moshkowitz, Menachem 1564 

Moskowitz, Chaya S. 

CRA9513, 9552 

Moskowitz, Craig 2008, 2089 

Moskvina, Ekaterina A. 

e19012 

Mosley, Jane e19522 

Mosquera, Juan Miguel 4649 

Moss, Ralph W e13102 

Moss, Rebecca Anne 2534, 

TPS3112 

Moss, Wendy 9589 

Mosse, Yael P. 9500 

Mostafa Kamel, Yasser 

Mostafa 9117 

Mostafa, Magda 5557 

Mostafa, Nael 2013 

Mostaghel, Elahe A. 4520 

Mostert, Bianca 10504 

Motamed, Kouros e15542 

Motamed-Khorasani, Afsaneh 

e17521 

Motamedinia, Piruz e15021 

Motley, Christine 6025 

Motoi, Noriko e18017 

Motola, Daniel e11098 

Motomura, Kazuyoshi 1103, 

1106 

Motomura, Takashi e14536 

Motoshima, Kohei 7569 

Motsinger-Reif, Alison A. 

10515 

Mott, Judith H. e13522 

Motta, Leonardo e21042 

Mottolese, Marcella 1050, 

e14042, e18021 

Motzer, Robert John 4501, 

4532, 4542, 4546, 4604, 

TPS4682, TPS4683, 6092, 

e15070 

Mouarrawy, Doraid 10540 

Mouchet, Nicolas e19037 

Mouillet, Guillaume 7057 

Moul, Judd W. 4670, e15113 

Mould, Diane R. 2597 

Moulder, Stacy L. 515, 527, 

10510, 10559, 10613 

Mouliere, Florent 10505 

Moulinoux, Jacques Philippe 

e15131 

Moulton, Brian e13520 

Mounier, Nicolas 5075, 

8002, 8005, 8021, 8046, 

8048, 8077, e15574 

Mountz, James M 3019 

Moura, Shari e19522 

Mourad, Waleed Fouad 5531, 

5559, 5581, e15138 

Mouradov, Dmitri 3623 

Mourah, Samia 8048 

Moureau-Zabotto, Laurence 

10042 

Mouret, Jean-Francois 10562 

Mouret-Reynier, Marie-Ange 

1051, 5018 

Mourey, Loic LBA4567^, 

TPS4692^ 

Mourlane, Frederic 2575 

Mouro, Larissa R 1075 

Mouroux, Jerome 7591 

Mourouzis, Iordanis e11073 

Moussa, Ali H. 8531 

Moussy, Alain LBA4007, 

10007, 10089, 

TPS10102^ 

Moutinho, Catia 3570 

Movassaghi, Kamran e15053 

Movva, Sujana TPS10103 

Mowat, Rex Bradford 1083 

Moxhon, Anne e14060 

Moy, Beverly 596, 599, 604, 

6095, 6128 

Moya Gomez(2), Paloma 

e11543, e19596 

Moya, Beatriz e12003 

Moya, Irene TPS3637 

Moye, Virginia Ann 5577 

Moyer, Ann M. 5077 

Moyers-Ruiz, Liliana TPS9148 

Moylan, Eugene J. 2062, 

e11569, e16506 

Moynihan, Timothy Jerome 

534 

Moyo, Victor M. TPS663, 

TPS3111, 7556 

Mozayen, Mohammad 7102, 

e14046 

Mozer, Pierre e15105 

Mozley, P. David 10573 

Mozzillo, Nicola 8534, 8573, 

8581, e19034 

Mpasi, Priscilla e18550 

MU, Hua 3038, 3040 

Mu, Zhenyu 8583 

Mubdi, Nidha Z. CRA9513 

Mucci, Lorelei 4555 

Mucciarini, Claudia 2057 

Muche, Rainer TPS1612 

Mudad, Raja e17564 

Muddu, Vamshi 5585, 

e16028, e17500 

Mudunuru, Uma 10605 

Muehlenbein, Catherine E. 

5533, e16053 

Mueller, Andreas 9059 

Mueller, Berit 1023, 10627 

Mueller, Carsten 8024, 8025 

Mueller, Stefan e15112 

Mueller, Volkmar 1090, 

TPS1146, 10599 

Mueller-Huebenthal, Jonas 

e13508 

Muffly, Lori S. 8060 

Muggeri, Alejandro Daniel 

e12511 

Muggia, Franco 5016, 5041, 

5078, e11010, e11529 

Mugishima, Hideo 9574 

Mugiya, Soichi e15098 

Muhr, Daniela 1537 

Muindi, Josephia e18118 

Muinelo-Romay, Laura 10534 

Muiruri, Charles 6102 

Mukai, Harumi 8094 

Mukai, Hirofumi 512, 540, 

585 

Mukai, Masatoshi e15065, 

e15069 

Mukherjee, Bhramar e12031 

Mukherjee, Debraj 2080 

Mukherjee, Srijita e14632 

Mukherji, Bijay e21135 

Mukherji, Deborah 4553, 

e15134, e15136 

Mukhopadhyay, Ashis 

e13030, e18043 

Mukhopadhyay, Pabak 551, 

TPS648 

Mukhopadhyay, Soma 

e13030, e18043 

Mukhopadhyay, Sutapa 8012 

Mukohara, Toru e16034 

Mukonje, Terence 1089 

Mulcahy, Hugh e13570, 

e21024 

Mulcahy, Mary Frances 3608, 

4049, 4077, 4102 

Mulder, Ina 8039 

Mulder, Sasja 9070 

Mulders, Peter LBA4518, 

4519^ 

Muldoon, C. 1543 

Muldoon, Leslie L. 2040 

Mulet-Margalef, Nuria 619 

Mulick Cassidy, Amy 4553, 

10525, e15134, e15136 

Mulkerin, Daniel 3101, 3103, 

e14554 

Mull, Ruslan e15576 

Mullady, Daniel e14584 

Mullan, Mohmaduvesh 

e19581 

Mullan, Paul B 10553 

Mullane, Kathleen M. 9067 

Mullane, Michael Russell 

9085, e14186, e14590 

Mullany, Lisa K e15583 

Mulle, Lynette 3001 

Mullen, John Thomas 10058 

Muller, Leandro Bizarro 

e14597 

Muller, Stephanie 4562 

Muller, Susan 5560 

Muller-Greven, Ga‘lle 2014 

Mullighan, Charles Grenfell 

9506 

Mullins, C. Daniel e14035, 

e14056, e14522, e14626, 

e14638, e15108, e15146, 

e15148 

Mullooly, Maeve 622 

Mulquin, Marcia 4569, 8088, 

8104, e18568 

Mulrenan, Heather a 5534 

Mulrooney, Daniel A. e16502 

Muluneh, Benyam 6042 

Mulvenna, Paula M e17519 

Mulvihill, Erica e14666 

Mummy, David G 6007, 

e14068 

Mun, Yong e11051 

Munck af Rosenschold, Per 

e18527 

Mundhenke, Christoph 556, 

1084, e13503 

Mundia, Abdul G. e13053 

Mundia, Mubasir e13053 

Munemoto, Yoshinori 

TPS3642 

Munhoz, Rodrigo Ramella 

e12513 

Munive, Carlos e11066 

Munkarah, Adnan 5088 

Munn, David 2501 

Munoz Llarena, Alberto 

e11525 

Muñoz Martin, Andrés Jesús 

e14058 

Munoz Platon(3), Enriqueta 

e19596 

Muñoz, Alberto e17522, 

e18031, e21009 

Munoz, Carmen 3096, 

e13540 

Munoz, Edgar e16566 

Muñoz, Eva e19023 

Munoz, Francisco e16500 

Munoz, Silvia 1588 

Muñoz-Couselo, Eva 509, 

566, 619 

Muñoz-Langa, José e17545, 

e18049 

Munoz-Mateu, Montserrat 

1001 

763s

Munoz-Sanchez, MM e19590 

Munsell, Mark F. 9061 

Munshi, Hidayatullah G. 

e14515 

Munster, Pamela N. TPS663, 

3006^, 3058, 4102, 4660, 

TPS8602, e13000, e13596 

Munzert, Gerd Michael 

3018^, 7557 

Munzone, Elisabetta 546, 

1049, 1115 

Muppidi, Samatha 8100, 

8101 

Mura, Donna 5027 

Murad, Andre 7506 

Murad, Faris e14584 

Murahashi, Mutsunori e13014 

Murakami, Haruyasu 7088, 

e21007 

Murakami, Keiichi e11017 

Murakami, Yoshihiro e21059 

Murali, Sujatha 3094 

Murata, Akihiko TPS3642 

Murata, Kohei e14091 

Murata, Paola 5595, e14104, 

e15159 

Murata-Hirai, Kaoru e21004 

Murawa, Dawid 10537 

Murawa, Pawel 10537 

Murawska, Magdalena 

e11553 

Murawski, Niels 8022, 8024, 

8025 

Muren, Caroline 2589 

Murgia, Viviana e14711 

Murgo, Anthony J. 8073 

Murgo, Roberto e21092 

Murias, Adolfo 10608, 

e11535, e21088 

Murillo, Raquel 1111 

Murli, Sumati e13114 

Murnane, Andrew e19605 

Muro, Kei 4067, 4082, 

e14500 

Muro, Kenji 2035 

Murone, Carmel 3534 

Murphy, Adrian Gerard 

e13570 

Murphy, Anne Marie 1553, 

6120, e16531 

Murphy, Barbara A. 9024, 

e16038, e19559 

Murphy, Cheryl F. 8530, 

8597 

Murphy, Christi 4102 

Murphy, Conleth G. e14111 

Murphy, Erin Sennett 2076, 

2100 

Murphy, James e13022 

Murphy, Janet E. 3594, 

e14615 

Murphy, Joan 5105 

Murphy, Kate e14111 

Murphy, Kevin C. 6071 

Murphy, Leigh TPS1136 

Murphy, Patrick Brian 618, 

TPS8115 

Murphy, Thomas J e14666 

Murphy, Valerie 7593 

Murray, H. A. e14022 

Murray, James L. 527, 

e11090 

Murray, Jonathan 4660 

Murray, Nevin 7020, e18079 

Murray, Nicholas TPS1144 

Murray, Paul Gerard e15091 

Murray, Samuel e21087, 

e21141 

Murray, Sharon Cornell 3000, 

5065 

Murray, Susan 2062, e11569 

Murray, Tom e15169 

Murtaza, Muhammed 544 

Murthy, Rashmi Krishna 527 

Murthy, Vedang e16021 

Murtra-Garrell, Nuria 7041 

Musa, Zahra 6077 

Muscarella, Peter e14501 

Muscato, Joseph J. TPS658 

Muschen, Markus 9555 

Muse, Kimberly I. 1549 

Musgrove, Elizabeth A. 504 

Musib, Luna C. 2566, 

TPS2616, 3021, e13114 

Muslimani, Alaa 628, e17015 

Musolino, Caterina e18564 

Muss, Hyman Bernard 

TPS656, 1524, 6015, 

6017 

Muss, Hyman 5577 

Mussari, Salvatore e14711, 

e21102 

Mustacchi, Giorgio 579, 586 

Mustafa, Rashid 1032 

Mustea, Alexander 5007 

Mustian, Karen Michelle 

9009, 9010, 9014, 9028, 

9141, 9142 

Musulen, Eva 4089 

Musuuza, Jackson S. 1598 

Mutale, Faith e16062 

Mutalima, Nora 9558 

Mutch, David Gardner 1519, 

1520, 5013, 5101, 

e15528 

Mutchler, Jan e16500 

Muth, Mathias e13503 

Muthen, Noemi 3044 

Muthukaruppan, Raman 4106 

Muto, Giovanni e15133 

Muto, Hiroki e13511 

Muto, Jun e14536, e14602 

Muto, Osamu e14062 

Muto, Tetsuichiro 3625 

Muto, Yoichi e14722 

Muus, Petra 6522 

Muwakkit, Samar e20004 

Muzaffar, Mahvish e14693 

Muzi, Mark TPS10635 

Muzii, Ludovico e15547, 

e15550 

Muzikansky, Alona 6136, 

7010, 7524 

Mwamburi, Mkaya 6553 

Mwandoro, Tibu N. 3047 

Myers, Jay T. 9520 

Myers, Jeffrey 5524 

Myers, Lee 1128 

Myers, Robert Edward 

e19570 

Mühlenberg, Thomas 10032^ 

Mykletun, Andrew 10061 

Mykulowycz, Kristine 4111 

Myles, Bevan H e14548 

Müller, Lothar 556, e15520 

Müller, Martin C 6503, 6510 

Müller, Stefan 5508 

Münstedt, Karsten 5005, 

5044 

Myo, Aung e13061 

Myrand, Scott 7554, 7583 

Myskowski, Patricia L. 

e19052 

Myssiorek, David e16052 

Mytilineos, Joannis 6567 

Mægbæk, Merete Lund 1579, 

e12023 

Möbs, Markus e15053 

Møller, Henrik 7026 

N 

N, Soumitra e18041 

Nabell, Lisle 1006 

Nabhan, Chadi 8072, 8080, 

e15120 

Nabholtz, Jean-Marc A. 

TPS646 

Nabholtz, Jean-Marc 1051 

Nabid, Abdenour TPS5600 

Nacci, Angelo e11001, 

e11547, e18048 

Nachman, James B. CRA9508 

Nacul, Mario Javier e11037 

Nadeau, Laura e17015 

Nadeau-Larochelle, Corinne 

634 

Nademanee, Auayporn 6545, 

e18530 

Nader, Helena Bonciani 

10568, e13016 

Nadig, Juerg e19648 

Nadler, Eric e20510 

Naermann, Regina 4600 

Nafa, Khedoudja 10560 

Nafissi, Julieta e14109 

Nag, Shona Milon 3011 

Nagai, Kanji 1552, 7044, 

e17526, e17554, e18054, 

e18064 

Nagai, Shigenori E 613 

Nagai, Yohei e13553 

Nagai, Yutaka 5086 

Nagalla, Balakrishna 6554 

Nagamatsu, Hiroaki e14080 

Nagamine, Shinji 1119 

Nagamitsu, Yuzo 10557 

Nagano, Hiroaki e14518 

Nagao, Shoji 5103 

Nagaoka, Akira e15057, 

e15088 

Nagaoka, Isao e14004 

Nagaraj, Gayathri 

Nagaraj, Kanakapura 

TPS664 

Ramanna e11027, e14675, 

e14721 

Nagarajah, James 10032^ 

Nagarajan, Rajaram e20007 

Nagarkar, R. 3089^ 

Nagarwala, Yasir M. TPS658 

Nagasaka, Tsuneki 5037 

Nagase, Michitaka 4002, 

4031 

Nagashima, Takeshi 1106 

Nagata, Hirohiko 9569 

Nagata, Kazuma 7528, 

10610 

Nagata, Misato e17538 

Nagata, Naoki TPS3642 

Nagata, Takuya e12028 

Nagatomo, Izumi e18056 

Nagayama, Satoshi 3625, 

e14145 

Nagel, Christa Irene e15501 

Nagengast, Wouter B. 

Naghashpour, Mojdeh 

10581 

e18503, e18506 

Nagourney, Robert Alan 

e14075 

Nagpal, Sunil 3619, e14046, 

e15554 

Nagre, Sandeep 3015, 10036 

Nagura, Naoya e13037 

Nagy, Cindy K 9064 

Nahi, Hareth 8019 

Nahleh, Zeina A. e11549 

Naidoo, Jarushka 2609 

Naidu, K. V. Jagannath Rao 

9055 

Naing, Aung 3106, 3107^, 

4639, 8551, 10510, 

10607, e13020, e13506, 

e13534, e13595 

Nair, Bijay P. e18548 

Nair, Bijay 8041, e18576 

Nair, Deepa e16021 

Nair, Kavita V. e16541, 

e16550 

Nair, Nita S. 1108, e11552 

Nair, Reena e17003 

Nair, Sudhir Vasudevan 

e16021 

Nair, Suresh G e16561 

Nair, Vidya 5582 

Naito, Sei e15057, e15068, 

e15071, e15088 

Naito, Seiji e15048, e15071, 

e15098 

Naito, Tateaki 7088, e21007 

Naito, Yoichi 585 

Najdi, Adil e11502 

Najera, Jose Eugenio 6546 

Nakabayashi, Mari e15170 

Nakagawa, Hidewaki 10520 

Nakagawa, Kazuhiko 6112, 

7003, 7017, 7028, 

TPS7110, 7521, 7602, 

e18060 

Nakagawa, Kei e14011 

Nakagawa, Ken 9569 

Nakagawa, Misako e11560 

Nakagawa, Wilson Toshihiko 

e14119 

Nakahama, Hiroko e19557 

Nakahara, Rie 7021 

Nakahara, Takahito e21059 

Nakai, Toshiyuki e17538 

Nakai, Yasutomo e15065, 

e15069 

Nakaigawa, Noboru 4626 

Nakajima, Go e21108 

Nakajima, Takako Eguchi 

e14123 

Nakajima, Takashi 7088 

Nakajima, Yuki 10542 

Nakakura, Eric K. 4126, 

e14542, e14551 

Nakamae, Hirohisa 6509^ 

Nakamori, Shoji 4031 

Nakamoto, Tomoko 5086 

Nakamura, Asako 2553 

Nakamura, Hiroaki 10073 

Nakamura, Hiroko 5084 

Nakamura, Kenichi 3524, 

5542, 6112, e14510 

Nakamura, Masato TPS3642 

Nakamura, Michio 3593, 

e14062 

Nakamura, Ryuji e14011, 

e19508 

Nakamura, Seigo 590, 

e13037 

Nakamura, Shinichiro 

TPS659, 6112 

Nakamura, Terukazu e15055, 

e15099 

Nakamura, Tsuyoshi e15048 

Nakamura, Yoichi 7515, 

7569 

Nakamura, Yukiko 7088, 

e21007 

Nakamura, Yusuke 10520, 

e13014, e13015, e13029, 

e13037, e13552, e13565 

Nakanishi, Katsuyuki 1103 

Nakanishi, Ryota e14033 


Nakanishi, Toru 5006 

Nakanishi, Yoichi TPS659, 

TPS7110, e13014 

Nakano, Hirofumi 7569 

Nakano, Takashi 7031, 7080 

Nakanoko, Tomonori e14601 

Nakao, Akimasa e14506 

Nakashima, Masanao e13029 

Nakashima, Osamu 4104 

Nakashiro, Koh-ichi 5584 

Nakatani, Akinori e14004 

Nakatani, Takeshi e18056 

Nakatomi, Katsumi 7569 

Nakatsuka, Seishi 7038 

Nakayama, Norisuke e14123 

Nakayama, Shoko e15057 

Nakayama, Souhei e18058 

Nakayama, Yoshie e19512 

Nakazawa, Atsuhito e19583 

Nakazawa, Yukie e18007 

Nakwan, Narongwit TPS9151 

Nam, Byung-Ho 4028 

Nam, Hae-Seong e13065 

Nam, Joo-Hyun e15559 

Nam, Seung-Hyun e19538 

Nam, Soon Yuhl 5586 

Namakydoust, Azadeh 2561 

Namal, Esat e14698 

Naman, Herve L. 568^ 

Namba, Yoshinobu e18007, 

e18025, e18134 

Namba, Yukiko e18019 

Namburi, Swathi 8103 

Namendys-Silva, Silvio A 

e15527 

Namer, Moise e19640 

Namiki, Masayuki 3084 

Namjoshi, Madhav 593, 

e19615 

Nanayakkara, Nuwan 529 

Nand, Sucha 6502 

Nanda, Nisha 6513, 6596 

Nanda, Rita 534, 1010 

Nandini, Marysingh e11043 

Nandini, P K 1093 

Nanji, Sulaiman 3632 

Nanjo, Shigeki 7528, 10610 

Nanni, Cristina e21006 

Nanni, Isabelle 8555, 10507 

Nanni, Oriana 1099, e11054 

Nannini, Margherita 10087 

Nanus, David M. 4649 

Naoki, Katsuhiko e18058 

Naoshy, Sarah e14028, 

e14030, e14061 

Nappi, Lucia e13509, 

e15034 

Naraev, Boris G. e14620, 

e15580 

Naraev, Boris e14600 

Narain, Niven R 3015, 

e14593 

Narala, Neeharika 2558 

Narang, Mohit 8037, e18556 

Naranjo, Arlene 9533 

Narayan, Kailash TPS5116, 

e15541 

Narayanan, Ramkishen 

e15039, e15046 

Nardelli, Giovanni B. e12037 

Nardone, Beatrice 2532, 

4063, 6623, e18571 

Narducci, Fabrice 5083 

Narducci, Filomena e18065, 

e18072 

Narimanov, Mekhty e14623 

Narine, Nadira e15011 

Narisawa, Takafumi e15057 

Narod, Steven 1123 


Narumi, Sodai 7563 

Narvaez, Jose Antonio 10052 

Nascene, David 2546 

Nascimento, Ellen Caroline 

e11014 

Nash, Anthony F e15141 

Nash, Garrett Michael 3583 

Nash, John e15536 

Nasim, Muhammad Yaser 

2552 

Nasioulas, George e21087, 

e21141 

Naskhletashvili, David R. 

e19012 

Naso, Virginia e17006, 

e18563, e18566 

Nason, Katie Sue e14689 

Nass, Dvora 2078 

Nasseri, Morad 2077 

Nassif, George e14157 

Nassir, Youram 8098, 

e18558 

Nasta, Sunita e18529, 

e18540 

Nasti, Guglielmo e14130 

Natale, Romain 5521 

Natale, Ronald B. TPS2621 

Natali, Maurilio e19002 

Nath, Rajneesh 6569 

Nathan, Cherie-Ann e16009 

Nathan, Hari 3596 

Nathan, Paul C. 6027, 6030, 

9556, 9586, 9591 

Nathan, Paul D. LBA8509, 

8523, TPS8605 

Nathan, Sunita 6552 

Nathanson, Katharine 1539 

Nathanson, Katherine L. 

1506, 3102 

Natrajan, Kavita 6573, 8108 

Natsugoe, Shoji 3558 

Nattam, Sreenivasa R. 4022 

Naucler, Gisela 3538 

Naudts, Bart e13073 

Naughton, Michael CRA1002, 

3047 

Naughton, Michelle Joy 9108 

Nauman, Deirdre J. e11042 

Naumov, George 3587 

Naumov, Inna 1564 

Nava, Hector R. e14712 

Navabi, Jafar 6556 

Navale, Lynn 5072 

Navaratnam, Sri e17518 

Navari, Rudolph M. 9064 

Navarrete, Alicia e15111 

Navarro Coy, Nuria 8015 

Navarro, Alejandro 509, 566, 

7041, 10511 

Navarro, Jose-Tomas 8005 

Navarro, Samuel e14589 

Navarro, Tasheda 6507, 

6508, 6515^ 

Navarro-Garcia, Lilian Monica 

e11098 

Navez, Benoit e14044 

Nawarawong, Weerasak 8097 

Nawfel, Mellas e11502, 

e11516, e14725, e14726, 

e18124 

Nawras, Ali e14098 

Nawrocki, Sergiusz LBA7000, 

e19561 

Nawrocki, Steffan T 3073 

Nayak, Asha e14694, e18024 

Naylor, Keith e16509 

Nazha, Aziz 6544, 6578, 

6589, 6597 

Neal, Christopher e13577, 

e21028, e21029 

Neal, Jennifer 6042 

Neal, Joel W. 7010, 7541 

Neaume, Julien e18005 

Nebot, Noelia 3000 

Nebozhyn, Michael 3531, 

3587 

Necchi, Andrea 4507 

Nechushtan, Hovav 535, 

10034 

Neciosup, Silvia P. e11066, 

e11087, e11518, e15036 

Necozione, Stefano e11041 

Nedelman, Jerry 2603 

Neelapu, Sattva Swarup 2528 

Neery, Maureen P. 10061 

Neff, Tanaya 10591 

Negassa, Abdissa e14019 

Neglia, Joseph Philip 

CRA9513, 9528, 9546, 

e16502 

Negoro, Shunichi 5045, 

7028, 7521, e18060, 

e18134, e19548 

Negri, Federica 4097 

Negri, Tiziana 10026 

Negrier, Sylvie CRA4502, 

4614, 4625, 8532 

Negron, Viviana e11015 

Nehaeva, Tatyana Leonidovna 

e13059 

Neidhardt, Eve Marie e16036 

Neif, Joao Antonio Junior 

e12021 

Nejjari, Chakib e11502, 

e18124 

Nekhlyudov, Larissa 6008 

Nekljudova, Valentina 556 

Nelius, Thomas e15103 

Nelkin, Barry 3020, 

TPS3117, 5508 

Nelli, Fabrizio e18065 

Nelson, Aaron L 9562 

Nelson, Alan e17529 

Nelson, Betty J 8502^ 

Nelson, Brian e13542 

Nelson, Christian J 9123 

Nelson, David e21122 

Nelson, Deborah 9110 

Nelson, Edward L. 6132 

Nelson, Garth D. 3514, 3526 

Nelson, Greg C e16536 

Nelson, Marisa 10097 

Nelson, Mark e14574 

Nelson, Peter 4520, 4521, 

4669, e15207 

Nelson, Rebecca A. 1117 

Nelson, Robert P 7107, 7108 

Nelson, Sarah J. 4660 

Nelson, Zenith e17547, 

e17550 

Nemec, Cheryl TPS4679 

Nemunaitis, John J. 2588, 

4593, TPS7610, 8594, 

e13101, e18047, e19055 

Neninger, Elia 2527, 2531 

Neogi, Tuhina TPS669 

Neoptolemos, John P. 4053, 

e14625 

Nepple, Kenneth Gerard 4594 

Nerenz, David R 1591 

Neri, Eric 9051 

Neri, Santo e18564 

Nerodo, Ekaterina e15519, 

e21127 

Nerodo, Galina A. e15519, 

e21127 

Neron do Nascimento, Yeni 

7506, e11087 

Neskovic-Konstantinovic, Zora 

TPS661 

Ness, Daniel 6574 

Ness, Kirsten K. 6030, 9526, 

9527, 9528 

Nessim, Carolyn 616 

Nestico, Jill e19041 

Nestle-Kraemling, Carolin 

e11556 

Neto, Hugo Sterman 2038 

Netto, Cristina 10593, 

e21042 

Neubauer, Andreas 6510 

Neubauer, Hans 5042, 

e21003 

Neubauer, Marcus A. 6109, 

7502 

Neubauer, Nikki Lynn 5039 

Neuberg, Donna S. 6606, 

6618, 6621, 9530 

Neubert, Sylvia 5044 

Neufeld, Caleb e13045 

Neugebauer, Julia Katharina 

554, 1600^, 10540 

Neuger, Anthony 2501, 

TPS2620 

Neugut, Alfred I. 4101, 

6078, 6118 

Neuhaus, Peter 4020 

Neuhaus, Ruth 8030 

Neumaier, Bernd 7603 

Neumann, Avivit 4564, 4619 

Neumann, Frank TPS6639, 

TPS6641 

Neumann, Svenja 6500^ 

Neumann, Tabea 4128 

Neumann, Thomas e17529 

Neumeister, Peter e18525 

Neumeister, Veronique 573, 

1121 

Neupane, Prakash e13551 

Neuss, Michael N. CRA1505 

Neuville, Agnes 10018 

Neuwelt, Edward A. 2040, 

2077 

Neuzillet, Yann e15145 

Nevala, Wendy Kay 8599, 

e21112 

Neven, Patrick 1020 

Neves, Sofia e18111 

Neveux, Nathalie e13056 

Neville, Alan John e16558 

Neville, Bridget A. 6026 

New, Pamela Z. 2098 

Newbold, Kate 5518, 5591 

Newcomb, Polly A. 3526 

Newman, Edward M. 2538, 

8073 

Newman, Nancy 6572, 

e18535 

Newman, Suzanne E. 2591, 

5050, e13063 

Newsom-Davis, Thomas 

e14574 

Newton, Robert Charles 

2500^ 

Newton, Robert 9558 

Ney, Gina 4591 

Ney, Jasmin Teresa 1523 

Neyns, Bart 2050, 2507, 

8517, e19026, e19027 

Nezu, Masahiko 585 

Ng Tang, Derek 2520^ 

Ng, Alice Wan-ying 5511 

Ng, Chaan S. TPS5114 

Ng, Daniel B 4666, e14028, 

e14030, e15186 

765s

Ng, Daniel e15050 

Ng, Dawn Marie e11050 

Ng, Elise 8574 

Ng, John e15162, e17562 

Ng, Kimmie e19586 

Ng, Patrick e13555 

Ng, Quan Sing 3098, 4100^, 

e16024 

Ng, Raymond C.H. 9041 

Ng, Sing Chau e14691 

Ng, Siobhan LBA4518, 

TPS4692^, e15112 

Ng, Su Ann 5578 

Ng, Tat Ming e18546 

Ng, Thian C 1064 

Ng, Wai Hoe 2066 

Ngai, Yenting 7562 

Ngamphaiboon, Nuttapong 

e19568 

Ngan, Roger K.C. 5511 

Ngan, Sam 3629 

Ngeow, Joanne Y. Y. 1508 

Ngo, Charlotte e15524 

Ngo, Justine V 6010 

Nguyen, Anne T 525 

Nguyen, Bichlien 10554 

Nguyen, Diana 10603 

Nguyen, Diane Duyen Thuy 

e21105 

Nguyen, Hoa 5012 

Nguyen, Hoang 6124 

NGuyen, Jean-Michel e19019 

Nguyen, Ly Minh 8594 

Nguyen, Lyly 1132 

Nguyen, Minh-Tri 1569 

Nguyen, Nhu-Nhu 6529 

Nguyen, Nicole e15154 

Nguyen, Paul Linh 4657 

Nguyen, Phuong T.B. e13542 

Nguyen, Phuoung 9544 

Nguyen, Rosa 6136 

Nguyen, Susan 2585 

Nguyen, Tan Dat 4091 

Nguyen, Teresa T. 7061 

Nguyen, Tina e15114 

Nguyen, Tuan 7554 

Nguyen, TX Quyen e15115 

Nguyen, Vinh e16026 

Nguyen-Tan, Felix 5530 

Niazi, Faiz 3003, 8511 

Niazi, Tamim e14020 

Nibu, Kenichi e16034 

Nicacio, Leonardo 4666, 

e15186 

Niccoli, Patricia 4118 

Nicholas, Garth Andrew 

e18079 

Nicholas, Richard W. 9537 

Nicholl, Michael Bruce 2519 

Nichols, Christine 9144, 

e19633 

Nichols, Craig R. 9001 

Nichols, Gwen L. e13600^ 

Nichols, Laura L 3516 

Nicholson, James 9539 

Nicholson, Steve TPS8605 

Nickolich, Myles 7087 

Nicol, Andrew John e13128 

Nicolai, Nicola 4507, 4629 

Nicolaizeau, Cyrielle 

TPS10634 

Nicolardi, Linda e13019 

Nicolas, Patrick e18003, 

e18020 

Nicolau, Ulisses Ribaldo 

e16046, e18078 

Nicoletti, Stefania Vittoria, 

Luisa 8529, 10615 

Nicoletto, Maria Ornella 

e12037 

Nicolini, Franck E. 6503, 

6513, 6596, 6604 

Nicolle, Delphine e15161 

Nicolson, Marianne 7583 

Niculescu, Liviu 4542 

Nicum, Shibani 3048, 3051 

Nie, Qiang 7039 

Nie, Shuming e21161 

Nieda, Mie e13128 

Niederacher, Dieter 5097, 

e21017, e21020 

Niedergethmann, Marco 4020 

Niederle, Bruno 5508 

Niederle, Norbert 3 

Niederwieser, Dietger 6626^, 

TPS6640, e16016 

Niedzwiecki, Donna 2585, 

3517 

Niegisch, Guenter 4522, 

4525, 4590 

Nieh, Peter e15006 

Niehr, Franziska e16018 

Nielander, Aldrik 4622 

Nielsen, Boye Schnack 3513 

Nielsen, G. Petur 10058 

Nielsen, Hans J. 3576 

Nielsen, Kirsten Marie 

e14517 

Nielsen, Patricia Switten 

e21110 

Nielsen, Torsten O. 1008 

Nielsen, Ulrik TPS663 

Niemierko, Andrzej 1122 

Nierodzik, Mary Lynn R. 

e16052 

Niessner, Heike 8526 

Niesvizky, Ruben 8033, 

8034, 8036, e18569 

Niethammer, Andreas G. 

7551 

Nieto, Antonio 10013 

Nieto, Yago 4533, 6540, 

8102 

Nieuwland, Marja 3065 

Nieva, Jorge J. 10574, 

e21074 

Nigam, Rita 2588 

Niggli, Felix 9573 

Niho, Seiji 1552, 7012, 

7044, 7070, e17513, 

e17526, e17554, e18054, 

e18064 

Niibe, Yuzuru e15533 

Niikura, Naoki 565 

Niitsu, Nozomi 8023 

Nijem, Ihsan 2567 

Nijs, Griet 2506, e13051 

Nikipelova, Elena A e21101 

Nikitin, Kirill D. 9060 

Nikkhah, Guido 2000 

Niknam, Bijan 6000 

Nikrad, Malti e21142 

Nikulin, Maxim P. e20501 

Nilakantan, Vani e19030 

Niland, Joyce C. 599, 1125, 

1562, e18018, e18530 

Nilsson, Monique B. 7096 

Nilsson, Sten LBA4512, 

4551, 4561 

Nimeiri, Halla Sayed 3605, 

4102 

Nimmannit, Akarin e14051 

Nin, Mikio e15065, e15069 

Ning, Yan 3540, 3549, 3584, 

3597, 3604, 3615, 3622, 

4026, 4088, 4096, 

e11018, e14031, e14034, 

e14052 

Ning, Yangmin M. 4569 

Ning, Yi 6611 

Ninomiya, Jun 613 

Ninot, Gregory 9074 

Nippgen, Johannes TPS10099 

Nir, Raphael 1055 

Niraula, Saroj 1019 

Nirodi, Chaitanya 10624 

Nishi, Hirotaka 10557 

Nishida, Hayato e15057, 

e15088 

Nishida, Hideji 10075 

Nishida, Toshirou LBA10008 

Nishigaki, Yutaka e18135 

Nishihira, Ryuichi e19583 

Nishikawa, Ryo TPS2104 

Nishikawa, Shingo e17540 

Nishimura, Hajime e13037 

Nishimura, Hideki e16034 

Nishimura, Jennifer 1031 

Nishimura, Kazuhiko e14004 

Nishimura, Kazuo e15048, 

e15065, e15069 

Nishimura, Kenji e15065 

Nishimura, Masaharu 7571, 

e18135 

Nishimura, Meiko e16034 

Nishimura, Reiki 588 

Nishimura, Ryuichiro 5103 

Nishimura, Sadako 5006 

Nishimura, Shintaro e21059 

Nishimura, Takashi e18134 

Nishina, Tomohiro 4002, 

4046, 4082, e14038, 

e14123, e14510 

Nishino, Kazumi e18007, 

e18025 

Nishino, Mizuki 7525, 7553 

Nishio, Kazuto TPS659, 

10569 

Nishio, Makoto 7003, 7028, 

7515, 7602, 10569, 

10604, e18004, e18014, 

e18017 

Nishio, Shin 5085 

Nishioka, Yuki 3079 

Nishiwaki, Morie 5084, 

e18064 

Nishiwaki, Satoshi 6533 

Nishiyama, Akihiro 7528, 

e18025, e18134 

Nishiyama, Hiroyuki e15004 

Nishizawa, Yusuke 3569 

Nissim, Ouzi 2078 

Nistér, Monica 4561 

Nitiruangjaras, Anupong 

e14639 

Nitsche, Ulrich 3510 

Nitta, Hidetoshi e21084 

Nitz, Ulrike 552 

Niu, Jiangong 600 

Niv, Yaron e14067 

Niwa, Yasumasa e14540 

Niwakawa, Masashi e15098 

Niwinska, Anna e11553 

Nixon, Andrew B. e13589, 

e21038 

Niyikiza, Clet TPS663 

Njiaju, Uchenna O e11554 

Njoh, Roland Fokwen e17011 

Njuguna, Festus 2601 

Noberasco, Cristina 2595, 

e13606 

Nobile, Francesco e18564 

Nock, Charles John TPS1616 

Noda, Akihiro e21059 

Noda, Hidehiro e13029 

Noe, Jeanne TPS656 

Noeding, Stefanie 554 

Nofech-Mozes, Sharon 1123 

Noga, Stephen J. e18558 

Nogami, Naoyuki 7042, 

7576, e18099 

Nogova, Lucia 1533, 3044, 

TPS3115, 7603 

Noguchi, Atsushi 1103 

Noguchi, Kohei 3022 

Noguchi, Shinzaburo 512, 

539, 540, 551, 559 

Noh, Dong Young 1133, 

e21160 

Noh, Dong-Young 1056, 

10621, e11532 

Noh, Sung Hoon TPS4142, 

e14504, e14652 

Noh, Yook-Hwan e13092 

Noize, Pernelle e14168 

Nokisalmi, Petri e13035 

Nolan, C. 1543 

Nolan, Carmel e12038 

Nolan, Craig 2008 

Nolan, Vikki G 9526 

Nole, Franco 546, 1049, 

1115, 5513 

Nolop, Keith B. 8502^ 

Nomori, Hiroaki 7038 

Nomura, Fumio 7046 

Nomura, Hironori e15065, 

e15069 

Nomura, Motoo e14500 

Nomura, Shosaku e18081 

Nonnenmacher, Anika 5572 

Nonomura, Norio 4632, 

e15065, e15069, e15098 

Nooka, Ajay K. 8086, 8100, 

8101 

Noonan, Anne M. 2545 

Noonan, Krista e11079 

Noonan, Sinead e21024 

Noone, Anne Michelle 6006 

Norden, Andrew David 2009 

Nordgren, Brian K. 8011 

Nordle, Orjan 4550 

Nordlinger, Bernard 3508 

Nordstrom, Beth L e13081 

Noriega-Iriondo, Maria 

Fernanda e15525 

Normanno, Nicola e14042, 

e14113, e18021 

Normolle, Daniel Paul 7071, 

8577 

Noronha, Vanita 5585, 

e13068, e16028, e17500 

Norris, LeAnn B. 9143 

Norris, Robin Elizabeth 9540 

Norris, Sarah 7604 

Norström, Carina e13518 

North, Marie- Odile e21014 

North, Richard T. e15054 

North, Scott A. 4536, 4538, 

4558, e16558 

North, Scott TPS4683 

Northfelt, Donald W. 

TPS2618, 3060, 6025, 

7073, e13052, e13086, 

e13501 

Northover, John 4004, 4029 

Northrup, Robert e19577 

Nortier, J. W. R. 526, 1080, 

10518, e16526 

Nortilli, Rolando 630 

Norton, Larry TPS1143 

Norwood, Thomas 6502 


Nos, Claude 5098, e15558 

Nosaki, Kaname 3045 

Nosov, Aleander TPS4696^ 

Nosov, Dmitry 4501, e15082 

Nosova, Kristin 2080 

Noto, Richard e13592 

Nott, Louise M. 3504, 

TPS4137 

Nottage, Kerri 9526, 9527 

Nottage, Michelle K. 8538 

Nourbakhsh, Ali e18560 

Novaes, Paulo Eduardo 

e15509 

Novarino, Anna 4017 

Novello, Silvia 7085, 

TPS7109, 7550, TPS7619, 

e18103 

Novetsky, Akiva Pesach 5013 

Novik, Alexey Viktorovich 

e13059 

Novik, Yelena e11529 

Novopashenny, Igor 1078 

Novotny, William F. 4560 

Nowacki, Amy S 2014 

Nowaczyk, Piotr 10537 

Nowadly, Cynthia e17535 

Nowak, Anna K. 7079^, 

9087 

Nowakowski, Grzegorz S. 

8053, 9057 

Nowara, Elzbieta 2522, 

3530, e14159 

Nowshad, Gul TPS6635 

Nowsheen, Somaira 621 

Noy, Ariela 6609, 8054, 

9004 

Noyes, David 2501, 2559 

Noyes, Katia 9091 

Noyes, R Dirk TPS657 

Nozawa, Hiroaki e14142 

Ntabaye, Moshi 6102 

Nteliopoulos, Georgios 10550 

Nuara, Michael TPS5602 

Nuber, Ulrike TPS4139 

Nucci, Marisa 5090 

Nuevo, Gema e17515 

Nugent, William 7022 

Nuguyen, Tuan Stevon 7583 

Nuijen, Bastiaan 2550 

Nuin, Paulo S 10622 

Nukiwa, Toshihiro 7086, 

7563, 7565, e18129 

Nukui, Tomoko 8528 

Numico, Gianmauro e19592 

Nunes, Joao Soares e14599 

Nuñez, Isaac TPS4679, 

e21021 

Núñez, M. Isabel 1041 

Nunez-Valencia, Carolina 

e19618 

Nuno, Miriam 2080, 2084, 

2087 

Nurkin, Steven J. e14712 

Nutt, Stephanie 9136, 

e19503 

Nutting, Charles W. 3590 

Nutting, Christopher e16007 

Nuver, Janine 4528 

Nuzhad, Afrin 9086 

Nuzzo, Carmen e14661 

Nuzzo, Gennaro 4110 

Nwankwo, Kenneth Chima 

e19572 

Nwe, Khin Khin e14055 

Nwogu, Chukwumere E. 

e17535 

Nyalendo, Carine 9563, 9570 

Nycum, Lawrence R. 5054 

Nyman, Jan LBA7000 


Nystrom, J. Scott 10579, 

10584 

O 

O Suilleabhain, Criostoir 

e14666 

O’ Keefe, Christine 6521 

O’ Sullivan, Michael GJ 

e11569 

O’Brien, Donna M. 6086 

O’Brien, James P. 5518, 

5591, 8594, e19055 

O’Brien, Joan 9515 

O’Brien, Mary 7081 

O’Brien, Maureen Megan 

e20007 

O’Brien, Neil A. 617, 633 

O’Brien, Robert 4577, 4582, 

4585 

O’Brien, Susan Mary 6501, 

6507, 6515^, 6516^, 

6517, 6528, 6578, 6587, 

6598, 6607, 6619^, 8032 

O’Brien, Thomas 7072^, 

e17531^ 

O’Bryan-Tear, C. Gillies 

LBA4512, 4551, TPS4694 

O’Bryant, Cindy L. e16541, 

e16550 

O’Byrne, Kenneth John 637, 

LBA7500, TPS7615, 

TPS7616, e19059 

O’Callaghan, Christopher J. 

3504, 3515 

O’Callaghan, Christopher J 

TPS2104, 3572 

O’Cathail, Sean Micheal 

2608, e13033 

O’Cearbhaill, Roisin Eilish 

5041 

O’Connell, Joseph P. 

TPS7615, e18093 

O’Connell, Michael J. 

TPS1615 

O’Connell, Michael 3512, 

3522, 3523, 3525 

O’Connor, Ashley TPS3117 

O’Connor, Juan Manuel 

e14598 

O’Connor, Kate e14687 

O’Connor, Miriam 581 

O’Connor, Owen TPS8110, 

e13569 

O’Connor, Robert 2536 

O’Day, Steven e13088 

O’Dea, Pauline 2062 

O’Donnell, Anne e15054 

O’Donnell, Colin e15176 

O’Donnell, Margaret R. 1592 

O’Donnell, Patrick 10596 

O’Donnell, Peter H. 4522, 

e13120^ 

O’Donnell, Robert e13573 

O’Donoghue, Diarmuid 

e13570, e21024 

O’Donovan, Norma 617, 622, 

632, 633, 637, e13520 

O’Dorisio, Thomas M. 4085, 

e14600, e14620, e15580 

O’Driscoll, Lorraine 617, 633 

O’Dwyer, Peter J. 4111, 

TPS4134, 4596, e13602, 

e13604 

O’Dwyer, Peter J 2500^ 

O’Grady, Elizabeth 3613 

O’Keefe, Graeme Joseph 

e15056 

O’Keefe, Margaret e16506 

O’Keefe, Sylvia e12038 

O’Keeffe, Margaret e14666 

O’Mahar, Shannon Eileen 

6570 

O’Malley, A. James 6045 

O’Malley, David M. e15585 

O’Malley, Meaghan Working 

2602 

O’Malley, Rebecca Leigh 

e15046 

O’Malley, Rebecca e15039 

O’Mara, Ann M. 9047, 9099, 

9112, 9144, e19633 

O’Neil, Bert H. 3532, 4052, 

e13109 

O’Neill, Anne M. 605, 6025 

O’Neill, Anne 1021, 5501 

O’Regan, Kevin N. 8552 

O’Reilly, Adrienne M. 8081 

O’Reilly, Derek e21037 

O’Reilly, Eileen Mary 4057, 

9105 

O’Reilly, Kathryn E. 8544 

O’Reilly, Seamus 1559, 

2062, e11569, e14666, 

e16506 

O’Rourke, Donald TPS2107 

O’Rourke, Pat 3078 

O’Shannessy, Daniel 3016, 

e21028 

O’Shaughnessy, Joyce 547, 

596, 604, TPS666, 1016, 

1017, 1018, TPS1140^ 

O’Shaughnessy, Matthew 

e15211 

O’Shea, Alan e16506 

O’Shea, Tanya e13520 

O’Sullivan, Brendan e13507, 

e13554 

O’Sullivan, Brian 5571, 

TPS5600, 10050 

O’Sullivan, Conor 4526 

O’Sullivan, Jacintha e13570, 

e21024 

O’Sullivan, Joe M. LBA4512, 

4551 

O’Toole, Dermot 4036 

O’Toole, Sandra 504 

Oades, Kahuku e14164 

Oaknin, Ana 5001, 

LBA5002^, 5017^, 5038, 

5068, e15575 

Oates, Jacqueline Rose 

e14088 

Oba, Hanako 613 

Oba, Koji TPS3642 

Obad, Susanna e13567 

Obajimi, Millicent e11554 

Obara, Wataru e15068 

Obasaju, Coleman K. LBA4, 

7002, e18138 

Obasaju, Coleman 5533 

Obayashi, Tomohiko e14540 

Obel, Jennifer Carrie 4049 

Oberg, Ann L. e15132 

Oberg, Kjell E. 4122 

Oberholtzer, Carl TPS7609 

Oberlin, Odile 9510, 

TPS9597^ 

Obermiller, Angela Mae 9110 

Oberndorfer, Stefan 2071 

Oberthur Johnson, Laura 

e17017 

Obertin, Stephanie e14180 

Obertova, Jana TPS4677, 

e15028 

Obi, Shuntaro e14622 

Obi-Tabot, Eliot e15193, 

e15198 

Oborski, Matthew J 3019 

Oboyle, Erin e19635 

Obrador, Antonia 10079 

Ocak Arikan, Ozlem e15047 

Ocana, Alberto 558, 6043 

Ocean, Allyson J. 4043 

Ochi, Takanori e14004 

Ochiai, Atsushi 1552, 4012 

Ochiai, Hiroki 10531 

Ochiai, Kazunori 5003 

Ochiai, Takumi e14004 

Ochiai, Toshiya e14518 

Ochoa de Olza, Maria 3096 

Ochoa, Roberto Enrique 

1071, e18109 

Ochsenreither, Sebastian 

2523 

Ockene, Judith 1501 

Ocvirk, Janja e14083 

Oczko-Wojciechowska, 

Malgorzata e14159, 

e21049 

Oda, Hiroyasu e19546 

Oda, Katsutoshi 5037 

Oda, Tsuneyuki e19583 

Odani, Akira 10075 

Oddoux, Carole e15191 

Odenike, Olatoyosi 6562, 

6582 

Odintsova, Anastasiya 

Sergeevna e15543 

Odunsi, Kunle 2510, 2588, 

e11563 

Oechsle, Karin 4597 

Oeffinger, Kevin C. 6001, 

6030, 6073, CRA9513, 

9514, 9552, 9586 

Oei, Paul e15050 

Oelmann, Elisabeth 3004 

Oelschlager, Kristen M. 7106, 

8543 

Oeltjen, Amy R 4062 

Oermann, Eric Karl 2091 

Oesterreich, Steffi 525 

Oestreicher, Judith e13511 

Oettle, Helmut 4020, 4034, 

4044 

Offit, Kenneth e15022 

Offutt, Julie e19030 

Ogan, Ken e15006 

Ogata, Ryo e19583 

Ogata, Yoshitaka e18007, 

e18141 

Ogata, Yutaka 3558, e14077 

Ogawa, Carolina 

MATSUBAYASHI e21151 

Ogawa, Masao e14518 

Ogawa, Osamu 10520, 

e15048 

Ogawa, Takenori e16020 

Ogawara, Daiki 7569 

Ogbagabriel, Selam 3580 

Ogbata, Obiageli Uchenna 

7025 

Ogburn, Emma TPS660 

Ogden, Angela 3033 

Ogdie, Alexis R 6579 

Oger, Emmanuel e19037 

Ogino, Atsuko e18099 

Ognjanovic, Miodrag 1576 

Ognjanovic, Simona 1576 

Oguchi, Masahiko 8050 

Ogundiran, Temidayo O 

e11554 

Ogura, Kaoru 9577 

Ogura, Mariko 10541 

Ogura, Michinori 8023, 8029, 

TPS8118 

Ogura, Takashi e19583 

Ogura, Takeshi e14540 

767s

Oguri, Senri 5556 

Oh, Do Youn 1003 

Oh, Do-Youn LBA1, 3076, 

3624, e14136, e14617 

Oh, Jeong Hoon 8536, 

e15181 

Oh, Ji-Eun e18050 

Oh, Nahmgun e14121, 

e14181 

Oh, Shiaki 10548 

Oh, Sung Tae 10093 

Oh, Sung Yong 4064, 8029, 

e14686 

Oh, William K. 4516, 4524, 

4623, 4656, 6065, 

e21016, e21032 

Ohanian, Maro 6587 

Ohashi, Kadoaki 7532 

Ohashi, Kazuteru 6533 

Ohashi, Yasuo 4035, e19556 

Ohashi, Yoshiaki e14635 

Ohdan, Hideki e14091 

Ohe, Yuichiro 1552, 6112, 

7003, 7017, 7044, 

TPS7612, e17513, 

e17526, e17554, e18054, 

e18064 

Ohga, Takefumi e14033, 

e14601 

Ohgino, Keiko e18058 

Ohi, Masaki e14541 

Ohinata, Aki 4060 

Ohkawa, Shinichi 4035, 4042 

Ohki, Masahiro 3079 

Ohlfest, John 2546 

Ohlmann, Carsten Henning 

4590, e15195 

Ohmachi, Ken 8023 

Ohmann, Christian 4590, 

e16033 

Ohmatsu, Hironobu 1552, 

7044, 7515, e17513, 

e17526, e17554, e18054, 

e18064 

Ohmori, Tohru e13029 

Ohnmacht, Ute 3005 

Ohno, Shinji 588 

Ohrling, Katarina 4015 

Ohsugi, Jun e13015 

Ohsumi, Shozo 540 

Ohta, Hideaki 9574 

Ohta, Naohiro 3607 

Ohtsu, Atsushi 3079, 4067, 

4081, TPS4139 

Ohtsu, Hajime e14601 

Ohuchi, Kohta e19611 

Ohue, Masayuki 3524, 3607 

Ohyanagi, Fumiyoshi 10569, 

10604, e18004, e18014, 

e18017 

Oikawa, Masaya e14011 

Oikonomopoulos, Georgios 

e11073, e11519 

Oing, Christoph 4597 

Oishi, Takayuki e19611 

Oizumi, Satoshi 7086, 7571, 

e18129, e18135 

Ojeda, Belen 1120, 10555 

Ojeda, Juan 6599 

Ojeda, Sandra 8537 

Ojong-Ntui, Martin e11084 

Oka, Daizo e15065 

Oka, Ryota 5584 

Oka, Yoko 9053 

Okabayashi, Koji 10531 

Okabe, Kazunori e17517 

Okabe, Takafumi e18060 

Okada, Daisuke 10542 

Okada, Hideaki e18036, 

e18042 

Okada, Morihito 7031 

Okada, Toshiaki 7560 

Okada, Yoshinari e19611 

Okafuji, Kouhei e18141 

Okajima, Masazumi e14091 

Okamoto, Hiroaki 6112, 

7012, 7017, 7028, 7515, 

e18099 

Okamoto, Isamu 4002, 

TPS7110, 7521, 7590, 

7592, TPS7618, e18060 

Okamoto, Norio e18036, 

e18042 

Okamoto, Tatsuro e13090 

Okamura, Atsuo e17020 

Okamura, Haruki e21004 

Okamura, Takuho 565 

OKane, Patricia 9018 

Okano, Shinji e13014 

Okazaki, Keito e19521 

Okazaki, Toshihiko e13014 

Okhovat, Jean-Phillip e18549 

Oki, Eiji 3558, e14033, 

e14601, e14722 

Oki, Yasuhiro 8070 

Okigami, Masato e21053 

Okinaga, Shoji 7563 

Okines, Alicia Frances Clare 

LBA4000 

Okita, Hajime 9574 

Okoshi, Yasushi 8094 

Oksanen, Minna e13035 

Oksuzoglu, Omur Berna 1596, 

e11540 

oktay Tanyildiz, Gulsah 

e20000 

Oktay, Kutluk 1097 

Okten, Ilker 1596 

Okubo, Satoshi e14004 

Okuda, Kentaro e13029 

Okuda, Ryo e19583 

Okudera, Koichi 7086, 7561 

Okugawa, Yoshinaga e14029, 

e14039, e14541, e21053 

Okumura, Yoshitomo 7080, 

10585 

Okunnu, Marita 3015 

Okuno, Keiko e18060 

Okuno, Scott H. 10003, 

TPS10099 

Okur, Yillar e16005, e19575 

Okusaka, Takuji 4031, 4035, 

4042, TPS4135, TPS4146 

Okutur, Kerem e14698 

Okuyama, Takako e18025 

Olatoye, Dare 4559 

Olaussen, Ken 10556 

Olaverri Hernandez, A. 

e19590 

Olbara, Gilbert 2601 

Olcese, Cristina 575 

Old, Lloyd J. e17558 

Oldenburg, Jan 4508, 4637 

Oldenhuis, Corina N. 4132 

Olek, Sven 5053, 5070 

Olijade, Oludamilola e13109 

Olin, Michael 2546 

Oliner, Kelly S. 2535, 2594, 

4005, 5502, 5504^ 

Olino, Kelly e13559 

Oliva, Claudia 2531 

Oliva, Cristiano 10055 

Oliva, Stefano 645 

Olivari Tilola, Silvia 9054, 

e19530 

Olive, Daniel e15155 

Oliveira, Celia Tosello 1092 

Oliveira, Harley F. e12512 

Oliveira, Harley Francisco 

e19628 

Oliveira, Ivanir Martins 

e14027 

Oliveira, Joao e13119 

Oliveira, Mafalda 509, 566, 

619, TPS652, 10511 

Oliveira, Mario e14673 

Oliveira, Thiago Bueno 

e16046 

Oliveria, Susan A. 1590, 

1591 

Olivier, Kenneth R e14507 

Olivo, Martin Sebastian 7093 

Olivotto, Ivo A. LBA1031 

Ollari, Maria Grazia 9120 

Olmedo Garcia, Maria Eugenia 

e16029 

Olmos, David 1545, 2540, 

4553, 5022, 10039, 

10086, e15136 

Olocco, Ricardo e21025 

Olopade, Olufunmilayo I. 534 

Olopade, Olufunmilayo I 

e11554 

Olopade, Olusola C e11554 

Olowokure, Olugbenga 

Olanrele TPS3116, e14714 

Olpin, Jeffrey 3057 

Olsen, Brian e21133 

Olsen, Ingrid Holst 4015 

Olsen, Jon 9110 

Olsen, Mark R. LBA4 

Olsen, Steven R. LBA1 

Olshinka, Liran e14571 

Olson, Erin Macrae 609, 

6089 

Olson, Garth T 5549, 

TPS5602 

Olson, Jeffrey J. 3055 

Olson, Jillian 6108 

Olson, John A. 503 

Olson, Karin Lou 9131 

Olson, Kristin 3566 

Olson, Lawrence Karl 2056 

Olson, Thomas Arthur 9539 

Olson, Tim e16540 

Olson, Walter C. e19028 

Olson, William C. e21131 

Olsson, Hakan Lars 1594 

Olszanski, Anthony J. 2554, 

8530 

Olszewska, Malgorzata 

TPS2619, TPS4700 

Olszewski, Adam J. 1034, 

8044, 8045 

Olszewski, Wlodzimierz 

Tadeusz 8548 

Olungu, Christine 10096 

Olusanya, Abimbola O 

e19013 

Oluwasola, Abideen Olayiwola 

e11554 

Olver, Ian N. e19553 

Olvera-Caraza, Daniela 1607 

Omar, Haniza 4106 

Omarini, Claudia 631 

Omata, Masao e14622 

Omene, Coral Oghenerukevwe 

e11529 

Omenge, Elkanah 5107 

Omholt, Katarina 8588 

Omlin, Aurelius Gabriel 3022, 

4553, e13601, e15134, 

e15136 

Omollo, Raymond e20504 

Omoniyi-Esan, Ganiyat 

Oluwatoyin e12022 

Omuro, Antonio Marcilio 

Padula 2006, 2008, 2028, 

2089 

Onar-Thomas, Arzu 9518 

Onate-Ocana, Luis F. e19618 

Oncel, Mufide e11008 

Ondovik, Michael S. 8012 

Ondrey, Frank G. 5500 

Oneko, Olola 6102 

Ong, Anna 4048 

Ong, Eugene 1064 

Ong, Michael 3080, 10525, 

e13599 

Ong, Teng Jin e18100 

Ong, Whee Sze e18515 

Ongarello, Stefano e13594 

Onitilo, Adedayo A. 555, 563, 

6063, 9061, e14160 

Ono, Akira 7088, e21007 

Ono, Hidetaka e14624 

Ono, Mayumi 7540 

Ono, Rei e17020 

Ono, Sachiyo e21007 

Ono, Yoko 6567 

Onoe, Takuma 5045 

Onofri, Azzurra e21070 

Onozawa, Yusuke 5542 

Onsrud, Mathias 5008 

Onukwugha, Ebere e14035, 

e14056, e15108, e15146, 

e15148 

Onur, Handan 1572 

Ooi, Boon Phoe 4106 

Ooi, Edie Jian Jiek 4106 

Oommen, Nikhil Babu 4553 

Oostendorp, Linda JM 9036 

Oosterhuis, J W 7009 

Oosting, Sjoukje 4528, 

10581 

Ooyama, Takuma 5086 

Opdam, Mark 562 

Opocher, Enrico 4110 

Oppenheim, David 5522 

Oppido, Piero Andrea 2085 

Oppong, Bridget A. 575 

Oprea, Corina 3080 

Oprea, Tudor I. TPS5602 

Or, Reuven e13013 

Orange, Clare e14110 

Orange, Clélia 2605 

Orbach, Daniel 9536 

Orbay, Ozge e11507 

Orcun, Seza e18555 

Ord, Celine B e14555 

Ordentlich, Peter 567 

Orel, Nadezhda Fedorovna 

e19005 

Orera Clemente, Maria 

e12003 

Orfeuvre, Hubert e11019 

Orgiano, Laura 9006 

Orita, Hajime e14139 

Orlandi, Armando e14156, 

e16553 

Orlandi, Ester 5555 

Orlandi, Massimo 10611 

Orlandini, Cinzia 629 

Orlando, Laura e11001, 

e11547 

Orlov, Sergey V 7029, 

LBA7500, 7551 

Orlova, Kristina 

Vyacheslavovna e19005 

Orlowski, Robert Z. 8018^, 

8035, 8040, 8093, 

TPS8112, TPS8113 

Ormanns, Steffen 4041 

Ormerod, Anne e16557 

Ormianer, Mati 1564 


Oro, Anthony E 8579, 

e19048^ 

Oronzi, Irma 5093, 5094, 

e15550 

Orr, Maria 1548 

Orsi, Franco e14607 

Orsi, Jennifer M. 6120, 

e16531 

Orsini, Christine TPS667 

Orsini, James M. 7590 

Orsini, James 7592, 

TPS7618 

Orsini, Lucinda S. 4033 

Ortega Ruiperez, Carolina 

e19590 

Ortega, Alette e18028 

Ortega, Cinzia 4627, e15073, 

e15133 

Ortega, Luis e20513 

Ortega, Vanesa 566, 619 

Ortega, Vanessa 509 

Ortego, Javier 3553 

Ortiz Duran, Rosa Maria 

4089, e14120 

Ortiz, Marcos e14521 

Ortiz-Romero, Pablo L. 8076 

Ortmann, Uta 554, TPS1146, 

1600^, 1602 

Ortner, Petra Angelika 

e19540 

Ortuño-Pacheco, Guzman 

e11024 

Oruezabal, Mauro e11074 

Orui, Hayato 7080 

Oruzio, Daniel V. 3588 

Osada, Takuya 2585, 10563 

Osann, Kathryn 6132 

Osarogiagbon, Raymond U 

7025, 7069, 7072^, 

e17531^ 

Osborne, C. Kent 606 

Osborne, Cynthia R. C. 1017, 

e19609 

Osborne, Karen 551 

Osborne, Raymond 5110 

Osborne, Richard 5046 

Osei-Boateng, Kwabena 

e14611 

Oshima, Takashi 4070, 

e14624 

Oshimi, Kazuo 8050 

Oshiro, Takashi TPS3642 

Oshita, Fumihiro 7012 

Oshitanai, Risa 565 

Oskay-Özcelik, Gülten 5044 

Osman, Iman 8544, 8550, 

8557, 8565, 8571, 8589, 

e19003, e19018 

Osoba, David 6002 

Osorio, Cynthia ABT 1522 

Osowski, Susanne 7001 

Ospovat, Inna 10034 

Ostapoff, Katherine T e13563 

Oster, Gerry e12024, 

e15197, e16573, e18107, 

e19630 

Oster, Jean-Philippe e16560, 

e18089 

Osterlund, Pia J. CRA3503, 

4015 

Ostroff, Rachel e21012, 

e21142 

Ostrovnaya, Irina 4581^, 

4592, e15022 

Ostrowska, Beata e18512 

Osunkoya, Adeboya O. 

e15006 

Osuorji, Ikenna e14163 


Osvaldt, Alessandro Bersch 

e13546 

Oswald, Michaela 1046 

Ota, David M. 503 

Ota, Ikuyo 8094 

Ota, Mitsuyoshi e14047, 

e14050 

Oteiza, Katharine 4045 

Otero, Jorge M. e12039 

Otero, Silvina e15521 

Othieno-Abinya, Nicolas 

Anthony e20504 

Othman, Fauzi e19632 

Othman, Youmna 9520 

Othus, Megan 6502, 8525, 

8527 

Otley, Clark 8590 

Oto, Yuji e13029 

Otsuka, Hiroko e13046, 

e13050 

Otsuka, Kojiro 10610, 

e18025, e18134 

Otsuka, Kyoko 7528, 10610 

Otsuka, Shannon e18110 

Ott, Marion Gabriele 7544 

Ott, Patrick Alexander 2589 

Ottaiano, Alessandro e14130 

Ottaviani, Davide 4627 

Ottensmeier, Christian H.H 

7081, 8566 

Ottensmeier, Christian 2583, 

TPS8605 

Otterson, Gregory Alan 2610, 

7513, 7546, 7600, 

TPS7619, e18018 

Ottesen, Lone Harild 4108 

Ottesen, Rebecca A 599, 

1125, 1562 

Ottevanger, P. B. 5061 

Ottevanger, Petronella B 9036 

Otto, Geoff 3533, 7510 

Ou, Sai-Hong Ignatius 2610, 

7000, 7508, 7530, 7533, 

7557, 7596, 7599, 7600, 

e18126, e18128, e18140 

Ou, Sai-Hong 7083 

Ou, Wei 7034 

Ou, Yen-Chuan e15047, 

e15064 

Ouafik, L’houcine 8555 

Ouali, Monia 10009, 10067, 

10096 

Ouatas, Taoufik TPS4698^ 

Oubel, Estanislao e13547 

Oudard, Stephane 1095, 

4510, LBA4567^, 4583, 

4642, TPS4696^, 5067, 

e15040, e15161, e19640 

Oude Munnink, Thijs H. 

10581 

Ouellet, Danielle LBA8500^ 

Ouellette Freve, 

Johann-Francois e19591 

Ould Kaci, Mahmoud TPS647 

Oulla, Karima e11516 

Oura, Shoji 1119 

Ouyang, Xuenong 9017, 

e18033 

Ovalle, Valentina e14002 

Ovechkina, Yulia e13542 

Overbury, Rebecca S. e21077 

Overkamp, Friedrich 

TPS3641^, e15044 

Overman, Michael J. 3544, 

3556, 3561, 3598, 4037, 

4054, 4116, 9072 

Owen, Kate 6527 

Owen, Roger G. 8015 

Owens, Brian L e14160 

Owens, Pamela e18551 

Owonikoko, Taofeek Kunle 

2576, 3037, 3049, 3094, 

5560, 5570, 7048, 7059, 

7097, 7512, 10625, 

e13026, e21045 

Owugah, Tina TPS6638 

Owusu, Cynthia 9034, 9109, 

9123, e18133 

Owzar, Kouros 2533 

Oxnard, Geoffrey R. 7524, 

7547 

Oya, Mototsugu 9569, 

e15068 

Oyan, Basak 6550 

Oyen, Wim J.G. 3035, 

e13111 

Oza, Amit M. 3013, 3082, 

5001, 5010, 5019, 5020, 

5022, 5025, 5026, 5110, 

9003, e13001, e13598, 

e19616 

Ozaka, Masato e14677 

Ozaki, Michitaka 10578 

Ozaki, Toshifumi 9574 

Ozanne, Elissa e16504 

Ozawa, Taijirou e16032 

Ozaydin, Sukru 6550 

Ozbalak, Murat 6550 

Ozcimen, Ata e15104 

Ozdemir, Handan e11023 

Ozdemir, Nuriye 638, 

e11033, e11093, e14526 

Özdemir, Nuriye 1596, 

e13031 

Ozdener, Fatih 3565 

Ozdogan, Mustafa e14070, 

e19024 

Ozen, Haluk e15122 

Ozen, Ozlem e15572, 

e15573 

Ozenne, Gervais TPS7111 

Ozer Stillman, Ipek 6553 

Ozet, Ahmet 6550 

Ozguroglu, Mustafa e15112, 

e21143 

Ozisik, Yavuz Yasin e11020 

Ozisik, Yavuz e11092 

Ozkan, Elgin e21006 

Ozkan, Metin e14089, 

e14670 

Ozkaya, Enis 1097 

Ozkaynak, Mehmet Fevzi 

6537 

Ozmen, Vahit 9046 

Ozono, Seiichiro e15071, 

e15098 

Oztop, Ilhan 638 

Oztuna, Derya Gokmen 1596 

Ozturk, Akin e14698 

Ozturk, Mehmet Akif e21143 

Ozturk, Mustafa 6550 

Ozyilkan, Ozgur e11011, 

e11023, e11026, e11045, 

e11515, e14174 

Ozyoruk, Derya e20000 

P 

Paasche-Orlow, Michael 9004 

Pabla, Maninder e14632 

Pac, Joaquin 7011 

Paccagnella, Adriano 5513 

Pacchiarotti, Alberto e19002 

Pace, Andrea 2037, 2085 

Pace, Kenneth T 4633 

Pace, Margaret e13562 

Pace, Thaddeus 9122 

Pacetti, Paola 10611 

Pacheco, Jose 1048 

Pacheco, Luisa Silva e14597 

Pachman, Deirdre R. 9075 

Pachmann, Katharina 10600, 

e21063 

Pachon Ibanez, Jeronimo 

e16037 

Pachter, Jonathan A 1057 

Pachynski, Russell Kent 

e21071 

Pacini, Furio 5591 

Pack, Svetlana TPS7609 

Packeisen, Jens 10627 

Padbury, Rob TPS3643 

Padhani, Anwar R. 1066 

Padhya, Tapan 5564 

Padilla, Juan e12041 

Padrini, Robeto e13019 

Padua, Fernando Vidigal 643, 

e14680, e14728, e18078 

Paesmans, Marianne 3559, 

e18006 

Paetzold, Sylvie e19031 

Páez, David 3597, 3604, 

4026, 4096, e11018, 

e14034, e14052, e14104, 

e18057 

Pagani, Gianmatteo 1115 

Pagani, Olivia 9022 

Paganin, Fabrice 1574 

Page, David L 1005 

Page, Elizabeth 1545, 4653 

Page, Ray D. 7590, 7592, 

TPS7618 

Pagès, Cécile e13594 

Pages, jean-Christophe 3520 

Pagés, Mario 3536 

Paglialunga, Luca e18101 

Pagliaro, Lance C. 4533, 

e15092 

Pagliuchi, Marco e13098 

Pahernik, Sascha 4539 

Pai, Ashok P. 4607 

Pai, P. S. 5585 

Pai, Sara I 5506 

Paik, Paul K. 7014, 7505 

Paik, Seung-Woon TPS4149 

Paik, Soonmyung LBA506, 

LBA1000, 1025, TPS1142, 

3512 

Paintaud, Gilles TPS662 

Pairet, Geraldine e14044 

Pais-Costa, Sérgio Renato 

e14657 

Paiusco, Paola e19595 

Paiva Jr, Tadeu Ferreira 

e14680 

Paiva, Bianca Sakamoto 

Ribeiro e19602 

Paiva, Carlos Eduardo 

e14173, e19528, e19584, 

e19602 

Paiva, Henrique Soares 

e19552 

Paiva, Marcelo e11513 

Pajares, B. 4630 

Pajares, Bella 10616 

Pal, Sumanta Kumar 2538, 

4504, 4536, e15084, 

e15114, e15178, e16563 

Pal, Tuya 1585 

Palacios, Amalia 3571 

Palacios, Gemma 10512 

Palacka, Patrik TPS4677, 

e15028 

Palaia, Thomas e15504 

Palanichamy, Kamalakannan 

e19040 

Palapattu, Ganesh S. 

TPS4678 

769s

Palassini, Elena 10026, 

10053, 10065 

Palazzo, Juan 3621 

Palefsky, Joel 4030 

Palepu, Prakruthi R. 1535, 

7586, 9032, 10522 

Palesandro, Erica 10066, 

e20512 

Palescandolo, Emanuele 

2020, 5011 

Palese, Michael 4623 

Palesh, Oxana 9051, 9113, 

e16564 

Paley, Carole S. 8012, 

e16537 

Paliwal, Prashni TPS6634 

Palka, Magda e11527, 

e12015, e17502, e17503, 

e17515 

Pall, Georg e14719 

Palla, Shana L. 8536, 9127 

Pallares, Cinta e18057, 

e18130 

Paller, Channing Judith 3009, 

4559 

Palli, Swetha e16542 

Pallis, Athanasios G. 7081, 

7564 

Pallisgaard, Niels 5052 

Pallotta Guadalupe, Maria 

10074 

Pallotti, Maria Caterina 

10087 

Palma, Alejandra 9063 

Palma, David 6130, 7009 

Palma, Giuseppe e11052, 

e13539 

Palmbos, Phillip Lee 4591 

Palmer, Daniel H. TPS4150, 

e14625 

Palmer, Frank L. 5562 

Palmer, Gary A. 1015, 3533, 

7529, 10559, 10590 

Palmer, J. Lynn 9002, 9023, 

9025, 9062, 9063, 9096, 

e19643 

Palmer, Joycelynne 6547, 

8089, e18542 

Palmer, Steven C 9145 

Palmerini, Emanuela 10022, 

10026 

Palmero, Edenir Inez 1522 

Palmero, Ramon 7542, 

e18137 

Palmieri, Diane 505 

Palmieri, Giovannella e15034, 

e19038 

Palmieri, Giuseppe 8581, 

e14094, e18021 

Palmisano, Joseph N 6097 

Palomares, Melanie R. 1562, 

e15114 

Palomba, Grazia 8581, 

e14094 

Palomba, Maria Lia 6609, 

8054 

Palomo Colli, Miguel Angel 

e20005 

Palos, Guadalupe R. e19625, 

e19629 

Palozzo, Angelo Claudio 

e15072 

Palti, Yoram e14616 

Palumbo, Antonio Pierangelo 

TPS8112, TPS8113, 

TPS8114 

Palumbo, Michael Ostaric 

9557 

Palumbo, Raffaella 589 

Pamidighantam, Suresh 9055, 

e12501 

Pampaloni, Miguel H 8580, 

e13592 

Pan, Chong-xian 4607 

Pan, Edward 2099 

Pan, Hongming 7519^ 

Pan, Jian-ji 5535, 5538 

Pan, Jianmin e16545 

Pan, Linda S. 2589, 

TPS8111, 8547, e17558 

Pan, Qiong 10042 

Pan, Qiulu 8596 

Pan, Summer 8078, 10051, 

e18546, e20509 

Pan, Xueliang Jeff 609 

Pan, Yumei 6038 

Pan, Zhiying 5504^ 

Panageas, Katherine 2006, 

2518, 8575, 8598 

Panagiotarakou, Meropi 

e17557 

Panasci, Lawrence C. 1099 

Pancholi, Minjal J 7033 

Pande, Amitkumar U. 4006 

Pandey, Apurva e21105 

Pandey, Romy e14642 

Pandha, Hardev S. 4653, 

TPS4692^, e15517 

Pandit-Taskar, Neeta 

TPS9595 

Pandite, Lini 4605, e15059, 

e15085, e15087 

Pandya, Deep 10516 

Pandya, Kishan J. 7018 

Pandya, Naimish B. 6028, 

6060, 6075 

Pandya, Shuchi Sumant 2566 

Pang, Angela 1064, 1575, 

e19523 

Pang, Herbert CRA9013, 

e13589, e21038 

Pang, See-Tong e15064 

Pang, Vincent 1597 

Pang, Zuoliang e18013 

Pani, Giuseppe e14711 

Panka, David J 8516 

Pankow, Wulf 9033 

Panneerselvam, Ashok 4014, 

e15047, e15064 

Panni, Stefano 4097 

Panopoulos, Chris G. e11519 

Panos, Rebecca 10576 

Panse, Jens Peter e19610 

Pant, Alok e15523 

Pant, Rajive e20508 

Pant, Shubham 3008, 3041, 

3067, 3097, e17012 

Pantaleo, Maria A. 10087 

Pantazatos, Dionysios e21116 

Pantel, Klaus 1090, 

TPS1146, 10540, 10599 

Panting, Lisa 8593 

Pantos, Christos e11073 

Pantuck, Allan J. e13045 

Panu, Lori e16009 

Panzone, Filomena e19634 

Pao, William 6038, 7094, 

7532, 7568, 7589 

Paolicchi, Elisa 10611 

Paolini, Jolanda 4644 

Papa, Anselmo e11039, 

e11514, e12510, e19620 

Papa, Sophie 3100 

Papachristou, Irini 3044, 

TPS3115, 7603 

Papadimitrakopoulou, Vassiliki 

5524 

Papadimitriou, Christos A. 

592, 5033 

Papadimitriou, Konstantinos 

9090 

Papadopoulos, Iordanis 

e21027 

Papadopoulos, Kyriakos P. 

2512, 2555, 3001, 3019, 

3029, TPS3110, e13025, 

e13077, e13599, e13602, 

e13604 

Papadopoulos, Nicholas E. 

8514, e19009, e19014, 

e19039 

Papadopoulou, Eirini e21087, 

e21141 

Papagikos, Michael A. 5503, 

5515 

Papaiah Susheela, Sridhar 

e19619 

Papaioannou, Alexandra 

e14001 

Papakostidi, Aristoula e21098 

Papalini, Francisco e21025 

Papamichail, Michael 625, 

e15125 

Papanikolaou, Alexandros 

5033 

Papanikolaou, Xenofon 8041, 

e18548 

Papayannidis, Cristina 6531 

Pape, Ulrich-Frank 4128 

Papin, Jason A 8597 

Papini, Enrico 1604 

Pappa, Vassiliki e21027 

Pappagallo, Giovanni L. 7577, 

e15160, e18026 

Pappas, Theodore N. e14724 

Pappo, Alberto S. 8504, 

9509 

Pappou, Efi 625, 2508, 

e15125 

Papsdorf, Kirstin 2000 

Paquet, Agnes 603, 608, 614 

Paquette, Ronald 6503, 6624 

Parafioriti, Antonina 10022 

Paraiso, Isbou e21014, 

e21046 

Parambi, Ron J. 5594, 

e16059 

Paramio, Jesus 4584 

Parashar, Deepak e14100 

Parchment, Ralph E. 3031 

Pardanani, Animesh Dev 

6614, TPS6639, TPS6641 

Pardee, Timothy S. 6524^ 

Pardo, Beatriz 5068, e15575 

Pardo, Nuria 4579, e12504 

Pardo, Wandaly Ibis e18547 

Pardoll, Drew M. CRA2509, 

2510, 5506, e13559 

Paré, Laia e14052, e14104, 

e18057 

Parekh, Hiral D. e17010 

Parent, Teresa e17547, 

e17550 

Parente, Barbara e18111 

Parente, Phillip e15152 

Parganiha, Arti e14006 

Parham, David 9509, 9535 

Parham, Laura R 10532 

Parhar, Tarnjit 3610 

Paridaens, Robert 1020 

Parienti, Jean-Jacques 

TPS7112 

Parikh, Kunal e14656 

Parikh, Nila 3561 

Parikh, Omi CRA4502 

Parikh, Rohan e14627 

Parikh, Unnati e14632 

Parise, Carol 1582, 1606 

Parise, Robert A 2553 

Parise, Sara e16026 

Park, Bernard J. 7024 

Park, Byeong-Woo 2542 

Park, Byung-Kiu 9579 

Park, Chan Hee 3606 

Park, Cho Hyung e14558 

Park, Chul-Kee 2041 

Park, Daniel e15171 

Park, Deric M. 3037 

Park, Elyse R. 6048, 6106, 

9101 

Park, Hee Sook 1003, 

e14688, e19554 

Park, Hyeon Jin 9579 

Park, Ilwoo 4660 

Park, In Hae 1003 

Park, In Ja 3556 

Park, In-Ae e11532 

Park, Inkeun 10085, e14543, 

e15080 

Park, Jae Hong 6532 

Park, Jae-Gahb 3624 

Park, Jangchul e17510, 

e18145 

Park, Jenny e21159 

Park, Jeong-Yeol e15559 

Park, Jin Hyun 7566 

Park, Jinha Mark 1035 

Park, Jinny e14137, e14685 

Park, Jong Ho e17523 

Park, Joon Oh 4011, 4064 

Park, Joong-Won 4033, 4103 

Park, Joonoh e13094 

Park, Julie R. 9533, 9534 

Park, Jun Seong e18519 

Park, Jun Won e21043 

Park, Keon Uk e14570 

Park, Keon-Woo 4064 

Park, Keunchil 7004, 7104, 

7549, 7557, TPS7614, 

e16003, e18093, e18148 

Park, Kwonoh 5586, e15080 

Park, Kyong Hwa 2542, 

e12029 

Park, Kyu Hyun e14081 

Park, Kyu Joo 3624 

Park, Kyung 4649 

Park, Kyung-Mi 3076, 

e13092, e14572 

Park, Lee Chun e13094, 

e16003, e18148 

Park, Min Keun e14114 

Park, Min-Jung 2041 

Park, Noh Jin 2587 

Park, Rachel S. 4577, 4580, 

4585 

Park, Sang Min 9066 

Park, Se Hoon 4064, e13094 

Park, Seong Yong e16534 

Park, Seongjoon e15080 

Park, Seung Woo e19538 

Park, Seung-Il 4093, 7510, 

e14573 

Park, Silvia 644, 7104, 

e13094, e16003, e18148 

Park, Sook Ryun 4028 

Park, Sophie 6523, 6534, 

8026 

Park, Steven I. TPS8109, 

e13074 

Park, Sun Jin e14128 

Park, Sung Kyu e14688, 

e19554 

Park, Wungki e14169, 

e14170 


Park, Yeon Hee 644, 1003, 

2542 

Park, Yeon Ho e14685 

Park, Yo An e13092 

Park, Young Soo e14543 

Park, Young Suk 3531, 4064, 

e13044, e13094, e14072 

Park, Young-Hun 6564 

Park, Young-Iee 4028, 

e14572 

Parker, Alex 3533 

Parker, Bethany H. e14078 

Parker, Charla A. 594 

Parker, Chris LBA4512, 4551 

Parker, Douglas 8543 

Parker, Imelda 581, e13520 

Parker, Joel S 10500 

Parker, Lynn 5095 

Parker, Matthew 9518 

Parker, Pablo Miguel 8089 

Parker, Patricia A. 6054, 

9031 

Parker, Susan 2510 

Parli, Teresa 8020 

Parlour, Louise 5527 

Parmakhtiar, Basmina 8524 

Parmar, Mahesh 4509, 6091 

Parmar, Simrit 8102 

Parmar, Vani 1108, e11552 

Parmentier, Gilles 10562 

Parmiani, Giorgio 8513, 8529 

Parmigiani, Giovanni 2005 

Parnaby, Adam e15198 

Parnes, Howard L. 3043, 

4569 

Parnis, Francis 7079^ 

Parno, Jeff 3016, 7030 

Parot, Xavier 4129 

Parpia, Sameer LBA1031 

Parra, Juan Francisco 4089 

Parras, Manuela e11517 

Parrella, Paola e21092 

Parrilla, Lucia e15033 

Parsons, Henrique Afonseca 

9063, e13534 

Parsons, Michael W. 1076, 

2018 

Parsons, Ramon 10516 

Parsons, Stephen H 8082 

Parthan, Anju e11077 

Parthasarathy, Mala e13121 

Parthasarathy, Ramya 3087 

Partridge, Ann H. 1100, 

6025, 9008, 9071, 9084, 

9100, e16515 

Parulekar, Wendy 500, 4509, 

TPS5600 

Parvathaneni, Upendra 5503, 

5515, 9008 

Parvin, Jeffrey e19053 

Paschold, Eugene Henry 7584 

Pasciuti, Giulia e11039, 

e11514, e19620 

Pascoletti, Gaetano 1044 

Pascual, Tomas 642, 

e15033, e15552 

Pasello, Giulia 7082 

Pasero, Christine e15155 

Pasetka, Mark e15180 

Pashos, Chris L 6122, 8037, 

e18556, e18561 

Pasini, Felice e13019 

Pasion, Kristine A. e13574 

Paskett, Electra D. CRA9013 

Pasqual, Nicolas 10562 

Pasquier, Florence e11012 

Pasquini, Enzo LBA4001 

Pass, Harvey e17528, 

e21012 


Passalacqua, Rodolfo 4097, 

9120 

Passamonti, Francesco 

6514^, 6625^, 6626^, 

TPS6639 

Passardi, Alessandro 4017 

Passaro, Antonio e18065 

Passioukov, Alexandre 5522, 

7544 

Pastan, Ira 2503^, 7030 

Pastina, Pierpaolo e13098 

Pastrana, Miguel Angel 

e11035 

Paszat, Lawrence Frank 1123, 

6027, 6134 

Paszkiewicz-Kozik, Ewa 

e18512 

Patal, Payal 6629 

Patchett, Matthew 6595 

Patel, Akshal e11544 

Patel, Amit S. e16527 

Patel, Anand 8072 

Patel, Bijal e17524 

Patel, Devalben 1535, 7586, 

10522 

Patel, Jai Narendra e13109 

Patel, Jay 9507 

Patel, Jyoti D. LBA4, 3083 

Patel, Kiran 3102, 3528, 

LBA8509, 8510, e19046 

Patel, Krina K. 8093 

Patel, Manali I. 6050 

Patel, Manish R. 3631, 

TPS8115 

Patel, Mital 2076, 2092, 

2093, 2096, 2100 

Patel, Monaliben e14175 

Patel, Nayana e15176 

Patel, Neema e17004 

Patel, Oneel e15117 

Patel, Pooja Nandwani 

e15505 

Patel, Poulam M 8517 

Patel, Premal H. TPS2616, 

3021, e13114 

Patel, Priti 8086, e18569 

Patel, Purvi D. 5562 

Patel, Sapna Pradyuman 

8514, e19009, e19014, 

e19039 

Patel, Shejal B e19551 

Patel, Shreyaskumar 10071, 

TPS10101, e19520 

Patel, Snehal G. 5545^, 

5562 

Patel, Tejal Amar 2015 

Patel, Uday Bharat e14097 

Patel, Vihas 9086 

Patel, Vipul e15171 

Patel, Yash R. e15179 

Patel-Donnelly, Dipti 3069, 

8098 

Paterlini-Brechot, Patrizia 

7591 

Paterson, Daniel 1057 

Pathak, Ashutosh Kumar 

TPS2613 

Pathak, Prathamesh 570 

Pather, Selvin TPS9153 

Pathy, Sushmita 5104 

Pati, H P e17000 

Patil, Chirag 2080, 2087 

Patil, Dattatraya Hari e14692 

Patil, Poonam e14710, 

e15516 

Patil, Ritesh 625, 2508, 

2529 

Patil, Shekhar e11511, 

e12030, e14721, e18041 

Patil, Sujata 557, 575, 1006, 

1118, 4532, 6001, 9104, 

10618 

Patil, Vijay 5585, e16028, 

e17500 

Patnaik, Amita 2512, 2555, 

3001, 3019, TPS3110, 

e13025, e13576, e13599, 

e13600^, e13602, e13604 

Patnaik, Mrinal M. 6614 

Patrick, Patricia e15504 

Patrick-Miller, Linda J. 9106, 

e15173 

Patrikidou, Anna 10044 

Patruno, Rosa e21113, 

e21134 

Patt, Debra A. 6109 

Patt, Richard H. TPS4152, 

e14566 

Pattabiraman, Nagarajan 

e13545 

Pattali, Shinoj e14186, 

e14590 

Pattaras, John e15006 

Patterson, Christopher J 

8042, 8106, 8107, 

e18575 

Patti, Marco G. 10090 

Patton, J. Scott e13581 

Paty, Philip 3577, 3583 

Patyna, Shem 4118 

Patzak, Ingrid 2504 

Paucar, Daniel 8598 

Pauels, Hans-Gerd e18532 

Paul, Devchand 547 

Paul, Diane B. 9047 

Paul, Doru 6123 

Paul, MJ e19562 

Pauligk, Claudia 4080, 4083, 

4090, 10552, e14557, 

e21063 

Paulk, M. Elizabeth e16500 

Paulli, Marco e13103 

Paulsau, Antonello e15194 

Paulson, Guillermo e15571 

Paulus, Jessica e14005 

Pautier, Patricia 5028, 5083, 

10042, 10098 

Pavel, Marianne E. 4014, 

4122, 4128, e14564 

Pavese, Ida e18065 

Pavey, Emily S 3617 

Pavia, Orestes Antonio 1060, 

e11015, e18547 

Pavia-Jimenez, Andrea 

TPS4678 

Paviot, Alexandre 5565 

Pavlakis, Nick 3515, 7079^, 

e19642 

Pavlicek, Adam 3509 

Pavlick, Anna C. 2589, 

8503^, 8508, 8550, 8557, 

8565, 8567, 8589, 

e13598, e19003 

Pavlidis, Nicholas 573, 592, 

10575 

Pavlov, Dmitri 6512 

Pavlovitz, Brian 6572 

Pawaskar, Dipti K e13006 

Pawitan, Yudi 4561 

Pawlik, Timothy M. 3616 

Pawlik, Timothy M 3596, 

4055, 4114 

Pawlinski, Rafal e14505 

Pawloski, Pamala A. e14160 

Pawlowski, Ryszard 10561 

Paydas, Semra 6550, e19024 

Payne Ondracek, Rochelle 

e15203, e15204 

Payrard, Sandrine 8057 

Paz, Isaac Benjamin 1035 

Paz, Maria fe e21158 

Paz-Ares, Luis G. 7542, 

TPS7615, e13605, e18100 

Paz-Ares, Luis 2042, 3062, 

LBA7507, 7544, TPS7616, 

TPS9149^, e16037 

Paz-Querubin, Emma R 

e14124, e18516 

Paz-Querubin,, Emma e19638 

Pazart, Lionel e19623 

Pazdur, Richard 3074 

Pazzola, Antonio e14094 

Peach, James TPS10633^ 

Peachey, Lynnda LBA4001 

Peachey, Matt 9004 

Peacock, Nancy Walker 1018, 

4127 

Peacock, Stuart 549^ 

Pearlberg, Joseph 7556 

Pearlstone, David B. 1132 

Pearse, Maria TPS4690 

Pearse, Roger N 8036 

Pearson, Alexander T. 4573 

Pearson, Andrew DJ 9542, 

9583 

Pearson, Richard 8520 

Pearson, Sarah R LBA4001 

Pecchio, Silvia 627 

Pechacova, Zdenka e14631 

Peck, Rahul e18095 

Peck-Radosavljevic, Markus 

e14681 

Pecora, Andrew e18507, 

e19641 

Pecorari, Giancarlo 5546, 

5548 

Pecorelli, Sergio L. e15549 

Pectasides, Dimitrios G. 573, 

5033, e21027 

Pectasides, Eirini 5576 

Pedani, Fulvia 5548, e11524 

Peddareddigari, Vijay Gopal 

Reddy 3000, 3023 

Peddi, Prakash e16009 

Peddi, Prashanth 8536 

Pedersen, Hans Christian 

e21129 

Pedersen, Joanna Vitfell 

10038 

Pedersen, Kasper 632, 2536 

Pedersen, Lars Moeller 8074 

Pedrazzoli, Paolo e13103 

Pedulla, Lillian Vitale e19637 

Peer, Avivit 4564, 4619, 

e15058 

Peereboom, David M. 2018, 

2076, 2092, 2100, 

TPS2107 

Peeters, Dieter 10504 

Peeters, Justine 10545, 

10597, e21013 

Peeters, Marc 3535, 3559, 

3581, 4050, e13051 

Peeters, Olivier 8559 

Pegoraro, Cristina e13019 

Pegourie, Brigitte 8014 

Pegram, Mark D. LBA1, 608 

Peguet, Elodie e14148 

Pei, Jianming 4605 

Pei, Jun e12013, e13528, 

e18088 

Peila, Elena e11524 

Peintinger, Florentina 515 

Peiper, Matthias e11556 

Peipp, Matthias e18565 

Peiretti, Michele 5090 

Peiro, Rafael e16025 

771s

Peisker, Uwe 10600 

Peker, Deniz e18503, 

e18506, e21123 

Pekle, Karen 8036 

Pelayo, Eva e11028 

Pelayo, Miguel Ricardo 5564 

Pelegrin, Andre 5069 

Peligros, Isabel 4089 

Pelizon, Christina H. TPS653, 

TPS654^ 

Pella, Nicoletta 3612 

Pellacani, Giovanni 8578 

Pellegatta, Serena 2083 

Pellegrino, Antonio e18048 

Pellegrino, Arianna e18065 

Pellegrino, Renata e16041 

Peller, Patrick J. 2031 

Pelles-Avraham, Sharon 5078 

Pelling, Katy TPS651 

Pelloski, Christopher E. 9544 

Pelmus, Manuela TPS1139 

Pelt, Gabi W. van e14151 

Peltonen, Nina e15564 

Pelusio, Adina e13044 

Pelzer, Uwe 4044, e14533 

Pemberton, Kristine 3048 

Pemmaraju, Naveen 6544, 

6578, 6592, 6597 

Pena, Carol Elaine e15086 

Peña, Jose Maria 3601, 

e14093, e14144 

Pena, Omar 7068 

Pena-Llopis, Samuel 4616 

Penalver, Juan-Carlos 7011 

Penault-Llorca, Frederique 

Madeleine 543, 568^, 

1011 

Penault-Llorca, Frederique 

1051 

Pendergast, Jane F 6034 

Pendharkar, Dinesh e16057 

Pendse, Deepa 4581^, 

e15022 

Pendurti, Gopichand e18537 

Penel, Nicolas 2540, 10005, 

10006, 10007, 10010, 

10013, 10014, 10018, 

10020, 10023, 10027, 

10035, 10042, 10056, 

TPS10102^ 

Peng, Feng e13538, e18033 

Peng, Guangbin 2554, 5533, 

7002 

Peng, Shiwen 5506 

Peng, Xianghong e13110 

Peng, Yingwei 1583 

Peng, Zhuochun 4561 

Pengo, Stefano 10022 

Penn, Dolly 6104 

Pennacchioli, Elisabetta 

e19035, e19036 

Pennathur, Arjun 7074 

Pennell, Nathan A. 2081, 

7010, e17563, e18046, 

e18085 

Pennella, Eduardo J. LBA4 

Pennella, Eduardo 5533, 

e16053 

Penning, Trevor 4520 

Pennington, Kenneth L. 4043 

Pennock, Gregory K. 

TPS10099, e13088 

Pensabene, Matilde 1554 

Penson, Richard T. 5012, 

5029 

Pentheroudakis, George E. 

592, 5033, 10575 

Pentland, Alice P 9027 

Pentlow, Keith S. 5509^ 

Pentsova, Elena 2008 

Pentz, Rebecca D. e13026 

Penuel, Elicia M. e13048 

Pénzváltó, Zsófia e21005 

Peock, Susan 1545 

Peoples, George Earl 625, 

2508, 2529 

Pepe, Carmela e18061, 

e18098, e19626 

Peppercorn, Jeffrey M. 6095, 

6128 

Peppone, Luke Joseph 9009, 

9010, 9014, 9028, 9141, 

9142 

Pera, Miguel 3586 

Peralta, Sergi e18030 

Percy, Andrew 4543, 4635 

Perdikouri, Eleni Isidora 

e18098 

Perdona, Gleici da Silva 

Castro e19628 

Perdue, Nikole 2563 

Perea, Rachelle 3032 

Perea, Sofia 602, e11006 

Pereda, Teresa e14116 

Pereira, Allan Andresson Lima 

e11014 

Pereira, Augusto Akikubo 

Rodrigues 643, e14680, 

e14728, e18078 

Pereira, Bruno dos Santos 

Vilhena e14027 

Pereira, Deolinda LBA5002^, 

e15532 

Pereira, Jose Rodrigues 7503, 

7506, 7512, e18078 

Pereira, Verónica 3536, 

e13540 

Perel, Yves 9517 

Perello, Antonia e11036 

Perelman, Marina e17509 

Perelman, Michael Sidney 

e19544, e19567, e19578 

Perentesis, John Peter 9541, 

9581, e20007 

Perepu, Usha S. 8061 

Perera, Nicole 1535, 7586 

Peretz, Tamar 10034 

Perey, Lucien e11048 

Perez Callejo, David e11527, 

e12015, e17502, e17515 

Perez Garcia, Jose Ignacio 

10555 

Perez Ramirez, Sara e12003 

Perez Regadera, Jose Fermin 

e15033 

Pérez Segura, Pedro 2045 

Perez Verdera, Palmira 

e11021 

Pérez Villanueva, Heynar 

e20005 

Perez, Cesar Augusto e17564 

Perez, Crystal 2512 

Perez, Diego 602, e11535, 

e14116, e21088 

Perez, Edith A. 605, TPS653, 

LBA1000, CRA1002, 1005, 

1021, 1083, TPS1140^, 

2015, e13501 

Perez, Eloy 9554 

Perez, Francisco Javier 

e11545, e15144, e17545 

Perez, Francisco Jose e11517 

Perez, Iratxe TPS10101 

Perez, Javier e18011 

Perez, Jose Ricardo TPS6640 

Perez, Kimberly 4098 

Perez, Marta 9558 

Perez, Omar D. 2101 

Perez, Quionia e15149, 

e18044 

Perez, Solene 10562 

Perez, Sonia A. 625, 2508, 

e15125 

Perez, Thomas B e21060 

Perez-Carrion, Ramon 1111, 

e11074, e11081 

Perez-Cruz, Pedro Emilio 

9049, e19528, e19584 

Perez-Cruz, Pedro Emilio 

9023 

Perez-Fidalgo, Jose Alejandro 

1074, TPS3637, e11523, 

e14589 

Perez-Garcia, Jose Manuel 

509, 566, 619, 3003, 

3014 

Perez-Gonzalez, Nuria 5520, 

e15094, e18069, e18106, 

e21015 

Perez-Gracia, Jose Luis 

TPS4674, 8572, e15041, 

e18008 

Perez-Moreno, Pablo Diego 

TPS7612 

Perez-Rivas, L.G. 4630 

Pérez-Ruiz, Elisabeth e14115, 

e14116 

Perez-Soler, Roman 7573, 

e18113 

Pérez-Valderrama, Begoña 

TPS4674, e15149 

Perez-Villa, L. 4630, e14115 

Peria, Fernanda Maris 

e12512, e19628 

Pericay Pijaume, Carles 

e14097 

Pericay, Carles 3571, 3586, 

TPS3637, 4079, e14041 

Pericleous, Marinos e14696, 

e17543 

Perin, Alessandra e12037, 

e15160 

Perin, Tiziana 10554 

Perini, Rodolfo F. e13592 

Perisanidis, Beata e14095, 

e14099 

Perkins, Geraldine 10525 

Perkins, Sherrie L 9501 

Perkins, Susan M. 4534, 

e14683 

Perkkio, Mikko 9590 

Perlewitz, Kelly Shea 10011^ 

Perlman, Elizabeth 9534 

Perlroth, Daniella 4666, 

e15186 

Perng, Reury-Perng e18132 

Pernod, Gilles 1580 

Pernot, Simon 4087 

Perol, David 4614, 4625, 

7574, 10006, 10092, 

10095, 10562, e16560 

Perol, Maurice 7574, e16560 

Peron, Julien 601, e14730 

Perona, Rosario 3601, 

e14093, e14144 

Peronto, Erica 6524^ 

Peros, George e21027 

Perotti, Antonella 3080 

Perou, Charles M. 1008, 

1027, 1524, 10500 

Perraud, Yves e15109 

Perrin, Allison e14525 

Perrin, Paul e15182 

Perrino, Matteo 2580, 7061, 

7082, e21139 

Perrone, Federica 10016 

Perrone, Francesco TPS4151, 

LBA5003, e18021 

Perrone, Giuseppe e18021 

Perrone, Tania e19612 

Perrot, Delphine 10014 

Perruccio, Katia e21096 

Perry, James R. TPS2104 

Perry, Matthew 4640, 

e15100 

Persico, Justin e11548 

Persigehl, Thorsten 2541 

Persky, Daniel Oscar 

TPS8109, e18534, e18536 

Persky, Mark 5581 

Person, Bernadette e14148 

Personeni, Nicola e14672 

Pertschuk, Daniel 2101 

Pertschy, Danielle e15540 

Pervez, Nadeem e15540 

Pesavento, Tony e16554 

Pescarmona, Edoardo 1050 

Pesce, Catherine 557 

Pesce, Veronica e14598 

Peschaud, Frederique 8540 

Pesek, Milos e18062 

Pesonen, Sari e13035 

Pestell, Richard G. e13545 

Pestova, Ekaterina e21060, 

e21111 

Petain, Aurélie e13036 

Petekkaya, Ibrahim e11020, 

e11080, e11092, e11509 

Petenko, Natalia N. 2524 

Petermann-Meyer, Andrea 

e19610 

Peters, Ann-Marie e17558 

Peters, Christopher A. 6031, 

TPS9150 

Peters, Godefridus J 10611 

Peters, John 4611 

Peters, Katherine B. 2027, 

2074^, 2090^, 2094^, 

2095^ 

Peters, Lester J. 5571 

Peters, Martin 5005 

Petersen, Gloria M. e14594 

Petersen, Judith A. CRA6009 

Petersen, Peter Meidahl 

e18527 

Petersen, Volker 4065 

Peterson, Amy C. TPS668, 

TPS4695 

Peterson, Gilbert e13571 

Peterson, Lanell TPS3109 

Peterson, Lindsay e14684 

Peterson, Patrick 1068, 7075 

Peterson, Scott 3024 

Peterson, Susan K. e13026 

Petillo, David 4624 

Petillon, Marie-Odile 8014 

Petit, Robert G. 5106, 

e15546 

Petit, Thierry TPS646, 

TPS653, 1051, e11012, 

e11542, e15535 

Petito, Emily 3020 

Petoka, Renana e14731 

Petrakova, Katarina 559, 

e11047 

Petrella, Teresa M. e13049 

Petrelli, Fausto e19612 

Petrelli, Nicholas J. TPS1615 

Petri, Roberto 3612 

Petricoin, Emanuel e14151, 

e15549 

Petridou, Eleni e20002 

Petrik, David W. 6071 

Petrini, Mario 8006 

Petro, Daniel P. 3037, 3049 


Petro, Robin M. 6127 

Petrocelli, Teresa e13107 

Petroff, Brian K. 520 

Petroianu, Andy e12018 

Petroni, Gina R. 3047, 8530 

Petropoulos, Christos J. 603, 

608, 614 

Petros, John e15187 

Petrosiute, Agne 9520 

Petrova, Tatyana e13059 

Petrow, Peter e15524, 

e15535 

Petru, Edgar LBA5000, 5031 

Petruzelka, Lubos B. e11047, 

e14631 

Petry, Christoph 542 

Petry, Vanessa e11513 

Petrylak, Daniel Peter 4522, 

4525, 4656, 4662, 

TPS4675^, TPS4693 

Pettaway, Curtis A. 9031 

Pettengell, Ruth 8056 

Petty, Nathan 8041, e18548 

Petty, Russell LBA4001 

Peuser, Bettina TPS3639 

Peuvrel, Lucie e19019 

Peylan-Ramu, Nili 10034 

Peynircioglu, Bora TPS4148 

Peyrade, Frederic 5516^, 

5521, 6633, e16044, 

e16051, e16055 

Peyrat, Patrice e14730 

Peyro Saint Paul, Helene P. 

TPS667 

Peyton, James D. 7035 

Peyton, Michael e18077 

Pezaro, Carmel Jo 4553, 

e15134, e15136 

Pezet, Denis 10505 

Pezzutto, Antonio e14140, 

e15053, e18552 

Pfeffer, Raphael M. e14143 

Pfeffer, Ulrich e21065 

Pfeiffer, Per 3538, 3548, 

e14053, e14517, e14633 

Pfeiffer, Sebastian 8004 

Pfeiler, Georg 514 

Pfister, David A. e15195 

Pfister, David G. 5509^, 

5514, 5537, 5545^, 6001 

Pfister, Thomas D. 3031 

Pfisterer, Katharina 5572 

Pfreundschuh, Michael 1523, 

6510, 6584, 8004, 8022, 

8024, 8025 

Phalen, Adrien e15164 

Pham, Deborah e15577 

Pham, Huyen e13531 

Pham, Minh Thy e16523 

Pham, Tam 584, TPS10631 

Pham, Thang V e18094 

Phan, Alexandria T. 4085, 

4641, 9002 

Phan, Alexandria 4639 

Phan, Jack 5561, 5589 

Phelan, Vanessa H 5560 

Phelps, Andrea C. 9116, 

9132 

Phelps, Andrea Catherine 

9102 

Phelps, Michael E. 10012 

Philip, Jennifer e16562 

Philip, Philip Agop 3579, 

4019, e14163, e14519, 

e14609, e14610 

Philips, George 4592 

Philips, Santosh 525 

Phillipe, Colucci 6619^ 


Phillips, Callista Maria 

e14001 

Phillips, Christine L. 9581 

Phillips, Claire TPS2104 

Phillips, Jennifer 6584 

Phillips, Joanna J 2026 

Phillips, Jonathan 4060 

Phillips, Kelly-Anne TPS1136, 

1502, 9022 

Phillips, Larry 3087 

Phillips, Luann 9547, 

e18522 

Phillips, Martin 5062^ 

Phillips, Paula 6108 

Phillips, Penny 3572 

Phillips, Teresa A. 520 

Phillips, Tycel Jovelle 9085 

Phipps, Amanda I. 3526 

Phoenix, Timothy 9518 

Phuan, Crystal e14155 

Phung, Yen e14118 

Phuphanich, Surasak 2080, 

2084, 2087, TPS2107 

Piacentini, Federico 631 

Piana, Raimondo 10055 

Pianetti, Gerson Antonio 

e13008 

Pianowski, Luiz F e19552 

Piao, Yongzhe 4092, e14575 

Piao, Yuji 2011 

Piato, Jose R. e11513 

Piazik, Breanne Lee 6013 

Piazza, Dario e14676 

Picaud, Francois 601 

Piccaluga, Pier Paolo e13569 

Piccart-Gebhart, Martine J. 

507, 512, 540, 551, 559, 

596, 604, TPS649, 1022, 

3559, e13605, e21010 

Picci, Piero 10022, 10079 

Picciotti, Giovanna 9098 

Piccirillo, Maria Carmela 

e14130 

Piccolini, Ezio 7084 

Pichinuk, Edward e13018 

Pichler, Josef 2034 

Pichler, Martin e14066, 

e18525 

Pichon, Audrey e15145 

Pichon, Christophe e21138 

Pickering, Curtis R. 5524 

Pickett-Gies, Cheryl Ann 529 

Picone, Antonio e18039 

Picone, Giuseppe e12512 

Picozzi, Vincent J. 4038 

Picus, Joel 3047, 4118, 

4571, 10088 

Piderman, Katherine M. 1610 

Piedmonte, Marion 1519 

Piekarz, Richard 2553, 7103, 

9144, e19633 

Pienkowski, Tadeusz 9046, 

e11553 

Pier, Thomas e13537 

Pierantoni, Chiara e21070 

Pierce, Aisling 622, 1042 

Pierce, Sherry 6544, 6578, 

6597, 6603, 6607 

Pierga, Jean-Yves TPS646, 

10562 

Pieri, Gabriella 5513 

Pierobon, Mariaelena e14151, 

e15549 

Pierotti, Marco TPS9155 

Pierpoint, Ann 3043 

Pierre, Andrew 9032 

Pierre, Bonnette e18102 

Pierron, Gaëlle 9510 

Pierson, Namali e17012 

Pietanza, Maria Catherine 

7014, 7052, 7527, 

e17558, e19647 

Pietra, Claudio e19577 

Pietrabissa, Andrea e13103 

Pietragalla, Antonella 5059 

Pietrantonio, Filippo 7581, 

e21118 

Pietri, Elisabetta e11054 

Pietrobon, Ricardo e14544, 

e14562 

Piette, Francois e18505 

Pietzner, Klaus 5080, 

e15531 

Pignata, Sandro LBA5003, 

5017^ 

Pignochino, Ymera 10066 

Pignon, Jean-Pierre 3063, 

3507, 4032, 7007, 10556 

Piha-Paul, Sarina Anne 3106, 

3107^, 8551, 10510, 

10607, e13020, e13595 

Pike, Ian e21091 

Pike, Laura 6527, e13541 

Pikul, Frank e16513 

Pilcher, James 4640 

Pilegaard, Han Kristian 7001 

Pilegaard, Hans e21110 

Pileri, Stefano A e13569 

Pileri, Stefano 8006 

Pilger, Adak e19597 

Pilgrim, Charles Henry Caldow 

TPS3643 

Pili, Roberto 4550, 4619, 

4665, TPS4687, 10609, 

e15042, e15058 

Pilla, Lorenzo 8513, 8529 

Pillai, Raji 10584 

Pillai, Rathi Narayana 10625 

Pillay, Sada 2042 

Pilling, Amanda B. 7504 

Pilon-Thomas, Shari 2511 

Pilotti, Silvana 10026 

Pilotto, Sara 630 

Pilz, Korinna 3018^ 

Pimentel, Richard 9561 

Pin, Elisa e14151 

Pina, Filomena e14673 

Pinato, David James 2608, 

3022, e13033 

Pinchev, Mila 1578 

Pinder, Mary Colleen 7065, 

e17559 

Pinder, Sarah TPS665 

Pineda, Estela 3536 

Pineda, Rosa 1120 

Pingpank, James F. e14184 

Pinhal, Maria Aparecida Silva 

10568, e13016, e21151 

Pinheiro, Laura C 6001, 

6101 

Pinho, Marco C 2009, 2012, 

2025, 2059, 3036 

Pinilla-Ibarz, Javier 6503, 

6568, 6575, 6588, 6605, 

6608 

Pink, Daniel 10032^ 

Pink, Desmond B. e21090 

Pinker-Domenig, Katja 10570 

Pinna, Antonio Daniele 4110 

Pinney, Emmett e21051 

Pino, Maria Simona e14661 

Pinotti, Graziella LBA4001 

Pinski, Jacek K. e15153 

Pinson, Stephane 10049 

Pinter, Matthias e14681 

Pinter-Brown, Lauren C. 

8028, 8060 

Pintilie, Melania 5105, 9131, 

e14535 

Pinto Marin, Alvaro TPS4672 

Pinto, Antonio 8066, 8083 

Pinto, Carmine e14040, 

e14042, e14113, e18021, 

e19592 

Pinto, Flavio Augusto Ismael 

643, e14680, e18078 

Pinto, Joseph A. 1024, 2097 

Pinto, Joseph e11066, 

e11518 

Pinto, Navin R. 9516 

Pinto, Peter A. TPS4680, 

TPS4701 

Pinton, Sandra 4661 

Piperdi, Bilal e18113 

Piperno-Neumann, Sophie 

8532, 8546, 10005, 

10006, 10023, 10056 

Piperopoulou, Fani 

Athanasiadou e20002 

Pippen, John E. 547 

Piras, Alessandra 9006 

Pircher, Tony J 584, 

TPS10631 

Pires Da Silva, Ines Esteves 

Domingues 8571 

Pirker, Robert 7007 

Pirl, William F. 6004, 6048, 

6062, 6076, 6106, 9016, 

9030, 9101 

Piro, Eugenio e18564 

Pirolli, Melissa 1581 

Pirollo, Melanie 6021 

Pirooz, Nicholas 8010 

Pirron, Ulrich TPS6643^ 

Pirtoli, Luigi e13098 

Pirvulescu, Cristina 541 

Pirzkall, Andrea 2567, 2568, 

5575, e13048 

Pisa, Federica Edith 3612 

Pisanello, Anna 2057 

Pisano, Carmela LBA5003 

Pisansky, Thomas Michael 

4595 

Piscopo, Giovanna e11052, 

e13539 

Pishvaian, Michael J. 2590, 

3095, TPS3638, e14009, 

e14569, e14658 

Pisle, Stephen T 4671 

Pistamaltzian, Nikolaos 

Fragkiskos e11519, 

e15125 

Pistelli, Mirco e14663 

Pisters, Katherine 9072, 

e18018 

Pisters, Louis L. 9029 

Pisters, Peter W. T. 10088 

Pistola, Lorenza e18101, 

e21094 

Pitcher, Brandy 6015 

Pitini, Vincenzo e18039 

Pitot, Henry Clement 2510 

Pitou, Celine 3001 

Pitsiava, Dimitra e14567 

Pitt, Michael 4555 

Pittaluga, Stefania 8051 

Pittman, Kenneth B. 7512, 

e17544, e19513 

Pitz, Marshall W. 2051, 

e17518 

Piulats Rodriguez, Jose Maria 

LBA4518 

Piva, Eleonora 627 

Pivot, Xavier B. 568^, 597^, 

1567, 1568 

Piwnica-Worms, David 503 

773s

Piwnica-Worms, Helen 3047 

Pizzo, Fabrizio TPS9155 

Pizzolitto, Stefano 3612 

Plakovic, Mary K. 9094 

Plamondon, Louis 1055 

Plana, Maria e18030 

Planchard, David 7531, 

7557, 10556 

Plancher, Corine 8546, 

e15535 

Planci, Kezban Nur e14698 

Plante, Marie 5001 

Plastino, Francesca e14156 

Platero, Suso J. e17541 

Platica, Ovidiu e12016 

Platt, Jonathan J e14054 

Platten, Michael 2000 

Platz, Timothy Alan e14712 

Platzek, Ivan 10068 

Plaza, Carlos 4040 

Plazaola, Arrate 1001, 

10500, 10512, 10595, 

10616 

Plescia, Janet e13504 

Plesner, Torben 8019 

Pless, Miklos e18012 

Plessis, Virginie TPS9154 

Plestina, Stjepko 9097 

Pleyer, Uwe 2054 

Plimack, Elizabeth R. 

TPS2618, 4526, TPS4679, 

e19580 

Ploeen, John e14134 

Ploquin, Anne 2540 

Plotkin, Scott Randall 6136 

Plotti, Francesco 5093, 

5094, e15547, e15550, 

e15551, e15553 

Pluard, Timothy J. 534, 3047 

Plummer, John 2604, 

TPS9153 

Plummer, Ruth 2552, 3000, 

3048, 3051, 3052, 3100 

Plunkett, William 6528 

Pluschnig, Ursula 10570 

Pluzanski, Adam e12011 

Poch, Michael Adam e15203, 

e15204 

Pochettino, Paolo 10055 

Podda, Maurizio 8505 

Poddubnaya, I. e20501 

Poddubnaya, Irina e11528 

Podolski, Paula e21126 

Podratz, Karl C. 5004 

Poeschel, Viola 8022, 8024, 

8025 

Poestlberger, Sabine 514 

Pogge von Strandmann, Elke 

8079 

Poggi, Rosalba 2057, 2061 

Pognan, Francois 9562 

Pogoda, Katarzyna e11553 

Pohl, Gerhardt 7101 

Pohlman, Brad L. 8055, 

8081 

Poillucci, Victoria 2074^ 

Pointreau, Yoann 5505 

Poire, Xavier 6582 

Poiree, Maryline e20006 

Poissonnet, Gilles 5521, 

e16044, e16055 

Poklepovic, Andrew Stewart 

e21058 

Poku, Kofi 639 

Polascik, Thomas 4670 

Polaskova, Pavlina 2009, 

2012, 2025 

Polcari, Anthony e16544 

Polders, Larissa 8532 

Poli, Rossana 4097 

Polikoff, Jonathan TPS657, 

LBA1000, 4550 

Polite, Blase N. 2561, 6137, 

e16509 

Polivka, Marc 2023 

Polivka, Valentine 10027, 

e16036 

Pollack, Jonathan e14037 

Pollak, Michael N. 519, 538, 

561, e15118 

Pollard, Stephanie e15054 

Pollett, Aaron 5026 

Polli, Anna 7533, 7599, 

7600 

Pollmanns, Anke 552 

Pollock, Brad H. e16566 

Pollock, Raphael E. 10000 

Polo, Valentina 7082 

Polsky, David 8574, e19003 

Polterauer, Stephan 5111 

Polycarpe, Emmanuel 

Mohandas e19500 

Polychronis, Athanasios 583 

Polychronopoulou, Sophia 

e20002 

Polyzos, Aristidis 7564 

Polyzos, Nikolaos P. 5066 

Poma, Allen 9077 

Pomel, Christophe 568^ 

Pomerantz, Mark M 4543, 

4635 

Pommier, Pascal e16036 

Pommier, Yves 3031 

Pompei, Luciano e12514 

Pompili, Alfredo 2085 

Pompili, Cecilia e21070 

Pompilus, Farrah e12515 

Pon, Vickie e15154 

Ponce, Mario e18109 

Pond, Gregory Russell 4522, 

4644, 5587, 9021, 

e21083 

Pondenis, Holly e21145 

Poniewierski, Marek S. 6129, 

9135 

Ponniah, Sathibalan 625, 

2508, 2529 

Pons, Francesc e15007 

Pontes Valero, Maria Jose 

10013 

Ponti, Antonio 4110 

Ponto, Sarah Nicks 6020 

Ponzone, Riccardo 627 

Pook, David William e15056 

Pool, Mark 7067, e18117 

Poole, Christopher John 

TPS654^, TPS665, 5001, 

5046, e11062 

Poole, Karen 6091, e16007 

Poon, Darren M. C. e15110 

Poon, Donald 6100, 10051, 

e20509 

Poon, Jensen T.C. e14032 

Poon, LM 6540 

Poon, Patricia 5511 

Poon, Ronnie Tung Ping 

e14545 

Poon, Ronnie Tung Ping 

4103, TPS4147, TPS4149 

Poon, Ronnie Tung-Ping 4108 

Poonamallee, Uday e21026 

Poortmans, Philip M. 8039 

Pop, Marius e15535 

Pop, Simona e13017 

Popa, Mihaela A. 2528 

Popa, Xitlally 2527 

Popalzai, Muhammad Jawad 

e14704, e18574 

Popat, Sanjaykumar 7081 

Popat, Uday R. 6540, 6546, 

8040, 8102 

Pope, Janice 549^, 582 

Pope, Lorna 3022, 10525 

Popiel, Brenten e14012 

Poplawska, Lidia e18512 

Popovic, Kosta e19062 

Popovici, Vlad Calin 3509, 

3511, 3575 

Popplewell, Leslie 6545, 

6582 

Porat, Yaara e14616 

Porcu, Luca 4629 

Porcu, Pierluigi e18508 

Porfiri, Emilio e15091 

Porneuf, Marc e14148 

Porntepkasemson, Apirudee 

e19608 

Porrata, Luis F. 8600 

Porrati, Paola 2083 

Porro, Maria Grazia 2543 

Porsok, Stefan e19020 

Porta, Camillo 4006, 

CRA4502, 4541, 4627, 

TPS4683 

Porta, Rut 7542, e18137, 

e18143, e19542 

Portales, Fabienne 3633 

Portell, Craig Anthony 8071 

Porter, Aaron T. 6034 

Porter, Christopher R. 4669, 

e15207 

Porter, David L. e18540 

Porter, Jennifer 7525, 7588 

Porter, Ryan Frederick 7032, 

7107, 7108 

Portera, Chia C. 3543, 3552 

Portier, Bryce P. 620 

Portnow, Jana 3108 

Portuesi, Rosa Alba Valentina 

5094, e15550, e15553 

Portwine, Carol 9556 

Posada, Juan G. 10037 

Posadas, Edwin M. 4586, 

4654 

Posner, John 3100 

Posner, Marshall R. 5501, 

5582, e16060 

Posner, Mitchell 10090 

Possinger, Kurt e14140 

Post, Sean M. 10506 

Postelnick, Michael J 2532 

Postigo, Antonio e21035 

Poston, Graeme John 3508, 

3613 

Postorino, Maurizio e18564 

Postow, Michael Andrew 

2518, 8515, 8549, 8575 

Potenza, Enrico e18026 

Pothuri, Bhavana 5016 

Potkul, Ronald e13121 

Potler, Hannah 1026 

Potosky, Arnold L. 4651, 

6006, 9130 

Pott, Dirk 4065 

Potter, Beth e21066 

Potter, Kristin 9571 

Potter, Nicholas 3580 

Potter, Vanessa 7013, 7583 

Potts, James 9529 

Potvin, Kylea R. 1036 

Potz, Brittany 557 

Pouessel, Damien LBA4567^ 

Poulot, Virginie e18075, 

e18089 

Poupon, Marie-France e15161 

Pourtsidis, Apostolos e20002 

Poveda, Andres LBA5002^, 

5068, 10079, e15575 

Powazniak, Yanina e14109 

Powderly, John 4505 

Powell, Alex 10067 

Powell, Arfon e14110 

Powell, Bayard L. 6524^, 

6526 

Powell, C. Bethan 5022 

Powell, Eric 4041 

Powell, Erin Diana e14073 

Powell, Isaac 1560 

Powell, Matthew A. 5013, 

5101 

Power, Derek Gerard 1559, 

2062, e14666, e14687, 

e15078, e16506, e19059 

Power, Derek G e11569 

Powers, David e16513 

Powers, Jacquelyn 1506 

Powers, Jay P e13580 

Powers, Jean 7093 

Powers, John Joseph 6575 

Powers, Penny 10509 

Powles, Thomas 4529, 4611 

Pozdnyakova, Victoria e19049 

Pozo-Kaderman, Christina 

e19646 

Prabhash, Kumar 5585, 

e13068, e13127, e16021, 

e16028, e17500 

Prabhu Das, Irene 6046 

Prabhu, Aruna Laxman 1108, 

e11552 

Prabhu, Roshan Sudhir 2047 

Prabhu, Sujit S. 2019 

Prabhudesai, Shilpa A. 

e11043, e12030 

Prachand, Vivek N. 10090 

Pracht, Marc e19037 

Prado, Yolanda e11042 

Prados, Michael 2026 

Prady, Catherine 1036 

Praet, Michel TPS4140 

Prager, Gerald e15083 

Prakash, Deepa Meda e21132 

Prakash, Gaurav e18518 

Pramana, Setia 4561 

Prashanth, Gothlu 

Ramachandra e14675, 

e14721 

Prashanth, Jayanna e11511 

Prasnikar, Nicole 4083, 4090 

Prat, Aleix TPS656, 1008, 

1524, 10500 

Prati, Veronica e15073, 

e15133 

Pratschke, Johann e14719 

Prausová, Jana 3505 

Prayer, Daniela 2053 

Prayson, Richard 2014 

Prearo, Fernando Mauro Lima 

e19537 

Prébet, Thomas 6523 

Precivale, Maristela 7506 

Preet, Mohan e15097, 

e18504 

Prendergast, Brendan M 

e14555 

Prentice, Ross L 1501 

Presant, Cary A. e11562, 

e13003 

Prescott, Stephen 4 

Presley, Carolyn J. 1030 

Presley, Chris e17529 

Press, Michael F. 4010 

Press, Oliver W. 8001 

Pressler, Heather M 4671 

Preston, Megan e15585 


Pretet, Jean-Luc 10507 

Preusser, Matthias 2024, 

2053, 2071, e21033 

Price Hiller, Julie A. e14073 

Price, Alicia e21045 

Price, Allan 7081 

Price, Douglas K. 3043 

Price, Gregory 7101 

Price, Karen N. 504, 9022 

Price, Samantha e18509 

Price, Timothy Jay 3504, 

3515, 3534, 3535, 3572, 

3578, e13007, e19513 

Priebe, Anna M. e15568 

Priebe, Waldemar e18557 

Priedane, Eugenia e14061 

Priego, Victor M. 1018 

Priest, John R. 9521, 9522 

Prieto, Veronica E e14734 

Prieto, Victor 8537 

Prigerson, Holly Gwen 6012, 

9015, 9037, 9102, 9146, 

e16500 

Prim, Nathalie 10507 

Primrose, John Neil 3508 

Prince, Jenny 3022 

Prince, Mark E e16014 

Princet, Isabelle e19555 

Prinsen, Hetty 9070 

Prinzler, Judith 523, 1023 

Prior, Celia e15041 

Prior, John 10033 

Priou, Franck LBA4567^, 

4583 

Pritchard, Kathleen I. 500, 

512, 524, 538, 539, 540, 

551, 559, 561, 596, 604, 

6049, e19545 

Pritchard-Jones, Kathy 9510 

Privett, Melissa C. 5014 

Probst, Stephan 4083, 4090 

Procopio, Giuseppe 4627, 

4629 

Proctor, Janie e15054 

Proia, David A 3090 

Prokai, Laszlo e13557 

Pronzato, Paolo 579, 7577, 

e21065 

Proost, Johannes H 4528 

Propert-Lewis, Cerys 10039 

Prost, Jean-Francois 5069 

Protheroe, Andrew 4599 

Protsenko, Svetlana e13059 

Protter, Andrew A 564, 3072 

Proux, Laetitia 3547 

Provan, Pamela 550 

Provencher, Louise 634, 

LBA1000, 1025, 9138 

Provencio, Mariano 1531, 

6633, 7540, 8062, 

e11035, e11527, e12015, 

e17503, e18011, e18521 

Provencio-Pulla, Mariano 

e17502, e17515 

Proverbs-Singh, Tracey 

e19621, e21016 

Prudkin, Ludmila 7041 

Prudkin, Ludmilla 509 

Pruneri, Giancarlo 519, 546 

Pruvot, Francois-Rene 3506 

Pryma, Daniel A. e13592 

Przybyl, Joanna 9536, 10538 

Przybylo, Jennifer A. e15022 

Pshak, Thomas J. e15176 

Psyrri, Amanda 573, 5574, 

5576 

Ptaszynski, Konrad 10538 

Pu, Xia 7608 


Puccetti, Maurizio 10601, 

e18045 

Puchades Roman, Iciar 

e14097 

Puchalski, Thomas 2583, 

3059 

Puchtler, Gerhard 3588 

Puduvalli, Vinay K. 2003, 

2022, 2029^, 2030, 2036, 

2064 

Puente, Javier TPS4674, 

10564, e15041 

Puertolas, Teresa 10512, 

10595 

Puggina, Anna e18010 

Puglisi, Fabio 1044, e13058, 

e13070, e15091 

Puglisi, Martina 3004 

Puhalla, Shannon 1038, 

3049 

Puhlmann, Markus 4606, 

5038 

Pujade-Lauraine, Eric 

LBA5000, LBA5002^, 

5018, TPS5112, 9079 

Pujol, Eduardo e18015 

Pujol, Jean-Louis 7013, 

LBA7507 

Pulido, Marina e14023 

Pulignano, Giovanni 645 

Pulitzer, Melissa 8515 

Pulivarthi, Kalyan 9127, 

e19599, e19643 

Pulvirenti, Alfredo 1007 

Puma, Francesco e21094 

Pun, Yat Wa 7011 

Pundalika, Mohan e19619 

Punglia, Rinaa S. 6022 

Pungliya, Manish e18041 

Punnoose, Elizabeth e21122 

Punt, Cornelis J. A. e13111 

Puntoni, Matteo 519 

Pupic, Gordana e21136 

Pupo, Alexandra e14673 

Purcell, Fay M. e14582 

Puri, Tarun 2072 

Purim, Ofer e14067, e14571 

Purohit, Om Pra-Kash 511 

Purvis, Joseph D. TPS4134 

Pushpalatha, 

Kameshwarachari e15518 

Pusic, Andrea 9042, 9043 

Pustowka, Annette 10031 

Pusztai, Lajos 515, 545, 581, 

612, 1012, 1047, 10559, 

10613 

Putnam, Joe B. 4062, 7008 

Putt, Mary e18507 

Puttabasavaiah, Suneetha 

1557 

Puttawibul, Puttisak 551, 

e14639 

Putter, Hein 516, 517, 526 

Puyraveau, Marc 7057 

Puzanov, Igor 3102, 4117, 

4506, 4545, 8501, 8510, 

8519 

Pyle, Doug e16505 

Pyman, Jan 5073 

Pyo, Hongryull 7004 

Pytel, Peter 9534 

Pytynia, Kristen B. 5528 

Pöttler, Marina e15083 

Q 

Qaqish, Bahjat F. 6093 

Qazilbash, Muzaffar H. 6546 

Qazilbash, Muzaffar 8040, 

8102 

Qi, Huanpeng e13524 

Qi, Jing 2541, e13064 

Qi, Lin 4628 

Qi, Yingwei 7555, 7605, 

e13052 

Qi, Yuan 545 

Qi, Zhengyun 4612 

Qian, Dapeng e21131 

Qian, Jiang 2013, 3532, 

7512 

Qian, Mark 3077 

Qian, Meng 8574, e19003 

Qian, Wendi 4121 

Qian, Xiaoping 4068, 

e14509, e21034 

Qian, Ximei e21161 

Qian, Yi e15172 

Qiang, Zhou e14648 

Qiao, Wei 2011, 3598, 9072, 

10021 

Qin, Jing e14575, e17512 

Qin, Li-Xuan 10002, 10003, 

10004 

Qin, Na e18142 

Qin, Qin 3532 

Qin, Rui 1557, 4047, 4099, 

5025, 5077, e15132 

Qin, Shukui TPS649, 

LBA4537, 7559, 8554, 

e18100 

Qin, Xinyu 4092, e14575 

Qin, Yangda 5558 

Qiu, Ji Qing 10543 

Qiu, Meng 4638 

Qiu, Miao-zhen e14655 

Qiu, Xiaoping 1535, 7586, 

10522 

Qiu, Xin 1535, 6005, 7586 

Qu, Angela Q. 4522, 4525 

Qu, Jinrong TPS2619 

Qu, Kevin Z. 8596 

Qu, Kevin 5510 

Qu, Tao e14502, e14668 

Qu, Xiaoyu e15207 

Qu, Zengqiang 4008 

Quaas, Alexander 2504 

Quadrini, Silvia e14082, 

e18065, e18072 

Quadt, Cornelia 508, e13605 

Quaglia, Alberto e21091 

Quah, Thuan Chong e20003 

Qualls, Clifford 1558 

Quan, Lan-Ping e14502 

Quant, Eudocia Carmen 2009 

Quaranta, Annamaria e11547 

Quaresma, Luisa e14673 

Quarshie, William O. 7037 

Qubaiah, Osama M. e17010 

Queenan, Maria B e19016 

Queirolo, Paola 8511, 8513, 

8517, 8529, 8573 

Quek, Marcus Lee e15008, 

e15014 

Quek, Richard Hong Hui 

1593, 8078, 10051, 

e18515, e18546, e20509 

Quellhorst, George J e21011 

Quenet, Francois 3633 

Quer, Miquel 5590, 5595 

Queralt, Bernardo 4079, 

e14120 

Queralt, Cristina 7540, 

10596 

Quereshy, Fayez A. e14032 

Quereux, Gaelle e19019 

Querleu, Denis 5083 

Quero, C. 4630 

Querzoli, Patrizia 10554 

Quesada, Jose e15036 

Quesenberry, Peter J. 

e21116, e21157 

Quevedo, Paloma e11517 

Quiao, Rui Fang e15191 

Quick, Donald 8073 

Quigley, Jane 1581 

Quijano, Yolanda 602, 4040 

Quillin, John 1563 

Quimbo, Ralph A. e16542 

Quindós Varela, Maria 

e15076, e15077, e15079 

Quinn, Cecily 1042 

Quinn, David I. 4, 4506, 

4511, 4547, 4563, 4663, 

10503, e13084, e13531, 

e15005, e15153 

Quinn, Gwendolyn P. e21155 

Quinn, Michael TPS5116 

Quinn, Raven 7035, 7567, 

7587, 10530, e21023 

Quinn, Ryan e13555 

Quinn, Ryann 8036 

Quinn, Stephen 2604, 

TPS9153 

Quinn, Tim e21085 

Quintana, Ana 5590 

Quintana, Maria Jesus 1120, 

5595 

Quintanal, Nelson 2515 

Quintanilla-Fend, Leticia 

8526 

Quintas-Cardama, Alfonso 

6527, 6587, 6589, 10506 

Quinten, Chantal 6002, 

6090, 7607 

Quintero, Guillermo e18070 

Quintyne, Keith Ian e16551 

Quiring, John e14501 

Quirino, Michela e16553 

Quiroz, Anteo 8580 

Quoix, Elisabeth A. TPS7111, 

TPS7610 

Quoix, Elisabeth 7057, 

10507 

Quon, Doris 3015, 10036 

Quon, Harry e16062 

Quon, Jennifer L. e15150 

Quon, Peter 6553 

Qureshi, Sofia 8102 

Qureshi, Zaina P. e19639 

Quyyumi, Arshed e21045 

Qvortrup, Camilla 3538, 

e14053 

R 

R, Nalini Kilara e11536 

Raab, Marc 8020 

Raab, Rachel Elizabeth 

e11550 

Raad, Roy e20004 

Raba, Katharina e21017, 

e21020 

Rabah, Raja 9578 

Rabascio, Cristina 2083 

Rabault, Bertrand e13605 

Rabbe, Nathalie e18075 

Rabbitt, Jane E 2026 

Rabe, Kari G. 6571 

Raben, Adam 5530 

Raben, David 7018 

Rabeneck, Linda e12034 

Raber, Martin N. 4130, 4131 

Rabey, Jonathan e15042 

Rabin, Michael S. 7553, 

7588, 10592, e18018 

Rabin, Tatiana e14143 

Rabinovitch, Rachel TPS657, 

TPS9150 

775s

Rabinowits, Guilherme 5501, 

5582, 9086 

Rabossi, Guillermo e14109 

Raby, Samuel 10530, 

e21023 

Raca, Gordana 6562 

Racadot, Severine e14730, 

e16036 

Rack, Brigitte Kathrin 554, 

1072, 1081, 1090, 1600^, 

1602, 10540, 10599 

Radebach, Katrina 5523 

Radecka, Barbara 505, 603 

Rademaker, Alfred 610, 

3083, 6623 

Rader, Janet Sue 5101 

Rader, Michael E. 4642, 

e15172 

Radford, John A. 8056 

Radhakrishnan, Deepa 1508 

Radhakrishnan, Kavita 6537 

Radheshyam, Nayak e11027 

Radhi, Saba e21105 

Radich, Jerald P. TPS6636 

Radinsky, Robert 3580 

Radjabi, Amir Reza e15576 

Radona, Marietta 3007 

Radosa, Marc P. e15566 

Radosavljevic, Davorin 

e12020 

Radova, Lenka 1087 

Radovich, Milan 7032, 7107, 

7108 

Radu, Aurelian e21138 

Radulovic, Sinisa e12020 

Radvanska, Eva 9592 

Radvanyi, Laszlo George 

8514, e19014 

Radwan, Rachel R e15565 

Radzikowska, Elzbieta 4632 

Rae, Frances TPS10633^ 

Rae, James M. 525 

Raefsky, Eric 1086 

Raemaekers, John M. M. 

8039 

Raetz, Elizabeth A. 9507, 

CRA9508, 9543, 9548 

Raez, Luis E. 5500, 5503, 

e13032, e17564 

Raffel, Glen 6569 

Raffeld, Mark 2503^, 

TPS7609, e18568 

Rafferty, Stephen W 4671, 

e15167 

Rafferty, Teresa 535 

Raffy, Olivier 1574, TPS7111 

Rafi, Rezvan 1009 

Rafii, Saeed 5046, e11062 

Raftopoulos, Harry e19635 

Ragab, Anan 3050 

Raghav, Kanwal Pratap Singh 

3544 

Raghavan, Derek 4 

Raghavendra, Akshara 1124 

Raghavendra, Rao M. 1093, 

e11043, e11511, e12030 

Ragulin, Yury 7558 

Ragulin-Coyne, Elizaveta 

e14691 

Ragusa, Mark e21094, 

e21096 

Raha, Paromita 3058 

Rahal, Arslane Skander 

10044 

Rahal, Chahinez 10044 

Rahal, Chahineze 10062 

Rahatli, Samed e11011, 

e11023, e11026, e11045, 

e11515, e14174, e15572, 

e15573 

Rahili, Amine 5075 

Rahma, Osama E. 2577, 

2578 

Rahman, Mahbubur e14008 

Rahnenfuehrer, Joerg 10551 

Rai, Hema e21114 

Rai, Shesh e16545, e21144 

Railey, Elda 6053 

Raimondo, Luca 5546, 5548 

Raimundo, Karina 6583 

Raina, Vinod 6593, e11013, 

e17505, e17511, e18518, 

e18573 

Raines, Ronald T. TPS3113 

Rainfray, Muriel 9012 

Raisch, Dennis W 2532, 

4063 

Raiti, Concetta e13019 

Raizer, Jeffrey J. 2006, 2035 

Raj, Ganesh 4616, TPS4678 

Raj, Renju V. e16503 

Raja, Madras A. e20508 

Raja, Rajiv 5575 

Rajagopalan, Prabhu 3012, 

3019, 3046, 4050, 4103 

Rajan, Arun 7033, 7103, 

TPS7609 

Rajan, Sabrina 544 

Rajan, Sudhan e19619 

Rajangam, Kanya 8035 

Rajapaksa, Ranjani 2513 

Rajaram, Veena e20001 

Rajdev, Lakshmi e14019 

Rajec, Jan TPS4677, e15028 

Rajguru, Saurabh e14554 

Rajkovic, Aleksandar 1501 

Rajkumar, Krishnappa 

e14675 

Rajkumar, S. Vincent 

TPS8116 

Rajkumar, Vincent 8096, 

8105 

Rajpar, Laetitia 10556 

Raju, Robert N. TPS3111 

Raju, Savitha e15565 

Rajurkar, Swapnil Padmakar 

e11562, e13003 

Raker, Richard K e13066 

Rakovitch, Eileen 1123 

Rakus, John Frank e19018 

Rakyan, Vardhman 10550 

Ram, Prahlad T 8530 

Ramacci, Carole TPS10634 

Ramadori, Giuliano e13039, 

e14707, e21128 

Ramaekers, Ryan C. 9110 

Ramaiya, Nikhil H. 7553 

Ramakant, Pooja e19562 

Ramakrishna, Satvik 7054 

Ramalingam, Ashok TPS9150 

Ramalingam, Lekshmi 

e14184 

Ramalingam, Suresh S. 2576, 

3049, 3094, 7048, 7059, 

7512, 7516, TPS7613^, 

TPS7615, 10625, e21045 

Ramalingam, Suresh S 5560, 

5570, 7097 

Ramamoorthy, Sonia e14069 

Ramamurty, S e13522 

Raman, Siva P 4045 

Ramanathan, Michelle Leana 

e14092 

Ramanathan, Muthalagu 6569 

Ramanathan, Ramesh K. 

2579, 3019, 3033, 3037, 

3060, 4013, 4019, 

e13576 

Ramani, Rupal 9034, 9109, 

9123 

Ramchandren, Rod 8028 

Ramée, Jean François 

LBA3500^, e14148 

Ramfidis, Vassilios e17557 

Ramies, David A. 535, 4007, 

4504, 5547, 7514, 8531 

Ramirez Morales, Rafael 

e14563 

Ramirez, Amelie G. e16566 

Ramirez, Arturo e21148 

Ramirez, Jacqueline 2611 

Ramirez, Jose Luis 10596 

Ramirez, Mildred M. 6116 

Ramirez, Nicolas e11565 

Ramirez, Robert A. 7072^, 

e17531^ 

Ramirez-Fort, Marigdalia K. 

e19624 

Ramirez-Morales, Rebeca 

e12027 

Ramlau, Rodryg 3579, 

LBA7000, 7090, 9117 

Ramnath, Nithya 2602, 

e17535, e18118 

Ramnauth, Hemwattie 

e19004 

Ramon y Cajal, Santiago 566, 

3014, 7041 

Ramon y Cajal, Teresa 1120, 

10555, e18057 

Ramondetta, Lois M. 9134 

Ramondino, Stefano 5096 

Ramos Vazquez, Manuel 

10616, e15067, e15076, 

e15077 

Ramos, Alexis 10502 

Ramos, Carlos Almeida 2558 

Ramos, Clarissa CA e15562 

Ramos, Rafael 10079 

Ramos, Teresa e14147 

Ramos-Lamboy, Valmarie 

e11015 

Rampello, Elvira e13019 

Rampersaud, Edward N. 

e13045 

Rampias, Theodoros 5574 

Ramsey, Sara 3041, 3097 

Ramsey, Scott David 6007, 

6077, e14068, e14141, 

e14146, e15175, e15183, 

e16524, e18097 

Ramsey, William Jay 2571, 

e19008 

Ramskold, Daniel 10539 

Rana, Durgesh N e15011 

Rana, Vishal 8096 

Ranasinghe, Weranja Kalana 

Bodhisiri e15117 

Ranchicchio, Prabha e18074 

Randolph, Sophia 8520 

Rane, R. C. 3089^ 

Ranganathan, Anjana 7077, 

7092 

Ranganathan, Gayatri 6553 

Ranganathan, Sulabha 531 

Rangel, Claudia e18028 

Ranger-Moore, Jim 4041 

Rani, Sweta 617 

Ranieri, Girolamo e21113, 

e21134 

Ranki, Annamari 8076 

Ranki, Tuuli e13035 

Rankin, Cathryn J 4113 

Ransom, David e13007, 

e16004 

Ranson, Malcolm 3000, 

3004, 3030, 3048, 3051 

Rao, Archana C. e11089 

Rao, Chandra 7092, 10533 

Rao, Ganesh 2019 

Rao, Gautam G. e16546 

Rao, Manoj e15014 

Rao, Nalini K 1093, e11027, 

e11511, e12030 

Rao, Nikhil G 5564 

Rao, Rekha 10549, e13568 

Rao, Shantha 512 

Rao, Shyam S. 5537, 5545^ 

Raoelfils, Ines 543 

Raoul, Jean Luc LBA4003 

Raoul, Jean-Luc 4118 

Rapalino, Otto 2059 

Rapetti, Simonetta e18103 

Rapisardi, Stefania e15544 

Rapke, Tal e15152 

Raponi, Mitch 4041 

Rapoport, Aaron e19565 

Rappold, Erica 596 

Raptis, Anastasios 6563 

Raptis, George e21032 

Rasalan, Teresa 2518 

Rasche, Herbert 6610 

Rasco, Drew Warren 2512, 

3001, 3019, TPS3110, 

e13025, e13602, e18076 

Rashid, Asif e14662 

Rashtian, Afshin TPS9150 

Rasinski, Kenneth 9586 

Rask, Sara e14001 

Raskin, Leon e12026 

Rasmussan, Karen 3630 

Rasmussen, Erik 5072 

Raso, Maria G 7023 

Raspagliesi, Francesco 

LBA5003, 5096 

Rastelli, Francesca 9098 

Rastogi, Priya LBA506, 

LBA1000, 1025, TPS1142 

Rastogi, Shishir 9580 

Ratain, Mark J. 2533, 2611, 

6117, e13106 

Ratanatharathorn, Voravit 

6549 

Rath, G K e15518 

Rath, Goura Kishore e11082 

Rath, Goura Kishor 2072 

Rath, Michelle Genevieve 

1547 

Rath, Niharika e14632 

Rathbone, Dustin 10002 

Rathkopf, Dana E. 4513, 

LBA4518, 4548, TPS4697 

Rathmell, Kimryn 4617, 

TPS4686 

Rathore, Bharti e13124 

Rathore, Ritesh e13124 

Ratner, Elena 5099, e13125, 

e15526, e15581 

Ratner, Lee 4030, 8005 

Ratti, Margherita 4097 

Rau, Kun-Ming 4103 

Raubitschek, Andrew Antony 

639, 6545 

Rauch, Michael 2007 

Rauch, Philippe 10517 

Rauckhorst, Myrna 2526, 

TPS4701 

Rauh, Jacqueline e14138 

Raunig, David e13082 

Rauscher, Garth e16531 


Raut, Chandrajit P. 1547, 

5090, 10017 

Rauthan, Amit e14710, 

e15516 

Rauw, Jennifer 2572 

Ravaggi, Antonella e15549 

Ravandi, Farhad 6501, 6528, 

6544, 6558, 6576, 6587, 

6589, 6592, 6597, 6603, 

6607, TPS6637 

Ravaud, Alain 4583, 4606, 

9012 

Ravdin, Peter e14684 

Rave-Fraenk, Margret e13039, 

e21128 

Ravel, Patrice e13578 

Ravi, Vinod 10071, e19520 

Ravic, Miroslav 8079 

Ravindranath, Yaddanapudi 

9578 

Ravn, Jesper 7001 

Rawal, Sudhir e15101 

Rawl, Susan e16557 

Ray Coquard, Isabelle 636, 

10062 

Ray, Anna M. e15205 

Ray, Saurabh 570, e12515, 

e13038, e16571 

Ray, Ujjal Kanti e13030 

Ray, Vani e19030 

Ray-Coquard, Isabelle Laure 

LBA5000, 10027, 10095 

Ray-Coquard, Isabelle 1095, 

2583, LBA5002^, 5018, 

5067, 10005, 10006, 

10007, 10010, 10014, 

10020, 10056, 10092, 

10562 

Raymond, Eric 2554, 2557, 

4118, e13594, e14553, 

e14660 

Raynaud, Jean-Pierre e15145 

Raynov, Julian e14501 

Rayson, Daniel TPS658, 

1036 

Raza, Azra 3081, 6624 

Razak, Albiruni R.A. 3082, 

3101, e13001 

Razak, Albiruni e19616 

Razavi, Pedram 1556 

Razis, Evangelia 573, e15040 

Razzaque, Saqib e14715 

Razzini, Giorgia e11071 

Razzouk-Cadet, Micheline 

8077, e15574 

Re, Alessandro 8046, 8058 

Rea, Daniel 516, 517, 530, 

TPS665, e11062 

Rea, Delphine 6503 

Rea, Domenica e11052, 

e13539 

Rea, Silvio e11041 

Read, Nancy E 5530 

Read, William L. 3055 

Ready, Neal e13032, e17558 

Reagan, John Leonard 

e21116 

Real, Francisco X e12033 

Reaman, Gregory H. 9543, 

9587 

Reamer, Margaret 7071 

Reames, Bradley Norman 

6020 

Reardon, David A. 2027, 

2090^, 2094^, 2095^, 

TPS2103 

Reber, Howard A. e14582 

Rebersek, Martina e14083 


Rebollo, Joseba 3064, 

e16000 

Reboredo, Margarita e14595, 

e21002 

Rebours, Vinciane 4133 

Reburiano, Eunicia 8089 

Recchia, Francesco e11041 

Reche, Encarni 10082 

Rechis, Ruth 9136, e19503 

Recht, Abram 6022, 7040, 

7054, 7055 

Recinos, Violette 2076, 2100 

Recio, Manuel 1111 

Reck, Martin 2573^, 7013, 

7030, TPS7113, LBA7507, 

7536, TPS7611, e13113 

Reckamp, Karen L. 3023, 

3108, 7518, 9068 

Reckova, Maria TPS4677, 

e15028 

Reddick, Cathy TPS1148, 

TPS4147 

Reddy Goteke, Vamshi 

Krishna 6554, e18544 

Reddy, Akhila Sunkepally 

9002, e19599 

Reddy, Indraneel e11097, 

e12004 

Reddy, Manjula 2583 

Reddy, Pavan S. 9000, 9142 

Reddy, Prem-veer e15174 

Reddy, Sangeetha Meda 1561 

Reddy, Suresh K. 9002, 

e19528, e19584 

Reddy, Vijay Anand Palkonda 

9568 

Reddy, Virgil 6622 

Redfern, Charles H. TPS4697 

Redman, Bruce G. 8504, 

8525 

Redman, Bruce TPS2613, 

4546, 8587 

Redman, Mary Weber 7517, 

7552, 7570 

Redner, Robert 6563 

Redon, Christophe E. 2553, 

3031 

Redondo, Andres 10052, 

e13085 

Redondo, Maximino e14116 

Redwan, Bassam 10080 

Reece, Donna Ellen 8020, 

TPS8112, TPS8113 

Reed, Angela D. e15179 

Reed, Carolyn E 4062 

Reed, Damon R. 10003, 

10048, 10070, 10084 

Reed, Galen 4660 

Reed, Mark E. 5014 

Reed, Michael 7054, 7055, 

e17560 

Reed, Nicholas 4121, 4122, 

LBA5000 

Reed, Robert 1529 

Reed, Shelby D. 1525 

Reeder, Craig B. 8010, 8034, 

8043, 8053 

Reeder, Kimberley Alex 

e15549 

Reeder-Hayes, Katherine 

Elizabeth 6017, 6029, 

6096, 6104 

Reedijk, Michael 1019, 5019 

Reeler, Anne 580 

Rees, Miranda 567 

Rees, Robert 1013 

Rees, Rowland e15100 

Reese, Emily S e15108 

Reese, Jane TPS1616 

Reeve, Bryce B. 6002, 6107, 

7607, 9047, 9144, 

e19633 

Reeves, Leslie e13581 

Refaat, Tamer 1069 

Regan, David H. e19615 

Regan, Eileen 4027, 4125 

Regan, Kelly E. 9584 

Regan, Meredith M. 504, 

e15170 

Regazzi, Ashley Marie 4581^, 

e15022 

Rege, Jessicca TPS1145 

Regine, William 4041 

Regitnig, Peter 515 

Regnier-Rosencher, Elodie 

8591 

Rego, Juliana Florinda De 

Mendonga e12513 

Reguart, Noemi 7540 

Rehman, Farah 3050 

Rehrauer, William M. e13537 

Reich, Elsa 5078 

Reich, Richard 5564 

Reichardt, Annette 10032^ 

Reichardt, Peter LBA10008, 

10010, 10032^ 

Reiche, Jana 3519^ 

Reichel, Carol e19510 

Reichle, Albrecht 6500^, 

6610 

Reid, Alison Helen 4553 

Reid, Gregory K. 3039 

Reid, Joel M. 9581, e13086 

Reid, Julia E. 7023 

Reid, Tony R. e14069, 

e14078, e14079 

Reid, Tony 4055 

Reidy, Diane Lauren 4047, 

4057, 9105, e14112 

Reifenberger, Guido 2000, 

2067 

Reig, Beatriu 1126 

Reig, Óscar 3536 

Reijneveld, Jaap 2071, 6090 

Reilly, Patrick J e13038 

Reimer, Daniel 5080 

Reimer, Toralf 5080 

Reina, Juan J e14671 

Reiner, Anne S. 2006 

Reiner, Johnathan e17543 

Reiner-Concin, Angelika 

e14087 

Reiners, Katrin S. 8079 

Reinert, Anne 3006^, 3058 

Reinhard, Todd 8528 

Reinhardt, Carsten 2522, 

3530 

Reinholz, Monica Madden 

1083 

Reinke, Denise K. TPS10100 

Reinke, Petra 8030 

Reinthaller, Alexander 

LBA5000, 5031, 5080, 

5111 

Reiriz, Andre B. 606 

Reis, Isildinha M. 595 

Reiser, Marcel 1533, 8022, 

8024, 8025, 8031, 10526, 

CRA10529 

Reiser, Vadim 1564 

Reisman, Arlene 7596 

Reisman, David 10522 

Reitter, Sonja e18525 

Reitz, Richard E 5510 

Rejeb, Narmyn e13594 

Rekhtman, Natasha 7505, 

10560 

Reklaitis, Gintaras V e18555 

Rekman, Janelle e14154 

Relander, Thomas 10024 

Rembak-Szynkiewicz, Justyna 

e21049 

Remenar, Eva 5516^ 

Remillard, Stephen P. 10029 

Remy, Herve 9560 

Ren, Chao e14653 

Ren, Chen 3017, 3081 

Ren, Guo-xin 5593 

Ren, Henning 5524 

Ren, Li e14000 

Ren, Min 8594 

Ren, Shengxiang 7520, 

7535, 10527, e18123 

Ren, Xiu Bao LBA4537, 8554 

Ren, Zhenggang 4008 

Renard, Vincent 4622 

Renbarger, Jamie L. 2601 

Rendleman, Justin 8557 

Renehan, Andrew e14015 

Rengan, Ramesh 6070, 

7050, 7098, e17534, 

e18032 

Rengucci, Claudia 10601 

Reni, Michele 4017 

Renne, Salvatore Lorenzo 

4120 

Rennert, Gad 1578 

Rennert, Hedy S 1578 

Renninger, Markus e19021 

Renouf, Daniel John 3527, 

6018, e14048, e14588 

Renouvel, Florence e11551 

Renschler, Markus F. 7590 

Renschler, Markus Frederic 

7592, TPS7618 

Rensvold, Diane M 3028 

Renton, Corrinne 9021 

Resci, Federica e17006, 

e18563, e18566 

Rescigno, Pasquale e15034 

Reske, Tom e11030 

Resteghini, Carlo 5555 

Rettenmaier, Christopher 

e15500 

Rettenmaier, Nicholas 

e15500 

Retter, Avi S. 3075 

Rettig, Klaus 9114 

Rettig, Matthew 4665 

Retz, Margitta 4530, 4590, 

e15195 

Reu, Frederic J. 8035 

Reuben, James M. 594, 

1047, 8091, 9002, 9072, 

9081, 9083, e13582 

Reungwetwattana, Thanyanan 

1565 

Reusch, Uwe 8059, e18532 

Reuss, Alexander LBA5002^, 

5005 

Reutemann, Patricia e19025 

Reuter, Christoph W. e15190 

Reveiz, Ludovic e12039 

Revnic, Julia e19544 

Rey, Annie 5028, 5083, 

10098 

Rey, Augustin A. TPS5112 

Rey, Jean-Baptiste 1095, 

5067 

Rey, Severino 3064 

Reychler, Herve 5519 

Reyderman, Larisa 2552, 

e18063^ 

Reyes, Carolina M. 6007 

Reyes, Jose 639 

Reyes, Ruben 10605, 

e13568 

777s

Reyes-Rivera, Irmarie 

CRA3503 

Reyna Asuncion, Bernadette 

7597 

Reyners, An K.L 5017^ 

Reynes, Gaspar 2045 

Reyno, Leonard M. 4568 

Reynolds, Alison e13570 

Reynolds, C. Patrick 8073, 

e15103 

Reynolds, Craig H. LBA4, 

e18063^ 

Reynolds, Jana e11069 

Reynolds, Joe TPS663 

Reynolds, John 6505^ 

Reynolds, Kerry 9136 

Reynolds, Marleta e20001 

Reynoso, Jose e14700 

Reyt, Emile e16013 

Rezaei, Mansour 6556 

Rezai, Mahdi 554 

Rezvani, Katy 10550 

Rha, Sun Young TPS4142, 

e12029, e14081 

Rha, Sun Young 4077, 4536, 

4538, 4544^, TPS4683, 

e14580, e14652, e15064 

Rhee, Ina Park e13000, 

e13113 

Rhee, Jiyoung 4028, e14580 

Rhees, Brian e20507 

Rhiem, Kerstin 3044 

Rhoads, Kim F 6010 

Rhode, Peter e13088, 

e15010 

Rhodes, Dan e14164 

Rhondali, Wadih 9049, 9080, 

e19603, e19613 

Ribalta, Teresa 2045 

Ribas, Antoni 8502^, 8503^, 

8504, 8518, 8521, 8525, 

8527, 8567, TPS8603, 

e13045 

Ribeiro, Adriana Regina G. 

e11058, e14680, e14728 

Ribeiro, Heber Salvador de 

Castro e14728 

Ribeiro, Karina Braga 9523 

Ribeiro, Maria Leonor 6044 

Ribeiro, Maria-Jose 10625 

Ribeiro, Thiago Neto e12018 

Ribelles, Nuria 10500 

Ribera, Josep-Maria 8005, 

8058 

Ribero, Dario 4110 

Ribi, Karin 9022, e19648, 

9045, 9059 

Ribrag, Vincent 2539, 8057, 

8068 

Ricarte-Filho, Julio Cezar M. 

5509^ 

Riccardi, Alberto 589 

Riccardi, Riccardo 9517 

Ricci, Angela M 6537 

Ricci, Claudio e14647 

Ricci, Fabio e11514, 

e19002, e19620 

Ricci, Jean-Francois 539 

Ricci, Marianna 10615, 

e18045 

Ricci, Rossana 10615 

Ricci, Sergio LBA4001 

Ricci, Veronica e13098 

Ricci, Vincenzo 3540, 3549 

Ricciardi, Giuseppina R. R. 

e11056 

Ricciardi, Roberto 5093, 

5094, e15547, e15550, 

e15551, e15553 

Riccio, Gennaro e13539 

Rice, Audie 8087 

Rice, Carol e16538 

Rice, David C. 4069, 4078, 

4086 

Rice, Thomas W. e14611, 

e14665 

Ricevuto, Enrico e14010, 

e15200 

Rich, Barrie S. 8586 

Rich, Elizabeth Shima 6552, 

e16503 

Rich, Tara e18046 

RiChard, Jamie e15021 

Richard, Marie-Aleth 8555, 

8568 

Richard, Sandrine e19640 

Richard, Scott Daniel e15578 

Richardet, Eduardo arnoldo 

e11501 

Richardet, Eduardo e11044, 

e18114, e18125 

Richardet, Martin Eduardo 

e11044, e11501, e18125 

Richards, Catherine A. 6118 

Richards, Donald A. LBA4, 

2516, TPS3111, LBA3501, 

9117, e14501, e18047 

Richards, JoAnne S e15583 

Richards, Jon M. 8508, 

e13088 

Richards, Kristen 8537 

Richards, Paul D. 1017 

Richardson, Andrea 576 

Richardson, Blakely S. 1603 

Richardson, Debra L. e15501 

Richardson, E. 561 

Richardson, Gary Edward 

e19514 

Richardson, Jaime 2087 

Richardson, Paul Gerard Guy 

8012, 8016, 8017, 8019, 

8020, 8033, 8043, 8095, 

TPS8112, TPS8113, 

e18572^ 

Richardson, Stacie e18139 

Richardson, Steve 569, 571, 

6098, e11002 

Richardson, William 4041 

Riche, Christian e14148 

Richel, Dirk 4094 

Richer, Jennifer K. 564, 

TPS668 

Richert-Boe, Kathryn E. 

e12024, e15197, e18107, 

e19630 

Richhariya, Akshara e12024, 

e15197, e18107, e19514, 

e19630 

Richie, Jerome P. 4521 

Richie, Mary Ann 6558, 6585 

Richly, Heike 2086, e13605 

Richman, Joni TPS3638, 

e14501 

Richter, Barbara 5005 

Richter, Rolf 5031, 5034, 

5071, e15531, e19597 

Richter, Stephan 10068 

Richter, Sue 1555, 3082, 

e15017, e15020 

Ricigliano, Mark 3066 

Rick, Oliver e15026 

Ricke, Jens TPS4148, 

e14630 

Ricker, Charite Nicolette 

1124 

Ricker, Justin L. 3532, 7512, 

e13583 

Rickmann, Mariana e21035 

Ricordeau, Philippe e14065 

Riddell, Angela M TPS4143 

Rider, Alex e16570 

Rider, David N. 5077 

Ridge, John A. 10064 

Ridgway, Paul F 10050 

Ridner, Sheila H e16038, 

e19534, e19559 

Ridolfi, Kimberly 555, 563, 

6063 

Ridolfi, Ruggero 8513, 8529 

Ridwelski, Karsten 4072, 

4095^ 

Riechelmann, Rachel Pimenta 

e14702 

Riechelmann, Rachel 6055 

Riedel, Richard F. 10010 

Rief, Winfried e11040^ 

Rieke, Damian 5517 

Riely, Gregory J. 3083, 7014, 

7033, 7052, 7527, 7531, 

7532, 7533, 7580, 7599, 

7600 

Riera-Knorrenschild, Jorge 

e14152 

Riesco Martinez, Maria C. 

e14171 

Riesco, M. Carmen e14058 

Riess, Hanno 2554, 4020, 

4044, 4050, TPS4135, 

8030, e14533 

Riess, Jonathan 10574 

Riester, Markus 4577, 4585 

Riethdorf, Sabine 1090, 

10599 

Rietschel, Petra 10003 

Rifa, Julio e11036 

Rifai, Aya e17015 

Rifkin, Robert M. 8037, 

8064, e18556 

Riga, Anne 4109 

Rigacci, Luigi 8006 

Rigas, James R. 7022, 7541, 

e14514 

Rigatos, Sotirios 583 

Riggs, Heather Dawn e16557 

Righini, Christian e16044, 

e16051, e16055 

Rigo, Raul 3096 

Riisnaes, Ruth 10525, 

e13601 

Rijavec, Erika 7577, 7581, 

e21065 

Riker, Adam Irwin e19008 

Riley, Sarah 5501 

Rimassa, Lorenza 4006, 

e21139 

Rimawi, Mothaffar F. 606, 

TPS654^ 

Rimely, Endre 2077 

Rimes, Sue A 6116 

Rimm, David 517, 573, 

1121, 5576, e21106 

Rimmer, Yvonne L. 4531 

Rimner, Andreas 7043 

Rimsza, Lisa M. 8001, 

e18534, e18536 

Rinaldi, Giulia e11039, 

e11514, e19620 

Rinaldi, Yves LBA3500^ 

Rinard, Katherine e15103 

Rinck, Jose A. e15122, 

e18078 

Rincon, Raul 5520, e15094, 

e18069, e18106, e21015 

Rinderknecht, Jeannine 

Desiree e19017 

Ring, Andrej 10059 

Ringash, Jolie 5571, 

TPS5600, 6002, 7607 

Ringel, Ralf 640 

Ringert, Rolf-Hermann 

e15156, e15158 

Ringom, Rune e13518 

Rini, Brian I. TPS2614, 

4503, 4536, 4538, 4546, 

4609, TPS4679, TPS4684, 

e15095 

Rino, Yasushi 4070 

Rio Frio, Thomas e14059 

Rios, Maria 10056, 10092, 

10095 

Rios, Mary Beth 6501 

Rios, Paola e12039 

Rios, Sandra 1041 

Rios-Perez, Jorge Arturo 

1085, TPS1138 

Riou, Francois 9074 

Ripaldi, Mimmo 6603 

Ripamonti, Carla 9005 

Ripoche, Veronique 7554 

Rippin, Gerd 2573^ 

Riquelme, Alejandro e21104 

Riquet, Marc 7024 

Risch, Harvey TPS1614 

Rischin, Danny TPS5116, 

5571, e13054, e15541 

Risendal, Matthew e18550 

Rishi, Arun K 9578 

Risk, Janet 5543 

Riska, Henrik 7001 

Riska, Shaun M e15132 

Riss, Joseph e13045 

Risse, Marie-Laure TPS4696^ 

Ristagno, Ross e14714 

Risueno, Noelia e14097 

Ritch, Paul S. e14613 

Ritchie, Christine 6080 

Ritchie, Ellen K. TPS6637 

Ritenour, Chad e15006 

Ritgen, Matthias 6500^ 

Ritter, Barbara 2504 

Ritter, Gerd e11563 

Rittweger, Karen 3578, 

TPS7616 

Rivarola, Edgardo G. J. 9038, 

e11037, e15507, e15508 

Rivas Ruiz, Francisco e14116 

Rivas, Carlos e19569 

Rivelli, Thomas Giollo e16568 

Rivera, Daniel e12027 

Rivera, Gabriel 8103 

Rivera, Lorna e16500 

Rivera, Ragene Ruth 547 

Rivera-Rodriguez, Noridza 

e18547 

Rivero, Elisabeth e11035 

Rivero, Gustavo e17018 

Riviere, Alain TPS7112, 7575 

Riviere, Isabelle TPS2619, 

TPS4700 

Rivoire, Michel e14730 

Rivoltini, Licia 5555, 8529 

Rix, Peter J. 4548, TPS4697 

Rixe, Olivier TPS2103, 

TPS3116, 7556, e16017 

Rizack, Tina 1045, 5100 

Rizel, Shulamith 548 

Rizk, Nabil P. 4061 

Rizvi, Naiyer A. TPS2615, 

TPS2621, 7014, 7052, 

7527, 7578 

Rizvi, Syed 4081 

Rizzi, Anna e14018 

Rizzi, Rita 6584 

Rizzieri, David 6525, 

TPS6636 


Rizzo, Pietro e18048 

Rizzo, Virginia e15010 

Ro, Jungsil 1003, 2542 

Roa, Wilson TPS2104 

Roach, Jim 4056 

Robak, Tadeusz 8018^ 

Robb, Caroline M. e21018 

Robbins, Anthony 6011 

Robbins, Edward T e17531^ 

Robbins, Jared R. 5088 

Robbins, Joan M. 2101 

Robbins, Samuel G e17531^ 

Robert, Caroline 1566, 8501, 

8502^, LBA8509, 8512, 

8591, 8601, e19022 

Robert, Francisco 2610, 

3034, 7502 

Robert, Jacques e14023 

Robert, Rhonda J. 9096 

Roberts, Catherine H. e18550 

Roberts, Christopher e15209 

Roberts, Heidi 10522 

Roberts, Ian SD 4599 

Roberts, Kenneth B 1030, 

4651 

Roberts, Lewis R. 4033 

Robertson, Cary N. 4670, 

e15194 

Robertson, Chris 1509, 1510 

Robertson, Jane D e13541 

Robertson, John M. 3545 

Robertson, Philmore 9547, 

e18522 

Robidoux, Andre LBA506, 

616, LBA1000, 1025, 

TPS1139 

Robin, Marie 6534, 6542 

Robin, Yves Marie 10018 

Robinet, Gilles TPS7112, 

e16560 

Robins, Deborah A 2516 

Robins, Harlan 6631 

Robins-Browne, Kate 9124 

Robinson, Austin e18549 

Robinson, Bruce 5591 

Robinson, David 4668 

Robinson, Eliezer e16505 

Robinson, Giles W. 9518 

Robinson, Kim e21013 

Robinson, Lary 7024 

Robinson, Max 5543 

Robinson, Patricia A. e16531 

Robison, David J e18541 

Robison, Katina 5100 

Robison, Leslie L. 6030, 

9505, CRA9513, 9514, 

9526, 9528, 9531 

Robles Irizarry, Lizbeth 2076, 

2093, 2100 

Robles, Robert Leon TPS6636 

Roboz, Gail J. 6577 

Robson, Mark E. 10097 

Robson, Matthew 3088^ 

Robson, Tammy 516, 517 

Roca, Enrique Luis e14521, 

e14598 

Roca, Fernanda e15570 

Rocca, Andrea e11054 

Rocchi, Palma e15155 

Rocco, James W. e16059 

Rocha Lima, Caio Max S. 

4049 

Rocha, Eduardo 7095 

Rocha, Rafael Malagoli 643 

Rochard, Sophie e14148 

Roche, Henri Hubert 1011, 

10076 

Roche, Henri 543 

Roche, Sandra 2536 


Rochet, Nicole M. 8600 

Rochlitz, Christoph 9059 

Rock, Colleen e13047 

Rock, Edwin P. TPS4134 

Rock, Hans 2079 

Rocque, Gabrielle Betty 9039 

Roda Perez, Desamparados 

2567, 2568, 3021, 

e13048, e14589 

Roddie, Huw 8015 

Rodeghier, Mark e14697 

Rodell, Timothy C. TPS3638, 

e14501 

Rodenhuis, Sjoerd 10013 

Roder, Heinrich e18096, 

e18100 

Roder, Joanna e18096, 

e18100 

Rodgers, Kristen e18147 

Rodier, Jean-Francois e11542 

Rodig, Scott J. 3053 

Rodin, Gary 9003, e16567 

Rodkey, Travis e13516 

Rodler, Eve T. 10011^, 

TPS10103 

Rodolakis, Alexandros 5033 

Rodolfo, Monica 5555 

Rodon Ahnert, Jordi 508, 

509, 2042, 3005, 3014 

Rodon, Jordi 566 

Rodon, Philippe 8014 

Rodrigo, Esteban 10082 

Rodrigues, Ana Maria Santos 

e12018 

Rodrigues, George 6130, 

7009 

Rodrigues, Helena 5567 

Rodrigues, Heloisa Veasey 

e13534 

Rodrigues, Isabelle 2070 

Rodrigues, Kristen 8512 

Rodrigues, Manuel Jorge 601 

Rodrigues, Newton Augusto 

Ferreira 643, e18078 

Rodriguez de Antona, Cristina 

4620, 10546, e15041 

Rodriguez de la Borbolla, 

Maria e11075 

Rodriguez Garcia, Sofia 

e15033 

Rodriguez Garrote, Mercedes 

e16029 

Rodriguez Lopez, Carmela 

e14733, e19505 

Rodriguez Paniagua, Jose 

Manuel 7011 

Rodriguez Villalva, Silvia 

e16025 

Rodriguez, Cesar 1001 

Rodriguez, Cleofe e15001 

Rodriguez, Cristina P. 7029, 

e14611, e14665, e16045, 

e18046 

Rodriguez, Cynthia e11061 

Rodriguez, Delvys 1531 

Rodriguez, Estelamari 7049 

Rodriguez, Isabel e11517 

Rodriguez, Luis 8596 

Rodriguez, Margarita 3066 

Rodriguez, Maria Alma 8067, 

e16574, e18530, e19625, 

e19629 

Rodriguez, Maria Carmen 

e19576 

Rodriguez, Melissa 8036 

Rodriguez, Miro e12041 

Rodriguez, Paulo 6580 

Rodriguez, Pedro Camilo 

2527 

Rodriguez, Rufo 4089 

Rodriguez, Vivian 1563 

Rodriguez-Antona, Cristina 

9073 

Rodriguez-Bigas, Miguel A. 

3556, 4060 

Rodriguez-Freixinos, Victor 

5068 

Rodriguez-Galindo, Carlos 

9523, 9539, 9545 

Rodriguez-Lescure, Alvaro 

1001, 1008 

Rodriguez-Marquez, Cristina 

1111 

Rodriguez-Moreno, Juan 

Francisco e15111 

Rodriguez-Morera, Anna 

e19542 

Rodriguez-Pascual, Jesus 

4040, e15111 

Rodríguez-Rigueiro, Teresa 

e14595, e21002 

Rodrigueza, Wendi V. 

TPS3110 

Rodriquenz, Mariagrazia 

e14156 

Roecken, Cristoph 4107 

Roeland, Eric e14069, 

e14078, e14079 

Roengvoraphoj, Monic 

e13567 

Roepman, Paul 3510, 10545 

Roesel, Siegfried 556 

Roesler, Rafael e13546 

Roessler, Bernhard 3530 

Roeth, Alexander 2007, 8031 

Roewert-Huber, Joachim 

8535, e19022 

Roff, Kate TPS4145 

Rogak, Lauren J. 9047, 

9104, 9144, e19633, 

e19647 

Rogan, Jane TPS10633^ 

Rogerio, Jaqueline Willemann 

4608, 8028 

Rogers, Anna R 8543 

Rogers, Anna e19506 

Rogers, Gary S e11548 

Rogers, Jane 4060 

Rogers, John S. 7546 

Rogers, Karl e11562, e13003 

Rogers, Lisa R. TPS1616 

Roggenkamp, Betty 1553, 

6120 

Roggero, Enrico 4661 

Roggin, Kevin K. 10090 

Rogowski, Sabine 2040 

Rogowski, Wojciech e21099 

Roh, Jae Kyung e14081, 

e14084 

Roh, Jae Kyung 3531 

Roh, Sang Young e14558, 

e19614 

Rohan, Thomas e14005 

Roig, Jose Vicente 3586 

Roiter, Ignazio 1604 

Roitman, Janna 6114 

Rojas Llimpe, Fabiola Lorena 

e14040 

Rojas, Jose Ernesto e15036 

Rojas, Luis 7107, 7108, 

9571 

Rojas, Maria TPS4146 

Rojat-Habib, Marie-Christine 

8555 

Rojo, Federico 4580, 4582, 

4585, 5520, 10616, 

e14147, e15094, e18069, 

e18106, e21015 

Rojo, Sandra Viviana e14521 

Rokitta, Denis 3044 

Roland, Joseph e15582 

Rolet, Fanny 10505 

Rolfe, Lindsey 4041, e13028 

Rolfo, Christian Diego 4587, 

7058, 10594, e12012 

Rolland, Alain e19058 

Rolland, Frederic LBA4567^ 

Rolle, Cleo E e17549 

Rolli, Luigi e17546 

Rollot, Florence TPS667 

Rom, Joachim 1096 

Rom, William e21012 

Romagosa, Cleofe e21021 

Romaguera, Jorge Enrique 

8067 

Romain, Ahmed Jerome 9074 

Roman, Laslo 8539 

Roman, Lynda e13084 

Roman, Orvelin e13581 

Roman, Ruth Ann 2521, 

8549, 8598 

Romaniuk, Chris 8564 

Romano, Anna 8573, e19034 

Romano, Carmen e14130 

Romano, Emanuela e19050 

Romano, Giampiero e18048 

Romano, Karen S. 3582 

Romano, Olivier e14560 

Romeder, Franz 4074 

Romejko-Jarosinska, Joanna 

e18512 

Romera, Alejandro 10564 

Romero, Atocha e14147 

Romero, Ignacio 5068, 

e15575 

Romieu, Gilles 532 

Romigh, Todd 1508 

Romkes, Marjorie 8528 

Rommel, Christian 626 

Rommel, Denis 5519 

Ron, Ilan-Gil 535 

Roncalli, Massimo 7061, 

7585, e14672, e18104 

Roncella, Silvio e17533 

Rondena, Roberta 9005 

Rondini, Ermanno LBA4001 

Rondon, Gabriela 6529, 

6540, 8102 

Rong, Tie-hua e18121 

Ronnett, Brigitte M. 1519 

Ronot, Maxime e14553 

Ronzoni, Monica 3518 

Rooney, Cliona M. 2558 

Root, Dana 2587 

Root, Elizabeth J. 1547 

Roothumnong, Ekkapong 

e14051 

Roque, Dana Marie e15526 

Roque, Dario R. 5100 

Rosa, Roberta e13509 

Rosales, Beatriz e19636 

Rosati, Gerado LBA4001 

Rosati, Gerardo e14040 

Rosati, Kayla 1045, 4098 

Rosbrook, Brad 4546 

Roschewski, Mark J. 8088, 

8104, e18568 

Roscoe, Joseph 9113, 9141, 

e16056 

Rose, Brent Shane 6121 

Rose, Inga 5523 

Rose, Jeffrey Scott e14178 

Rose, Jim 8060 

Rose, Mathieu e15193, 

e15198 

Rose, Michal G. 6033 

Rose, Shelonitda e13598 

779s

Rose, Steven C. 3590 

Rosell, Rafael 3093, 4068, 

4579, 7011, 7095, 7522, 

7531, 7540, 7542, 

TPS7613^, 10596, 

e14509, e14521, e18114, 

e18130, e18131, e18137, 

e18143 

Roselli, Mario TPS4151 

Rosello Keranen, Susana 

1074, e14589 

Rosemurgy, Alexander 4055, 

TPS4134, e14501 

Rosen, Alexander 6129 

Rosen, Alyx C. e19052, 

e19624 

Rosen, Barry 5107 

Rosen, Bruce R. 2059 

Rosen, David I e13086 

Rosen, Fred R 1611 

Rosen, Lane R e17524 

Rosen, Lee S. 3032, 3034, 

3042^, 3631, e13000, 

e13598 

Rosen, Mark Alan 4596 

Rosen, Neal 10618 

Rosen, Peter J. 3010 

Rosen, Steven T. 610, 

TPS1134, 2532, 4063, 

e18523 

Rosenbaum, Cara Ann 2561 

Rosenbaum, Eli 4564 

Rosenbaum, Paul R. 6000 

Rosenberg, Anne Louise 

e11505 

Rosenberg, Jonathan E. 

TPS2618, 4522, 4525, 

4543, 4577, 4580, 4582, 

4585, 4592, 4635, 

e15007 

Rosenberg, Joshua Daniel 

e21061 

Rosenberg, Martin e19635 

Rosenberg, Per e13095^, 

e13097^, e13108^ 

Rosenberg, Robert 3510, 

TPS10632 

Rosenberg, Shoshana 9100 

Rosenberg, Steven A. 8576, 

e14179 

Rosenblat, Todd L. 6609, 

6613 

Rosenblatt, Joseph David 

8027, e13079 

Rosenfeld, Nitzan 544 

Rosenko, Liudmila e19049 

Rosenman, Julian e17547, 

e17550 

Rosenow, Joshua M. 2035 

Rosenshein, Neil B. 5055 

Rosenstock, Julio 1509, 1510 

Rosenthal, David Ira 5530, 

5561, 5589 

Rosenthal, Mark 4531, 

e13054 

Rosenthal, Seth A e21026 

Rosenzweig, Margaret Quinn 

1085, 1589 

Roses, Daniel F. e11010 

Rosina Duarte, Eva 9063 

Rosing, Hilde 2550, e13028 

Rosmorduc, Olivier 4032, 

TPS4148 

Rosner, Gary L. 4559 

Rosovsky, Rachel Pam 

Greenerger 7010 

Ross, Douglas T. 516 

Ross, Eric A 1502, 4526 

Ross, Fiona 8015 

Ross, Gillian 10060 

Ross, Graham 533^, 597^, 

598^, e11055^ 

Ross, Helen J. 7029, 7555 

Ross, Jeffrey S. 3533, 7510, 

10590, e17541 

Ross, Joseph 1595 

Ross, Mikel TPS3112 

Ross, Richard N. 6000 

Ross, Robert W. 3105 

Ross, Robert W 4516, 4577, 

4582 

Ross, Ronald K 4575 

Ross, Sharona B. e14501 

Rosselli Del Turco, Marco 

1500 

Rossello, Rosalba e11056 

Rosser, Charles Joel e15010 

Rossetti, James M. 6620 

Rossetti, Maria Grazia 

e13098 

Rossetto, Ciro 5513 

Rossi, Adriana C. 8036 

Rossi, Cristina 10593 

Rossi, David 4084 

Rossi, Edmund A e13005 

Rossi, Elisa e21018 

Rossi, Emma C e15561 

Rossi, Gabriela R. 2571, 

e19008 

Rossi, Giorgia 9054, e19532, 

e19533 

Rossi, Giuseppe 8006 

Rossi, Jean-Francois 8018^, 

8020 

Rossi, John 10545 

Rossi, Lorena e14082 

Rossi, Luigi e11039, 

e11514, e12510, e19620 

Rossi, Maura e13569 

Rossi, Peter John e15006 

Rossoni, Gilda 7076, 7581 

Rosti, Giovanni e13019 

Rota, Luigina e14018 

Rota, Selene 623 

Roth, Arnaud 3509, 3511, 

3575, 3595, TPS4140, 

10033 

Roth, Daniela 10593 

Roth, Diane 3019 

Roth, Jack A. 7043 

Roth, Joshua A. 560 

Roth, Laura 2503^ 

Roth, Patrick 2007, 2055 

Roth, Stephan L. e11556 

Rothbard, Marianna TPS669, 

TPS1614 

Rothe, Achim 8079 

Rothenberg, Stephen M. 

4566, e16059 

Rothenberger, David A. 6016 

Rothhammer-Hampl, Tanja 

4034 

Rotmensz, Nicole 1049, 

1115, 1500 

Rotoloni, Christina e14689 

Rottey, Sylvie 4622, 5504^, 

e13594, e15115 

Rouanet, Philippe 568^, 

3633 

Roubec, Jaromir e18062 

Roughley, Adam e16570 

Rougier, Philippe R 3562, 

3579 

Rougier, Philippe 3508, 

3547, TPS3634, 4087 

Roupret, Morgan e15105 

Rouquette, Isabelle 10507 

Rourke, Sean 9021 

Rousseau, Raphael F. 

TPS9596, TPS9597^ 

Rousseau, Vanessa 4032, 

10556 

Roussel, Claire 1568 

Roussel, Helene e13578 

Roussel, Murielle 8009, 8014 

Routt Barnes, Sheri e19577 

Rouyer, Magali e14168 

Rouyer, Marie TPS10634 

Rouzier, Roman 568^ 

Rovati, Bianca 4017, e13103 

Rove, Kyle O. e15176 

Rovere, Giulia e18103 

Rovere, Rodrigo e12035 

Roveta, Annalisa 7082, 7084 

Rovithi, Maria e18094 

Rowbottom, Jacqui 5001 

Rowe, Julie e14684 

Rowe, Richard 6113 

Rowell, Jessica Lauren 

e15187 

Rowland, Christine 6113 

Rowland, Julia Howe 6006, 

9130 

Rowland, Kendrith M. 7073 

Rowland, Suzanne e14015 

Rowley, Steve 1021 

Roxburgh, Campbell SD 

3611, e14054, e14092, 

e14117 

Roy, Amit TPS2622, 8541 

Roy, Josee-Anne TPS1139 

Roy, Larry 2612 

Roy, Rajasree TPS5601 

ROY, Rakesh - e19517 

Roy, Siddharth 10515 

Roy, Vivek 8033 

Royce, Melanie 1558 

Royce, Trevor Joseph 4658, 

6032, 6037 

Royer-Joo, Stephanie 3543, 

3552 

Royer-Pokora, Brigitte 3550 

Roz, Elena e14042, e18021 

Rozanec, Natalie 6005 

Rozmovits, Linda e11000 

Rozmus, Cathy L. 9096 

Rozzini, Renzo e14018 

Rua, Oliver e15036 

Ruan, Libin e14523 

Ruane, Thomas e16552 

Ruatta, Fiorella e15073, 

e15133 

Rubanov, Oleg 4023 

Rubenstein, Jonathan B. 

e18502 

Rubenstein, Marvin e13513, 

e13532, e15119 

Rubie, Herve 9517, 10076 

Rubin, Eric H. e13599 

Rubin, Mark A. 4649 

Rubin, Mark S. 7587, 8556, 

10530, e21023 

Rubin, Peter 1016 

Rubin, Stephen D. 531, 610 

Rubini, Michele e14041 

Rubino, Barbara 4588 

Rubino, Corrado 8581 

Rubino, Luca 7585, e14672, 

e18104, e21139 

Rubinsak, James R. LBA4 

Rubinstein, Daniel B. e13018 

Rubinstein, Larry 2606, 

3529, 10603 

Rubinstein, Paul G. 1611, 

8085, e14590 

Rubio Salvador(2), Ana Rosa 

e11543, e19596 

Rubio, Belen e18015 

Rubio, Gustavo 5520, 

e15094, e18069, e18106, 

e21015 

Rubio, Itziar e11525, 

e17522, e18031, e21009 

Rubio, Maria Jesus 5031 

Rubio, Marie Therese 6534 

Rubio-Viqueira, Belen 1531 

Ruby, Jeannine Alberts 3563 

Ruch, Joshua Michael 

e14519, e14578 

Rucinska, Monika e19561 

Ruckdeschel, John C. 7029 

Ruckser, Reinhard e14087 

Ruco, Luigi e14042 

Ruda, Roberta 2037, 2075 

Rudas, Margaretha 542, 

10570 

Rudd, Robin 7562 

Ruddy, Kathryn Jean 9071, 

9100 

Rudek, Michelle A. TPS3117 

Rudengren, Cecilia 9054 

Rudenko, Elena G. 9060 

Rudich, Steven e14714 

Rudin, Charles M. 1573, 

3024, 7532, 7589, 

e18147 

Rudin, Claudius 8015 

Rudman, Sarah Maria 4555 

Rudnick, Jeremy 2080, 2084, 

2087 

Rudnicka, Halina 10582 

Rudzinski, Erin R. 9535 

Ruebe, Christian 8022 

Rueda, Antonio 8062, 

e14116 

Ruediger, Thomas 1023 

Ruehle, Kathleen e19565 

Ruehlman, Peter 4127 

Ruel, Christopher 3108, 

e15114 

Ruf, Peter 2584 

Ruff, Paul 3505 

Ruffion, Alain e15182 

Rugge, Massimo e18130 

Ruggeri, Enzo Maria e18065 

Ruggeri, Enzo e12514, 

e14082 

Ruggeri, Maria Grazia e19595 

Ruggieri, Eustachio e21134 

Ruggieri, Pietro 10022 

Ruggiero, Alessandro 10091 

Rugo, Hope S. 512, 539, 

540, 551, 559, 599, 

CRA1002, 1006, 

TPS1140^, 1526, 3058, 

9107, e11096 

Ruhstaller, Thomas 9059 

Ruiz Borrego, Manuel 1001, 

e11081 

Ruiz de Lobera, Abigail 

e11525, e21009 

Ruiz de Porras, Vicenç 9129 

Ruiz Sanchez, Daneli e15525 

Ruiz, Amparo 1001, 1008, 

1059 

Ruiz, Ana L. 7049 

Ruiz, Irune 4089 

Ruiz, Marco A e11030 

Ruiz, Wilson e12041 

Ruiz, Yelitza e14102 

Ruiz-Garcia, Ana e18093 

Ruiz-Opazo, Nelson e13574 

Ruiz-Sauri, Amparo e15575 

Ruiz-Valdepeñas, Andrea 

e11527, e12015, e17502, 

e17503, e17515 


Rummel, Mathias J. 3 

Rumyantzeva, E e11528 

Rundle, Twana e19588 

Runnebaum, Ingo B. e15566 

Ruocco, Raffaella 1554 

Ruperez Blanco, Ana Belen 

e12003, e14058 

Rupin, Matthieu TPS648 

Ruppert, Amy S. e18508 

Ruppert, Anne-Marie 10507 

Rusakov, Igor e15047 

Rusch, Valerie W. 1541, 

4061, 7014, 7066 

Ruscito, Ilary 5070 

Rush, Janet 6530 

Rushing, Daniel A. 9571, 

10010 

Rusinek, Dagmara e14159 

Russell, Christy Ann 1065 

Russell, Greg B. 6127 

Russell, Karen Bullock 

e13589 

Russell, Ludivine e19625, 

e19629 

Russell, Prudence e17539 

Russell, Stephen J. 8096, 

8105, TPS8116 

Russell, Valerie 2521 

Russell, Wesley Alan e18502 

Russo, Antonio e11056, 

e14042, e18021 

Russo, Domenico 6531 

Russo, Filippo 8066, 8083, 

e20512 

Russo, Leila 1022 

Russo, Lucianna e14711, 

e15160 

Russo, Moises e14002 

Russo, Stefania 1044, 

e13058, e13070 

Russo, Suzanne M. e17547, 

e17550 

Rustin, Gordon J. S. 3048 

Ruszniewski, Philippe 4014, 

4071, 4133, e14660 

Rutgers, Emiel J. 1022 

Ruth, Karen 1544, 6061 

Ruther, Nancy R. 6074 

Rutherford, Thomas J. 5099, 

e13125, e15526, e15581 

Rutkowski, Piotr LBA8500^, 

LBA8509, 8548, 

LBA10008, 10033, 10096, 

10538, e19022 

Rutledge, James e11562, 

e13003 

Rutstein, Mark D. TPS3634, 

TPS4675^, 5012 

Ruud, Christopher O. e11069 

Ruvalcaba Limon, Eva 

e15527 

Ruxer, Robert L. 3069 

Ruzich, Janet C. 9028 

Ruzzo, Annamaria 3518, 

3540 

Ryan, Aoife M 1559 

Ryan, Charles J. 3058, 

LBA4518, 4549, 4664, 

4667, e15137 

Ryan, Christine 3047 

Ryan, Christopher W. 4586, 

10011^, TPS10103 

Ryan, David P. 3528, 3594, 

4021, 4027, 4112, 4125, 

e14615 

Ryan, Julie L. 9027 

Ryan, Paula D. 1009, 

e11085 

Rybak, Christina 1544 


Rybicki, Lisa A. 1076, 8071, 

e14611, e14665 

Rybka, Witold B. 8090 

Rydall, Anne 9003 

Rydstrom, Karin 8074 

Rymeski, Beth A e20007 

Rymkiewicz, Grzegorz e18512 

Ryoo, Baek-Yeol 4082, 

10085, 10093, e13092, 

e13104, e14543, e14617 

Ryoo, Hun-Mo e14570, 

e19538 

Rüschoff, Josef 3600, 

e14161, e14162, e14167 

Rytting, Michael E. 6501 

Ryu, Jeong Seon e13065 

Ryu, Keun Won 4028 

Ryu, Min-Hee 4082, 10085, 

10093, e13092, e13104, 

e14543, e14580 

Rzyman, Witold 10561 

Rödel, Claus e14161, 

e14162 

Rödel, Franz e14161, 

e14162 

S 

S K, Raghunath e15101 

S, Nirmala Srikantaiah 

e11536 

S, Ramesh Bilimagga 1093, 

e11511, e11536, e12030, 

e14721 

Sa Cunha, Antonio e14168 

Sá, Lilian Andrade e19628 

Saab, Raya Hamad e20004 

Saad, Alain 8026 

Saad, Everardo D. 3557, 

e13055 

Saad, Fred 4510, 4519^, 

4558, e15202, e19514 

Saad-Hossne, Rogerio e14173 

Saada, Esma 5521, 10062 

Saadeh, Charles e21105 

Saarelainen, Sami Kristian 

e15564 

Saavedra-Perez, David 

e18028 

Saba, Hanna M. 7005 

Saba, Nabil F. 2576, 5560, 

5570, 7048 

Sabaawy, Hatem E. e13543 

Sabado, Rachel Lubong 2589 

Sabariz, Luis 10595 

Sabate, Josep Maria 1120 

Sabatino, Susan A 6052 

Sabatti, Chiara 10513 

Sabbatini, Armando e21070 

Sabbatini, Paul 5041 

Sabbatini, Roberto TPS4683 

Sabeh, Farideh 8099 

Sabel, Michael 2000, 2067 

Sabet, Amir e14565 

Sabet, Salwa Farouk e21055 

Sabichi, Anita Lyn 5592 

Sabin, Pilar 8062 

Sabir, Noreen 6612 

Sablin, Marie-Paule e13017 

Sabloff, Bradley e14547 

Sabo, Roy T. e18550 

Sabourin, Jean-Christophe 

5565, e14010, e14129 

Sabzevari, Helen TPS2617 

Saccaro, Steven J. 9061 

Sacchi, Stefano 8006 

Sacco, Cosimo LBA5003, 

e15160 

Sacco, Rosario e21113 

Sacconi, Andrea 3521 

Sachdev, Deepali e13590 

Sachdev, Jasgit C. TPS1137 

Sachdev, Pallavi 5518, 

e19055 

Sachdeva, Kush 6021 

Sacher, Adrian G. 7606 

Sachs, Karen L e21060, 

e21111 

Sacks, Natalie 2562 

Sada, Yvonne 3542 

Sadaf, Tabinda e16043 

Sadahiro, Sotaro 3607 

Sadak, Karim Thomas 9587 

Saddekni, Souheil e13087 

Sadeghi, Sarmad 1514 

Sadek, Ibrahim 6573 

Sadelain, Michel TPS2619, 

TPS4700 

Sadetsky, Natalia e19060 

Sadhashiv, Santhosh 6620 

Sadighi, Zsila Sousan 2022 

Sadikov, Aleksander e16505 

Sadim, Maureen 1561 

Sadis, Seth e14164 

Sadoun, Alain 5069 

Sadowinski Pine, Stanislaw 

e20005 

Sadrzadeh, Hossein 6606, 

6617, 6618, 6629 

Saeb-Parsy, Kasra e15011 

Saeed, Anwaar Mohammed 

e21085 

Saeed, Kamran e16043 

Saeed, Sadiya 10525 

Saeger, Sally TPS2622 

Saeki, Hiroshi e14033, 

e14601 

Saeki, Sho e13072, e18059 

Saeki, Toshiaki TPS659 

Saenz, Alberto e15144 

Saetaew, Manit e13023 

Saez, M.I. 4630, TPS4672 

Safferman, Allan Zachary 

7598 

Saffery, Claire LBA4000 

Safgren, Stephanie L. e13086 

Safina, Sufia 531 

Safont, M. José 3571, 3586, 

e14097 

Safra, Tamar 5078 

Safran, Howard 4049, 4098, 

9117 

Safwat, Mohab W. e15039, 

e15046 

Safwat, Reham e16002 

Sagalowsky, Arthur I. 4616, 

TPS4678, e15192 

Sagan, Christine 543, 

e21117 

Sagara, Yasuaki 588 

Sagasser, Jaqueline e13100^ 

Sagatys, Elizabeth e18503, 

e18506 

Saggese, Mariangela 8066 

Saggio, Jennifer 9540 

Saghatchian, Mahasti e11019 

Sagiv, Eyal 1507 

Saglam, Sezer e14628 

Saglio, Giuseppe 6506, 

6509^ 

Saha, Debabrata 10624 

Saha, Sukamal 3619, 

e14045, e14046, e15554 

Sahai, Vaibhav e14515 

Sahani, Dushyant e14615 

Sahar, Sumrin 6612 

Sahasrabudhe, Deepak M. 

e15132 

Sahebi, Firoozeh 6545, 8038, 

8089 

Sahin, Aysegul A. 1130 

Sahin, Berksoy e11088 

Sahin, Ugur e11020, 

e11092, e11509 

Sahmoud, Tarek 512, 540, 

551, 559, TPS648, 4081 

Sahmoun, Abe E e21125 

Sahoo, Tarini Prasad 

LBA7507 

Sahovic, Entezam A. 6620 

Sai, Yang 3038, 3040 

Saiag, Philippe 1566, 8540, 

8591, 8601 

Saiagh, Soraya e19019 

Said, Jonathan W. e13045 

Said, Rabih 10607 

Saida, Isamu e14622 

Saida, Yoshihisa 3569 

Saif, Wasif M. 3522, 3523, 

3525 

Saigal, Kunal 595, e16001 

Saigí, Eugeni 4079 

Saigusa, Susumu e14029, 

e14039, e14541, e21053 

Saijo, Nagahiro 6112, 7003, 

7017, 7028 

Saijo, Yasuo 7561 

Saikia, Junmi e15084 

Sailer, Scott Lee 9537 

Sailors, Mary H 6551, 8091, 

9083, 9140 

Saini, Ashima e11084 

Saini, Kamal V.S. e21010 

Saint-Martin, Jean-Richard 

1055, e13549 

Saint-Pierre, Christine 634 

Saintigny, Pierre 5524 

Sainz de la Cuesta, Ricardo 

1111 

Sainz Jaspeado, Miguel 3096 

Sairi, Alisa 10051, e20509 

Sait, Sheila N.J. 6565 

Saita, Naoki e18059 

Saito, Akihisa 5084 

Saito, Hideyuki e13072 

Saito, Hiroshi 7521 

Saito, Kanako e19546 

Saito, Kayoko e21108 

Saito, Kazutaka e15071 

Saito, Mari 1106 

Saito, Naoko e19611 

Saito, Norio 3524, 3569 

Saito, Ryota 7086, 10569, 

10604, e18004, e18014, 

e18017 

Saito, Tatsuro e18064 

Saito, Yuki 565 

Saiura, Akio 3625, e14506 

Saji, Shigetoyo 3607 

Sajjad, Monique 1585 

Sakaguchi, Masahiro e18126 

Sakai, Asao e17540 

Sakai, Hiroshi 7012, 7028, 

7515, 10542 

Sakai, Kazuko 10569 

Sakairi, Yuichi 7046 

Sakakibara, Tomohiro 7086, 

7565 

Sakamaki, Hisashi 6533 

Sakamoto, Junichi 1106, 

3607, TPS3642, e14123 

Sakamoto, Kazuhiro e14139 

Sakamoto, Michiie 4104 

Sakamoto, Susumu e18127 

Sakamoto, Yasuo e13553 

Sakamoto, Yoshihiro e14506 

Sakar, Burak e14628 

781s

Sakata, Shinya e18059 

Sakata, Yuh 3593, e14062 

Sakatani, Toshio 10569, 

10604, e18004, e18014, 

e18017 

Sakellis, Chris 8552 

Sakihama, Hideyasu 10578 

Sakr, Amr Yehia 5557 

Sakr, Bachir Joseph 1034, 

1045, 5040 

Sakr, Rita 10618 

Saks, Sam TPS10100 

Sakurada, Mutsumi e14139 

Sakurai, Toshihiko e15057, 

e15088 

Sakuramoto, Shinichi 4012 

Sakuyama, Naoki e14004 

Sala, Nuria 1588 

Salajka, Frantisek e18062 

Salamon, Hugh 5074 

Salani, Ritu e15585 

Salanova, Ruben e14109 

Salas, Sébastien 10042 

Salat, Christoph e13095^, 

e13097^, e13108^, 

e21067 

Salati, Michele e21070 

Salaun, Pierre-Yves TPS646 

Salazar, Maria Teresa e12033 

Salazar, Ramon 3510, 3571, 

4122, TPS10632 

Salcedo, Maite 7041 

Saleh, Mansoor N. LBA3501, 

TPS3640, TPS4697 

Salek, Tomas TPS4677, 

e15028, e19020 

Salem, Ahmed Abdel-Fattah 

e15024 

Salem, Ayman Maher e21055 

Salem, Jonas Hauben e14101 

Salem, Marwa 552 

Salem, Mohamed E. 2081, 

5534, e14609 

Salem, Naji e15155, e19539 

Saleri, Jessica 9120 

Salerno May, Kilian e14659, 

e14712, e19041 

Sales De Gauzy, Jerome 

10076 

Sales, Elizabeth 5029 

Salesi, Nello e19501 

Saletan, Stephen 4014 

Salgado, Roberto 507, 

e21010 

Salgia, Ravi 7508, 7533, 

7596, 7599, 7600, 

e17549 

Salhi, Yacine e15007 

Salice, Placida e18026 

Salido, Marta 4580 

Salim, Muhammad 1036 

Salimi, Ghobad 6556 

Salinas, Claudia A. e15205 

Salkeni, Mohamad Adham 

TPS3116, e16017 

Sallan, Stephen E. 9530 

Salles, Gilles A. 2539, 8021, 

8068 

Sallman, David A e18520 

Salloum, Ramzi George 4647, 

e18144 

Salman, Reem 1113, 

e19601, e21147 

Salmasi, Amirali H e15214 

Salmen, Jessica 1600^ 

Salmon, Asher 10034 

Salmon, Isabelle e19026 

Saltarelli, Francesca e17006, 

e18563, e18566 

Saltel, Pierre 9080 

Saltman, Benjamin TPS5601, 

e16026 

Saltz, Leonard 3563, 3583, 

6073, 9094, e14112 

Salud, Antonia 3586 

Salud, Antonieta e14041, 

e14097 

Salva, Silvia 2515 

Salvador Bofill, Francisco 

Javier e11081 

Salvador Bofill, Javier 10608 

Salvador, Christopher G. 6553 

Salvador, Javier e11075, 

e11535, e21088 

Salvador, Wenimar e17547 

Salvadori, Barbara 629 

Salvagni, Stefania 4006 

Salvajoli, Joao Victor e15509, 

e16046 

Salvat, Jacques 9011 

Salvati, Mark e16053 

Salvatierra, Alejandro e14521 

Salvatore, Lisa 3518, 3540, 

3546, 3549, 3555, 3585, 

3597 

Salvesen, Helga B 5010 

Salvini, Jessica 3521, 

e21018, e21095 

Salvini, Piermario 623 

Salvioni, Roberto 4507, 4629 

Salvucci, Marzia 6531 

Salwen, Helen 9534 

Salz, Talya 6073 

Salzberg, Marc Oliver e18012 

Salzer, Wanda L. CRA9508 

Samadi, David B. e15164 

Samalin, Emmanuelle 3633, 

4087 

Samanez Figari, César 

e18524 

Samaniego, Felipe 8067 

Samant, Meghna 528 

Samant, Sandeep 5500 

Samaras, Panagiotis 3595 

Sambataro, Daniela e15544, 

e18026 

Samlowski, Wolfram E. 8527, 

10614 

Samoilova, Olga S 8018^ 

Samonigg, Hellmut 514, 

TPS3641^, 10501, 

e14066 

Sampaio, Carlos e11087 

Sampath, Sagus TPS5602 

Samper, Esther e21035 

Sampson, John Howard 

2090^, 2094^, 2095^, 

TPS2103 

Samrao, Damanzoopinder 

5091 

Sams, Katherine 9108 

Samsa, Julia e18046, 

e18085 

Samson, Benoit LBA3500^, 

3572 

Samson, Solene e14065 

Samson, Susan e11096 

Samstein, Benjamin 4101 

Samuel, Leslie M. TPS3637 

Samuel, Thomas A. 8531 

Samuels, Judith 7049 

Samuels, Michael 7049, 

e16001 

Samuelson, Megan I e15580 

Samura, Osamu 5084 

San Juan del Moral(1), 

Alberto e11543, e19596 

San-Miguel, Jesùs F. 8095, 

TPS8112, TPS8113, 

e18572^ 

Sanabria, Sandra 2568, 

e13048 

Sanborn, Rachel E. 7546, 

e13550 

Sanchez Rovira, Pedro 1059, 

10616 

Sanchez Torres, Jose Miguel 

e18011 

Sanchez Torres, Jose Miguel 

e18055 

Sánchez, Antonio 3618, 

e18011, e18521 

Sanchez, Belen 4579 

Sanchez, Bertha E. e15174 

Sanchez, Eric e18549 

Sanchez, Jose Angel e19515 

Sanchez, Jose Javier 4068, 

4579, 10594, e14521, 

e18130, e18131, e18137, 

e18143 

Sanchez, Jose Luis e19576 

Sanchez, Jose Miguel 7011, 

7540 

Sanchez, Lara 9073 

Sanchez, Lorena e15111 

Sanchez-Avila, Carmen 1570 

Sanchez-Hernandez, Alfredo 

e15149, e17545, e18011, 

e18049, e18053 

Sanchez-Lara, Karla e19594 

Sanchez-Muñoz, Alfonso 

10616 

Sánchez-Ollé, Gessamí 509, 

566, 619, 3014 

Sanchez-Pla, Alex 10511 

Sánchez-Rovira, Pedro 1011, 

10608 

Sanchez-Simon, Raquel 

10500 

Sanchez-Tillo, Esther e21035 

Sancho, Aintzane e11525, 

e17522, e18031, e21009 

Sancho, Blanca 642 

Sancho, Francesc e14552 

Sancho, P e19023 

Sanda, Martin G. 4521 

Sanda, Takaomi e13586 

Sandadi, Samith 2586 

Sandanayaka, Vincent 1055, 

e15200 

Sandberg, Rickard 10539 

Sandecki, Anita TPS4687 

Sanden, Mats Olot 10528, 

10575, e21008 

Sandene, Erin K. TPS3638 

Sander, Chris 4527 

Sander, Cindy 8533, 8547 

Sanders, Heather 8596 

Sanders, Joyce 562 

Sanders, Karen 4509 

Sanders, Lea 1084 

Sanders, Melinda 510, 1024 

Sanders, Sheri e21152 

Sandhu, Gurdarshan Singh 

4594 

Sandhu, Shahneen Kaur 

4553, e13601, e15134, 

e15136 

Sandhu, Sonia 8085 

Sandin, Rickard 6092, 

e16530 

Sandler, Alan 7094, 

TPS7609 

Sandler, Andrew TPS4673 

Sandor, George 9529 

Sandor, Victor TPS6643^ 

Sandoval-Sus, Jose D e18109 

Sandoval-Tan, Jennifer 7519^ 

Sands, Colleen B. 6095, 

6128 

Sands, Robert e15193 

Sanfilippo, Nicholas e16052 

Sanfilippo, Roberta 10053, 

e19549 

Sanford, Tiffany 3630 

Sanft, Tara Beth 9007, 

e16511 

Sang, Jim 3090 

Sangai, Takafumi 1054, 

e14662 

Sangale, Zaina 7023 

Sangalli, Claudia 10065 

Sangha, Randeep e13011 

Sangiolo, Dario 10066 

Sangro, Bruno TPS4148, 

e14654 

Sanhes, Laurence 8026 

Sanjay, Gupta e14664 

Sanjuan, Xavier 10052 

Sankhala, Kamalesh 10036 

Sanmamed, Miguel F. 8572 

Sanmartin, Elena 7058, 

7060, 10594 

Sanmugarajah, Jasotha 

e19598 

Sanna, Stefano e17546 

Sano, Fumiho e17517 

Sano, Go e18127 

Sano, Takeshi 4012, 10541 

Sanpajit, Theeranun 4108 

Santaballa, Ana 5068, 

e11081, e15575 

Santacruz, Mayra e15571 

Santagata, Sandro 2020 

Santamaria-Galicia, Julieta 

e12027 

Santamarina Cainzos, Isabel 

e14595, e15076, e15077, 

e15079 

Santana, Iuri amorim 2038 

Santana, M. Christina 6097 

Santana, Rosane O e16046 

Santana-Davila, Rafael 1089, 

e17555 

Santander Lobera, Carmen 

TPS4672 

Santarpia, Libero 1012 

Santarpia, Mariacarmela 

7522, 7542, e18039 

Santegoets, Saskia 2562 

Santel, A. e13597 

Santella, Regina 4101 

Santi, Patricia e19552 

Santiago Crespo, JA e19590 

Santiago, Karen J. e11015, 

e18547 

Santiesteban, Eduardo Rafael 

2527 

Santillo, Barbara 1500 

Santin, Alessandro 5099, 

e13078, e13125, e15526, 

e15581 

Santinami, Mario 8513, 

8529, 8559 

Santinelli, Alfredo e21070 

Santini, Daniele 4627, 9005, 

10063, e14135 

Santini, Donatella e14647 

Santini, Fernando Costa 

e11014 

Santomé, Lucía e15067, 

e15076, e15077 

Santoni-Rugiu, Eric 10617 


Santoro, Armando 615, 623, 

2580, 3007, LBA4001, 

4006, 4115, 4117, 4545, 

7061, 7082, 7085, 7585, 

TPS10101, e13095^, 

e13097^, e14672, 

e18100, e18104, e21139 

Santoro, Joseph e15138 

Santos Borges, Giuliano 

e12035 

Santos Cores, Jesus e14097 

Santos Ortega, Manuel 

e16025 

Santos, Carlos F. 2528 

Santos, Cristina 9090 

Santos, Edgardo S. e13032, 

e16001, e17564, e18109 

Santos, Elizabeth S. 643, 

e18078 

Santos, Elizabeth Santana 

e14680 

Santos, Erika Maria Monteiro 

e14119 

Santos, Evandro Airton Sordi 

dos e12512 

Santos, Fábio Nasser e11058 

Santos, José Sebastião 

e14599 

Santos, Marcos Antonio 3063 

Sanyal, Arun e14581 

Sanz, Ignacio 1111 

Sanz, Julian 10564 

Saphner, Thomas James 605 

Sapino, Anna 10554 

Sapolsky, Jeffrey 2503^ 

Saponara, Maristella 10087 

Sappington, Sandra 6132 

Sapunar, Francisco J. 

TPS4140 

Saracino, Valeria e18048 

Saragiotto, Daniel F. e14702 

Saralli, Erminio e19002 

Saran, Frank TPS9596, 

10060 

Sarangarajan, Rangaprasad 

3015, e14593 

Sarangi, Manas ranjan 7102 

Sarantopoulos, John 3060, 

3073, 3078, 4603, 

e15116 

Sardesai, Sagar D 6565 

Sargent, Daniel J. 2004, 

3502, 3514, 3526, 3564, 

3576, 3617, 10602 

Saric, Nera e21126 

Sarici, Saim Furkan e11020 

Sarina, Barbara 6541 

Sarkar, Fazlul H. 1560, 

e21057 

Sarkar, Sudipa 10558 

Sarkaria, Jann Nagina 2031, 

2032, 7073, e14507 

Sarker, Debashis 3022 

Sarkisian, Saro 8533 

Sarma, Deesha 1577 

Sarma, Syam e14141, 

e14146, e15183, e18097 

Sarnaik, Amod 2511 

Sarno, Francesca 3068 

Sarno, Maria Anna 1554 

Sarno, Mark J. e15113 

Sarobba, Maria Giuseppa 

LBA7501 

Sarr, Celine 2543 

Sarta, Catherine e16058 

Sartelet, HervÃ© 9563, 9570 

Sarti, Manuela 4661 

Sarti, Samanta e11054 

Sarto, Gloria 1501 


Sartor, A. Oliver LBA4512, 

4513, 4515, 4551, 4652, 

TPS4696^, 10623, 

e15130 

Sartore-Bianchi, Andrea 3570 

Sartorelli, Alan e13125 

Sartorius, Ute 3562, 3603, 

e14043 

Sarvadikar, Ajit 4553 

Sasada, Shinji e18036, 

e18042 

Sasada, Tetsuro e13046, 

e13050 

Sasajima, Yuko 5085 

Sasaki, Clarence 5529, 5532 

Sasaki, Fumiaki 9577 

Sasaki, Hidefumi 7510, 7532 

Sasaki, Jiichiro 7045, 

e13072, e18059 

Sasaki, Katsuhiro 8094 

Sasaki, Koji 8040 

Sasaki, Masaoki 585 

Sasaki, Miyuki e18134 

Sasaki, Naoki 5037, e15579 

Sasaki, Ryohei e16034 

Sasaki, Shinichi e18019 

Sasaki, Takaaki e18135 

Sasaki, Toru 10557 

Sasaki, Yasutsuna 3084, 

3088^ 

Sasako, Mitsuru 4012 

Sasane, Medha 10094, 

e16537, e20511 

Sasano, Hironobu e11530 

Sasatomi, Teruo e14077 

Saseen, Joseph e16541 

Saskin, Refik 1123 

Sassa, Naoto e15068 

Sasse, Andre Deeke e14150 

Sassi, Salem 2530 

Sassolas, Bruno 1566, 8601 

Sastre, Javier CRA3503, 

3571, 4119, e14147 

Sastre, Xavier e15524, 

e15535 

Satchithananda, Keshthra 

e21137 

Satele, Daniel 6133 

Sathaiah, Magesh e14184 

Sathya, Abhinay 6130 

Sathya, Jinka 4509 

Sathyanarayanan, Sriram 

3531, 3587, 4054 

Sato, Atsushi 4035 

Sato, Ayuko 7080 

Sato, Fumiaki e21031 

Sato, Kaori e19586 

Sato, Kazuhiko TPS659, 

e11007 

Sato, Keiko e19557 

Sato, Keita e18127 

Sato, Kenichi 7046 

Sato, Koichi e14139 

Sato, Masayo e16537 

Sato, Ryo e18059 

Sato, Takami 8560, e19016 

Sato, Takashi e18058 

Sato, Tomomi e11060 

Sato, Toshihiko 3524, 3607 

Sato, Tsuyoshi e14004 

Satoh, Hiroyuki 9569 

Satoh, Toyomi 5006 

Satomi, Ryousuke e18058 

Satou, Mototaka e15065 

Satouchi, Miyako 7003, 

7070, 7521, e18060, 

e18134 

Satpute, Shailesh R. 4534 

Satram-Hoang, Sacha 6007 

Satre, Jose Manuel 4587 

Sattler, Christopher A. 4009 

Satwani, Prakash 6537 

Sauer, Annette 6566 

Sauerland, Maria Cristina 

6610 

Saunders, Ed 1545 

Saunders, Mark P. e14015 

Saura, Cristina 508, 509, 

566, 619, 3014, 3021, 

10511 

Saura, Ryuichi e17020 

Saura, Salvador e18015 

Saussele, Susanne 6510 

Sausville, Edward A. 6611 

Sauter, Craig Steven 2008, 

2089 

Sauter, Guido 10501 

Sauter, Matthias 4632 

Sautiere, Jean-Loup 568^ 

Sauve, Anthony e13545 

Sava, Teodoro e15160 

Savage, Dionne T 4055 

Savage, Kerry J. 8060 

Savage, Sharon H 5563 

Savarino, Graziana e21065 

Savas, Burhan e14070 

Savas, Sevtap 7586 

Savignoni, Alexia 9538 

Savin, Michael A. 3069 

Savin, Michael 3590 

Savini, Agnese e21070 

Savion, Naftaly 2556, 

e13080 

Savoldo, Barbara 2558 

Savona, Michael R. TPS6636 

Savona, Steven R. TPS5601 

Savulsky, Claudio Isaac 2552 

Savva-Bordalo, Joana e15532 

Savvoukidis, Theodoros 

e14707 

Sawa, Toshiyuki 7017 

Sawada, Satoshi e14500 

Sawada, Takashi 3079 

Sawaki, Akira e14510 

Sawaya, Raymond 2019 

Sawitzki, Birgit e15053 

Sawyer, Emma 1545 

Sawyer, Michael B. 3504 

Sax, Cornelia 2071 

Saxena, Ashish e18029 

Saxena, P.U. Prakash 5526 

Saxena, Renu e17000 

Saxman, Scott 7502 

Saxton, Jerrold P. e14611, 

e14665 

Saya, Hideyuki 635 

Sayar, Hamid TPS6637 

Saydam, Serdar e11507 

Sayer, Herbert G e15026 

Saylor, Philip James 4566 

Sbar, Eric TPS2615 

Sbenghe, Maria Magdalena 

e19016 

Sbidian, Emilie 5554 

Scafati, Chiara e18023, 

e18101 

Scagliotti, Giorgio V. 3579, 

7549, 7551, 7599 

Scagliotti, Giorgio TPS7109, 

TPS7619 

Scala, Stefania e11052, 

e13539 

Scaletta, Giuseppe 5093, 

5094, e15547, e15550, 

e15551, e15553 

Scambia, Giovanni LBA5003, 

5059, e13095^, e13097^ 

Scanni, Alberto LBA7501 

Scapulatempo Neto, 

Cristovam e14599 

Scardina, Angela 3020 

Scardino, Peter T. e15196 

Scarlattei, Maura e18096 

Scarpa, Aldo 4076, e14042, 

e14625 

Scarpelli, Giovanni e19038 

Scarpi, Emanuela 1099, 

10615, e11054, e17546 

Scartozzi, Mario e14040, 

e14086, e14561, e14663, 

e15074 

Scelzi, Elvira e19595 

Scepura, Barbara 7033 

Schaapveld, Michael 8039 

Schache, Andrew 5543 

Schacherer, Christopher W 

8536 

Schachter, Jacob 8517 

Schackert, Hans K. 3550 

Schad, Arno TPS4140 

Schadendorf, Dirk 8501, 

8505, LBA8509, 8511, 

8518, 8526, 8532 

Schaefer, Claus 4072 

Schaefer, Fritz Werner 1084, 

e13503 

Schaefer, Inga-Marie e21128 

Schaefer-Hesterberg, Gregor 

8535 

Schafhausen, Philippe 5516^, 

6511 

Schairer, Catherine 1521 

Schalke, Berthold 7105 

Schall, Thomas J. 2043, 

e13580 

Schallier, Denis C. C. 4622 

Schally, Andrew V e15153 

Schalper, Kurt 573 

Schapira, Lidia 1122, 9071, 

9100 

Scharl, Anton J. 2560 

Schatlo, Bawarjan 2068 

Schattner, Mark TPS4144 

Schaub, Betty 9564 

Schaub, Richard 2500^ 

Schauer, Dominic e14099 

Schauer, Matthias e14527 

Schechter, Geraldine P. 8103 

Scheel, Birgit 2573^ 

Scheeren, Ferenc 2514 

Scheetz, Janet S. e17002 

Scheff, Ronald J. e18029 

Scheffler, Matthias 3044, 

TPS3115, 7603, 10526 

Scheffold, Christian 4513 

Schefter, Tracey E. 4062 

Scheier, Benjamin 7526 

Scheithauer, Bernd W. 2008b 

Scheithauer, Werner 

LBA3500^, e14681 

Schell, Michael J. 2544, 

2559, e21155 

Schellenberg, Devin e14537 

Schellens, Jan H. M. 2540, 

2550, 2596, e13028, 

e13596 

Schellens, Jan HM e13594, 

e13598 

Scheller, Herbert 5051 

Schellhammer, Paul F. 4, 

4571, 4648 

Schelman, William R. 3101, 

3103, e13601, e14554 

Schem, Christian 1084, 

e13503 

Schenk, Marcus 4539 

Schenk, Nora TPS6640 

783s

Schenkein, David P. 6606 

Schepp, Wolfgang 4072 

Scher, Howard I. 4513, 

4516, 4517, LBA4518, 

4519^, 4548, 4558, 4562, 

TPS4689, TPS4697, 

TPS4700 

Scherer, Stefan TPS3635^, 

10581 

Scherer-Rath, Michael 

e19560 

Scherle, Peggy A 2500^ 

Schernhammer, Eva S 1556 

Scherpereel, Arnaud 

TPS7112, e18006, e18066 

Schetelig, Johannes 6584 

Scheulen, Max E. 2086, 

8532, 10032^ 

Schiano De Colella, 

Jean-Marc 8026 

Schiantarelli, Clara 8046 

Schiavo, Roberta 3570 

Schiavon, Gaia 10063, 

10091, e14135 

Schiavone, Paola e11001, 

e11547 

Schiff, Bradley A. e16058 

Schiff, David 2006, 2031, 

TPS2107 

Schiff, Susan 6035 

Schiffer, Charles Alan 6506 

Schiffman, Joshua David 

9525, 9561 

Schild, Steven E. 6108, 

7073, 7605 

Schilder, Jeanne e15561 

Schilder, Russell J. 3029 

Schilder, Russell 5021 

Schildgen, Oliver e18000 

Schildgen, Verena e18000 

Schildhaus, Hans-Ulrich 1533 

Schiller, Gary J. TPS6637 

Schiller, Joan H. 7516, 7589 

Schilling, Joerg Peter e19540 

Schilsky, Richard L. e13106 

Schimanski, Carl Christoph 

TPS3641^ 

Schimmoller, Frauke 8531 

Schimp, Veronica L. 5012 

Schindlbeck, Christian 1600^ 

Schindler, Fernanda e19552 

Schink, Julian C. 1553, 

5039, 6120, e15523 

Schinzari, Giovanni e16553 

Schipper, Joerg e16033 

Schipper, Matthew J e14603 

Schirm, Sabine 3590 

Schirmacher, Peter e18016^ 

Schirripa, Marta 3518, 3540, 

3546, 3549, 3555, 3585, 

3597, e13057, e14040 

Schirrmacher-Memmel, Silke 

4539 

Schlaak, Max 3044, e19031 

Schlag, Peter M. 3508 

Schlag, Rudolf 4065 

Schlattmann, Peter TPS4138 

Schlegel, Mariette 10596 

Schlegel, Uwe S. 2040, 8031 

Schleicher, Jan e15026 

Schlesinger, Andreas 1533, 

10526, CRA10529 

Schlichting, Michael 3562, 

3574, 3591, e14043 

Schlom, Jeffrey 2526, 2577, 

TPS2617, TPS3638, 

TPS4701 

Schloms, Anna 9094 

Schlossman, Robert L. 8012 

Schlumberger, Martin 5508, 

5518, 5569, 5591 

Schmalenberg, Harald 4080, 

4083, 4090, e21063 

Schmalfeldt, Barbara 5001, 

5005, e13100^ 

Schmandt, Rosemarie e13516 

Schmeler, Kathleen M. 5027 

Schmelz, Hans U. 4530 

Schmelzel, Mark e16513 

Schmid, Jasmin e12031 

Schmid, Martina e19032 

Schmid, Peter 624 

Schmid, Roland M. 4034 

Schmid-Bindert, Gerald 7554 

Schmidinger, Manuela 

e15083, e15090, e19502 

Schmidt, Brian L. e16052 

Schmidt, C. Max e21048, 

e21121 

Schmidt, Emmett V. 3531 

Schmidt, Henrik 8545 

Schmidt, Joachim 10080 

Schmidt, Lindsay A. 2602 

Schmidt, Manuel 4636, 

e14152 

Schmidt, Marcus 542, 556, 

640, 1077, 10551 

Schmidt, Mary Lou 9533 

Schmidt, Rodney 5515 

Schmidt-Hieber, Martin 

e18552 

Schmidt-Wolf, Ingo GH 4636 

Schmiegel, Wolff H. 3550 

Schmier, Johann Wilhelm 

10040 

Schmitt, Anita 6567 

Schmitt, Michael 6567 

Schmitt, Nicola 6527 

Schmitt, Thomas 10040, 

10041^ 

Schmitt-Bormann, Beate 

TPS4139 

Schmitz, Arndt 10536, 

10537, e21017 

Schmitz, Joerg e15044 

Schmitz, Kathryn TPS669 

Schmitz, Norbert 6543, 

8004, 8022, 8024, 8025 

Schmitz, Sandra 5519 

Schmitz, Shu-Fang 9059 

Schmitz, Stephan H. 1533, 

10526, CRA10529 

Schmoll, Hans-Joachim 3522, 

3523, 3525, 3578, 

e14152, e19579 

Schmucker-Von Koch, Jospeh 

6002, 7607 

Schmulewitz, Nathan e14714 

Schmutzler, Andreas Gerd 

1084 

Schnabel, Catherine A. 561, 

10530, 10588, e21019 

Schnadig, Ian D. 3024, 

e15089 

Schneebaum, Schlomo 8534 

Schneeweiss, Andreas 554, 

1059, 1077, 1090, 1096, 

TPS1146, 1600^, 1602, 

10540, e13095^, e13097^ 

Schneider, Anneliese 4034 

Schneider, Bryan J. 7546 

Schneider, Bryan P. 6025, 

7032, 7107, 7108 

Schneider, Charles e18122 

Schneider, Coursen 4517 

Schneider, Guenther 4107 

Schneider, Jeffrey Gary 

e21114 

Schneider, Lars 8505 

Schneider, Robert e11064, 

e11529 

Schneider, Vanessa 6567 

Schneider-Kappus, Wolfgang 

4065 

Schneiderman, Rosa S. 

e14616 

Schnell, Patrick 7598 

Schnell, Roland 1533, 3044, 

10526 

Schneller, Folker 2573^ 

Schnittger, Susanne 6510, 

6610 

Schoen, Michael TPS3641^ 

Schoenegg, Winfried 640, 

1077 

Schoenewolf, Nicola L 8563 

Schoengen, Alfred 8535 

Schoettle, Glenn P e17531^ 

Schoffski, Patrick 535, 1020, 

2540, 4622, 5508, 

LBA10008, 10009, 10013, 

10091 

Schofield, Penelope 6111 

Schofield, Penny e18068 

Scholl, Suzy Marie Elisabeth 

e15535 

Scholz, Christian Winfried 

8031 

Scholz, Christoph 1072, 

1600^, 1602 

Scholz, Hans-Jorg e15112 

Schoor, Oliver 2522, 3530 

Schorb, Elisabeth 2040 

Schore, Reuven J. 9543 

Schorge, John O. 5029, 

e15545, e15568 

Schori, Clara e16055 

Schorno, Kevin e13568 

Schott, Roland e18005 

Schott, Sarah 1090 

Schotzinger, Robert J 4671, 

e15167 

Schouten, Viviane 6535^ 

Schpero, William Lewis 6013 

Schrader, Iris 554, 1077 

Schrader, Mark 4530 

Schrag, Deborah 3537, 6003, 

9047, e19586 

Schraml, Peter 2055 

Schreeder, Marshall T. 

6518^, 8032 

Schreier, Jörg 1600^ 

Schriner, Megan 9110 

Schroder, Henrik 9590 

Schroeder, Brock e21019 

Schroeder, Jan 640 

Schroeder, Sebastian Edoardo 

Artur 8575 

Schroeder, Wendy e21152 

Schroeder, Willibald 5005 

Schroers, Roland 8031 

Schrof, Inga 5051 

Schroff, Matthias 4636, 

e14152 

Schrope, Beth e14708 

Schroth, Gary P. 10539 

Schroyens, Wilfried A. 2506 

Schrump, David S. 7103 

Schubert, Erin K 1088, 

TPS3109 

Schubert, Joerg 8022 

Schubert, Jörg 6543 

Schuchert, Matthew J. 7071, 

7074 

Schuchter, Lynn Mara 3102, 

8503^, 8534, 8567 

Schueller, Katharina 10540 

Schueneman, Aaron e14585 

Schuette, Kerstin TPS4148 

Schuette, Wolfgang TPS7109, 

7554, e18016^ 

Schuetz, Florian 1090, 1096 

Schuetze, Scott 10003, 

10028 

Schuh, Anna 6584 

Schuhmacher, Christoph 

4095^ 

Schuler, Gerold e19032 

Schuler, Markus Kajo 10068 

Schuler, Martin H. 2086, 

LBA7500, 7557, 7558, 

10032^, 10046, e13605 

Schuler-Thurner, Beatrice 

e19032 

Schulick, Richard D. 3596, 

e13559 

Schully, Sheri D 3567 

Schulman, Kevin A. 1525, 

6047, 6051 

Schulmann, Karsten 3550, 

4083 

Schulte, John e19058 

Schulte, Nathan 7534 

Schulte, Wendy e21090 

Schultes, Birgit Corinna 4056 

Schultheis, Beate e13597 

Schultz, Christopher J. 2001 

Schultz, Johan 6557 

Schultz, Kris Ann 

Pinekenstein 9521, 9522 

Schulz, Christoph 4072 

Schulz, Holger CRA10529, 

e13100^ 

Schulz, Stephanie e14619 

Schulz, Ulrike 1084 

Schulze, Mathias 3588 

Schumacher, Claudia 1077 

Schumann, Christian 7531 

Schupp, Clayton 6050 

Schuster, Stephen J. e18529, 

e18540 

Schuster, Tibor 10012 

Schusterbauer, Claudia 3010 

Schutt, Tessa e15010 

Schutz, Fabio A. B. 4577, 

4580 

Schutz, Fabio Augusto Barros 

4543, 4582, 4585, 4635, 

e15007 

Schuur, Eric e21022 

Schwaab, Thomas e15039, 

e15042, e15046, e15204 

Schwachula, Tim 5053 

Schwarb, Heike 10033 

Schwarer, Anthony P. 6505^ 

Schwartz, Ann G. 6038, 

7037, 7063, 7593 

Schwartz, Antonia e21128 

Schwartz, Benjamin M 5062^ 

Schwartz, Brian E. 4006, 

4117, 4545, 8519 

Schwartz, Cindy L. 9503, 

9524 

Schwartz, David L. TPS5601, 

e16026 

Schwartz, Edward L e18113 

Schwartz, Erich 10574 

Schwartz, Gary K. 8549, 

8575, 8598, 10002, 

10003, 10004, 10019, 

TPS10099, TPS10103, 

e13588, e13600^, e14586 

Schwartz, Gary e21125 

Schwartz, Jonathan D. 

TPS4675^, 5012 


Schwartz, Kendra L. 6023, 

e15147 

Schwartz, Kenneth A. 2056 

Schwartz, Lawrence H. 2541, 

4507, e13064, e19647 

Schwartz, Marc D 1608 

Schwartz, Myron E. 4033, 

e14729, e14732 

Schwartz, Peter E. TPS1614, 

5099, e13125, e15526, 

e15581 

Schwartzberg, Alison e21077 

Schwartzberg, Lee Steven 

1016, TPS1137, 2569, 

3085, 7002, 7502, 

e19511, e21077 

Schwarz, Donald E. 10037 

Schwarz, Luis Jesus 2097, 

e11518, e15036 

Schwed, Daniel 7077 

Schwed-Lustgarten, Daniel 

7092 

Schwedler, Kathrin 556 

Schweizer, Charles 7030 

Schwentner, Christian e19021 

Schwentner, Lukas 1078, 

1082 

Schwiep, Frances 10094, 

e20511 

Schwock, Joerg e14535 

Schäfer, Henning S e13515 

Schäfer, Reinhold e21005 

Schöder, Heiko 4517 

Schöffski, Patrick 3018^, 

10030, 10047 

Schönemann, Constanze 

e15053 

Schønnemann, Katrine 

Rahbek e14517, e14633 

Sciacca, Dorotea e18002 

Sciamanna, Chris 7055 

Sciandivasci, Angela 546, 

1049, 1115 

Sciot, Raf 9536, 10030 

Sclafani, Francesco 615 

Scoazec, Jean-Yves 4129 

Scola, Michael A. 10530, 

e21023 

Scorilas, Andreas 5574, 

10606 

Scott, Alastair 3516 

Scott, Amie 9042, 9043 

Scott, Andrew Mark 8547, 

e13054, e15056 

Scott, Brian J. 2052 

Scott, Charles B. e19606 

Scott, Clare L. 5073 

Scott, Jeffrey A. e16540, 

e16552 

Scott, Richard W 9119 

Scott, Sasinya N. 4604 

Scotte, Florian e19640 

Scotto, Luigi e13569 

Scriboni, Sonia 9098 

Sculier, Jean Paul e18006 

Scurr, Michelle R. 10039, 

10060, 10086 

Scurr, Michelle 10038 

Seah, Davinia Shien 6089 

Seal, Brian S. e14013, 

e14016, e14035, e14056, 

e14106, e14141, e14146, 

e14522, e14626, e14638, 

e15146, e15148, e15175, 

e15183, e18097 

Sears, Alan K. 625, 2508, 

2529 

Seay, Thomas E. TPS657 


Sebag-Montefiore, David 

4004, 4029 

Sebastian, Lucille T 7079^ 

Sebastian, Martin 2573^ 

Sebastian, Nikhil 9544 

Sebban, Catherine 8068 

Sebe, Philippe e15105 

Sebesta, Christian e14087 

Sebio, Ana e14104 

Sebrow, Dov e15164 

Sebti, Rani e19641 

Seckl, Michael 2608, e13033 

Secord, Angeles Alvarez 5101 

Secreto, Charla e13517 

Sedda, Tito e14094 

Sederias, Joana 2051 

Sedlacek, Scot M. 547 

Sedlmaier, Benedikt 5512 

Sedova, Michaela 4081 

See, Lionel e18528 

See, Siewju 2066 

Seedhouse, Claire 1014 

Seeger, Grant R. 9001 

Seehofer, Daniel TPS3641^ 

Seery, Virginia Jean 8516 

Seetalarom, Kasan TPS7614 

Seetharam, Raviraja e14019 

Seetharam, Shobha 3059 

Seetharamu, Nagashree 

e16052, e18139 

Seftel, Matthew D. 8002 

Segal, Michal e14586 

Segal, Neil Howard 4057, 

9105 

Segalla, J.G.M. 5017^, 7512 

Segati, Romana e13019 

Segawa, Yoshihiko 7042, 

7560 

Segelov, Eva e13054 

Seggewiss-Bernhardt, Ruth 

2504 

Seghers, Amelie Clementine 

e19026, e19027 

Segnan, Nereo 1500 

Segni, Jessica 6123 

Seguí-Palmer, Miguel Angel 

1001, 10500, 10616 

Seguin, Carole TPS1139 

Segura Gonzalez, Eduardo 

Raul e20513 

Segura, Miguel F. 8550, 

8565 

Sehl, Mary Elizabeth e11003 

Sehn, Laurie Helen 8049 

Sehouli, Jalid 5031, 5034, 

5044, 5047, 5053, 5058, 

5064, 5070, 5071, 5080, 

5087, e13095^, e13097^, 

e13100^, e13108^, 

e15520, e15531, e19558, 

e19597 

Sehovic, Marina 6100 

Seibers, Nicholas e13041 

Seidel, Christoph 4631 

Seidensticker, Max e14630 

Seider, Michael J. TPS9150 

Seidman, Andrew David 

1016, TPS1145 

Seif, Alix Eden 1504 

Seifert, Michael 514 

Seijo, Luis Miguel e18008 

Seimetz, Diane 2584 

Seisler, Drew K. 9075 

Seiter, Karen 6520 

Seitz, Gerhard 10554 

Seitz, Jean Francois 4087, 

4091 

Seitz, Jean-François 4036 

Seitz, Robert S. 516 

Seiwert, Tanguy Y. 5500, 

5517 

Seke, Mihalj LBA4512, 4551 

Sekeres, Mikkael A. 6521, 

6522 

Seki, Nobuhiko 1530, 

e18099 

Sekijima, Masaru e21031 

Sekine, Ikuo 7070 

Sekulic, Aleksandar 8579 

Selbach, Johannes 640 

Selby, Brian 4519^ 

Selby, George Basil e17010 

Selby, Peter John 6091 

Selby, Rick e14679 

Selchuk, Vladimir Yur’evich 

e19005 

Selcukbiricik, Fatih e21143 

Selder, Sonja 1092 

Seligman, Mark e11042 

Selinger, Cristina 504 

Selistre, Simone Geiger 

10593 

Sella, Avishay 4564, 4619, 

e15058 

Sella, Tal 1507, 1564 

Sellami, Dalila B. 3099 

Selle, Frédéric 5017^, 5018, 

5067 

Sellecchia, Rita 5591 

Selleslag, Dominik L. D. 

TPS6637 

Selva, Julio Cesar 2515 

Selvarajah, Shamini 4585 

Semba, Hiroshi e13072 

Semenova, Anna Igorevna 

e13059 

Semiglazova, Tatyana 9046 

Semlani, Neha TPS3112 

Semmes, Oliver John e15113 

Sempoux, Christine e14044, 

e14060 

Semrad, Thomas John 3566 

Sen, Fatma e14628 

Sen, Urmi e11522 

Sena, Susana e15570 

Senan, Suresh 7009 

Senapedis, William 1055, 

e13549 

Sencan, Orhan 3565 

Sendrup, Sarah Louise 2565 

Sendur, Mehmet Ali Nahit 

e11009, e11033, e11093, 

e13031 

Senellart, Helene e13010 

Sener Dede, Didem e11011 

Sener, Nur 638 

Senff, Tina 10552 

Seng Yue, Corinne 6619^ 

Seng, Sonia Maria e21016 

Sengar, Manju e17003 

Sengelov, Lisa TPS4696^ 

Sengeløv, Lisa e15115 

Sengupta, Sandip 1123 

Sengupta, Saubhik e13030 

Senju, Hiroaki 7569 

Sensi, Elisa 3521, 3585 

Senzer, Neil N. 3024, 3029, 

LBA3501, e13040, e14546 

Seo, Youngho e21026 

Seoane, J, e15552 

Seoane, Joan 2042, 10511 

Seol, Miee 6564 

Seon, Ben K. 3034, 3042^ 

Seow, Hsien 6039 

Sepkowitz, Kent 6101 

Sepucha, Karen 6025 

Sepulveda, Antonia 4111 

Sepúlveda, Juan Manuel 

2042 

Sepulveda, Juan 4584, 4620, 

e15149 

Sequist, Lecia V. 7010, 

LBA7500, 7509, 7524, 

7525, 7532, 7543, 7546, 

7547, 7556 

Serafini, Aldo N. e13592 

Serdengecti, Suheyla e21143 

Sereni, Maria Isabella e15549 

Sereno, Maria 1570, 9073, 

e11028, e18015 

Sergeev, Urii e15029 

Sergi, Concetta e18026 

Serke, Monika Heidi 1533, 

TPS7109, 10526 

Serke, Monika 7575, 

CRA10529 

Seronde, Audrey e14129 

Serpe, Roberto e19634 

Serpico, Danila 3014 

Serra, Javier 3586 

Serra, Luigi 10601 

Serra, Olbia e18030 

Serra, Patrizia 10601, 10615 

Serra, Stefano 4109, 

e14524, e14535, e14592 

Serrano, Carole 9560 

Serrano, Davide 519, 1500 

Serrano, Gloria 5520, 

e14147, e15094, e18069, 

e18106, e21015 

Serrano, M. Jose 10608 

Serrano, Sergio Vicente 

e14599 

Serrano, Silvia J e18114 

Sertoli, Mario Roberto 8576 

Seruga, Bostjan 558, e16505 

Servent, Véronique e11012, 

e11070 

Servitja, Sonia e11545 

Servois, Vincent 8546 

Serwatowski, Piotr 7090 

Sesikeran, Nanditha 9055 

Sessa, Cristiana 3003, 3048, 

3080, TPS5112 

Seth, Tulika e17000 

Sethi, Seema 1560, e21057 

Seto, Takashi 3045, 7012, 

7521, 7602 

Sette, Giovanni e13512 

Settle, Stephen H 8584 

Settleman, Jeff 5575 

Setton, Jeremy 5537 

Seufferlein, Thomas 

TPS1612, TPS3636, 4034, 

e14564 

Sevestre, Marie-Antoinette 

1580 

Sevilla, Isabel 4119, e14115, 

e14671 

Sevin, Emmanuel CRA4502, 

5018, 9079 

Sevinc, Alper e19024 

Sexton, Rachel 3078 

Seymour, Lesley 2547, 7007, 

7093, 7511, 10602, 

e18079 

Seymour, Matthew T. 

TPS4143, 6091, e16007 

Seynaeve, Caroline M. 516, 

517, 526, 1080, 10504, 

10518 

Sferruzza, Anthony 5510, 

8596 

Sfiniadakis, Ioannis e21098 

Sgarbossa, Gigliola e19595 

Sgroi, Dennis 561 

785s

Sha, Dan 3564 

Sha, Huifang e13528 

Shaaban, Hamid e12025 

Shacham, Sharon 1055, 

4634, e13549, e13586, 

e15200 

Shada, Amber L 8530, 8597 

Shadduck, Richard K. 6620 

Shadman, Mazyar 1527 

Shaeffer, David e14632 

Shafa, Bob B. 2101 

Shafey, Mona 6548 

Shaffer, Thomas 6028, 6060, 

6075 

Shah, Amit 1128 

Shah, Bijal D. 6568, 6608, 

e18503, e18506, e21123 

Shah, Bijal Dinesh e18509 

Shah, Binay Kumar e17005 

Shah, Dhruvil R e19001, 

e19013 

Shah, Gaurav D. 4632, 

10619 

Shah, Jatin J. 8037, 8093, 

e18556 

Shah, Jatin P. 5545^, 5562 

Shah, Kajal e13068 

Shah, Katherine Sanvidge 

e18553 

Shah, Krunal Jitendrakumar 

2530, 3030 

Shah, Manali e13531 

Shah, Manan 8036 

Shah, Manish A. 4061, 

e14586 

Shah, Manisha H. 4047, 

4126, 5508, 5518, 5591, 

e14542, e14551 

Shah, Mazhar Ali e16043 

Shah, Mira e15512 

Shah, Monjri 5036 

Shah, Neil P. 6504, 6506 

Shah, Nina 6546, 6551, 

8040, 8102, 9081, 9082 

Shah, Parth K. e15124 

Shah, Payal D. 1506 

Shah, Preeti 10025 

Shah, Raj J. 4055 

Shah, Raj e14632 

Shah, Riyaz N.H. LBA7500, 

7583 

Shah, Ruchita R. 1028, 1130 

Shah, Shetal N. TPS4684 

Shah, Shilpa Rashmikant 

e15213 

Shah, Trushil e17021 

Shah, Vallabh 1558 

Shaha, Ashok R. 5545^ 

Shahabi, Vafa 8593, 

TPS8603 

Shahan, Mark N. TPS3113 

Shaheen, Mahmoud e20508 

Shaheen, Montaser F. 3009 

Shahid, Tanweer e18043 

Shahidi, Mehdi LBA7500 

Shahinian, Vahakn B. e15147 

Shaik, Mohammed saifullah 

3619, e14046 

Shaikh, Arif 6040 

Shaikh, Asif 3572 

Shak, Steven 552, 1005, 

1021, 3512 

Shakes, LaShaina e13588 

Shalgi, Ruth 2556, e13080 

Shamash, Jonathan 4529, 

4531 

Shamberger, Robert C. 9537 

Shames, David S. 5575 

Shammo, Jamile M. 6577 

Shamonki, Jamie 1105 

Shan, Minghua LBA4512, 

4551, e18100 

Shan, Wen Wen 7020 

Shanafelt, Tait D. 6571, 

e13517 

Shanahan, Marie e19588 

Shang, Aijing TPS9596 

Shang, Shulian 8550, 8557 

Shang, Yuqin 628 

Shani, Adi e14143 

Shankar, Anjali e11097, 

e12004 

Shankar, Lalitha 10602 

Shankaran, Veena 6077, 

e14068 

Shannon, Keith A. e13599 

Shannon, Kevin 6582 

Shao, Guoliang e14605 

Shao, Minhua e13528 

Shao, Qian e13524, e14735 

Shao, Yongzhao 8550, 8557, 

8574, e19003 

Shao, Zhimin 531, e13036 

Shapira, Iuliana 1046 

Shapira-Frommer, Ronnie 

5022 

Shapiro, Charles L. 609, 

1007, CRA9013 

Shapiro, Daniela e15210 

Shapiro, Geoffrey 2566, 

3028, 3039, 3053, 3062, 

TPS3118, 7508, 8531, 

e13598 

Shapiro, Irina M 1057 

Shapiro, Jeremy David 3504, 

3515, 3572, TPS4692^, 

e15047 

Shapiro, Lauren Quinn 5537 

Shapiro, Marc A. e18046 

Shapiro, Richard L. 8550, 

8557, 8565, e19003 

Shapiro, Richard 8589 

Shapiro, Roman 6043 

Sharabi-Nov, Adi e14025 

Sharan, Krishna 5526 

Sharawat, Surender Kumar 

9549, 9551, 9580 

Sharif, Saima 3512 

Sharifi, Nima 4645 

Sharkey, Robert M. 3091 

Sharma, Anand K. 5503 

Sharma, Atul 5540, 6593, 

e18518, e18573 

Sharma, Dayanand 2072, 

e15518 

Sharma, Dhruv B 6003 

Sharma, Hari 6600 

Sharma, Kamal 6616, 

e18500 

Sharma, Kamalesh 4645 

Sharma, Manish e13106 

Sharma, Mehar C e17505, 

e18518 

Sharma, Nancy e14600, 

e14620, e15143 

Sharma, Navesh K 3590 

Sharma, Neelesh e17563 

Sharma, Om Prakash e16012 

Sharma, Padmanee 2520^, 

TPS4673, TPS4691, 

e15092 

Sharma, Poonam e17549 

Sharma, Priyanka 9000 

Sharma, Puza P. e11067 

Sharma, Raj Govind e12014 

Sharma, Rameshwaram 

e16012 

Sharma, Ricky A e13587 

Sharma, Rohini e21093 

Sharma, Shantanu e16012 

Sharma, Shelly 9527 

Sharma, Sonam e18032 

Sharma, Sunil 3007, 3057, 

7029, 10549, 10605, 

e13548, e14090, e14177, 

e15115 

Sharma, Vipra e16565 

Sharma, Vivek R. e21072, 

e21144, e21149 

Sharman, Jeff Porter 3069, 

6122, 6507, 6518^, 8032 

Sharp, Linda 521, 2599, 

6036, e13096, e16514 

Sharpe, Dunbar 2589 

Sharpe, Rowena TPS10633^ 

Sharples, Katrina e15054 

Sharvashidze, Ineza O. 

e11086 

Shasha, Daniel e15138 

Shashidhar, H P e12030 

Shashidhara, P e11511 

Shastry, Mythili 618 

Shaughnessy, John D. 

e18548 

Shaw, Alice Tsang 3007, 

7010, 7503, 7508, 7533, 

7589, 7596, 7599, 7600 

Shaw, Ashley 4121 

Shaw, Edward G. 2008b, 

2047, 9108 

Shaw, Emily TPS10633^ 

Shaw, James Edward e19551 

Shaw, Mary e19647 

Shaw, Richard 5543, e16042 

Shaw, Robin J. e12027 

Shaw, Sally 1035 

Shawver, Laura K. e15555 

Shaya, Fadia T. e14522, 

e14626, e14638 

Shazer, Ronald L. TPS8113 

Shea, Sofia M 8530 

Shea, Thomas C. e13074 

Sheahan, Kieran e13570, 

e21024 

Shechter, Sharon 1055, 

e15200 

Shedden, Kerby A e17530 

Sheehan, Christine E 3533 

Sheehan, Jonas e11544 

Sheehan, Margaret e14687 

Sheehy, Niall 8552 

Sheehy, Patricia S 8042, 

8107, e18575 

Sheehy, Patricia 8043 

Sheehy, Patrick Frank 2569 

Sheeran, Lisa 9124 

Sheets, Nathan Christopher 

e15184 

Shehata, Christina 518 

Sheikh, Arif 5050 

Sheikh, Nadeem A. 2563, 

4650 

Sheikh, S. 3089^ 

Sheikh-Salah, Moktar 6095, 

6128 

Sheinfeld, Joel 4532 

Shekar, Mamatha e21159 

Sheldon, John M. e14632 

Sheldon, Lisa Kennedy 

e19515 

Shelkey, Julia 7040, e15121 

Shell, Scott A. e21120 

Shellenberger, Thomas D. 

e16030 

Shelton, Joseph e15006 

Shen, Chan e14550 

Shen, Changyu e21099 

Shen, Dong 503, e12503 

Shen, Hong e14026 

Shen, Jie 4068, e14509, 

e21034 

Shen, John P. e14069 

Shen, Li TPS4687 

Shen, Liji TPS4696^ 

Shen, Lin 3040, 4081, 

e14122, e14604 

Shen, Ronglai 5545^ 

Shen, Steven S. 4586, 

e15003 

Shen, Wei 1068, 7075, 

e18138 

Shen, Xian 2532, 4063 

Shen, Xiaodong 535, 4007, 

7514, 8531 

Shen, Yi e18013 

Shen, Yufeng 10516 

Shen, Yun TPS2614, 

TPS2615 

Shen, Zhenbin 4092, e14575 

Sheng, Xi Nan 8506, 8561, 

8562, e15051, e15052 

Shenkier, Tamara Nina 549^, 

582 

Shenolikar, Rahul 6060 

Shenouda, George TPS5600 

Shenoy, Aditya e18068 

Shepard, Harold Michael 

2579 

Shepard, Nancy 9107 

Shepherd, Frances A. 1535, 

1583, TPS2615, LBA7000, 

7007, 7093, 7511, 7586, 

10522, e18079 

Shepherd, Lois E. 500, 501, 

524, 538, 561, 1008, 

e11005 

Shepherd, Scott e14110 

Shepherd, Stacie Peacock 

TPS1138, 3049, 3054 

Sheppard, Karen E 8520 

Sher, David J 5579, 5582 

Sher, David 7067 

Sher, Tamara G. 6117 

Sherer, Stefan 10512, 10595 

Sheridan, Elizabeth 4553 

Sherman, Christopher G. 

4613 

Sherman, David H. e12026 

Sherman, Eric Jeffrey 5509^, 

5514, 5537, 5545^ 

Sherman, Laurie Jill LBA8509 

Sherman, Marion E. 1598 

Sherman, Mark E 1519, 

10603 

Sherman, Matthew L. 607, 

e15170, e19609 

Sherman, Morris 4033 

Sherman, Stephen L. e16510 

Sherman, Steven A e14028, 

e14030 

Sherman, Steven I. TPS3117, 

5508, 5518, 5547, 5591 

Sherman, William H. e14708 

Shermock, Kenneth M. 

e15175, e15183 

Sherrill, Gary Bradley e13109 

Sherwood, Anna 6631 

Sherwood, James 1548 

Shet, Tanuja 1108 

Shete, Jitendra e16002 

Sheth, Pulin 1124 

Shethia, Maithili A 4037 

Shetty, Aditya V. 4615 

Shetty, P. 3089^ 

Shi, Hongliang 2597 

Shi, Lehua 4008 


Shi, Li e18073 

Shi, Lizheng 6600, e15130 

SHI, Meiqi 7548 

Shi, Michael 2543, TPS4147, 

TPS4683 

SHI, Peipei 3001 

Shi, Qian 3526, 3564, 3576, 

3617, 4009, 4075 

Shi, Rong e15529 

Shi, Runhua e14667, 

e16009 

Shi, Shan Rong 4575 

Shi, Shu-zhen e14668 

Shi, Ting 2014 

Shi, Weiji 5537 

Shi, Wenyin e19507 

Shi, Xiaojin 3045 

Shi, Yi e18116 

Shi, Yuanjun TPS4693 

Shi, Yuankai 1534, 7533, 

7559, 7596, e14606 

Shia, Jinru 3583 

Shiau, Chung-Wai e14516 

Shibata, Atsushi e15098 

Shibata, Henry R. LBA506 

Shibata, Kazuhiko 7521 

Shibata, Stephen 2538, 

3108, e14182, e14586 

Shibata, Taro 5006, 7003, 

7017, 7028 

Shibayama, Takuo 7560 

Shibuta, Kenji 588 

Shibuya, Kazutoshi e18127 

Shibuya, Masahiko e18099 

Shichijo, Shigeki e13046, 

e13050 

Shields, Anthony Frank 

e14163, e14519, e14609 

Shields, Carol L 8560 

Shields, Jerry A 8560 

Shields, Lisa B.E. 2058 

Shields, Mario A. e14515 

Shiels, Meredith S. 6070 

Shien, Kazuhiko e17517 

Shifrin, Alexander L. 1540 

Shiga, Kiyoto e16020 

Shigaki, Hironobu 10523 

Shigematsu, Yoshiki 10585 

Shigeoka, Yasushi TPS659, 

10073 

Shih, Jen-Fu e18132 

Shih, Kent C. 3006^, 4027, 

4127, 7567, 7587, 8556 

Shih, Le-Ming e14538 

Shih, Tiffany Ting-Fang 1079 

Shih, Ya-Chen T. e14549, 

e14550 

Shiiba, Kenichi e14011 

Shiina, Shuichiro e14622 

Shilkrut, Mark e14603 

Shim, Byoung Yong e14072 

Shim, Hyun-Jeong e14649 

Shim, Hyunsuk 3055 

Shim, Joomee e15140 

Shima, James e21159 

Shimabukuro, Kelly Anne 

e14069, e14078, e14079 

Shimada, Andrea Kazumi 

e11014 

Shimada, Hiroyuki 9533, 

9534, 9564 

Shimada, Kazuaki e14506 

Shimada, Ken e14123 

Shimada, Masaaki e14596 

Shimada, Mitsuo 3558 

Shimada, Muneaki 5103 

Shimada, Takanobu e16034 

Shimada, Temiko e18060, 

e18134 


Shimada, Yasuhiro 3524, 

3569, e14126 

Shimamoto, Takashi 8029 

Shimamura, Hiromune 

e14011 

Shimamura, Takeshi e14047 

Shimizu, Chikako 10519, 

e11065, e19535 

Shimizu, Eiji 7521 

Shimizu, Junichi e17510, 

e18145 

Shimizu, Kazuo 1112 

Shimizu, Kazuyuki 8097 

Shimizu, Kimihiro 7012 

Shimizu, Seiichi 8094 

Shimizu, Shigeki e18126 

Shimizu, Toshiki e18081 

Shimizu, Toshio e13025 

Shimizu, Yasuhiro e14540 

Shimizu, Yasushi e17520 

Shimko, Sara 6616, e18500 

Shimodaira, Hideki 4002, 

e19611 

Shimokawa, Mototsugu 3558 

Shimokawa, Tsuneo e18099 

Shimokuni, Tatsushi 10578 

Shimoyama, Tatsu TPS3642 

Shimozaki, Shingo 10075 

Shin Ogawa, Luisa 3086 

Shin, Dong Bok TPS4142, 

e14137, e14685 

Shin, Dong Moon 2576, 

3094, e13110 

Shin, Dong M 5560, 5570, 

e21161 

Shin, Dongbok e14572 

Shin, Eun Soon 7089, 

e13065 

Shin, Hee Jung e11508 

Shin, Hee-Chul 1056, 1133, 

e11532, e21160 

Shin, Hyun Soo e18501 

Shin, Im-Hee 3606 

Shin, Jae-Gook 3592 

Shin, James e18147 

Shin, Ji Hoon 4093 

Shin, Jung-Young e18050 

Shin, Sang Joon 3606, 

e14072, e14081, e14084 

Shin, Soyoung TPS2621 

Shin, Sung Kwan e14559 

Shinagawa, Atsushi 8094 

Shinde, Arvind Manohar 1035 

Shingoji, Masato e21054 

Shinkai, Tetsu 6112, 7017, 

7028, 7549, 7576, 

e18099 

Shinkura, Nobuhiko e21031 

Shinoda, Kazunobu 9569 

Shinohara, Nobuo e15068, 

e15071, e15098, e15127 

Shinohara, Takeshi e19583 

Shinozaki, Eiji 10541, 

e14038, e14145 

Shintani, Satoru 5584 

Shio, Yutaka e13015 

Shiokawa, Rie 3022 

Shiono, Masatoshi e19611 

Shioyama, Yoshiyuki 7045 

Shiozawa, Toshihiro e18064 

Shipe-Spotloe, Janice 8533, 

8547 

Shipley, Dianna 7100, 7587 

Shipley, Janet 9510 

Shirabe, Ken e14536, 

e14602 

Shirafuji, Naoki 9053 

Shirai, Takao e13029 

Shirai, Toshiharu 10075, 

e20505 

Shirane, Masatoshi e18064 

Shirar, Kristen Leigh 7107 

Shirar, Kristen L 7106, 7108 

Shirasaki, Ryosuke 9053 

Shiroki, Ryoichi e15068 

Shirouzu, Kazuo e13046, 

e13050, e14077 

Shiroyama, Takayuki e18141 

Shirvani, Shervin Mohajer 

7062 

Shitara, Kohei 4067, e14500 

Shivakumar, Swamy e14675 

Shivakumar, Swarna e21132 

Shivapurkar, Narayan e14009 

Shmueli, Einat 1507 

Shockley, Nancy 8560 

Shockro, Laura 9084 

Shoemaker, J. Samantha 

6060, 6075 

Shohet, Jason 9534 

Shoji, Tadahiro 5103 

Shoni, Melina 5011 

Shook, Stephanie TPS9150 

Shore, Neal D. 4510, 4642, 

4662, TPS4698^ 

Shore, Neal TPS4697 

Shores, Carol G. 5539 

Shouery, Marwan 9042, 

e19647 

Shouldis, Jennfier 7077 

Shourbaji, Rania Ayman 

5531, 5559, 5581, 

e15138 

Shovlin, Margaret 8051 

Showalter, Timothy Norman 

e11505, e15012, e15163, 

e19507 

Shows, Joseph Ryan e14667 

Shpall, Elizabeth J. 6529 

Shparyk, Yaroslav e15037 

Shrager, Joseph B 7008 

Shreenivas, Aditya V. e16060 

Shrivastav, S. 3089^ 

Shrivastava, Shyam K 

TPS5116 

Shroff, Rachna T. 4051, 

4054 

Shtalrid, Mordechai e19529 

Shtivelband, Mikhail 7512 

Shu, Hui-Kuo George 3055 

Shu, Jihong e16011 

Shu, Sei e13502 

Shu, Yongqian 9017 

Shuai, Yongli 8533 

Shubhakar, Poornima 3009 

Shuda, Masahiro 8577 

Shukla, N. K e11013, 

e17505 

Shukuya, Takehito 7088, 

e21007 

Shulkes, Arthur e15117 

Shulman, Katherina 1578 

Shulman, Lawrence N. 1021, 

e19503 

Shumak, Rene e12034 

Shuman, Andrew G 9121 

Shumway, Nathan M. 625, 

2508, 2529, 9058 

Shuping, Jo e21066 

Shurell, Elizabeth 10000 

Shurin, Galina e21001 

Shurin, Michael e21001 

Shuryak, Igor e15162, 

e17562 

Shustov, Andrei R. 8070 

Shvidel, Lev e19529 

Shyr, Yu 6038 

Si, Lu 8506, 8561, 8562, 

e15051, e15052 

SI, Yongfeng 5558 

Siakavellas, Spiros e21098 

Sica, Gabriel 7097 

Sicchieri, Renata D 1075 

Sicklick, Jason Keith e14069 

Siddiqi, Rabia 9565 

Siddiqi, Tanya 6547 

Siddique, Mohammad Hasan 

6612 

Siddiqui, Bilal Karim 7107 

Siddiqui, Javed e15205 

Siddiqui, Jehan 3504 

Sideras, Kostandinos 1083, 

10509 

Sideri, Mario e19036 

Sidhom, Mark TPS4690 

Sidhu, Gurinder Singh 

e15097, e18504 

Sidhu, Roger 3535 

Sidoni, Angelo e21094 

Sieber, Markus TPS3639 

Sieber, Oliver 3623 

Sieber, Paul 4510, 4550 

Siebert, Fred W e21111 

Siedlecki, Janusz A 8548, 

10538, e19022 

Siefker-Radtke, Arlene O. 

4506, 4523 

Siegal, Gene P. e13087 

Siegel, Abby B. 4101 

Siegel, Cara e14112 

Siegel, David Samuel DiCapua 

8016, 8035 

Siegel, Petra 8535 

Siegel, Robert D. 9047, 

e16532 

Siegel, Robert S. e11084 

Siegel, Samantha 9578 

Siegfried, Anne 8518 

Siegfried, Jill 7071, 7074, 

e21012 

Siegmann, Katja C. 1067 

Siemionow, Vlodek 1076 

Siena, Salvatore 3502, 3570, 

3581, TPS3637, 5513, 

7550, TPS9155, e13095^, 

e13097^ 

Sierocinski, Thomas 4565 

Sierra, Enrique 3586 

Sierra, Marta Isabel e18044 

Sieuwerts, Anieta M 10504 

Sifuentes, Erika e12027 

Siggillino, Annamaria 

e18023, e18101, e21094 

Signorelli, Carlo e18065 

Signoretti, Sabina 4543, 

4582, 4585, 4635 

Signorovitch, James E. 4612, 

e14621 

Sigurdson, Elin R. 3605, 

6061 

Sikora, Katarzyna Otylia 3511 

Sikov, William M. 1034, 

1045, 10508 

Silasi, Dan-Arin e15526 

Silber, Jeffrey H. 6000 

Silberstein, Peter T. e14641, 

e16554 

Silcocks, Paul TPS8605 

Silginer, Manuela 2055 

Silletta, Marianna 10063 

Silliman, Rebecca A e11003 

Silling, Gerda 6610, 8004 

Silva, Alejandro J. e15584 

Silva, Antonio P. 508 

Silva, Eric TPS6637 

Silva, Gualdino e14673 

787s

Silva, Jose D. 5567 

Silva, Milton Jose B e14680, 

e14728 

Silva, Rosa Rita e15074 

Silvain, Christine 3520 

Silver, Bruce A. 8032 

Silver, Joel 6555, e18543 

Silver, Richard T. 6624 

Silverman, Craig I. 5530 

Silverman, Lewis B. 9530 

Silverman, Michael H. 

e14731 

Silverman, Paul e15212 

Silverman, Paula TPS655 

Silvestri, Alessandra e14151 

Silvestri, Rosangela e11071 

Silvestris, Nicola 4627 

Sima, Camelia S. 1541, 

7014, 7052, 7066, 7527, 

7580, e19647 

Simcock, Richard 5527 

Simeone, Diane M. 4591 

Simeone, Ester 8513, 8529, 

8573, e19034 

Simeonova, Anna 5596^ 

Simes, John 3504, 3515, 

3534, 3572, 5081, 

e13007 

Simi, Paolo e13057 

Simko, Jeffrey 2564 

Simkova, Iveta 9592 

Simmonds, Peter 511 

Simmons, Christine E. 6084, 

9111 

Simms, Lorinda 7502 

Simon, George R. 2544, 

2559, TPS7619, e18112 

Simon, Helene e11019 

Simon, Iris 3510, e21013 

Simon, Jordi Rovira TPS9154 

Simon, Laurence e11542 

Simon, Marike Anna e19610 

Simon, Matthias 2000 

Simon, Michael S. e14005 

Simon, Noah e15005 

Simon, Richard 2578 

Simon, Ronald 10501 

Simon, Sergio D. TPS661, 

e12021 

Simon, Wolfgang 1072, 1081 

Simoncini, Edda 645 

Simone, Charles B. 7098, 

e17534 

Simone, Nicole L. e11505 

Simonelli, Matteo 2580, 

4117, e21139 

Simonoska, Rusana 5536 

Simonson, Rachel 8516 

Simpkins, Fiona 5065 

Simpson, Dayna e13028 

Simpson, Jennifer 6545, 

e18542 

Simpson, Pamela S. e18122 

Sims, Robert Brownell 2564, 

4648, 4650, TPS4673 

Sin, VC 5511 

Sina, Sokol e14647 

Sinclair, Natalie Faye 1045, 

10508 

Singal, Amit G e14165 

Singavi, Arun e18507, 

e19641 

Singer, Barak e14731 

Singer, Christian F. 514, 

1537, 10501 

Singer, Eric A. TPS4680 

Singer, Samuel 10001, 

10002, 10015, 10019 

Singer, Susanne e19610 

Singh Riyat, Malkit e20504 

Singh, Abhijai e14186 

Singh, Akshita e11552 

Singh, Amar e17511 

Singh, Arun D 8071 

Singh, Arun S. 3015 

Singh, Baljit e11064 

Singh, Balraj e21107 

Singh, Dharam Pal e16012 

Singh, Harpreet 2522, 3530 

Singh, Harvinder 9103 

Singh, Hitesh e11069 

Singh, J. K. 3089^ 

Singh, Jasmeet Chadha 

e11529 

Singh, Jaspreet e15012 

Singh, Jaswinder TPS3640, 

e14632 

Singh, Juswinder 8032 

Singh, Madhu Sudan e16562 

Singh, Mamta 9544 

Singh, Mandeep 4106 

Singh, Navneet e18009 

Singh, Nishith K. 2526, 

TPS2617, TPS4701 

Singh, Onkar 2598 

Singh, Pankaj R 628 

Singh, Preet Paul 6614 

Singh, Rajkumar Bikramjit 

5104 

Singh, Randeep 9559 

Singh, Sharat 4011, 10535, 

e14584, e21017 

Singh, Shivendra TPS8606 

Singh, Simron 5502 

Singh, T. Trevor e15554 

Singh, T.Trevor 3619 

Singh, Veena 10588, e21019 

Singh, Zeba e18576 

Singhal, Anil 8020, 

TPS8112, TPS8113, 

TPS8114 

Singhal, Jyotsana e13557 

Singhal, Nimit 4531, 

e17544, e19513 

Singhal, Sandeep K. e21010 

Singhal, Seema 6623, 8035 

Singhal, Sharad S. e13557 

Sinha, Ishan e19030 

Sini, Claudio 7577, e21065 

Sini, MariaCristina 8581 

Sinibaldi, Victoria J. 4564, 

4619, e15058, e15188 

Sinicrope, Frank A. 3514, 

3564, 3617, 4009, 4075 

Sinicrope, Pamela S 3567 

Sinn, Bruno Valentin 522, 

523, 4020 

Sinn, Hans-Peter 1096 

Sinn, Marianne 4020, 4044, 

e14533 

Siolos, Spyros 5574 

Sipkins, Dorothy 6562 

Sipos, Laszlo 2 

Siqueira, Sheila Aparecida 

Coelho e15562 

Siracusano, Licia 7061, 

7585, e18104 

Siraj, Muhammad Ahsan 

e21138 

Sire, Christian 5505 

Sirera, Rafael 7058, 7060, 

10594 

Siritanaratkul, Noppadol 8097 

Siriwardana, Melany e18505 

Sirtaine, Nicolas 507 

Sirulnik, L. Andres 6514^, 

6625^, 6626^, TPS6642^ 

Sirvent, Nicolas e20006 

Sisani, Michele e15185 

Sismondi, Piero 627 

Sisti, Valerio 4084 

Sit, Laura 9104, e19633 

Sitarik, Mark A. 6109 

Sittampalam, Kesavan 10051, 

e13061, e20509 

Siu, Lillian L. 3027, 3077, 

3082, 3101, 3504, 3572, 

5587, TPS5600, e13001, 

e13107, e13603 

Siu, Lillian e19616 

Siu, Steven 4105 

Sivanand, Sharanya 4616 

Sivapalasuntharam, Asha 

e18068 

Sivarajan, Kulumani M 

TPS3635^ 

Siveke, Jens T 4115 

Sixtova, Dimka e18062 

Siziopikou, Kalliopi P. 

TPS657, TPS1134 

Sizoo, Eefje 2071 

Sjoquist, Katrin Marie 

TPS3643, TPS4137, 5081 

Skaar, Todd C. 525 

Skaarup, Jesika e11517 

Skailes, Geraldine 7562 

Skapek, Stephen 1576, 9535 

Skarlos, Dimosthenis V. 573 

Skarlos, Dimosthenis-Vasilios 

e15040 

Skeel, Roland T. e14098 

Skiadaresis, Julia 9076 

Skibber, John Michael 3556 

Skikne, Barry 6522 

Skiles, Jodi L 2601 

Skinner, Donald G 4575 

Skinner, Eila C. 4571, 4576, 

4588, 4589 

Skinner, Eila C 4575, 4578 

Skinner, William Kempton 

e16058 

Skitzki, Jospeh J. e14172, 

e18537, e18539, e19041 

Skladowski, Krzysztof A. 

5504^ 

Sklar, Charles A 9514 

Sklar, Larry A. TPS5602 

Sklarin, Nancy T. 10514 

Skokan, Margaret 7061, 

7534, 10580 

Skol, Andrew e15086 

Skolnik, Jeffrey e13599 

Skoog, Lambert 4561 

Skovlund, Eva 3548 

Skrickova, Jana e18062 

Skrzypski, Marcin Tomasz 

10561 

Skuse, David e19581 

Slack, James L. 8053 

Slaets, Leen 1022 

Slager, Susan L 6571 

Slamon, Dennis J. 8592 

Slater, Sarah LBA4000 

Slaughter, James e15582 

Slavkovic, Vesna e13066 

Sleckman, Bethany G. 4022 

Sledge, George W. 505, 605, 

1005, 1027, 6025, 6053, 

9020, e21099 

Sleer, Leanne Sophia 2517 

Sleigtholm, Richard 6561 

Sleijfer, Stefan 2593, 2596, 

10091, 10504 

Slepushkina, Nadejda e21011 

Slichenmyer, William J. 4501 

Slingluff, Craig L. 8530, 

8597, e19028, e19062 

Sliwkowski, Mark X. 5575 

Sloan, Andrew E. TPS1616, 

TPS2107 

Sloan, Brittany e13032 

Sloan, David e16035 

Sloan, Jeff A. 1557, 1610, 

3617, 6108, 6133, 9001, 

9047, e11051, e16572 

Sloan, Philip 5543 

Sloane, Robert e15141 

Slomovitz, Brian M. 5027 

Slone, Jeremy 9558 

Slotman, Ben J. 7009 

Slovin, Susan F. 4548, 

TPS4700 

Sluiter, Wim J. 10581 

Small, Alexander C. 4623, 

TPS4676, 6065, e21032 

Small, Art e11077 

Small, David I. e18061, 

e18098 

Small, David e19626 

Small, Eric Jay 4, 2564, 

4513, 4515, LBA4518, 

4592, 4593, 4655, 4660, 

4664, 4667, e15137 

Small, Isabele Avila 7506, 

e14027 

Small, William 1069, 4049, 

TPS5116 

Smalley, Robert J e15565 

Smallridge, Robert C. 5544 

Smart, James 8566 

Smeland, Sigbjorn 10081 

Smetzer, Leslie e13025 

Smid, Marcel 10504 

Smirnov, Denis A e21146 

Smit, Egbert F 7009, 7543, 

7607, e18094 

Smith, Alan D. e14532 

Smith, B. Douglas 6629 

Smith, Barbara L. 1122 

Smith, Benjamin D. 6124, 

7062 

Smith, Brian 3056, 8061 

Smith, Cardinale B. 6065, 

7064 

Smith, Carly J 9511 

Smith, Carmen J. 6034 

Smith, Carrie L. e15557 

Smith, Catrin Tudur 8523 

Smith, Christopher G 3516 

Smith, Clare e21147 

Smith, Cornelia e14689 

Smith, Daryn W. 1560, 

e15081, e17528 

Smith, Daryn 5534 

Smith, David A. TPS1143, 

2516, 3023, TPS3111, 

e18047, e18063^ 

Smith, David C. CRA2509, 

3025, 3077, 4505, 4506, 

4513, e13603 

Smith, David M 6137 

Smith, David LBA4000, 

TPS4143, e14587 

Smith, Deborah A. 610, 

e13596 

Smith, Denis 3506, 4036, 

4118, e14168 

Smith, Dennis M. e21048, 

e21121 

Smith, Dennis Wesley e19509 

Smith, Donald 3090 

Smith, Donna M. e13121 

Smith, Ellen M. Lavoie 

CRA9013 

Smith, Emma-Louise e19550 

Smith, Frederick P. 7587 


Smith, Garrett TPS4145 

Smith, Gary L 2606 

Smith, Heind 4081 

Smith, Ian C. 7503, e13599 

Smith, Ian Edward 596, 604 

Smith, Jennifer A e19571 

Smith, Jillian K 4059 

Smith, Judith A. 5041 

Smith, Julia Anne e11010, 

e11529 

Smith, Ken R 9525, 9561 

Smith, Kristin e20001 

Smith, L. Mary 9576 

Smith, Larry R e19058 

Smith, Lauren A 8574 

Smith, Lauren B 9121 

Smith, Lon S. 2555, e13025, 

e13602, e13604 

Smith, Lon 2512 

Smith, Lynette 9501, e17549 

Smith, Mary Lou 6053 

Smith, Matthew Raymond 

4510, 4513, LBA4518, 

4566, 4642, 4644, 6045 

Smith, Milton T e14714 

Smith, Mitchell R. 8081 

Smith, Mitchell Reed 

e13079, e19580 

Smith, Myles JF 10050 

Smith, Nick e14587 

Smith, Pamela Ann e13536 

Smith, Paul D. 7503, e13599 

Smith, Paul 1581 

Smith, Richard V. e16058 

Smith, Robin e19644 

Smith, Scott E. 6582, 

e13079 

Smith, Sonali M. 8060, 

8072, 8075 

Smith, Stephen James 

e14503 

Smith, Susan C. 6516^ 

Smith, Thomas J. 9075, 

e19564^ 

Smith, Thomas J e18144 

Smith, Timothy 6017, 6029 

Smith, Webb A 9526 

Smith-Machnow, Victoria 

TPS3641^ 

Smith-Marrone, Stephanie 

5514 

Smithers, Bernard Mark 

TPS4145, 8559 

Smithers, Mark TPS4141, 

8534 

Smits, Evelien L. 2506 

Smits, Evelien e13051 

Smitt, Melanie 532 

Smolej, Lukas 6584 

Smolenski, Kathy N. 2018 

Smolkin, Mark E 8530 

Smoll, Nicolas Roydon 2068 

Smorenburg, Carolien H. 

1080 

Smorodinsky, Nechama 

e13018 

Smylie, Michael 8539 

Smyrk, Thomas C. 3514 

Smyth, Elizabeth C TPS4143 

Smyth, Emily Nash 1068, 

7101, e18138 

Smyth, Fiona Elizabeth 8547, 

e15056 

Smyth, Lillian e19601 

Snedecor, Sonya J. e15189 

Sng, Natasha J 7523 

Snider, Jessica N. TPS1137 

Sninsky, John J. 10586 


Snitcovsky, Igor M. L. e21040 

Snook, Adam e14619 

Snowdon, Jaime 5032 

Snuderl, Matija 2010 

Snyder, Carrie 1538 

Snyder, Claire Frances 6026, 

6028, 6080, 9103 

Snyder, David 1592 

So, Ping Fai Peter TPS7614 

So, Sam e14037 

So, Tomoko 10585 

Soares, Fernando Augusto 

1522 

Soares, Fernando A e20506 

Sobecks, Ronald M. 8055 

Sobol, Hagay e12502 

Sobol, Joseph TPS9147 

Sobol, Robert W. TPS1138 

Sobrero, Alberto F. 3502, 

3535, 4042 

Socci, Nicholas D 4527 

Socinski, Mark A. LBA4, 

LBA7000, 7513, 7590, 

7592, TPS7618 

Soe, Aye Min e13099 

Soehrman Brossard, Sophia 

5522 

Soejima, Kenzo e18058 

Soejima, Yuji e14536, 

e14602 

Soeling, Ulrike 554 

Soerensen, Bente Thornfeldt 

7001 

Soerensen, Flemming Brandt 

3573 

Soergel, Fritz 3044 

Soetekouw, Patricia M.M.B. 

e13028, e15115 

Soffietti, Riccardo 2037, 

2075 

Soh, I Peng Thomas 1064, 

e13002, e19523 

Soh, Junichi e17517 

Soh, Lay-Tin 10051, e20509 

Sohal, Davendra 4111, 

e13602 

Sohji, Sunao e15212 

Sohl, Jessica 6089 

Sohn, Byeong Seok 10093 

Sohn, Christof 1090, 1096 

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Sohn, Joo Hyuk 1003, 2542 

Sohn, Sang Kyun 3554, 

6536, 6538, e14074, 

e18533 

Soini, Barbara e14711 

Sokol, Lubomir 2099, 6608, 

8084, e18503, e18506, 

e18509, e21123 

Sokol, Lubosh 6568 

Solak, Mustafa e11020, 

e11092 

Solassol, Jerome 10507 

Solberg, Arne 4508 

Soldi, Raffaella 3057, 

e14090 

Solé, Claudio J. e14002 

Sole, Claudio Vicente e14002 

Solé, Juan M. e14002 

Solé, Sebastián e14002 

Solé, Vicente e14002 

Soler, Christine e20006 

Soler, Claude e15109, 

e21056 

Solima, Eugenio 5096 

Soliman, Hatem Hussein 

1585, 2501, TPS2620 

Soliman, Pamela T. 1513, 

5027 

Solin, Lawrence J. 1005 

Solis, Luisa 10506 

Solis-Trapala, Ivonne 5527 

Solit, David B. 4527, 5030 

Solleza, Franco 10061 

Solomayer, Erich 10599 

Solomayer, Erich-Franz 1090, 

TPS1146, 1523 

Solomon, Benjamin J. 7508, 

7511, 7596, 7600, 7601, 

e13054 

Solomon, Benjamin Maurice 

6571 

Solomon, James A e19048^ 

Solomon, Maria Teresa 2515 

Som, Peter M. 5578 

Somaiah, Neeta TPS10099, 

e18112, e19580 

Somani, Naresh 3011 

Somashekar, Mohan Kumar 

e11536 

Somashekhar, S. P. e14710, 

e15516 

Sombroek, Cherita 8039 

Somer, Robert A. CRA1002, 

e12008 

Somers, Elizabeth Brooke 

e21028 

Somlo, George 1010, 1035, 

1070, 1592, 3108, 8035, 

8038, 10545, 10597, 

e21013 

Sommer, Harald Leo 554, 

1072, 1081, 10540, 

e15520 

Sommerfeld, Alex e14612 

Sommerfeld, James 9544 

Sommerfeldt, Silvia e14099 

Somorat, Bhattacharjee 

e11027, e14721 

Son, Byung Ho e11504, 

e11508 

Son, Crystal 6101 

Son, Jeewoong 3076, e14572 

Son, Seyoung 4093 

Sondak, Vernon K. 8504, 

8521, 8525, 8527, 10048 

Sondel, Paul M. e19047 

Sonderfan, Andrew J 3086 

Sone, Takashi e17540 

Sonet, Anne 8065 

Song, Cheryn e15080 

Song, Eun-Kee e14580 

Song, Gina 5050, e13063 

Song, Ho June 4093 

Song, Ho Young 4093 

Song, Hong-Suk e14570 

Song, Ik Chan e14529 

Song, Kyo Young e14558 

Song, Meijuan e14643 

Song, Paul Y. 3015, e14593 

Song, Si Yeol 5586, 7004 

Song, Tianqiang 4008 

Song, Weifeng e14508 

Song, Xiangqun 7091 

Song, Xinni 587 

Song, Yan e14668 

Song, Yang 10010 

Song, Ying e11095 

Song, Yiyi e12013 

Song, Yong 7559, e18082, 

e18116 

Song, Yong-Mao e14024 

Sonis, Stephen T. 9024, 

9119 

Sonja, Betschart e19648 

Sonke, Gabe S. 5001 

Sonnemans, Hetty 1129 

Sonnenblick, Amir 10034 

Sonneveld, Pieter 8095 

Sonoo, Hiroshi 1119 

Sonpavde, Guru 4522, 4524, 

4525, 4586, 4603, 4623, 

4643, 4644, TPS4675^, 

TPS4676, TPS4678, 6065, 

e15002, e15003, e21016 

Soo, Ross A. 2551, 3002, 

7512, e13002, e13061 

Sood, Anil 5015 

Sood, Suman Lata e14578 

Soon, Yu Yang 2016, 5553 

Soong, Richie Chuan Teck 

2551 

Soori, Gamini S. 1557, 3545, 

6133 

Soraya, Sami sahnoun 

e11034 

Sorbye, Halfdan 3508, 3538, 

3548, 4015, e14053 

Sorensen, A. Gregory 2009, 

2012, 2025, 3036 

Sorensen, Flemming Brandt 

3513 

Sorensen, Gregory A 

TPS10635 

Sorensen, Jens Benn 7001, 

10617 

Sorenson, Leslie 9019 

Sorescu, George P. e14591 

Soria Rivas, Ainara e16029 

Soria, A e19023 

Soria, Claudine e21156 

Soria, Irene e13085 

Soria, Jean-Charles 2539, 

2540, 3000, 3012, 3021, 

3026, 3063, 3080, 3104, 

4540, 4614, 4618, 5522, 

7007, 7529, 10556, 

e13118 

Soria, Jeannette e21156 

Soriano, Carmen e19576 

Soriano, Jordi e14120 

Soriano, V. e19023 

Sorio, Roberto LBA5002^, 

LBA5003 

Sorlini, Cristina 7544 

Sos, Martin TPS3115, 7532, 

7603 

Sosa, Aarón 3536 

Sosinska-Mielcarek, Katarzyna 

505 

Soslow, Robert A 5043 

Sosman, Jeffrey Alan 3102, 

4545, 8502^, 8503^, 

8507, 8504, 8510, 8519 

Sotiriou, Christos 507, 515, 

e21010 

Soto Parra, Hector J. e18096 

Soto-parra, Hector e18026 

Sotomayor, Eduardo M. 2099, 

6568, 6575, 6608, 8084, 

e18503, e18506, e18509, 

e21123 

Sottile, Roberta 1044, 

e13058, e13070 

Sottotetti, Federico 589 

Souadka, Abdelilah e14133 

Souadka, Amine e14133 

Soubeyran, Pierre-Louis 2023, 

9012 

Souhami, Luis 2008b 

Soulie, Michel LBA4567^ 

Soulieres, Denis e18136, 

e19591 

Soulos, Pamela R. 1030, 

4651, e15150 

Soupos, Nikolaos 5033 

789s

Sousa, Carlos Eduardo Pires 

643 

Sousa, Susana e15532 

Soussain, Carole 2023 

South, Natalie L. 9575 

Southerland, Cindy 2074^ 

Southey, Melissa C 1502 

Souza Crovador, Camila 

e19528, e19584, e19602 

Souza, Cristiano de padua 

e14173 

Souza, Sulene Cunha 606 

Sovak, Mika A. 5054 

Soveri, Leena-Maija 4015 

Soverini, Simona 6531 

Sˇ pacek, Jirí 5001 

Spacek, Martin 6584 

Spada, Daniele 4084 

Spadola, Giuseppe e19035, 

e19036 

Spaeth, Dominique 568^ 

Spaeth-Schwalbe, Ernst 

TPS3639 

Spafford, Michael TPS5602 

Spaggiari, Lorenzo 7023 

Spaggiari, Paola e14672 

Spagnoli, Giulio C e21126 

Spain, Pamela 6046 

Span, Paul e13111 

Spaner, David 10622 

Spangenberger, Holger 

e13508 

Spannberger, Thomas 2053 

Spano, Jean-Philippe 641, 

1095, 5067, 6110, 10078, 

e11551, e18505 

Sparagana, Steven 10619 

Sparano, Joseph A. 1005, 

1010, 1021, 4030, 8005 

Sparano, Joseph 1027, 9020 

Sparreboom, Alex 2549 

Spasic, Jelena e12020 

Spatti, Gian Battista 5096 

Spatz, Alan e18061 

Speaker, Stephanie 8036 

Specht, Jennifer M. 1088, 

TPS3109, e13596 

Specht, Lena e18527 

Specht, Michelle Connolly 

1122 

Speck, Rebecca M e19531 

Specterman, Sergio 10074 

Spector, Mathew E e16014 

Spector, Nelson 6505^ 

Spector, Yael 10575, e21008 

Speer, Tod e16010 

Speer, Vanessa e11556 

Speers, Caroline 3527, 6014, 

6018, e14048, e14176 

Speiser, Daniel E e19050 

Speiser, Paul 5071 

Spelda, Stanislav e18062 

Spelman, Amy 9029 

Spencer, Elysia Sophia 4669, 

e15207 

Spencer, Jennifer e19527 

Spencer, Kathy 9115 

Spencer, Shawn D. 4671 

Spencer, Shawn D 3042^ 

Spencer, Stuart e13541 

Spengler, Werner 7572 

Speranza, Giovanna 3031, 

3087, 3529 

Sperber, Fanny 1564 

Sperduti, Isabella 4076, 

e12514, e14082, e14661, 

e18065, e18072 

Sperinde, Jeff 603, 608, 614 

Speyer, James L. 5016, 

e11064, e11529 

Speyer, Mark e19588 

Speyer, Sue TPS3638, 

e14501 

Spicer, Darcy V. 1065 

Spicer, James F. 3022, 

3100, 5522, 7544 

Spicka, Ivan 8018^ 

Spickhoff, Frank 1600^ 

Spiegel, David 9051, e14006 

Spiegelmann, Roberto 2078 

Spiekermann, Karsten 6510 

Spielberger, Ricardo Tomas 

8089 

Spier, Catherine M 8001 

Spigel, David R. LBA4, 

CRA2509, TPS2615, 7035, 

7100, TPS7113, 7509, 

7549, 7567, 7587, 

TPS7616, 10530, e13076, 

e13113, e21023 

Spillane, Donna e14111 

Spillane, Susan 2599 

Spina, Michele 8005, 8046, 

8058 

Spindler, Karen-Lise Garm 

3573 

Spinelli, Gian Paolo e11039, 

e11514, e12510, e19620 

Spinelli, Tulla e19530 

Spinnato, Francesca e18002 

Spira, Alexander I. LBA7000, 

e18063^ 

Spittler, Aaron John 7107, 

7108 

Spitzer, Thomas R. 6618 

Spivey, Tara L 8576 

Spleiss, Olivia 8503^ 

Spoelstra, Nicole S. 564 

Sporchia, Andrea 3570 

Sportelli, Peter LBA3501 

Sposto, Richard 1065, 

e19506 

Spradlin, Natalie M. 6068 

Spraggs, Colin F. 10532, 

e15059 

Sprangers, Miriam 6002 

Spranklin, Laura Jane e17506 

Spratlin, Jennifer L. 3013 

Sprauten, Mette 4637 

Sprecher, Emmet 10558 

Sprenger, Thilo 3600, 

e14161, e14162, e14167 

Spriggs, David R. 2586, 5043 

Springett, Gregory M. 4043 

Springfield, Sanya 6086 

Sprod, Lisa 9009, 9010, 

9028, 9141, 9142 

Sprott, Kam M. 1091, 

e21146 

Spruyt, Odette 2604 

Spry, Nigel TPS4145, 

TPS4690 

Spunt, Sheri L. 9527 

Squarcina, Paola 5555 

Squiban, Patrick J. e13009, 

e13010 

Squire, Jeremy 2051 

Squires, Jennifer 2545 

Squires, Matthew TPS1148, 

6514^, 6625^ 

Sreenivas, Vishnu kumar 

9549, 9551 

Sreenivasappa, Shylandra B. 

e14590 

Sridhar, Kala e15017 

Sridhar, P S e11027, e14675 

Sridhar, Papaiah Susheela 

e14721 

Sridhar, Srikala S. 2572, 

4522, 4525, e15020, 

e15177^ 

Srimuninnimit, Vichien 551, 

7519^, e11022, e15064, 

e20514 

Srinath, B S e11511, 

e12030 

Srinivas, Nuggehally R 

e13548 

Srinivas, Sandy 4506, 4610, 

e15005, e15154 

Srinivas, Shanthi e18516, 

e19638 

Srinivasan, Alagiri e15510 

Srinivasan, Ramaprasad 

TPS4680 

Srinivasan, Sankar 1534 

Srinivasan, Shankar 8016, 

8037 

Sriuranpong, Virote 7519^, 

TPS7614, e20514 

Srivastava, Deo Kumar 9527, 

9531 

Srivastava, Deokumar 9526 

Srivastava, Geetika 8096 

Srivastava, Kirti e19516 

Srivastava, Shiv e15207 

Srkalovic, Gordan 7512 

Srour, Samer Ali e17012 

Srovnal, Josef e14556 

St. Cyr, Brianna 10575 

St. Germain, Diane C. 6086 

Staak Junior, Marcos Cesar 

e12035 

Staals, Eric L. 10022 

Staar, Susanne 5512, 7001 

Stabler, Stacy Marie e19566 

Stacchiotti, Silvia 10006, 

10022, 10026, 10053, 

10065 

Stack, Edward C. 4577, 

4580, 4582, 4585 

Staddon, Arthur P. 10009, 

10010, 10067 

Stadler, Rudolf 8076 

Stadler, Walter Michael 2526, 

TPS2613, 4022, 4522, 

4550, 4617, 4655, 4667, 

8075, 10028 

Stadtmauer, Edward Allen 

e18540 

Staebler, Annette e15577 

Staehler, Michael D. 4539, 

e15044 

Staehler, Sandra S. 9571 

Staffurth, John 4558 

Stafkey-Mailey, Dana 9143 

Stahl, Phillip R. e15168 

Staib, Peter 6610 

Stalbovskaya, Viktoriya 6514^ 

Staley, Charles A. 3605, 

e14169, e14170 

Stallard, Nigel TPS665 

Stallings, Holley e16532 

Stalmeier, Peep FM 9036 

Stam, Anita 2562 

Stamatopoulou, Sofia 10606, 

e11073 

Stamatoulas, Aspasia 6523 

Stamatovic, Ljiljana 9046 

Stambler, Nancy 4662 

Stambolic, Vuk 1019 

Stambrook, Peter e16017 

Stampfer, Martha 1012 

Stampino, Corrado Gallo 

2595, e13606 

Stan, Radu V. e13567 

Stancu, Alexandru e13093 

Stanelle, Eric J. 8586 

Stanford, Marianne 2588 

Stang, Andreas 580 

Stanganelli, Ignazio 8581 

Stanhope, Lucy J 1502 

Stapleford, Liza Jane 9122 

Staren, Edgar Donald 5049 

Stark, Daniel P. 4531 

Starling, Gary 8087 

Starlinger, Patrick e14095, 

e14099 

Starmans, Maud HW e17539 

Starodub, Alexander 4603, 

TPS4676 

Staroslawka, Elzbieta TPS649 

Starr, Mark e21038 

Stash, Diane e15116 

Stasi, Irene 629 

Stassi, Giorgio e21095 

Staszewski, Harry e18554 

Staszkiewicz, Rafal 603 

Stathis, Anastasios 3003, 

3082 

Stathopoulos, George 583 

Stati, Valeria e11039, 

e11514, e12510, e19620 

Stattin, Pär 4668 

Stauch, Kathrin 4628 

Stauch, Martina 3519^, 

3588, 3 

Stauder, Heribert 4072 

Staudinger, Matthias e18565 

Stavraka, Chara 2608, 3022, 

e13033 

Stayner, Lee-Anne 3082 

Stea, Baldassarre TPS2107 

Steadman, Kenneth 2590 

Stearns, Valerie T. e21121 

Stearns, Vered 518, 525, 

1006, 1128, 9103, 10509 

Stebbing, Justin 3546, 3597, 

4088, 9103, e11018, 

e21137 

Steeg, Patricia Schriver 505 

Steeghs, Neeltje 2596, 

e13605 

Steegmann, Juan Luis 6506 

Steegmann, Juan Luis 6505^ 

Steel, Jason C e21064 

Steel, Malcolme 3629 

Steensma, David P. 6103, 

6621 

Steer, Christopher B. 

LBA5000 

Stefan, Holdenrieder e21067 

Stefanek, Michael Edward 

6006 

Stefani, Laetitia 9079 

Stefani, Micaela 586 

Stefanick, Marcia L 1501 

Stefanos, Mona 6508 

Stefanski, Jolanta TPS2619, 

TPS4700 

Steffensen, Karina Dahl 5052 

Steg, Adam D. 5036 

Stega, Jeanetta e14729, 

e14732, e15576 

Stegelmann, Frank 6510 

Steger, Guenther G. 514, 

e21033 

Stegmaier, Petra e16033 

Stehman, Frederick B. 

e15561 

Steidl, Stefan 6574 

Steidle, Christopher P 

e15199^ 

Stein, Andrew Marc 2543 


Stein, Anette 8505 

Stein, Anthony Selwyn 1592 

Stein, Barbara 2506, e13051 

Stein, John Peter 4575 

Stein, Lincoln D. e13107 

Stein, Mark N. 2526, 2539, 

TPS3112 

Stein, Rob TPS665 

Stein, Sandy 10584 

Stein, Stacey e14534 

Stein, Stacy e11529 

Stein, Wilfred Donald e13122 

Steinberg, Joyce Leta 

TPS668, 8587 

Steinberg, Michael S. 1017 

Steinberg, Seth M. 505, 

2528, 2577, 3043, 4569, 

5020, 8051, e18568 

Steinbrecher, Jill Elise 4548, 

TPS4697 

Steiner, Aline e15109, 

e21056 

Steiner, Gabriel e15044 

Steiner, Mitchell S. e19582, 

e19585 

Steiner, Thomas e15044 

Steinger, Brunhilde e16520 

Steinhauer, David e17529 

Steinhauer, Hjalmar B. 8024 

Steinhoff, Ann-Katrin 1067 

Steinke, Verena 3550 

Steinmetz, Kristina e14557 

Steinstraesser, Lars 10059 

Steis, Ronald G. TPS2103 

Stella, Mattia e14730 

Stella, Philip J. TPS657, 

1025, 7605, e16552, 

e18118 

Stelljes, Matthias 6500^, 

6610 

Stelma, Foekje 9070 

Stemkowski, Stephen e18560 

Stemmer, Salomon M. 548, 

1092, 2556, e13080, 

e14731 

Stemmer, Salomon TPS661 

Stemmer-Rachamimov, Anat 

2010 

Stempel, Michelle 557, 

1118, e11531 

Stenehjem, David D. 6583 

Stenholm, Linnea 10552 

Stenning, Sally P TPS4143 

Stenzl, Arnulf e15195, 

e19021 

Stepanek, Vanda M.T. 10510 

Stepanski, Edward J. e15061 

Stephens, Craig 4563, 7582, 

7594, e12007 

Stephens, Deborah Marie 

e18508 

Stephens, Peter 3052 

Stephens, Philip J 1015 

Stephens, Philip 3533, 4649, 

7510, 7529, 10524, 

10559, 10590, e17541, 

e19004 

Stephens, Sonya e17544 

Stephens, Talitha e15162 

Stephenson, Andrew J. 4652 

Stephenson, Joe 4593, 4662, 

4665 

Stephenson, Patricia 7508 

Stephenson, Robert A 2564 

Sterchele, James A. 6553, 

e13081 

Stergiopoulos, Spyros e21027 

Stern, Howard 5575, e13048 


Stern, Lee e14028, e14030, 

e14627, e15043 

Stern, Ralph H. e12026 

Sternberg, Cora N. 4501, 

4519^, 4522, 4525, 4570, 

TPS4683, e15003, e15059 

Sterry, Wolfram 8535 

Stetler-Stevenson, Maryalice 

2503^, 8051, 8088, 

e18568 

Steuer, Conor E 8101 

Steurer, Stefan 10501 

Steven, Neil Matthew 2583 

Steven, Neil TPS8605 

Stevens, Craig William 7065, 

e17559 

Stevens, Glen 2076, 2100 

Stevens, Sandy e16533 

Stevenson, James 7077, 

7092, 7098, e18032 

Stevenson, Kristen 9530 

Stevenson, Laura TPS4143 

Stewart, A. Keith 8010, 

8013, 8035, 8053 

Stewart, Alex e21012, 

e21142 

Stewart, Andrew 6046, 6056, 

6088 

Stewart, Clinton F. e13584 

Stewart, Douglas Allan 6548 

Stewart, Elizabeth e13584 

Stewart, Frances P. 2563 

Stewart, John H. 6127 

Stewart, Larissa 8537 

Stewart, Rena e21045 

Stewart, Robert 4633 

Stewart, Tyler 1132 

Stiede, Kathryn 8032 

Stieglitz, Heather e16500 

Stieler, Jens 4020, 4044, 

4050, e14533 

Stien, Kathy J. e16572 

Stiff, Patrick J. 4022, 

e13121 

Stilidi, Ivan S. e20501 

Stilwell, Jackie L. e21148 

Stimpson, Sarah Jane 3080 

Stinchcombe, Tom 7513, 

TPS7619 

Stineman, Margaret G 

e19531 

Stingl, Julia TPS1612 

Stinson, Jennifer 9556 

Stintzing, Sebastian 3519^, 

3541, 3588, TPS3639, 

4072 

Stirewalt, Derek L. 2523 

Stitzenberg, Karyn Beth 6104 

Stobiecka, Ewa e14159, 

e21049 

Stock, Richard e15164 

Stock, Wendy 6562, 6582, 

e13120^ 

Stocken, Deborah TPS4150 

Stocker, Susan e14642 

Stockerl-Goldstein, Keith 

8011 

Stockler, Martin R. 4531, 

TPS4681, TPS5116, 

7079^, 7511, 9087, 9126, 

e16501, e19642 

Stockman, Paul 6527 

Stoeckle, Eberhard 10096 

Stoecklein, Nikolas H. 

e21017, e21020 

Stoecklein, Nikolas e14527 

Stoeger, Herbert 10501 

Stoehlmacher-Williams, Jan 

2573^, 4090, 5504^, 

10552 

Stoelben, Erich 1533, 

TPS7109, 7603, 10526, 

CRA10529, e18000 

Stoemmer, Peter E. e14076, 

e15013 

Stoenescu, Adela 5007 

Stoermer, Kati M e16508 

Stoetzer, Oliver J. e21067 

Stoffels, Ingo e19031 

Stoger, Herbert 514 

Stokes, Maurice 1113 

Stokes, William A. 4658, 

6032 

Stokes, William Allen 6037 

Stokoe, Christopher T. 547 

Stoller, Ronald G. TPS1138, 

3037, 3054 

Stoller, Ronald 3049 

Stone, Nelson e15164 

Stone, Rebecca Lynn 5027 

Stone, Richard M. 6103, 

6526, 6606, 6617, 6621, 

e13586 

Stopeck, Alison e16528 

Stopfer, Jill 1506 

Stoppa, Anne-Marie 1580, 

e19539 

Storino, Claudio e15521 

Stork, Linda C. 9546, 

TPS9594 

Stork, Lisette 3510, 10545 

Stork-Sloots, Lisette 577, 

10554, TPS10632, 

e21013 

Storm, Courtney D. 6095, 

6128 

Storniolo, Anna Maria 525, 

6053, 10509 

Storoz, Cristina e15202 

Stott, Will e16045 

Stotz, Michael e14066 

Stouthard, Jacqueline 10504 

Stovall, Marilyn 9505, 

CRA9513, 9514, 9528 

Stoyianni, Aikaterini 10575 

Stradella, Agostina 5595, 

e14104, e15159 

Strahs, Andrew Louis 4132, 

4501, e13041, e15082 

Straley, Kimberly 6606 

Strasser, Florian e19648 

Stratmann, Antje e21017, 

e21020 

Straubinger, Robert M 

e13006 

Straughn, John Michael 

e13087 

Straus, David J. 8054 

Strauss, Gary M. 1532, 4545, 

10579 

Strauss, Hans-Georg 5007, 

5031 

Strauss, James Fredric 10037 

Strauss, Lewis C. TPS4134 

Strauss, Marcie e16542 

Strausz, Janos 7557 

Strauß, Arne e15156, 

e15158 

Stravodimos, Kostas e15040 

Stravodimou, Athina e11048, 

e17007 

Street, Thomas 6122, 8037, 

e18556 

Streicher, Howard 2501 

Streit, Michael R. W. 8501 

Streitenberger, Patricia 10074 

Stremitzer, Stefan 3613, 

e14095 

Strenger, Rochelle 1045 

Strevel, Elizabeth Laureen 

5019, 5025 

Stricker, Ingo 10059 

Stricker, Thomas 5517, 9534 

Strickland, Andrew H. 

TPS3637 

Strickland, Stephen Anthony 

TPS6637 

Strickler, John H. 3039 

Striefler, Jana Kaethe 4020, 

e14533 

Strik, Herwig Matthias 2079 

Strimpakos, Alexios S 

e17508, e17557 

Strina, Carla e11546 

Stringer, Bradley 3077 

Strippoli, Antonia e14156 

Strobel, Deike e19032 

Stroebel, Philipp 7105 

Stroh, Mark 3009 

Strola, Giuliana 2600 

Strom, Brian L. 1503 

Strom, Charles m 2587 

Strong, Laura E. TPS3113 

Strope, Seth A. 4594 

Strosberg, Jonathan R. 2534, 

2612, 4047, 4099, 4125, 

4126, e14542, e14551, 

e14579, e14610, e14627 

Strother, Douglas R. 9533 

Strother, Robert Matthew 

5107 

Stroyakovsky, Daniel 5017^ 

Struble, Erika J. 9058 

Strudel, Martina e11039, 

e11514, e12510, e19620 

Struemper, Herbert 5065 

Strumberg, Dirk e13597 

Strutz, Juergen 5512 

Strychor, Sandra 3049 

Stryker, Scott 1581, 4659, 

e15147, e15169 

Stuart, August 6616, e18500 

Stuart, Bruce C. 6028, 6060, 

6075 

Stuart, Joshua M. 503 

Stuart, Robert K. TPS6637 

Studeny, Matus e15037 

Studer, Cristina e19648 

Stuebs, Patrick e14630 

Stuermer, Andrea 7105 

Stukel, Therese A. 6027 

Stump, Tammy K 6021 

Stupp, Roger 2001, 2034 

Sturgeon, Jeremy F. G. 4535, 

e14020 

Sturgis, Erich M. 2558 

Stuurman, Frederik 2550, 

e13028 

Styczen, Hanna 3600 

Styler, Michael e15522 

Styles, Amy e11076 

Stylianou, Spyros e13525 

Ståhl, Birgitta 7539 

Stöckle, Michael 4590, 

e15195 

Su, ChunXia 7535, 10527 

Su, Ih-jen e11068 

Su, Jian 7039, e18090 

Su, Jie 9032 

Su, Pei-Fang 7589 

Su, Qiaojuan e21159 

Su, Wayne 6553 

Su, Wen-Hui 5109 

Su, Wu-Chou 4007, LBA7500 

791s

Su, Xinying 4124 

Su, Yu-Chieh e16008 

Su, Zhaohui e11051 

Suárez, Ana 602, e11006, 

e11517 

Suarez, Cristina TPS4679, 

e15001, e15041, e21021 

Suarez, Eloah Rabello 10568, 

e13016 

Suarez, Javier 3586 

Suarez-Almazor, Maria 8536, 

e19631 

Suarez-Garcia, Ines e11028 

Subbiah, Ishwaria Mohan 

e13020 

Subbiah, Shanmuga e14641 

Subbiah, Vivek 10021, 

e13020 

Subiza, Jose Luis 10564, 

e13085 

Subklewe, Marion 8030 

Subramaniam, Deepa Suresh 

2590, 3095 

Subramanian, Somasundaram 

e19005 

Subramonia-Iyer, Subramony 

e21133, e21154 

Subtil, Fabien 4091 

Subudhi, Sumit Kumar 4516 

Suciu, Stefan 8532 

Suckstorff, Ivonne 2584 

Sud, Shelly 6083 

Suda, Margaret 5579 

Sudaka, Anne 5521 

Suder, Aneta 3022 

Sudhakar, S e14675 

Sudhakar, Tummala 6546 

Sudo, Kentaro 4046 

Suehara, Yoshiyuki 7578 

Suenaga, Mitsukuni 10541, 

e14145 

Suetsugu, Atsushi e14014, 

e21051 

Sufliarsky, Jozef TPS649 

Sugar, Elizabeth 4045, 

e14585 

Sugar, Linda M. 4613 

Sugawara, Shunichi 7086, 

7515, 7565, 7571, 

e18129, e19521 

Sugi, Kazurou e17517 

Sugi, Naoko Hata e13511 

Sugie, Tomoharu e21004 

Sugihara, Eiji 635 

Sugihara, Kenichi e14091, 

e14127 

Sugimori, Kazuya 4035 

Sugimoto, Hiroyuki e18081 

Sugimoto, Kiichi e14139 

Sugimoto, Mikio e15127 

Sugimoto, Naotoshi 4002 

Sugino, Keishi e18127 

Sugio, Kenji TPS7110 

Sugita, Hirofumi 7066 

Sugiyama, Eri 7044 

Sugiyama, Shunsuke e19611 

Sugiyama, Tomohide e13029 

Sugiyama, Toru 5003, 5103 

Suh, Cheol Won e18501 

Suh, Cheolwon 7004, 8023, 

e13104, e18052 

Suh, Dong-Hoon e15503 

Suh, Eugene 9586 

Suh, John H. 2018, 2076, 

2092, 2100 

Suh, K. Stephen e18507 

Suhail, Ali M. e21039 

Suhaimi, Nur-Afidah Binte 

3589 

Sujoy, Victoria 595 

Sukari, Ammar 2081, 5534, 

7593, e16019 

Sukeepaisarnjaroen, Wattana 

4108 

Sukegawa, Gen e15038 

Suki, Dima 2019 

Sukor, Sumainizah 622 

Sukov, William R. 4009 

Sukumar, Saraswati 518, 

e13559 

Sukumaran, Shawgi e19550 

Sukumaran, Sujita e13500, 

e13577, e21029 

Sukumaran, Sunitha e17555 

Suleiman, Yaman 4534, 

7032, 7107, 7108 

Sulkes, Aaron 548, e14571 

Sullivan, Adam 9116 

Sullivan, Amy 6038 

Sullivan, Clare e16515 

Sullivan, Daniel 2501, 2534, 

TPS2620, 3077, 5020, 

8013, e13603 

Sullivan, Frank e15126 

Sullivan, Irene e19646 

Sullivan, Ivana 5590, 5595, 

7041, e15159, e18057 

Sullivan, Kristen 6122, 8037, 

e18556 

Sullivan, Laura A 5029 

Sullivan, Maryann e14125, 

e19638 

Sullivan, Peggy S 10588 

Sullivan, Ryan J. 8516, 8569 

Sullivan, Sean D e14141, 

e14146, e15175, e15183, 

e18097 

Sullivan, Timothy J. 2043, 

e13580 

Sulman, Erik P. 2001, 2002, 

8584 

Sultan, Sadaf e13039, 

e21128 

Sultana, Rebeka 1014 

Suman, Saurav e15181 

Suman, Vera J. 503 

Suman, VeraJean 534, 5544, 

e13086 

Sumi, Minako 7070, 9574 

Sumino, Hiroshi 1103 

Summer, Stephen J. 9575 

Summers, Deborah 8560 

Summers, Yvonne J. e18095 

Sumner, Dyana K. 7052, 

e19647 

Sumpter, Katherine Anne 

TPS4143 

Sumstand, Darin 2546 

Sun Myint, Arthur e14149 

Sun, Can-Lan 1592, 9512 

Sun, Canlan 8038 

Sun, Charlotte C. 1518, 

6116, 9134, e13026 

Sun, Dandan 8597 

Sun, Di 9548 

Sun, Guigin e15563 

Sun, Guihua 10545 

Sun, Haibo 7034 

Sun, Han e18076 

Sun, Hong 9059 

Sun, Hongliu e14098 

Sun, Jian 5593 

Sun, Jiayuan e17551 

Sun, Jong-Mu 7004, 7104, 

e18148 

Sun, Julia e15540 

Sun, Kai e15183 

Sun, Lihong 10563 

Sun, Luhong e18557 

Sun, Mai e15560 

Sun, Peng 3528, 8510 

Sun, Peter 1609, e12042, 

e15096 

Sun, Qiang TPS649 

Sun, Shiliang e14620 

Sun, Si e11567, e11568 

Sun, Sophie 549^, 7020 

Sun, Virginia 9068, e16563 

Sun, Weihong 1585 

Sun, Weijing 3522, 3523, 

3525, 4077, 4111 

Sun, Weimin 2587 

Sun, Wenyong e21080 

Sun, William 6624 

Sun, Xia 4068 

Sun, Xiaojiang e17527 

Sun, Xindong 4073 

Sun, Xiu 614 

Sun, Yan 7519^, 7559 

Sun, Yihong 4092, e14575 

Sun, Yong-kun e14668 

Sun, Yongkun e14606 

Sun, Yu-Nien 5072 

Sun, Yuanjue 9017 

Sun, Yuanlu 5538 

Sun, Yuliang 626, e13579 

Sun, Zhuoxin 504 

Sunaga, Noriaki e18037 

Sunakawa, Yu 3088^ 

Sunami, Eiji e14142 

Sundaram, Shankar e15116 

Sundby Hall, Kirsten 10081 

Sunderkötter, Cord 8505 

Sundstrom, Stein 7001 

Sundstrøm, Stein 7027 

Suneja, Gita 6070 

Suner, Ali 638 

Sung, Max W. 4043 

Sung, Myung-Whun 5552 

Sunkavalli, Venkata Ratnam 

9055 

Sunkavalli, Venkataratnam 

e12501 

Sunpaweravong, Patrapim 

e14639, e20514 

Sunpaweravong, Somkiat 

e14639 

Sunwoo, John 2514 

Sunyach, Marie-Pierre 10042 

Supko, Jeffrey G. 4112 

Suppapanya, Nittaya e12001 

Suppiah, Kathiresan e18122 

Suraokar, Milind B. 7078 

Surapaneni, Aparna e15097 

Surapaneni, Rakesh 1127, 

e12008 

Sure, Ulrich 2086 

Sureda, Anna 8002 

Suri, Anuj 5063 

Susanne, Jungwirth 2024 

Suschak, Jessica 1091 

Suskan, Emine e20000 

Sussman, Jeffrey J. e14714 

Sussman, Jonathan 6035, 

6039 

Sutaria, Jaini e17021 

Suter, Thomas 532 

Sutherland, Heather J 8018^ 

Sutherland, Robert L. 504, 

TPS1136 

Sutphen, Rebecca 1608 

Sutradhar, Rinku 6039 

Suttle, Ben B 2593 

Sutton, John E. e14514 

Sutton, Steve e21155 

Suva, Larry J. e21039 

Suvannasankha, Attaya 

e18555 

Suvorov, Alexander 8018^ 

Suwa, Yusuke e14050 

Suzuki, Akihiro 4069, 4078, 

4086, e14547, e14669 

Suzuki, Haruko 7021 

Suzuki, Hidekazu e18036, 

e18042 

Suzuki, Hidenori e16032 

Suzuki, Hiroyuki e13015 

Suzuki, Kenji 7012, 10548 

Suzuki, Kenshi 8097 

Suzuki, Kousuke e14722 

Suzuki, Osamu e15533 

Suzuki, Ritsuro 6533 

Suzuki, Tatsuya 8029 

Suzuki, Toshiro 7086 

Suzuki, Yasuhiro 565 

Suzuki, Yasukuni e14510 

Suzumura, Tomohiro e17538 

Svabova, Veronika e19020 

Svane, Inge Marie 2565, 

2574 

Svegliati Baroni, Gianluca 

e14561 

Svensson, Liz TPS5598 

Svetlovska, Daniela TPS4677, 

e15027 

Svoboda, Jakub e18529, 

e18540 

Svoboda, Marek 1087 

Swaby, Ramona F. 605, 

6025, e11085 

Swain, Sandra M. LBA506, 

533^, 597^, 598^, 

LBA1000, 1025, TPS1142, 

10603, e11055^, e16543 

Swaisland, Helen 3048, 3051 

Swallow, Carol Jane 10050 

Swallow, Elyse e14621 

Swami, Nadia 9003, e16567 

Swami, Umang 3093 

Swann, R. Suzanne 

LBA8500^, 8501 

Swanson, Gregory P. 4509 

Swanson, Kenneth D. e21078 

Swanton, Charles TPS650 

Swart, Rachel Elizabeth 529 

Swatkowski, Pamela L 

e21111 

Sweeney, Christopher 4513, 

4555, 4603, TPS4694 

Sweeney, HelenAnne 1598 

Sweeney, John P. e15078 

Sweeney, Thomas J. 9115 

Sweep, Fred C.G.J. e13111 

Sweet, Joan e15118 

Sweet, Kendra Lynn 6568, 

6575, 6588, 6608, 8084 

Sweetenham, John W. 8032, 

8055, 8071 

Sweis, Randy F. 4573 

Swensen, Ron E. 5082^ 

Swern, Arlene S 6122, 

e18556 

Swieboda-Sadlej, Anna 4042 

Swift, Lonnie e13587 

Swift, Regina A. 8098, 

e18549, e18558 

Swinton, Nelda e19626 

Swisher, Elizabeth M. 5073 

Swisher, Stephen 4069, 

4078, 4086, 7023, 7043, 

7047, 7062, e14547, 

e14548 

Switaj, Tomasz 8548 

Switzky, Julie C. 8501 


Sycova-Mila, Zuzana 

TPS4677, e15028 

Sydes, Matthew Robert 4509, 

10081 

Syed, Fayaz ahmed e12501 

Syed, Nelofer e18567 

Syh, Jarron e17524 

Syh, Joseph e17524 

Sülberg, Heiko e14162 

Sym, Sun Jin e14137, 

e14685 

Symanowski, James Thomas 

e15210 

Symmans, William Fraser 

515, 545, 1012, 10559 

Symon, Zvi e14143 

Synold, Timothy W. 3078, 

3108, e15114 

Syrigos, Konstantinos N. 

7554 

Syrigos, Kostas N e17508, 

e17557 

Syto, Mary 6577 

Szabatura, Audrea e16515 

Szabo, Eva 7033, 7103 

Szabo, Miklos e13102 

Szabo, Peter e21140 

Szabo, Stephen 569, 571, 

e11002, e14106, e14141, 

e14146, e15183, e18097, 

e19615 

Szallasi, Zoltan 10571 

Szarka, Christine E. e19519 

Szasz, Attila Marcell e21005 

Szcylik, Cezary TPS4683 

Szczudlo, Tomasz K. 6505^ 

Szczylik, Cezary TPS4135, 

4501 

Sze, Ming 6111, e16507 

Szerlip, Nicholas 2081 

Sziraki Kiss, Valeria e21140 

Szlosarek, Peter Wojciech 

e18567 

Sznol, Mario CRA2509, 

TPS2613, 4505, 8507, 

8508 

Szostakiewicz, Barbara 505 

Szubert, Alexander 8015 

Szumera-Cieckiewicz, Anna 

10538 

Szyldergemajn, Sergio A. 

2539 

Szymonifka, Jackie 4027, 

8041, 9585, 10058 

Sørensen, Henrik Toft 1579, 

e12023 

T 

Ta, Matthew e16523 

Taback, Bret 1107 

Tabarroki, Ali 6521 

Tabata, Masahiro 2607, 

7042, 7560, 7576, 

e18027 

Tabata, Toshiharu e19508 

Tabata, Tsutomu e14029 

Tabatabai, Ghazaleh 2055, 

2067, TPS2105, 8526 

Tabayashi, Koichi e19508 

Tabbara, Imad A. e11084 

Tabei, Toshio 613 

Taber, Angela Marie 4098 


Tabernero, Josep 509, 566, 

619, 2567, 2568, 3003, 

3014, 3021, 3059, 3062, 

3502, 3505, 3510, 3531, 

3539, 3574, 3578, 3579, 

3587, 3614, TPS3634, 

TPS3637, 4053, 7041, 

10511, e13048, e13114, 

e13605 

Tabouret, Emeline 2060, 

e19539 

Tachibana, Isao e18056, 

e18141 

Tachikawa, Ryo 7528, 10610 

Tacyildiz, Nurdan e20000 

Tada, Hirohito TPS7110, 

7521 

Taddei, Gian Luigi e14042, 

e18021 

Taffurelli, Giovanni e14647 

Taft, David R. 3081 

Tagawa, Scott T. 4649 

Tagawa, Tomoko 1035 

Taghian, Alphonse G. 1122 

Taghizadeh, Niloofar 1502 

Tagieva, Naila e18005 

Tagliaferri, Pierosandro 

e13098, e14577 

Taha, Said 2048 

Tahar, Zoubir e15142 

Tahara, Makoto 3079, 5504^, 

5542, TPS5598 

Tahir, Ammara H 6612 

Tai, Ming-Hui 6075 

Tai, Tak Hing P. e16572 

Tai, Wai Meng David 3589, 

5551, 5580, e14155, 

e18546 

Tai, Wei-Tien e14516 

Tai, Yu-Chong 4663, e15153 

Tai, Yu-Zu 8106 

Taïeb, Julien 3574, 4018, 

4053, 4087, 9026^ 

Taieb, Sophie 4618 

Taillandier, Luc 2023 

Taillibert, Sophie TPS662, 

TPS2106 

Taioli, Emanuela 1046 

Taira, Kaoru e14518 

Taira, Koichi e18036, 

e18042 

Taira, Tetsuhiko e18064 

Tait, Diana M. e14088 

Tait, Nancy 9103 

Tajika, Masahiro e14540 

Tajiri, Tatsuro 9577 

Tak, Won-Young 4103 

Takabatake, Daisuke 

TPS1147 

Takada, Jun 10073 

Takada, Minoru 7000, 7521, 

10577, e18128 

Takaesu, Yotaro 10557 

Takagi, Keigo e18127 

Takaha, Natsuki e15055, 

e15099 

Takahara, Masatoshi e19521 

Takahari, Daisuke e14500 

Takahashi, Atsushi 10520, 

e13014, e15068 

Takahashi, Hideaki 4046 

Takahashi, Hidekazu e19611 

Takahashi, Kazuhiro 10519 

Takahashi, Kazuhisa e18019 

Takahashi, Maiko e11060 

Takahashi, Masato 1119, 

TPS1147 

Takahashi, Masayuki e15068, 

e15098 

Takahashi, Masazumi e14624 

Takahashi, Michinaga e14011 

Takahashi, Naoki 8023, 

e14126 

Takahashi, Naoto 8023 

Takahashi, Norihiko 10578 

Takahashi, Ryo e18007, 

e18056 

Takahashi, Ryuji e13046, 

e13050 

Takahashi, Shin e19611 

Takahashi, Shunji e15038, 

e19512 

Takahashi, Takao 3558, 

TPS3642 

Takahashi, Tiago Kenji 

e21040 

Takahashi, Toshiaki 7088, 

e21007 

Takai, Yujiro e18127 

Takamochi, Kazuya 10548 

Takamori, Hiroshi e21084 

Takamura, Kei 7561, 7571, 

e18135 

Takano, Atsushi e13552, 

e13565 

Takano, Masashi 5006, 5037, 

e15579 

Takano, Toshimi TPS659 

Takao, Shintaro TPS1141 

Takasa, Akiyuki e19583 

Takashima, Atsuo 4031, 

e14510 

Takata, Ryo 10520 

Takayama, Hitoshi e15065, 

e15069 

Takayama, Tatsuya e15071 

Takayanagi, Hiroyuki e11007 

Takebe, Naoko 3078, 10004, 

10005, e13106 

Takechi, Hirokazu e11560 

Takeda, Koji 6112, 7003, 

7017, 7028, TPS7110, 

7549, e18036, e18042 

Takeda, Masayuki e18060 

Takeda, Shugaku 4604 

Takeda, Yuichiro 7017 

Takeda, Yutaka e14518 

Takehara, Kazuhiro 5084 

Takei, Hiroyuki 613, 1106 

Takemoto, Mitsuhiro 7045, 

e15533 

Takemoto, Shuji 5085 

Takemura, Shigekazu e14518 

Takemura, Shinichi e14011 

Takeoka, Hiroaki 3045 

Takeshima, Nobuhiro 5103 

Takeshita, Jumpei 7528, 

10610, e18025 

Taketa, Takashi 4069, 4078, 

4086, e14547 

Taketomi, Akinobu 10578 

Takeuchi, Akihiko 10075, 

e20505 

Takeuchi, Hideya e14722 

Takeuchi, Hiroya e14045 

Takeuchi, Kengo e18017 

Takeuchi, Masahiro 7012, 

7515 

Takeuchi, Yoshiko e18007, 

e18056 

Takeyoshi, Izumi 613 

Takigawa, Nagio 2607, 7042, 

7045, 7560, 7576, 

e18027 

Takiguchi, Nobuhiro 3524 

Takiguchi, Yuichi 7046, 

7515, 10542 

Takii, Yasumasa 3524 

Takimoto, Chris H.M. 3078 

Takiuchi, Hiroya 3088^, 

e14510 

Takizawa, Ken 5103 

Takuwa, Teruhisa 7031, 

7080, 10585 

Takvorian, Anna e15053 

Talalay, Paul TPS8606 

Talamantes, Tatjana e13557 

Talamini, Renato 8058 

Talamo, Giampaolo 8090 

Talamonti, Mark S. 4049 

Talamonti, Mark e14642 

Talano, Julie 6537 

Talavera, Pablo e20513 

Talbot, Denis Charles 4121, 

7081 

Talcott, James Austin 6107 

Tallam, Celestine 2601 

Tallman, Martin S. 6532, 

6601 

Talluri, Jyothsna 7102 

Talluto, Craig Charles 

TPS2616 

Talpaz, Moshe 6503, 6624, 

8017 

Talwar, Sumit 6114 

Tam, Alda e14664 

Tam, Vincent Channing 

e14073, e16558 

Tamagawa, Hiroshi TPS3642 

Tamagawa, Koji 3607 

Tamai, Hideyuki e14622 

Tamaki, Kentaro e11530 

Tamaki, Nobumitsu e11530 

Tamandl, Dietmar e14095, 

e14099 

Tamari, Roni 8005 

Tamaru, Satoshi e19546 

Tambaro, Francesco Paolo 

6517, 6603 

Tambo, Yuichi e17540 

Tamboli, Pheroze 4624 

Tamborini, Elena 10026 

Tamburelli, Mercedes e15570 

Tamimi, Rulla M. 9071, 

9100 

Tamiya, Motohiro e18036, 

e18042 

Tamm, Eric P. 4051 

Tamura, Kenji 10519, 

e11065, e19535 

Tamura, Takao e14510 

Tamura, Tomohide 6112, 

7003, 7017, 7028, 7070, 

7602 

Tan, Angelina D. 6108 

Tan, Antoinette R. 611, 

1025, 2534, 3054, 

TPS3112, e13596 

Tan, Benjamin R. 2525, 

e15116 

Tan, Bo e14645 

Tan, Charmaine e14155 

793s

Tan, Chee Seng 1064, 

e19523 

Tan, Chun-Wen e14026 

Tan, Cong 3551 

Tan, Daniel S. W. 5551, 

e16024 

Tan, Daniel Shao-Weng 3007, 

3098 

Tan, Daryl C.L. 8097, 

e18528, e18546 

Tan, Eng Huat 5580, 7575 

Tan, Eng-Huat 2598, 3098, 

5551, e16024 

Tan, Eugene 2603, TPS4147 

Tan, Francis 4106 

Tan, Glaiza L.A. e13574 

Tan, Iain B. 3589, 8078 

Tan, Iain BeeHuat e14155 

Tan, Jonathan 7604 

Tan, Kai e14523 

Tan, King L. 8003 

Tan, Leonard 1593, 8078, 

e18515 

Tan, Mann Hong 10051, 

e20509 

Tan, Min-Han 3589, 4536, 

4538 

Tan, Ming Tony 7546, 9103 

Tan, Puay Hoon 5551, 5580 

Tan, Sing-Huang 2551 

Tan, Soek Siam 4106 

Tan, Soo Yong 1593, e18515 

Tan, Soo Yong 8078, 

e18528, e18546 

Tan, Thuan Tong 3098, 

e18546 

Tan, Wah Siew 3589 

Tan, Wei 6565, 6602, 

e13006, e14659, e17535 

Tan, Weiwei 2610, 7508 

Tan, Wen-Lee 2551 

Tan, Winston e13501 

Tan, Wu Meng e18546 

Tan, Yongqiang 2541 

Tan, Yuying 1063 

Tana, Silvia 5555 

Tanaka, Akiko e19521 

Tanaka, Fumihiro 7080, 

10585 

Tanaka, Hidenori e17538 

Tanaka, Hiroshi e11065 

Tanaka, Junji 6533 

Tanaka, Kaoru e18060 

Tanaka, Keiji 8094 

Tanaka, Koji e14029, 

e14039, e14541, e21053 

Tanaka, Kosuke 7528, 10610 

Tanaka, Kuniya e14047, 

e14050 

Tanaka, Maki 588 

Tanaka, Masao 4035, e14506 

Tanaka, Toshiki e17517 

Tanaka, Tsutomu e14540 

Tanaka, Yoshihiro e13014 

Tanaka, Yoshimasa e21004 

Tanaka, Yoshinobu 8029 

Tanasanvimon, Suebpong 

e19645 

Tanca, Francesca Maria 4627 

Tanco, Kimberson e19603, 

e19613 

Tanda, Francesco e14094 

Tandon, Vickram 10586 

Tandstad, Torgrim 4508 

Taneja, Charu e12024, 

e15197, e18107, e19630 

Tang, Bi Xia 8506, 8562, 

e15051, e15052 

Tang, Cha-Mei 6581, e21079 

Tang, Colin TPS4690 

Tang, Gong LBA506, 

LBA1000 

Tang, Jie LBA4537, 7551 

Tang, Laura H. e14586 

Tang, Lichen e11567, 

e11568 

Tang, Patricia 3013, 6082, 

e14073, e21083 

Tang, Rui 2535, 2594, 3009, 

4005 

Tang, Sujie 1124 

Tang, Tiffany 8078, e18515 

Tang, Ya-Ling e14629 

Tang, Yiyun 7598, 7600 

Tang, Yu e14511 

Tang, Yuen Fong e14545 

Tang, Zhaoqing 4092, 

e14575 

Tang, Zuojian 9507 

Tangen, Catherine M. 4, 

4511, 4547, 4571, 4663, 

10503 

Tangirala, Muralikrishna 

4666, e15186 

Tangoku, Akira e11560 

Tani, Kenzaburo e13014 

Tani, Tohru e11564 

Taniere, Philippe e13507, 

e13554 

Tanigawa, Go e15065, 

e15069 

Taniguchi, Cullen M 10629 

Taniguchi, Hirokazu e14126 

Taniguchi, Naoyuki e17520 

Taniguchi, Shuichi 6533 

Tanimoto, Azusa 10569, 

10604, e18004, e18014, 

e18017 

Tanimoto, Mitsune 2607, 

7042, 7045, 7560, 7576, 

e18027 

Tanino, Hirokazu 1119, 

TPS1141 

Tanioka, Maki 5045, e19548 

Taniyama, Kiyomi 5084 

Taniyama, Tomoko e19535 

Tanizawa, Yutaka e14635 

Tannapfel, Andrea 10059 

Tanner, Lanier 10004 

Tannir, Bayane TPS4149 

Tannir, Nizar M. 4533, 4609, 

4615, 4624, 9002, 9029, 

e15092 

Tannock, Ian 6043, 9003, 

9021, e13001 

Tanvetyanon, Tawee 2559, 

5564, 7024, 7065, 

e17559 

Tanwandee, Tawesak 

TPS4149, e13061 

Tanzawa, Hideki 10542 

Tanzawa, Yoshikazu 10075 

Tao, Hiroyuki e17517 

Tao, Jianguo e21123 

Tao, Li e14648 

Tao, Min 8554 

Tao, Miriam 1593, 8078, 

e18515, e18546 

Tap, William D. 10002, 

10003, 10004, 10012, 

10019, TPS10099, 

TPS10100, TPS10103 

Taphoorn, Martin J. B. 2, 

6002, 6090, 7607 

Tapia, Gonzalo e14058 

Taplin, Mary-Ellen 4519^, 

4520, 4521, 4665, 

TPS4695 

Taran, Florin-Andrei 1090, 

e21003 

Taran, Tanya 512, 551, 559, 

TPS648 

Tarantini, Luigi 645 

Tarassoff, Peter G. 6559, 

6627, 6632 

Tarazi, Jamal Christo 4546 

Tarazona, Noelia e14589 

Tarbell, Nancy 9537, 9585 

Tarco, Emily 1054 

Tarella, Corrado 8030 

Targarona, Eduardo e14104 

Tarhan, Cagla e15572, 

e15573 

Tarhini, Ahmad A. 8522, 

8528, 8533, 8547, 

TPS8606 

Tarifa, Antonio e21086 

Tarleton, Kenneth 9025 

Tarnai, Robert 6501 

Tarnawski, Rafal e14159, 

e21049 

Taron, Miquel 4068, 4579, 

7007, 7011, 7522, 7540, 

7542, 10596, e14509, 

e14521, e18130, e18131, 

e18137, e18143 

Tarpgaard, Line Schmidt 

3548 

Tarpin, Carole e19539 

Tarpinian, Karineh 9103 

Tarrant, Teresa K. e13063 

Tarraran, Loredana 10066 

Tarrío, Nuria e14595 

Tartarini, Roberta 10611 

Tartour, Eric 5554 

Tashakkor, Amir Yashar 6085 

Tashiro, Haruko 9053 

Tasian, Sarah Kathleen 9506 

Taskinen, Minna 8074 

Tasneem, Asba 6047, 6051 

Tassone, Pierfrancesco 

e14577 

Tatangelo, Fabiana e14130 

Tatarian, Talar e11084 

Tateishi, Souichirou 1103 

Tateishi, Ukihide 4626, 8023 

Tatersall, Martin 10006 

Tateyama, Miki 3593 

Tatla, Raman e16547 

Tatli, Ali Murat e14070 

Tatsumi, Mitsuaki 8023 

Tatsuta, Noriaki 3086 

Tattersall, Martin HN 9087, 

9126 

Tatzreiter, Georg e14087 

Taub, Robert N. e13064, 

e13066, e13067 

Taube, Janis M. CRA2509, 

5506 

Tauber Jakab, Katalin e21140 

Tauber, Rudolf 5047 

Tauchert, Felix 4080 

Taunton, Jack 8544 

Tavakkoli, Fatemeh e13075 

Tavares, Renato TPS6640 

Tavassoli, Fattaneh 1109 

Tawashi, Manal e13602, 

e13604 

Tawbi, Hussein Abdul-Hassan 

TPS1138, 3049, 3054 

Tawbi, Hussein 8528, 8533, 

TPS8606, TPS10103 

Tay, Cheong Kiat Julian 

e19523 

Tay, Kevin 1593, 8078, 

10051, e18515, e18546, 

e20509 

Tay, Miah Hiang 4103 

Tayi, Ravi e19544, e19567, 

e19578 

Taylor, Barry S. 4527 

Taylor, Clare TPS2619, 

TPS4700 

Taylor, Gretchen Elizabeth 

4055 

Taylor, Ian 7530, TPS7615 

Taylor, Julie 9048 

Taylor, Marianne 549^ 

Taylor, N Jane 1066 

Taylor, Paul 7013, 7583, 

e18095 

Taylor, Sally e19588 

Taylor, Sara Kristina 549^ 

Taylor, Sarah A. e13551 

Taylor, Sarah H 7608, 

e15181 

Taylor, Stephanie 2081, 

e14609 

Taylor-Stokes, Gavin e16570 

Tazbirkova, Andrea e13128 

Tchakov, Ilian 3048, 3051, 

5001 

Te Loo, Dunja Maroeslea 

W.M. 9550, 10077 

Tea, Muy-Kheng Maria 1537 

Teachey, David T. 9506 

Teal, Christine B. e11084 

Tebbutt, Niall Christopher 

3515, 3534, 3614, 

TPS3643 

Tecimer, Coskun e14698 

Tedder, Thomas 2514 

Tee, Goh Yeow 6512, e18528 

Tefera, Eshetu e16543 

Tefferi, Ayalew 6614, 

TPS6639, TPS6641 

Tegze, Bálint e21005 

Teh, Bin Tean 4624, 8078, 

e18515 

Tehfe, Mustapha Ali e18136 

Tehfe, Mustapha e17507, 

e18120 

Teijeira, Lucia e21086 

Teira, Pierre 9563, 9570 

Teishima, Jun e15068 

Teitelbaum, April H. e17017 

Teitelbaum, April e16539 

Teitelbaum, Ursina R. 4111, 

e13602 

Teixeira, Adriana e12040 

Teixeira, Manoel Jacobsen 

2038 

Tejani, Mohamedtaki 

Abdulaziz 10064 

Tejeda, Nicole e21071 

Tejerina, Eva 10547 

Tejiram, Shawn 10070 

Tejpar, Sabine 3509, 3511, 

3531, 3575, 3587 

Tejura, Bindu TPS4693 

Tejwani, Sheela 3078 

Tekautz, Tanya M. 2076, 

2100 

Teker, Fatih e14107 

Tekin, Deniz e20000 

Tekin, Salim Basol e14526 

Tekkis, Paris P e14132 

Teknos, Theodoros Nicholas 

e16014 

Teleni, Laisa Vicki e19550 

Telera, Stefano Maria 2085 

Teletaeva, Gulfiya Midhatovna 

e13059 

Telfer, Margaret C. e18534 

Tello, Sebrina A TPS4678 

Teltsch, Dana e13081 


Temam, Stéphane 5505, 

5522 

Tembhare, Prashant 8088, 

e18568 

Temel, Jennifer S. 6004, 

6048, 6062, 6106, 7010, 

7099, 9004, 9030, 9101 

Temiz, Suleyman e14618 

Temkin, Sarah Madhu 

e16546 

Tempelhoff, G.-F. e13100^ 

Tempero, Margaret A. 3105, 

4048 

Temple, Graham e15037 

Temple, Larissa K. F. 3583, 

6073 

Templeton, Arnoud 9059 

Tenen, Daniel G. 7523 

Tenen, Daniel G e13505 

Teng, Gaojun e14605 

Teng, Yun 6000 

Tenglin, Richard Charles 

1083 

Tennant, Lucinda 2571, 

e19008 

Tennevet, Isabelle 5505 

Teo, Melissa 10051, e20509 

Teo, MinYuen 2062, e14705, 

e15093, e17561, e19059 

Teo, Yi Ling e13023 

Teofilovici, Florentina 3086, 

3094, TPS7613^ 

Teoh, Gerrard 8097 

Teomete, Mehmet e16015 

Teot, Lisa A. 10081 

Tepperberg, James H e21111 

Ter Voert, E. e13111 

Terachi, Toshiro e15071 

Terada, Mizuho 565 

Teragni, Cristina 589 

Terai, Hideki e18058 

Terajima, Hiroaki e14518 

Teramukai, Satoshi 588 

Terao, Mayako 565 

Terashima, Masaaki e18060 

Terashima, Masanori 4012, 

e14635 

Terauchi, Fumitoshi 5003, 

10557 

Terauchi, Takashi 8023 

Terebelo, Howard R. 8037, 

e18556 

Terlizzo, Monica 3613 

Terpos, Evangelos 8095 

Terracciano, Luigi 7061 

Terranova, Corrado 5093, 

e15547, e15550 

Terrasa, Josefa e12012 

Terrell, Deirdra e17001 

Terrenato, Irene 1050 

Terriat, Beatrice 1580 

Terrier, Philippe 9536, 

10018, 10044 

Terry, Mary Beth 1502 

Tertian, Gerard 6523 

Terui, Yasuhito 10541 

Tesch, Hans 554, 1023 

Teschendorf, Christian 

TPS3639 

Tesfaye, Anteneh A. 3619, 

7102, e14046, e15554 

Tessen, Hans Werner 6566 

Testa, Enrica 4084 

Testa, Isabella 4629 

Testa, Joseph 4605, 7083 

Testelin, Sylvie e16013 

Tester, William J. 7051 


Testori, Alessandro 8502^, 

8513, 8529, 8532, 8534, 

e19035, e19036 

Teten, Rachel Threet 1608 

Tetteh, Ernestina e13599 

Tetterton, Jill 2074^ 

Teule, Alex 4119 

Teulon-Navarro, Isabelle 5069 

Tevaarwerk, Amye 555, 563, 

3101, 6063 

Tew, William P. 5056, 5057, 

5108, 9034, 9109, 9123, 

e18133 

Tewari, Krishnansu Sujata 

1519 

Thakar, Alok 5540 

Thaker, Premal H. 5013, 

5101, 9134 

Thakkar, Jigisha P. e12036 

Thakral, Charu e18535 

Thakur, Archana e13089 

Thaler, Howard T. e19566 

Thaler, Josef 4074 

Thalgott, Mark K. 4590 

Thall, Peter F. e14548 

Thalmann, George 4661 

Tham, Chee Kian 2066, 

4100^ 

Tham, Ivan Weng Keong 

2016, 5553 

Thanvilay, Dominic- Vidaroun 

9563 

Thariani, Rahber e16524 

Thariat, Juliette 10035, 

10042, e16013 

Tharkar, Shweta 10614 

Tharnish, Mark 9110 

Thatcher, Nick LBA7000, 

TPS7612 

Thaw, Sunn Sunn Htet 

e21125 

Thayer, Mathew 9555 

Theaker, Jeffrey 8566 

Theaux, Ricardo Alejandro 

e21025 

Theeler, Brett James 2022 

Thein, Mya Sanda e13042 

Thelen, Paul e15156, 

e15158 

Theocharis, Stamatios 

e21098 

Theodore, Christine 

LBA4567^, TPS4696^ 

Theodoulou, Maria 10514 

Theoleyre, Sandrine e21117 

Thépot, Sylvain 6523 

Therasse, Patrick e13061 

Theriault, Richard L. 599, 

6116 

Thery, Jean Christophe 1095, 

5067 

Theuer, Charles P. 3034, 

3042^, e21038 

Thézenas, Simon 3633 

Thibodeau, Stephen N. 3514 

Thiébaut, Anne e14065 

Thieblemont, Catherine 8021, 

8048 

Thiel, Eckhard 2007, 2054, 

8031 

Thiel, Falk 5007 

Thielemans, Kris 2507 

Thienprayoon, Rachel e19536 

Thierry, Alain R. 10505 

Thiery- Vuillemin, Antoine 

TPS4696^ 

Thies, Svenja 2055 

Thiessen, Brian 2051 

Thigpen, J. Tate 1519 

Thiis-Evensen, Espen 4015 

Thijssen, Bas 2550 

Thippeswamy, Ravi Shankar 

9559 

Thirlwell, Michael P. 1025 

Thirman, Michael J. 6562 

Thirot-Bidault, Anne 4018 

Thiruvenkatam, Radhika 9518 

Thng, Choon Hua 1064, 

4100^ 

Tholander, Bengt 5017^ 

Thomas, Anish 7033, 7103, 

TPS7609 

Thomas, Charles R. 5596^, 

7018, e14555 

Thomas, David e13585 

Thomas, Deborah A. 6501, 

6578, 6585, 6592 

Thomas, George TPS3116, 

9541 

Thomas, Gerry 1094 

Thomas, Gillian TPS5116 

Thomas, Hala TPS3116 

Thomas, J TPS1144 

Thomas, James P. e14613 

Thomas, Jay 9068 

Thomas, John 2066 

Thomas, Luc 8512, 8578, 

8591 

Thomas, Michael 2573^, 

LBA7507, 7599, e18016^, 

e18100 

Thomas, Pascal e16560 

Thomas, Sachdev P. 

TPS3635^, 4022, 7073, 

7555, e18556 

Thomas, Sachdev P 8037, 

8075 

Thomas, Scott 3058 

Thomas, Sheeba K. 8091, 

8093, 9082, 9140 

Thomas, Sheila e16542 

Thomas, Tarita O. e18523 

Thomas, Xavier G. 6559 

Thomassin, Jeanne e15155 

Thomeer, Michiel 7013 

Thomes-Pepin, Jessica 

e15561 

Thompson, Alastair Mark 

9022 

Thompson, Carrie A. 9057 

Thompson, Cheryl L 1569 

Thompson, Dana Shelton 

3033 

Thompson, David e17012 

Thompson, Dawn e15162 

Thompson, Emilda 4553, 

e15136 

Thompson, Ian Murchie 4, 

4511, 4547, 4571, 4663, 

10503 

Thompson, James E 6565, 

6602 

Thompson, Jennifer TPS4681 

Thompson, John A. 3077, 

8504, e13088, e13603 

Thompson, John F 8534, 

8559 

Thompson, John TPS8116 

Thompson, Joyce LBA4001 

Thompson, Lisa A. e16541 

Thompson, Lisa A e16550 

Thompson, Lora 7065, 

e17559 

Thompson, Michael A. 

e16561 

Thompson, R. Houston 4657 

Thompson, Simon TPS9148 

Thompson, Stephen F 4666, 

e14028, e14030, e15186 

Thomson, Damien B. 4531 

Thomson, Erin 593 

Thomssen, Christoph 552, 

580 

Thongprasert, Sumitra 1534, 

7519^, e13061, e18063^ 

thor Straten, Per 2565, 2574 

Thor, Ann D. e21099 

Thorat, Mangesh A. 505 

Thorn, Molly 6114 

Thornton, Bob 10573 

Thornton, Claire 9539 

Thorpe, Villette 3025 

Thorsen, Cristina e16504 

Thota, Narender Kumar 6554, 

e18544, e18545 

Thota, Ramya e14641 

Thota, Swapna e15023 

Thotakura, Vijaya 5582 

Thottakam, Bensita M.V 

e15011 

Threatt, Stevie 2094^, 2095^ 

Throngprasert, Sumitra 

TPS4147 

Thu, Minn Minn Myint 5551, 

5580 

Thueroff, Stefan e15194 

Thulkar, Sanjay 5104 

Thumar, Jaykumar 

Ranchodbhai e14534 

Thunberg, Allen L TPS9152 

Thurlimann, Beat J. K. 9022, 

9059 

Thurm, Craig 10528, e21008 

Thurm, Holger C. TPS7616 

Thurn, Kenneth Ted 3058 

Thuss-Patience, Peter C. 

TPS4138 

Thway, Khin 9510, 10038, 

10525, e13601 

Thwin, Malar e13099 

Thyparambil, Sheeno e21068 

Thyss, Antoine 6633, 8077, 

10042, 10062 

Tiab, Mourad 8009, 8014 

Tian, Erming e18548 

Tian, Gary G. TPS10099 

Tian, Ming e12013 

Tian, Qiang e14153 

Tian, Song e21011 

Tian, Wei e13526 

Tian, Ying 3535 

Tiangco, Beatrice 7549 

Tibau Martorell, Ariadna 

1120, 10555 

Tibau, Ariadna e14552 

Tibbetts, Randal S. e13537 

Tica, Stefani 6623 

Tidwell, Michael 6611 

Tie, Jeanne e16516 

Tiedemann, Rodger Edwin 

8053 

Tiemann, Katharina e13503 

Tiemsim, Maricel Cordero 

1064 

Tier, Katherine 8566 

Tiersten, Amy 5016, e11522, 

e11529 

Tiezzi, Daniel G. 1075 

Tiftik, Nalan e15104 

Tijani, Lukman Adeoju 

e21105 

Tijssen, Cees 2 

Tilburt, Jon C. 4657, 6126 

Tiley, Stephen e11550, 

e17547 

Tilgen, Wolfgang 8505 

795s

Tillmanns, Todd D. 5014, 

e15514 

Tilly, Herve 8021, 8057, 

8068 

Timcheva, Constanta TPS661, 

9046 

Timmer, Wolfgang e19530, 

e19532, e19533 

Timotheadou, Eleni 5033, 

e15040 

Tims, David e21146 

Timsit, Yoav E 9562 

Tin, Aung Soe e20003 

Tin, Sanda e13582 

Tinhofer, Inge e16018 

Tinquaut, Fabien 9079 

Tinsley, Sara 6588 

Tinterri, Corrado 10554 

Tinton, Nicolas e14044 

Tirabosco, Roberto 10063 

Tirado Gomez, Laura Leticia 

e15527 

Tirapelli, Daniela P. C. 

e12512 

Tirapelli, Daniela Pretti da 

Cunha e19628 

Tirelli, Umberto 8046, 8058 

Tiribelli, Mario 6531 

Tirier, Christian 4065 

Tirona, Kattleya M 5587 

Tirrell, Stephen 3077 

Tiseo, Marcello e18096 

Tishler, Roy B. 5501, 5579, 

5582, e16060 

Tisol, William e17555 

Titarova, Yulia Y 9060 

Titov, Dmitry e15029 

Titus, Mark Anton 4556 

Tiu, Ramon Velasquez 6521 

Tiutiunnik, Pavel e14717 

Tiwari, Aradhana e21150 

Tjalma, Wiebren 1129 

Tjulandin, Sergei TPS661, 

e14623, e15025, e15029 

Tkaczuk, Katherine Hanna 

1039, 9103, 10572 

To, Ka Fai e14085 

Tobeña, Maria e14041, 

e14104 

Tobermann, Anja e17516 

Tobimatsu, Kazutoshi 4046 

Tobinai, Kensei 8023, 8029, 

8050 

Toblli, Jorge E e19569 

Tobros, Kimberly 6005 

Tocchetti, Carlo G. e11052, 

e13539 

Tochon-Danguy, Henri 

e15056 

Tod, Michel e15182 

Todaro, Matilde e21095 

Todd, Jonathan 6032 

Todd, Knox H. 6125 

Todenhoefer, Tilman e19021 

Todoroff, Karen e14118 

Toepelt, Karin 7603 

Tofanetti, Francesca Romana 

e18101, e21094 

Toffart, Anne-Claire 7529 

Toh, Chee-Keong e15064 

Toh, Han Chong 4100^ 

Toh, Uhi e13046, e13050 

Toh, Yasushi e14601 

Tohnai, Iwai 5556 

Tohyama, Osamu e13511 

Toi, Masakazu TPS648, 

e21004, e21031, e21052 

Toi, Yukihiro e19521 

Toita, Takafumi 5086, 

e15533 

Toiyama, Daisuke e15055 

Toiyama, Yuji e14029, 

e14039, e14541, e21053 

Tokes-Fuzesi, Margit e21140 

Tokuda, Yutaka 540, 565 

Tokumura, Carolina e12041 

Tokunaga, Masanori e14635 

Tokunaga, Shinya 4002, 

e18036, e18042 

Tokunaga, Shoji 3558 

Tokura, Akemi 5086 

Tolaney, Sara M. 1006, 

1026, 9084 

Tolaney, Sara 535, 3053 

Tolba, Khaled A. e16001 

Tolcher, Anthony W. 2512, 

2555, 3001, 3019, 3025, 

TPS3110, e13025, 

e13077, e13599, e13602, 

e13604 

Toledo, Carolina 2515 

Toledo, Frederico G.S. 3019 

Tolentino, Krysteena e13526 

Tolia, Maria e21098 

Tollali, Terje 7027 

Tollenaar, Rob A e14151 

Toller, Isabella 2575 

Toloui, Helen Nicole 10525 

Toloza, Eric M. 10070 

Tolstov, Yanis 8577 

Tom, Ashlyn 4045 

Tomao, Federica e11039, 

e11514, e19620 

Tomao, Silverio e11039, 

e11514, e12510, e19620 

Tomasello, Chiara e18039 

Tomasello, Gianluca 4097 

Tomasevic, Zoran e18531, 

e21030 

Tomasevic, Zorica 505, 

e18531, e21030 

Tomassetti, Paola 4014, 

e14647 

Tomaszewski, Garin e14690 

Tomaszewski, Joseph E. 

3031, 10603 

Tomatis, Mariano 4110 

Tombal, Bertrand 4510, 4652 

Tomblyn, Michael B. 2099, 

TPS9150 

Tomczak, Piotr 4501, 4606 

Tome, Yasunori 10072 

Tomeczko, Janusz 7090 

Tomei, Sara 8576 

Tomezzoli, Anna 4076 

Tomida, Mikio 10542 

Tomii, Keisuke 7528, 10610 

Tomilo, Mark e14164 

Tomimatsu, Nozomi 10624 

Tominaga, Shigeru e18019 

Tominaga, Shusei e13060 

Tomioka, Hideo e16034 

Tomirotti, Maurizio LBA7501 

Tomita, Dianne 1062, 

e19511 

Tomita, Naohiro 3524, 3607 

Tomita, Yoshihiko e15057, 

e15068, e15071, e15088, 

e15098 

Tomizawa, Yoshio 7017, 

e18037 

Tomonaga, Nanae 7569 

Toner, Aidan e15126 

Toner, Guy C. 4531 

Tonev, Anton e21100 

Tong, Joanna e14085 

Tong, Shan 639 

Tong, Wilson P. e18140 

Tonini, Giuseppe 3518, 

4627, 10063, e14135 

Tonkin, Katia Sonia e16528 

Tonkin, Katia e15540 

Tono, Yasutaka e19546 

Tonolla, Sabina 8563 

Tonorezos, Emily S. 9552, 

9586 

Tontchev, Anton e21100 

Toomey, Kathleen 8037, 

e18556 

Toor, Amir A. e18550 

Topalian, Suzanne Louise 

CRA2509, 2510, 5506, 

8507 

Topham, Allan 3621 

Topilow, Arthur 1540 

Topliss, Duncan 5518 

Topp, Max S. 8079 

Topp, Max 6500^ 

Topp, Monique 5073 

Topp, Stefan A. e21020 

Toppo, Laura 4097 

Toptan, Tuna 8577 

Torbenson, Michael S. 3616 

Torchia, James 2513, 

e13555 

Torday, Laszlo 2522, 3530 

Toretsky, Jeffrey 9575 

Torigian, Drew A. 7092 

Torii, Yoshitaro e18081 

Torp, Kari 1504 

Torralvo, Helena Fragata 

e12021 

Torrea, Natalia e14057 

Torrecabota, Joan e11036 

Torregrosa, Maria Dolores 

e11074 

Torregroza, Maria Patricia 

e14714 

Torrejon, Davis Yuri 619 

Torrents, A. e13540 

Torres, Alejandra e15178 

Torres, Barbara 10082 

Torres, Esperanza e14115 

Torres, Harrys A. e17016 

Torres, Karen E. e15124 

Torres, Luis M. e19544, 

e19567 

Torres, Michelle 5076 

Torres, Mylin Ann 9122 

Torres-Galea, Patricia 

e14076, e15013 

Torres-Torres, Blanca 1041 

Torres-Vigil, Isabel 9025 

Torresani, Michele TPS9155 

Torri, Valter TPS7109, 

e19034 

Torricelli, Francesca e18074 

Torrisi, Rosalba 623 

Torrubia, M Sofia 10555 

Torsello, Angela e14661 

Torta, Riccardo e11524 

Tortora, Giampaolo 630, 

4076, 4541, e13509, 

e14661 

Torzilli, Guido 4110 

Toscano, Michele 1608 

Toschi, Luca 7061, 7585, 

e18104 

Tosello, Celia e11087 

Tosetto, Miriam e13570, 

e21024 

Toshima, Takeo e14536, 

e14602 

Tosi, Diego 5069 

Tosi, Mario e14010 

Toso, John F 5065 

Tosolini, Alessandra e13598 

Tosti, Giulio e19035, e19036 

Toth, Jennifer 7054, 7055, 

e17560 

Totoonchian, Farhoud 6556 

Touboul, Chantal 1566 

Touboul, Emmanuel e11551 

Tougeron, David 3520 

Toulgoat, Frederique 2082 

Toumpanakis, Christos 

e14696, e17543, e19581 

Tountas, Nikolaos e21027 

Tourani, Jean Marc 3520 

Tourani, Jean-Marc e19555, 

e19640 

Tournat, Helene e13578 

Tournigand, Christophe 

2537^, LBA3500^, 

e13095^, e13097^, 

e19623, e19640 

Tourovskaia, Anna e17529 

Tousseyn, Thomas 8030 

Towers, Russell 10618 

Towne, Penny 4041 

Townsend, Amanda Rose 

3534 

Townsley, Carol A. 3013, 

e19522 

Toy, Elizabeth W. 7562 

Toyoda, Masanori e16034 

Toyokawa, Hideyoshi e14518 

Toyooka, Shinichi 7521, 

e17517 

Toyota, Brian e13123 

TR, Arul Ponni e11536 

Trabulsi, Edouard John 4526, 

e15012 

Tracy, Michael 1009 

Traeger, Lara 6106, 9030 

Traina, Fabiola 6521 

Traina, Tiffany A. TPS668, 

1006, TPS1143, TPS1145, 

10514 

Trakarnsanga, Atthaphorn 

3583 

Tralongo, Paolo e18002 

Tramontano, Angela 6004 

Tran, Ben 3082, 4058, 4535, 

e13107 

Tran, Benjamin 2044 

Tran, Hai T. 3598, 5592, 

e15075, e15085, e15087 

Tran, Huyen 7051 

Tran, Namphuong 4521, 

4556 

Tran, Sinhan 8547, e17558 

Trappe, Ralf Ulrich 8030 

Trappey, Alfred F 625 

Trapsa, Daniela 3013 

Trarbach, Tanja 4032 

Trassard, Martine 10018 

Traut, Alexander 5051 

Travers, Debbie 6119 

Travis, Lois B. 1536 

Travis, William D 7014, 7052 

Traynor, Anne M. 5544, 

e13537, e16010 

Treat, Joseph 7002 

Tredan, Olivier TPS662, 

1051, 9079, 10562 

Tredaniel, Jean TPS7111 

Trefzer, Uwe 8501, 8505, 

LBA8509, 8518, 8559 

Trehu, Elizabeth G. 3105 

Treiber, Gerhard 4107 

Treisman, Jonathan S e19030 

Tremblay, Lise LBA7000 

Tremblay-Lemay, Rosemarie 

634 


Trent, Jonathan C. 10088, 

e13519, e19520 

Treon, Steven P. 8042, 8043, 

8106, 8107, e18575 

Trepel, Jane B. 3043, 3087, 

4569, TPS4701, 7033 

Trepel, Martin e15168 

Tresca, Patricia TPS662 

Tresch, Emmanuelle e14560 

Tresguerres, Maria e18044 

Trevarthen, David R. 5566 

Trevino, Jose Gilberto 

TPS4136 

Trevino, Kelly Marie 9015 

Trevino, Lara Anne 9010, 

e16056 

Trevisan, Elisa 2037, 2075 

Trevisan, Felipe A. e12512 

Trevisani, Franco 4115 

Tribius, Silke 5512 

Tribolo, Antonella e11524 

Triche, Timothy J. 4565, 

9535, 9564 

Tricomi, Marco TPS9155, 

10053 

Trieu, Vuong N. e15542 

Trifan, Ovidiu C. 3615, 7584 

Trifanov, Dmitriy e20503 

Trifanov, Vladimir e20503 

Trifilio, Steven M 4063, 6623 

Trigo Perez, Jose Manuel 

4630, LBA7000 

Triller, Raoul 8578 

Trillsch, Fabian 5071 

Trimble, Edward Lloyd 

TPS5116 

Trinh, Long 6587, 6598 

Trinkaus, Kathryn 2525 

Trinkaus, Martina 6084 

Trinkaus, Mateya Elizabeth 

e19642 

Triolo, Renza e21102 

Tripathy, Debu 1065, 1124, 

1526, 9144, e19506 

Tripodo, Claudio 8083 

Trippa, Lorenzo 2005 

Tripsas, Christina 8042, 

8106, 8107, e18575 

Triscott, Joanna e13123 

Tritschler, Isabel 2055 

Trivanovic, Dragan 9097 

Trivedi, Digisha e17009 

Trivedi, Meghna S. e18529 

Troalen, Frederic 5028 

Trocchi, Pietro 580 

Troicki, Filip e14157 

Trojan, Jorg 4006, 4083 

Trojan, Lutz 4539 

Trojanec, Radek 1087 

Trojanowski, Tomasz 603 

Trojniak, Marta Paulina 

e15072 

Tromp, Brenda J. 2583 

Tron, Victor 5032 

Troncone, Giancarlo e13509, 

e14010, e14042, e18021, 

e19038 

Troncoso, Patricia 4521, 

4556 

Trop, Isabelle 616 

Trope, Claes 5008 

Troppan, Katharina e18525 

Trosman, Julia R. 1553, 

6120, e16531 

Trotman, Judith 9126 

Trotti, Andy 5564, 5571 

Trouilloud, Isabelle 4018 

Troutman, Sarah M 4671 

Trova, Vittorio e14094 


Troxel, Andrea B. 7092 

Truant, Stephanie 3506 

Trucco, Matteo Maria 10025 

Trucza, Eva e21140 

Trudeau, Maureen E. 531, 

e11000, e11050 

Trudel, Geralyn C. TPS6634 

Trudel, Geralyn Carol e15151 

Trudel, Suzanne 8013 

True, Lawrence D. 4520, 

4521 

Truemper, Lorenz 6543 

Trufelli, Damila 5588 

Truini, Mauro e21065 

Truman, Matt 7519^ 

Trump, Donald L. e18118 

Trumper, Lorenz H. 8052 

Trumpp, Andreas 1090 

Trunzer, Kerstin 8503^ 

Truong, Minh Tam e16059 

Truong, Mylene e19645 

Truong, Thach-Giao 3058, 

4048 

Trusk, Patricia B e21120 

Tryakin, Alexey e14623, 

e15025, e15029 

Tryfonopoulos, Dimitrios 

e11519, e13520 

Trümper, Lorenz 8004 

Tryon, Pamela e15114 

Trypsianis, Grigorios e17553 

Tsai, Chun-Ming 1534, 

LBA7500, TPS7614, 

e18132 

Tsai, Kenneth Yee 8537 

Tsai, Ni-Chun 6545, 6547 

Tsai, Yi-Fang 1079 

Tsang, Janice TPS651, 

TPS661 

Tsang, Kwong Yok TPS4701 

Tsangaris, Theodore N. 1128 

Tsao, Anne S. 7078, 7083 

Tsao, Che-Kai 4623, 

TPS4676, 6065, e21016 

Tsao, Claire 8020 

Tsao, Ming Sound 1036, 

1535, 2051, 7007, 7586, 

10522 

Tsao, Philip S e21153 

Tsao-Wei, Denice D 4575 

Tsao-Wei, Denice e15153 

Tsapralis, Nikos 10606, 

e11073 

Tschaika, Marina 4636, 

e14152 

Tschirschmann, Miriam 5080 

Tschoepe, Inga 3104, 

e13010 

Tseng, Jennifer F. 4059, 

e14691 

Tseng, Ling-Ming TPS651, 

1079 

Tsiambas, Evangelos e21098 

Tsianakas, Athanasios e19031 

Tsiatas, Marinos 5033 

Tsigani, Theodora 4123 

Tsimafeyeu, Ilya 3070 

Tsimberidou, Apostolia Maria 

3106, 3107^, 8551, 

10510, 10607, e13020, 

e13534, e13595, e19004 

Tsolaki, Eleftheria 592 

Tsottles, Nancy e16061 

Tsoukalas, Grecory 10606, 

e11073 

Tsoukalas, Nikolaos 10606, 

e11073, e21098 

Tsuboi, Masahiro TPS7110 

Tsubota, Noriaki 7080 

Tsuchida, Masanori 7012 

Tsuchihara, Katsuya 1552, 

e14038 

Tsuchihashi, Zenta 8593 

Tsuchiya, Hiroyuki 10072, 

10075, e20505 

Tsuchiya, Noriko e19583 

Tsuda, Hiroshi 5003 

Tsuda, Hitoshi TPS1147, 

5085, 10519 

Tsuda, Masahiro 4002 

Tsugawa, Koichiro 590 

Tsui, Dana 544 

Tsuji, Akihito 3558, e14510 

Tsuji, Wakako e21052 

Tsuji, Yasushi e14062 

Tsujimura, Akira e15065, 

e15069 

Tsujimura, Tohru 7080 

Tsujino, Kayoko e15533 

Tsujino, Kazuyuki 7000, 

e18128 

Tsujitani, Shunichi e14033 

Tsukamoto, Kazuhiro 7569 

Tsukamoto, Tadashi e14518 

Tsukamoto, Taiji e15048 

Tsukasaki, Kunihiro 8050 

Tsumura, Takehiko 4002 

Tsunoda, Takuya e13014, 

e13015 

Tsurusawa, Masahito 9574 

Tsurutani, Junji TPS659 

Tsutani, Yasuhiro 7031 

Tsuya, Asuka 7088, e21007 

Tsuyuki, Shigeru 588 

Tsuzuki, Tomoyuki e14596 

Tsvirkun, Viktor e14717 

Tsymzhitova, Natalia e20501 

Tu, Dongsheng 524, 3504, 

3515, 3572 

Tu, Eugene e21047 

Tu, Shi-Ming 4533 

Tu, Wen-yong 5593 

Tubbs, Raymond R. 620, 

e18085 

Tubiana-Mathieu, Nicole 

1051, LBA3500^ 

Tucci, Marco 10063 

Tuck, Alan 1123 

Tuck, David P. 10558 

Tucker, Eric e21122 

Tucker, Margaret A. 1603 

Tucker, Thomas 5095 

Tucker-Seeley, Reginald D 

6012 

Tuda, Banri 565 

Tudur-Smith, Catrin TPS8605 

Tuerk, Ingolf e15123 

Tufa, Gemechu 580 

Tuff, Alice TPS10633^ 

Tufman, Amanda TPS7617 

Tumedei, Maria Maddalena 

10601 

Tumolo, Salvatore 3547 

Tumulo, Salvatore e14711 

Tun, Nay Min e13099, 

e18024 

Tunariu, Nina 2530, 3080, 

10038, e15134 

Tuncer, Ersin e11083 

Tung, Nadine M. 1009 

Tung, Stewart Yuk 4105, 

5511 

Tunkyi, Adrian e21078 

Tuominen, Rainer 10521 

Turak, Esra Ermis e14670 

Tural, Deniz e21143 

Turan, Mehmet Ozhan 5055 

Turbiez, Isabelle TPS662 

Turbiglio, Marco 10055 

Turcich, Michelle e13106 

Turco, Diana L. 1549 

Turcott, Jenny 7068, e19594 

Turcotte, Simon e14179 

Turhal, Serdar 9050, 

e14526, e16015 

Turik, Michael 2516 

Turin, Ilaria e13103 

Turk, Mary 577 

Turkbey, Ismail B. TPS4701 

Turker, Ibrahim e11540 

Turki, Hajer 4087 

Turley, Helen 1066 

Turna, Hande e19024, 

e21143 

Turnbull, Barry e18575 

Turner, Christopher D. 6503 

Turner, Crystal 9019 

Turner, Evadne Jane 7604 

Turner, Gareth D 4599 

Turner, Nancy A 9562 

Turner, Robert e21047 

Turner, Sandra TPS4690 

Turnwald, Brian 6109, 

e16536 

Turpin, Anthony e11500 

Turriziani, Adriana e16553 

Turtiaien, Tarita TPS10633^ 

Turturro, Francesco 8093 

Tuscano, Joseph M. e13573 

Tuthill, Ralph 8504 

Tutrone, Ronald TPS4697 

Tutt, Andrew 10586 

Tuttle, Robert Michael 5509^ 

Tuveson, David A. 4056 

Tveit, Kjell Magne 3548 

Tvsvgk, Tilak 9580 

Twardowski, Przemyslaw 

3108, 4506, 4511, 4547, 

4663, 10503, e15084, 

e15114, e15178 

Twelves, Christopher 

TPS1140^, 2540, 2552, 

3522, 3523, 3525, 

e13083 

Twist, Clare 9533 

Tyagi, Seema e17000 

Tye, Lesley 7508 

Tykodi, Scott S. 2510, 

e21148 

Tyler, Allison Janine e15208 

Tyler, Carl V 1598 

Tyler, Douglas S. 10563, 

e14724 

Tymrakiewicz, Malgorzata 

1545 

Tyner, Jeffrey 9555 

Tyree, Seth D 5539 

Tyroller, Karin LBA7000 

Tysarowski, Andrzej 8548 

Tyson, Leslie B. e19647 

Tyszkiewicz, Tomasz e14159 

Tzabari, Moran 2556, e13080 

Tzanis, Kimon e15040 

Tzen, Kai-Yuan e14576 

Tzovaras, Alexandros 10606, 

e11073, e21098 

U 

Uberti, Joseph P. 6549 

Uccellini, Lorenzo 8576 

Ucci, Giovanni e19592 

Uchida, Junji e18025 

Uchida, Keiichi e14029, 

e14541, e21053 

Uchida, Toshiki 8023 

Uchiyama, Hideaki e14602 

Uchiyama, Tetsuyuki e14011 

797s

Uchiyama, Tomotaka e21108 

Udovitsa, Dmitry TPS651 

Ueda, Eiji e15098 

Ueda, Shinya 4002 

Ueda, Takashi e15055 

Ueda, Takeshi 4503 

Uehara, Kanou e11530 

Uehara, Masahiro TPS659 

Uehara, Takeshi 4111 

Uemura, Hiroji 4626 

Uemura, Hirotsugu e15048, 

e15098 

Uemura, Motohide e15065, 

e15069 

Ueno, Hideki 3625, 4035, 

e14506 

Ueno, Makoto 4031 

Ueno, Masashi 3625, e14145 

Ueno, Naoto T. 594, 1047, 

1102 

Ueno, Takayuki e21031, 

e21052 

Ueoka, Hiroshi 7042 

Uesugi, Mai e13511 

Uetake, Hiroyuki e14127 

Uges, Donald R.A. 4528 

Uharek, Lutz 6543 

Uhm, Joon H. 2031 

Uike, Naokuni 8023 

Ujiie, Hideki 10542 

Ukimura, Osamu e15060, 

e15212 

Ulasov, Ilya 2014 

Ulaszek, Jodie 6535^ 

Ulcickas Yood, Marianne 

1526, 1590, 1591 

Ule, Ulla Jo 9061 

Uleer, Christoph 552 

Ulhoa-Cintra, Alice e21036 

Ulivi, Paola e18045 

Ulivieri, Alessandra e19033 

Ullmann, Martin TPS2622 

Ulloa, Adolph e11549 

Ulloa, Victor e12041 

Ullrich, Stephen 8537 

Ulmer, Hans Ulrich 1602 

Ulrich, Jens e19031 

Umeda, Tomoko e11564 

Umekawa, Kanako e17538 

Umemura, Shigeki 1552, 

7044, e17513, e17526, 

e17554, e18054, e18064 

Umesh, Anita e21159 

Unal, Emel e20000 

Uncu, Dogan e13031, 

e14526 

Underhill, Craig 3572, 

TPS4137 

Underwood, Willie e15046, 

e15204 

Undevia, Samir D. 10003, 

10028 

Unger, Jackie e11550, 

e17008 

Unger, Joseph M CRA6009, 

7570, 8001, 9018 

Unger, Pamela D e15191 

Unno, Michiaki e14011 

Untch, Brian R. e14724 

Untch, Michael 523, 541, 

1114 

Upadhyay, Sunil 7562, 7583 

Upadhyaya, Gargi H. 6591 

Upanal, Nazeerahamad N. 

e14166 

Ura, Takashi 4002, e14123, 

e14500 

Urakami, Shinji e15038 

Uram, Jennifer e14585 

Uramoto, Hidetaka 10585 

Urata, Yoshiko e18060 

Urba, Susan e16014 

Urba, Walter John 8508 

Urbach, David 6027 

Urbain, Remi 5069 

Urbanova, Dagmar 9592 

Urbanowitz, Gladys TPS4683 

Urbauer, Diana 1520, 6054, 

9134 

Urbine, Terry Francis e17529 

Urbini, Benedetta 2057 

Urbini, Milena 10087 

Uren, Aykut 9575 

Urken, Mark 5581 

Urun, Yuksel 1572, 1596 

Urva, Shweta Ramesh 3099 

Urzua, Lorena e12027, 

e15527 

Usakova, Vanda e15027, 

e15028 

Usari, Tiziana 2610 

Uselman, Ryan R. e13590 

Usharani, Malur R. 1093 

Ushijima, Kimio 5006, 5085 

Uslu, Ruchan 3565 

Usmani, Saad Zafar 8041, 

TPS8116, e18548, e18576 

Usó, Marta 7058, 7060, 

10594 

Ustoyev, Yelena 10002, 

10004 

Ustuner, Zeki e21050 

Usui, Kazuhiro 7086, 7561, 

7565 

Usui, Noriko 8050 

Usul Afsar, Cigdem e13523 

Uthe, Regina 610 

Utiger, Urs e19648 

Utikal, Jochen LBA8509 

Utkan, Gungor 1572, 1596 

Utsumi, Tomoki e18126 

Uttenreuther-Fischer, Martina 

Maria 606, TPS649, 

TPS651, 3104 

Uyeji, Jennifer 8596 

Uyeturk, Ummugul e11540 

Uygun, Kazim e14618 

Uysal Sonmez, Ozlem e11540 

Uysal, Mukremin e14070 

Uyterlinde, Wilma 7019 

Uzan, Catherine 5083, 10098 

Uzunaslan, Didem 10514 

Uzzan, Bernard e18003, 

e18020 

Uzzo, Robert G. 4500, 4526 

V 

V, Murali Subramanian 

e11536 

Vaccarella, Salvatore e14042 

Vaccaro, Lisa e16507 

Vaccaro, Vanja 630, 4541, 

e14661 

Vachani, Anil 7595 

Vachani, Carolyn 6135 

Vadell, Catalina 1531 

Vadhan-Raj, Saroj 4037, 

9002, e19520 

Vaena, Daniel A. e15010, 

e15143 

Vaessen, Christophe e15105 

Vago-Ady, Nora TPS662, 

8546 

Vahanian, Nicholas N. 2501, 

2571, 4049, e19008 

Vahdat, Linda T. 1010 

Vaidya, Bhavesh 7092 

Vaillant, Brian D. 2002 

Vaishampayan, Ulka N. 4, 

4506, 4525, 4536, 4538, 

e15081 

Vaishnaw, Akshay 3062 

Vaissiere, Nathalie 7001 

Vajpayee, Neerja 6572, 

e18535 

Vakar-Lopez, Funda e15207 

Vakiani, Efsevia TPS4144 

Valachis, Antonis 5066 

Valadares, Adriana D e16046 

Valdes, Frances 3108 

Valdez, Riccardo 8053 

Valdiviezo, Natalia e15033 

Valduga, Francesco e14711 

Valea, Fidel A. 5101 

Valencia, Alfonso 3068 

Valent, Alexander 10556 

Valent, Francesca 1044, 

e13058, e13070 

Valenti, Marco 4572 

Valentine, Erin 3587 

Valentini, Antonella 2057 

Valentino, Joseph e16035 

Valeria, Visconte 6521 

Valerio, Maria Rosaria e11056 

Valero, Vicente 515, 527, 

594, 1029, 1104, 10613 

Valgus, John 6042 

Valigi, Paolo e21096 

Vallabhaneni, Geetha D. 

7048, e14169, e14170 

Valladares Ayerbes, Manuel 

e15079 

Valladares-Ayerbes, Manuel 

e14595, e21002 

Valle, Juan W. 4118, 4121, 

4122, e14625, e21037 

Vallee, Audrey e21117 

Vallejo, Carlos Teodoro 

e11021 

Vallejos Sologuren, Carlos 

e18524 

Vallejos, Carlos S. e11518, 

e15036 

Vallejos, Carlos 2097 

Valleriani, Mario e19002 

Vallier, A-L TPS660, 

TPS1144 

Vallone, Marcy TPS3640 

Valluri, Satish e14013, 

e14016, e14106, e14141, 

e14146, e15183 

Valmadre, Giuseppe TPS7109 

Valo, Isabelle 10018 

Valori, Vanna Maria e21092 

Valota, Olga e15070 

Valsecchi, Matias Emanuel 

8560, e19016 

Valsecchi, Matias E 536 

Valteau Couanet, Dominique 

9560, 9572 

Valverde, Claudia María 

10052, e21021 

Valverde, Ivana 4579 

Valvo, Francesca e21118 

Vamvakas, Lampros 7564 

van ’t Veer, Laura J. 1022 

Van Akkooi, Alexander 

Christopher Jonathan 8535, 

e19022 

Van Allen, Eliezer Mendel 

10502 

Van Alstine, Lindsay Joy 4532 

Van Arkel, Cornelis 4539 

van Berge Henegouwen, Mark 

I. 4094 

van Berkel, Cees e19617 

van Besien, Koen 6535^, 

e13120^ 

Van Binst, An 2050 

Van Brunt, Kate e16528 

Van Brussel, Thomas 1020 

van Coevorden, Frits 10096 

Van Cutsem, Eric 3502, 

CRA3503, 3505, 3509, 

3532, 3539, 3562, 3574, 

3578, 3579, 3581, 3591, 

3602, 4007, 4081, 4118, 

TPS4134 

van de Vaart, Paul 7019 

Van de Velde, Ann 2506 

van De Velde, Cock JH 10518 

Van De Velde, Cornelis J. H. 

516, 517, 526 

Van De Velde, Helgi 2583, 

8018^ 

Van de ven, Carmella 

e13022, e21150 

Van Den Abbeele, Annick D. 

510 

van den Akker, Jeroen 1022 

Van Den Bent, Martin J. 2 

Van Den Brink, Marcel R. M. 

6539 

van den Eertwegh, Alfons JM 

2562, TPS4689 

Van den Eynde, Marc 3559, 

e14044, e14060 

van den Heuvel, Michel M 

7019 

van den Hoff, Joerg 10068 

Van Den Neste, Eric 8046 

Van Den Wyngaert, Tim 1129 

van der Elst, A 7009 

Van Der Graaf, Winette T.A. 

2593, 3035, 5061, 9036, 

10009 

Van Der Hoeven, Dharini 

e13516 

Van Der Hoeven, Jacobus 

TPS10632 

van der Holt, Bronno 10091 

van der Meulen, Egbert 

e15199^ 

van der Noll, Ruud e13596 

van der Straaten, Tahar 526 

van der Werf-Langenberg, 

Mirte e16526 

Van Deventer, Hendrik 

e13074 

van Diest, Paul J. 562 

van Doorn, Leni 4132 

Van Driessche, Ann 2506 

Van Es, Suzanne C. 10581 

Van Ewijk, Reyn 1082 

van Goethem, Mireille 1129 

van Haaften, Gijs e13515 

Van Hazel, Guy A. 3515 

Van Hazel, Guy 3505, 4118 

van Herk-Sukel, Myrthe 

e16526 

Van Herpen, Carla 2593, 

5061, 8511, 9070 

Van Hummelen, Paul 2020 

Van Imhoff, Gustaaf Willem 

8039 

van Ingen, Hein 3026 

Van Laarhoven, Hanneke 

W.M. 3035, 9070, e13111, 

e19560 

Van Laere, Steven J. 1047 

Van Laethem, Jean Luc 3559, 

4006 

Van Laethem, Jean-Luc 2583, 

4050, 4053, TPS4135 


Van Le, Linda 1519, 2591, 

5050, e13063 

van Leeuwen, Flora E. 8039 

van Lessen, Antje e15053 

Van Loan, Marta 4547 

Van Loon, Katherine 4038 

Van Looy, Thomas 10030 

van Marck, Veerle 1129 

Van Meerbeeck, Jan P. 7081 

Van Nuffel, An M. T. 2507 

van Oort, Inge M e15112 

Van Poppel, Hendrik e13061 

Van Puyvelde, Katrien 9035 

Van Remortel, Piet e13073 

Van Rhee, Frits 8041, 

e18548, e18576 

Van Riet, Ivan 2507 

van Schaik, Ron H. N. 526 

Van T Veer, Laura 10597 

Van Tendeloo, Viggo F. 2506 

Van Tendeloo, Viggo e13051 

van Tets, W F 7009 

Van Tine, Brian Andrew 

TPS10099, TPS10103 

van Tinteren, Harm 1080, 

e13028 

Van Veldhuizen, Peter J. 

3078, 4511, 4663, 10503, 

e13535, e13551 

Van Veldhuizen, Peter 4510, 

e15115 

Van Vlieberghe, Hans 4006 

Van Vugt, Vincent 2052 

Van Wert, Michael 9132 

van’t Veer, Laura 3065 

VanCriekinge, Mark E. 4660 

Vandam, Jacquez e14679 

Vander Velde, Nancy S. 6600 

Vanderburg, Sky 6102 

Vandermeer, Lisa 10620 

Vanderschaeghe, Simon 8532 

Vanderwalde, Ari M. 5502 

VanderWalde, Noam Avraham 

5539 

Vanderweele, Tyler J. 9116, 

9132 

Vandewalker, Kristen MN 

e21026 

Vandoni, Irene 8046 

VanDraanen, Leah e15180 

Vanhoefer, Udo J. e13100^ 

Vank, C. e13597 

Vankayala, Hema M. e15081 

VanLaeken, Nancy 9043 

Vanlemmens, Laurence 1051, 

e11012 

Vanmali, Vaibhav 1108, 

e11552 

Vanmany, Sengdao e21111 

Vannier, Jean-Pierre e21156 

Vannier, Michael 4022 

Vannucchi, Alessandro M. 

6514^, 6626^, TPS6641, 

TPS6642^, TPS6643^ 

Vannucci, Jacopo e21094 

Vanorle, Katrien 9035 

Vansteenkiste, Johan F. 3007, 

6058, 7013, e18100 

Vansteenkiste, Johan 7503 

Vaporciyan, Ara A. 4086, 

7043 

Vaquer, Jose 2515 

Vaquero, Eva Cristina e21035 

Varadan, Vinay 10508 

Varadarajan, Prakash 5541 

Varadhachary, Gauri R. 4051, 

4054, 4130, 4131, 10584 

Vardakis, Nikolaos e18105 

Vardhanabhuti, Saran 1539 


Vardy, Janette L. 4644, 9021 

Varela Ferreiro, Silvia 

e18040, e18146 

Varela Ponte, Rafael e14733, 

e19505 

Varela, Silvia e18070 

Varella-Garcia, Marileila 

7061, 7504, 7508, 7534, 

7552, 7589, 10580, 

e14071, e21018 

Varga, Andrea 3012, e13118 

Vargas, Carlos A. e12039 

Varghese, Anna M. 7052, 

7527, 7580 

Vargo, Dennis e13041 

Vari, Sabrina e14661 

Varin, Rémi e21156 

Varlet, Pascale TPS9596 

Varlotto, John M. 7040, 

7054, 7055, e17560 

Varma, Ankur 527 

Varricchio, Clara 1500 

Varughese, Joyce e13078 

Vasconcelos, Ines 5053, 

5070 

Vashi, Pankaj G e14012 

Vasile, Enrico 10611 

Vasovic, Suzana 9046 

Vassal, Gilles TPS9596 

Vassel, Svetlana 6123 

Vassilaki, Ismini 8588 

Vassilakopoulou, Maria 573, 

5576 

Vassilev, Lyubomir T e13600^ 

Vassilopoulou-Sellin, Rena 

4641 

Vastola, Francesca e13019 

Vatandoust, Sina e19513 

Vaughan, E. Darracott e15196 

Vaughn, David J. 1503, 

1539, 4522, 4596, 9145 

Vauthey, Jean-Nicolas 3598, 

4116 

Vavala, Tiziana TPS7619, 

e18103 

Vay, Christian e21020 

Vaz, M. Angeles e21104 

Vazquez Estevez, Sergio 

TPS4672, e12012, 

e18040, e18055, e18146 

Vazquez Osorio, Jose Lorenzo 

e11028 

Vazquez Sequeiros, Enrique 

e12033 

Vazquez, Adrienne Marie 

e17564 

Vazquez, Francisca 10534, 

e14733 

Vazquez, Jesus e13105 

Vazquez-Estevez, Sergio 

e15067, e15076, e15077, 

e17545, e18070 

Vecchiarelli, Silvia e14647 

Veccia, Antonello e14711, 

e15160 

Vecht, Charles J 2 

Vedrine, Lionel 1580 

Veenstra, David L e16524 

Vega, Estela e15033, e15552 

Vega, Iranzazu 4079 

Vega-Saenz de Miera, Eleazar 

8544, 8565 

Vehling-Kaiser, Ursula 3519^, 

3588, TPS3639, 4023, 

4072 

Veit-Friedrich, Iris 9573 

Velasco, Roser 9090 

Velcheti, Vamsidhar e21106 

Velculescu, Victor E. 3068 

Velehorschi, Wiorika 7056 

Velez, Michel e17564 

Vella, Alessandro 1500 

Vella, Laura J 8542 

Vellayappan, Balamurugan A 

5553 

Vellos, Ted e15014 

Velten, Michel 1584, e11542 

Veltri, Enzo e19501 

Vemuganti, Geeta K 9568 

Vendel, Yvette e11012 

Vendrely, Veronique 4091 

Venegas, Diego 2531, 

e12041, e12043 

Vengco, Isabelita 2589 

Venhaus, Ralph Rudolph 

2589, TPS8111, 8547, 

e17558 

Venkannagari, Sreedhar 

10549 

Venkatakrishnan, Karthik 

2597 

Venkataraman, Ganesh 4056 

Venkatramani, Rajkumar 9564 

Venna, Suraj S. e19000, 

e19025 

Venner, Peter 4 

Vennin, Philippe e11500, 

e12502 

Venook, Alan Paul 3105, 

3528, 4102, e14581, 

e19046 

Venselaar, Hanka 9550 

Ventrucci, Cristiano 3061 

Venturi, Claudia 6531 

Venturini, Filippo 3570 

Venturini, Marco 1073, 

e19592 

Venturino, Paola 7577 

Venugopal, Parameswaran 

6552, e16503 

Vera Badillo, Francisco Emilio 

6043 

Vera, Ruth 3586, e14097, 

e14120, e21086 

Verdail, Francys C 7008 

Verdeguer, Amparo 10082 

Verduyn, Cora e19010 

Veremeychuk, T. e11528 

Vergamini, Lucas B. 9523 

Vergara, Ismael A. 4565 

Vergara, Lori 8073 

Verger, Eugenia 2045 

Vergidis, Joanna 3560 

Vergnenegre, Alain 7522, 

7540, 7542, 7574, 

e16560, e18130 

Vergo, Maxwell Thomas 4102 

Vergote, Ignace B. LBA5000, 

LBA5002^, 5034, 5038, 

5052, 5058, 5071, 5072, 

5087, TPS5112, e13095^, 

e13097^, e13108^ 

Verheij, Marcel 7019 

Verheul, Henk M.W. e18094 

Verhoef, Gregor E.G. 8030 

Verhoef, Gregor 8065 

Verma, Ashok Kumar e16023 

Verma, Sunil LBA1, e16547, 

e16558 

Verma, Udit N. 3605 

Verman, Radha e21061 

Vermeij, Joanna 4622 

Vermeulen, Jessica 2583 

Vermorken, Jan Baptist 562, 

5504^, 5516^, TPS5599, 

8532 

Vermund, Sten H. 9558 

Verna, Elizabeth 4101 

Vernick, Jerome 1540 

Veronese, Maria Luisa 8517 

Veronese, Silvio LBA7501 

Veronesi, Umberto 1500 

Verrecchia, Francesco 

e19035, e19036 

Verri, Cristian 4572 

Verrico, Monica e11039, 

e11514, e12510, e19620 

Verrielle, Veronique 543 

Verrill, Clare 4599 

Verschraegen, Claire F. 3009 

Verschuur, Arnauld 9517 

Verslype, Chris 4007, 

TPS4148 

Verso, Melina e19612 

Verstegen, Naomi E 7009 

Verstovsek, Srdan 6587, 

6624, TPS6642^, 

TPS6643^ 

Vertakova-Krakovska, Bibiana 

e15028 

Vervenne, Walter 4539 

Vervliet, Johan 1129 

Verweij, Jaap 2540, 2593, 

10013, 10054, 10091 

Verzoni, Elena 4629 

Vescio, Robert A. 8098, 

e18558 

Vesole, David H. 8011 

Vessella, Robert 4520, 

e15113 

Vestermark, Lene Weber 

4015, e14517 

Vetto, John T. 8504 

Vettori, Josiane Cheli e19628 

Vey, Norbert 6523, TPS6637, 

e18526 

Veys, Isabelle e21010 

Viada, Carmen 2527 

Viale, Agnes 4527 

Viale, Giuseppe 504, 1022, 

4120 

Viana, Benjamin e14158 

Viana, Luciano S. e14599 

Viardot, Andreas 6500^, 

8025 

Viau, Philippe e15574 

Vicario, Giovanni e19595 

Vicente, Angeles e11024 

Vicente, David 8062 

Vicente, Vicente 7095, 

e11024 

Vichaya, Elisabeth G. 6551, 

9082, 9118, 9140 

Vicioso, Luis 10500, e14115 

Vickers, Andrew J. 4668 

Vickers, Michael M. e14073 

Vickers, Selwyn M. 6016 

Victor, Charles e16547 

Victor, Joel 4098 

Victoria, Iván 3536 

Victorino, Ana Paula Ornelas 

e14101 

Vidal Boixader, Laura 

e13540, e15575 

Vidal, Jose e18053 

Vidal, Laura 5068 

Vidal, Liath 548 

Vidal, Maria 509, 566, 619 

Vidal, Michel e13056 

Vidal, Silvia e15527 

Vidal, Yolanda 10534, 

e14733, e19505 

Vidal-de-Miguel, Guillermo 

1570 

vidal-Millan, Silvia 6599 

Vidaurre, Tatiana e11518 

Vidaurreta, Javier e15507 

799s

Videtic, Gregory M.M. 

e14611, e14665 

Vidiri, Antonello 2085 

Vieillefond, Annick 4583 

Vieira, Fernando Meton 7506, 

e14101 

Vieira, Nivaldo Farias e12512, 

e19628 

Vieira, Thibault e18075, 

e18102 

Vieito, Maria 10534, e14733, 

e19505 

Viens, Patrice TPS1613 

Vierling, John 4116, e19631 

Vieser, Eva 2504 

Vigani, Antonella e17533 

Viganò, Maria Grazia 7076, 

7085 

Vigil, C. E. 2097 

Vigil, Carlos Enrique 6602 

Vigil, Carlos E 6565 

Vigna, Leonardo e19033 

Vigna, Paolo Della e14607 

Vigneau, Fawn D. 7037 

Vigneron, Daniel B. 4660 

Vignetti, Marco 6531 

Vignot, Stéphane 641, 6110, 

7529, e11019 

Vigouroux, StÃƒÂ©phane 

6534 

Vigouroux, Stephane 6542 

Viguier, Jérôme 1567, 1568, 

e14129 

Vij, Brinder e19566 

Vij, Ravi 8011, 8016, 8020, 

8035, TPS8112, TPS8114, 

e18551 

Vijarnsorn, Chodchanok 9529 

Viktil, Ellen e14637 

Vila, Luis 5590 

Vilardell, Felip 4089 

Vilardell, Loreto 1588 

Vilas Boas, Viviane e11059 

Vilcot, Laurence 10044 

Vilgrain, Valérie 4618, 

e14553 

Villa Guzman, José Carlos 

TPS4674 

Villa, Diego 549^ 

Villa, Eugenio 4017 

Villà, Salvador e12504 

Villablanca, Judith 9533 

Villacampa, Felipe 4584, 

4620 

Villaflor, Victoria Meucci 5500 

Villalona-Calero, Miguel Angel 

5020 

Villalva, Claire 3520 

Villamil, Beatriz Perez 10564 

Villani, Gina M. e13099 

Villano, John L. 2073, 

e12036 

Villanueva Silva, Maria Jose 

10608, e11535, e18040, 

e18146 

Villanueva, Cristian 1011, 

5504^, e11019 

Villanueva, Geraldine e19594 

Villanueva, Noemi e18044 

Villanueva, Rafael e18030 

Villanueva, Ronald 1540 

Villareal, Reina 1558 

Villarin, Eligie 584 

Villarreal-Garza, Cynthia 

Mayte 1607, e11016, 

e12027 

Villasboas, Jose Caetano 595, 

608 

Villasboas, Tercia Reis 

e12021 

Villatoro, J Carlos 5595 

Villatoro, R. 4630, e14116 

Villeda, Virgilio Alexander 

e11031 

Villella, Jeannine A e15504 

Villines, Gary e18576 

Vilmar, Adam 10617 

Vin, Harina 8537 

Vinas, Elaine e19646 

Vincent, Andrew D. 562, 

7019 

Vincent, Linda V. e11096 

Vincent, Mark David e21120 

Vincent, Tiffaney 9506 

Vincent-Salomon, Anne 601 

Vincenzi, Bruno 4627, 

10063, e14135 

Viner, Jaye TPS2618, 

TPS2621, e18073 

Vinholes, Jeferson J.F. 606 

Vinik, Aaron 4118 

Vinks, A.A. 9541 

Vinogradova, Liliya Igorevna 

e15543 

Vinolas, Nuria 1531, e12000, 

e12012, e18011 

Viny, Aaron D 10021 

Vinyals, Juan M 10052 

Violante, Assunta e19002 

Viqueira, Andrea e15111 

Virchow, Isabel 2086 

Viret, Frédéric LBA3500^, 

4032 

Virgo, Katherine S. 1100, 

1608, 6006, 6008, 6079, 

6081, e15528, e19593 

Virk, Navneet 4563 

Virk, Shakeel 3515 

Virzì, Vladimir 4627 

Visa, Laura 4079, e21035 

Viscusi, Johnny e13598 

Vishnubhatla, Sreenivas 

5104, 9580 

Vishnubhatla, Sreeniwas 6593 

Viskov, Christian e13117 

Visser, Otto 8039 

Visseren Grul, Carla M. 7554 

Visseren-Grul, Carla LBA7507 

Vistisen, Kirsten 3538 

Visvanathan, Kala 521 

Visvikis, Antonios e15040 

Viswanathan, Chitra e19645 

Viswanathan, Shankar e16058 

Vital, Anne 2023 

Vitale, Alessandro e14563 

Vitale, Antonella 6531 

Vitalini, Cristina e19549 

Vitek, Pavel e14631 

Viterbo, Rosalia 4526 

Viteri Ramirez, Santiago 

3093, 7540, e18131, 

e18137, e18143 

Vito, Courtney 1035, 1117 

Vitolins, Mara 9108 

Vitolo, Umberto 8006 

Viudez, Antonio e14057, 

e14120, e21086 

Vivancos, Ana 509, 3014, 

10511 

Vivenza, Daniela 2600 

Viviers, Louis TPS9596 

Vlachos, George 5033 

Vladimirova, Liubov Yu 

e11558, e20503 

Vladislav, Ioan Tudor 7106 

Vlahovic, Gordana 3077, 

e13603 

Vletter - Bogaartz, Judith M. 

526 

Vnencak-Jones, Cindy L 7532 

Vo, Lien e14164 

Vocke, Cathy TPS4680 

Voduc, David 1008 

Voegeli, Anne-Claire 10507 

Voehringer, Matthias 

TPS3641^ 

Voest, Emile E. 2540, 2550, 

2596, e13028, e13596 

Vogel, Ulrich 1067 

Vogelbaum, Michael A. 2018, 

2076, 2100, 2101 

Vogelius, Ivan Richter e18527 

Vogelzang, Nicholas J. 4, 

4511, LBA4512, 4513, 

4525, 4547, 4551, 4558, 

4662, 4663, 4665, 

TPS4675^, TPS4683, 

TPS4686, 7514, 10503, 

e15063, e15089, e15210 

Vogl, Steven E. e11005 

Vogl, Thomas J. e14131 

Vogl, Ursula Maria e15090 

Vogt, Andreas 8577 

Vogt, Luc 9012 

Vogt, Ulf 10627 

Vohra, Nasreen A. 10070 

Voi, Maurizio e13101 

Voillat, Laurent 8026 

Voit, Christiane A. 8535, 

e19022 

Vokes, Everett E. 5500, 

5517, 7513 

Volandes, Angelo E. 9004, 

9105 

Volchenboum, Samuel Louis 

9583, 9584, e20008 

Vollmer, Laura 8577 

Volm, Matthew e11529 

Voloschin, Alfredo Daniel 

3055 

Volovat, Constantin D. 9125 

Volpe, Silvia e21095 

Voltolini, Luca 7024 

Volzone, Francesco 8066, 

8083 

vom Dorp, Frank 4590 

von Abel, Ekkehard 10540 

von Blomberg, Mary E 2562 

von Boehmer, Lotta 2573^ 

Von Briel, Thomas 3595 

Von Broen, Ingo TPS4146 

Von Euler, Mikael e13035 

Von Euw, Erika Maria 8592 

von Gruenhagen, Ulrich 3 

Von Gruenigen, Vivian E. 

TPS1614 

von Hofe, Eric e15125 

Von Hoff, Daniel D. 2516, 

3033, 4013 

von Kalle, Thekla 9573 

von Knebel Doeberitz, Magnus 

3550 

von Mehren, Margaret 

LBA10008, 10013, 10064, 

10088 

Von Minckwitz, Gunter 522, 

523, 541, 556, 1023 

Von Moos, Roger CRA3503, 

3595, e19648, 9059, 

10033, e13605, e18012, 

e19514 

Von Pawel, Joachim 7536 

Von Roenn, Jamie H. 610, 

TPS1134 

von Rohr, Lukas 9059 

Von Weikersthal, Ludwig 

Fischer 4023, 4539 

von Wichert, Goetz 

TPS3641^, 4032, 4034 

Vona, Karen L e19041 

Vonk, Judith M. 1502 

vonMehren, Margaret e19580 

VonMerveldt, Dendra 

TPS4678 

Voon, Pei Jye e13002, 

e19523 

Voon, Pei-Jye 1064 

Voorhees, Peter Michael 6526 

Vora, Lalit 1035 

Vora, Nilesh e14075 

Vora, Sujay A. 6108 

Vose, Julie 8047, 8060, 

8063 

Vosganian, Gregory Sumpao 

e21061 

Voss, Martin Henner 4532, 

4604 

Voss, Stephan D 9500 

Vouis, Jan e19532 

Voutsadakis, Ioannis e17007 

Vozzhaev, Alexander V. 9060 

Vrbanec, Damir TPS661, 

9046 

Vredenburgh, James J. 2027, 

TPS2103 

Vredenburgh, James J 2074^, 

2090^, 2094^, 2095^ 

Vreeland, Timothy J 625, 

2508, 2529 

Vrelust, Inge 2506 

Vrignaud, Patricia e15161 

Vrooman, Lynda M. 9530 

Vuento, Maarit e15564 

Vugrin, Davor e12044 

Vukelja, Svetislava J. 547, 

1017 

Vukovic, Vojislav M. 

TPS7613^ 

Vulsteke, Christof 1020, 

3018^ 

Vultaggio, Giuseppe e19595 

Vuong, Te e14020 

Vutukuru, Suresh TPS6640 

Vuylsteke, Peter 5001, 

e14060 

Vyas, Rakesh e15505 

Vyas, Shachi 2521 

Vyzula, Rostislav e11072, 

e18062 

Vågberg, Jan 6557 

W 

Waalen, Jill e21061 

Waanders, Esme 9550 

Wachsman, William 4030 

Wactawski-Wende, Jean 1501 

Waczulikova, Iveta e19020 

Wada, Noriaki 585, 1106, 

TPS1147 

Wada, Randal K. 6537 

Wada, Satoshi e13559 

Wada, Yasuhiro 10519 

Wada, Yumiko 3086, 3090 

Waddell, Tom Samuel 

LBA4000 

Wade, James Lloyd 9018, 

e15115 

Wade, Mark 3057, e13548, 

e14177 

Wadehra, Madhuri 1052 

Wadghiri, Youssef Zaim 

e19015 


Wadleigh, Martha 6526, 

6621 

Wadlow, Raymond Couric 

4021 

Wadsley, Jonathan LBA4000, 

6113 

Wadsworth, Trad 5570 

Wagenius, Gunnar e14531 

Wagenseller, Aubrey G 8530, 

8597 

Wages, David e18047 

Wagie, Terry 9019 

Wagle, Nikhil 5011, 10502 

Wagner, Andrea 3502 

Wagner, Andrew J. 1547, 

10029, e13600^ 

Wagner, Jeffrey D. 8534 

Wagner, Lars M. 9541 

Wagner, Ludwig 2024 

Wagner, Lynne I. 605, 5566, 

6076, 8007, 9016, 9020, 

9106, 9532, e15173 

Wagner, Manfred e17536 

Wagner, Margaret 2516 

Wagner, Michael 10061 

Wagner, Steffen 556 

Wagner, Stephanie Glacy 

9571 

Wagner, Susanne 7023 

Wagner, Teresa M. U. 1537 

Wagner, Volker Jean 

TPS8604, e19043, 

e19044, e19045, e19060 

Wagner, Walter 4530 

Wagner, Wolfgang e13091 

Wagner-Johnston, Nina D. 

6518^ 

Waguespack, Steven 4641 

Waheed, Sarah 8041, 

e18548, e18576 

Wahid, Fadilah Abdul e18528 

Wahl, Richard L. 10509, 

e13592 

Wai, Daniel 9564 

Waikins, Kate e13542 

Wainberg, Zev A. 3552 

Wainer, Zoe e17539 

Wainman, Nancy 1036 

Wakatsuki, Takeru 3518, 

3540, 3546, 3549, 3597, 

3604, 3615, 3622, 4026, 

4088, 4096, e11018, 

e14031, e14034, e14052 

Wakayama, Akihiko 5086 

Wakefield, Matthew 5073 

Wakelee, Heather A. 6050, 

7541, 10574 

Wakuda, Kazushige 7088 

Waldeck, Kelly 8520 

Waldman, Frederic 2587, 

5510, 8596, 10586 

Waldman, Scott A e14619 

Waldron, John N TPS5600, 

10522 

Waldschmidt, Dirk 4023 

Waldstrøm, Marianne 5052 

Walecki, Jerzy TPS4148 

Walewski, Jan Andrzej 

e18512 

Walker, Andrew e21107 

Walker, Dana Marie 1504 

Walker, Gregg 1608 

Walker, Luke N. 3024 

Walker, Mark S. 5014, 

e15061, e21077 

Walker, Michael 10576, 

10584 

Walker, Paul R. e11550, 

e17008, e17547, e17550 


Walker, Steven M. 10553 

Walker-Corkery, Elizabeth 

9004 

Walkiewicz, Marzena e17539 

Walko, Christine Marie 

e13074, e13109 

Wall, Gregory e21159 

Wall, Louise e13026 

Wallace, Andrew e18095 

Wallace, Audrey S e17525 

Wallace, Elaine Margaret 

e14592 

Wallace, James Alfred 

TPS3640, 4022 

Wallace, Michael J. 515, 

4116, e14664 

Wallace, Paul K 6565 

Wallace, Robert B 6034, 

e14005 

Wallace, Sarah G. 5503, 

5515 

Wallenstein, Gudrun e15037 

Waller, Anna 6119 

Waller, Edmund K. 2576, 

e21045 

Wallin, Bruce 7030 

Wallin, Johan 3005 

Wallis, John W. 503 

Wallis, Matthew 544 

Wallwiener, Diethelm 1067, 

5042, e11040^, e15577, 

e21003 

Wallwiener, Markus 1067, 

1090, e21003 

Walpole, Euan Thomas 3508, 

TPS4145, e19550 

Walsh, Bridget 10509 

Walsh, Cathy 9589 

Walsh, Elaine e12038 

Walsh, Garrett L 4086 

Walsh, Mark Doughty 5050 

Walsh, Naomi 632, 633, 637, 

e13520 

Walsh, Wendy 1036, 2051, 

5010, 7093 

Walsh, William Vincent 6569 

Walshe, Janice Maria e17561 

Walshe, Margaret B. e12031 

Walston, Steve e19040 

Walter, Clare e16538 

Walter, Kim 5575 

Walter, Roland B. 1527 

Walter, Steffen 2522, 3530 

Walter, Thomas 4071, 4109, 

e14524, e14592 

Walterhouse, David 9509 

Walters, Christy Lynn 5060 

Walters, Ian B. 3504, 3572, 

7584 

Walters, Kelly Kaiser 7067, 

e18117, e21069 

Walters, Matthew J. 2043, 

e13580 

Walther, Philip John 4670 

Walz, Jochen e15155 

Wampfler, Jason A. 1610 

Wan, Wen e21058 

Wandel, Simon 8511 

Wanders, Jantien 2552 

Wands, Jack 4098 

Wanebo, Harold J. 5576, 

e13561 

Wang, Alice M. 10586 

Wang, Andrew 4658, 6037 

Wang, Bailiang 10559 

Wang, Benjamin e18063^ 

Wang, Biyun 10567, e11567, 

e11568 

Wang, Bushi 7557, 7558 

Wang, Cathy 10622, e18549 

Wang, Changli 7520 

Wang, Chen-Chi e16006 

Wang, Cheng-Ping e16050 

Wang, Chenguang e13545 

Wang, Ching-Ping e16006 

Wang, Christopher Gene 

7072^, e17531^ 

Wang, Chun-Wei e16050 

Wang, Chunting e13538 

Wang, Cong 4092, e14575 

Wang, Dan 5091 

Wang, David X. 5503 

Wang, Ding 2013, 2018, 

3078 

Wang, Dong 7559 

Wang, Emily 10545 

Wang, Ena 8576, 10565 

Wang, Eric 3590 

Wang, Erjian 2595, e13606 

Wang, Eunice S. 6526, 6565, 

6602 

Wang, Fan e13584 

Wang, Fang-zheng e13558 

Wang, Fen 2013 

Wang, Fuli e14643 

Wang, Haibin 7036 

Wang, Hao 4055, 5506, 

e14509, e16061, e21034 

Wang, Hong Qiang 2087 

Wang, Hong e21161 

Wang, Hongkun 2590, 3095 

Wang, Hongshan 4092, 

e14575 

Wang, Hongwei 5543, 

e15193 

Wang, Hsiu-Po e14576 

Wang, Huamin 4130, 4131 

Wang, Huei 4642 

Wang, Hui 4008 

Wang, Hung-Ming e16050 

Wang, J-J e14699 

Wang, James 3039, e13602, 

e13604 

Wang, Jennifer e19014 

Wang, Jia Hua TPS4149 

Wang, Jian hua 4073 

Wang, Jian-guo e14505 

Wang, Jian-qiu e13558 

Wang, Jian-Wei e14024 

Wang, Jiang e14714, e16017 

Wang, Jianhua e14605, 

e14645 

Wang, Jianmin 9518 

Wang, Jiayu e11025, e11538 

Wang, Jie 7520, 7537, 7545, 

e12503, e18022, e18035 

Wang, Jin e14648, e18033 

Wang, Jin-Wan e14502, 

e14668 

Wang, Jing 7096, 10612 

Wang, Jingyuan 4656 

Wang, Jinhua 9507 

Wang, Jinwan LBA4537 

Wang, Jue e15015 

Wang, Jun e17504, e21103 

Wang, Kai 10524, e17541 

Wang, Lan-Ying e16024 

Wang, Le e15522 

Wang, Lei Ping e11568 

Wang, Lidong 4591 

Wang, Lihua 3031 

Wang, Lin-Pei e14629 

Wang, Lina 4563 

Wang, Linda C 8552 

Wang, Ling Zhi 4100^ 

Wang, Ling 6625^ 

Wang, Ling-Zhi 2551, 

e13002 

Wang, Lisa 3082, 4092, 

5019, 8585, e14575 

Wang, Lisu 8593 

Wang, Liwei e14508, e14539 

Wang, Liya e14734 

Wang, Lu 7505, 7578, 

e14548 

Wang, Luhua e14511 

Wang, Lulu 2098 

Wang, Lv hua 4073 

Wang, Maoqiang e14605 

Wang, Meihua 2001, 2008b, 

2047 

Wang, Michael 8017, 8035, 

8093, e18557 

Wang, Min 6000 

Wang, Mingjun 4643 

Wang, Peng 3037 

Wang, Ping 1068, 7075, 

e18013, e18138 

Wang, Qian 9008 

Wang, Qiang 7536, e14617 

Wang, Qin e14583 

Wang, Qing 604 

Wang, Qiong J. e14179 

Wang, Qun e18013 

Wang, Ren-sheng 5535, 

e16054 

Wang, Rong 1595, 6628 

Wang, Rongfu F 4643 

Wang, Rui-Yu TPS6635 

Wang, S. L. 4644 

Wang, Sa 6501 

Wang, San Ming 1538 

Wang, Shuhuai e11095 

Wang, Si-Yu 7034 

Wang, Song e19043, 

e19044, e19045 

Wang, Ting Ting 1064 

Wang, Trent P e14124, 

e14125, e14727, e19639 

Wang, Wei e11521, e13530 

Wang, Wei-Lien 10071 

Wang, Weidong 5597 

Wang, Weigang TPS4675^ 

Wang, Weili e17530 

Wang, Wen e14645 

Wang, Wenqing e14511 

Wang, Wenquan TPS1145 

Wang, Wenshi 2511 

Wang, Xiaoen e14700 

Wang, Xiaofei F. 7513 

Wang, Xicheng e14604 

Wang, Xin Shelley 6551, 

8091, 9072, 9081, 9082, 

9083, 9099, 9112, 9118, 

9140 

Wang, Xiuqiang 2587 

Wang, Xiuyan TPS2619, 

TPS4700 

Wang, Xu e21161 

Wang, Xuan 4008 

Wang, Xue e13564 

Wang, Xuefei 4092, e14575 

Wang, Xuemei 4054, 9072, 

e15075, e15092 

Wang, Xufang 4612, e14525, 

e14621, e14627 

Wang, Yan 3040 

Wang, Yanna 4092, e14575 

Wang, Yanxia e14645 

Wang, Yicheng 4643 

Wang, Ying 1047 

Wang, Yipeng 1058, e14164 

Wang, Yixin 10504 

Wang, Yongsheng e18051 

Wang, Yongyu TPS4147 

Wang, Yu e13580, e16039 

Wang, Yu-Chieh 10539 

801s

Wang, Yuan e15124 

Wang, Yunfei 547 

Wang, Yuyan 7537 

Wang, Zeng e17512 

Wang, Zhaohui e14118 

Wang, Zhen 620 

Wang, Zhensheng e14512 

Wang, Zhibo e14169, 

e14170 

Wang, Zhihong Joanne 9578 

Wang, Zhijie 7537, 7545, 

e18022, e18035 

Wang, Zhiqiang e13021 

Wang, Zhixiao e16521 

Wang, Zhong Hua 10567, 

e11568 

Wang, Zuoheng 5529, 5532 

Wang-Gillam, Andrea e14584 

Wani, Sachin e14584 

Wapnir, Irene e11032 

Ward, James Edward e16509 

Ward, John Francis e15194 

Ward, Kevin 5570, e14608 

Ward, Malcolm e21091 

Ward, Patrick J. 7567 

Ward, Tim H e15141 

Warde, Padraig Richard 4509, 

4535 

Wardelmann, Eva 10031 

Wardley, Andrew M. TPS660 

Wariabharaj, Darshan 

TPS6638 

Warlick, Christopher e15211 

Warloe, Trond e14637 

Warneke, Carla L 10607 

Warner, Andrew 7009 

Warner, Douglas 5072 

Warner, Ellen 1542, 1555, 

e12034, e19545 

Warner, Richard e21109 

Warnick, Ronald TPS3116 

Warr, Julia e15180 

Warren, Graham Walter 1529, 

e14659, e14712 

Warren, Robert S. 3517 

Warsch, Sean e16001 

Warsi, Ghulam 8012, 8028 

Wartenberg, Markus e19502 

Wasada, Izumi 8050 

Wasan, Harpreet S 3516, 

e21093 

Washam, Charity L. e21039 

Washington, Sierra 5107 

Washio, Marie e14004 

Wasielewska, Teresa TPS2619 

Wason, James 4531 

Wassberg, Cecilia 7539 

Wassermann, Johanna 601, 

e14553 

Wassmann, Karl 4516 

Watanabe, Hideki e13511 

Watanabe, Hiroyoshi 9574 

Watanabe, Jun e14047, 

e14050 

Watanabe, Kana 7565 

Watanabe, Kazuteru e14047, 

e14050 

Watanabe, Kenichiro 9577 

Watanabe, Koshiro 7012, 

e18099, e19556 

Watanabe, Masahiko 3071, 

4026, 4088, e14091 

Watanabe, Masayuki 10523, 

e13553 

Watanabe, Reiko e21007 

Watanabe, Tomoo e14004 

Watanabe, Toru 10554, 

e19557 

Watanabe, Toshiaki e14142 

Watanabe, Yasuyoshi 10519 

Waterhouse, Anna 511 

Waterhouse, David Michael 

7035, 7100, 7567 

Waterhouse, Jim e14006 

Waterkamp, Daniel 3614 

Waterman, Gabriel N. e18549 

Waters, Justin S. LBA4000 

Waterston, Ashita Marie 

TPS3637 

Watkin, Nicholas 4640, 

e15100 

Watkins, Brynmor A 9119 

Watkins, David J. 3531, 3587 

Watkins, Stanley P. 10509 

Watkinson, Anthony TPS4150 

Watson, Mark 503, 3047 

Watson, Melanie 8101 

Watson, William 633 

Watt, Christopher D. 4111 

Watt, Stuart e13107 

Wattel, Eric 6523 

Waxman, Ian TPS2614 

Waxman, Irving 10090 

Wayne, Jennifer L. 8081 

Wazaefi, Yanal 8578 

Wazer, David E. e11548 

Wear, Sandra Marija 8011 

Weaver, Amy 5004, 5076, 

8590 

Weaver, David T. 1057, 1091 

Weaver, JoEllen 577 

Weaver, Valerie e11096 

Webb, Christopher e13066 

Webber, Kate 9044 

Weber Hauge, Petra e14531 

Weber, Beatrice E. 1051, 

9079 

Weber, Béatrice LBA5002^ 

Weber, Damien C. 2068 

Weber, Denis TPS6642^ 

Weber, Dirk 2543 

Weber, Donna M. 8012, 8093 

Weber, Hans-Jochen e18572^ 

Weber, Jeffrey S. 2511, 

3102, 8508, 8510, 8582, 

8587, e13088, e15010 

Weber, Jeffrey 8503^ 

Weber, Jill M. 2612, 4125, 

e14579, e14715 

Weber, Karsten E. 542 

Weber, Michael J 8530 

Weber, Randal S. e16030 

Weberpals, Johanne Ingrid 

5019, 5032, e15537 

Webster, Edvelyn 10535 

Webster, Jennifer A e14160 

Webster, Kevin P. 5544 

Webster, Marc A. e21083 

Webster, Scott e21129 

Wechsler, Janine e21014, 

e21046 

Wedding, Ulrich 9114 

Wee, Sandra K 6074 

Weekes, Colin D. 3017, 

4050, 4052, e13006 

Weeks, Jane C. 599, 1125 

Weems, Garry Alan 4574 

Wege, Henning 4115 

Wegener, William A. 4043 

Wegner, Brett 8054 

Wei, Andrew 6527 

Wei, Jia 4068, e14509, 

e21034 

Wei, Jun 2011 

Wei, Li 3055 

Wei, Min e13531 

Wei, Ning e13004 

Wei, Qi 9029 

Wei, Sen e17514 

Wei, Weidong e11091 

Wei, Ye e14000 

Wei, Yuquan e13538 

Wei, Zhigang 7545 

Weibel, Kelcy C 8061 

Weichenthal, Michael 8505 

Weichselbaum, Ralph R. 

e11512 

Weickhardt, Andrew James 

3534, 7504, 7526 

Weide, Benjamin 8526 

Weideman, Prue C 1502 

Weidler, Jodi Marie 603, 608, 

614 

Weidmann, Eckhart 3 

Weigang-Koehler, Karin 2554 

Weigel, Brenda 9500, 9540, 

9541, 9581 

Weigel, Marion T. e13503 

Weikert, Steffen 4636, 

e15044 

Weil, Marcie K. 3031, 3087, 

3529 

Weil, Robert J. 2014, 2018, 

2076, 2100 

Weil, Susan 5062^ 

Wein, Alan J. e15196 

Wein, Axel 4072 

Weinberg, Benjamin e14658 

Weinberg, Jeffrey 2019 

Weinberg, Lori Elizabeth 

5089 

Weinberg, Uri TPS2106, 

e14616 

Weinberg, Vivian K. 2564, 

3517, 4593, 4660, 

e15137 

Weiner, Bryan 6104 

Weiner, Louis M. 2590, 

TPS3638, e14569 

Weiner, Michael e16557 

Weingart, Saul e16515, 

e16559 

Weinhold, Kent 2585 

Weinreich, David M. 5072 

Weinreich, David Michael 

4606 

Weinrich, Scott 3509, 3511 

Weinschenk, Toni 2522, 

3530 

Weinstein, Howard J. 9502 

Weinstein, John N. 7096 

Weinstock, Chana 1039, 

10572 

Weintraub, Sheri 5596^ 

Weir, Barbara 4585 

Weir, Genevieve 2588 

Weis, Joachim 6002, 7607 

Weis, John R. 3057, e14177 

Weiselberg, Lora Rose 1046 

Weiser, Martin R. 3583 

Weiskopf, Kipp 2514 

Weismann-Brenner, Alina 

e14067 

Weiss Smith, Sheila e16519, 

e16537 

Weiss, Alan 4006 

Weiss, Geoffrey R. 8530 

Weiss, Glen J. 2516, 2534, 

3019, 3033, 3046, 3060, 

3062, e19048^ 

Weiss, Jared e16062 

Weiss, Lawrence M. e21019 

Weiss, Mark Adam 6122, 

6609 

Weiss, Matthias 6054, 

e16549 

Weiss, Robert H 4634 

Weiss, Rudolf 8005 

Weiss, Stephen 8099 

Weiss, Talia 9123 

Weissfeld, Joel L. e21012 

Weissler, Mark C 5539, 5577 

Weissman, Irving L 2523 

Weitbruch, Delphine e11542 

Weith, Ekaterina 4636, 

e14152 

Weitman, Steven D. e16566 

Weitzel, Jeffrey N. 1010, 

CRA1505 

Welch, Mary Roberta 2089 

Welch, Stephen 3013, 5019, 

6082, e19616 

Welcher, Rosanne e21129 

Weldon, Christine B. 1553, 

6120, e16531 

Welin, Staffan 4015 

Weller, Michael 2000, 2007, 

2055, 2067, TPS2105 

Wells, Karen 1590, 1591 

Wells, Nancy L. e16038, 

e19600 

Wells, Robert J. 9096 

Wells, Samuel A. e13122 

Wells, Susanne I e16017 

Wellstein, Anton e14009, 

e14569 

Welsh, James 4069, 4078, 

4086, 7062, 7096, 

e14547, e14669 

Welslau, Manfred LBA1, 640, 

3, e13100^ 

Welz, Stephan e16033 

Wen, Hongxiu 1538 

Wen, Patrick Y. 2005, 2009, 

2012, 2025 

Wen, Sijin 4556, 6516^, 

e13506, e13595, e15181 

Wen, Wenhsiang e20507 

Wen, Yu-Ye 10598 

Wen, Yvonne TPS3112 

Wen, Zou Bing e14648 

Wendt, Thomas e16033 

Wendtner, Clemens Martin 

10031, 10054 

Weng, David Edward 3029 

Weng, Peggy 4010 

Weng, Wen-Kai 2514 

Weng, Xiaoduan e18136 

Wenham, Robert M TPS3114, 

5025, e13601 

Wenk, Kurt S e19025 

Wenners, Antonia Sophie 

1084, e13503 

Wenzel, Lari B. 6132 

Wenzel, Ralph 6136 

Wernecke, Klaus Dieter 5512 

Werner, Dominique e14557 

Werner, Jochen 5512 

Werner, Lillian 4577, 4580, 

4582, 4585, 6617, 6618 

Werner, Lynn 7092 

Werner, Theresa Louise 

e13548, e13596 

Werner-Wasik, Maria 2001, 

e19507 

Weroha, Saravut John 5077 

Wertz, Marie 2060 

Werutsky, Gustavo e11087 

Wesenberg, Finn 9590 

Wesley, Johnna D. 2563 

Wessalowski, Ruediger 10054 

Wesseling, Jelle 562, 10554 

Wessels, Judith A. M. 10518 

Wessels, Judith A.M. 526 

West, Dennis P. 2532, 4063, 

6623, e18571 


West, Howard Jack 7517, 

7552 

West, James K. 4059 

West, William W e17549 

Westbroek, David 1131 

Westeel, Virginie 7057, 

TPS7111, 7574, e16560, 

e18089 

Westermann, A.M. e13095^, 

e13097^ 

Westermann, Jörg e15053 

Westin, Shannon Neville 

1513 

Westlin, William 8032 

Weston, Brian 4069, 4078, 

4086, e14547 

Westphal, Manfred 2033, 

2067 

Westra, William H. 5506, 

5566 

Wetzel, Antje e19540 

Wetzler, Meir 6513, 6520, 

6565, 6596, 6602, 6604 

Wex, Thomas 4107 

Wexler, Leonard H. 9503, 

9545 

Weyker, Paul e13066 

Weyman, Elizabeth A. e16059 

Weynand, Birgit 5519 

Whalen, John 6553 

Whalen, Michael e15019, 

e15021 

Whalen, Micheal e15018 

Wheater, Matthew 8566 

Wheatley-Price, Paul 6083, 

e19527 

Wheeler, Chris 2084 

Wheeler, Christopher Jay 

2087 

Wheeler, Helen e12507 

Wheeler, Stephanie B. 6017, 

6029, 6096, 6104 

Wheeler, Thomas M. 4643 

Wheelock, Alyse 9107 

Whelan, Jeremy 6115, 

10063, 10081 

Whelan, Timothy Joseph 500, 

LBA1031, 6035, 9020 

Wheler, Jennifer J. 3106, 

3107^, 8551, 10510, 

10607, e13020, e13506, 

e13534, e13595, e19004 

Whisnant, John 3060 

Whisnant, Mindy 6054 

White, Alison Marie e16004 

White, Carol B 6053 

White, Darrell 8020, 

TPS8112, TPS8114 

White, Emily 1527 

White, Jeff 4531 

White, Kevin P. 5517 

White, Nicole MA 4633 

White, Rebekah Ruth 

e14544, e14724 

White, Shane e17539 

White, Therese 2528 

White-Koning, Melanie 2549 

Whitehead, Robert P. 4019 

Whiteside, Theresa 8528 

Whiting, Samuel H. e14501 

Whitlow, Ann B. 5050 

Whitman, Eric D. e19057 

Whitmarsh, Karen A e18068 

Whitmore, James Boyd 4648, 

4650, e15120 

Whittaker, Sadie 1062 

Whittaker, Sean 8076 

Whittemore, Alice S 1502 


Whittington, Richard 3605, 

4030 

Whitworth, Jenny M. 5060 

Whorf, Robert C. 8556 

Wiater, Katarzyna 10538 

Wichmann, Gunnar e16016 

Wick, Jo e13551 

Wick, Michael Jude e13025 

Wick, Wolfgang 2000, 2034 

Wickart-Johansson, Gun 

e14531 

Wickerham, D. Lawrence 

TPS1615 

Wickham, Thomas J. TPS663 

Wickrema, Amittha 6535^, 

e13120^ 

Widemann, Brigitte C. 6530 

Widhalm, Georg 2053, 2071 

Widmark, Anders LBA4512, 

4551 

Wiebe, Karsten 10080 

Wiebe, Lauren Allison e14613 

Wiechert, Andrew e15545 

Wiechno, Pawel J. LBA4512, 

4551 

Wieczorek, Agnieszka Anna 

e18552 

Wieczorek, Stefan 1523 

Wiedenmann, Bertram 4122, 

4128, e14564 

Wiederholt, Peggy A e16010 

Wiegand, Phillip e16053 

Wiegand, Volker 2573^ 

Wiegel, Thomas e15199^, 

e16033 

Wieland, Scott 10036 

Wierda, William G. 6516^, 

6517, 6584, 6598, 6603 

Wiernekowski, Jennifer 6035 

Wiernik, Peter H. 6595 

Wierzbowska, Agnieszka 

6559, 6632 

Wiese, David e14045, 

e14046, e15554 

Wiesner, Jason B e21026 

Wiesneth, Markus 6567 

Wiestner, Adrian 6581 

Wiezorek, Jeffrey S. 3581 

Wigginton, Jon CRA2509, 

2510, 2521, TPS2613, 

4505, 7509, 8507 

Wigler, Devin e19586 

Wihl, Jessica 5052 

Wiita, Elisee e13518 

Wikstrom, Katarina 10553 

Wiktor, Anne E. 4009 

Wilbaux, Melanie e15182 

Wilcken, Nicholas 550, 9087 

Wilczynski, Sharon 1035 

Wild, Aaron Tyler 4045, 4055 

Wildes, Tanya Marya e18551 

Wildiers, Hans 529, 1020, 

9035 

Wilding, George 4, 3101, 

3103, e13601 

Wilding, Greg 3582 

Wilding, Gregory E. 4654, 

e15204 

Wiley, Tim e19577 

Wilfong, Lalan S. e14501, 

e16536 

Wilgenhof, Sofie 2507, 

e19026, e19027 

Wilhelm, Christian 8004 

Wilhelm, Francois 3017, 

3081 

Wilhelm, Sibylla 8022 

Wilhelm, Stefan 6566 

Wilke, Hansjochen TPS4139 

Wilke, Lee G 1107 

Wilkerson, Julia 2548, 

e13122, e14064 

Wilkerson, Matthew D 7006 

Wilkinson, Kathy e16561 

Wilkinson, Neal W. e14659 

Wilkinson, Rosemary 1545 

Wilky, Breelyn A. 10025 

Willemen, Yannick e13051 

Willems, Luc e18006 

Willerding, Gregor 2054 

Willett, Christopher e14724 

Willey, Jie S. 594 

William, Basem M. 8047 

William, William 7047 

Williams, Andrew E e14160 

Williams, Cathy 8018^ 

Williams, Charles C. 2559, 

7065, e17559 

Williams, Christopher Kwesi 

Oladipupo e17013 

Williams, Daphne 8541 

Williams, Denise E 2543 

Williams, Farah J 2608 

Williams, Gretchen M 9521, 

9522 

Williams, Jacqueline P 9027 

Williams, James Andrew 

2595, e13606 

Williams, Janet L. e19589 

Williams, Jennifer 1055 

Williams, Julie C e14505 

Williams, Lisa Simone 596, 

604 

Williams, Loretta A. 6551, 

8091, 9081, 9082, 9083, 

9140, e19589 

Williams, Mark e19062 

Williams, Melanie A. 6070 

Williams, Michael E. 8007 

Williams, Michael V. 4531 

Williams, Noelle S. 4616 

Williams, P. Mickey 3529, 

5020 

Williams, Paul e14164 

Williams, Richard Fred e17550 

Williams, Richard Thomas 

3581 

Williams, Sarah Jane 5046 

Williams, Scott G. TPS4690 

Williams, Stephanie A. e11084 

Williams, Steve e21012, 

e21142 

Williams-Elson, Irene e15010 

Williamson, Dan 9510 

Williamson, Elizabeth A. 

TPS5602 

Williamson, Stephen K. 

e13535, e13551 

Williamson, Todd E. e14106 

Williford, Susan Kidwell 9108 

Willinek, Winfried e14565 

Willis, Carl Rogaston e11562, 

e13003 

Willis, Nick e13522 

Willis, Scooter 1027, e21099 

Willman, Cheryl L. 6502, 

9506 

Willson, Anna 2015 

Wilmink, Johanna 4094 

Wilner, Keith D. 7508, 7596, 

7598, 7599, 7600 

Wilsdon, John B. e13522 

Wilson, Alex e15011 

Wilson, Andrew J e15582 

Wilson, Bethany Cox e21000 

Wilson, Carmen Louise 9528 

Wilson, Charles e14100 

Wilson, Dale e15554 

Wilson, David O 7071, 7074 

Wilson, David e14061 

Wilson, Don 3610 

Wilson, J. Frank 6052 

Wilson, James Matthew e17519 

Wilson, John 599 

Wilson, Kate 3534, TPS4145, 

e13007 

Wilson, Keith e16017 

Wilson, Leslie e15154, 

e19571 

Wilson, Manda e19647 

Wilson, Matthew W. e13544 

Wilson, Nicole Maire e18553 

Wilson, Peter M.D. 3584, 

3622, e14034 

Wilson, Peter 4529 

Wilson, Richard H. 3516 

Wilson, Richard K. 503, 9518 

Wilson, Tim 5575 

Wilson, Timothy G. e15084, 

e15178 

Wilson, William A. e16035 

Wilson, Wyndham Hopkins 

2503^, 2528, 8005, 8051 

Wilt, Marc e11542 

Wiltshire, Kirsty TPS4690 

Wiltshire, Robin 4542 

Wimberger, Pauline LBA5002^, 

5007, 5031, 5042, 5044, 

e13095^, e13097^, 

e13100^, e13108^ 

Winch, Chad TPS2104 

Winchester, David J. 1033, 

1101, 1116, 6040 

Winchester, David Porter 

1033, 1101, 1116, 6040 

Windemuth-Kiesselbach, 

Christiane 8052 

Winder, Thomas 3584, 

e14031 

Winderlich, Mark 6574 

Winer, Eric P. 510, 535, 

CRA1002, 1026, 6015, 

9084, e21010 

Winer, Eric S. 9117 

Winer, Eric TPS658, 1009, 

6089, 9071, 9100, 10558, 

e16515 

Winfree, Katherine B. 7075, 

e18138 

Wingate, Patti 4098 

Wingmo, Inga-lill 4561 

Winick, Naomi Joan 

CRA9508, 9543, 9548, 

e19536 

Winkelman, J. e13588 

Winkelmann, Cornelia 4023 

Winkler, Annette 9059 

Winkler, Peter 9573 

Winquist, Eric 4535, 5504^, 

TPS5600, e15177^, 

e19616 

Winrich, Barbara 4021 

Winslow, John William 603, 

608 

Winter, Christian 4601 

Winter, Eva 4530 

Winter, Kathryn A. 4041 

Winterhalder, Ralph C. 3595, 

9059 

Winterle, Natalie e14554 

Winton, Elliott F. 6624 

Winzer, Harald e15566 

Wirapati, Pratyaksha 3509, 

9510 

Wirth, Lori J. 5501, 5508, 

5579, 5594, e16059 

Wirth, Manfred e15195 

803s

Wischnewsky, Manfred 1078 

Wischnik, Arthur 1072, 1081 

Wise-Draper, Trisha e16017 

Wisinski, Kari Braun 555, 

563, 6063 

Wislez, Marie TPS7111, 

e18075, e18089, e18102 

Wisnivesky, Juan P. 4623, 

6065, 7064, e15513 

Wissel, Paul Stephen 4111 

Wistuba, Ignacio I. 7023, 

7078, 7597, 10506 

Witek, Matthew e14619 

Witkiewicz, Agnieszka e19016 

Witkowski, Elan R. 4059, 

e14691 

Witowski, Steven 8032 

Witt, Lisa A e21000 

Witta, Samir E. e13101, 

e18077 

Witte, Maria 8526 

Witteles, Ronald 4610 

Witten, Matthew R. e21114 

Witter, Merle 8527 

Witteveen, Petronella 

LBA5002^ 

Witthuhn, Ralf 4601 

Wittig, Burghardt 4636, 

e14152 

Wittlinger, Michael 5512 

Witzig, Thomas E. 8043, 

8053, TPS8118 

Wloch, Mary K e19058 

Wo, Jennifer Yon-Li 4021, 

e14615 

Woda, Bruce 6569 

Woditschka, Stephan 505 

Woehrer, Adelheid 2024, 

2053 

Woelber, Linn Lena 5007, 

5034, 5058 

Woell, Ewald 4074, 4095^ 

Woerns, Marcus A 4115 

Wogu, Adane 6129, 9135 

Wohnrath, Durval R. e14599 

Woike, Michael 4631 

Wojcicki, Anne 10097 

Wojciechowski, Tomasz 

e15500 

Wojtowicz-Praga, Slawomir 

7573 

Wojtukiewicz, Marek TPS649 

Wolanski, Andrew 3053 

Wolanskyj, Alexandra P. 6614 

Wolchok, Jedd D. 2518, 

2521, 8508, 8512, 8515, 

8539, 8549, 8575, 8583, 

8598, TPS8603 

Wold, Gwyn e13028 

Wolden, Suzanne L. 5537, 

CRA9513 

Wolf, Gregory T. e16014 

Wolf, Hans-Heinrich e19579 

Wolf, Holly J 10580 

Wolf, Judith 5027 

Wolf, Juergen 1533, 3044, 

TPS3115, 7603, 

CRA10529 

Wolf, Jurgen 10526 

Wolf, Martin 2504 

Wolf, Max 8002 

Wolfe, Joanne 9076 

Wolfer, Anita e11048 

Wolff, Antonio C. 1128, 6026 

Wolff, Greg G. e12024, 

e15197, e18107, e19630 

Wolff, Hendrik A. 3600 

Wolff, Robert A. 4038, 4051, 

4054, 4060 

Wolff, Steven N. 6038 

Wolfgang, Christopher Lee 

3596, 4045, 4055 

Wolfgarten, Matthias Kim 

1077 

Wolfman, Judith 518 

Wolfson, Julie Anna 9512 

Wolin, Edward M. 4014, 

e14610 

Wolkeinstein, Pierre 10049 

Woll, Penella J. 7562 

Woll, Penella 6113 

Wollins, Dana CRA1505 

Wollner, Mira 9052 

Wollschlaeger, Kerstin 5005 

Wollschleger, Dennis J 

e19615 

Wolmark, Norman LBA506, 

538, 611, TPS657, 

LBA1000, 1025, TPS1142, 

TPS1615, 3512, 3545 

Wolpin, Brian M. e19586 

Wolpin, Seth 9008 

Wolter, Pascal 4622 

Wolters, Regine 1078 

Womack, Chris 4124 

Womer, Richard 9503, 9537 

Won, Hye Sung e14634 

Won, Jong-Ho e14688, 

e19554 

Won, Minhee 2047 

Wong, Andrea LA 1064, 

2551, 3002 

Wong, Bob 9137 

Wong, Chung-Kwun Amy 

6005 

Wong, Eric e18541, e21078 

Wong, F. Lennie 9505 

Wong, Hai Ming e12006 

Wong, Helen 8564, e15128, 

e15135, e18068 

Wong, Hilda e14545 

Wong, Hing C. e13088, 

e15010 

Wong, Jan H. e11550 

Wong, Janice C. 6087 

Wong, Karina 584, TPS10631 

Wong, Kit Man 10522 

Wong, Kwong-Kwok e15583 

Wong, Lilly 3006^ 

Wong, Linda 582 

Wong, Lucas 3078 

Wong, Michael K.K. 3042^, 

4608, 4612 

Wong, Nicole TPS3643, 

TPS4137 

Wong, Rachel e14088 

Wong, Rebecca TPS4141, 

9131, 10522 

Wong, Richard J. 5545^ 

Wong, Sandra L. 6020 

Wong, SC Cesar e14085 

Wong, Shirley S. 5038 

Wong, Siu-Fun 9018, e16523 

Wong, Stephen 2098 

Wong, Stuart J. 5583, 

e16053 

Wong, Terence e13116 

Wong, William 6108 

Wong, Winston 6098, e16540 

Wong, Yu-Ning 1544, 4522, 

4525, 4526, 6021, 6061, 

e14021, e19580 

Woo, Henry TPS4690 

Woo, Hyun Young e14566 

Woo, Jacky e13500, e13562, 

e13575, e13577, e21028, 

e21058 

Wood, Bradford J 2545, 

TPS4701 

Wood, Charlotte 9543 

Wood, Christopher G. 4500, 

9029, e15075, e15092 

Wood, Karen TPS4682 

Wood, Laura S. 4609, 

TPS4684, e15095 

Wood, Lauren V. 10589 

Wood, Leslie 3073 

Wood, Lori 4536, 4538 

Wood, Marie CRA1505 

Wood, Matthew D. e14514 

Wood, Patricia Ann 2543 

Wood, William C. 1005 

Woodman, Ciaran e13507 

Woodman, Richard Charles 

6509^ 

Woodman, Richard John 

e19550 

Woodman, Scott Eric e19009 

Woodman, Scott e19039 

Woodruff, Teresa K. e20001 

Woods, Ryan 582, 3527, 

6014 

Woodward, Wendy A. 594, 

1047, 1102, e13582 

Woodward, William J. 10011^ 

Woopen, Hannah e15531 

Wooten, Kathleen 10572 

Wooten, Michael e14030 

Worden, Francis P. e16014 

Worden, Rebekah 3083 

Worman, Melissa 1536 

Wormann, Bernhard J. 6610 

Wormanns, Dag e13547 

Worni, Mathias e14544, 

e14562 

Worth, Laura L 6540 

Wotherspoon, Andrew 

LBA4000, e14088 

Woulfe, Bernie e16551 

Woyach, Jennifer Ann 6508 

Wozniak, Agnieszka 10030 

Wozniak, Antoinette J. 2081, 

7018, 7029, 7083, 7517, 

7552, 7593, e17528 

Wozniak, Timothy F. 3545, 

e18122 

Wrangle, John e18147 

Wreschner, Daniel H. e13018 

Wright, Alan e21152 

Wright, Alexi A. 5011, 

e16500 

Wright, Brian 4013, 10630, 

e15209 

Wright, Frances e19545 

Wright, Gavin e16501, 

e17539 

Wright, Jason D. 5013, 5101, 

6078 

Wright, Jason Dennis 6118 

Wright, Jean L. 595 

Wright, Jim R. TPS5600 

Wright, John Joseph 2553, 

TPS3112, 4569 

Wright, Jonathan 511 

Wrin, Joe 3534 

Wroblewski, David 8553 

Wroblewski, Kristen 9586 

Wroblewski, Susan TPS661 

Wroclawska-Swacha, Monika 

M e18572^ 

Wronski, Samantha 6553 

Wu, Abraham Jing-Ching 

4061 

Wu, Benjamin 529, 5038 

Wu, Bor-Wen e17558 

Wu, Cassandra TPS8118 

Wu, Changping 9017 

Wu, Chengyu e14700 

Wu, Christina Sing-Ying 609, 

e14178, e14658 

Wu, Colleen 10629 

Wu, Eijean e19506 

Wu, Eric Q. 1037, 6594, 

6600, 10094, e11076, 

e16571, e20511 

Wu, Fang e16054 

Wu, Fei 3551 

Wu, Frank S. LBA8509 

Wu, Han-chieh e11068 

Wu, Hillary H. TPS3111 

Wu, Hong-Gyun 5552 

Wu, Hui 626, e13579 

Wu, Jianrong 9502, e13584 

Wu, Jie e14701 

Wu, Jing 2029^, 2091, 

e12010 

Wu, Jingyang 2534 

Wu, Jonn 7020 

Wu, Kehua 2611, e13106 

Wu, Lin 10596, e13600^ 

Wu, Meina 7537, 7545, 

e18035 

Wu, Minghui e13564 

Wu, Nian 10004 

Wu, Pei-Fang 1079 

Wu, Ping 8015 

Wu, Qi e18033 

Wu, Qian 5530 

Wu, Quinfei e19647 

Wu, Shao-xiong e18121 

Wu, Shenhong 9088, 9092, 

e13591, e15140, e18571, 

e19624 

Wu, Shi Xiu e18013 

Wu, Terry e17524 

Wu, Timothy 3105 

Wu, Tsung-Teh 4009 

Wu, Wei e14701 

Wu, Weiguo e13562, 

e13575, e21058 

Wu, Wen Shuo e18132 

Wu, Wenting 2004, 2031 

Wu, Xiao-cheng 6052 

Wu, Xiaoyuan e14645 

Wu, Xifeng 7608, e14153 

Wu, Xiwei 10545 

Wu, Yi Long 7039, 7519^, 

7520, 7533, 7559, 

e13510, e18035, e18090 

Wu, Yuehan TPS5602 

Wu, Yun 1054, 1130, 10559 

Wu, Zheng e14569 

Wucherpfennig, Kai 2502 

Wuchter, Patrick 10040 

Wuendisch, Thomas 4600 

Wuerflein, Dieter e17536 

Wujcik, Debra 9137 

Wulf, Gerald 6543, 8004 

Wunderlich, John R e14179 

Wustner, Jason 3016 

Wuthrick, Evan John 5530, 

e19507 

Wyatt, Gwen TPS9150 

Wyen, Christoph 8005, 8046, 

8058 

Wyld, David 3572, 9087 

Wyld, Peter J. 9542 

Wymenga, Machteld 1080 

Wynendaele, Wim 4622 

Wynes, Murry W. 7552, 7597 

Wyngaard, Peter e14164 

Wypij, Jackie M. e21145 

Wyrwicz, Lucjan 10561 

Wyss, Annah 6119 

Wöckel, Achim 1078, 1082 


X 

Xanthakis, Ioannis 5033 

Xanthopoulos, Eric 7050, 

7098, e17534, e18032 

Xavier, Patricia e11087 

Xenidis, Nikolaos e14567 

Xi, Liqiang TPS7609 

Xia, Chang 3056 

Xia, Lin e14539 

Xia, Menghang 10025 

Xian, Shuang e13538 

Xiao, Han 5514 

Xiao, Hugh 2597 

Xiao, Lianchun 4069, 4116, 

4615, e14547, e14669 

Xiao, Lin e15117 

Xiao, Shaowen 10045 

Xiaoyan, Chen e13036 

Xiaoyu, Shawn 5503, 5515 

Xiazhen, Yu e14153 

Xie, Conghua 5535 

Xie, Hao 2092 

Xie, Hong 8018^ 

Xie, Jiansong 3580 

Xie, Li e14509, e21034 

Xie, Sherlly 4559 

Xie, Tao 3509 

Xie, Wanling 4521, 4538 

Xie, Xian-Jin 4616, e14165, 

e15066 

Xie, Xiaoming e11091 

Xie, Yang e14153 

Xie, Zhi e13510 

Xin, Song 8554 

Xin, Yan 2567 

Xing, Heming e19055 

Xing, Jun e13529 

Xing, Ligang e14643 

Xing, Pu-Yuan e14502 

Xiong, Jian ping 7548 

Xiong, Liwen 1551, e12010, 

e17551 

Xiong, Shigang e15153 

Xiong, Shunbin 10506 

Xiros, Nikolaos e21027 

Xiu, Joanne 5523 

Xiu, Qingyu 7520 

Xiu, Xia e14511 

Xu, Binghe TPS649, TPS1135, 

e11025, e11537, e11538 

Xu, Chun-fang e15059 

Xu, Cindy 559 

Xu, Fei e13021 

Xu, Feng 4638 

Xu, Jian-Ming 3040, 

LBA10008 

Xu, Jianmin e14000 

Xu, Jiasen e18142 

Xu, Jishu 1515 

Xu, Lian 8042, 8106, 8107 

Xu, Liang Guo e14071 

Xu, Lu 3025 

Xu, Min e11520, e20001 

Xu, Na 532 

Xu, Ning-Zhi e14502 

Xu, Nong 7559 

Xu, Peng 5597 

Xu, Ping e11061, e15177^ 

Xu, Qing 9017 

Xu, Qinghua 3551 

Xu, Rui-hua e14653, e14655 

Xu, Shaofa e18013 

Xu, Shidong e18013 

Xu, Shuichan 3006^ 

Xu, Wei Xu e13004 

Xu, Wei 1535, 6005, 7586, 

9021, 9032 

Xu, Xiao wei 8561, 8562 

Xu, Xunhai 10516 


Xu, Yang e14538 

Xu, Yanqing 9557 

Xu, Yaping e14678, e17527 

Xu, Ye 3551 

Xu, Yihuan 5012 

Xu, Ying e14549, e14550 

Xu, Yingxin e14061 

Xu, Yong e14648, e18033 

Xu, Younong 2585 

Xu, Zijie S. 6093 

Xuan, Lixue e11538 

Xue, Cong 5538 

Xue, Hong-Ling TPS4149, 

e15047, e15064 

Xue, Liquan 3090 

Xue, Mei 553 

Xue, Xiaonan 8005 

Xue, Zhengyu e15059 

Xyrafas, Alexandros e18105 

Y 

Ya-Qin, Li e16017 

Yachnin, Jeffrey TPS4696^, 

e15115 

Yaegashi, Nobuo 5087 

Yagata, Hiroshi 590 

Yagmurdur, Mahmut Can 

e11023, e11026, e11515 

Yahalom, Joachim 2006 

Yakoub-Agha, Ibrahim 6534, 

6542 

Yakushev, Vadim A. 9060 

Yalcin, Bulent TPS4148 

Yalcin, Selim e11011, 

e11023, e11026, e11045, 

e11515, e14174, e15572, 

e15573 

Yalcin, Suayib 3565, e20514 

Yalçintas Arslan, Ülkü 638, 

e11540 

Yale, Steven e16549 

Yam, David e15180 

Yamada, Yasuhide e14123, 

e14126, e14510 

Yamagishi, Atsushi e15057 

Yamaguchi, Akito e15127 

Yamaguchi, Hironori e14530 

Yamaguchi, Hiroyuki 7569 

Yamaguchi, Ken D. 5074 

Yamaguchi, Kensei 4002, 

e14510 

Yamaguchi, Motoko 8050 

Yamaguchi, Nise Hitomi 

e16505 

Yamaguchi, Ou e19583 

Yamaguchi, Risa e11017 

Yamaguchi, Satoshi 5103 

Yamaguchi, Shigeki 3524, 

3607, e14091 

Yamaguchi, Takayoshi e14622 

Yamaguchi, Taketo 4031, 

4035 

Yamaguchi, Takuhiro 1530 

Yamaguchi, Tatsuro e14123 

Yamaguchi, Tomohiro 4046 

Yamaguchi, Toshiharu 3625, 

10541, e14145 

Yamaguchi, Yoko e17554, 

e18064 

Yamamichi, Noboru 1119 

Yamamoto, Chiriko 3625 

Yamamoto, Hiromasa e17517 

Yamamoto, Hiroyuki e14635 

Yamamoto, Junji 3625 

Yamamoto, Kuniharu e14011 

Yamamoto, Makoto e18135 

Yamamoto, Naohito 1119 

Yamamoto, Naoto TPS1147 

Yamamoto, Nobuyuki 6112, 

7003, 7017, 7028, 7088, 

LBA7500, 7551, 7602, 

e18093, e21007 

Yamamoto, Noriko 10541 

Yamamoto, Norio 10075, 

e20505 

Yamamoto, Satomi 7000, 

e18128 

Yamamoto, Seiichiro 3569, 

e14091 

Yamamoto, Shinya e15038 

Yamamoto, Suguru e18007, 

e18056, e18141 

Yamamoto, Tadashi 9053 

Yamamoto, Yutaka 588, 

e11017 

Yaman, Sebnem e11009, 

e11033, e11093, e13031 

Yamana, Hideaki e14077 

Yamanaka, Kentaro e21059 

Yamanaka, Takeharu TPS659, 

e14038 

Yamane, Yuki 1552, e18064 

Yamao, Kenji 4031, 4035, 

e14540 

Yamaoka, Toshimitsu e13029 

Yamashita, Hideomi e15533 

Yamashita, Hiroharu e14530 

Yamashita, Keishi 3071, 

3084, 3088^ 

Yamashita, Koji 1112 

Yamashita, Motohiro 7012 

Yamashita, Yoshiki e19546 

Yamashita-Kashima, Yoriko 

e13502 

Yamauchi, Hideko 590, 

10048, e13037 

Yamauchi, Yoshikane 7038 

Yamazaki, Hiroko e13076 

Yamazaki, Kentaro e14038, 

e14123 

Yamoah, Kosj e15163 

Yan, Feng-qin e13558 

Yan, Haolin e16054 

Yan, Houling e19606, 

e19639 

Yan, Jingsheng e15066 

Yan, Kun e14701 

Yan, Li e13599 

Yan, Max 504 

Yan, Xiaowei (Sherry) e15536 

Yan, Yibing TPS2616 

Yanagi, Hidenori e14541 

Yanagisawa, Satoru e19508 

Yanagitani, Noriko 10569, 

10604, e18004, e18014, 

e18017 

Yancey, Mary Ann 8088, 

8104, e18568 

Yang, Allen S. 8073 

Yang, Anthony D e19001, 

e19013 

Yang, Arvin 8508 

Yang, Connie L 9591 

Yang, Dan e13519 

Yang, David T e13537 

Yang, Di 6056 

Yang, DongQing e21116 

Yang, Dongyun 3518, 3540, 

3546, 3549, 3584, 3597, 

3604, 3615, 3622, 4026, 

4088, 4096, 4563, e11018, 

e14031, e14034, e14052 

Yang, Eddy Shih-Hsin 621 

Yang, Fan e17504, e21103 

Yang, Feng e14651 

Yang, Guang 8042, 8106, 

8107, e14153 

Yang, Heidi 6600 

Yang, Hengxuan 4106 

Yang, Hongbo 4612 

Yang, Huibin 4591 

Yang, Huiyi e18142 

Yang, Hwai-I e17014 

Yang, James Chih-Hsin 

LBA7500, 7557, 7558 

Yang, Jennifer e13549 

Yang, Jianliang e14606 

Yang, Jianyong e14605 

Yang, Jijin e14605 

Yang, Jinji 7039, e18090 

Yang, Jui-Chen 4608 

Yang, Li 3040, 3551 

Yang, Lin e14668, e18098 

Yang, Ling TPS4146 

Yang, Lixin 1070 

Yang, Lu 7537, 7545, 

e18022, e18035 

Yang, Pan-Chyr 1534, 7533, 

e13061 

Yang, Ping 1610 

Yang, Qun-ying e12503 

Yang, Renjie e14605 

Yang, Sheng e14606 

Yang, Sherry X. 10603 

Yang, Tong e17514 

Yang, Tsai-Shen 4007 

Yang, Wei Tse 594 

Yang, Wei e14701 

Yang, Weizhu 4008 

Yang, Woo Ick 3606 

Yang, Xiaopin e14523 

Yang, Ximing J 605 

Yang, Xinjie e18142 

Yang, Xinqun 5038 

Yang, Xuening 7039 

Yang, Xuezhong e14658 

Yang, Yang 5097 

Yang, Yongping 4008 

Yang, Yu 3077 

Yang, Yue e18013 

Yankelevich, Maxim e13089 

Yann-Alexandre, Vano 601 

Yannopoulou, A 583 

Yano, Michihiro 9574, 9577 

Yano, Shuya 1063 

Yano, Tokujiro e13090 

Yanovich, Saul e19565 

Yao, Bin 7549, TPS8604 

Yao, James C. 4014, 4126, 

e14542, e14549, e14550, 

e14551, e14662 

Yao, Jianchao 4562 

Yao, Katharine 577, 1033, 

1101, 1116, 6040 

Yao, Lie e14651 

Yao, Masahiro 4626 

Yao, Xiaopan 6033, e14534, 

e21106 

Yao, Yang 9017 

Yao, Yanwen e18082 

Yap, Jeffrey T. 510 

Yap, Mei Ling 5105 

Yap, Timothy Anthony 2530, 

5022, 10525 

Yap, Yoon Sim 9041, e13023 

Yarde, Erin 3047 

Yardley, Denise Aysel 567, 

618, 1018, 1086, 1526 

Yarlagadda, Naveen e14659 

Yarlett, Daniel 6072 

Yarney, Joel e15163 

Yarnold, Paul R 2532 

Yaron, Yifah 5508 

Yasenchak, Christopher A. 

535, 3069, 7514 

Yashiro, Hideki 7038 

805s

Yasuda, Hiromi e14029 

Yasuda, Hiroyuki 7523 

Yasuda, Makoto 5003 

Yasuda, Yosuke e15038 

Yasui, Hirofumi 4002, 4082, 

e14510 

Yasui, Yutaka 6030 

Yasunaga, Yutaka e15065, 

e15069 

Yatabe, Yasushi 7521, 

e18145 

Yau, Christina 10586 

Yau, Cindy Y. F. 3013 

Yau, Stephen 5511, 7549 

Yau, Thomas Cheung 4108, 

e14545 

Yau, Tsz Kok 5511 

Yavuz, Gulsan e20000 

Yaya, Ricardo 3618, 10547 

Yazbek, Gabriel e19640 

Ychou, Marc 3502, 3506, 

3633, 4087, 4091, 10505 

Ye, Chen Yang 3040 

Ye, Dingwei LBA4537, 4628 

Ye, Fei 8544, e21014, 

e21046 

Ye, Josephine 3086 

Ye, Ming 4073, 7520 

Ye, Sheng e18517 

Ye, Sheng-Long 4008 

Ye, Wei-Wu e17512 

Ye, Xiaobu e17552 

Ye, Xun 3551 

Ye, Yang e13595 

Ye, Zhishen 4510 

Yeap, Beow Yong 4021, 

7579, 9585, 10058, 

10592 

Yeap, Shang Heng 550 

Yeazel, Mark W. 6030 

Yee, Cecilia e15147 

Yee, Douglas e13590 

Yee, John 7020 

Yee, Lorrin 3059 

Yeend, Susan e19513 

Yeganegi, Homa 8011 

Yeh, Benjamin M. 4102 

Yeh, Dah-Cherng 1079 

Yeh, Jen Jen e14505 

Yeh, Kun-Huei 4081 

Yeh, Su-Peng e17014 

Yelamanchili, Radhika e14001 

Yelensky, Roman 1015, 

3533, 4649, 7510, 7529, 

10524, 10559, 10590, 

e17541, e19004 

Yellapragada, Sarvari e17018 

Yellin, Ori 8098, e18558 

Yen, Chia-Jui 4103, 4108, 

e14617 

Yen, Katharine 6606 

Yen, Yun 1070, 10545, 

e15178 

Yendamuri, Saikrishna S. 

e14712, e17535 

Yenidunya, Gulsah e21143 

Yennurajalingam, Sriram 

9002, 9023, 9063, 9065, 

9127, e19528, e19599, 

e19602 

Yeo, Wee-Lee 7523 

Yeo, Winnie 4103, e14528 

Yepes, Ethel 2589 

Yerasuri, Durga e14163 

Yermilov, Irina 6057 

Yerushalmi, Rinat 548 

Yetisyigit, Tarkan e14526 

Yeung, Alex 4593 

Yeung, Annie e12017 

Yeung, Choh L 9511 

Yeung, S. J. 6125 

Yi, Anthony 2080 

Yi, Jing 5054 

Yi, Min 1028, 1130 

Yi, Nengjun 1561 

Yi, Sandy TPS6636 

Yildirim, Asif e15122 

Yildiz, Ferah e15572, 

e15573 

Yildiz, Ozcan e21143 

Yildiz, Ramazan 638 

Yilmaz, Bahiddin e14107 

Yilmaz, Emrullah 10612 

Yilmaz, Mette K. N. 3548, 

e14517 

Yilmaz, Ugur 3565, e20514 

Yim, Barbara 9085 

Yim, John H 1035, 1117 

Yim, Vincent 10003 

Yim, Yeun Mi e11051, 

e14068, e16539 

Yin, Wei e13041 

Ying, Weiwen 3086 

Ying, Wendy e19514 

Yip, Desmond e13007, 

e14703 

Yip, George W e21041 

Yip, Sonia TPS4145 

Yip, Stephen 3628 

Yock, Torunn I. 9585 

Yoda, Satoshi e18058 

Yoh, Kiyotaka 1552, 7044, 

e17513, e17526, e17554, 

e18054, e18064 

Yohji, Itoh 1534 

Yokoi, Kohei 7021 

Yokoi, Takashi e18081 

Yokosuka, Osamu e14622 

Yokota, Soichiro e18025 

Yokoyama, Akira 6112, 7003, 

7017, 7028, 7515, 

e19556 

Yokoyama, Ryohei 9574 

Yokoyama, Takuma e19556 

Yom, Cha Kyong 1056 

Yonas, Bekuretsion 580 

Yoneda, Kazue 7080, 10585 

Yonemori, Kan 10519, 

e19535 

Yonese, Junji e15038 

Yoneyama, Kimiyasu 585 

Yong, Candice e15148 

Yong, Kol Jia e13505 

Yong, Kwee e18572^ 

Yong, Wei-Peng 2551, 3002, 

4100^, e13002 

Yong, William H. 2101 

Yong-Hing, Charlotte Jane 

e14565 

Yoo, Changhoon 10085, 

e11508 

Yoo, George H. 5534, 

e16019 

Yoo, Simon 8579 

Yook, Jeong Hwan 10093 

Yoon, Chan Seok 1053 

Yoon, Dok Hyun 4093, 5586, 

e13104 

Yoon, Harry H. 4009, 4075 

Yoon, Hwi Joong e14128 

Yoon, Hyungeun e18126 

Yoon, Jeong Lim 1105, 

e19029 

Yoon, Jong Hyung 9579 

Yoon, Jung-Hwan 4103 

Yoon, Ki Tae e14566 

Yoon, Kyong-Ah e18119 

Yoon, Sam S. 10058 

Yoon, Sang Min e18501 

Yoon, Sung-Soo e18572^ 

Yoong, Jaclyn 9101 

York, Sergernne 6501 

Yoshida, Atsushi 590, 

e13037 

Yoshida, Chikashi 8094 

Yoshida, Kazuhiro 3558, 

3607 

Yoshida, Kimihide e17510, 

e18145 

Yoshida, Koji e13014, 

e13015, e13029, e13037 

Yoshida, Kozue e19611 

Yoshida, Masahiro e19583 

Yoshida, Motoki 3088^ 

Yoshida, Shigetoshi 7046 

Yoshida, Takahiro e15065 

Yoshida, Takashi 613 

Yoshida, Tatsuya e18054 

Yoshida, Tsukihisa e13090 

Yoshida, Yoshio e15539 

Yoshii, Akihiro e18037 

Yoshikawa, Hiroyuki 5006 

Yoshikawa, Takaki 4070 

Yoshikawa, Takayuki e21007 

Yoshimori, Kouzou e19556 

Yoshimura, Kiyoshi e13559 

Yoshimura, Naruo 7017, 

e17538 

Yoshino, Ichiro 7046 

Yoshino, Kunitoshi e16032 

Yoshino, Reiko e18037 

Yoshino, Takayuki 3079, 

3502, e14038 

Yoshino, Tomoko e21007 

Yoshino, Yuki e19611 

Yoshioka, Hiroshige 6112, 

7521, 7528, e18025, 

e18134 

Yoshioka, Masakata e18019 

Yoshioka, Toshiaki e15065, 

e15069 

Yoshioka, Yasuko e18019 

Yoshiya, Shohei e14536, 

e14602 

Yoshizawa, Carl N. 549^, 

1021 

Yoshizawa, Carl 1005 

Yoshizumi, Tomoharu 

e14536, e14602 

Yost, Kathleen J. 1610 

Yothers, Greg 3512, 3522, 

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You, Benoit 5110, 8068, 

e15182 

You, Jee Man 1133, e21160 

You, John J. 6049 

You, Si Young e14558 

You, Y. Nancy 3556, 4060 

You, Zhiying e13087 

Younan, Rami 9138 

Younas, Mariam e18510 

Younes, Anas 8067, 8079 

Younes, Mamoun e15003 

Young, Anne Mary 2530 

Young, Brandon F 1027 

Young, Brian 6108 

Young, Debra R. 2021 

Young, Elliana J. 527, 10613 

Young, Lillian L 4575 

Young, Mary Elizabeth 1128 

Young, Nancy 6103 

Young, Richard J. 5571, 

8520 

Young, Robyn R. TPS1137 

Young, Ruth T. e14503 

Young, Tracy e11562 

Youngson, Bruce 1123 

Younos, Ibrahim 2511 

Yousef, George M. 4613, 4633 

Yousif, Nasser Ghaly e11046 

Yousif, Saif e11053 

Youssef, Youssef M. 4633 

Youssoufian, Hagop TPS1143, 

e13040 

Yovine, Alejandro Javier 

TPS1148 

Yovino, Susannah G. 2017 

Ysebeart, Loic 8048 

Yu Min Lee, Ursula Joan 3515 

Yu, Baofa e14716 

Yu, Bin 8582 

Yu, Chang Sik 3568, 10093 

Yu, Changhong 4552, 4652, 

5562, e15070 

Yu, Chih-Chia e16008 

Yu, Chong-Jen 7519^, 

TPS7614 

Yu, Choon Geok 4106 

Yu, Ding e18033 

Yu, Elaine e11051, e14068, 

e16539 

Yu, Evan Y. 4506, 4513, 

4514, 4557, 4654, 

e15206 

Yu, Gang e18142 

Yu, Hao 7548 

Yu, Helena Alexandra 3083, 

7052, 7527, 7580 

Yu, James B. 1030, 4651, 

6019, e15150 

Yu, Jiaye e21011 

Yu, Jie-Kai e14026 

Yu, Jinming 4073, e21115 

Yu, John 2080, 2084, 2087 

Yu, Kenneth H. 4057, 9105 

Yu, Kim Wai 1035 

Yu, Kwok Hung e15110 

Yu, Lei e17542 

Yu, Lixia 4068, e14509, 

e21034 

Yu, Mandi 1536 

Yu, Margaret K. TPS666 

Yu, Menggang e16010, 

e21016 

Yu, Mimi C 4575 

Yu, Minshu 2545 

Yu, Qitao 5538 

Yu, Ren 6122 

Yu, Rong e11068 

Yu, Seung Shin e19574 

Yu, Shi Ying 5097, e18100 

Yu, Simon e14528 

Yu, Wei TPS7616 

Yu, Xiang-Qing TPS2618 

Yu, Xinhua 7025, 7069 

Yu, Xinmin e17512 

Yu, Xinshuang e14643 

Yu, Xujie 6522 

Yu, Yanhong e15563 

Yu, Yuefei e21105 

Yu, Zheng e13121 

Yuan, Constance 8088, 

e18568 

Yuan, Dongmei e18082, 

e18116 

Yuan, Jianda 2518, 2521, 

8575, 8583 

Yuan, Jinyu e15070 

Yuan, Ma Dai e14648 

Yuan, Peng TPS1135, 

e11025, e11538 

Yuan, Shuanghu e21115 

Yuan, Shuqiang e14674 

Yuan, Ying e14024, e14026 

Yuan, Zheng 2516 

Yuasa, Miyuki 3002 


Yuasa, Takeshi 4536, 4538, 

e15038, e15098 

Yuce, Deniz 9050 

Yucel, Birsen e11083, 

e16005, e19575 

Yucel, Idris e14107 

Yue, Binglin 7065, e17559 

Yue, Guang H. 1076 

Yue, Huibin 8579, 8585 

Yuen, Eunice 3008 

Yuen, Kwok Keung 5511 

Yuki, Satoshi 3593, e14038, 

e14062 

Yukisawa, Seigo e14677 

Yule, Murray 9542 

Yumuk, Fulden e16015 

Yun, Hwan Jung e14529 

Yun, Jeong H 536 

Yun, Jina e14688, e19554 

Yun, Lingsong e14003 

Yun, Mi Jin e14559 

Yun, Rui 8087 

Yun, Ya-Lin 6038 

Yun, Young Ho 9066 

Yunes Ancona, Alejandro 5502 

Yung, W. K. Alfred 2003, 

2029^, 2030, 2036, 2064 

Yunokawa, Mayu 10519, 

e11065, e19535 

Yunus, Furhan 5500, 5503 

Yusuf, Anny 2062 

Yvonnet, Vanessa e15161 

Z 

Zaanan, Aziz 4018 

Zabel, Brian e21071 

Zabel, Frauke 554 

Zabel, Maciej 10537 

Zabkowska, Katarzyna e21099 

Zaborek, Piotr 

Zacarias Föhrding, Luisa 

9046 

Zaccarelli, Eleonora 

e21020 

e11039, 

e11514, e12510, e19620 

Zach, Leor 2078, e14143 

Zachee, Pierre TPS6640 

Zadnik, Vesna 558 

Zafar, Faiza 8036 

Zafar, Syed Farhan e14692 

Zafar, Yousuf 6102 

Zaffaroni, Nadia 4507 

Zagaya, Ciara 4022 

Zage, Peter E. 9534 

Zagel, Miriam e17516 

Zager, Jonathan S. 10048 

Zagonel, Vittorina 586, 2049, 

3555, 3585, 4115, 

e12037, e14040, e14563 

Zagst, Patricia D. 3029, 

e14690 

Zahaf, Katia 7591 

Zahlmann, Gudrun TPS9596 

Zahnow, Cynthia A. e18147 

Zahurak, Marianna TPS3117 

Zaia, John 8089, e18542 

Zaidi, Aisha Salman e17019 

Zaidi, Ali H e14689 

Zaidi, Bushra 8583 

Zain, Jasmine M. e13079 

Zairi, Fahed 2070 

Zaja-Milatovic, Snjezana 6038 

Zajac-Kaye, Maria TPS4136 

Zajchowski, Deborah A. 5074, 

e15555 

Zajda, Katarzyna e12011 

Zakari, Ahmed 4127 

Zakeri, Kaveh 6121 

Zakharova, Tatiana e15025, 

e15029 


Zaki, Bassem I. e14514 

Zaki, Mohamed H. 8016 

Zaknoen, Sara L. 6577, 7546 

Zakotnik, Branko 558 

Zakowski, Maureen Frances 

10560 

Zakrzewski, Sandra e13121 

Zalcberg, John Raymond 

3504, 3515, 3572, 

TPS4141, TPS4145 

Zalcberg-Renault, Ilana 

e14101 

Zalcman, Gerard 3000, 7057, 

TPS7112, 7574, e16560, 

e18089 

Zalewski, Pawel e15017 

Zalis, Mariano e14101 

Zalles, Carola M. 518, 520 

Zalupski, Mark M. 4039, 

e14519 

Zamagni, Claudio 532, e13057 

Zamagni, Elena e21006 

Zaman, Khalil 9059, e11048 

Zamba, Gideon e14620 

Zambetti, Milvia 545 

Zamboni, Beth A. 5050 

Zamboni, William 2591, 

5050, e13063 

Zambrana Tevar, Francisco 

1570, 9073, e11028 

Zambrowicz, Brian 4085, 

e14564 

Zamechek, Leah B. e21082 

Zamek-Gliszczynski, Maciej 

3008 

Zamora, Esther 7041 

Zamora, Pilar e11081 

Zamora, Victor e14598 

Zampa, Germano 4572, 

e14082 

Zampino, M. Giulia e19036 

Zamudio Osuna, Michelle 

e15525 

Zanaboni, Flavia 5096 

Zanconati, Fabrizio 10554 

Zander, Dani 7054 

Zander, Thomas 1533, 

TPS3115, 7603, 10526, 

CRA10529 

Zandstra, Fran e19625, 

e19629 

Zanetta, Sylvie LBA4567^, 

5505, e13009 

Zang, Dae Young TPS4142, 

e14572, e14580 

Zang, Qingqiao e13004 

Zanghì, Mariangela e11056 

Zangos, Stephan e14131 

Zaniboni, Alberto 1073, 

3555, e14018 

Zanichelli, Maria Aparecida 

6509^ 

Zannella, Vanessa e15118 

Zanoni, Vanessa e11546 

Zanotti, Kristine M. 5089 

Zanotti, Laura e15549 

Zanus, Giacomo e14563 

Zanzonico, Pat TPS9595 

Zaorsky, Nicholas George 

e19507 

Zapas, John L. LBA1000 

Zapka, Jane 6086 

Zappa, Magaly 4133, e14660 

Zappala, Stephen M e15196 

Zarba, Juan Jose e14521 

Zaren, Howard e16561 

Zaritskey, Andrey 6512 

Zarotsky, Victoria e17017 

Zarour, Hassane M. TPS8606 

Zastrow, Leonhard 5064, 

e19558 

Zastrow, Stefan e15195 

Zatloukal, Petr LBA7000, 

7575, e18062 

Zaucha, Jan M. 8030, 8077 

Zauderer, Marjorie Glass 1541 

Zaugg, Kathrin 3595 

Zaun, Silke e11040^, 

e18016^ 

Zavadil, Jiri 8544, 8565, 

9507, e19018 

Zavaglia, Katia 629 

Zavala, Diego G e18028 

Zavala, Jose D 8075 

Zavala, Laura 9034, 9109, 

9123 

Zaveleva, Elina 3070 

Zaveri, Shabber e14710, 

e15516 

Zavos, Apostolos 5066 

Zawam, Husam e18001 

Zayas, Myriam 9565 

Zazo, Sandra 5520, e14147, 

e15094, e18069, e18106, 

e21015 

Zazpe, Cruz e14120, e21086 

Zazulina, Victoria 7503 

Zbieranowski, Ingrid J. 4613 

Zbuk, Kevin M. e14001 

Zbynek, Bortlicek e11072, 

e18062 

Zdzienicki, Marcin 8532, 

8548 

Zebary, Abdlsattar 8588 

Zebracka, Jadwiga e14159 

Zechmeister, Jenna R. 

e15548 

Zee, Benny C.Y. 4105, 5511, 

e14706 

Zee, Ying Kiat 2551, 3002, 

4100^ 

Zeger, Erik L. e14157 

Zeger, Gary 7582, 7594, 

e12007 

Zeh, Herbert e14184 

Zehr, Pamela e15010 

Zeidan, Amer e16537 

Zeillinger, Robert 5034, 

5058, 5071 

Zeimet, Alain G 5034, 5058 

Zeis, Matthias 8004 

Zeitouni, Nathalie e19041 

Zeitzer, Jamie 9051 

Zelayas, Pedro Guillermo 

e15556 

Zeldenrust, Steven R. 8096, 

8105, TPS8116 

Zelenetz, Andrew David 8054, 

8069, e18530 

Zelenka, Peter e14087 

Zelko, Frank 9532 

Zellars, Richard C. 1128 

Zellmann, Klaus 3588 

Zemanova, Milada e14631, 

e18062 

Zemoura, Leila e18102 

Zen, Yoh e21091 

Zeng, Xiangqun 628 

Zeng, Xiao e21011 

Zeng, Xuemei e14689 

Zeng, Zhihong TPS6635 

Zengerling, Friedemann 4530 

Zengin, Nurullah 3565, 

e11011, e11033, e11093, 

e13031 

Zenka, Roman M e15132 

Zenz, Thorsten 6519 

Zerche, Peter 580 

Zeringue, Angelique 4594 

Zernovak, Oleg TPS6638 

Zeuli, Massimo e14661 

Zevon, Michael 1529 

Zeynalova, Samira 8024, 8025 

Zha, Yuanyuan 2561, 2582 

Zhai, Yirui e14511 

Zhan, Ping 4124 

Zhang, Alicia 5502 

Zhang, Baohui 9102 

Zhang, Bin 3010, TPS8109 

Zhang, Chen-ping 5593 

Zhang, Chong 555, 563, 

6063, e13537, e16010 

Zhang, David Y. 8544 

Zhang, Deng e21133 

Zhang, Gu e21080 

Zhang, Helong 7559 

Zhang, Hong 1029, 1104, 

e19631 

Zhang, Hong-Tu e14502 

Zhang, Hua 3546, 3597, 

e11018 

Zhang, Hui 7530, 7590, 

7592, TPS7618, e18142 

Zhang, Jian 3038, e11567, 

e11568 

Zhang, Jiandong e14643 

Zhang, Jianjun 7047 

Zhang, Jingbo 4542 

Zhang, Jinghui 9518 

Zhang, Jingsong e13564 

Zhang, Joshua 4132, 4501, 

e15082 

Zhang, Jun e17547 

Zhang, Kathy 3581 

Zhang, Lan-jun e18121 

Zhang, Lei e13069, e14700 

Zhang, LI 5524, 5538, 7091, 

7519^, 7520, 7548, 7559, 

e13021, e13036 

Zhang, Liang e18557 

Zhang, Ling 6588, e18115, 

e18503, e18506, e21123 

Zhang, Lu 6567 

Zhang, Nan e21051 

Zhang, Ning 600, 9091 

Zhang, Penglie e13580 

Zhang, Peter e11068 

Zhang, Pin e11025, e11538 

Zhang, Qian Nan 8561 

Zhang, Qian e13516 

Zhang, Qiang 5530, 5583 

Zhang, Qing 5553, e18548 

Zhang, Quanwu e15193 

Zhang, Qunling e11568 

Zhang, Shanwen 10045 

Zhang, Sheng e15132 

Zhang, Shucai 7520, 7559, 

e18142 

Zhang, Suzhan e14024 

Zhang, Tao e18033, e19603, 

e19613 

Zhang, Tong e13107 

Zhang, Wendy TPS4692^ 

Zhang, Wu 3518, 3540, 

3546, 3549, 3584, 3597, 

3604, 3615, 3622, 4026, 

4088, 4096, e11018, 

e14031, e14034, e14052 

Zhang, Xi 8596, e18033 

Zhang, Xiang-Hua e18050 

Zhang, Xianglan e18092 

Zhang, Xiao 5032 

Zhang, Xiaodong e14604 

Zhang, Xiaohua 9017 

Zhang, XiaoJing 4628 

Zhang, Xiaotian e14604 

Zhang, Xiaotun 4669 

807s

Zhang, Xinmin e16022 

Zhang, Xu Dong 8553 

Zhang, Xu-Chao e13510, 

e18035 

Zhang, Xuchao 7039, e18090 

Zhang, Ya 515 

Zhang, Yanwei e17551, 

e18038 

Zhang, Yi 561, 10588, 

e21019 

Zhang, Yi-Fang e13510 

Zhang, Ying e21111 

Zhang, Yingjian 10567 

Zhang, Yingjie e13524, 

e13529 

Zhang, Yingzi e21080 

Zhang, Yiping 3031, 7091, 

7520, 7548, 7559, 

e17512 

Zhang, Yixiang 10029 

Zhang, Yong TPS1148, 

TPS4147, e14700, e16054 

Zhang, Yongping 10567 

Zhang, Yu e14648 

Zhang, Yufeng 600 

Zhang, Yuji e15132 

Zhang, Yujian e15124 

Zhang, Zhe 10509 

Zhang, Zheng TPS5114, 

TPS10635 

Zhang, Zhi-Yong e18077 

Zhang, Zhi-yuan 5593 

Zhang, Zhigang 5537, 8054 

Zhang, Zhong-guo e14036 

Zhao, Binsheng 2541, 

e13064, e19647 

Zhao, Chong 5535, e13021 

Zhao, Dave e16060 

Zhao, Fei 10566 

Zhao, Fengmin 6076, 9016, 

9099, 9106, 9112, 

e15173 

Zhao, Hong 2098, 4616 

Zhao, Hongyun e13021 

Zhao, Hui 7036, e21103 

Zhao, Huijun 10620 

Zhao, Jinxiu e16561 

Zhao, Liping e13021 

Zhao, Lujun e14511 

Zhao, Ming 2044, e14700 

Zhao, Naiqing 4092, e14575 

Zhao, Ni 5577 

Zhao, Qiang e14662 

Zhao, Weiqiang 5566 

Zhao, Xiaoying e16039 

Zhao, Yingdong 10565 

Zhao, Yu e18087 

Zhao, Zhongyun e19043, 

e19044, e19045, e19060 

Zhenfu, Fu 5568 

Zheng, Chunlei e11568 

Zheng, Di e18077 

Zheng, Hao W. 9543 

Zheng, Lei 4045, e14585 

Zheng, Leizhen 9017 

Zheng, Min 1540 

Zheng, Ping TPS657 

Zheng, Rongsheng 9017 

Zheng, Shu e14026 

Zheng, Wang fang 5568 

Zheng, Wei 9017 

Zheng, Yong-Qing e17512, 

e18142 

Zheng, Yuanda e17527 

Zheng, Zhao-xu e14668 

Zhi, Jianguo e13600^ 

Zhi, Xin e15116 

Zhi, Xiuyi 7520 

Zhimin, Shao e11567 

Zhong, Dafang e13036 

Zhong, Fengming e14124, 

e14125, e14727 

Zhong, Hua e21001 

Zhong, Lai-ping 5593 

Zhong, Lixian e15154 

Zhong, Liz 3098 

Zhong, Mei e15563 

Zhong, Runbo e21001 

Zhong, Wenzhao 7039, 

e18090 

Zhong, Xiaoyin 2021 

Zhong, Yunshi e14000 

Zhong, Zhandong Don 5038 

Zhou, Ai-Ping 4628, e14668 

Zhou, Caicun 7519^, 7520, 

7535, 7557, 7559, 7600, 

10527, e18100, e18123 

Zhou, Chen e14568 

Zhou, Cong e21037 

Zhou, Dan 3086 

Zhou, Daohong e18576 

Zhou, Fei e14539 

Zhou, Gang 2513 

Zhou, He 4056 

Zhou, Hong 2503^ 

Zhou, Jenny e11549 

Zhou, Jianying 7559 

Zhou, Jun e14122, e14604 

Zhou, Lin e14648, e18086 

Zhou, Lisa Ya 10574 

Zhou, Min 10567 

Zhou, Qian 3594 

Zhou, Qin 5030, 5108 

Zhou, Qing 7039 

Zhou, Qinghua e17514 

Zhou, Songwen 7520 

Zhou, Tianni 9504 

Zhou, Weiping 4008 

Zhou, Xi Kathy 10514 

Zhou, Xian C 10509 

Zhou, Xiangdong 2013 

Zhou, Xiao 4037, e19520 

Zhou, Xiaofei 2597, 5021 

Zhou, Xiaolei 6626^ 

Zhou, Yang TPS669, 

TPS1614 

Zhou, Yangsheng 8042, 

8106, 8107 

Zhou, Yi e14502 

Zhou, Yunping e18560 

Zhou, Zheng-Yi 1037 

Zhou, Zhiwei e14674 

Zhou, Zu li e21103 

Zhu, Andrew X. 4021, 4112, 

TPS4146, e14615 

Zhu, Dexiang e14000 

Zhu, Fang 1517 

Zhu, Guang ying 4073 

Zhu, Guopei e16039 

Zhu, Han-guang 5593 

Zhu, Hong-Xia e14502 

Zhu, Jay-Jiguang TPS2107 

Zhu, Jian-fei e18121 

Zhu, Jiang e14648 

Zhu, Jin TPS2616, 3021 

Zhu, Jingqiang 5550 

Zhu, Jinxian e16054 

Zhu, Joy 2579 

Zhu, Jun TPS8118 

Zhu, Kangshun 4008 

Zhu, Ling e17009 

Zhu, Liting 501, e11005 

Zhu, Min 2535, 2594 

Zhu, Pei Hong 10622 

Zhu, Peixuan 6581, e21079 

Zhu, Qian 3002 

Zhu, Qingfeng e14538 

Zhu, Shu chai 4073 

Zhu, Xiaolei e15140 

Zhu, Yanrong 6016 

Zhu, Yongxue e16039 

Zhu, Yuan e14049 

Zhu, Yue 1039 

Zhu, Yunzhong 7519^ 

Zhu, Yuping e14049 

Zhuang, Sen Hong e13122 

Zhuang, Tingting 3095 

Zhuang, Xusheng e14523 

Zhuang, Zhixiang 9017 

Zhukovsky, Donna S. 9096, 

9134, e19528, e19584 

Zhukovsky, Eugene 8059, 

e18532 

Zhuo, Minglei 7537, 7545, 

e18022, e18035 

Ziani, Leslie e19046 

Zibert, John Robert e19056 

Zichi, Dom e21142 

Zidan, Abdel-Aziz 9565 

Zidan, Jamal e14025 

Zidan, Marwan 9578 

Ziebarth, Angela 5036 

Ziegelmann, Matthew e15211 

Ziegenfuss, Jeanette Y. 1565, 

4657 

Ziegler, Mark A. 4055 

Ziegler, Regina G 1521 

Zielinski, Christoph 2053, 

TPS7113, e15083, 

e15090, e21033 

Zielonka, Tania e18507 

Ziemendorff, Gabriele 10540 

Ziepert, Marita 8022, 8025 

Zighelboim, Israel 5013, 

5101 

Zijlstra, Andries e21090 

Zijlstra, Jose M 8039 

Zikos, Efstathios 6002, 6090, 

7607 

Zilembo, Nicoletta 7550, 

7581 

Zimmerman, Pamela 6108 

Zimmerman, Todd M. 8034 

Zimmermann, Annamaria 

LBA7507, 7554 

Zimmermann, Benedikt 4565 

Zimmermann, Camilla 9003, 

e16567 

Zimmermann, Heiner 8030 

Zimmermann, Ute 8540 

Zimmermann, Uwe 4539 

Zingaretti, Costantino 4084 

Zingone, Adriana 8088, 

8104, e18568 

Zinner, Ralph 10607 

Zinser, Juan Wolfgang e11016 

Zintl, Patrik 10013 

Zinzani, Pier Luigi 8052, 

e13569 

Ziparo, Vincenzo e17006 

Zippelius, Alfred 2573^ 

Ziske, Carsten 6058 

Zissimopoulos, Athanasios 

e17553 

Zitt, Matthias e14719 

Ziv, Ravit e13018 

Zivanovic, Maureen 8056 

Zivanovic, Oliver 5090 

Zivi, Andrea 4553 

Ziviani, Luciene Fabres 

e12021 

Zlotecki, Robert TPS4136 

Zo, Jae Ill e16534, e21043 

Zogopoulos, George 4058 

Zok, Jolanta e21099 

Zola, Fabio Eduardo e12512 

Zoli, Wainer 10601, e18045 

Zomorodi, Meghan e19644 

Zonder, Helene B. e19644 

Zonder, Jeffrey A. 6549, 

8013, 8020 

Zongo, Nayi 641 

Zonnenberg, B. A. 4632, 

10619 

Zoratto, Federica e11039, 

e11514, e12510, e19620 

Zorludemir, Suzan e11088 

Zorman, Darko 558 

Zornosa, Carrie C. 4126, 

e14542, e14551, e18018 

Zorza, Grégoire e13036 

Zorzi, Alexandra Patricia 9591 

Zorzi, Jane 10509 

Zou, Li qun e18514 

Zou, Qing 4628 

Zou, Shuangmei e14511 

Zou, Yiyu e18113 

Zou, Zhengyun 4068, 

e14509, e21034 

Zouvani, Ioanna e15030 

Zovato, Stefania 10063 

Zrounba, Philippe e16036 

Zsiros, Emese 5039 

Zu, Maoheng e13004 

Zubel, Angela 3003, 8511 

Zuber, Markus e14045 

Zubkus, John D. 7100 

Zubritsky, Lindsey 607, 

e14520, e15170 

Zucali, Paolo A. 4545 

Zucali, Paolo Andrea 2580, 

7082, e21139 

Zuckerman, Ilene H. 6028, 

6060, 6075 

Zudaire, Mari-a I. e18008 

Zugazagoitia, Jon e20513 

Zugmaier, Gerhard 6500^ 

Zuhlke, Kimberly A. e15205 

Zukin, Mauro 7506, 7511 

Zulfikar, Bulent 9567 

Zulfiqar, Muhammad e14176 

Zullig, Leah L. 5539, 6102 

Zullo, Marzio Angelo 5094, 

e15551 

Zuluaga Toro, Tania 

TPS4136, e14612 

Zulueta, Javier e18008 

Zumbo, Paul 9507 

Zuo, Zhixiang 5517 

Zupo, Simonetta e18021 

Zuradelli, Monica 615, 623 

Zureik, Mahmoud 1574 

Zureikat, Amer H e14184 

Zurita, Amado J. 4533, 4556, 

e15075, e15085, e15087 

Zustovich, Fable 2049, 

e12037, e15160 

Zvirinska, Lenka e13112 

Zwaan, Michel 9517, 

TPS9594 

Zwahlen, Daniel Rudolf 3595 

Zwart, Nynke 4528 

Zwarthoed, Colette 8077, 

e15574 

Zwas, Tzila S. e17509 

Zwenger, Ariel e11021 

Zwick, Carsten 8022, 8024 

Zwingers, Thomas 1072, 

1600^, 1602 

Zwischenberger, Joseph 

Bertram e14562 

Zyczynski, Teresa Maria 

e15165 

Zylberberg, Ricardo e17548 

Zylis, Dimosthenis 10606 


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